| Medical Policy |
| Subject: Allogeneic, Xenographic, Synthetic, Bioengineered, and Composite Products for Wound Healing and Soft Tissue Grafting | |
| Document #: SURG.00011 | Publish Date: 09/28/2022 |
| Status: Revised | Last Review Date: 05/12/2022 |
| Description/Scope |
This document addresses the use of soft tissue (e.g., skin, ligament, cartilage, etc.) substitutes in wound healing and surgical procedures. There is a wide array of uses for such products, including use as a cover for wounds related to disease processes (e.g., diabetes, peripheral artery and venous disease, recessive dystrophic epidermolysis bullosa), coverage or support of surgical and other wounds (e.g., complex abdominal wall repair, breast, and other types of reconstructive procedures), use as a surgical reconstructive material during surgical procedures (e.g., ligament augmentation or substitution, slings for internal organs, trauma, fistula repair, congenital defects), structural support of soft tissues (e.g., injection laryngoplasty, cosmetic augmentation), treatment for dermal and other burns, use in nerve grafting procedures, and many others. Tissue-engineered skin is a significant advance in the field of wound healing and was developed due to limitations associated with the use of autografts.
For the purposes of this document the following terms are defined as below:
Note: The use of fresh, unfrozen, unprocessed allogeneic cadaver-derived skin grafts is not addressed in this document.
Note: This document does not address the use of meshes or patches of non-biologic origin when used for standard hernia repair procedures.
Note: This document does not address products used to treat osteochondral defects.
Note: For additional information please see:
| Position Statement |
Medically Necessary:
I. Breast reconstruction surgery
The following products are considered medically necessary when used for breast reconstruction surgery:
II. Burns
The following products are considered medically necessary when used for the treatment of full-thickness or deep partial-thickness burns:
*Note: “AlloSkin,” “AlloSkin RT™” and “Alloskin™ AC” are different products. AlloSkin is a fresh-frozen product, AlloSkin RT is a fresh irradiated product (not frozen) and Alloskin AC is an acellular dermal matrix product. Please see the investigational and not medically necessary section below for the position on AlloSkin RT™ and Alloskin™ AC.
III. Complex abdominal wall wounds
The following products are considered medically necessary for the surgical repair of complex abdominal wall wounds:
IV. Diabetic foot ulcers
The following products are considered medically necessary for the treatment of diabetic foot ulcers that have not healed with standard conservative therapy (such as surgical debridement, complete off-loading, and standard dressing changes) attempted for at least 1 month but not greater than 52 weeks:
V. Dystrophic epidermolysis bullosa
The following products are considered medically necessary for the treatment dystrophic epidermolysis bullosa:
VI. Lower extremity dermal wounds
The following products are considered medically necessary for the treatment of lower extremity dermal wounds that have not healed with standard conservative therapy (such as surgical debridement, complete off-loading, standard dressing changes, and compression therapy) attempted for at least 1 month but not greater than 52 weeks:
VII. Ocular indications
Allogeneic amniotic membrane-derived grafts or wound coverings, including, but not limited to the following, are considered medically necessary for the reconstruction of large conjunctival resections, treatment of corneal injuries and as an adjunct to surgical procedures involving the cornea:
*See Investigational and Not Medically necessary section for the use of other Vendaje products.
VIII. Venous stasis ulcers
The following products are considered medically necessary for the treatment of chronic venous stasis ulcers when the wound has been present for at least 1 month and has been unsuccessfully treated with compression therapy for at least 14 days:
Not Medically Necessary:
The following products are considered not medically necessary when criteria above are not met and for any use not listed above:
Investigational and Not Medically Necessary
The use of all other allogeneic, xenographic, synthetic, and composite products for wound healing or soft tissue grafting, including but not limited to the following products, is considered investigational and not medically necessary for all uses:
| Rationale |
General considerations
There are currently a wide variety of products available for soft tissue grafting and wound treatment. These products differ in species source (e.g., human cadaveric, synthetic, bovine, porcine, equine, a combination of several types, etc.), tissue source (e.g., dermis, pericardium, intestinal mucosa, etc.), bioburden reduction (e.g., nonsterile, sterile), additives (e.g., antibiotics, surfactants), delivery formats (e.g., wet packaged, freeze-dried), and preparation requirements (e.g., multiple rinses, rehydration). Additionally, they are procured, produced, manufactured, or processed in sufficiently different manners that they cannot be addressed and evaluated as equivalent products. This is made evident not only in the wide range of shelf-life recommendations for these types of products, but also in the descriptions of their physical properties. Additionally, there are a limited number of comparative studies available addressing the clinical outcomes for allographic, xenographic, and composite products, and the results are heterogeneous. What comparative data is available demonstrates a wide range of outcomes, with some studies reporting no differences and others indicating significant differences in the rate of healing, incidence of seroma and infection, surgical failure, and other outcomes. Therefore, each product is assessed on the basis of the available scientific evidence specific to that product rather than considering groups of products as belonging to a class (for example, acellular dermal matrix products) and then evaluating all members of that class as though they were therapeutically equivalent. While this approach has certain merits, within each possible class that could be constructed there are products that have no full-text, peer-reviewed, published studies available to evaluate the clinical utility or draw a conclusion as to whether that particular product is therapeutically equivalent to another similar but studied product. Products for which there is a lack of quality published and peer-reviewed evidence to consider are considered investigational and not medically necessary. For other products, there may be one or more published studies of varying quality. The use of blinding in studies for these types of products may pose a challenge due to the nature of the products compared to standard therapies, as well as other factors. However, investigators should strive to design and apply rigorous study methodologies to minimize possible sources of bias within their trials.
Below, we summarize the findings of the most recent or most rigorous studies available. Please note that the discussion below is not meant to be an exhaustive review of the evidence available, but to address the most significant studies available for each product. Many studies have been omitted because they were considered poorly designed or underpowered to adequately demonstrate efficacy for a more general population.
Non-Product Specific Acellular Dermal Matrix (ADM) Studies, Multiple Product Studies, Meta-analyses, and Systematic Reviews
The use of ADM products of various origins has been proposed for both immediate and two-stage breast reconstruction surgeries and has become widely used and accepted. However, the current evidence of these techniques has been understudied and the data that has been made available is not from rigorously designed and conducted randomized controlled trials (RCTs).
To properly address the question of both safety and efficacy, the MultiCentre Canadian Acellular Dermal Matrix trial (MCCAT) has begun recruitment in a two-arm parallel superiority trial that will compare one-stage ADM facilitated implant breast reconstruction with two-stage tissue expander and implant breast reconstruction (Zhong, 2013). The results addressing this pressing issue are eagerly anticipated.
In 2012, two well-designed meta-analysis studies were published that evaluated the available peer-reviewed published evidence addressing the use of ADMs for use in breast reconstruction procedures. Ho and colleagues conducted their meta-analysis using 16 studies that met their inclusion criteria. They noted that analysis of complication rates was limited by the small number of studies and the small sample size of study participants. Additionally, they commented that the overall quality of the evidence was low. Five studies were included that had data for both subjects who received ADM and those who did not. Overall, they found that the ADM group had significantly higher complication rates for seroma, infection, and reconstructive failure when compared with the non-ADM group. ADM-assisted breast reconstructions were found to be almost 4 times as likely to be complicated by seroma, nearly 3 times as likely to become infected, and 3 times as likely to have a reconstructive failure as breast reconstructions performed without the use of ADM. After exclusion of outlier data, they found that the pooled odds ratio (OR) of developing skin flap necrosis in ADM reconstructions was three-fold higher than non-ADM reconstructions.
Kim and others conducted a meta-analysis on 44 studies that met their inclusion criteria. The results found that there was an increased rate of total complications with ADM use when compared to non-ADM reconstructions (15.4% vs. 14.0%). For specific complications, this finding continued to apply; specifically for seroma (4.8% vs. 3.5%), infections (5.3% vs. 4.7%), and flap necrosis (6.9% vs. 4.9%). However, the rate of hematoma was greater in the control cohort (1.5% vs. 1.0%). The rate of reconstructive failure was very similar in both cohorts, 3.8% vs. 3.8%. When looking at the studies that provided comparative data between ADM and non-ADM groups in the same study, the authors noted that there was an increase in the risk of total complications (relative risk [RR], 2.05; 95% confidence interval [CI], 1.55 to 2.70), seroma (RR, 2.73; 95% CI, 1.67 to 4.46), infection (RR, 2.47; 95% CI, 1.71 to 3.57), and reconstructive failure (RR, 2.80; 95% CI, 1.76 to 4.45) in the ADM group vs. the non-ADM group. These findings call into question the practice of using ADM for breast reconstruction surgery.
A systematic review of ADM use for abdominal wall reconstruction was published by Zhong and others (2011). They report on a total of 30 articles that met inclusion criteria, specifically mentioning that they did not identify any level I or II studies addressing this issue. They included 4 level III and 26 level IV studies. Among their findings they report wide variation in indications for ADM use and poorly defined terminology used to define subject populations (e.g., abdominal wall reconstruction, high-risk/recurrent/complex/large ventral hernia and high-risk/contaminated wound). The incidence of postoperative hernia varied widely, with some studies reporting 0% and others reporting 80%. Out of the 30 studies reviewed, three used porcine ADM, one a synthetic composite mesh, and one a bovine-derived ADM. No separate data was provided for these studies. The remainder of the studies used allogeneic ADMs. Within the literature, there was significant variation with regard to placement of ADMs within the surgical field, with ADM used as underlay/inlay, interposition, overlay/onlay or sandwiched (underlay and overlay) repairs. The type of fascial repair (bridged vs. reinforced) also had significant impact on outcomes. They state that in cases where fascial re-approximation was achieved, ADM used in a reinforced repair with fascial re-approximation was significantly better than that used in a bridged repair without fascial re-approximation. With the significant variation in selection criteria, ADM types, and surgical techniques, this pool of evidence should not be used to evaluate the use of ADM for abdominal reconstructions in a global manner, and each study should be weighed on its own merits.
Ibrahim and colleagues (2013) conducted a large retrospective study using data from the American College of Surgeon’s (ACS) National Surgical Quality Improvement Program (NSQP) database. The study investigated 30-day outcomes in 19,100 cases that involved tissue expander implant-based breast reconstruction surgeries. A subset of 3301 (17.3%) cases involved the use of ADMs as part of the surgical procedure. It was reported that, overall, the rate of complications was not statistically different between cases that used ADMs (n=175, 5.3%) and those that did not (n=776, 4.9%) (p=0.396). This rate is much lower than the rate of complications reported in previous studies. It should be noted that there are several major limitations of this study, including the fact that the data was derived retrospectively from a large database with no randomization, no blinding, and no concurrent comparison groups. Additionally, the ACS does not use a standardized definition for the term “complications.” This presents a major problem, considering that there may be significant heterogeneity in the major study endpoint data. Also of import is that the data in the NQSP database is derived from academic medical centers, and no data from community hospitals and private clinics is included. It is unclear whether or not this had an impact on complication rates. Finally, there were significant differences between groups at baseline with regard to age, race, and type of reconstruction, which may have introduced significant bias into the analysis.
In 2017, Lee and others published a meta-analysis investigating the use of ADMs for implant-based breast reconstruction. A total of 17 studies were included, with only one being a prospective RCT and the others having retrospective nonrandomized designs. There were 12 studies available involving comparisons with FlexHD, DermaMatrix, and aseptic or sterile AlloDerm products. In the meta-analysis comparing FlexHD and aseptic AlloDerm, involving a total of six studies, both products showed similar pooled risks for all complications. For comparisons between DermaMatrix and aseptic AlloDerm, the results from four studies likewise found no differences between the pooled risks of complications. Finally, the meta-analysis of four studies comparing the aseptic or sterile forms of AlloDerm demonstrated that the pooled risks for the complications did not differ. The authors concluded that these products have similar risks of complications.
Sorkin (2017) reported the results of a retrospective controlled study involving 1297 subjects who underwent expander/implant-based breast reconstruction procedures with either ADM (n=655) or no ADM (n=642). At 2 years post-procedure, no significant differences were seen between groups with regard to overall complications (OR, 1.21; p=0.263), major complications (OR, 1.43; p=0.052), wound infections (OR, 1.49; p=0.118), or reconstructive failures (OR, 1.55; p=0.089). No significant differences were reported in patient-reported outcome scores, including satisfaction with breasts, psychosocial well-being, sexual well-being, physical well-being, and postoperative pain.
Schnarrs (2016) reported the results of a retrospective non-randomized controlled trial involving 126 subjects who underwent 170 breast reconstruction procedures involving the use of aseptic AlloDerm (n=143), sterile AlloDerm (n=19), FlexHD (n=18), and hMatrix (n=32). The authors reported no significant differences between groups with regard to complication rates (p>0.05). They also reported that both smokers and large-breasted subjects (≥ 500 g) were at significantly higher risk for complications vs. nonsmokers and non-obese subjects (p<0.01 and p<0.03, respectively). The conclusion was that there were no significant differences between products with regard to complications. However, the study design, including disparate group sizes, limits the generalizabity of these findings. Results from more rigorously designed and conducted trials would be helpful in better understanding the comparability of various soft tissue grafting products used in breast reconstruction procedures.
Products addressed in the Medically Necessary statement
Allogeneic amniotic membrane-derived grafts or wound coverings used for ophthalmologic indications.
Allogeneic amniotic membrane-derived products have a history of longstanding use for the management of select ophthalmologic wounds and reconstruction of large conjunctival resections where there is limited access to autologous tissue for transplant, or when allogeneic transplant is not appropriate. These types of products come in a wide array of forms, including cryopreserved, fresh-frozen, lyophilized, irradiated, stored in mineral oil, and others. Most products used are obtained directly from tissue banks and not marked by any particular manufacturer. However, several products are commercially marketed, including AnmioGraft and Prokera.
Reconstruction of large conjunctival resections
The treatment of large conjunctival resections, commonly needed for the surgical treatment of cancerous lesions of the eye, is a challenge due to the finite amount of conjunctival tissue available for local conjunctivoplasty or rotational flaps. In such cases, the use of amniotic membrane-derived products have become the standard-of-care option to provide adequate grafting materials to successfully complete these types of procedures, and multiple weak case series studies have been published to support this use (Asoklis, 2011; Dalla Pozza, 2005; Gündüz, 2006; Hanada, 2017; Paridaens, 2001; Tanaka, 2016, Tseng, 1997).
Bullous keratopathy in individuals who are not candidates for curative endothelial or penetrating keratoplasty
Amniotic membrane-derived products are one of several modalities used for treatment of bullous keratopathy due to corneal endothelial dysfunction. Given that amniotic membrane-derived products do not address the underlying endothelial disease, their role in treating bullous keratopathy is palliative rather than curative; for this reason, it is a reasonable alternative for individuals who are not candidates for curative endothelial or penetrating keratoplasty. Supporting evidence includes a prospective RCT of 40 subjects treated with amniotic membrane transplantation or anterior stromal puncture (Paris F dos S, 2013). At 90- and 180-days post-procedure, the presence of a regular epithelial surface was higher in the amnion group than in the control group (60% vs. 16.7% at 90 days, p=0.006; and 50% vs. 6. 3% at 180 days, p=0.008). At 180 days follow-up there was no statistical difference between the two groups in pain severity (p=0.391) or duration (p=0.715). Georgiadis (2008) published the results of a prospective case series study involving 81 subjects with bullous keratopathy treated with cryopreserved amniotic grafts. They reported that 71 (87.6%) eyes became asymptomatic with healed epithelium at a mean of 21 months follow-up. Repeated amniotic transplantation was needed for 7 subjects and 3 underwent penetrating keratoplasty. Visual acuity improved in 64 (79%) subjects and remained unchanged in 14. No complications were recorded. Multiple other weak case series studies describe positive results from the use of amniotic graft products for bullous keratopathy (Chansanti O, 2005; Espana EM, 2003; Pires RT, 1999; Siu, 2015; Srinivas, 2007; Stefaniu, 2014).
Acute chemical burns of the ocular surface
Acute chemical burns of the ocular surface can be challenging to treat due to the lack of transplantable or resectionable autologous tissue. Use of amniotic membrane-derived products has been shown to reduce inflammation and promote healing. The use of this type of graft has been described in two prospective RCTs. The first involved subjects (44 eyes) with acute moderate grade ocular burns treated with amniotic graft (n=20) or standard medical care (n=24) (Tamhane, 2005). Standard medical care involved the use of topical prednisolone acetate (1%), ofloxacin, sodium ascorbate (10%), sodium citrate (10%), preservative-free lubricants, homatropine (2%), oral vitamin C (500 mg) and antiglaucoma therapy including timolol maleate 0.5% drops and/or oral acetazolamide if required. The authors reported that the log mean percentage reduction in size of epithelial defect by day 7 was 7.43 ± 0.89 after amnion treatment vs. 6.23 ± 1.10 with control treatment (p=0.01). However, there was no difference between the two groups in eyes with severe burns. Additionally, no difference between groups was noted in the final visual acuity, symblepharon formation, corneal vascularization, and tear function tests at 3 months. The second RCT involved 100 subjects with moderate to severe ocular burns treated with amniotic graft (n=50) or standard medical care (n=50) (Tandon, 2011). The rate of epithelial healing was reported to have been significantly better in the amnion group vs. controls (p=0.0004). No other differences between groups were reported with regard to final visual outcome, symblepharon formation, corneal clarity and vascularization with or without amniotic membrane transplantation. In addition to these RCTS, multiple underpowered case series studies have been reported demonstrating beneficial results with amniotic grafts for ocular chemical burns (Arora, 2005; Kheirkhah, 2008; Prabhasawat. 2007; Tejwani, 2007; Uçakhan, 2002; Westekemper, 2000).
Persistent corneal epithelial defects that do not respond to conservative therapy
The prompt treatment of persistent corneal epithelial defects that do not respond to conservative therapy is critical due to the risk of the development of corneal ulcers, corneal melt, and perforation. While first-line treatment of corneal defects include topical lubricants, antibiotics, therapeutic contact lenses and patching, when these methods fail, the use of amniotic membrane-derived products has become the standard of care. In severe cases, the option of corneal transplantation is available, but that procedure entails its own significant risks, and less invasive methods are often tried first. One prospective RCT evaluated 19 subjects with corneal thinning treated with amnion (n=9) or allograft cornea (n=10) (de Farias, 2016). All subjects showed significant increase in final thickness in the area of thinning at 180 days postoperatively, but those who received corneal transplant had a slight but significantly higher final thickness (p=0.48). Regardless of the surgical technique, all subjects showed epithelialization. No difference between groups was noted for post-op corneal opacity. Subjects undergoing amnion grafting showed an 89% decrease in neovascularization, whereas none was reported in the corneal transplant group. Final corrected distance visual acuity was better in subjects submitted to AMT. In addition to this study, additional weak case series studies have been published demonstrating beneficial outcomes (Dekaris, 2010; Gris, 2002; Lee, 1997; Letko, 2001; Prabhasawat, 2001; Seitz, 2009).
Corneal perforation when corneal tissue is not immediately available or as adjunct to corneal transplantation in individuals with active inflammation
As noted above, the use of corneal transplant is the preferred method of treatment for corneal perforation. However, the temporary use of amniotic membrane-derived products has been a standard temporary option when transplant tissue is not immediately available or if there is ongoing active inflammation. Multiple weak case series studies have described the successful use of amnion-derived grafting products for this purpose (Hick, 2005; Prabhasawat, 2001; Rodríguez-Ares, 2004; Solomon, 2002).
Corneal ulcers or corneal melts that do not respond to conservative therapy
Similar to the treatment of persistent corneal epithelial defects, treatment of corneal ulcers or corneal melts (also known as keratolysis) that do not respond to conservative therapy is critical to avoid the development of corneal perforation. While corneal ulcers and corneal melts may result from a wide range of etiologies, a common characteristic is underlying inflammation. The use of amniotic membrane-derived products is accepted as an adjunctive treatment along with treatment of the primary cause of the condition when use of topical lubricants, antibiotics, or therapeutic contact lenses fails. Multiple weak case series studies have been published supporting this approach (Chen, 2006; Hanada, 2001; Kruse, 1999; Prabhasawat, 2001; Sheha, 2009; Solomon, 2002; Tok, 2015).
Neurotrophic keratitis that does not respond to conservative therapy
Neurotrophic keratitis, similar to persistent corneal epithelial defects, corneal ulcers, and corneal melts, presents a significant risk of corneal perforation when unresponsive to conservative therapy such as topical lubricants, antibiotics, therapeutic contact lenses and patching. As with those other conditions, treatment of refractory neurotrophic keratitis with amniotic membrane-derived products has become widely accepted as standard of care and described in several underpowered case series studies (Chen, 2000; Iveković, 2002; Khokhar, 2005; Suri, 2013; Uhlig, 2015).
Partial limbal stem cell deficiency in conjunction with superficial keratectomy
Limbal stem cell deficiency is characterized by a loss or deficiency of the stem cells in the limbus that are vital for re-population of the corneal epithelium. Total limbal stem cell deficiency is commonly treated with limbal cell transplantation; partial limbal stem cell deficiency is commonly treated with an approach which includes grafting with amniotic membrane-derived products in conjunction with superficial keratectomy to remove the diseased tissue (Kheirkhah, 2008; Sangwan, 2004).
Extensive, double, or recurrent pterygium in which there is insufficient healthy tissue to create a conjunctival autograft
A pterygium is a triangular, fleshy fold of tissue that extends from the conjunctiva and encroaches onto the cornea. The size and growth rate of pterygia vary, and when vision is affected, surgery is often indicated. Treatment of pterygium is most commonly done with autograft or bare scleral techniques. Multiple RCTs have demonstrated that for both primary and recurrent pterygium, treatment with autograft was superior to treatment with amniotic membrane-derived products (Küçükerdönmez, 2007; Luanratanakorn, 2006; Prabhasawat, 1997; Tananuvat, 2004). This is supported by the American Academy of Ophthalmology in their 2013 report titled Options and Adjuvants in Surgery for Pterygium (Kaufma, 2013), as well as Cochrane review (Clearfield, 2016). However, when there is extensive, double, or recurrent pterygium in individuals who have insufficient healthy tissue to create a conjunctival autograft, the amniotic membrane-derived products may be used.
Moderate or severe Stevens-Johnson syndrome involving the cornea and/or conjunctiva
For moderate or severe Stevens-Johnson syndrome (SJS), there are few treatment options, and the use of amniotic membrane-derived products has been widely accepted as the standard of care. A prospective RCT published by Sharma (2016) involved 50 subjects with acute SJS who were assigned to treatment with either amnion (n=25) or medical therapy (n=25). The authors reported that best-corrected visual acuity at 6 months was significantly better in the amnion group vs. controls (p=0.042). Mean tear film breakup time and Schirmer test results were also significantly better in the amnion group vs. controls (p=0.015 and p=0.001, respectively). Conjunctival congestion persisted in 44% of control subjects vs. 4% in the amnion group at 6 months (p=0.03). Corneal haze, limbal stem cell deficiency, symblepharon, ankyloblepharon, or lid-related complications were not reported in the amnion group, but the control group experienced corneal haze (44%, p=0.001), corneal vascularization and conjunctivalization (24%, p=0.03), symblepharon (16%, p=0.12), ankyloblepharon (4%, p=1.00), ectropion and entropion (8%, p=0.47), and trichiasis and metaplastic lashes (24%, p=0.03). Several weak case series studies have also demonstrated favorable outcomes (Gregory, 2011; Honavar, 2000; John, 2002; Shammas, 2010; Tomlins, 2013).
Other ocular conditions
Amniotic membrane-derived products have been investigated for the treatment of other conditions, including glaucoma and dry eye. The treatment of glaucoma has been studied in two controlled trials. The first, published by Mahdy (2010), was a nonrandomized controlled trial involving 30 pediatric subjects with glaucoma treated with either trabeculectomy with mitomycin C or trabeculectomy with mitomycin C plus lyophilized amniotic membrane. The authors reported that operative success occurred in 80% of amnion group subjects and 60% of control subjects. Mean postoperative intraocular pressure was significantly decreased in both groups. However, the intraocular pressure gradually increased throughout the follow-up visits, with significantly higher intraocular pressure in the amnion group vs. controls up to 18 months (p<0.05). Complications such as inflammation, choroidal detachment, or toxic keratopathy were not noted in the amnion group but were noted in the control group. The authors concluded that trabeculectomy with amniotic membrane transplantation and mitomycin C can effectively control the elevated intraocular pressure in pediatric patients with glaucoma without significant postoperative complications. The other study by Sheha and others (2008) was a prospective RCT of 37 eyes with glaucoma undergoing trabeculectomy with mitomycin C and amnion (n=19 eyes) or trabeculectomy with mitomycin C alone (n=18). Complete success, defined as intraocular pressure < 22 mm Hg without glaucoma medications, was reported in 93.7% of amnion-treated eyes and 60% control eyes at 6 months (p=0.03), and 80% and 40% at 12 months (p=0.03). Intraocular pressure decreased significantly in both groups at 12 months (p<0.0001). Early postoperative hypotony developed in 16.7% of control eyes owing to excessive filtration but none of the amnion group eyes (p=0.1). Encapsulated bleb occurred in 38.9% of control eyes but in 5.3% of amnion-treated eyes (p=0.02). While these studies have demonstrated significant benefits, the use of amniotic membrane-derived products has not yet become widely accepted as standard practice. A wide array of other less invasive treatment options are currently available which provide significant relief to this population.
Short term treatment of dry eye has also been a proposed use for amniotic membrane-derived products. One RCT has been published addressing this treatment option (John, 2017). The underpowered prospective RCT involved 17 subjects with dry eye disease treated with either cryopreserved amnion (n=8) or standard care (n=9). The authors stated that pain and visual disturbances decreased significantly in the amnion group but not in the control group (no p values provided). No differences between groups were reported for visual acuity. Dry Eye Work Shop (DEWS) measures were significantly improved vs. controls (no p values provided). No differences between groups were reported for corneal topography measures. Central corneal nerve density, dendritiform cell density and corneal sensitivity was greater in the amnion group (no p values provided). While these reported findings seem beneficial, the small sample size and lack of proper statistical data do not allow reliable conclusions. Two case series studies have also demonstrated beneficial outcomes (Cheng, 2016; McDonald, 2018, described below). Use of amniotic membrane-derived products also limits visual acuity. However, this treatment has not been widely accepted as a standard treatment approach in the clinical setting. Many effective less invasive treatments are available for dry eye.
Several branded amniotic-membrane derived products have been the subject of published peer-reviewed studies. These are described below:
Prokera
Prokera is a composite product consisting of amniotic membrane tissue in between two rings of clear, flexible material. It was cleared through the FDA’s 510K process and is intended for use in eyes in which the ocular surface cells have been damaged, or underlying stroma is inflamed and scarred. The device is inserted between the eyeball and the eyelid to maintain space in the orbital cavity and to prevent closure or adhesions.
To date, the largest study published addressing the use of Prokera was a retrospective case series study involving 97 eyes of 84 subjects with severe dry eye refractory to maximal medical management (McDonald, 2018). Subjects had superficial punctate keratitis (86%), filamentary keratitis (13%), exposure keratitis (19%), neurotrophic keratitis (2%), and corneal epithelial defect (7%). After treatment with Prokera for a mean of 5.4 days, 74 (88%) of subjects demonstrated an improved ocular surface. Dry eye workshop score (DEWS) was reduced significantly from 3.25 at baseline to 1.44 at 1 week, 1.45 at 1 month, and 1.47 at 3 months (p<0.001 for all). A total of 10 eyes (10%) required repeated treatment to complete healing. Apart from discomfort during CAM placement, there were no adverse events.
Another underpowered retrospective case series study involved placement of Prokera in 58 subjects undergoing penetrating keratoplasties (PKP) in high-risk recipients (Nguyen, 2014). Twelve subjects underwent their first PKP and 46 had repeat PKP. The authors reported that risk factors for graft failure included repeat PKP (79.3%), corneal neovascularization (51.7%), preexisting glaucoma (46.6%), and presence of anterior synechiae (37.9%). Both first and repeat PKP groups had similar survival rates until 6 months (75% vs 74%, OR, 1.06, p=1.00). At 12 months, the first PKP group showed a better survival rate (67% vs 43%, OR, 2.60, p=0.20). Eyes with > 3 risk factors had a higher graft failure rate (OR, 5.81, p=0.003).
Vlasov (2016) reported on the use of Prokera in 80 subjects undergoing photorefractive keratectomy. Subjects were treated with either Prokera (n=40) or high-oxygen-transmissible bandage contact lens (Acuvue Oasys, n=40). No significant differences between groups were reported with regard to visual outcomes, corneal clarity, and optical quality of the cornea. The Prokera group experienced 1 case of spontaneous extrusion, 1 case of delayed epithelial healing, 2 cases of persistent defect, 4 cases of corneal infiltrates, and 1 case of nongranulomatous uveitis. Four cases of corneal infiltrates were reported in the control group. The authors concluded that the use of Prokera for post- photorefractive keratectomy wound healing remains speculative.
The use of amniotic-membrane derived products has been proposed for a wide variety of other indications, which may be addressed further in this document. These types of products may be used for a large number of other non-ocular indications. However, except where otherwise indicated, such use has not been widely accepted by the practicing community.
AlloDerm Regenerative Tissue Matrix (Aseptic)
AlloDerm Regenerative Tissue Matrix, also known as AlloDerm RTM, is an aseptic human-derived decellularized grafting product which is regulated through the U.S. Food and Drug Administration (FDA) Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/P) process as human tissue for transplantation. This aseptic product is being phased out of the market by the manufacturer beginning in 2021. This is due to the increasing use of the sterile version of this product, also known as AlloDerm Regenerative Tissue Matrix, AlloDerm Ready to Use (RTU) and AlloDerm SELECT RTM.
There are over a dozen weak case series studies and nonrandomized controlled trials published in the peer-reviewed medical literature describing the use of aseptic AlloDerm to partially or completely enclose an implanted breast prosthesis during post-mastectomy breast reconstruction (Becker, 2009; Bindingnavele, 2007; Breuing, 2005, 2007; Gamboa-Bobadilla, 2006; Preminger, 2008; Salzberg, 2006, 2011; Spear, 2008; Woo, 2017). The goal of using aseptic AlloDerm for this type of procedure is to reduce complications related to contracture, periprosthetic atrophy, and development of thin capsules. The results provided in these case series studies indicate good symmetry, increased soft tissue padding, and decreased rippling and implant visibility. While the available data is limited regarding the long-term benefits and outcomes of this procedure, it has become a widely used and accepted method of breast reconstruction. Expert opinion of breast surgeons supports the use of aseptic AlloDerm for this indication.
However, care must be taken when selecting aseptic AlloDerm for use in breast reconstruction. A retrospective, nonrandomized controlled study by Weichman and others published in 2012 found significant complication rates with its use. In their study, 407 consecutive subjects underwent 628 immediate 2-stage breast reconstructions either with aseptic AlloDerm (n=442, 70.3%) or without aseptic AlloDerm (n=186, 29.6%). The authors reported that major complications were significantly increased in the aseptic AlloDerm group (15.3% vs. 5.4%, p=0.001). Complications included infection requiring intravenous antibiotics (8.6% vs. 2.7%, p=0.001), flap necrosis requiring excision (6.7% vs. 2.7%, p=0.015), and explantation of the tissue expander (7.7% vs. 2.7%, p=0.004).
The treatment of infected or contaminated abdominal wall wounds and defects is difficult. Standard fascial prostheses such as polypropylene and polyester mesh, which are routinely used for non-complex cases, may exacerbate wound infection, fistula and adhesion formation, and erosion, leaving few real options for such individuals. The use of aseptic AlloDerm for the treatment of complex abdominal wall wounds has been reported in over 30 peer-reviewed journal articles (Espinosa-de-los-Monteros 2007; Glasberg, 2006; Lee, 2009; Lin, 2009; Maurice, 2009; Patton, 2007; Vertrees, 2009). These studies demonstrate a high rate of successful wound healing with relatively low numbers of complications. As with the use of aseptic AlloDerm for breast reconstruction, aseptic AlloDerm for complex abdominal wall wounds has been widely used and is an accepted treatment method, although data is limited regarding the long-term benefits and outcomes of this use. Expert opinion of surgeons who routinely treat these types of wounds supports the use of aseptic AlloDerm for this indication.
At this time, there is limited data addressing the use of aseptic AlloDerm in treating chronic wounds. There is very limited evidence available regarding the use of aseptic AlloDerm in the treatment of burns or for surgical reconstruction procedures such as in the treatment of lid retraction in individuals with Graves’ disease or in the prevention of Frey’s Syndrome. Additionally, aseptic AlloDerm has been proposed for use in a wide variety of other surgical applications.
The use of aseptic AlloDerm has been proposed for the treatment of various nasal and oral surgeries, including palatal fistula. At this time, there are only a limited number of underpowered studies addressing this use in clinical trials (Helling, 2006; Steele, 2006). These studies show promising results but are underpowered and use weak study designs. Additional studies are needed to demonstrate the efficacy of this use of aseptic AlloDerm.
In the one available clinical trial of aseptic AlloDerm in people with lid retraction due to Graves’ disease, only 14 participants were studied in a non-blinded fashion (Sullivan, 2003). While the findings of this study were promising, further controlled studies with larger numbers of participants are needed to confirm the efficacy of this procedure.
There are currently two studies available in the peer-reviewed literature addressing the use of aseptic AlloDerm for treatment of burns. The first study involved 19 participants randomized to aseptic AlloDerm with an autograft overgraft vs. aseptic AlloDerm with an allograft overgraft which was replaced with an autograft overgraft after 1 week (Munster, 2001). Graft uptake was not different between groups. Immediate use of aseptic AlloDerm with thin autograft was associated with more healing than spilt thickness grafts. The second study involved 52 nonrandomized participants all of whom received aseptic AlloDerm covering to radial arm free flap donor sites (Sinha, 2003). The results of this study indicated that there were minimal contractures or restrictions to the healed graft. While these studies suggest some benefit from the use of aseptic AlloDerm for burns, larger randomized trials are needed to confirm efficacy of this procedure.
At this time, there are two available studies in the peer-reviewed literature regarding the use of aseptic AlloDerm to treat Frey’s syndrome. The first involved 64 participants randomly assigned to the use of aseptic AlloDerm placement in the parotid bed following removal of the parotid gland vs. no aseptic AlloDerm (Govindaraj, 2001). While the rate of gustatory sweating in the aseptic AlloDerm group was found to be statistically lower than the control group, the aseptic AlloDerm group also had an almost three-fold increase in complications, including both a higher frequency of seroma as well as one wound infection. In a second study, 30 participants were randomized into 3 groups; (1) superficial parotidectomy with placement of aseptic AlloDerm, (2) superficial parotidectomy without placement, and (3) deep-plane rhytidectomy (Sinha, 2003). The incidence of both subjective and objective Frey’s syndrome was significantly higher in group 2 when compared to both groups 1 and 3. However, given the small numbers of subjects in each group, the results of this study do not allow strong conclusions to be drawn as to the effectiveness of this procedure.
Overall, the available evidence addressing the use of aseptic AlloDerm for breast and complex abdominal reconstruction procedures demonstrates significant benefits in relation to health outcomes. While AlloDerm has been used for a wide variety of other indications, as discussed above, such uses have been poorly studied and have not been widely accepted by the practicing community.
AlloDerm Regenerative Tissue Matrix (also known as AlloDerm SELECT RTM and AlloDerm Ready To Use [RTU]) (Sterile)
Another AlloDerm product, also known as AlloDerm Regenerative Tissue Matrix and formerly known as AlloDerm SELECT RTM, AlloDerm Ready To Use, and AlloDerm RTU, is a sterile product that is reportedly easier to use. The manufacturer of the AlloDerm products, Allergan, is phasing out use of the aseptic AlloDerm product in favor of the sterile version of this product.
The sterile product is similar to the aseptic AlloDerm product in origin and processing and is treated as human tissue for transplantation under the FDA’s HCT/P process. Both products are derived from donated cadaveric dermis and undergo the same aseptic tissue processing. However, the sterile AlloDerm product undergoes additional sterilizing with electron beam radiation. Additionally, whereas aseptic AlloDerm is freeze-dried prior to packaging and requires rehydration prior to use, sterile AlloDerm is not freeze-dried and requires no rehydration.
Weichman (2013) conducted a nonrandomized controlled, consecutive series study of subjects undergoing either immediate breast reconstruction with tissue expander or permanent implants. For the first year of the study, all subjects requiring reconstruction with acellular dermal matrix received aseptic AlloDerm (n=58; 90 breasts). At the 1-year point, subjects meeting the same criteria were all treated with sterile AlloDerm (n=64; 105 breasts). Concurrently, the investigators followed all individuals undergoing breast reconstruction without the need for acellular dermal matrix, and who underwent submuscular coverage (n=223; 351 breasts). For the most part, the two AlloDerm groups were equivalent with the exception that the aseptic group was noted to have statistically significantly larger mean specimen weight and higher body mass index (BMI) vs. the sterile group (p=0.0485 and p=0.0376, respectively). The sterile group also had a higher incidence of nipple-sparing surgeries (p=0.0021). With regard to complications, the sterile group had significantly fewer overall infections vs. the aseptic group (8.5% vs. 20%, p=0.0088). However, there were no significant differences between groups with regard to explantations (sterile=2 vs. aseptic=6, p=0.147) or major infections requiring antibiotics (sterile=4.7% vs. aseptic=12.2%, p=0.069). The incidence of seroma, hematoma, and skin flap necrosis were not different between groups. When comparing the sterile group vs. the submuscular coverage group, the sterile group had significantly higher incidence of immediate permanent implantations (p=0.0001) and nipple-sparing surgeries (p=0.0012), as well as greater tissue expander size, initial tissue expander fill and percentage tissue expander fill. Both groups were found to have similar outcomes with regard to skin flap necrosis, overall infection, need for explantation and the incidence of seroma and hematoma. Univariate analysis found that risk factors for increased infectious complications included breast with flap necrosis (p=0.0003), those in which aseptic was used (p=0.0004), and those with seroma (p=0.0012). In addition, diabetes was an independent risk factor, and individuals with diabetes were 2.9 times more likely to suffer complications (p=0.037). The authors identified the differences between the sterile and tissue expander groups to be possible confounding factors in this study. The authors conclude that the use of sterile AlloDerm is acceptable and mitigates the risk of infectious complications compared to aseptic AlloDerm.
In 2015, Lewis and others published the results of a retrospective case series study of subjects receiving aseptic AlloDerm (n=93) or sterile AlloDerm (n=74) as part of either breast reconstruction or breast augmentation procedures to investigate the incidence of complications and “red breast syndrome” (RBS). While the decrease in individual complications, including seroma, necrosis, and RBS were not significant between groups, the overall complication rate was significantly in favor of the sterile group (p=0.046). Based on aggregate complication rate on a per-breast basis, the absolute risk reduction with sterile AlloDerm was reported to be 14.9%. The authors concluded that the use of the sterile AlloDerm product resulted in fewer complications when compared to aseptic AlloDerm.
Parikh (2018) reported the results of a retrospective cohort study involving 1285 consecutive subjects undergoing 2039 immediate prosthetic breast reconstructions. Subjects underwent treatment with either aseptic (n=612, 910 breasts) or sterile (n=673, 1129 breasts) AlloDerm. The authors reported that the aseptic group experienced a significantly higher rate of explantation compared to the sterile group (18.0% vs. 12.0%, p=0.0036). No significant differences were reported with regard to the between-group rates of surgical site infection, wound dehiscence, mastectomy flap necrosis, seroma, or hematoma. Multivariate regression analysis indicated that subjects in the aseptic group did have higher odds of explantation vs. the sterile group (OR, 1.570, p=0.0161).
The results of these studies, in conjunction with the previously reported evidence from aseptic AlloDerm, have demonstrated a significant outcome benefit of the sterile AlloDerm product. This product is accepted as substantially equivalent to the aseptic AlloDerm product. These products are sourced and processed in an identical manner, with the addition of a sterilization process in the case of the sterile product. This addition has not been demonstrated to have any negative impact on the performance of the product, and there is building evidence that there is some benefit derived from its sterilized nature.
Overall, the available evidence addressing the use of sterile AlloDerm for breast and complex abdominal reconstruction procedures demonstrates significant benefits in relation to health outcomes. While AlloDerm has been used for a wide variety of other indications, including insufficient conjunctiva (Park, 2017), such uses have been poorly studied and are not widely accepted by the practicing community.
AmnioBand
AmnioBand is a dehydrated human placental membrane comprised of amnion and chorion. It is treated as human tissue for transplantation under the FDA’s HCT/P process. This product is available in both sheet or membrane form and particulate or injectable form.
There are currently a few weak studies published on the use of the sheet/membrane from in human subjects. DiDomenico (2016) described an RCT involving 40 subjects with chronic nonhealing DFUs assigned to receive continued standard of care or treatment with the membrane form of AmnioBand plus standard care. Subjects were followed until wound closure or 12 weeks, whichever came first. The authors reported that at 6 weeks, 70% (14/20) of the AmnioBand group was completely healed vs. 15% (3/20) of the controls. At 12 weeks, 85% (17/20) of the AmnioBand group were completely healed vs. 25% (5/20) of controls (mean time to healing 36 days vs. 70 days, respectively). Only one adverse event and one serious adverse event were reported in the AmnioBand group, although neither was deemed graft related by the authors.
This same group published a retrospective crossover study to evaluate the effectiveness of the membrane form of AmnioBand in subjects that failed to respond to the standard care treatment in the above mentioned RCT (DiDomenico, 2017). This report involved 11 subjects, and 9 (82%) wounds healed with AmnioBand. The mean wound area decreased from 1.7 cm² to 0.2 cm² (p=0.0005), with a corresponding mean percentage area reduction of 92%. Of the 2 wounds that failed to meet the definition of healed in this study, 1 DFU decreased in area by 91% and the other by 26%.
An evaluator blinded RCT was published involving 80 subjects with DFUs assigned to treatment with the membrane form of AmnioBand (n=40) vs. continued standard care (n=40) (DiDomenico, 2018). Subjects failed a minimum of 4 weeks of standard care prior to entry into the study. At 6 weeks, 12 subjects in the control group (30%) and 2 from the AmnioBand group (5%) were withdrawn from the study due to failure to have their wounds decrease at least 50%. These subjects were considered treatment failures. Complete wound healing at 6 weeks, the primary endpoint, was reported in 68% of the AmnioBand group vs. 20% of the control group subjects (p<0.0001). At 12 weeks, complete healing was reported in 85% of AmnioBand subjects vs. 33% of control subjects (p<0.0001). Mean time to heal at 6 weeks was 29.2 days vs. 39.5 days, respectively (p<0.0001). At 12 weeks, mean time to heal was 37 days vs. 67.3 days (p<0.0001), respectively. The HR for treatment with AmnioBand vs. standard care was 4.25. There were 11 adverse events (AEs) reported, with 3 in the AmnioBand group and 8 in the control group. All involved localized pedal infections initially treated with antibiotics. A total of 4 serious adverse events were also reported, with 1 in the AmnioBand group and 3 in the control group. All were related to foot infections requiring hospitalization, with the majority progressing to osteomyelitis and IV antibiotic treatment and debridement as necessary. No adverse events were found to be graft related.
Glat (2019) reported on an RCT involving a group of 60 subjects with DFUs comparing the membrane form of AmnioBand to Apligraf (n=30 each). All subjects had failed at least 4 weeks of standard care. Time to heal within 6 weeks was 24 days in the AmnioBand group vs. 39 days in the Apligraf group (p=8.0x10-6, hazard ratio (HR), 5.8). The proportion of wounds closed within 6 weeks was 77% in the AmnioBand group vs. 23% in the Apligraf group (no p-value reported), and at 12 weeks the data indicated 90% and 40%, respectively (p=4.9x10-5). Mean time to heal at 12 weeks was 32 days and 63 days, respectively, (p=3.2x10-5). Percentage area reduction (PAR) at 12 weeks was 98% for the AmnioBand group vs. 44% in the Apligraf group (no p-value reported). Serious adverse events occurred in 3 AmnioBand subjects and 4 Apligraf subjects, all of which were severe infections (between group comparison p=0.52).
The results of these studies demonstrate that DFUs failing standard care subsequently treated with the membrane form of AmnioBand have significantly better results with regard to complete wound closure and time to heal when compared to standard care and to at least one other product available on the US market. The use of the membrane form of AmnioBand for other conditions is not widely supported by the practicing community.
At this time there are no studies available addressing the use of the particulate or injectable form of AmnioBand. Further investigation is needed to assess the safety and efficacy of this form of the product.
Apligraf
Apligraf is a composite grafting product composed of agarose, L-glutamine, hydrocortisone/bovine serum albumin, bovine insulin, human transferrin, triiodothyronine, ethanolamine, O-phosphoryl-ethanolamine, adenine, selenious acid, DMEM powder, and HAM’s F-12 powder. It has been approved through the FDA’s Premarket Approval (PMA) process. It has been considered for a wide variety of uses, but primarily for treatment of diabetic ulcers and burn wounds.
Veves and others published the results of a RCT addressing the use of Apligraf for the treatment of neuropathic diabetic ulcers (2001). In this trial, 208 subjects were randomly assigned to be treated with either Apligraf (n=112) or standard care (n=96). At the 12-week follow-up, 63 (56%) subjects in the Apligraf group achieved complete wound healing vs. 36 (38%) in the control group (p=0.0042). The Kaplan-Meier median time to complete closure was 65 days for Apligraf, significantly lower than the 90 days observed in the control group (p=0.0026). The rate of adverse reactions was similar between the two groups, with the exception of individuals with osteomyelitis or lower-limb amputations, both of which were less frequent in the Apligraf group. Steinberg and colleagues conducted an RCT following the methodology used by Veves et al (2010). This study involved 72 subjects, 33 of whom received treatment with Apligraf and 39 control subjects who received standard care. However, this study was discontinued early, due to non-safety-related reasons. The authors do not elaborate on this further. Because this study was stopped before full enrollment, results from this study are underpowered for demonstrating statistically significant differences. However, even though the study was halted prematurely, the results are similar to those reported by Veves; in particular, the Steinberg study showed significant (p=0.049) superiority of Apligraf to achieve complete healing at 12 weeks follow-up in comparison to the control group. These results, taken together, support the use of Apligraf for the treatment of foot ulcers.
Apligraf has been investigated for the treatment of other indications, including burns. Only one peer-reviewed published study has been published at this time addressing burns (Waymack, 2000). In this randomized controlled trial, 40 subjects with burn injuries were treated with either meshed autograft covered by meshed allograft or meshed autograft covered by Apligraf. There was no difference in take rate or the median days to 75% graft take. The unblinded investigators rated 22 (58%) of the Apligraf sites as superior to controls, 10 (26%) equivalent to controls, and 6 (16%) worse than controls (p=0.0037). Pigmentation of the Apligraf sites was also rated as superior to control sites at 2 years (p=0.0005), and normal vascularity was seen in 18 (47%) of Apligraf sites vs. 6 (16%) of controls for the same time period (p value not provided).
The use of Apligraf for the treatment of DFUs and VSUs is well established and supported by both the published literature. Its use for other indications has not yet been established or accepted by the practicing community.
Biobrane
Biobrane, a synthetic product composed of a silicone film bonded to a nylon fabric base, has been approved through the FDA’s PMA process. Data regarding the use of synthetic Silicone/Nylon Membrane wound dressing (e.g., Biobrane) has been described in four separate randomized controlled trials (RCTs) in peer-reviewed published medical journals (Barret, 2000; Feldman, 1991; Gerding, 1990; Lal, 2000). All of these studies found that in comparison to their various control groups the use of Biobrane significantly improved pain scores and healing times.
Additionally, the use of Biobrane has been reported in an underpowered case series study of 18 subjects with Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis (SJS-TEN) (Rogers, 2017). The authors reported that there were no complications, infections, premature removals, or Biobrane-associated sepsis in 24/25 applications (96%). Time to healing was 13 (12-16) days, and mean burn center length of stay was 34 days. This weak study demonstrates promising data regarding the safety and efficacy of Biobrane for SJS and other conditions.
Based on clinical practice standards, relevant expert opinions, the above-mentioned evidence, and the overall clinical experience with Biobrane, an acceptable level of safety and efficacy has been established for the use of this product in the treatment of burns and Stevens-Johnson Syndrome. The evidence for use of this product for other indications is unestablished and not widely accepted by the practicing community.
DermACELL
DermACELL, a product composed of acellular human dermis, has been studied for a limited number of indications, including chronic lower extremity wounds in individuals with diabetes and breast reconstruction. It is treated as human tissue for transplantation under the FDA’s HCT/P process.
The most rigorous study to date was a prospective non-blind RCT involving 168 subjects with DFUs assigned in a 2:2:1 fashion to treatment with DermACELL (n=71), conventional care (n=69), or Graftjacket (n=28) (Walters, 2016). At 16 weeks post intimal treatment, subjects in the DermACELL group were reported to have a significantly higher proportion of completely healed ulcers vs. the conventional care group (67.9% vs 48.1%; p=0.0385) but no significant differences vs. the Graftjacket group (67.9% vs 47.8%; p=0.1149). The DermACELL group also did not exhibit a greater average percent reduction in wound area vs. either comparison group (conventional care=91.4% vs 80.3%; p=0.0791; Graftjacket group=91.4% vs 73.5%; p=0.0762). No differences between groups were reported with regard to severe adverse events (p≥0.05).
Another large study was a retrospective consecutive case series study involving 140 subjects undergoing breast reconstruction treated with either sterile AlloDerm or DermACELL (n=70, each group) (Zenn, 2016). Subjects were selected on either side of the time point when the investigators switched from using sterile AlloDerm to DermACELL. No statistical differences were reported between groups with regard to complications, including the incidence of seroma, infection, implant loss, and unplanned return to the operating room.
Pittman and others (2017) published the results of a retrospective review of 58 subjects who underwent breast reconstruction with either DermACELL (n=30) or sterile AlloDerm (n=28). The authors reported that 74% of the AlloDerm subjects underwent immediate reconstruction with tissue expanders vs. 56% of the DermACELL group. Mean initial expansion volumes were 193 ml and 188 ml, respectively. In those subjects having direct-to-implant procedures, the mean implant size was 463 cc and 443 cc, respectively. Unfortunately, no p-values were provided for these comparisons, but the authors stated that no statistical differences were found. Likewise, no differences between groups were noted with regard to unilateral vs. bilateral reconstruction and breast irradiation. The DermACELL group had significantly shorter time to drain removal (15.8 vs. 20.6 days, p=0.017). A significantly higher rate of “red breast”, defined as self-limiting erythema in the absence of skin edema or induration in an otherwise asymptomatic subject isolated to the lower pole of the breast in the distribution of the acellular matrix graft, was reported in the AlloDerm group (13 vs. 0, p=0.0001). No differences between groups was noted with regard to hematoma, seroma, flap necrosis, or cellulitis requiring oral antibiotics. Delayed wound healing was reported as occurring more frequently in the AlloDerm group (20% vs. 8%); however, the significance of this is unclear as no p-values were provided. While these findings are promising, the small sample size, retrospective and unblinded nature of the methodology impairs the strength of this study.
Cazzell (2017) conducted an RCT involving 132 subjects with chronic DFUs undergoing treatment in a 2:2:1 fashion with either DermACELL (n=53), conventional care (n=56), or GraftJacket (n=23). Subjects were followed through 24 weeks, with endpoint measurement at 12, 16, and 24 weeks. A single application of DermACELL resulted in significantly greater wound closure rates vs. conventional care at all three endpoints (p=0.0123, p=0.0003, and p=0.0008, respectively), and significantly higher healing rate vs. conventional care at week 16 and week 24 (p=0.028 and p=0.489, respectively). GraftJacket did not show a significantly greater healing rate over conventional care at any of these time points, but small numbers of subjects may have impacted that finding. Closed ulcers in the DermACELL group remained healed at a significantly greater rate vs. the conventional care arm at 4 weeks post study termination (100% vs. 86.7%; p=0.0435). No significant difference was noted between the GraftJacket group vs. the conventional care group for healed wounds remaining closed. Again, small numbers of subjects introduce significant potential bias into this observation.
Chang (2017) reported a retrospective comparative series study of 47 subjects who underwent breast reconstruction using FlexHD Pliable (n=18), aseptic AlloDerm (n=15), or DermACELL (n=14). The authors reported that there were no differences in the rates of seroma, infection, or skin flap necrosis. Additionally, there were no cases of red breast, expander explanation, or failed reconstruction in any group. Time to drain removal was significantly shorter in FlexHD and DermACELL subjects compared to aseptic AlloDerm (20 days vs. 15 days vs. 26 days, respectively; p=0.01).
Another retrospective comparative series study comparing the use of DermACell vs. sterile AlloDerm was reported by Powers in 2021. In this study, 79 subjects undergoing prepectoral breast reconstruction received treatment with either DermACell (n=41) or sterile AlloDerm (n=38). The DermACell group had a higher rate of bilateral (p=0.03) and direct-to-implant (p=0.001) reconstructions, higher average initial fill volume (p<0.001), and longer average drain duration (p=0.006). Additionally, the follow up time in the AlloDerm group was significantly longer (p<0.001). The authors reported that the postoperative infection rate was significantly higher in the AlloDerm group (26.8% vs. 5.3%; p=0.014). Infections were reported in 11 AlloDerm subjects, all of which were considered major and treated with either intravenous antibiotics or return to the operating room. Infections were reported in 2 DermACell subjects, 1 which was treated orally and the other treated with IV antibiotic therapy. No p-values were provided for the between-group differences. Two of the 11 AlloDerm subjects were treated with IV antibiotics. The remaining 9 subjects required operative intervention for either explantation (n=-3) to expedite chemotherapy/radiotherapy or attempt at salvage with implant replacement and quantitative polymerase chain reaction-tailored antibiotic beads (n=6). This report is supportive of the use of DermACell vs. AlloDerm. However, the methodological weakness inherent in this study limits the generalizability of the findings.
Other weak non-comparative studies have also been published describing significant benefits due to DermACELL (Bullocks, 2014; Ortiz, 2017; Yonehiro, 2013).
While relatively new to the market, DermACELL has been subject to multiple published clinical trials, including several RCTs and reasonably sized case series studies. The clinical experience with this product had demonstrated an acceptable level of safety and efficacy for use in the treatment of diabetic foot ulcers and during breast reconstruction procedures. The evidence for use of this product in other procedures or for other indications is still unclear and further investigation is warranted.
Use of DermACELL for the treatment of large, complex diabetic foot ulcers (DFUs) with exposed probed tendon or bone was described by Cazzell (2019). This case series study involved 61 subjects with Wagner grade 3 or 4 DFUs between 4 to 52 weeks in duration. The authors reported that the entire per-protocol population (n=47) achieved 100% granulation with a mean time to 100% granulation of 4.0 weeks. The mean percent wound area reduction was 80.3% at 16 weeks. DFUs 15 cm or smaller were substantially more likely to close compared to DFUs larger than 29 cm (p=0.0008) over a 16-week duration. No complications related to the use of DermACELL were reported. These findings are promising, but the small population and poor study methodology make it difficult to generalize these findings to a wider population.
The use of DermACELL for use in breast reconstruction procedures and treatment of DFUs has been well established. However, the use of this product for other indications has not been, and is not widely accepted by the practicing community.
DermACELL AWM and DermACELL AWM Porous are two products also available on the market. They are not substantially different from the original DermACELL product, having the same tissue origin and processing. They are just different formats of the original DermACELL and are considered equivalent for the purposes of this document.
Dermagraft
Dermagraft is a composite grafting product composed of cryopreserved human fibroblastin and allograft collagen scaffold that has been approved through the FDA’s PMA process. The use of Dermagraft has been described in several peer-reviewed studies (Gentzkow, 1996; Marston, 2003; Warriner, 2011). The largest and most rigorous of these was a RCT involving 355 subjects with venous stasis ulcers (VSUs) randomized to receive compression therapy plus Dermagraft (n=186) vs. compression therapy alone (n=180) (Harding, 2013). The endpoint was the proportion of subjects healed by 12 weeks. No differences were found between groups, with 34% (64/186) of subjects in the Dermagraft group experiencing healing by week 12 vs. 31% (56/180) in the control group (p=0.235). However, a significant difference was reported for subjects with ulcers ≤ 12 months duration, with 52% (49/94) of the subjects in the Dermagraft group healed at 12 weeks vs. 37% (36 /97) of the control subjects (p=0.029). For ulcers ≤ 10 cm2, no differences were identified in complete healing at week 12 (p=0.223). The most common adverse events (AEs) were wound infection, cellulitis, and skin ulcer. The frequency of AEs did not markedly differ between the treatment and control groups.
The results of another RCT were reported by Marston and colleagues (2003). This study involved 314 subjects with diabetic foot ulcers (DFUs) present for at least 2 weeks; 245 of these were considered chronic ulcers (> 6 weeks). Of the 245 chronic ulcer subjects, 19% (46) did not complete the 12-week study period. All participants were randomized to receive treatment with Dermagraft (n=130) or standard care (n=115). The final analysis showed that among subjects with chronic ulcers, the Dermagraft group healed significantly better at 12 weeks than standard care (30% vs. 18%, p=0.023). Additionally, for subjects with forefoot or toe ulcers, 29.5% of the Dermagraft-treated ulcers were closed compared to 19.6% of the controls (p=0.065). Similar findings were reported for heel ulcers, with 33% vs. 8% of ulcers healed, respectively (p=0.01). Dermagraft-treated subjects were significantly faster to heal (p=0.04), and at 12 weeks, the median percent with closure was 91% for the Dermagraft group compared to 78% for the control group (p=0.044).
Another RCT using Dermagraft was published by Gentzkow et al (1996). This study involved 50 subjects with DFUs randomized to receive treatment with either standard of care (n=13) or one of three Dermagraft regimens plus standard care: (1) one piece of Dermagraft applied weekly for a total of 8 pieces and 8 applications (n=12); (2) two pieces of Dermagraft applied every 2 weeks for a total of 8 pieces and 4 applications (n=14); and (3) one piece of Dermagraft applied every 2 weeks for a total of 4 pieces and 4 applications (n=11). At 12 weeks, the percentage of subjects who achieved complete wound closure was significantly higher in the high frequency Dermagraft (Group 1) than in the control group (50.0% vs. 7.7%, p=0.03), and the percentage that achieved at least 50% closure was 75% in Group 1 vs. 23.1% in controls. No recurrences were reported at the 14-month follow-up period.
Label warnings and precautions indicate that Dermagraft is contraindicated for use in ulcers that have signs of clinical infection or in ulcers with sinus tracts.
Dermagraft was granted an FDA Humanitarian Device Exemption (HDE) (2002) for the treatment of dystrophic epidermolysis bullosa.
The use of Dermagraft for the treatment of DFUs and dystrophic epidermolysis bullosa is well established. However, use of this product for other indications has not, and is not widely accepted by the practicing community.
DermaMatrix
DermaMatrix, a product composed of acellular human dermis, has been studied for a variety of indications. It is treated as human tissue for transplantation under the FDA’s HCT/P process. Below are discussions of several of the most recent controlled studies.
The use of DermaMatrix was evaluated in a retrospective, nonrandomized controlled trial involving 50 subjects who were assigned to undergo breast reconstruction with DermaMatrix (n=25) or aseptic AlloDerm (n=25) (Becker, 2009). The authors reported that there were no significant differences between groups with regard to complication rates. Both groups exhibited good incorporation, with evidence of neovascularization. A larger retrospective non-controlled study was done which involved 173 subjects receiving breast reconstruction and implantation of either aseptic AlloDerm (n=49), DermaMatrix (n=110), FlexHD (n=62), or no implantation (n=64) (Brooke, 2012). The authors reported no significant differences between groups with regard to overall complication rates between the implanted and control groups (p=0.48) or between implant groups (p=0.47).
Athavale and colleagues published the results of a retrospective, non-controlled study of the complication rate for parotid reconstruction surgery involving 100 subjects who received treatment with either aseptic AlloDerm (n=69) or DermaMatrix (n=31) (2012). Sixty-nine AlloDerm implants were associated with a total of 5 complications (7%), whereas 31 DermaMatrix implants were associated with a total of 8 complications (26%) (p=0.0107). Subgroup analyses found that for subtotal parotidectomies, the incidence of complications was found to be 8% for the AlloDerm group and 37% for the DermaMatrix group (p=0.004). The authors conclude that:
…this study suggests that DermaMatrix was associated with increased postoperative complications compared with AlloDerm when used for reconstruction of parotidectomy defects. To better define the complication profile of AlloDerm versus DermaMatrix in the postoperative parotid bed, a prospective study should be considered to determine implant performance following parotidectomy reconstruction.
Michelotti (2013) conducted a retrospective, nonrandomized controlled study of 73 subjects with breast cancer who underwent 284 tissue expander reconstructions. Subjects had received treatment with no ADM use (n=64 reconstructions), or with the use of aseptic AlloDerm (n=49 reconstructions), DermaMatrix (n=110 reconstructions), or FlexHD (n=64 reconstructions). Overall, there were 18 (6.3%) seromas reported in all 284 reconstructions. In the subjects who received treatment with ADMs (n=220 reconstructions), there were 17 (7.7%) seromas reported; 2 in the AlloDerm group, (11.76%), 6 in the DermaMatrix group (35.29%), and 9 in the FlexHD group (52.94%) (p=0.016). Within the limited scope of this underpowered nonrandomized or blinded study, the results of this study demonstrate that the use of DermaMatrix appears to be similar to AlloDerm with regard to the occurrence of postoperative seromas, and significantly better than FlexHD. This study highlights that there are significant differences in the clinical performance of different ADMs, and further investigation into this issue is warranted.
The design and methods of a moderately sized RCT were reported by Argarwal in early 2015. This trial, known as the BREASTrial, was designed to compare aseptic AlloDerm to DermaMatrix for immediate breast reconstruction procedures. The planned follow-up time was 2.5 years. Argarwal and others randomized 128 subjects to undergo reconstruction with either AlloDerm (n=64, 101 breasts) or DermaMatrix (n=64, 98 breasts) at the beginning of the study. The protocol describes three phases of the study. Phase I is from time of mastectomy and tissue expander placement to the definitive reconstruction procedure. Phase II is from definitive reconstruction to 3 months postoperatively. Finally, Phase III is from 3 months to 2 years postoperative. The primary outcome is the incidence of complications and secondary outcomes include: expander dynamics; degree of biointegration; impact of radiation therapy, chemotherapy, smoking, obesity and diabetes; duration of drains; and patient satisfaction. While the surgeons and subjects were aware of group assignment, the pathologist who evaluated the implant for biointegration was blinded to assignment. Results from Phase I of the BREASTrial have been reported by Mendenhall (2015). In the AlloDerm group, 5 subjects lost their tissue expander vs. 11 losses in the DermaMatrix group (p=0.11). The overall complication rate was 36.2%; for the AlloDerm group it was 33.6% vs. 38.8% in the DermaMatrix group (p=0.52). The only complications that were significantly different between groups were early loss of the implant defined as less than 45 days (1.0% for AlloDerm vs. 6.1% for DermaMatrix; p=0.049) and loss due to skin necrosis (1.0% for AlloDerm vs. 47.1% for DermaMatrix; p=0.027). The authors also reported that less time was needed in the AlloDerm group for complete expansion vs. DermaMatrix (42 days vs. 70 days; p<0.001). The results of Phase II, from the time of definitive reconstruction to 3 months post-operative were published in 2017 by Mendenhall and colleagues. The authors reported an overall complication rate of 16.6%, with under half of them (7.5%) being classified as “major” complications requiring inpatient or operative management. The most common complications were infection (4.6%), wound dehiscence (3.5%), skin necrosis (2.9%), and hematoma (0.6%). Overall implant loss rate was 2.9%. No differences were reported between the AlloDerm and DermaMatrix groups with regard to complications. Only obesity was reported as an independent predictor of complications. The results from Phase III are pending.
Finally, as mentioned above, Lee and colleagues (2017) published a meta-analysis investigating the use of ADMs for implant-based breast reconstruction. A total of 17 studies were included, with only one being a prospective RCT and the others having retrospective non-randomized designs. There were 12 studies available involving a comparison with FlexHD, DermaMatrix, and aseptic AlloDerm or sterile AlloDerm. For comparisons between DermaMatrix and aseptic AlloDerm, the results from four studies likewise found no differences between the pooled risks of complications. Finally, the meta-analysis of four studies comparing aseptic AlloDerm or sterile AlloDerm demonstrated that the pooled risks for the complications did not differ. The authors concluded that these products have similar risks of complications compared to aseptic AlloDerm.
Based on clinical practice standards, relevant expert opinions, the above-mentioned studies, and the overall clinical experience with DermaMatrix, an acceptable level of safety and efficacy has been established for the use of this product in breast reconstruction procedures. However, use of this product for other indications has not been widely accepted by the practicing community.
EpiCord
EpiCord, a dehydrated umbilical cord allograft, is treated as human tissue for transplantation under the FDA’s HCT/P process. A double-blind RCT published by Tettelbach (2018) addressed the safety and efficacy of the EpiCord product and involved 155 subjects with DFUs assigned in a 2:1 fashion to treatment with either EpiCord (n=101) or standard care with alginate wound covering (n=54). The per-protocol analysis included 134 subjects who completed the 12-week study period (n=86 EpiCord [85%], n=48 controls [89%]). All subjects had type 1 or 2 diabetes-related foot ulcers 1-15 cm2 present for at least 30 days and non-healing despite 2 weeks of optimal conservative therapy. The ITT analysis showed that the EpiCord group was more likely to heal within 12 weeks vs. control subjects (70% vs. 48%, p=0.0089). This finding was upheld in the per-protocol analysis, with healing rates at 12 weeks being 81% in the EpiCord group and 54% in the control group (p=0.0013). Additionally, of those wounds that were deemed to have had adequate debridement (n=107, ITT population), 96% of the EpiCord-treated wounds healed completely within 12 weeks, vs. 65% of the control treated wounds (p<0.0001). At the 16-week follow-up, 73% of the EpiCord and 54% of the control subjects had complete healing (p=0.0199). In the per-protocol population, 85% vs. 60% of wounds were healed, respectively (no p-values provided). Of the wounds healed in the 12-week trial period, 96% of EpiCord-treated wounds and 85% of the control-treated wounds remained healed at 16 weeks (no p-values provided). Adverse events were recorded in 75 subjects, with a total of 160 adverse events recorded, however none were attributed to the treatment dressings.
Based on clinical practice standards, relevant expert opinions, the above-mentioned studies, and the overall clinical experience with EpiCord, an acceptable level of safety and efficacy has been established for the use of this product for the treatment of DFUs. However, use of this product for other indications has not been widely accepted by the practicing community.
EpiFix
EpiFix is a product composed of allographic amniotic membrane and is regulated by the FDA’s HCT/P process as human tissue for transplantation. The use of EpiFix has been proposed for the treatment of various conditions including burns and corneal injuries. There are several peer-reviewed published studies available describing the use of materials derived from allographic amniotic membrane. However, the available evidence addressing EpiFix has been very limited. Three underpowered case series studies describing the use of EpiFix have been published (Forbes, 2012; Sheik, 2013; Zelen, 2013a). These studies involved very small numbers of subjects; 5, 4, and 11, respectively. Such evidence provides limited data demonstrating the safety and efficacy of this product.
A non-blinded RCT involving 25 subjects with DFUs assigned to either standard care (n=12) or treatment with EpiFix (n=13) was reported by Zelen and others (2013c). The authors report significantly reduced ulcer surface area at both week 4 and at week 6 (p<0.001). The mean reduction in ulcer size was most marked at the end of week 1, when the mean reduction in wound size was noted to be 20% for the control group and over 80% in the EpiFix group. At 4 weeks, none of the subjects from the control group (0%) were healed, whereas 10 of the 13 subjects in the EpiFix group (77%) had wounds that had completely epithelialized (p<0.01). At 6 weeks, 1 of the 12 subjects from the control group (8%) was healed and 12 of the 13 subjects in the EpiFix group (92%) were healed (p<0.001). For those subjects that healed, mean time to complete healing was 5 weeks in the control group (n=1) versus 2.5 ± 1.9 weeks in the EpiFix group (n=12). At the 6-week evaluation, 12 of the 13 subjects in the EpiFix group had healed completely. In early 2014, follow-up data from this trial was published (Zelen, 2014a). The authors reported that 11 of the 12 subjects from the initial RCT control group who had failed treatment were subsequently treated with EpiFix. The report included data from 18 of the total 24 subjects treated with EpiFix from both cohorts who had complete follow-up data to 12 months. The authors reported that 17 of the 18 subjects (94.4%) continued to have fully healed wounds at 12 months of follow-up.
Serena (2014) reported the results of an unblinded RCT involving 84 subjects with VSUs assigned to receive treatment with either EpiFix plus multi-layer compression therapy (n=53) or multi-layer compression therapy alone (n=31). The primary study outcome was the proportion of subjects achieving 40% wound closure at 4 weeks. The authors reported that 62% in the Epifix group vs. 32% in the control group met the primary endpoint (p=0.005). Furthermore, after 4 weeks, in wounds treated with Epifix, the mean size of the wound decreased 48.1% vs. 19.0% for controls.
Zelen (2014b) published the interim results of a second unblinded RCT involving 60 subjects with DFUs randomized in a 1:1:1 fashion to receive treatment with either EpiFix, Apligraf, or standard wound care (n=20 per group). At the 4- and 6-week endpoints, the proportion of EpiFix subjects achieving complete wound closure was 85% and 95%, significantly higher (all adjusted p-values ≤ 0.003) than for the subjects receiving Apligraf (35% and 45%) or control treatment (30% and 35%). After 1 week, wounds treated with EpiFix had reduced in area by 83.5% vs. 53.1% for Apligraf subjects. The median time to healing was significantly faster (all adjusted p-values ≤ 0.001) with EpiFix (13 days) vs. 49 days for the Apligraf group and 49 days for control subjects. A follow-up publication to that study with a total of 100 subjects was published in 2015 (Zelen, 2015). The final subject distribution for this study was 35 subjects in the EpiFix group, 33 subjects in the Apligraf group, and 35 subjects in the standard wound care group. The reported 12 week compete closure rate was reported to be 97%, 73% and 51%, respectively (p=0.00019). Compared to standard care, subjects treated with EpiFix had a significantly higher probability of healing (HR=5.66, adjusted p=1.3x10-7), while no difference in probability was reported between the Apligraf and standard care groups. Subjects treated with Apligraf were less likely to heal than those treated with EpiFix [HR=0.30, unadjusted p=5.8x10-5]. The mean time-to-heal within 12 weeks was 23.6 days in the EpiFix group, 47.9 days in the Apligraf group, and 57.4 days in the standard care group (adjusted p=3.2x10-7). The results of this additional paper confirm the findings originally reported, that EpiFix provides significant healing benefits for individuals with diabetic foot ulcers.
Another RCT involved 109 subjects with VSUs who were treated with either EpiFix combined with multilayer compression dressing (n=52) or multilayer compression dressings alone (n=57) (Bianchi, 2017). The investigators reported that subjects receiving weekly application of EpiFix and compression were significantly more likely to experience complete wound healing than those receiving control treatment (60% vs. 35% at 12 weeks, p=0.0128, and 71% vs. 44% at 16 weeks, p=0.0065). Both the time-to-heal and higher probability of complete healing within 12 weeks were significantly improved in the EpiFix group vs. controls (p=0.0110 and p=0.01, respectively).
Based on this evidence, specifically the data provided in the Bianchi (2017), Serena (2014) and Zelen (2014b) studies, the use of EpiFix appears to provide significant clinical benefit when compared to standard compression therapy alone in the treatment of VSUs and DFUs. Furthermore, the criteria presented in the medically necessary statement for EpiFix in the Position Statement section above is based on the subject inclusion criteria of these two studies.
Tettelbach (2018) reported the results of an RCT involving 110 subjects with DFUs treated with either EpiFix (n=54) or standard care (n=56). Of these, 98 subjects successfully completed the study, 47 in the EpiFix group and 51 in the control group. The authors reported that both the intent-to-treat (ITT) and per-protocol analysis revealed that EpiFix subjects were significantly more likely to have complete healing vs. control subjects (ITT: 70% vs. 50%, p=0.0338, per-protocol: 81% vs. 55%, p=0.0093). A Kaplan-Meier analysis comparing time-to-heal demonstrated significantly improved time to heal in the EpiFix group vs. controls (log-rank p<0.0187). Additionally, Cox regression analysis showed that EpiFix subjects were more than twice as likely to heal completely within 12 weeks vs. control subjects (HR, 2.15; p=0.003). At the final follow-up at 16 weeks, 95% of EpiFix-healed ulcers and 86% of control group healed ulcers remained closed. The authors concluded that their results confirmed that EpiFix is an efficacious treatment for lower extremity ulcers in a heterogeneous patient population.
In 2015, Patel and others published the first study to address the use of EpiFix as a protective measure for the prostatic neurovascular bundle during nerve-sparing robot-assisted prostatectomy. This prospective study involved 58 potent and continent subjects who underwent the procedure compared to 58 propensity-matched subjects who underwent the same procedure without the use of EpiFix. It was reported that continence at 8 weeks returned in 81.0% of the EpiFix subjects vs 74.1% of the control subjects (p=0.373). Mean time to continence was enhanced in the EpiFix subjects vs. controls (1.21 months vs. 1.83 months; p=0.033). Potency at 8 weeks returned in 65.5% of the EpiFix subjects vs. 51.7% of the controls (p=0.132). Mean time to potency was enhanced in the EpiFix group vs. controls (1.34 months vs. 3.39 months; p=0.007). The authors concluded that the use of EpiFix appeared to hasten the early return of continence and potency in subjects following nerve-sparing robot-assisted prostatectomy. However, the results of this weak unblinded nonrandomized study need to be further investigated and a large well-controlled blinded trial is warranted.
Toman (2021) published the results of a retrospective case-control study involving 286 subjects who underwent Mohs micrographic surgery of the face, head, or neck with the use of EpiFix or autologous tissue-based procedures, including full-thickness skin grafts and flaps (n=143, respectively). In univariate analysis, the authors reported that subjects in the EpiFix group had no postoperative complications vs. the autologous tissue group subjects (97.9% vs. 71.3%, p=<0.0001, RR=13.67). The EpiFix group also experienced significantly fewer infections (p=0.004), better scar cosmesis (p<0.0001), fewer scar revisions (p<0.0001), and fewer surgical reinterventions at the index site (p=0.0007). The autologous tissue group required fewer mean (SD) follow-up visits (2.5 vs. 3.4, p<0.0001). In a multivariate analysis controlling for defect surface area, operation time, age, medical history, and gender, use of autologous tissue remained an independent significant risk factor for infection or additional operation (OR, 11.71, p<0.0001). The authors also reported the results of an analysis that included cosmetic outcomes. The results indicated that the odds of infection, additional operation, poor scar cosmesis, or scar revision were 19-times higher in autologous group (OR,18.76, p<0.0001). Finally, they found that being female was also associated with 3-times greater odds of having a cosmetic complication (OR, 2.84, p=0.010).
Based on clinical practice standards, relevant expert opinions, the above-mentioned studies, and the overall clinical experience with EpiFix, an acceptable level of safety and efficacy has been established for the use of this product for the treatment of DFUs and VSUs. However, use of this product for other indications has not been widely accepted by the practicing community.
EZ Derm
EZ Derm is a product composed of porcine acellular dermis and cleared through the FDA’s 510K process. The available evidence addressing the use of the EZ Derm brand porcine derived decellularized fetal skin is limited. Data from two moderately sized retrospective case series studies have been published. The first involved 157 subjects with partial-thickness burns treated with EZ Derm (Troy, 2014). The authors reported 19 complications, including premature separation of graft (n=9, 16%), infection (n=4, 3%), and need for excision (n=6, 4.5%). The other study involved 164 subjects, also with burns (Burkey, 2016). The authors reported a significant decrease in average narcotic dose following treatment (p<0.001) and fewer dressing changes needed (p<0.001). Only 4 (2.4%) subjects developed infections, although only one of these infections was at the site of the study graft.
Additionally, two trials from over a decade ago addressing the use of EZ Derm for the treatment of burns have been published (Healy, 1989; Vanstraelen, 1992). The Vanstraelen study concluded that hypertrophic scarring occurred in 25% of xenograft-dressed sites, but none was seen in the comparison group. Several allergic reactions were reported to the porcine xenograft. The conclusions of the Healy study found, in comparison to burned participants treated with Jelonet®, individuals treated with EZ Derm did not vary significantly in terms of bacterial colonization rate, need for surgical treatment, time for spontaneous healing, analgesic requirements or frequency of dressing changes.
Based on clinical practice standards, relevant expert opinions, the above-mentioned studies, and the overall clinical experience with DermaMatrix, an acceptable level of safety and efficacy has been established for the use of this product for the treatment of burns. However, use of this product for other indications has not been widely accepted by the practicing community.
FlexHD
FlexHD is an acellular hydrated dermis product and is treated as human tissue for transplantation under the FDA’s HCT/P process. For the most part, the data addressing the use of FlexHD is from retrospective, nonrandomized controlled studies. The largest of these was published by Palaia and colleagues in 2015. This study involved 450 subjects undergoing immediate two-stage implant breast reconstructions who received treatment with either AlloDerm (n=134) or FlexHD (n=316). It is unclear which form of AlloDerm, aseptic or sterile, was used in this study. Demographics between the two groups were similar, with the exception that the FlexHD group had a significantly greater mean expander fill volume (p=0.0134). The authors reported no significant differences between groups with regard to seroma formation, incidence of infection, or explantation. There was a significant difference between groups with regard to rate of extrusion, with 6.2% reported for the AlloDerm group vs. 1.9% for the FlexHD group (p=0.0062). Another large retrospective nonrandomized controlled study involved 417 subjects (592 breasts) who received breast reconstruction following radiation therapy for breast cancer (Seth, 2012). In this study, 137 subjects received reconstruction with FlexHD and 280 underwent standard reconstruction without implantation. The authors noted significant differences in the baseline characteristics between groups, with the FlexHD group having a larger body mass (p=0.0001) and more nipple-sparing mastectomies (p=0.04). Postoperatively, the FlexHD group was noted to have received larger intraoperative fill volumes (p<0.0001). No significant differences were noted between groups with relation to complications (p=0.19). However, it was reported that when stratified for radiation exposure, the FlexHD group had a lower risk of complications (p=0.003). The control group was seen to have a higher rate of extrusion (p=0.01) and pain and tightness (p=0.0005). Liu (2014) reported the results of a retrospective, nonrandomized controlled study of 382 subjects (547 reconstructions) who underwent immediate implant-based breast reconstruction with the use of FlexHD (n=97), aseptic AlloDerm (n=165), or either immediate or two-stage reconstruction with no ADM (n=120). The authors reported that subjects who received treatment with ADMs were significantly more likely to have delayed healing (20.2% vs. 10.3%, p=0.009). Furthermore, a multivariate analysis identified that FlexHD posed a significantly greater risk of implant failure compared to AlloDerm (p=0.042). This study provides more data demonstrating that not all ADMs are equivalent, and that significant differences in clinical results may be seen between products. Another large retrospective case series involved 255 subjects (369 breasts) who underwent breast reconstruction (Seth, 2013). This study compared the use of FlexHD (n=159; 233 breasts) to aseptic AlloDerm (n=96; 136 breasts). This study found no significant differences between groups with regard to total complication rate including flap necrosis (p=0.849), IV antibiotic use (p=0.09), hematoma (p=0.431), seroma (p=1.0), and dehiscence (p=1.0).
In 2016, Sobti described a study involving 233 subjects undergoing breast reconstruction with FlexHD (n=101) or AlloDerm (n=132). The study involved the use of either aseptic or sterile AlloDerm (31.1% vs. 68.9%) as well as a mix of FlexHD Pliable/Perforated, FlexHD Pliable, or FlexHD Structural (80.2%, 18.8%, and 0.9%, respectively). No significant differences were reported with regard to infection rate (p=0.92), rates of seroma (p=0.25), hematoma (p=0.96), explantation (p=0.38), or delayed wound healing (p=0.70). Another retrospective non-controlled study, also discussed in the DermaMatrix section below, involved 173 subjects receiving breast reconstruction and implantation with aseptic AlloDerm (n=49), DermaMatrix (n=110), FlexHD (n=62), or no implantation (n=64) (Brooke, 2012). The authors reported no significant differences between groups with regard to overall complication rates between the implanted and control groups (p=0.48) or between implant groups (p=0.47). Finally, Rawlani and others (2011) conducted a large case series study describing the use of FlexHD during tissue expander breast reconstruction. During a mean follow-up time of 44 weeks, 121 subjects underwent several expansions prior to expander-to-implant exchange. Complications occurred in 20 (16.5%) of the subjects including nine soft tissue infections, eight partial flap necroses, and two seromas. Eleven subjects ultimately required explantation. Subjects undergoing radiation therapy (n=26) were significantly more likely to have complications (30.8% vs. 13.7%).
Michelotti (2013) conducted a retrospective, nonrandomized controlled study of 73 subjects with breast cancer who underwent 284 tissue expander reconstructions. Subjects had received treatment with no ADM use (n=64 reconstructions), or with the use of aseptic AlloDerm (n=49 reconstructions), DermaMatrix (n=110 reconstructions), or FlexHD (n=64 reconstructions). Overall, there were 18 (6.3%) seromas reported in all 284 reconstructions. In the subjects who received treatment with ADMs (n=220 reconstructions), there were 17 (7.7%) seromas reported; 2 in the AlloDerm group, (11.76%), 6 in the DermaMatrix group (35.29%), and 9 in the FlexHD group (52.94%) (p=0.016). Within the limited scope of this underpowered nonrandomized or blinded study, the results of this study demonstrate that the use of FlexHD appears to be inferior to AlloDerm or DermaMatrix with regard to the occurrence of postoperative seromas. This study highlights that there are significant differences in the clinical performance of different ADMs, and further investigation into this issue is warranted.
In 2013, Bochicchio and colleagues published the results of a prospective, consecutive case series study involving subjects undergoing complicated hernia surgery. Between January 2005 and December 2007, 55 consecutive subjects were treated with aseptic AlloDerm. From February 2008 to January 2010, 40 subjects received treatment with FlexHD. The authors reported that at 1 year follow-up, all (100%) of the AlloDerm subjects and 11 (31%) FlexHD subjects were diagnosed with a recurrence requiring surgical revision. This difference is quite startling, but is mitigated by the fact that, as the authors point out, there were significant differences between groups in the operative technique used. As such, the results reported are of little use in helping to understand the differences between FlexHD and AlloDerm with regard to safety and efficacy since there is significant bias in the study design.
Cahan and colleagues (2011), evaluated a new surgical approach to breast reconstruction. This study involved 98 subjects undergoing 159 mastectomies using either FlexHD or aseptic AlloDerm. The authors report that successful reconstruction was achieved in 93% of cases. Complications were seen in 23% of subjects, including dehiscence, seroma, full-thickness necrosis and infection. Removal of the implant was needed in 5 cases as a result of persistent infection (5%). Unfortunately, no data was provided enumerating the number of subjects receiving each product nor was any data provided comparing outcomes between product groups. The relative performance of FlexHD in this setting is unclear.
A case series study involving the use of FlexHD for post-mastectomy breast reconstruction was published by Vu (2015). This prospective study reported on the outcomes of 41 subjects who underwent 72 procedures conducted by a single surgeon. The surgical complication rate was 12.5% (9 of 72 breasts) and included hematoma (n=2) and skin flap necrosis (n=7). Resolution of six of these complications occurred with surgical interventions. The seventh subject experienced complete failure of reconstruction. The authors noted a complete lack of infections or seromas in this study. Responses to the self-administered BREAST-Q questionnaire were received from 97.6% of subjects and demonstrated satisfaction with breasts and psychosocial and sexual well-being had all returned to baseline values at 6 months postoperatively (p=0.903, p=0.321, p=0.479, respectively). Interestingly subjects who underwent postoperative radiation therapy reported lower satisfaction with their breasts as well as lower sexual satisfaction (p=0.004 and 0.006, respectively). These results are interesting, especially the lack of seroma and infections.
Broyles (2021) published the results of a prospective unblinded RCT involving 230 subjects who had undergone 387 breast reconstruction procedures with either FlexHD Pliable (113 subjects, 187 breasts) or sterile AlloDerm (117 subjects, 197 breasts). The authors reported no statistical difference between groups was found with regard to overall graft-related complications (4.3% vs. 7.1%, p=0.233). They did report the rate of complications was significantly higher for obese subjects (OR, 1.14, p=0.001) as well as for those receiving prepectoral graft placement (OR, 4.53, p=0.001).
The body of evidence addressing the use of FlexHD is predominantly retrospective nonrandomized controlled studies, with a few case series also available. While this methodology is not particularly robust, the data from studies are consistent in identifying lower or equivalent complication rates when compared to aseptic AlloDerm and other ADMs. Based on this evidence, expert opinion supports the use of FlexHD as an adjunct to breast reconstruction surgical procedures, and such use has become the standard of care. However, use of this product for other indications has not been widely accepted by the practicing community.
Fresh Frozen Unprocessed Allograft Skin for Burns (including AlloSkin and TheraSkin. Please see TheraSkin section below regarding for treatment of wounds)
The use of fresh, unfrozen, unprocessed skin allograft has been used as a treatment of serious burn injuries since the First World War and it has become an accepted standard therapy. The current process for the collection and preparation of these allografts involves several steps, starting with the harvesting of the skin sample from carefully selected cadaver donors. Following harvesting, initial serological and microbial testing takes place to screen for communicable diseases, including HIV and hepatitis. Next, the sample is bathed in a solution of various chemicals, including antibiotics, for several hours to several days to kill or inactivate possible pathogens. The tissue is then packaged aseptically for shipping and clinical use. The shelf life of this type of product is approximately 3 days from the time of harvesting, and it must be used within this time. One complexity in the use of this type of product is that, in urgent clinical situations, the results of final, definitive pathological tests are not usually available until approximately 10-14 days after harvesting. This means that, in urgent clinical situations, the clinician using the product is expected to use it prior to being assured of absolute clearance of pathogens. This concern, as well as other issues such as shelf life, etc., has led to the use of fresh frozen (cryopreserved) skin allograft as an acceptable alternative product for the treatment of burns for over 40 years. This product is processed in a similar manner to the fresh unfrozen products, but it is frozen once the initial screening is completed, and it is not released for use until after the definitive pathology reports have been completed. This additional step of freezing also allows for a shelf life of up to 5 years, which makes it more easily accessible for use in urgent medical situations. However, there is some evidence that indicates that this type of product loses some degree of viability due to the cryopreservation process, which may have an impact on its clinical effectiveness. However, this issue has not been well studied.
There are several brands of fresh, frozen, unprocessed allograft, including AlloSkin and TheraSkin. These products are treated as human tissue for transplantation under the FDA’s HCT/P process.
A small number of studies have been published in the peer-reviewed literature addressing the use of TheraSkin. Landsman and colleagues (2010) conducted a single-center, retrospective, uncontrolled case series study of 188 subjects with VSUs and diabetic foot ulcers. The authors used historical controls for comparison, many of which were derived from previously published RCTs. The follow-up time was 20 weeks. The authors reported that at the 12-week follow-up, 60.4% of diabetic ulcers and 60.7% of venous ulcers were closed. At 20 weeks, those numbers increased to 74.1% and 74.6%, respectively. Neither of these differences was statistically significant. The authors conclude that TheraSkin is “highly effective” for the treatment of both VSUs and diabetic foot ulcers. No superiority was found, and in the absence of the desired outcome, the authors proffer that TheraSkin is equivalent to the control treatment. However, such conclusions reflect an inappropriate interpretation of the data from this effectiveness trial, which was not initially designed to test for equivalency, but superiority. To answer the question of equivalency, the authors would have had to have used an equivalency or non-inferiority study design, which would have utilized a different initial hypothesis and different set of assumptions.
DiDomenico and others (2011) conducted a non-controlled comparative trial of TheraSkin compared to Apligraf involving 28 subjects with diabetic foot ulcers, 16 of whom received TheraSkin and 12 received Apligraf. At 12 weeks, 66.7% of the TheraSkin subjects and 41.3% of the Apligraf subjects had closed wounds. These numbers changed only slightly at 20 weeks, to 66.7% and 47.14% respectively. The authors concluded that TheraSkin was more efficacious in healing diabetic foot ulcers. However, it should be noted that randomization problems in this study resulted in uneven blocks of subject enrollment in the two cohorts, and the small sample size was not sufficiently powered to conclude whether TheraSkin was more effective than Apligraf.
Sanders (2014) reported the results of an underpowered RCT involving 23 subjects with DFUs randomized to receive treatment with either Dermagraft (n=12) or TheraSkin (n=11). At 12 weeks follow-up, 7 (63.6%) subjects in the TheraSkin group and 4 (33.3%) in the Dermagraft group were healed (p=0.0498). At the end of the 20-week evaluation period, 90.91% of TheraSkin subjects vs. 66.67% of the Dermagraft subjects were healed (p=0.4282). Time to healing in the TheraSkin group was significantly shorter (8.9 weeks) than in the Dermagraft group (12.5 weeks) (log-rank test, p=0.0323). The authors noted that the results of this study are similar to previous outcomes reported using these treatment modalities (see above studies) and suggest that, after 12 weeks of care, DFUs managed with TheraSkin are approximately twice as likely to heal as DFUs managed with Dermagraft, with approximately half the number of grafts required. However, they are careful to comment that, “Research confirming these results with a larger sample size and in individuals with different types of wounds is warranted.”
Towler (2018) reported the results of a prospective RCT comparing Apligraf (n=12) to TheraSkin (n=15) for the treatment of VSUs. The authors reported no statistical differences between groups with regard to time to complete healing at 12 or 20 weeks (p=0.294 and p=0.569, respectively). Additionally, no differences were noted between groups with regard to the number of grafts needed (p=0.119). No adverse events were reported for either group. The authors concluded that both products are safe and effective to treat VSUs. However, the study was limited by small sample size, lack of blinding and other methodological issues.
In 2018, Choi reported on the use of cadaver allograft (n=698) vs. conventional treatment (n=584) in subjects with burns involving > 30% body surface area. In both unmatched and propensity-matched subject groups, 90-day in-hospital mortality was significantly better in the allograft group vs. controls (31.7 vs. 39.7% for unmatched comparisons and 37.8 vs. 47.3% for propensity matched comparisons). Logistic regression analyses showed a significant association between cadaver skin allograft and lower 90-day in-hospital mortality in the propensity-matched groups (OR, 0.42).
The use of fresh, unfrozen, unprocessed skin allograft products has been a part of standard medical practice for the treatment of burns for almost a century. However, concerns regarding the risk of disease transmission and shelf life continue to be an issue, and other products have been proposed as an alternative. One of the most commonly used alternative products is fresh frozen skin allograft. Unfortunately, the current level of evidence addressing the safety and efficacy of fresh frozen skin allograft is weak. No solid conclusions can be made regarding the superiority, equivalency, or inferiority of these types of products in relation to other treatment options. However, despite this lack of evidence, a decades-long anecdotal track record for these products, easy access and availability, and a higher degree of certainty that the product is free from communicable pathogens has led to their acceptance as the standard of care in the burn treatment community. The use of fresh frozen skin allograft beyond the treatment of burns has not been established and is not widely accepted by the practicing community.
Grafix PRIME (see below for other Grafix products, including GrafixPL PRIME and Grafix CORE)
Grafix PRIME is a grafting product derived from allogeneic amniotic membrane. It is treated as human tissue for transplantation under the FDA’s HCT/P process. A similar product, GrafixPL Prime, is also available. The difference between these products is that Grafix Prime is cryopreserved, and GrafixPL Prime is lyopreserved (a method of dehydration).
Lavery and others (2014) conducted an RCT involving 97 subjects with DFUs who were randomized to receive treatment with either Grafix PRIME (n=50) or standard care (n=47). The proportion of subjects achieving complete wound closure was reported to be significantly higher in the Grafix group (62%) vs. the control group (21%, p=0.0001). Median time to healing was 42 days in the Grafix group vs. 69.5 days in the control group (p=0.019). Fewer Grafix-treated subjects experienced adverse events (44% vs. 66%, p=0.031) and wound-related infections (18% vs. 36.2%, p=0.044). Among the study subjects that healed, ulcers remained closed in 23 of 28 subjects (82.1%) in the Grafix group vs. 7 of 10 subjects (70%) in the control group (p=0.419). The authors concluded that treatment with Grafix significantly improved DFU healing compared with standard wound therapy and reduced DFU-related complications.
In 2018, a follow-up study was published by this group reporting on the results of 24 subjects who had failed treatment in the control group and crossed over to treatment with Grafix Prime (Lavery, 2018). The authors reported a 65.4% complete healing rate at a median of 34 days of treatment. These subjects also experienced fewer adverse events and wound-related infections than subjects followed in the initial study period reported above (adverse events, p=0.019; infections, p=0.116).
In 2016, Johnson and others published a report of a retrospective nonrandomized study comparing the outcomes from two separate cohort studies involving Grafix PRIME (n=40) or Epifix (n=39) for the treatment of a variety of wounds including VSUs, surgical wounds, DFUs, arterial ulcers, pressure ulcers, and ‘other’ wounds. The authors reported that the proportion of wounds achieving complete wound closure was 63.0% (29/46) for the Grafix group and 18.2% (10/55) for the Epifix group (OR=7.5, p<0.0001) for all treated wounds combined. When analyzed by wound type, the results indicated that treatment with Grafix group had a significantly higher rate of completely closed VSUs (70% vs. 7%, p=0.0024) and surgical wounds (81.9 vs. 18.2%, p=0.009). The small number of subjects, and retrospective, non-random, and unblinded methodology used in this study impair the generalizability of the results.
Another published case series study addressed the use of Grafix PRIME and included 67 wounds in 66 subjects with either DFUs (n=27), VSUs (n=34), or other chronic wounds (n=6) (Regulski, 2013). At 12 weeks, 51 of 67 wounds (76.1%) were healed. By wound type, 23 of 34 (67.6%) VSUs and 23 of 27 (85.2%) DFUs were healed at 12 weeks. The average time to closure in these wounds was 5.8 (± 2.5) weeks. No significant differences were reported between the two wound type groups, and no adverse events or recurrences were reported.
Raspovic (2018) reported a retrospective case series analysis of 360 subjects with 441 DFUs treated with Grafix PRIME or Grafix CORE using data from Net Health’s Wound Expert electronic health records database. The mean size of the index wound was 5.1 cm2 with 3.9 mm depth. Mean wound duration prior to study treatment was 102 days. The mean duration of treatment with a Grafix product was 89.3 days (median 56.0). Complete wound closure at the end of treatment occurred in 59.4% of subjects. Median time to closure was 42.0 days with a median of 4 graft applications. The proportion of closure decreased as wound size increased, with 72.3% of wounds between 0.25 cm2 to 2 cm2 having complete healing at a median of 21 days and 4 applications. For wounds larger than 25 cm2, only 27.8% achieved complete healing at a median of 105 days and 11 applications. The authors did not provide any data regarding the percentage of subjects receiving treatment with Grafix PRIME vs. those receiving Grafix CORE.
Ananian (2018) reported the results of a single-blind non-inferiority RCT comparing Grafix PRIME vs. Dermagraft in 62 subjects (31 in each group) with chronic DFUs. At the end of the 9-week study period, 100% reepithelialization occurred in 48.7% of Grafix subjects and 38.7% of Dermagraft subjects, meeting the endpoint of non-inferiority, defined for this study as a treatment effect difference of 20% (p=NS). At 28 days post-initial study application, a 50% or greater reduction in wound area was reported in 70.8% of Grafix subjects and 67.7% of Dermagraft subjects. The percent average reduction in wound size at the end of the study period was 86.3% in the Grafix group vs. 78.1% for the Dermagraft group (p=NS). The Grafix group had a mean of 5.3 applications vs. 4.4 applications to achieve 100% reepithelialization (p=NS).
Based on clinical practice standards, relevant expert opinion, the above-mentioned studies, and the overall clinical experience with Grafix PRIME, an acceptable level of safety and efficacy has been established for the use of this product for the treatment of DFUs. However, use of this product for other indications has not been widely accepted by the practicing community..
GraftJacket
GraftJacket is an acellularized human skin-derived product and is treated as human tissue for transplantation under the FDA’s HCT/P process.
One randomized controlled trial compared the use of standard surgical debridement followed by GraftJacket placement vs. standard surgical debridement alone (20 participants in each group) (Brigido, 2004). The findings of the study demonstrated significant differences between the two groups, with the experimental group demonstrating much faster healing progression. While the results of this study are promising, the small sample size, as well as its single-blind design, limits its utility. The same authors conducted a second RCT with 28 subjects with chronic DFUs who were assigned to receive either GraftJacket (n=14) or standard care (n=14) (Brigido, 2006). At 16 weeks, 12 of 14 (85.7%) of the GraftJacket subjects demonstrated complete wound closure, compared with 4 of 14 (28.6%) in the control group (p value not provided). Subjects treated with GraftJacket demonstrated a statistically significant higher percentage of wound healing with respect to wound area, and clinically significant differences in wound depth and wound volume (p<0.001).
Reyzelman (2009) reported the results of an RCT involving 85 subjects with diabetic foot ulcers assigned to receive treatment with either GraftJacket (n=46) or standard care (n=39). The authors reported significantly better complete and mean healing times in the GraftJacket group (69.6% and 5.7 weeks) compared to the controls (46.2% and 6.8 weeks) who received standard care (p=0.029). Furthermore, there was a significantly higher non-healing rate for the control group (53.9%) compared with the study group (30.4%) at 12 weeks (p=0.015). Neither the subjects nor the investigators were blind to group assignment.
A prospective non-blind RCT involving 168 subjects with DFUs assigned in a 2:2:1 fashion to treatment with DermACELL (n=71), conventional care (n=69), or Graftjacket (n=28) (Walters, 2016). At 16 weeks post intimal treatment, no significant differences in the proportion of completely healed ulcers vs. the conventional care group was found (67.9% vs 47.8%; p=0.1149). No differences between groups were reported with regard to severe adverse events (p≥0.05).
Cazzell (2017) conducted an RCT involving 132 subjects with chronic DFUs undergoing treatment in 2:2:1 fashion with either DermACELL (n=53), conventional care (n=56), or GraftJacket (n=23). Subjects were followed through 24 weeks, with endpoint measurement at 12, 16, and 24 weeks. GraftJacket did not show a significantly greater healing rate over conventional care at any of these time points. No significant difference was noted between the GraftJacket group vs. the conventional care group for healed wounds remaining closed. However, as noted above, the results of this comparison for GraftJacket are significantly hampered by small numbers of subjects, and the results should be viewed with that in mind.
GraftJacket has also been proposed for use in shoulder surgery to repair soft tissue injuries. Barber and colleagues (2012) reported on an RCT involving 42 subjects with rotator cuff injuries randomized to undergo repair with GraftJacket (n=20) or standard surgical procedures (n=22). At the 2-year follow-up period, significant benefits were noted on several scales, including the American Shoulder and Elbow Surgeons (ASES) (p=0.035) and Constant (p=0.008) assessment tools. No significant difference was seen on the University of California, Los Angeles (UCLA) tool (p=0.43). Imaging studies found that at 2 years, 85% of the GraftJacket group had intact grafts, compared to only 40% in the standard care group (p<0.01). A prospective case series study by Gupta and others (2012) involved 24 subjects with rotator cuff tears treated with GraftJacket and followed for 3 years postoperatively. The authors report significant improvements with regard to pain, (p=0.002), mean active forward flexion and external rotation (p=0.002), mean shoulder abduction (p=0.0001), supraspinus strength (p=0.0003), and ASES scores (p=0.0003). Ultrasonography showed 76% of repairs were fully intact, with the remainder of subjects with partially intact repairs.
Marks and colleagues (2017) reported on a study involving the use of GraftJacket for the treatment of 60 subjects with osteoarthritis at the first carpometacarpal (CMC I) joint who underwent treatment with either trapeziectomy with suspension-interposition arthroplasty using the flexor carpi radialis (FCR) tendon (n=29) or GraftJacket (n=31). They reported that baseline Michigan Hand Outcomes Questionnaire (MHQ) total scores significantly increased from 51 to 83 in the FCR group and 53 to 76 in the GraftJacket group by 12 months (p<0.05 for both). No differences between groups were reported (p>0.05). Complications were reported in 5 FCR-related subjects, and 10 in the GraftJacket group (p=0.24). Revision surgery was required for 1 allograft subject. They concluded that the use of the FCR tendon or GraftJacket for trapeziectomy with suspension-interposition arthroplasty leads to similar outcomes, but with more complications, mainly tendon irritations, associated with GraftJacket. They noted that they “only use the allograft in cases of severe instability requiring a larger amount of suspension-interposition material or for revision procedures after failed suspension-interposition with the FCR tendon.”
Based on clinical practice standards, relevant expert opinions, the above-mentioned studies, and the overall clinical experience with GraftJacket, an acceptable level of safety and efficacy has been established for the use of this product for the treatment of lower extremity dermal wounds. However, use of this product for other indications has not been widely accepted by the practicing community..
Integra Bilayer Matrix Wound Dressing
Integra Bilayer Matrix Wound Dressing is a composite grafting material made from cross-linked bovine tendon collagen and glycosaminoglycan and a semi-permeable polysiloxane (silicone) layer. It has been cleared through the FDA’s 510K Premarket Notification process. The use of this product has been found to be efficacious in the post-excisional treatment of full-thickness or deep partial-thickness burns when autografting is not feasible. This conclusion is supported by well-designed randomized studies (Branski, 2007; Heimbach, 2003).
Othman (2021) reported the results of a retrospective case series study involving the use of Integra Bilayer Matrix Wound Dressing for the treatment of cutaneous scalp defects in 127 subjects older than 60 years of age. The reconstructive procedures were conducted in a 2-stage fashion, with the wound first being treated with Integra followed by split-thickness skin grafting between 3-4 weeks afterwards. A total of 107 (84%) subjects were successfully reconstructed. The 20 subjects who had treatment failure were more likely to have a history of radiotherapy (30% in the failure group vs. 12% in the success group, p<0.04). Place of service was noted as a significant factor in treatment failure, with 25% of subjects treated in the inpatient setting having failure vs. 8% of subjects treated in the outpatient setting (p<0.034). The authors noted that postoperative wound infection was significantly associated with reconstructive failure (30% vs. 6.5%, respectively; OR, 6.4, p<0.006). The results of this study are promising, but the weak methodology used does not allow generalization of these findings to a wider population.
Based on clinical practice standards, relevant expert opinions, the above-mentioned studies, and the overall clinical experience with Integra Bilayer Matrix Wound, an acceptable level of safety and efficacy has been established for the use of this product for the treatment of burns. However, use of this product for other indications has not been widely accepted by the practicing community.
mVASC
mVASC is a product derived from processed subcutaneous allogenic microvascular tissue and is treated as human tissue for transplantation under the FDA’s HCT/P process. It is derived from the structural elements of microvascular tissue of human donors and includes inherent non-viable cells and signaling factors.
In 2021 Gould and colleagues reported on the results of a prospective single blind RCT involving 100 subjects with DFUs who were treated with either standard care with collagen alginate dressing or standard of care with mVASC (n=50 per group). Subjects were followed for 12 weeks. The authors reported that the percentage of wounds closed at 12 weeks was significantly better in the mVASC group vs. the control group (74% vs 38%, p=0.0003), and the odds of healing by 12 weeks in the mVASC group was 9-fold vs. the control group (OR, 9.0; p=0.00008). The change in percent of wound area reduction was similarly found to be significantly in favor of the mVASC group beginning at week 4, with the mVASC group having a mean percent wound area reduction of 76%, over 3-fold more than the mean percent wound area reduction seen in subjects in the control group (p=0.009). Finally, the mean time to healing was significantly faster for the mVASC group vs. controls (54 days vs. 64 days, p=0.009). Measurement of a secondary endpoint, wound perfusion, indicated a consistent decrease in the mean ingress rate in the mVASC-treated wounds, corresponding to an increase in perfusion of 60%. The control group demonstrated a consistent increase in the mean ingress rate, indicating a significant decrease in perfusion (67%). Additionally, based on results of the Semmes-Weinstein monofilament (SWM) exam, mVASC group subjects had a significant improvement in peripheral neuropathy at 12 weeks vs. control group subjects (118% vs. 11%; p=0.028). No adverse events (AEs) or serious adverse events (SAEs) related to the study treatment were reported.
While this is the only published clinical trial of the use of mVASC, it is a well-designed and conducted study and demonstrated significant benefits of the use of this product vs. standard care in the treatment of DFUs. Potential benefits from the use of mVASC for other indications are unclear and such use has not been widely accepted by the practicing community..
Oasis
Oasis is a grafting product composed of decellularized intestinal mucosa of porcine origin and has been cleared through the FDA’s 510K process.
The first study addressing Oasis was published by Mostow and colleagues in 2005. They described a randomized controlled trial (RCT) involving 62 participants who received Oasis and compression therapy for VSUs vs. a control group of 58 participants who received compression therapy alone. The authors reported significantly better healing rate in the Oasis group over the control group at 12 weeks. Another publication described a RCT involving individuals with DFUs (Neizgoda, 2005). The experimental group included 37 participants who were treated with the Oasis graft and 36 who were treated with Regranex gel. As with the previously described trial, the authors reported significantly improved results with the Oasis graft.
Romanelli and colleagues describe a study comparing Oasis against a product not currently available in the U.S., Hyaloskin (2007). The result of this trial, while favorable to Oasis, is not particularly useful in the evaluation of Oasis. This is due to the fact that the comparison product is unknown here in the U.S. and there is no currently available scientific literature addressing its use in the clinical setting.
The same group published a second RCT involving 50 subjects with either mixed venous/arterial ulcers (n=25) or venous ulcers (n=25) (Romanelli, 2010). Participants were randomized to receive treatment with either Oasis or standard petrolatum impregnated gauze and followed for 8 weeks. At the completion of the study, the authors reported that for all measures the Oasis group was significantly superior compared to the control group, including average healing (5.4 weeks vs. 8.3 weeks, p=0.02) and complete wound closure (80% vs. 65%, p<0.05). Granulation of tissues increased from 50% to 65% in the Oasis group and decreased in the control group (p<0.02). The Oasis group also required fewer dressing changes, more than doubling the time between dressing changes.
Cazzell (2015) reported the results of an unblinded RCT involving 82 subjects with neuropathic ulcers treated with either Oasis (n=41) or standard care (n=41). Subjects were followed for 12 weeks or complete ulcer closure. The Oasis group had a significantly greater proportion of wounds closed by 12 weeks vs. controls at all measurement times (54% vs. 32%, p=0.021). The time to closure for ulcers that achieved closure was 2 weeks earlier in the Oasis group vs. controls (9 vs. 11 weeks, respectively). The probability of wound closure at 12 weeks was 62% for the Oasis group vs. 40% for controls. Median reduction in ulcer area was significantly greater for Oasis at each weekly visit (p<0.05 for all). The most important predictor of wound closure in regression analysis was group assignment (HR, 2.005; p=0.049). No significant differences between groups with regard to adverse events were reported.
Based on clinical practice standards, relevant expert opinions, the above-mentioned studies, and the overall clinical experience with Oasis, an acceptable level of safety and efficacy has been established for the use of this product for the treatment of lower extremity dermal wounds.
Additionally, several studies have been published addressing the use of Oasis products for the treatment of burns. The first (Salgado, 2014) involved a total of 5 subjects treated with both Oasis and silver-containing cellulose hydrofiber (Aquacel AG) at different burn sites on the same subject. This study reported on the histomorphometric outcomes, which demonstrated favorable results in favor of the Oasis product. Measurement of epithelial maturation within the repair areas were considered significantly more phenotypically structured after 7 days of treatment with Oasis vs. the Aquacel-treated wounds at 7 days (6.2 vs. 3.2, p=0.029). No infections or “irritation” were reported. Both products were naturally expelled in all subjects by 7 days. The Vancouver Scar Scale score for vascularity, pigmentation, and pliability indicated more favorable results in the Oasis group (3.6 vs. 7.2, p=0.025). The unblinded nature of the study, in addition to the low power and other methodological weaknesses do not allow generalization of the findings across larger populations.
A retrospective unblinded case-control study was reported published by Glik in 2017. This study involved 30 subjects treated with either Oasis (n=6) or Suprathel (n=24). Histopathological specimens were harvested for evaluation from the subjects at 14 and 21 days. The authors provide qualitative observations of the healing process, including comments regarding product adherence to the wound, progression of epithelialization, and pain levels. However, no quantitative data in these factors were reported. While the authors state that Oasis provides clinical benefit in the treatment of burn wounds, their report is of little value due to the lack of quantitative data to support their findings. Additionally, as with the Salgado study above, significant methodological weaknesses in this study do not allow generalization of the findings across larger populations.
While this evidence is promising, the use of Oasis for burns and indications other than lower extremity dermal wounds has not been widely accepted within the practicing community.
OrCel
OrCel is a living skin equivalent (composite cultured skin) composed of human allogeneic skin cells cultured in layers of Type I bovine collagen that has been approved through the FDA’s PMA process. This product was granted an FDA HDE in 2001 for use in children with recessive dystrophic epidermolysis bullosa (RDEB), who are undergoing reconstructive hand surgery. However, there is still little clinical data to support the use of OrCel for other applications and such use has not been widely accepted by the practicing community.
PriMatrix
Primatrix is a product derived from acellular bovine dermis and has been cleared through the FDA’s 510K process. To date, there are only a limited number of small studies addressing its use in humans. One retrospective, nonrandomized controlled series involved 68 subjects with either diabetic foot wounds (n=40) or VSUs (n=28) who received treatment with either Apligraf (n=34) or PriMatrix (n=34) (Karr, 2011). The number of subjects with each type of wound receiving treatment with Apligraf or PriMatrix was equal, with 20 diabetic foot wounds and 14 VSUs in each group. For diabetic foot ulcers, the Apligraf-treated group’s time to complete healing was 87 days, the PriMatrix was 37 days. The average number of graft applications was 2 in the Apligraf group and 1.5 in the PriMatrix group. For VSUs, the time to complete healing was 63 days in the Apligraf group and 32 days in the PriMatrix group. The Apligraf group had 1.7 graft applications compared to 1.3 in the PriMatrix group.
Another retrospective, nonrandomized controlled series involved 20 subjects with Charcot neuropathy and chronic non-healing ulceration treated with either PriMatrix (n=12) or standard wound care (n=8) (Kavros, 2012). The mean time to healing in the PriMatrix group (116 days) was significantly shorter than in the control group (180 days) (p<0.0001). A significantly faster rate of healing was observed with PriMatrix (87.9 mm3/wk) compared with control (59.0 mm3/wk) (p<0.0001). The authors conclude that, “The significantly faster rate of healing and steeper slope of volume reduction in the PriMatrix group warrants further investigation into its effects on healing of neuropathic ulcerations and potential limb salvage.”
Lantis and others (2021) reported the results of an unblinded RCT involving 226 subjects with treatment resistant DFUs treated with either PriMatrix plus standard care or standard care. The authors state that the study was terminated early due to the COVID-19 pandemic. They conducted a modified intent-to-treat analysis on a total of 207 subjects, 103 in the PriMatrix group and 104 in the standard care group. Additionally, a total of 161 subjects completed the study per modified protocol, with 79 receiving PriMatrix and 82 standard care. The modified intent-to-treat analysis found that PriMatrix treated subjects had a significantly greater number of wounds achieve complete wound closure vs. those treated with standard care (45.6% vs. 27.9%, p=0.008). Similar findings were reported in the modified per-protocol analysis (59.5% vs. 35.4%, p=0.002). The odds of complete wound closure at 12 weeks were reported to be 2.2 times greater in the PriMatrix group (p=0.008). No significant differences were noted with regard to median time to closure within 12 weeks (43 days vs. 57, p=0.36). The mean and median number of PriMatrix applications to achieve closure per wound was 1.4 and 1. No adverse events or serious adverse events related to the use of PriMatrix or the procedure were reported. The authors concluded that a single application of PriMatrix plus standard care offers a safe, faster, and more effective treatment of DFUs than standard care alone.
Based on clinical practice standards, relevant expert opinions, the above-mentioned studies, and the overall clinical experience with PriMatrix, an acceptable level of safety and efficacy has been established for the use of this product for the treatment of lower extremity dermal wounds. However, use of this product for other indications has not been widely accepted by the practicing community.
StrataGraft
StrataGraft is an allograft product derived from human dermis with a layer composed of neonatal immortalized keratinocytes (NIKS) seeded on murine collagen embedded with allograft dermal fibroblasts. This product is treated as human tissue for transplantation under the FDA’s HCT/P process. A small phase I/II comparative trial of StrataGraft to cryopreserved cadaver skin was conducted by Schurr (2009) to assess autograft take in 15 subjects 2 weeks after coverage. At the 2-week time point the authors reported that the StrataGraft subjects exhibited a fully stratified epidermis with multilamellar lipid sheets and barrier function as well as robust human β defensin-3 mRNA levels. Analysis revealed no differences in autograft take between wound sites pretreated with StrataGraft skin substitute or cadaver allograft. No StrataGraft-related adverse events or serious adverse events were observed.
Holmes (2019) reported on the results of an open-label, controlled, randomized study of StrataGraft vs. autograft for the treatment of deep partial-thickness burns (3%-43% total body surface area) in 30 subjects who were assigned to treatment with ≤ 220 cm2 autograft; ≤ 440 cm2 of autograft; or ≤ 440 cm2 of StrataGraft. Two comparable wounds on each subject were randomized to receive StrataGraft tissue or autograft. By Day 28, the authors reported that no StrataGraft tissue treatment sites had undergone additional autografting. At 3 months, 93% and 100% of the StrataGraft tissue and autograft treatment sites achieved complete wound closure, respectively. The most common adverse event was pruritus (17%).
Gibson (2021) reported the results of an open label RCT involving 71 subjects with thermal burns on the torso or extremities. Two eligible wounds on each subject of comparable depth, severity, and size were randomly selected to be treated with either StrataGraft or autograft. Subjects were followed for 3 months for the measurement of the primary endpoints of mean percent wound healing and percentage of subjects achieving durable wound healing. The authors reported that 3 subjects received subsequent autografting of their StrataGraft-treated wound. Of the wounds initially treated with autograft, 2 required repeat autografts. The mean percent wound area requiring autograft in subjects who required autograft by 3 months was significantly in favor of the StrataGraft wounds (4.3% vs 102.1%, p<0.0001). At 3 months, 83.1% of subjects (n=59) had achieved durable wound closure for wounds treated with StrataGraft. Of the wounds treated with autograft, 85.9% (n=61) had similar results. No p-values were reported for between-group comparisons. All wounds reported closed at 3 months remained closed at 6- and 12-months follow-up. The authors reported that the StrataGraft group had a 92% durable wound closure rate at 3 months without a need for autografting. Mean donor-site pain intensity was observed through day 14 in StrataGraft donor sites compared with autograft donor sites, primarily due to the lack of autograft donor tissue use in the StrataGraft group (p<.0001). Similarly, mean donor-site cosmetic appearance was significantly better in the StrataGraft group, for the same reason (p<0.0001). At 12 months, no significant differences between groups were reported with regard to cosmetic appearance (p=0.43). Overall, these results demonstrate that the use of StrataGraft delivers similar healing rates for the treatment of burns while decreasing the need for autografts and the autograft-related complications.
The available evidence has demonstrated the clinical utility of StrataGraft for the treatment of Burns. However, use of this product for other indications has not been widely accepted by the practicing community.
Strattice
Strattice is an acellular dermal collagen product of porcine origin and has been cleared under the FDA’s 510k process. In 2012, three studies evaluating the use of Strattice were published. The largest was a retrospective, controlled study looking at the use of Strattice (n=96) vs. aseptic AlloDerm (n=90) for tissue expander breast reconstruction (Glasberg, 2012). The authors reported a significantly higher complication rate in the AlloDerm group (21.4% vs. 6.3%; p=0.0003), caused by the incidence of seromas (12.7% vs. 1.4%; p=0.0003). No other significant differences were reported, including capsule formation (2.4% for AlloDerm and 2.8% for Strattice). This study was not prospective, randomized, or blinded.
The second trial involved the use of Strattice for complex abdominal reconstruction (Itani, 2012). This case series study involved 80 subjects undergoing contaminated ventral hernia repair that were prospectively enrolled and treated with Strattice. Sixty subjects continued through the final 24-month follow-up (25% loss to follow-up). The authors reported that midline restoration was achieved with primary closure in 64 subjects with defects bridged in 16 subjects. At 24 months, 53 subjects (66%) experienced 95 wound events including seroma (n=23, 29%), infection (n=28, 35%), dehiscence (n=14, 18%), hematoma (n=7, 9%), and abscess (n=7, 9%). No grafts required complete excision. Hernia recurrence was reported in 22 subjects (28%) by month 24. There was no correlation between infection-related events and hernia recurrence.
The third study, by Patel and colleagues, was a retrospective case study also evaluating the use of Strattice for complex abdominal reconstruction (2012). This study involved 41 subjects with complex ventral hernias undergoing component separation with Strattice underlayment. Concomitant panniculectomy was conducted in 9 subjects (22%). The complication rate was 24.4% (10/41), with the majority of early complications being skin necrosis (n=9), but also included Strattice exposure (n=5). These subjects required intervention in the operating room (OR). Wound dehiscence and seroma were noted in 3 subjects respectively. One subject required skin grafting for wound closure.
Rosen (2013) published a study investigating the use of acellular matrix for the reconstruction of infected and contaminated abdominal wall defects. The study involved 128 subjects who received treatment with Strattice (n=102), aseptic AlloDerm (n=16), Biodesign (n=4), Xenmatrix (n=4), and BioA (n=4). Postoperative wound complications were identified in 61 (47.7%) subjects. The report indicated that predictors of wound complications included American Society of Anesthesiologists (ASA) score, diabetes, smoking, number of previous abdominal surgeries or hernia repairs, hernia defect size, and operative time. Hernia recurrence was identified in 40 (31.3%) subjects at a mean follow-up time of 21.7 months. The majority of recurrent hernias were asymptomatic, and 7 subjects underwent repair.
Use of Strattice was reported in a study of 41 subjects with complex abdominal wall defects at increased risk for perioperative complications (Patel, 2013). Reported comorbidities included coronary artery disease (63.4%), diabetes mellitus (36.6%), and chronic obstructive pulmonary disease (17.1%). The authors reported that fascial closure was achieved in 40 subjects (97.6%). Recurrent/complex hernia was present in 78% subjects. The overall complication rate was 22.0%, and included seroma (7.3%), wound dehiscence with Strattice exposure (4.9%), cellulitis (2.4%), and hematoma (2.4%). All subjects achieved abdominal wall closure with no recurrent hernias or need for Strattice removal.
Maxwell and Gabriel (2014) reported the results of a case series study of 106 subjects undergoing revision breast surgery with the use of Strattice. The mean follow-up time was 3.1 years, with 1 subject experiencing a complication, yielding an overall complication rate of 0.9%. All subjects’ presenting complaints resolved after revision surgery, with no recurrence of the presenting complaint during the follow-up period.
A retrospective case-control study of 80 subjects undergoing ventral hernia repair with either Strattice (n=40) or conventional open repair (n=40) was reported by Richmond (2014). Mean follow-up was 33.1 months. The authors reported that the defect size was greater in the Strattice group (mean, 372.5 vs. 283.7 cm2, p=0.01) as was the percentage Ventral Hernia Working Group Grade III/IV hernias (65.0% vs. 30.0%, p=0.03). Despite this, the number of recurrences were lower in the Strattice group (13.2% vs. 37.5%, p=0.02), and infection rates were lower as well (0% vs. 23%, respectively, p=0.002). Finally, the indications for reoperation, including recurrence or complications requiring reoperation, were also lower in the Strattice group (17.5% vs. 52.5%, p=0.002).
Huntington (2016) published the results of a retrospective nonrandomized comparative study involving 223 subjects who underwent open ventral hernia repair with AlloDerm (n=40), AlloMax (n=23), FlexHD (n=70), Strattice (n=68), or Xenmatrix (n=22). The mean follow-up was 18.2 months. The authors reported the hernia recurrence rate varied significantly by product, with 35% for AlloDerm, 34.5% for AlloMax, 37.1% for FlexHD, 14.7% for Strattice, and 59.1% for Xenmatrix (p=0.001). After multivariate analysis with Strattice as the comparator, AlloMax had a 3.4 higher OR for recurrence, FlexHD a 2.9 OR, and Xenmatrix a 7.8 OR. They concluded that the choice of biologic mesh affects long-term postoperative outcomes in ventral hernia repair, and Strattice had significantly lower odds of hernia recurrence compared with AlloMax, FlexHD, and Xenmatrix.
In 2016, Dikmans and colleagues published the results of a retrospective case series study involving the use of Strattice during single-stage breast reconstruction procedures in 88 subjects. Unilateral procedures were done in 60 subjects and bilateral in 25 (n=110 breasts). Minor complications reported included seroma (20.9%), skin necrosis (20.0%), wound dehiscence (11.8%), erythema/inflammation (14.5%) and infection (11.8%). The authors observed that the total complication rate was very high (78%), and although most complications were minor, reoperation was performed in 22.7%, with explantation of the implant in 11.8% of breasts. They concluded, “The use of a Strattice sheet in single-stage implant-based breast reconstruction may be a promising technique, but more evidence from prospective, randomized studies is necessary to justify its use.”
A retrospective review involving 41 subjects who underwent 52 breast reconstructions using ADMs was reported by Paprottka (2017). Subjects received treatment with either EpiFlex (n=15), Strattice (n=21), or Tutomesh (n=16). Follow-up was 36 months (range 12-54). Overall complication rate was 17%, with 7% for the EpiFlex group, 14% for the Strattice group, and 31% for the Tutomesh group. Capsular contracture occurred in 6%, more frequently in this study compared to the current literature. The authors recommended the use of human derived grafting materials (EpiFlex) over those from porcine of bovine sources.
Lohmander (2019) conducted a non-blinded RCT involving 135 subjects undergoing immediate breast reconstructions assigned to treatment with either Strattice (n=64) or with no ADM (n=65). Overall, the outcomes were similar between groups, but 4 subjects (6%) in each group had reconstructive failure with implant loss. However, the group treated with Strattice exhibited a trend of more overall complications and reoperations (p=0.070) and with higher risk of wound healing problems (p=0.013). The authors noted, “Further investigation of risk factors and patient selection in a long-term follow-up is warranted.”
Kalstrup (2021) reported the results of a retrospective case series study involving 154 subjects undergoing direct to implant breast reconstruction with Strattice. A total of 232 breasts were included in the report, which focused on complications and explantations. They reported that per-subject complications within 6 months included hematoma (4%), seroma (8%), infection (9%), necrosis, wound dehiscence and delayed wound healing (19%). The total complication rate per subject was 34%. Explantation occurred in 20 subjects (13%) of which 9 (6%) experienced implant loss. Significant predictors of explantation included preoperative radiotherapy (adjusted OR, 4.9; p=0.045). Smoking was also associated with risk of explantation, however, it was not found to be significant (adjusted OR, 4.0; p=0.050).
Wilson (2021) reported on a retrospective case series study of 166 subjects who underwent breast reconstruction with either Strattice (n=117, 51 bilateral) or submuscular reconstruction (n=49, 6 bilateral). In the Strattice group, 17 (10.1%) subjects had Baker 3/4 contractions vs. 6 (9.2%) in the submuscular group (p=0.85). Of the subjects with Baker 1/2 contractions, 6 (3.6%) Strattice subjects and 8 (13.6%) submuscular subjects had previously undergone revision surgery for prior capsular contracture (p=0.01). The authors reported that combining both of these findings provided an estimated rate of capsular contracture of 13.6% in the Strattice group vs. 21.2% in the submuscular group (p=0.14).
Also see Clemens, 2013 and Mazari, 2018 in the SurgiMend section below for an additional study involving Strattice.
The use for the treatment of other indications is still under investigation. Based on clinical practice standards, relevant expert opinions, the above-mentioned studies, and the overall clinical experience with Strattice, an acceptable level of safety and efficacy has been established for the use of this product for the surgical repair of complex abdominal wall wounds and breast reconstruction surgery. However, use of this product for other indications has not been widely accepted by the practicing community.
TheraSkin (Please see the ‘Fresh Frozen Unprocessed Allograft Skin for Burns’ section above for discussion of evidence addressing TheraSkin for burns)
Barbul (2019) published the result of a retrospective non-randomized propensity-matched controlled trial involving 1556 subjects with diabetic lower extremity wounds treated with either TheraSkin or standard of care (n=778 per group). Complete treatment data were available for only 376 TheraSkin group subjects (48.3%) and the modified intent-to-treat (MITT) group included 459 subjects (59%). In the MITT analysis, overall healing rates were 66.8% for the TheraSkin group vs. 55.9% for the control group (p=0.0045). Additionally, healing rates for Wagner grade 4 ulcers was significantly better in the TheraSkin group (66.7% vs. 40.0 %, p=0.04). A significant difference in healing rates was reported for wounds 90-179 days old, with TheraSkin demonstrating better results (65.1% vs. 46%, p=0.0073). No differences in healing rates were reported for wounds less than 90 days old. Additionally, no differences were reported in healing rates when stratified by wound location (lower leg, foot, or toe), or in the rate of amputations in the first 20 weeks post-treatment. With regard to percent area reduction (PAR), TheraSkin has significantly higher mean reduction vs. controls (63.6% vs. 57%, p=0.036). Interestingly, TheraSkin subjects were significantly more likely to be treatment compliant through completion of treatment (59% vs. 48.3%, p<0.0001). Recidivism data at 1 year was available for 684 TheraSkin subjects and 651 controls, indicating a high rate of treatment success in the TheraSkin group (40.2% vs. 35%, p=0.042). The odds of TheraSkin closure of a wound was calculated to be 1.59, indicating a 59% increase over standard of care.
Another retrospective non-randomized propensity-matched controlled trial was published looking at the use of TheraSkin plus standard of care vs. standard of care for the treatment of lower extremity wounds of multiple etiologies including diabetic ulcers, lymphedema, pressure ulcers, radiation injury, surgical wounds, trauma, venous ulcers, and arterial ulcers was reported by Gurtner (2019). The study included 1997 subjects in the TheraSkin group and 1997 control subjects who received standard of care only. Overall healing rates were significantly better in the TheraSkin group (68.3% vs. 60.3%, p<0.001). Mean percent area reduction was also better in the TheraSkin group (78.73% vs. 68.85%, p<0.001). When stratified by wound duration, the TheraSkin group had significantly better healing times vs. controls for wounds greater than 90 days (p<0.0001), 90 to 179 days (p=0.0195), and 180 days or greater (p<0.0010). Arterial, diabetic, pressure, radiation and trauma wounds all healed significantly better in the TheraSkin group (p=0.0325, p<0.0001, p<0.0001, p=0.05, and p=0.0311, respectively). Recidivism was not significant between groups at 12 months, nor was the mortality rate (32.6% vs. 34.4%, p=0.296; 4.6% vs. 5.4%, p=0.25, respectively). Amputation rates were 2.75 times higher in the control group vs. TheraSkin group (1.9% vs. 0.5%, respectively).
The results of these trials demonstrate significant benefits from treatment of chronic lower extremity dermal wounds with TheraSkin, including improvements in healing time and a healing rates, while not negatively impacting adverse event rates. However, other than for this indication and burns, the use of this product for other indications has not been widely accepted by the practicing community.
Products addressed in the Investigational and Not Medically Necessary statement
Affinity
Affinity is a cryopreserved human amnion-derived tissue allograft and is treated as human tissue for transplantation under the FDA’s HCT/P process. There is currently only one available study published on its use in human subjects.
Serena (2020) reported on the results of an unblinded prospective RCT involving 76 subjects with DFUs treated with either Affinity plus standard care (n=38) or standard care alone (n=38). Wound closure for the Affinity group was significantly greater than the control group at both 12 weeks (55% vs. 29%, p=0.02) and 16 weeks (58% vs 29%, p=0.01). At 16 weeks, wound closure was reported in 60% of Affinity subjects vs. 48% of control subjects (p=0.04). The authors reported that the probability of wound closure with Affinity vs. standard care increased by 75% (HR, 1.75). The authors concluded that the use of Affinity increased the frequency and probability of DFU wound closure. Additional data from well-designed trials are warranted to support these conclusions.
AlloMax
AlloMax is an acellular, non-cross-linked allograft dermis product and is treated as human tissue for transplantation under the FDA’s HCT/P process. The currently available evidence in the peer-reviewed published literature addressing the use of AlloMax is sparse. A case series study involving 65 subjects undergoing tissue expander breast reconstruction was described by Venturi (2013). The results of this study are limited but include a complication rate of 4.6% (3 subjects). These included one case of cellulitis and two cases of partial mastectomy flap necrosis requiring debridement. No seromas or explantations were reported. Histological verification of full graft incorporation was demonstrated in the first 20 biopsies. A second retrospective case series involving 203 subjects (348 breasts) undergoing mastectomy with immediate breast reconstruction was reported by Rundell in 2014. The authors reported that infection occurred in 6.6% of subjects, with 3.7% being major infections requiring intravenous antibiotics and 2.9% being minor infections requiring oral antibiotics only. Seromas occurred in 3.4% of cases and reconstruction failure occurred in 0.6% of cases. The authors stated that the analysis suggested that the complication prevalence was significantly higher in individuals with a BMI > 30 (p=0.03).
AlloPatch
AlloPatch is a product composed of acellular human dermis treated as human tissue for transplantation under the FDA’s HCT/P process.
At this time, there is limited evidence published in the peer-reviewed literature addressing the use of this product. The most rigorous study to date involved 45 subjects with chronic refractory DFUs (Zelen, 2016b). A total of 40 subjects in this investigator blinded RCT were assigned in a 1:1 fashion to either standard care alone (n=20) or AlloPatch plus standard care (n=20). AlloPatch grafts were applied weekly for up to 12 weeks. Initial ulcer size at baseline was greater in the AlloPatch group vs, controls (4.7 cm2 vs. 2.7 cm2). At 6 weeks, the authors reported that 65% of the AlloPatch group subjects were completely healed (13/20) vs. 5% in the control group (1/20). At 12 weeks, the proportions of DFUs healed were 80% and 20%, respectively. The mean time to heal within 12 weeks was 40 days in the AlloPatch group vs. 77 days for controls. No differences between groups were reported with regard to adverse or serious adverse events. The authors reported that, “Weekly application of HR-ADM is an effective intervention for promoting closure of non-healing DFUs.”
This group published a continuation study with an additional 40 subjects (n=20 per group) and results of the total 80 subject population were reported by Zelen in 2018. In the continuation population, the AlloPatch group had more smokers (7 vs. 1, p=0.044) and the control group was older (67 years vs. 55 years, p=0.008). At 6 weeks, 85% of the AlloPatch group vs. 15% of the controls were completely healed (p=2.7 x 10-6). The mean PAR in wounds was greater in the AlloPatch group (62% vs. 50%, p=2.7 x 10-6). Mean time to healing at the 6-week time point was 27 days for the AlloPatch group vs. 41 days for controls (p=9.9 x 10-7). At 6 weeks, 2 AlloPatch subjects (5%) and 19 control subjects (48%) were withdrawn from the study due to failure to have a 50% reduction in wound area. At 12 weeks, 80% of AlloPatch subjects and 30% of the control subjects had complete wound healing (p=8.4 X 10-6). At 12 weeks, mean time to heal was 38 days in the AlloPatch group vs. 72 days in the control group (p=3.9 x 10-7). After adjusting for age and baseline wound area, the HR for the AlloPatch vs. the control group was 8 (p=3.7 x 10-7). No adverse events related to the study treatment were reported.
Further investigation is warranted to fully evaluate the safety and efficacy of AlloPatch treatment for DFUs.
AMNIOEXCEL
AMNIOEXCEL is a dehydrated human amnion-derived tissue allograft and is treated as human tissue for transplantation under the FDA’s HCT/P process. There is currently only one available study published on its use in human subjects. Snyder (2016) reported on the results of a prospective, open label, randomized, parallel group trial involving 29 adults with type 1 or type 2 diabetes mellitus who have one or more ulcers presenting for more than 1 month with no signs of infection/osteomyelitis. Subjects were randomized in a 1:1 fashion to receive treatment with either standard care (SOC, n=14) or AMNIOEXCEL+SOC (n=15) until wound closure or 6 weeks. The authors reported that 35% of subjects in the experimental group achieved complete wound closure at or before week 6 vs. 0% in the SOC group (p=0.017). They observed that there was a more robust response noted in the per protocol population, with 45.5% of subjects in the experimental group achieving complete wound closure, while 0% of SOC alone subjects achieved complete closure (p=0.0083).
Amniofix
Amniofix is a product that consists of an injectable form of processed allogeneic amniotic tissue and is treated as human tissue for transplantation under the FDA’s HCT/P process. Only one RCT regarding its use has been published in the peer-reviewed published literature. Zelen and colleagues (2013b) report on 45 subjects with plantar fasciitis randomized in a single-blind fashion to receive one of three treatments: (1) standard care plus injection with 1.25 cc of sterile 0.9% saline (control group); (2) standard care plus injection with 0.5 cc Amniofix (0.5 cc group), and (3) standard care plus injection with 1.25 cc Amniofix (1.25 cc group). All subjects also received injection with 2 cc of 0.5% Marcaine plain, and the use of tramadol for pain was allowed as needed throughout the study. There were 15 subjects in each group. A total of 41 subjects (91.1%) completed the 8-week follow-up period. All 4 subjects who failed to complete the study were in the control group. The authors report that significant benefits were seen in all groups throughout the study compared to baseline on the American Orthopaedic Foot and Ankle Society (AOFAS) Hindfoot Scale (p<0.01). Additionally, the AOFAS scale outcomes were significantly higher for both Amniofix groups vs. controls (p<0.001). No differences were noted between the two Amniofix groups. At the end of week 1, the median reduction in pain was 3 points for controls and 6 points and 5 points for those receiving 0.5 cc and 1.25 cc of Amniofix, respectively (p<0.001; p=0.004). Using the Wong–Baker FACES Pain Rating Scale, a visual analog pain scale (VAS), controls reported moderate to severe pain throughout the 8-week study period. Both Amniofix groups reported a significant reduction of pain from very severe at baseline to within the mild to moderate range at 1 week and reported continuing reduction in pain over the study period (p<0.001), with no statistically significant difference between groups. Based upon the physical and mental scales on the SF-36v2 quality of life tool, it was reported that both Amniofix groups had significant improvements from baseline compared to controls. No difference between Amniofix groups was reported. At the end of the first follow-up week, significantly more subjects in both Amniofix groups vs. controls needed additional treatment with tramadol (57.1% of controls, 73.3% of the 0.5 cc group, and 100% of the 1.25 cc group). This was not significant for the 0.5 cc group vs. controls but was for the 1.25 cc group vs. controls (p=0.004) as well as the 1.25 cc group vs. the 0.5 cc group (p=0.032). At the second follow-up visit, rates of tramadol use were significantly lower in all groups (p>0.05 for all groups). No adverse events related to treatment were observed in any study subjects. This weak study indicates some benefit from the use of Amniofix for individuals with plantar fasciitis. However, due to the small study population and lack of investigator blinding, further research is warranted to fully understand the efficacy of this treatment method.
Amniotic Allografts – Not specified
There is an increasing body of evidence in the available peer-reviewed published literature addressing the use of allogeneic amniotic tissues for the treatment of a variety of uses, including ophthalmologic, obstetric, and burn conditions. A small number of these publications address branded products, which are addressed elsewhere in this document. However, the vast majority of the published studies involve the use of amniotic-derived products that are: (1) not specified by the authors, (2) branded products not commercially available in the U.S, or (3) materials that are locally sourced. Many of these studies are randomized controlled trials, but with small study populations (Abdulhalim, 2015; Amer, 2010; Andonovska, 2008; de Farias, 2016; Harvinder, 2005; Küçükerdönmez, 2007; Luanratanakorn, 2006; Paris, 2013; Sharma, 2016; Sheha, 2008; Tamhane, 2005; Tandon, 2011). These studies are heterogenous with regard to the type of amniotic graft used, including lyophilized, cryopreserved and glycerin preserved products. Furthermore, there is a wide array of indications addressed across these studies, with a critical mass of evidence not established for any particular one. Finally, due to the differences in the harvesting and processing procedures these materials undergo that may impact the physical properties of the materials, the findings of such studies cannot be used to support the use of amniotic-derived products as a group.
Artacent Wound
Artacent is a product composed of dehydrated acellular human amniotic membrane and is treated as human tissue for transplantation under the FDA’s HCT/P process.
Sledge (2020) reported on a study involving 26 subjects who were participants in an RCT that was discontinued due to logistical issues. All subjects had non-infected DFUs that had failed previous standard care and were treated weekly or biweekly with Artacent Wound. The primary endpoint of 100% healing at 12 weeks was reported in 17 subjects (65%). The incidence of adverse events potentially related to the grafting product was 12% (4/34) and serious adverse events were reported in 6% (2/34).
This data is interesting but does not provide data that is reasonably generalizable to a wider population of individuals with DFUs. Further investigation is warranted.
Artelon (Including CMC and TMC)
Artelon is a synthetic grafting material made from degradable polyurethaneurea cleared through the FDA’s 510K process. The only currently available study addressing this product is a RCT consisting of 109 subjects with osteoarthritis of the carpometacarpal joint of the thumb (Nilsson, 2010). In this study, 72 subjects were treated with Artelon and 37 were treated with standard tendon interposition arthroplasty. There was a significant loss to follow-up, with less than 50% of subjects having available data at the 1-year follow-up time point. The authors report that swelling and pain were more common in the Artelon group, and 6 implants were removed because of such symptoms. Interestingly, 5 of these subjects did not receive antibiotics preoperatively according to the study protocol. In the intention-to-treat analysis but not in the per-protocol analysis, significantly better pain relief (VAS) was obtained in the control group. Self-perceived disability evaluated by the DASH (disability of arm-shoulder-hand) questionnaire improved in both groups. However, these findings are not particularly useful, given the significant loss to follow-up reported.
At this time, the available peer-reviewed published articles addressing Artelon TMC are underpowered case series studies involving 13 and 15 subjects each (Jörheim, 2009; Nilsson, 2005; respectively). This level of evidence is inadequate to fully evaluate the safety and efficacy of this product. Further investigation is warranted.
Avance Nerve Graft
Avance nerve graft is a decellularized allogeneic product derived from donated peripheral nerve tissue and is treated as human tissue for transplantation under the FDA’s HCT/P process. The currently available evidence addressing the clinical use of Avance is limited.
The only currently available comparative trial involving this product was published by Means in 2016. This double-blind RCT involved 23 subjects with 31 digital nerve injuries treated with hollow conduit (n=9) or Avance processed nerve allograft (n=14). The authors reported that the Avance group demonstrated significantly greater recovery vs. conduit subjects as measured by results by static 2-point discrimination (5 ± 1 mm vs. 8 ± 5 mm, p<0.5). Among subjects with 6-month data available, all subjects in the Avance group returned to S3+ (8 of 8 digits) vs. 75% (9 of 12 digits) in the conduit group. A return to S4 was not statistically significant between groups. At 12 months, results of Semmes-Weinstein Monofilament (SWMF) assessment testing found that the Avance group had a significant improvement vs. controls (mean of 3.6 ± 0.7 vs. 4.4 ± 1.4, p<0.05) and recovery of protective sensation, equivalent to SWMF score of 4.31 or better, was reported in 100% of Avance-treated subjects vs. 75% of control subjects. No differences between groups were found with regard to results on the Disability of the Arm, Shoulder and Hand (DASH) questionnaire or assessment of thermal discretion or pain assessment at 12 months. While this study had a rigorous methodology, the small numbers of subjects and significant loss to follow-up (> 70%) hinder the utility of the results.
Brooks and others (2011) reported a case series study involving 108 subjects with nerve injuries. Outcomes were only available for 59 subjects (56%). The authors report “meaningful recovery” in 87% of subjects available for evaluation. A post hoc subgroup analysis demonstrated no significant differences with regard to nerve type, gap length, subject age, time to repair, age of injury, or mechanism of injury (p>0.05). No graft related adverse experiences were reported and a 5% revision rate was observed. The data presented is insufficient to allow full assessment of the safety and efficacy of the Avance nerve graft.
Safa (2019) reported a case series study involving data from the RANGER® registry involving 385 subjects who underwent 624 nerve repair procedures using Avance and were compared to historical data from subjects undergoing hollow tube conduit and/or autografts. Follow-up was 12 months for sensory nerves and 18 months for mixed/motor nerves. Overall response rate was reported to be 87%, with response being defined as “any improvement after repair based on either qualitative and/or quantitative assessments”. Meaningful recovery, defined as S3 or M3 or greater improvement as measured by the Mackinnon-Dellon Modification of the Medical Research Council Classification (MRCC) sensory and motor scale, was reported as 82% of subjects. By body region, meaningful recovery was reported as 83%, 53% and 100% for the upper and lower extremity and head/neck, respectively. The difference between upper and lower extremity was significantly different (n=0.01). Compared to historical comparisons, the author’s findings were not significantly different. For upper extremities, nerve gap lengths < 15 mm had significantly better meaningful recovery than those 50-70 mm (p=0.011). No differences in meaningful recovery stratified by gap length were reported for the lower extremities.
The results of these studies are promising. Further data from more rigorously designed and executed studies is warranted.
Avaulta
Avaulta is a composite product composed of polypropylene mesh with acellular cross-linked collagen of bovine origin and has been cleared through the FDA’s 510K process. The use of Avaulta Plus and Avaulta Biosynthetic Support System for the treatment of vaginal prolapse has been described in one prospective case series study involving 40 subjects (Bondili, 2012). Subjects were followed for up to 3 years (median 27 months (range 20-36). The primary outcome was quality of life (QoL) and patient satisfaction as measured by the International Consultation on Incontinence Modular Questionnaire–Vaginal Symptoms (ICIQ-VS) tool. Twelve subjects (30%) were undergoing a second procedure to address prolapse. Of the 40 subjects, 19 (47%) underwent anterior repair, 20 (5%) posterior repair, and 1 (2.5%) underwent both anterior and posterior procedures. Vaginal laxness improved significantly, with 67.25% of subjects reporting preoperative laxness which improved to 5% of subjects with laxness at follow-up (p<0.0001). Decreased vaginal sensation also improved, from 30% to 7.5% (p<0.01). Sexual activity was reported to improve from only 32% to 100% postoperatively. The authors report that 1 subject continued to have prolapse symptoms (2.5%), resulting in a 97.5% success rate (p<0.0025). Only 2 subjects (5%) needed to digitate the vagina to vacate their bowels, a significant decrease from 12 (57%) preoperatively (p<0.001). Vaginal pain decreased from 55% preoperatively to 2.5% postoperatively (p<0.0001). No surgical complications were mentioned.
A retrospective case series study by Oliveira and colleagues (2020) involved 97 subjects with ≥ stage II genital wall prolapse repair with Avaulta. Mean follow-up was 2.9 years with 12 subjects lost. Postoperative complications were experienced by 29.1% (n=23) of subjects, with one removal due to hematoma. Other complications included voiding dysfunction (n=10), urinary infection (n=7), vesicovaginal fistula (n=1), pelvic abscess linked to hysterectomy (n=2), and mesh exposure (n=6). For subjects with voiding dysfunction and bladder injury, a prolonged bladder drainage by a Foley catheter was required for a mean duration of 11.2 days. Four of the subjects with vaginal mesh exposure required additional surgery to partially remove the mesh in 3 cases and a colpoplasty procedure to cover the mesh in the remaining case. Self-reported improvements were reported with regard to vaginal discomfort (n=79 at baseline vs. 4 at last follow-up, p>0.01), pelvic heaviness (n=46 at baseline vs. 3 at last follow-up, p>0.01), and voiding dysfunction (n=16 at baseline vs. 2 at last follow-up, p>0.01). No anterior wall prolapse was present in 79.1% of subjects at last follow-up and stage I and II prolapse was reported in 19% and 3%, respectively. No apical and posterior prolapse was reported in 98.5% and 83.6%, respectively. Eight subjects (12 %) had recurrence at 3 years.
The results of these weak uncontrolled case series are promising. Further data from more rigorously designed and executed studies is warranted.
Belladerm
BellaDerm is a product composed of acellular human dermis and is treated as human tissue for transplantation under the FDA’s HCT/P process.
Solomon and others (2013) published the results of a retrospective case series study involving 47 subjects who underwent penis girth enhancement utilizing circumferential grafting with allograft material. The subjects received either aseptic AlloDerm (n=9), Belladerm (n=20), and Repriza (n=21). Mean follow-up was 11.25 months (range 1 to 120 months). The rate of infection, which the authors defined as an open wound with graft exposure, occurred in 20 (42%) of 47 subjects. Of these, 17 (36%) subjects had graft exposure only and 3 (6%) subjects sustained graft exposure and total graft loss. Graft exposure or loss occurred in 3 AlloDerm subjects, 9 Belladerm subjects, and 8 Repriza subjects. No AlloDerm subjects sustained graft loss, whereas 2 with Belladerm and 1 with Repriza did. No statistical differences between groups with regard to infection or graft loss was reported.
This study is too underpowered and the methodology too weak to sufficiently assess the safety or efficacy of any of these products for this procedure.
Biodesign
Please see ‘Surgisis’ section below.
Cardiocel
CardioCel is a product produced from bovine pericardial tissue and has been cleared through the FDA’s 510K process. At this time, the available published in the peer-reviewed literature addressing this product is limited. Pavy (2017) published the results of a retrospective series of 102 subjects who underwent procedures addressing variety of congenital heart diseases, including septal defects to pulmonary outflow disorders. No infections, intraoperative implantation difficulties or postoperative mortality were reported to be associated with CardioCel. Graft failure reoperations occurred in 5 subjects (5%), 4 of whom had the patch implanted for aortic angioplasty (2 in the ascending aorta and 2 in the aortic arch), and 1 subject had a monocusp replacement. The median time between the first and the second operation for graft failure was 245 (range 5-480) days. The authors concluded that, “Our experience shows that the patch is well tolerated in the septal, valvar and pulmonary artery positions. However, we experienced graft failures in infants in the aortic position.”
Bell and colleagues (2019) reported on the results of another series study involving 377 subjects with congenital heart defects who received surgical treatment with 501 Cardiocel patches. Median follow-up was 31 months (1-60 months), and 11 deaths (2.9%) were reported, with 1 reportedly related to Cardiocel. The authors reported no echocardiographic or radiological evidence of patch calcification in any subject. The overall freedom from reintervention at 3- and 5-years post-implantation was 96%. A total of 14 (2.8%) implants required 18 reinterventions (3.6%) at the site of implantation. No differences in performance of Cardiocel in neonates (0-28 days), infants (29-365 days) or children older than 1 year (p=0.22) were reported.
These results are promising, but data from larger, well-designed studies is needed to fully understand the safety and efficacy of Cardiocel use in the repair of congenital heart diseases.
Clarix
Clarix is a product composed of cryopreserved acellular human amniotic membrane and umbilical cord and is treated as human tissue for transplantation under the FDA’s HCT/P process.
Bemenderfer (2019) provided the only currently available published peer-reviewed study on this product. The unblinded non-randomized study involved 104 subjects undergoing total ankle arthroplasty who received skin closure with either Clarix (n=54) or standard care (n=50). The authors reported that use of Clarix significantly decreased the overall time to skin healing (28.5 days vs. 40 days; p=0.03). No differences between groups were reported with regard to reoperations, skin dehiscence, local wound care, or antibiotic prescriptions. These results are promising, but additional data from larger controlled studies is needed to understand the safety and efficacy of this product.
Conexa
Conexa is a product produced from acellular porcine dermis and has been cleared through the FDA’s 510K process. At this time, the only comparative trial published in the peer reviewed literature addressing the use of this product was reported by Maillot and others in 2018. This prospective non-randomized trial involved 32 consecutive subjects with large-to-massive rotator cuff tears assigned to treatment with 1) arthroscopic complete repair (repair group), 2) open repair and xenograft patch augmentation (patch group), or 3) arthroscopic debridement and tenotomy of the long head of the biceps (debridement group). Subjects were evaluated preoperatively and postoperatively at 3, 6, 12 and 24 months. The authors reported that the mean improvement in the Constant-Murley score was +29.1, significant for all groups at the final follow-up examination (p<0.01 for all). No differences were reported between the repair and patch groups. However, comparison between the debridement group and the patch group at 12 months and the final follow-up was significant (p<0.001), as was the comparison between the debridement group and the repair group (p<0.002). Complications occurred in 5 of 11 subjects in the patch group and only 1 in the repair group and none in the debridement group. The authors concluded that “the use of porcine dermis patches to augment repairs of massive and irreparable rotator cuff tears is not recommended because there is no benefit compared with repair without augmentation and patches result in more complications.”
CorMatrix
CorMatrix is a product produced from acellular porcine small intestinal submucosa and has been cleared through the FDA’s 510K process. At this time, there is very limited peer-reviewed published evidence addressing the use of CorMatrix. The data that is available addresses its use in cardiovascular surgical procedures. The largest of these studies is a retrospective, nonrandomized control study involving 111 subjects undergoing coronary artery bypass surgery (CABG) who had pericardial reconstruction with CorMatrix, compared to 111 control subjects who underwent a standard CABG procedure without pericardial reconstruction (Boyd, 2010). The authors reported that postoperative atrial fibrillation occurred in 39% of controls vs. 18% of CorMatrix subjects. No other results were significantly different. The safety and value of CorMatrix is difficult to interpret in this study, as it is the pericardial reconstruction procedure that seems to be the significant variable. Another publication by Quarti and colleagues (2011) describes the use of CorMatrix in a wide variety of cardiovascular surgeries, with no comparison groups provided. While the authors report no significant complications due to the use of CorMatrix, this study provides little in the way of helpful data to determine the safety and efficacy of this product. Similarly, Kelley and others (2017) reported the results of a retrospective case series study of 25 subjects who underwent anterior leaflet augmentation. They reported a 32% recurrence rate of mitral regurgitation and concluded that further research is needed. Finally, Ashfaq (2017) reported good results from the use of CorMatrix in an underpowered case series of 15 pediatric subjects undergoing atrioventricular (AV) septal defect repair. They reported 12 (80%) subjects either improved or had stable left AV valve performance remaining at "mild" or less insufficiency, two (13%) declined from "none" to mild, and one (7%) from declined from mild to "severe," No residual shunting or left ventricular outflow tract (LVOT) obstruction was noted at follow-up. Only one (7%) reoperation was performed after 3 years due to left AV valve zone of apposition dehiscence. No permanent pacemakers were needed, and no deaths were reported.
Hu and others (2021) reported the results of a retrospective cohort study of 38 pediatric subjects undergoing aortic valve repair with the aortic cusp extension procedures with either autologous pericardium (n=30) or CorMatrix (n=8). The authors reported that for the entire cohort the peak trans‐valvular gradient significantly decreased immediately postoperatively (p=0.0017). No significant changes were observed at the 5-year follow‐up timepoint (p=0.36). In the autologous group subjects with aortic stenosis at baseline the peak trans‐valvular gradient did not significantly change at follow‐up (p=0.12). The CorMatrix group had only 4 subjects with aortic stenosis at baseline, which did not allow for sufficient data for between‐group tests. Moderate-to-severe aortic regurgitation was reported in 28 (93%) of autologous group subjects at baseline, which improved to 11 (37%) postoperatively, but increased to 21 (70%) at follow‐up. Eight (100%) CorMatrix group subjects had moderate-to-severe aortic regurgitation, which improved to 3 (38%) postoperatively and increased to 7 (88%) at time of follow‐up. Between‐group data indicated a significant difference in favor of the autologous group (p=0.017). Freedom from reoperation at 5 years was significantly poorer in the CorMatrix group (12.5%) vs. the autologous group (62.5%, p=0.01). The most common reason for reoperation in the autologous group was for repair of moderate to severe aortic regurgitation and severe aortic regurgitation in the CorMatrix subjects. While no CorMatrix subjects had severe aortic regurgitation postoperatively, 88% developed it at 5 years follow‐up. The authors concluded that autologous pericardium may outperform CorMatrix for aortic valve repair using the cusp extension method. However, several methodological weaknesses of this study limit the generalizability of these findings and further study is warranted.
Overall, the data regarding the safety and efficacy of CorMatrix is incomplete and conflicting. Further investigation with larger well-designed trials is needed.
Cortiva
Cortiva allograft dermis is a product composed of acellular human dermis and is treated as human tissue for transplantation under the FDA’s HCT/P process.
Keifer and colleagues (2016) described a retrospective comparative trial involving 166 subjects who underwent 198 breast reconstruction procedures with either aseptic AlloDerm (n=98, 174 breasts) or Cortiva (n=68, 124 breasts). Follow-up data was limited to 60 days post-procedure. The authors noted that subjects in the Cortiva group were significantly older (p=0.002), heavier (p=0.008) and had a higher rate of hypertension (p=0.01). The results indicated that the Cortiva group had a significantly higher rate of mastectomy flap necrosis (p=0.02). However, a multiple linear regression model analysis did not identify matrix type as a predictive factor in developing mastectomy flap necrosis. Only BMI was identified as a predictive factor (p=0.036). The authors addressed the limitations of this study, noting the retrospective, unblinded methodology, limited geographical scope of the study, and short follow-up period. They concluded by stating further work should involve larger sample sizes, wider geographical scope, and longer follow-up time.
Parikh (2018) published the interim results from an ongoing prospective single-blind RCT comparing Cortiva vs. sterile AlloDerm for submuscular breast reconstruction. The report involved data from 59 breasts (Cortiva, n=31; AlloDerm, n=28). The authors reported no statistically significant differences with respect to time to drain removal, complications, fill volumes, patient-reported outcomes, or narcotic consumption. These results are promising, but the final analysis from this trial will provide a more complete picture of the safety and efficacy of Cortiva.
Urquia (2020) reported the results of a retrospective case series study involving 118 subjects (183 breasts) who underwent prepectoral breast reconstruction procedures using Cortiva. One or more major complications were observed in 21.19% of subjects (32 breasts, 17.49%). No statistical differences with regard to major complication rate was found between immediate vs 2-stage reconstruction procedures (p=0.824). Infection was the most common reason for reoperation (7.65% of all breasts). Prepectoral reconstruction procedures were successful in 89.62% of cases. Infection was the most frequent complication responsible for failure (52.63% of cases). A total of 10 breasts (5.4%) had Baker III/IV capsular contractures. Subjects with implants > 450 mL were statistically more likely to experience implant failure (p=0.018).
At this time the available evidence addressing the use of Cortiva for breast reconstruction is unclear. The results of the RCT described by Parikh are still pending but will allow a better picture of the clinical utility and performance of Cortiva.
The use of Cortiva for abdominal wall reconstruction was reported by Lindsey in 2020. This retrospective chart review involved 82 subjects who underwent abdominal wall reconstruction with either AlloDerm (n=53) or Cortiva (n=29). The overall complication rate was found to be not significantly different between groups (51.92% in the AlloDerm group vs. 72.41% in the Cortiva group, p=0.09921). No explantations were reported. This was the first description of Cortiva used for the treatment of abdominal wall reconstruction procedures. Additional data is needed to fully evaluate the clinical utility of this technique.
Cymetra
Cymetra, an injectable micronized particulate form of aseptic AlloDerm (decellularized human dermis), has been proposed as a minimally invasive tissue graft product. It is treated as human tissue for transplantation under the FDA’s HCT/P process. At this time, there are only three peer-reviewed published articles addressing the use of this product. All of these studies involve participants with vocal cord paralysis. One study by Morgan and colleagues (2007) was a retrospective, nonrandomized controlled trial involving 19 participants undergoing injection laryngoplasty with Cymetra or medialization laryngoplasty. The authors reported no significant difference between groups at 3 months follow-up. No long-term comparison data was provided. Another report of a retrospective case series study involving 10 participants who all received injection laryngoplasty was reported by Milstein et al (2005). The authors of this study reported significant improvement in voice quality, glottal closure, and vocal fold bowing. Of the study population, only 8 participants (40%) were found to have lasting benefit. Finally, Karpenko and others (2003) reported the results of a case series study (n=10). The results indicated that there were no significant quantitative or subjective voice quality improvements. They also stated that significant improvements were identified in maximum phonation time, relative glottal area, and subjective judgment of glottal competency. However, these results were not maintained at the 3-month study interval.
Enduragen
Enduragen is a product composed of porcine acellular dermal matrix and has been cleared through the FDA’s 510K process. McCord and others (2008) have published the only available study addressing the use of Enduragen. Their retrospective case series involved 69 subjects who underwent 192 reconstructive or cosmetic eyelid procedures with Enduragen grafts. Eight procedures were for spacers in the upper lid, 104 were for spacers in the lower lid, and 17 were for lateral canthal reinforcement. There were 13 eyelid complications, for a complication rate of 10%. Nine cases required surgical revision, and there were four cases of infection, all of which were successfully treated with oral and topical antibiotics. The results of this study are insufficient to adequately evaluate the safety and efficacy of Enduragen. Further research is needed.
Barmettler (2018) published the results of a prospective, randomized clinical trial involving 39 subjects (42 eyelids) undergoing lower eyelid retraction repair with spacer graft. Subjects were assigned to undergo their procedure with autologous auricular cartilage (n=19 eyelids), SurgiMend (n=11 eyelids), or Enduragen (n=12 eyelids). The authors reported no significant differences between groups with regard to 6-month measures including MRD2, conjunctival injection, tearing, discomfort, itching, corneal abrasions, or repeat procedures.
Fortiva
Fortiva is a product composed of porcine acellular dermal matrix and has been cleared through the FDA’s 510K process. The only currently available published peer-reviewed study addressing its use in a clinical setting was published by Maxwell in 2019, who reported on the results of a retrospective non-randomized controlled study investigating the use of Fortiva (n=72) compared to Strattice (n=98) and AlloDerm (n=59) in 229 subjects undergoing abdominal wall reconstruction. The incidence of recurrence of abdominal wall defect was significantly higher in the AlloDerm group (20.3%) compared with the Fortiva (10.2%) and Strattice groups (6.9%) (p=0.040). The 1-, 3-, and 5-year survival rates for the repair with Fortiva were 1.4% and 6.9%, and 0%. For Strattice, the results were 5.1%, 9.2%, and 10.2%, and for AlloDerm, 6.8%, 18.5%, and 20.3%. Although subjects in the AlloDerm group had the longest median hernia-free interval, 26.8 months (2-60 months), this was not found to be significantly different from Fortiva and Strattice (data not provided). The most common complication was surgical site infection (26.2%), followed by delayed healing (24.0%). Seroma formation was reported to have been significantly lower in the Fortiva group vs. the Strattice and AlloDerm groups (1.4% vs 13.3% vs 11.9%; p=0.021). This study indicates promising results; however, this data is limited and not methodologically robust. Additional investigation into the safety and efficacy of Fortiva is needed.
GalaFLEX
GalaFLEX is a synthetic bioabsorbable product composed of poly-4-hydroxybutyrate and was cleared through the FDA’s 510K process. The only currently available published peer-reviewed study addressing its use in a clinical setting was published in 2018 by Adams. This study was a case series report involving 62 subjects undergoing mastopexy procedures. The authors reported that 89.7% of subjects had successful ptosis correction and maintenance at 1 year. Both subject and surgeon satisfaction for breast shape, droop/sag of the breast, and maintenance of results at 1 year was reported as high. Adverse events deemed to be related to the device occurred in 5 subjects (8.0%), including nerve pain, breast swelling, ptosis, and 2 instances of asymmetry. It is not clear how the safety and efficacy of this product compares to other products, including those considered the standard of care for breast procedures. Additional comparative trials are warranted.
Gentrix
Gentrix is a product composed of porcine acellular urinary bladder and has been cleared through the FDA’s 510K process. The only currently available published peer-reviewed study addressing its use in a clinical setting was published by Wang and others in 2018. They reported on an underpowered unrandomized controlled trial involving 65 subjects who underwent paraesophageal hernia (PEH) repair with (n=32) or without (n=33) reinforcement with Gentrix. There was no difference reported between groups with regard to recurrence rates, size of recurrence, postoperative symptomatic or quality of life improvement. The authors noted that subjects in the unreinforced group who suffered recurrence had more severe symptoms and a higher rate of dissatisfaction. Of the 3 subjects with recurrences after Gentrix placement, reoperation demonstrated anterior failure where no reinforcement had occurred because of the posteriorly placed U-shaped graft. It is not clear how the safety and efficacy of this product compares to other products, including those considered the standard of care. Additional comparative trials are warranted.
Gore BioA
Gore BioA is a completely synthetic, bioabsorbable product composed of 67% polyglycolic acid and 33% trimethyl chitosan and was cleared through the FDA’s 510K process. Ommer and others published the results of a case series study involving 50 subjects with trans-sphincteric (n=28) or supra-sphincteric (n=12) anal fistula who were treated with Gore BioA (2012). Postoperatively, 1 subject developed an abscess which had to be managed surgically. In 2 subjects, the plug had fallen out within 2 weeks after surgery. Six months after surgery, the fistula had been healed in 20 subjects (50.0%). Three additional fistulas healed after an additional 7 to 12 months. The authors reported that the overall healing rate was 57.5% (23/40). However, they noted that healing rates differ significantly between the surgeons (from 0 to 75%), and also varied depending on the number of previous interventions. In individuals having had only drainage of the abscess, success occurred in 63.6% (14/22) whereas, in those having had one or more flap fistula reconstructions, the healing rate decreased slightly to 50% (9/18). Further study is warranted to better understand the impact of surgeon experience as well as optimal selection criteria for individuals requiring treatment for anal fistulas. Heydari (2013) described the results of a retrospective case series study involving 48 subjects with 49 anal fistulas treated with the Gore BioA. The overall healing rate was reported to be 69.3% (34/49 fistulas, 33/48 subjects). Eight subjects (24.2%) had complete healing by 3 months after surgery, 21 subjects (63.6%) had healed by 6 months, and 4 subjects (12.1%) had healed by 12 months. At 3 months, there were no reports of perineal pain or fecal incontinence. The authors reported no incidents of dislodged devices, anal stenosis, bleeding, or local infection.
In 2018 Jordan and others published the results of a retrospective comparative study involving 87 subjects undergoing breast reconstruction with mesh underlay reinforcement at 123 sites with either polypropelene mesh (n=58) or Gore BioA (n=65). The overall incidence of bulge or hernia was 11.4%. The Gore BioA group experienced significantly more bulges/hernias than the polypropylene mesh group (20% vs. 1.7%). They concluded that use of Gore BioA was associated with a 13.3-fold risk of bulge/hernia (p=0.016) and was not appropriate for anterior rectus fascia reinforcement following abdominal tissue transfer.
While these reports are promising, the lack of larger comparative trials impedes a full assessment of the efficacy of the GORE BioA device. Further investigation is warranted.
In 2017, the American Society of Colon and Rectal surgeons published a new Practice guideline for the management of anal fissures (Stewart, 2017). Their recommendations do not mention the use of grafts or plugs of any kind.
Gore® Acuseal Cardiovascular Patch
Gore® Acuseal Cardiovascular Patch is an expanded polytetrafluoroethylene (ePTFE) separated by an elastomeric layer and may be available both with and without covalently bound bioactive heparin. It has been cleared through the FDA’s 510K process. Stone (2014) published the results of a prospective randomized study comparing clinical outcomes of Acuseal vs. bovine pericardium patching (Vascu-Guard) when used for primary closure for carotid endarterectomy. This study involved 200 subjects assigned in a 1:1 fashion and the mean follow-up period was 15 months. They reported that mean hemostasis time was 4.90 min for Acuseal vs. 3.09 min for Vascu-Guard (p=0.027). The mean operative times were similar for both groups (2.09 hr vs. 2.16 hr, p=0.669). The incidence of reexploration for neck hematoma was higher in the Vascu-Guard group; 6.12% vs. 1.03% (p=0.1183). The incidence of perioperative ipsilateral neurologic events was 3.09% for Acuseal patching vs. 1.02% for Vascu-Guard patching (p=0.368). The respective freedom from ≥ 70% carotid restenosis at 1, 2, and 3 years were 100%, 100%, and 100% for ACUSEAL patching vs. 100%, 98%, and 98% for Vascu-Guard patching (p=0.2478).
Grafix CORE
Grafix CORE is a grafting product derived from allogeneic chorion membrane. It is treated as human tissue for transplantation under the FDA’s HCT/P process.
Frykberg (2016) reported the results of a prospective case series study involving subjects with complex DFUs ≤ 15 cm in their longest dimension and extending through the dermis with exposed muscle, tendon, fascia, bone, or joint capsule. All were treated with weekly applications of Grafix CORE. The intent-to-treat (ITT) population included 31 subjects and the per-protocol population included 27 subjects. The ITT subject population had significant co-morbidities, with 80% having hypertension, 60% current or former smokers, 55% having heart disease, and 45% having a previous partial foot amputation. Prior advanced treatment (for example, negative pressure wound therapy) for the index wound had occurred in 67.7% of subjects. At 16 weeks, 96.3% of the per-protocol group had 100% granulation of the index wound and complete closure occurred in 59.3%. The mean area reduction of the index wound at day 28 was 54.3% and 72.8% at 8 weeks. At the end of the 16-week study period the mean wound area reduction was 92.3%. No Grafix-related adverse events were reported. This study demonstrated the use of Grafix CORE in the healing of complex DFUs. However, the small study population and lack of controls hampers the generalizability of these results.
Raspovic (2018) reported a retrospective case series analysis of 360 subjects with 441 DFUs treated with Grafix PRIME or Grafix CORE using data from Net Health’s Wound Expert electronic health records database. The mean size of the index wound was 5.1 cm2 with 3.9 mm depth. Mean wound duration prior to study treatment was 102 days. The mean duration of treatment with a Grafix product was 89.3 days (median 56.0). Complete wound closure at the end of treatment occurred in 59.4% of subjects. Median time to closure was 42.0 days with a median of 4 graft applications. The proportion of closure decreased as wound size increased, with 72.3% of wounds between 0.25 cm2 to 2 cm2 having complete healing at a median of 21 days and 4 applications. For wounds larger than 25 cm2, only 27.8% achieved complete healing at a median of 105 days and 11 applications. The authors did not provide any data regarding the percentage of subjects receiving treatment with Grafix PRIME vs. those receiving Grafix CORE.
At this time the safety and efficacy of Grafix CORE, is uncertain. Additional well designed and conducted trials are warranted.
GrafixPL Prime
GrafixPL Prime is a grafting product derived from allogeneic amnion membrane. It is treated as human tissue for transplantation under the FDA’s HCT/P process. A similar product, Grafix Prime, is also available. The difference between these products is that Grafix Prime is cryopreserved, and GrafixPL Prime is lyopreserved (a method of dehydration).
Davis (2020) published the results of a prospective cohort study involving 40 subjects with foot ulcers treated with GrafixPL Prime once a week for 12 weeks. After 12 weeks of treatment, closure was achieved in 48% of subjects (n=19) with an average time to closure of 40.0 days. A total of 60% of subjects had a 50% wound area reduction, and significantly more subjects who achieved closure reached a 50% wound area reduction in 4 weeks compared with those who did not (73.7% vs 47.6%, p=0.093). Five subjects were identified to have no response to treatment, defined as a percent wound area reduction of < 30% by the end of the study. Subjects that did not achieve wound closure tended to be older (63 vs 59 years, p=0.011), have larger ulcers at baseline (7.8 vs 1.6 cm2, p=0.012), and have ulcers of longer duration (60.0 vs 130.0 days, p=0.062). Fifty-eight percent of subjects had at least one adverse event during treatment including infection (n=10), infection requiring hospitalization (n=2), hospitalization for non-foot related issues (n=4), and amputation (n=1). In addition to the clinical study, the authors reported a bench study assessing cellular viability of cryopreserved Grafix Prime vs. the lyopreserved GrafixPL Prime. The reported that cellular viability was equivalent between cryo- and lyopreserved amniotic tissues.
While these results are helpful in beginning to understand the clinical utility of GrafixPL Prime, additional data is needed for an adequate evaluation.
Hyalomatrix
Hyalomatrix is a synthetic wound covering product composed of a benzyl ester of hyaluronic acid. This product has been approved through the FDA’s PMA process. The currently available evidence addressing the use of Hyalomatrix is limited mostly to weak, uncontrolled, unblinded case series studies. Only one RCT has been published to date involving 16 subjects with VSUs, 9 of which were treated with Hylaomatrix and 7 treated with standard wound care (Alvarez, 2017). The authors reported that the incidence of wound healing at 12 weeks was 66.6% for the Hyalomatrix group vs. 14.2% for controls (p=0.066). At 16 weeks, the incidence of wound healing was 87.5% of subjects in the Hyalomatrix group vs. 42.8% in the control group (p=0.059). The mean time to healing in the Hyalomatrix group was 41 days compared with 104 days in the control (p=0.029). The largest studies available involve 300, 262, 79, and 57 subjects (Gravante, 2007; Caravaggi, 2003 and 2011; Gravante 2010, respectively). The Carravaggi study addresses chronic wounds while the Gravante studies address burns. The rest of the studies published involve significantly fewer than 30 subjects and encompass a variety of indications including various surgically created wounds (Faga, 2013; Landi, 2014; Onesti, 2014), traumatic wounds (Onesti, 2014; Vaienti, 2013), and chronic ulcers (Motolese, 2013). In summary, the body of literature addressing Hyalomatrix is limited to predominantly weak case series studies involving a heterogeneous collection of indications. While most of these studies demonstrate promising results, the uncontrolled, unblinded nature of these studies does not allow proper assessment of the safety and efficacy this product.
Integra OmniGraft Dermal Regeneration Template
Integra Dermal Regeneration Template is a composite grafting material made from bovine collagen, chondroitin-6-sulfate (C6S), and a semi-permeable polysiloxane (silicone) layer. It has been cleared through the FDA’s 510K Premarket Notification process.
In 2015, Driver and colleagues reported the results of an RCT involving 307 subjects with DFUs assigned to treatment with either standard care (n=153) or treatment with Omnigraft (n=154) and followed initially for 16 weeks or until confirmation of complete wound closure, and then for a further 12 weeks. The investigators reported that complete DFU closure during the treatment phase was significantly greater with Omnigraft vs. control treatment (51% vs. 32%; p=0.001). The median time to complete DFU closure was 43 days for Omnigraft subjects vs. 78 days for controls, in wounds that healed. The rate of wound size reduction was significantly better in the Omnigraft subjects (7.2% per week vs. 4.8% per week, p=0.012). They concluded that for the treatment of chronic DFUs, Omnigraft treatment decreased the time to complete wound closure, increased the rate of wound closure, improved components of quality of life and had less adverse events compared with the standard of care treatment.
Hicks and others (2020) reported the results of a case series study that included 85 subjects treated with Omnigraft who underwent surgical procedures for debridement of a DFU or gangrene resulting in complex post-surgical DFUs. Overall, 107 wounds were treated, with 45.8% involving the forefoot, 23.4% the heel, 19.6% the midfoot, 5.6% the ankle, and 5.6% the lower leg/Achilles tendon. Bone involvement due to acute or chronic osteomyelitis occurred in 71.7%. Most subjects were at high risk for amputation based on Society for Vascular Surgery Wound, Ischemia, and foot Infection (WIfI) classification score (6.4% were WIfI classification score 4). Overall success rate for all initial dermal regeneration template applications was 66.7%, with the majority of wounds (81.3%) receiving one dermal regeneration template application. Two applications were reported in 15.9% of cases and three applications in 2.8%. Mean time to complete healing was 198 ± 18 days. Location of the wound on the forefoot was associated with significantly better healing (hazard ration [HR], 5.2) as was the presence of bone involvement (HR, 1.86). While these results are promising, the lack of a comparison group and other methodological weaknesses limit their generalizability.
In 2021 Mogedas-Vergara described a retrospective cohort study involving 70 subjects with skin cancer undergoing scalp reconstruction procedures. All subjects were over 65 years or age. Each subject underwent 2-stage procedures involving a first stage where Integra Derma Regeneration Template was used followed by the application of a split-thickness skin graft after 3-4 weeks. The mean surface area treated was 23 cm2 and the mean interval between stages was 30.6 days. Seven subjects (10%) did not undergo a second-phase procedure due to rapid wound epithelialization. The Integra and skin graft success rates were 87.1% and 100% respectively. A total of 13 subjects (18.6%) developed infections. In 4 subjects (5.7%) the infection caused partial Integra loss, which was treated via debridement and antibiotics and no need to reconsider placement of the graft. Infection resulted in total loss of the Integra graft in in 9 subjects (12.9%) and healing was completed by second intention without major complications. Mean wound epithelization in this subgroup of 13 subjects was 60.33 days and no other complications were recorded. The results of this study are promising, but the weak methodology used does not allow generalization of these findings to a wider population.
Integra Flowable Wound Matrix
In 2017, Campitiello and colleagues published an RCT comparing Integra Flowable Wound Matrix vs. standard care for the treatment of 46 subjects with DFUs with irregular geometries. There were 23 subjects in each group who were evaluated once a week for 6 weeks. The authors reported that the overall complete healing rate was 69.56%, with the rate in the Integra group being 86.95% vs. 52.17% in the control group (OR=1.67, p=0.001). Mean time to healing was 29.73 days in the Integra group vs. 42.78 in the control group (p<0.000). The amputation and rehospitalization rates in the Integra group were 4.34% vs. 30.43% in controls (RR=0.16, p=0.028). The authors concluded that Integra Flowable Wound Matrix was significantly superior to the wet dressing, but that additional research will shed more light on the promising advantages of this material in healing diabetic foot ulcers.
Keramatrix
This product is composed of freeze-dried acellular animal-derived keratin and has been approved through the FDA’s 510K process. At this time, the most rigorous evidence is an underpowered nonrandomized controlled study involving 40 subjects with superficial or partial thickness burn injuries treated with Keramatrix, compared to 40 historical controls who received standard of care treatment (Loan, 2016). The results indicated a significantly faster mean healing time in the Keramatrix group vs. controls (8.7 days vs. 14.4 days, p<0.05), hospital inpatient days (0 days vs. 2.6 days, p<0.05), and number of outpatient appointments following initial therapy (1.2 vs. 3.3, p<0.05). No differences in complications were reported.
KeraSys
Kerasys is composed of decellularized xenogeneic porcine small intestinal submucosa and has been approved through the FDA’s 510K process. The only available study described in the published peer-reviewed literature addressing the use of this product was published by Nagi and others in 2013. Their study was a retrospective, noncomparative, consecutive case series of 42 eyes with tube-related exposure complications due to glaucoma drainage device surgery. KeraSys was used to cover the defect. The authors reported that 4 (10%) eyes experienced patch-related complications. Two had exposure at 8 months postoperatively, 1 had exposure at 13 months postoperatively, and 1 with exposure at 4 weeks postoperatively. They concluded that, “The effectiveness of the KeraSys patch graft is limited by the higher than expected early exposure rate found in this case series.”
Kerecis™ Omega3 (formerly MariGen Omega3)
Kerecis Omega3 is an acellular dermal matrix derived from fish skin and cleared through the FDA’s 510K process.
The available evidence addressing the clinical safety and efficacy of Kerecis is limited. A double-blind, parallel-group non-inferiority RCT involving 81 subjects with 162 full-thickness surgical wounds was reported by Baldursson in 2015. Each subject underwent the creation of two 4 mm full thickness wounds made on the proximal anteriolateral aspect of their non-dominant arm, 2 cm apart. Each subject had one wound treated with Kerecis and the other wound with Oasis porcine-derived graft product and were followed for 28 days. At the study endpoint, 95% (76/80) of wounds in the Kerecis group and 96.3% (79/82) of wounds in the Oasis group were healed. The authors reported that this result was within the 95% two-sided confidence interval for non-inferiority margin of 0.1. They also noted that the OR of a Kerecis-treated wound being healed vs. an Oasis-treated wound was 4.75 (p=0.041), indicating that Kerecis added significantly faster wound healing vs. Oasis. No significant immunological responses were noted in the Kerecis group. While the findings of this study are interesting, they do not provide data regarding performance of the product in the populations for which they are proposed, specifically, those with impaired healing and chronic wounds. The results involving experimentally created wounds are not useful in informing the discussion of the clinical utility of Kerecis Omega3 in the real-world setting for the treatment of individuals with impaired healing function.
Michael et al. (2019) published the results of a retrospective case series study involving 51 subjects with 58 DFUs treated with Kerecis. Offloading methods were described in 34 wounds. At 16 weeks, the mean reduction in wound surface area was 87.57%, with 60.35% (35/58) healed completely. In the same time frame, > 90% reduction in wound surface area was achieved in 74.14% (45/58) of wounds. Only 2 wounds were reported to not have any healing in 16 weeks, but both healed eventually at 24 and 36 weeks, respectively, the former following additional Kerecis Omega3 applications, and the latter with no additional applications. The lack of a control group, blinding and other methods of bias control significantly hamper the generalizability of these findings.
Another study addressing the clinical outcomes of Kerecis has been published (Yang, 2016). However, this study was very underpowered, involving only 5 subjects, and did not involve any comparison group. The value of this publication in understanding the generalizable safety and efficacy of Kerecis is limited.
Kirsner (2020) published the results of a double blind RCT involving 85 healthy subjects who had two investigator-created full thickness punch biopsy wounds randomly assigned to treatment with either Kerecis or EpiFix. A total of 170 wounds were treated. The authors stated that the Kerecis-treated wounds healed significantly faster than the EpiFix-treated wounds (HR, 2.37, p=0.0014). No differences between groups were reported with regard to adverse or serious adverse events. These results indicate that Kerecis is similar to EpiFix in the treatment of acute surgical wounds. However, as with the Baldursson study previously discussed, this study did not adequately reflect the actual real-world use of these products, such as for the treatment of refractory DFUs.
Lullove (2021) reported the results of a prospective single-blind RCT involving 49 subjects with chronic superficial DFUs treated weekly for 12 weeks with either Kerecis and standard care with moisture-retentive foam dressing and hydrogel as needed to retain adequate moisture balance (n=24) or standard care with collagen alginate dressing alone (n=25). At 12 weeks the Kerecis group included 21 (87.5%) and the control group had 13 (52.0%), for an overall loss to follow-up of 30.1%. At 12 weeks, 67% Kerecis wounds had fully closed vs. 32% in the control group (p=0.0152). At the same time point, the reduction of wound area was 97.3% in the Kerecis group vs. 76.8% in the control group (p<0.06). The loss to follow-up at 12 weeks, along with other methodological flaws hinder the generalizability of these findings.
Kim (2021) reported the results of a retrospective non-randomized controlled study involving of 56 subjects with acute or chronic deep dermal wounds who were treated once with Kerecis (n=16) vs. daily standard dressings (n=41). Choice of group was at the subjects preference. The control group had 9 subjects convert to surgical treatment before the end of the trial, for a total of 32 subjects (78%) completing the trial period. In the Kerecis group, 8 subjects had acute burns, 5 had acute traumatic wounds, and 1 DFU, 1 VSU and 1 pressure ulcer. In the control group, 15 subjects had acute burns, 11 had acute traumatic wounds, and 6 had other unspecified wounds. In the Kerecis group, it was reported that the graft was fully absorbed at an average of 5.56 ± 1.60 days following application, with an average healing rate of 77.7% at 2 weeks. There were no significant differences in wound healing rates between groups for subjects with traumatic wounds. For burn subjects, the mean healing rate was 86.5% in the Kerecis group vs. 61.1% in the control group (p=0.021). The overall average healing rate of all wound types treated with Kerecis was 77.7% vs. 53.3% for the control group (p<0.05). These results are promising in aggregate, but limited sample sizes limit generalizability, including how Kerecis preforms for certain wound types.
Overall, the body of evidence addressing the use of Kerecis Omega3 is limited. Additional investigation into the clinical utility of Kerecis is needed in the form of adequately-powered well designed and conducted trials of non-heterogenous wound types, with appropriately selected subjects and control groups.
MatrACELL
MatrACELL is a decellularized allograft product composed of human cardiovascular tissue treated as human tissue for transplantation under the FDA’s HCT/P process.
Currently the only study published regarding the use of this product was published by Hopkins (2014). This nonrandomized controlled study involved 108 consecutive subjects undergoing cardiovascular reconstructive procedures using MatrACELL pulmonary artery patches during pulmonary arterioplasty. A second retrospective cohort of 100 subjects who received arterioplasty patches using classical cryopreserved pulmonary artery allografts (n=59 subjects) or synthetic materials (n=41 subjects) was used for comparison. The reported results included that 106 subjects with 118 decellularized patches had no device-related serious adverse events, no device failures, and no evidence of calcifications on chest roentgenograms. In contrast, the control subjects experienced an overall 14.0% patch failure rate requiring device-related reoperations (p<0.0001) at mean duration of 194 ± 104 days (range, 25 to 477 days). The authors concluded that the intermediate-term data obtained in this study suggest favorable performance by decellularized pulmonary artery patches, with no material failures or reoperations provoked by device failure.
Additional study is warranted to fully evaluate the safety and efficacy of this product.
MatriDerm
MatriDerm is a decellularized dermis allograft product treated as human tissue for transplantation under the FDA’s HCT/P process. The largest available study involves 30 subjects undergoing nasal tip skin grafts non-randomly assigned to receive either conventional full-thickness skin grafting, retroauricular perichondrodermal composite grafts, or skin transplantation supplemented with MatriDerm (Riml, 2011). Ten subjects were assigned to each group. This retrospective study was conducted in a randomized and blinded manner by assigned reviewers using the Manchester scale. The authors report that 2 (20%) of the MatriDerm subjects developed fistulae and concluded that MatriDerm was not suitable for nasal tip reconstruction.
Another study by Haslik and colleagues evaluated the use of MatriDerm for the management of full-thickness skin grafts (2010). This underpowered case series study involved 17 subjects with upper extremity skin wounds, all of whom received MatriDerm in conjunction with unmeshed skin grafts. The reported take rate was 96%. A 12-month follow-up Vancouver scale score of 1.7 and DASH (disability of arm-shoulder-hand) score showed excellent hand function in subjects with burn injury and subjects with a defect due to the harvest of a radial forearm flap achieved satisfying hand function.
Further study with larger, better designed trials is required in order to fully evaluate the safety and efficacy of MatriDerm.
MediHoney
The use of honey has been proposed for the treatment of various skin conditions including burns, chronic ulcers, and superficial abrasions. It has been hypothesized that honey, with its antibacterial properties, can significantly improve skin healing when applied topically to skin wounds. Several randomized controlled trials have been published involving MediHoney, a product cleared through the FDA’s 510K process, most addressing the treatment of venous leg and foot ulcers. Jull and colleagues published the largest of these trials, which included 368 subjects randomized to receive treatment with either calcium alginate dressing impregnated with manuka honey or standard care with whatever dressings were appropriate for the individual at that time (2008). After following the participants for a total of 12 weeks of follow-up, the authors concluded that there was no significant difference in outcomes between the two groups. It was noted that the honey-treated group experienced significantly greater numbers of adverse events (p=0.013). Contradicting these findings is a study by Gethin and Cowman (2008). In this study, 108 subjects with venous ulcers were randomized to receive treatment with either honey dressing or standard hydrogel therapy. The findings were that the honey-treated group had significantly better results in terms of median reduction in wound size at 12 weeks (44% vs. 33%, p=0.037), but no significant differences between groups in other primary endpoints were reported.
The other most studied condition addressed in the literature is the treatment of burns. The largest study currently available addressing burns involved 150 subjects randomized to receive treatment with either silver sulphadiazine (SSD) or honey (Malik, 2010). Each subject acted as his or her own control, with one burn site randomly treated with SSD and the other with honey. The authors report that the honey-treated sites had significantly faster re-epithelialization and healing of superficial and partial thickness burns than the SSD sites (13.47 days vs. 15.62 days, p<0.0001). Additionally, the honey-treated sites achieved complete healing significantly faster than SSD sites (21 days vs. 24 days, p<0.0001).
Lund and colleagues compared the use of honey-coated dressing for breast malignant wounds. In this study, 67 subjects, 79% of whom had breast cancer, were randomized to receive treatment with either honey-coated dressing (n=34) or silver dressing (n=33). The authors report no significant differences between groups, and they concluded that the possible antibacterial effect of either treatment “could not be confirmed in these malignant wounds.”
At this time, the evidence addressing the use of honey for skin wounds is lacking. The current studies are mostly unblinded, controlled studies, and a large variety of controls have been used. These factors make comparison study outcomes difficult to interpret. Further investigation with large well-done blinded trials using standardized controls is warranted.
Menaflex (formerly “Collagen meniscus implant” or CMI)
Collagen meniscus implants (e.g., Menaflex) have been proposed as a treatment method for individuals with a damaged knee meniscus. Menaflex is a human-derived acellular collagen product treated as human tissue for transplantation under the FDA’s HCT/P process. At this time, there is only one large trial for this type of procedure (Rodkey, 2008). This study involved 311 subjects with irreparable injury of the medial meniscus or a previous partial medial meniscectomy. The study population was divided into two groups, those with prior meniscal surgery (chronic group) and those with no prior surgery (acute group). These populations were further randomized to receive either treatment with a collagen meniscus implant or a partial meniscectomy only. The mean duration of follow-up was 59 months (range, 16 to 92 months). Repeat arthroscopies done in the experimental group at 1 year showed significantly (p=0.001) increased meniscal tissue compared with that seen after the original index surgery. In the chronic group, participants who had received the collagen implant regained a significantly higher degree of pre-surgery activity than did the controls (p=0.02). This group also underwent significantly fewer non-protocol reoperations (p=0.04). The authors reported no significant differences between the two treatment groups in the acute arm of the study.
Zaffahnini and colleagues conducted a long-term trial of the performance of the Menaflex implant in 33 subjects. This nonrandomized controlled trial allowed subjects to choose treatment with either Menaflex (n=17) or partial medial meniscectomy (n=16). Subjects were evaluated at baseline, 5 years and then 10 years after surgery. At 10 years, the authors report that the Menaflex group showed significant improvement compared to meniscectomy with regard to visual analog scale for pain (p=0.004), International Knee Documentation Committee knee form (p=0.0001), Teger index (p=0.026), SF-36 Physical Health Index (p=0.026), and SF-36 Mental Health Index (p=0.004). Radiographic evaluation showed significantly less medial joint space narrowing in the Menaflex group than in controls (p=0.0003). There were no significant differences reported between groups regarding Lysholm score (p=0.062) and Yulish score (p=0.122). Genovese score remained constant between 5 and 10 years after surgery (p=0.5).
Another case series study of 22 subjects followed for 10 years was reported by Monllau and colleagues (2011). The results of this study demonstrated that several measures improved, including the visual analog pain scale and radiographic joint line narrowing. The Lysholm score was significantly improved, from 59.9 at baseline, 89.6 at 1 year (p<0.001), and 87.5 at 10 years (p<0.001). Failure rate was only reported to be 8% in the 25 subjects initially implanted.
Van Der Straeten published the results of a cohort study of 313 subjects who received treatment with the collagen meniscal implant and were followed for a mean follow-up of 6.8 years (2016). A total of 56.5% of the implants were still intact and in place; 27.4% had been removed. This included 63 implants converted to a knee arthroplasty (19.2%). The overall cumulative allograft survivorship was 15.1% at 24.0 years. Simultaneous osteotomy significantly deteriorated survival (0% at 24.0 years) (p=0.010). The authors stated that 61% of subjects underwent at least one additional surgery (range 1-11) for clinical symptoms after implantation. They concluded that the collagen meniscal implant did not delay or prevent tibiofemoral OA progression.
Another large cohort study was reported by Waterman (2016). This study involved 230 active-duty military personnel who underwent treatment with the collagen meniscal implant. A total of 51 complications occurred in 46 (21.1%) subjects, including a secondary tear or extrusion (9%). The authors reported that 10 subjects (4.4%) required secondary meniscal debridement at a mean of 2.14 years. Revision was done in 1 subject (0.4%) and 20 subjects (0.9%) subsequently underwent total knee arthroplasty. After implantation, 50 subjects (22%) underwent knee-related military discharge at a mean of 2.49 years postoperatively. They concluded that while there were low reoperation and revision rates, their investigation indicated that 22% of subjects who received implants were unable to return to military duty due to persistent knee limitations at short-term follow-up.
While these studies show that there is some potential benefit to the use of meniscal collagen implants in some populations, further data from rigorously designed and conducted trials is warranted to further understand the clinical implications of this technology.
Menaflex was originally cleared by the FDA in the 510K process. Subsequent to further review by the FDA, this clearance was revoked. The manufacturer, ReGen Biologics, Inc. went bankrupt shortly thereafter. The Menaflex device is currently not marketed in the U.S.
Neuragen
Neuragen collagen tube conduits are composed of bovine-derived acellular collagen and have been cleared through the FDA’s 510K process. This product is proposed for use in peripheral nerve repair.
At this time the most rigorous published trial of Neuragen was an unblinded RCT involving 44 subjects with ulnar or median nerve lacerations assigned to treatment with Neuragen (n=23) vs. direct fascicular repair or nerve grafting (n=21) (Boeckstyns, 2013). The authors reported that data for only 36 subjects (81%) were available at the 24-month follow-up visit. However, they do not provide information regarding which groups the dropouts were from. At 24 months no significant differences between groups were reported with regard to amplitudes, latenecies and conduction velocities. With regard to comparison to the contralateral hand, both groups remained significantly deficient on all electrophysiological measures. No surgical complications were reported. These results may indicate some benefit from the use of Neuragen, but the generalizability is hampered by missing information regarding subjects at 24 months, as well as methodological flaws such small study population and lack of blinding.
In addition to this study, several unblinded non-randomized controlled trials and multiple case series studies addressing the use of Neuragen have been published, with most involving small numbers of subjects (Ashley, 2006; Bushnell; Distinct, 2013; Erakat 2013; Farole, 2008; Haug 2013; Huber 2017; Karup, 2017; Lohmeyer, 2014; Rbia, 2019; Schmauss 2014; Taras, 2011; Wangensteen, 2010; Wilson, 2016). These studies involve weak methodologies and low power to control for bias. The clinical utility and generalizability of their conclusions is limited, and further study is needed in the form of larger, well-designed trials to fully evaluate the safety and efficacy of this product.
NeuraWrap
NeuraWrap nerve wrap is a product composed of bovine-derived acellular collagen and glycosaminoglycan and has been cleared through the FDA’s 510K process. This product is proposed for use in peripheral nerve repair.
At this time the available peer-reviewed published data addressing the clinical utility of NeuraWrap is limited to a small number of studies involving weak methodology and low numbers of subjects (Hibner, 2012; Kokkalis, 2016; Soltani, 2014). Additional evidence addressing the clinical utility of this product from large, well-designed, and conducted trials is needed to fully assess the clinical utility of this product.
Novosorb Biodegradable Temporizing Matrix (BMT)
Novosorb Biodegradable Temporizing Matrix (BMT) product is composed of porous biodegradable polyurethane foam and has been cleared through the FDA’s 510K process. This product has been proposed for the treatment of various dermal conditions including burns, ulcers, chronic wounds, etc.
At this time there is a limited number of methodologically weak studies published in the medical literature addressing the use of Novosorb for a variety of conditions (Li, 2021; Lo, 2021; Solanki, 2020). Additional investigation addressing the clinical utility of this product in the form of well-designed and conducted trials is warranted.
Ologen Collagen Matrix
Ologen Collagen Matrix product is composed of acellular porcine intestine and has been cleared through the FDA’s 510K process. The use of this product has been proposed for a variety of ophthalmological indications, however the published literature has been limited. The most rigorous trial to date was an open label, non‑randomized, prospective study involving 93 subjects undergoing phacotrabeculectomy assigned to receive treatment with mitomycin C (n=53) or Ologen (n=40). The authors reported that after 12 months follow-up there were no significant differences between groups with regard to best corrected visual acuity (p=0.151), intraocular pressure (p=0.254), mean number of medications used (p=0.91) or overall procedure success (p=0.745). No reported repeat procedures, blebitis or endophthalmitis were reported. This study indicates equal outcomes from the use of mitmycin C vs. Ologen during phacotrabeculectomy. However, the study was not designed as a non-inferiority trial and contained several methodological flaws that limit the generalizability of the reported findings. Further investigation in the form of well-designed and conducted studies is needed.
Pelvicol
Pelvicol is a porcine-derived acellular dermal collagen product cleared through the FDA’s 510K process. The use of Pelvicol was evaluated in 132 subjects with pelvic organ prolapse. This RCT involved 64 subjects who underwent anterior and posterior colporrhaphy and 68 who received colporrhaphy with Pelvicol. At 3 months follow-up, there were significantly more surgical failures and recurrences in the Pelvicol group, but by the 3-year follow-up period recurrence rates were similar. No significant differences were noted with regard to symptom resolution, sexual activity, or complications rates. The authors conclude that, “Pelvicol did not provide advantages over conventional colporrhaphy in recurrent pelvic organ prolapse concerning anatomical and subjective outcomes.”
Kahn (2015) published the results of an RCT involving 201 subjects undergoing surgical treatment for stress urinary incontinence. Subjects received treatment with either tension-free vaginal tape (TVT), autologous fascial sling (AFS), or Pelvicol. The authors reported that 162 (80.6%) subjects were available for follow-up at a median follow-up of 10 years. They reported the 1 year “success rates”, defined as being completely dry or improved, as 93% in the TVT group, 90% in the AFS group and 61% in the Pelvicol group. There were no significant differences between groups at 10 years. Comparing the 1- and 10-year success rates, there were significant reductions in the TVT and AFS groups (p<0.05 for both), but not for the Pelvicol group (p=1.0). Similar results were reported with the rates of “dry” subjects at 1 and 10 years, with rates for TVT reported as being 55% and 31.7%, 48% and 50.8% for AFS, and 22% and 15.7% for Pelvicol. These rates significantly favored AFS (p<0.001 vs. Pelvicol and p=0.001 vs. TVT). The Pelvicol arm of the study was discontinued by the data monitoring group after it was clear that the Pelvicol group had significantly poorer results vs. TVT and AFS. The results of this study indicate that the use of Pelvicol for the treatment of stress urinary incontinence may present a significant risk of harm compared to other available treatments, and further investigation may be warranted.
Peri-Strips Dry
Peri-Strips Dry is a product derived from decellularized bovine pericardium and cleared through the FDA’s 510K process. At this time there are only a limited number of peer-reviewed published article addressing the use of this product. Stamou and colleagues compared the use of Peri-Strips Dry (n=96) to standard care (n=91) in staple line reinforcement during sleeve gastrectomy procedures (2011). The authors reported that the use of Peri-Strips Dry significantly reduced the incidence of staple line bleeding (p=0.012) and intra-abdominal collections (p=0.026). Leak rate was not significantly reduced.
A similar study was conducted by Shah and others (2014) involving 100 subjects undergoing sleeve gastrectomy procedures and assigned to surgery with either Peri-Strips Dry staple line reinforcement (n=51) or standard care (n=49). Subjects were followed up for 30 days post procedure. No intra- or postoperative leaks were reported in either group. Staple line bleeds were reported to occur less in the Peri-Strips group vs. controls (45.1% vs. 79.6%, p=0.0005). Overall BMI did not impact staple line bleeds (pinteraction=0.072). However, subjects with BMI < 43 were significantly more likely to have staple line bleeds compared to subjects with BMI ≥ 43 (79.3% vs. 33%, p=0.0015). Subjects in the Peri-Strips group had less severe staple line bleeding vs controls, with moderate to severe bleeding occurring in 2 Peri-Strips group subjects vs. 6 controls (p=0.0002). Peri-Strips subjects also had shorter procedure times (58.8 minutes vs. 72.8 minutes, p=0.0153) as well as fewer hemostatic clips or sutures (19.6% vs. 67.3%, p<0.0001).
The results of these underpowered studies are promising. Further data from more rigorously designed and executed studies is warranted.
Permacol
Permacol is an acellular dermal collagen product derived from porcine pericardium that has been cleared through the FDA’s 510K process. Currently, the peer-reviewed published data addressing the use of Permacol is limited. A retrospective, nonrandomized controlled study of 37 subjects undergoing congenital diaphragmatic hernia repair was reported by Mitchell (2008). Subjects received treatment with either Permacol (n=29) or synthetic Gore-Tex (n=8), with a median follow-up of 57 months for Gore-Tex and 20 months for Permacol. Overall recurrences were reported in 8 (28%) Gore-Tex subjects with a median time to recurrence of 12 months. There were no recurrences reported in the Permacol group. These results are interesting, but due to the small sample size, retrospective nature and lack of randomization, it is not possible to generalize the results to other populations.
Roman (2021) reported the results of a retrospective case-control study of 209 subjects undergoing complete excision of large rectovaginal endometriotic nodules treated with (n=167) or without Permacol (n=42) mesh. No significant differences were reported in the rate of postoperative rectovaginal fistula formation (OR, 1.6) and the authors concluded that the use of Permacol mesh may not impact the rate of rectovaginal fistula formation compared to no mesh.
Vahtsevanos (2021) reported the results of a retrospective case-control study of 73 subjects who had undergone 76 parotidectomy procedures with (n=32) and without Permacol (n=44) to evaluate the impact on the incidence of Frey’s syndrome. At a mean follow-up of 26.3 months the incidence of Frey’s syndrome was significantly lower in the Permacol group (6.7% vs. 31.8%, respectively, p=0.031). The incidence of severe Frey’s syndrome was 3.12% in the Permacol group vs. 31.82% in the control group (p=0.002). The results of this study should be confirmed in a prospective trial.
Further investigation into the clinical utility of Permacol is needed.
Phasix-ST
Phasix-ST is a synthetic mesh product composed of poly-4-hydroxybutyrate cleared through the FDA’s 510K process. At this time, the only available published study addressing its use is a retrospective case series of 50 subjects undergoing PEH repair (Abdelmoaty, 2019). Subject data was collected from a prospective database of Phasix-ST-treated subjects who had elective, first-time laparoscopic PEH repair with 1-year follow-up. PEH repair combined with fundoplication was done in 29 subjects and PEH repair, fundoplication, and Collis gastroplasty in 21 subjects. Phasix-ST mesh was used for crural reinforcement in all subjects. The authors report no intraoperative complications with the mesh placement, and a diaphragm relaxing incision was performed in 2 subjects. The mean length of hospital stay was 2.8 days, and there was no major morbidity or mortality reported. At 1 year post procedure, recurrent hernia was found in 4 subjects. No subjects with Collis gastroplasty or a relaxing incision had a recurrent hernia, no reoperations were conducted, and no mesh infection or mesh erosion was reported. These results are promising but provide only limited short-term data from a weak non-comparative trial. Further investigation into the safety and efficacy of Phasix -ST is needed.
Promogran
Promogran is an acellular dermal collagen product of bovine origin cleared through the FDA’s 510K process. The use of Promogran has been evaluated in two RCTs. The first, by Veves and others, involved 276 subjects with DFUs randomized to receive treatment with either Pomogran (n=138) or moistened gauze (control group; n=138) (2002). At 12 weeks of treatment, there was no statistically significant difference between groups with regard to complete wound closure (p=0.12), in healing for either the subgroup of subjects with wounds of less than 6 months duration (p=0.056), or the group with wounds of at least 6 months duration (p=0.83). No differences were seen in the safety measurements between groups. The other study by Vin involved 73 subjects with VSUs randomly allocated to receive either Promogran (n=37) or a non-adherent dressing (Adaptic) (n=36). Only 29 subjects completed the 12-week study period (39.7%). No intent-to-treat analysis was provided. Because of this, the data reported is not particularly useful.
Further study is required to fully assess the safety and efficacy of Promogran.
PuraPly
PuraPly is an acellular dermal collagen product composed of a purified collagen matrix of bovine origin containing polyhexamethylenebiguanide (PHMB) cleared through the FDA’s 510K process.
Lintzeris (2018) published a case series involving 8 subjects with chronic wounds with a variety of etiologies including trauma (n=1), DFUs (n=1), pressure ulcers (n=3), VSUs(n=1), surgical wounds (n=1), and calciphylaxis ulcers (n=1). PuraPly was applied once weekly after debridement. The authors reported a mean of 5.8 PuraPly applications were used. A total of 6 wounds had complete healing at an average time to closure of 10 weeks. The 3 wounds that did not completely heal demonstrated improved wound appearance with 100% granulation with an average area reduction 61.4%.
Bain (2020) published the results of a prospective cohort study involving 307 subjects with wounds with a variety of etiologies including VSUs (n=67), DFUs (n=62), pressure ulcers (n=45), surgical wounds (n=54), and other wounds (n=79) treated with PuraPly. Subjects were followed for 32 weeks. The authors reported the mean number of PuraPly applications as 5.2. Full wound closure was 52% at 20 weeks, 62% at 26 weeks, and 73% at 32 weeks. Complete wound closure for VSUs was 73%, for DFUs was 51%, for pressure ulcers 62%, for surgical wounds 96% and 67% for other wounds. No adverse events or serious adverse events attributable to PuraPly were reported.
These results are interesting but limited by their weak methodology and not generalizable to a wider population. Further investigation is needed to fully understand the clinical utility of PuraPly.
Regeneten
Regeneten is an acellular dermal collagen product of composed of bovine collagen. It has been cleared through the FDA’s 510K process.
Clinical use of the Regeneten graft has been described in several studies. The first, published by Bokor and others (2016) described a case series study of 13 subjects with intermediate- to high-grade partial thickness rotator cuff tears who were followed for 2 years. At the end of the study 10 subjects with evaluable tears had demonstrable improvement in tear appearance on MRI, with 7 completely healed. The remaining 3 subjects had continued tears, but with continued improvement. No evidence of tear progression was reported. Clinical symptoms were shown to improve significantly in overall Constant-Murley shoulder scores (p≤0.01) and Constant-Murley pain score, (p≤0.001), as well as American Shoulder and Elbow Society (ASES) total score (p≤0.001), and ASES pain score (p≤0.001). No postoperative infections and no adverse events associated with the product were reported.
Schlegel reported the results of a prospective case series study involving 33 subjects with intermediate-grade or high-grade partial-thickness tears of the supraspinatus tendon treated with Regeneten and followed for 1 year. Intermediate-grade tears were reported in 12 subjects and or high-grade tears in 21. Of these, 11 were articular, 10 were bursal, 4 were intrasubstance, and 8 were hybrid). At 12 months, a total of 8 subjects (24%) had no visible defect on MRI, 23 subjects (70%) had a decrease in tear size by at least 1 grade. Only 1 subject (3%) had a tear that remained unchanged. No tears progressed to full-thickness tears in the subjects who followed the postoperative rehabilitation protocol. No revision procedures were reported. Overall, tendon thickness increased significantly (p<0.0001) based upon MRI evidence of new tissue growth over the bursal surface of the supraspinatus tendon. The ASES pain score improved significantly at 1 year, as did the ASES shoulder function score and ASES shoulder index score (p<0.001 for all). No device-related significant adverse events were reported.
McIntyre (2019) published the results of a retrospective case series study involving data from subjects with partial- and full-thickness cuff tears treated with Regeneten reported in the REBUILD registry. The registry included 203 subjects and 173 (85%) had complete 1 year follow-up data. Overall, 90 subjects had partial-thickness tears and 83 had full-thickness tears. Of the partial tear group, 16.7% were grade I tears, 37.8% grade II, and 45.5% grade III. Of the full-thickness tears, 4.8% were small, 50.6% medium, 30.1% large, and 14.5% massive. Other surgical procedures were conducted in conjunction with the graft placement, including acromioplasty (89.0%), acromioclavicular joint resection (39.9%), capsular release (12.1%), and biceps surgery (55.6%). At 12 months, the partial-thickness group has a statistically significant improvement with regard to outcomes on the single-assessment numeric evaluation (SANE), Veterans RAND 12-Item (VR-12) physical component, ASES, and Western Ontario Rotator Cuff (WORC) measures (p<0.05 for all). For the VAS pain and ASES scores, improvement was 84% and 83%, respectively, which met or exceeded each measure’s minimal clinically important difference (MCID). In the full-thickness group, a statistically significant improvement was reported at the 12 month point on the VAS, SANE, VR12 physical component, ASES, and WORC measures (p<0.05 for all). MCIDs were met or exceeded on the VAS and ASES tools in 72% and 77% of subjects, respectively. Revision surgery for complications was required in 8 subjects (4.6%). Indications included progression of a partial thickness tear to a full thickness tear, deep vein thrombosis and adhesive capsulitis, loose mobile graft remnant in the joint, recurrent effusions, and failure to heal. In the partial thickness group, 29 subjects (32.2%) required corticosteroid injections in the postoperative period for pain control, and 9 subjects (10.8%) in the full-thickness group required injections. The majority of post-operative steroid injections administered in the study were done in 2 centers accounting for 76% of injections. Nine sites did not administer any steroid injections.
Thon (2019) reported on the results of a prospective case series study of 23 subjects with large (n=11) or massive (n=12) full-thickness rotator cuff tears treated with Regeneten. In addition to complete rotator cuff repair, subjects underwent subacromial decompression (n=19), distal clavicle excision (n=17), biceps tenodesis/tenotomy (n=12), and suprascapular nerve release (n=5). Mean time to postoperative MRI was 13 months, and final ultrasound evaluation was 24 months. Complete healing on both measurements was reported to be 96%, with 2 treatment failures. No difference was found between the two tear groups with regard to final ASES scores (p=0.69). There were no postoperative infections or adverse events associated with the device.
The results of these studies are all promising, but the weak methodology and other flaws limit the generalizability of this data to larger populations. Additional studies are warranted to better understand the clinical utility of Regeneten for rotator cuff repair surgery.
Seamguard
Seamguard is a synthetic product composed of polyglycolic acid and trimethylene carbonate cleared through the FDA’s 510K process. It has been evaluated in only a few peer-reviewed published articles. The first, by Salgado and others, was a randomized controlled trial evaluating the use of Seamguard vs. extraluminal suturing or fibrin glue for open bariatric surgical procedures (2011). Twenty subjects were assigned to each group; however, enrollment in the fibrin glue group was stopped due to serious complications, including leaks requiring surgical intervention. The authors report that no significant differences were found between the Seamguard group and the suturing group. This study was not designed or powered to be a non-inferiority study, so these findings are not particularly useful in understanding the safety and efficacy of Seamguard.
In another study by Albanopoulos and colleagues, Seamguard was compared to staple line suturing in laparoscopic sleeve gastrectomy procedures (2012). This study enrolled 90 subjects, 48 who were assigned to the Seamguard group and 42 to the suturing group. As with the Salgado study, the authors reported no significant differences in measured outcomes. One exception to this was a 6.2% complication rate in the Seamguard group vs. no complications in the suturing group.
In 2013, Wallace published the results of a nonrandomized controlled study of 36 subjects undergoing pancreatectomy with the addition of Seamguard to the stapled stump closure. This group was compared to 18 historical controls undergoing the same procedure without Seamguard. Postoperative leak rate was reported in 8% in the experimental group vs. 39% in the control group. This study is limited due to its small population, use of historical controls and other methodological issues. The available data addressing the use of Seamguard is limited to weak studies with significant methodological flaws. Further investigation with robust trials is warranted.
Guerrier and others (2018) published the results of a retrospective review of 256 subjects undergoing laparoscopic sleeve gastrectomy. Subjects received treatment with staple line reinforcement with oversewing (n=28), reinforcement with Seamguard (n=115), or no staple line reinforcement (n=111). Intraoperative staple line bleeding was significantly reduced in the reinforcement group (22.3 vs. 37.8%, p=0.003). Gastric leaks were reported in 9 subjects (3.52%), with no difference between any reinforcement method (2.7 vs 2.1%, p=0.54). The authors did note that oversewing of the staple line was associated with higher incidence of stenosis, a serious complication with significant morbidity and mortality (p<0.01). The authors concluded that their study demonstrated that staple line reinforcement does not provide significant leak reduction but does reduce intraoperative staple line bleeding. However, this must be viewed in light of increased risk of stenosis development.
Suprathel
Suprathel is a synthetic copolymer consisting mainly of DL-lactide (>70%), trimethylenecarbonate, and e-caprolactone and was cleared under the FDA’s 510k process. The available evidence addressing the use of Suprathel is limited. An RCT involving 22 subjects with burn injuries treated with split-thickness skin grafts was reported by Schwarze in 2007. Each donor site was randomly selected and was treated with Suprathel or Jelonet. There was no significant difference between the two materials tested regarding healing time and re-epithelization, but a significantly lower pain score was reported for the subjects treated with Suprathel (p=0.0002). The same group reported the results of another RCT study involving 30 subjects with burn injuries (Schwarze, 2008). Wounds from each subject were randomly selected and partly treated with Omniderm and partly treated with Suprathel. There was no significant difference between the two products regarding healing time and re-epithelization. There was a significantly lower pain score for subjects treated with Suprathel (p=0.0072).
Rashaan (2017) reported the use of Suprathel in a population of 21 children with partial thickness burns. The authors reported a median reepithelialization time of 13 days (range 7-29), and 3 subjects required treatment with split skin grafts. There were 7 (33%) subjects with wound colonization before application of Suprathel, which increased to 12 (57%) during treatment. Only 1 subject developed a wound infection.
Nischwitz (2021) published the results of a prospective case series study involving 22 subjects with chronic leg wounds treated with Suprathel and followed for 8 weeks. Out of the original subject pool, 19 subjects completed the trial. No significant difference in average wound size was reported between baseline and 4 weeks (p=0.074). The wound size changed significantly between 4 and 8 weeks (p=0.031). Overall, the average wound size between baseline and 8 weeks decreased significantly (p=0.006). One wound was reported as healed at 4 weeks (5.3%) and two at 8 weeks (15.79%). When stratified by wound age < 12 months and > 12 months, the overall wound size had a significant reduction for both old and young wounds (p=0.002 and 0.03, respectively). Similar findings were reported for both diabetic (p=0.014) and non-diabetic wounds (p=0.028). No adverse event associated to the intervention had occurred in the study period.
Overall, the evidence for the use of Suprathel is weak, consisting of weak, poorly designed trials. Additional investigation in the form of well-designed and conducted trials is needed to understand the clinical utility of this product.
SurgiMend
SurgiMend is a product made from acellular fetal bovine dermis and is cleared under the FDA’s 510k process. The available peer-reviewed published literature addressing its use in humans is limited to a few studies. The largest of these was a nonrandomized, retrospective case series reviewing a single surgeon's 5-year experience of 440 consecutive, immediate breast reconstructions in 281 subjects (Butterfield, 2013). In 222 of these subjects, reconstruction were done using SurgiMend and the other 59 used aseptic AlloDerm. The investigators reported no significant differences in complication rates between the two products in the incidence of hematoma, infection, major skin necrosis, or breast implant removal. However, the incidence of seroma was significantly more common in the AlloDerm subjects (15.7%) than in the SurgiMend group (8.3%) (p<0.05). However, this finding must be considered in light of the fact that the AlloDerm group was followed, on average, for over twice the length of time (15.6 ± 8.79 months for SurgiMend vs. 32.8 ± 15.87 for AlloDerm; p<0.0001). The SurgiMend group had a significantly higher rate of any necrosis (11.0% [39/351] for SurgiMend vs. 3.4% [3/89]; p<0.0265). In a multivariate analysis, it was found that both a BMI > 30 kg/m2 and previous radiation therapy significantly increased the rate for complications and expander loss.
A retrospective, nonrandomized comparative trial involving 120 subjects undergoing complex abdominal wall reconstruction was reported by Clemens in 2013. Subjects received either SurgiMend (n=51) or Strattice (n=69) and were followed for a mean of 21 ± 9.9 months. Postoperative surgical complication rates between groups were not statistically different. However, intraoperative complications were significantly higher in the Strattice group vs. the SurgiMend group (7 vs. 0, p=0.02), and the overall complication rate for the SurgiMend group was reported as 25.5% vs. 36.6% for the Strattice group (p=0.04). The authors concluded that the two products appear to result in similar outcomes, but Strattice may result in higher rates of device failure.
Eichler (2015) reported on a retrospective, nonrandomized comparative trial involving 127 breasts undergoing reconstruction with either SurgiMend (n=63) or EpiFlex (n=64). All procedures were conducted by a single surgeon. The authors reported that gross complication rates were 11.1% for SurgiMend and 40.6% for EpiFlex (p=0.003). Red breast syndrome was reported in 3 SurgiMend and 9 EpiFlex subjects (p=0.003). Seroma occurred in 1 SurgiMend subject and 6 EpiFlex subjects (p=0.07). Revision surgery was needed in 3 SurgiMend and 8 EpiFlex subjects (p=0.21). This study reports favorable benefits for SurgiMend over EpiFlex. However, the small subject pool, lack of blinding and randomization, and retrospective nature of the study limit the utility of these findings.
The same group published another retrospective, nonrandomized comparative trial involving 54 subjects undergoing breast reconstruction procedures with either SurgiMend (n=18) or Tutomesh (n=27) (Eichler, 2017). No difference was noted in the rate of complications, consistent with other previous reports.
Endress (2012) reported the results of a retrospective, nonrandomized case series study involving of 28 subjects who underwent 49 breast reconstructions with SurgiMend compared to 91 subjects who underwent 123 control breast reconstructions with no additional grafting materials. The mean immediate fill volume in the SurgiMend group was 181.2 ± 148.3 mL and 117.7 ± 6.3 mL in the control group (p<0.001). The results show that the duration of drainage was significantly shorter in the SurgiMend group vs. controls (8.51 ± 0.4 days vs. 11.07 ± 5.1 days; p<0.015). No significant differences in the overall complication rate were noted (20.8% in the SurgiMend group, 13.0% in the control group). The authors provided a subgroup analysis that indicates that the SurgiMend group with complications had significantly longer drain removal time (9.48 vs. 7.97 days), larger initial fill volumes (238.1 vs. 145.3 mL), and a higher BMI (25.8 vs. 22.6 kg/m2) when compared with the complication-free subgroup. Unfortunately, these findings are hampered by the small subject population of the SurgiMend group.
Mazari (2018) reported the results of a retrospective controlled study involving 82 subjects (97 breasts) comparing Strattice (n=54 breasts) and SurgiMend (n=43 breasts) for implant-based immediate breast reconstruction. No differences were noted with regard to implant loss rate (p=0.077). The ADM loss rate was significantly higher in the Strattice group vs. the SurgiMend group (n=7 vs. n=0, p=0.014). Reoperation rates were significantly higher in the Strattice group vs. the SurgiMend group (n=17 vs. n=2, p=0.002). Incidence of red breast was significantly higher in the SurgiMend group (n=9 vs. n=3, p=0.022). No differences between groups were noted with regard to seroma, wound problems, or infection rates.
A retrospective case series study involving 111 subjects (147 breasts) undergoing immediate breast reconstruction with SurgiMend was reported by Scheflan in 2018. Overall rates of minor and major complications after a median follow-up of 24.3 months, were 25.2 percent and 12.9 percent, respectively. Seroma was the most common major complication (8.2%), with necrosis (6.1 %) the second most common. The rate of capsular contracture was 2.7% and explantation occurred in 2.7%. In a univariate analysis, smokers had a greater risk of major complications (p=0.013), and postoperative radiation therapy and obesity were associated with an increased risk of capsular contracture (p=0.006) and explantation (p=0.006), respectively. Multivariate analysis identified several factors that were associated with complications or explantation, including obesity (p<0.05), preoperative chemotherapy (p<0.001), and mastectomy weight (p<0.05). However, the authors note that these associations were in agreement with the results of other ADM studies, and that they do not appear to be unique to SurgiMend.
Asaad (2021) reported the results of a prospective RCT involving 90 subjects undergoing immediate tissue expander breast reconstruction receiving either SurgiMend or sterile AlloDerm (n=45 for each group). Only 68 subjects have completed data (n=36 SurgiMend and n=32 AlloDerm). The average follow-up was 38 months with a large range of 8-62 months. Postoperative complications were reported in 14 breasts (25%) in the AlloDerm group vs. 13 breasts (27%) in the SurgiMed group (p=0.85). While infection was the most common complication no differences between groups was reported (n=8 for SurgiMend vs. n=5 AlloDerm, p=0.25). Similarly, no differences between groups were noted for other major complications (p=0.17), complications requiring reoperation (p=0.27), and tissue expander loss (p=0.14). One case of capsular contracture was diagnosed clinically 1 year following tissue expander placement in the AlloDerm group. Implant loss was identified in 4 (7%) of the AlloDerm subjects and 8 (17%) SurgiMend subjects (p=0.14). This study is promising, but the significant loss to follow-up hampers generalization of the findings.
Overall, the available evidence for SurgiMend is insufficient to adequately demonstrate the comparative efficacy of this product to the existing standard of care. Additional prospective, randomized controlled studies would be helpful in addressing this issue.
Please see the Enduragen section for additional studies involving SurgiMend.
Surgisis (also known as Biodesign)
Surgisis, also known as BioDesign, is a product composed of decellularized intestinal mucosa of porcine origin and is cleared under the FDA’s 510k process. Several forms of Surgisis/Biodesign are available, including Anal Fistula Plug (AFP), 4-Layer Tissue Graft, Dural Graft, Hernia Graft, and others. Cook Medical, the manufacturer of this product changed the name of Surgisis products to Biodesign in 2008. However, the medical literature continues to refer to these products by their former name.
At this time, there are a large number of case series studies published on the use of the Surgisis anal fistula plug (AFP) (Champagne, 2006; Cintron, 2013; Ellis, 2010; Ky, 2008; O’Connor, 2006; Schwandner, 2009; Thekkinkattil, 2009). The vast majority of these involve very small sample sizes and short follow-up times. The uncontrolled nature of these studies minimizes the scientific value of this data.
Several RCTs are currently available addressing the use of Surgisis for the treatment of anal fistulae. The first study, reported by Ortiz et al., involved 43 subjects randomized to receive either endorectal advancement flap surgery or insertion of an anal fistula plug (2009). The drop-out rate was greater than 20% for each group. The authors reported that the relative risk for recurrence was 6.4 for those who received the plug intervention during the 1-year follow-up. Additionally, of the 16 who had previous fistula surgery, 9 had recurrence and 8 of these were from the plug group. Overall, the authors concluded that the anal fistula plug was associated with a low rate of fistula healing, especially in individuals with a history of fistula surgery. The second study included 60 subjects with perianal fistulas who were randomly assigned to receive treatment with Surgisis (n=31) or a mucosal advancement flap (n=29) (van Koperen, 2011). Both subjects and investigators were blinded to group assignment. At a follow-up of 11 months, the recurrence rates were 71% (n=22) in the Surgisis group vs. 52% (n=15) in the mucosal advancement flap group, which was not significantly different. Additionally, no significant differences were reported with regard to postoperative pain, pre- and postoperative incontinence scores, soiling, and quality of life. Senéjoux (2016) reported the results of an open-label, randomized controlled trial comparing seton removal alone (n=52) vs. Surgisis (n=54) in 106 subjects with Crohn's disease and at least one ano-perineal fistula tract drained for more than 1 month. The authors reported that fistula closure at week 12 was achieved in 31.5% of subjects in the Surgisis group vs. 23.1 % in the control group (p=0.19). No interaction in treatment effect was found when data was analyzed to control for case complexity (p=0.45). Adverse events at week 12 were reported in 17 subjects in the Surgisis group vs. 8 controls (p=0.07). The authors concluded that the use of Surgisis was not more effective than seton removal alone. In 2017, Bondi and others published the results of an RCT involving 94 subjects with cryptogenic trans-sphincteric anal fistulas assigned to treatment with either Surgisis (n=48) or mucosal advancement flap (n=46). The authors reported that the recurrence rate at 12 months was 66% in the Surgisis group and 38% in the flap group (p=0.006). While anal pain was reduced after operation in both groups, anal incontinence did not change in the follow-up period for either. No differences between the groups were reported with regard to pain, incontinence, or quality of life. The authors concluded that there was a considerably higher recurrence rate after the anal fistula plug procedure than following advancement flap repair.
Several studies have reported on the results from nonrandomized controlled, retrospective trials. Ellis and colleagues described the results of a study that involved 95 control subjects who had trans-sphincteric or rectovaginal fistulas repaired via advancement flap repair (2007). The experimental group included only 18 subjects who received treatment with Surgisis. The results indicated a significant benefit to the Surgisis procedure. Another study included 80 subjects who received treatment with either anal fistula plug or endorectal advancement flap (Christoforidis, 2009). The results of this trial demonstrated that treatment success was close to over twice as likely with the flap procedure compared to treatment with a fistula plug after a mean follow-up period of 56 months. Chung and colleagues (2009) reported on the results of a retrospective study that involved 245 subjects who underwent anal fistula repair surgery with either Surgisis (n=27), fibrin glue (n=23), Seton drain (n=86), or an endorectal advancement flap procedure (n=96). The results indicate that the rate of success was similar between the Surgisis group and the endorectal advancement flap group. Hyman and others conducted a study that involved 245 subjects who received one of seven procedures, including the Surgisis plug (n=43), endorectal advancement flap (n=4), Seton drain (n=34), fibrin glue (n=5), fistulotomy (n=156), and other unspecified procedures (n=3) (2009). In contrast to the findings of the Chung study, the authors reported that the Surgisis plug demonstrated the lowest success rate, with only 32% healed at 3 months vs. 87% for the fistulotomy group. In 2014, Blom reported on a case series study involving 126 subjects with anal fistulae treated in four different hospitals. After a median of 13 months, 30 (24%) of the fistulae had closed with no discomfort or secretion reported. The outcomes in the four hospitals varied from 13% to 33% with similar numbers of subjects in each hospital. A success rate of 12% was observed for subjects with anterior fistula compared with 32% for those with posterior tracks [HR for successful healing, 2.98] and 41% for those with a lateral internal opening (HR, 3.76). The authors concluded that their study demonstrated low success rates after the first plug-insertion procedure and that anterior fistulae were much less likely to heal compared with fistulae in other locations.
Jayne (2019) reported on the results of an RCT involving 304 subjects with anal fistula treated with either Surgisis or ‘surgeon’s choice” (e.g., fistulotomy, cutting seton, advancement flap or ligation of intersphincteric fistula tract [LIFT] procedure). The authors reported clinical evidence of fistula healing in 66 subjects (54%) in the Surgisis group vs. 66 subjects (55%) in the control group at 12 months. Furthermore, MRI data showed fistula healing in 54 subjects (49%) in the Surgisis group vs. 63 subjects in the control group. Overall, 12-month clinical healing rates were 55% in the Surgisis group vs. 64%, 75%, 53%, and 42% in the cutting seton, fistulotomy, advancement flap and LIFT procedure groups, respectively. The authors commented that overall, there was no significant difference between the use of Surgisis and other procedures.
A meta-analysis was reported by Lin (2019) that included 11 studies comparing the use of Surgisis to rectal advancement flap (RAF) for anal fistula repair in 810 subjects. They reported that the pooled analysis indicated that there was no significant difference between the use of Surgisis and RAF in terms of healing rate, recurrence rate and incidence of fistula complications. However, the pooled results of the 4 RCTS and 1 series study with long-term follow-up revealed that the RAF group had a significantly higher healing rate (OR, 0.32; p=0.01) and lower recurrence rate (OR, 4.45; p=0.009) than the AFP group. These results appear to support the use of RAF over Surgisis for anal fistula repair.
Jayne (2021) published the results of an open-label RCT involving 304 subjects undergoing anal fistula repair. Subjects were assigned to treatment with either Surgisis anal fistula plug (n=152) or surgeon’s preference (advancement flap, cutting seton, fistulotomy, Ligation of the Intersphincteric Fistula Tract procedure, n=152). At 12 months, the authors reported no significant differences between groups with regard to rate of clinical healing (54% in the Surgisis group vs. 55% in the surgeon’s preference group, p=0.83). Similar findings were reported with regard to MRI-confirmed healing (49 vs. 57%, respectively, no p-value provided). Additionally, no significant differences between groups were reported at 12 months on the St. Mark’s incontinence score (p=0.48), complication rate (23% vs. 20%, p=0.6), or rate of reintervention (23%. vs. 22%, p=0.96). These results indicate that the use of Surgisis is equivalent to other surgical approaches to anal fistula repair.
Due to the conflicting evidence discussed above, further data is needed in the form of large, well-done, double-blind RCTs in order to properly understand the efficacy of Surgisis for the treatment of anal fistulas.
Unlike the anal fistula plug product discussed above, Surgisis Gold is provided in larger sheets. Sarr and others (2014) conducted an RCT involving 380 subjects with body mass index (BMI) ≥ 35 kg/m2 scheduled to undergo open Roux-en-Y gastric bypass surgery. Participants were randomized to receive standard suture closure alone or Surgisis Gold as a reinforcing adjunct. The authors reported that complications were more common in the Surgisis Gold group with significantly more wound events and seroma formation compared with the suture closure alone group. At final follow-up of 2 years post-procedure, 32 of 185 (17%) subjects in the Surgisis Gold group and 38 of 195 (20%) in the control group developed an incisional hernia (p=0.6). Based on these findings, it would seem that the use of Surgisis Gold is not warranted, and further investigation is needed regarding the safety and efficacy of this product.
Korwar (2019) retrospectively reported the treatment of PEH in 154 consecutive subjects who underwent standardized laparoscopic suture repair of the hiatus with Surgisis reinforcement. Follow-up barium swallow was performed in 122 subjects (79.22%). Symptomatic recurrence was noted in 25 subjects (28.73%), and recurrence on barium swallow was noted in 25 subjects (20.4%). Both symptomatic and barium swallow recurrence were reported in 10 subjects (12.98%). The reoperation rate was 3.25%. The authors concluded that use of Surgisis Biodesign for PEH repair is safe. They further commented that there was a high recurrence rate in long-term follow-up, but that the majority of recurrences are small, asymptomatic, and the reoperation rate is very low.
Surgisis Biodesign was also described in the repair of pelvic floor reconstruction following levator abdominoperitoneal excision of the rectum (Thomas, 2019). This retrospective case series study involved 100 subjects, for whom 1-, 2-, and 5-year mortality rates were 3, 8 and 12%, respectively. The authors reported that 33 perineal wounds had not healed by 1 month, but no mesh was infected, and no mesh needed to be removed. Only 1 subject developed a symptomatic perineal hernia requiring repair. On review of imaging, an additional 7 asymptomatic perineal hernias were detected. At 4 years the cumulative radiologically detected perineal hernia rate was 8%.
Ravo (2019) described the results of a trial of 104 subjects with inguinal hernia repair with a continuous suture of transversalis to transversalis fascia repair reinforced with Surgisis. Long term follow-up was scheduled at 1 week, 1 month, 1 year, 3 years, 7 years, and 10 years, and was achieved in 100%, 100%, 99%, 93%, 89% and 85% of the subjects, respectively. The authors reported a recurrence rate of 1.9% (2 subjects, one at 1 week in a subject with bilateral IH and one at 7 years). The mean recovery time was 1.2 days (range 1-5 days). Mortality was 0(0%).
In 2021 Alexandridis and others reported the results of a retrospective case series involving 155 subjects with pelvic organ prolapse treated with Surgisis. A total of 138 (89.0%) subjects completed the 3-month clinical visit, with 12 of the 17 subjects not seen being contacted by telephone and included in the analysis of complications. At 3 months, 22 subjects (15.9%) had Pelvic Organ Prolapse Qualification system (POP0Q) stage ≥ 2. The overall recurrence rate for Surgisis-treated defects was 11.6%. Reoperations were reported in 13 (8.4%) subjects due to prolapse. Additionally, 7 subjects experienced prolapse-related symptoms postoperatively, but had no record of reoperation. This data represents a subjective failure rate of 12.9%. Perioperative and postoperative complications occurred in 56% of subjects. The most common complications were urinary (n=28) and pain (n=18). Major complications were reported in 8 subjects (5.3%). Persistent complications at 3 months were reported in 28% of subjects, including vaginal deformations, dyspareunia, stress urinary incontinence, urge urinary incontinence, and pain. Statistical analysis for recurrence identified a significant effect only for previous prolapse surgery at the same compartment as the Surgisis application (p=0.028). Other significant predictors for complications included lower age (p=0.034), smoking (p=0.022) and longer duration of surgery (p=0.003). The authors concluded, “The relatively high recurrence rates do not suggest a clear benefit from SIS graft use.”
Additional evidence is needed from larger, well-designed trials to fully understand the safety and efficacy of Surgisis/Biodesign for conditions other than anal fistulas.
Talymed
Talymed is a synthetic product composed of poly-N-acetyl glucosamine (pGIcNAc) isolated from microalgae and is cleared under the FDA’s 510k process. At this time, only a single RCT is available addressing the use of Talymed (Kelechi, 2011). In this reviewer-blinded trial, 82 subjects with VSUs were randomized to receive either standard care (n=20) or to 1 of 3 groups that received standard treatment combined with different treatment frequencies with Talymed: (1) applied only once, (2) applied once every other week, or (3) applied once every third week. Seven subjects were lost to follow-up, 5 from the 1 application group and 2 from the every 3-week group. Additionally, another 4 subjects were withdrawn from the study, 3 from the 1 application group and 1 from the every 3 weeks group. This left 62 subjects in the experimental group and 20 in the control group. At 20 weeks, the authors report that 45.0% (n=9 of 20) of subjects receiving standard care alone had complete healing, while 45.0% (n=9 of 20), 86.4% (n=19 of 22), and 65.0% (n=13 of 20) of subjects receiving Talymed only once, every other week, and every 3 weeks, respectively, had complete healing. This single study is insufficient to allow proper evaluation of the safety and efficacy of Talymed.
Tutomesh
Tutomesh is a product composed of decellularized bovine pericardium and is cleared under the FDA’s 510k process. The literature addressing this product is sparse at this time. A retrospective review with 41 subjects who underwent 52 breast reconstructions using ADMs was reported by Paprottka (2017). Subjects received treatment with either EpiFlex (not available in the US, n=15), Strattice (n=21), or Tutomesh (n=16). Follow-up was 36 months (range 12-54). Overall complication rate was 17%, and 7% for the EpiFlex group, 14% for the Strattice group, and 31% for the Tutomesh group. Capsular contracture occurred in 6%, more frequently in this study compared to the current literature. The authors recommended the use of human derived grafting materials (EpiFlex) over those from porcine of bovine sources.
Eichler (2017) published a retrospective, nonrandomized comparative trial involving 54 subjects undergoing breast reconstruction procedures using either SurgiMend (n=18) or Tutomesh (n=27) (Eichler, 2017). No difference in complications rates was noted, consistent with other previous reports.
Additional investigation into the safety and efficacy of this product is needed.
Vascu-Guard
Vascu-Guard is a decellularized product derived from bovine pericardium cleared under the FDA’s 510k process. . Please see the section for Gore® Acuseal Cardiovascular Patch above.
VIA Disc NP
VIA Disc is a processed human nucleus pulposus tissue allograft treated as human tissue for transplantation under the FDA’s HCT/P process.
The currently available published literature addresing this product is limited. Beall (2021) reported the results of the VAST RCT involving 218 subjects with single- or two-level degenerative disc disease assigned to treatment with either saline injection (n=39), conservative care (n=39), or VIA Disc (n=140). A total of 36 subjects (17%) were lost to follow-up or had withdrawn from the study by the 12 month follow-up point (n=7 [18%] saline group, n=12 [30%] conservative group, and n=17 [12%] VIA Disc group), leaving 182 subjects completing the trial. There were 58 subjects treated at least one intravertebral level outside of the predefined levels of degeneration for inclusion. Younger subjects were reported to have had a more favorable outcome vs. older subjects in regard to improvement in Oswestry Disability Index (ODI) for subjects less than the median age (32 years old, p=0.004). Clinically meaningful improvements were observed in the VIA Disc group, with a mean reduction in ODI of 27 at 12 months (no p-value provided). ODI-based function was noted to have worsened in the conservative care group during the first 3 months and all subjects in this group crossed over to the VIA Disc group in an unblinded fashion. Results for both VIA Disc groups were similar at 12 months. Mean pain reduction as represented by change in Visual Analog Scale of Pain Intensity (VASPI) at 12 months was reported to be 30.5, 34.0, and 46.7 for the saline, VIA Disc, and conservative/crossover groups, respectively. Mean functional improvement per ODI was 23.9, 27.4, and 36.5 respectively (no p-values provided). No differences between subjects treated at a single vs. two levels was noted. A modified intention-to-treat analysis indicated significant differences between the VIA Disc vs. saline groups, with a ≥ 15-point reduction in ODI measures (p=0.030). No significant differences were found between groups with regard to number of subjects achieving a 50% reduction in pain at 12 months (p=0.467). In an ad hoc analysis of responders in all groups, subjects in the VIA Disc and conservative/crossover groups achieved a statistically significant reduction in pain vs. saline group subjects (p=0.022). There were 66 (29.8%) total adverse events in the VIA Disc group vs. 5 (13.2%) in the saline group (no p-value provided). Twenty-three potentially VIA Disc-related events were reported, vs. none in the saline or conservative treatment only groups. The conservative/crossover group experienced 7 VIA Disc-related events (8.6% of subjects in the crossover group). Most events in the VIA Disc group were musculoskeletal and connective tissue related, with 41 total events (22.0%) and 14 VIA DISC-related events (9.2%). The most common event was pain. In the saline group no adverse events were reported, while the conservative/crossover group reported back pain as a related event in 2.9% of subjects.
A total of 11 serious adverse events were reported in the VIA Disc group (3.5%), with 6 considered possibly related to the treatment and/or procedure. Reported events included pain, back pain, bacteremia, and osteomyelitis. No serious events were reported in the saline group or conservative treatment only groups. One serious adverse event (2.6%) was reported in the conservative/crossover group (p=0.832). The 1 SAE in the crossover group was considered not related to treatment or procedure. The results of this trial indicate some potential benefit to the use of VIA Disc, but several methodological flaws limit the generalizability of this trial, including significant loss to follow-up, cross over of a large percentage of the control group to active treatment, loss of blinding, and others.
Hunter and colleagues (2021) published the results of a post hoc analysis of the VAST trial data exploring it stratified by age. They reported that subjects younger than 42 years of age experienced significantly more improvement from treatment with VIS Disc than those older than 42 when compared to those in the saline treatment group. Furthermore, they noted that in subjects older than 42 years of age, no differences between groups were seen with regard to functional benefit. As noted above, the VAST trial has several significant methodological flaws and additional investigation is warranted to assess the clinical utility of VIA Disc.
Veritas
Veritas is a decellularized product derived from bovine pericardium cleared under the FDA’s 510k process. The available evidence addressing Veritas is currently limited to a single RCT of 94 subjects assigned to treatment with either anterior colporrhaphy alone vs. colporrhaphy reinforced with Veritas bovine pericardium graft (Guerette, 2009). This study had significant loss to follow-up, with only 72 of 94 (76.6%) subjects at the 1-year time point and 59 of 92 (64.1%) at the completion of the study at 2 years. The authors report no significant differences between groups.
Quah (2019) published the results of a retrospective, non-randomized controlled trial involving 215 subjects undergoing mastectomy and implant-based reconstruction procedures with either Veritas (n=36) or TiLOOP® Bra (n=179), a product not currently approved for use in the U.S. In the Veritas group, 22 subjects underwent unilateral procedures and 7 underwent bilateral procedures. In the TiLOOP group 61 subjects underwent unilateral procedures and 59 subjects underwent bilateral procedures. The authors reported that the Veritas group had a higher rate of postoperative complications when compared with the TiLOOP group (54% vs. 14%, respectively; p<0.01%). This included higher rates seroma (51.4% vs. 1.7%, p<0.01), nonintegration of mesh (51.4% vs. 1.6%, p<0.01), implant rotation (16.2% vs. 1.6%, p<0.01), infection (18.9% vs. 2.1%, p<0.01), and wound breakdown (10.8% vs. 0.5%, p<0.01). Additionally, when compared to the TiLOOP group, the Veritas group also had a higher rate of major interventions (35.1% vs. 7.8%, p<0.01), minor interventions (18.9% vs. 2.2%, p<0.01), implant loss (8.1 vs. 1.7%, p=0.05), and unplanned return to theater (27% vs. 6.1%, p<0.01). The results of this trial indicate that Veritas, at least when compared to TiLOOP Bra, results in significantly poorer outcomes.
Additional investigation into the clinical utility of Veritas is warranted.
Xelma
Xelma consists of amelogenin proteins purified from porcine teeth, propylene glycol alginate (PGA), and water. It has not yet received marketing approval or clearance by the FDA. Amelogenin is a cell adhesion protein, and when suspended in a gelatinous matrix has been proposed to promote cellular growth. The use of Xelma was reported in a single-blind randomized trial involving 123 subjects with VSUs (Vowden, 2006). Subjects were assigned to receive treatment with either Xelma plus compression therapy (n=62) vs. a mixture of PGA and water plus compression therapy (n=61) and were followed for 12 weeks. The authors of this study state that Xelma outperformed the control group in multiple factors, including percentage of wound size reduction. However, no statistical analysis is presented to support these claims. No data on complication rates was provided. Further investigation into the clinical safety and efficacy is warranted.
Recommendations from Authoritative Organizations
In 2020 the American Academy of Ophthalmology published a report titled Bioengineered Acellular Dermal Matrix Spacer Grafts for Lower Eyelid Retraction Repair. In this document they reviewed the available literature and provided recommendations for the use of such products. They observed that there is no level I evidence available on this issue, and that the existing level II and level III studies have variable primary end points, study design limitations, and only short-term follow-up. Their conclusions included “…the materials used may fill an important gap in care for patients for whom no acceptable alternatives exist, but long-term safety and efficacy remain unknown.”
| Background/Overview |
Regulatory Processes for Grafting Materials
Soft tissue grafting materials find their way to U.S. market through several regulatory pathways. Oversight for all these pathways is provided by the U.S Food and Drug Administration (FDA).
The first and most rigorous regulatory path is the Premarket Approval (PMA) Process, which is detailed in the Code of Federal Regulations Title 21 Part 860. Devices required to undergo this process are those deemed to present the most risk of harm to the public. The PMA process involves several steps of pre-clinical and clinical trials (Phase 0 through III). Each step is reviewed by the FDA to evaluate safety and efficacy data. If the FDA finds the data presented acceptable, a larger and more robust study is authorized until Phase III trials have been completed. Devices which pass Phase III are deemed “Approved” by the FDA and may be marketed in the U.S. This path was used in only a small minority of products addressed in this document. More information regarding the PMA process can be found at: https://www.fda.gov/medical-devices/premarket-submissions/premarket-approval-pma.
The “510K” process, also referred to as the Premarket Notification (PMN) process, is named after Section 510(k) of the Food, Drug and Cosmetic Act. This section of the Act requires manufacturers of devices that qualify to notify the FDA of their intent to market a medical device at least 90 days in advance. This law applies to any device that: (1) is not required to undergo review under another pathway, (2) was not already in commercial distribution prior to May 28, 1976, and (3) is to be introduced into commercial distribution for the first time or reintroduced in a significantly changed or modified form that alters its safety or effectiveness. The regulations stipulate that devices applying for 510K clearance must demonstrate that they are substantially equivalent to a device with prior PMA approval or marketed prior to May 28, 1976. No significant new data addressing safety or efficacy is required during this process. Devices with this type of review may or may not have undergone rigorous clinical testing to establish the presence or absence of these attributes. Devices passing through this pathway are referred to as “cleared.” More information regarding the 510K process can be found at: https://www.fda.gov/medical-devices/premarket-submissions/premarket-notification-510k.
A Humanitarian Device Exemption (HDE) is a regulatory path similar to a PMA but is exempt from the effectiveness requirements of sections 514 and 515 of the Code of Federal Regulations Title 21 Part 860, which details the PMA process. A device approved under an HDE is referred to as Humanitarian Use Device (HUD). An HUD is defined as a “medical device intended to benefit patients in the treatment or diagnosis of a disease or condition that affects or is manifested in fewer than 4,000 individuals in the United States per year.” The HDE process is intended to facilitate the development of devices that could benefit individuals with rare conditions for whom medical devices are unlikely to be developed through the PMA process. Devices covered under this regulation are exempt from many of the PMA requirements, but have certain restrictions placed on their use outside the investigational setting. More information regarding the HDE process can be found at: https://www.fda.gov/medical-devices/device-approvals-denials-and-clearances/hde-approvals.
There is a specific pathway available for biological tissue derived from human sources deemed as “minimally manipulated.” The FDA Regulation of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/P) is addressed in the Code of Federal Regulations Title 21, volume 8, Part 1271 “Human Cells, Tissues, And Cellular and Tissue-Based Products.” These regulations detail the use of human autologous and allographic tissues for transplantation. They specify that “minimally manipulated” tissues undergo proper safeguards to prevent infection or other safety hazards. It should be made clear that products that reach the market through the HCT/P process do NOT require any testing to prove clinical safety or efficacy. Thus, their performance when used in the treatment of human subjects may or may not have been tested in clinical trials. Human-derived tissues that are deemed to have been more than minimally manipulated are required to undergo one of the other regulatory pathways described above. HCT/Ps are regulated under 21 CFR 1271.3(d)(1) and Section 361 of the PHS Act, which can be found at: http://www.fda.gov/BiologicsBloodVaccines/TissueTissueProducts/RegulationofTissues/ucm150485.htm.
In the vast majority of cases, soft tissue grafting products are considered devices by the FDA. However, in some rare cases, based upon the composition, preparation, and method of delivery, some products may be considered drugs and reviewed under the FDA’s drug regulatory process. Only one product addressed in this document has been so treated and is designated an Orphan Drug. This designation for drugs is similar to the HDE designation for devices. The Code of Federal Regulations Title 21, Part 316 details the “Orphan Drug” process and defines an Orphan Drug as a drug intended for use in a rare disease or condition as outlined in section 526 of the Act. As with HDEs, the Orphan Drug designation is intended to facilitate the development of drugs that could benefit individuals with rare conditions for whom drugs are unlikely to be developed through other regulatory processes. More information regarding the Orphan Drug designation can be found at: http://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/HowtoapplyforOrphanProductDesignation/default.htm.
Skin Wound Care
The skin is the largest organ of the body. It is composed of two layers, the epidermis, and the dermis, and provides functions critical to survival. The skin acts as a protective barrier to fluid losses and dehydration and it protects against infection and injury by providing a barrier to repel bacteria and other organisms. The skin provides sensory contact with our environment that tells us whether we are feeling light touch, pressure, pain, heat, or cold. Damage to the skin that is extensive or prolonged may interfere with these functions or with those of other body systems and may become life-threatening in some circumstances.
The treatment of burns and other wounds that have failed to heal despite conservative measures, referred to as chronic wounds, creates a significant burden on the population in terms of pain, disability, and decreased quality of life. Chronic wounds may be due to the effects of diabetes, venous insufficiency to the extremities, pressure due to prolonged periods in the same body position, and other types of skin injuries. They can be difficult to treat and may require treatment with various coverings, such as skin grafts or other materials to prevent infection, maintain an environment conducive to healing, or provide a medium for re-growth of new skin. Such coverings come in a wide array of types including synthetic materials, tissues from the individuals themselves (autologous), human donors (allogeneic), or from animals such as cows and pigs (xenographic), or any combination of these materials (composites).
Surgical Reinforcement Procedures
In a wide variety of surgical procedures, there may be a need for additional reinforcement of soft tissues to strengthen the structures being repaired, such as in abdominal wall repair or orthopedic reconstruction procedures. Traditionally this task is undertaken with the use of allogeneic cadaver-derived grafts or synthetic materials such as polypropylene and Gore-Tex®. However, in some cases such materials may not be appropriate, and other materials have been sought.
In other circumstances, the use of grafting materials has been suggested as substitute for surgery.
Product types:
Synthetic Products
Synthetic treatments include various forms of skin-like coverings, barriers, and devices to augment cartilage and other connective tissues. This category includes wound dressings, silicone/nylon membranes and material to augment or replace cartilage, tendons, and ligaments.
Completely synthetic wound dressings and other grafting products (e.g., Biobrane) are composed of man-made materials to form a covering for wounds. This type of product may consist of a wide array of materials including silicone, nylon, polypropylene, and polyester.
Allogeneic Products
There are currently several different types of allogeneic (human-derived) wound care products available. One type involves the use of donated human cadaver skin which is then treated with various methods to remove the cellular material and deactivate or kill pathogens (e.g., AlloDerm, GraftJacket, and Neoform Dermis). This process leaves only the collagen protein scaffold, which has been proposed as an acceptable medium for which new skin cells from the individual can populate and grow into when placed over a wound site.
Another type of allogeneic product includes composite products that may contain human skin cells, keratinocytes and/or fibroblasts (depending upon the product), which are imbedded into a decellularized collagen protein scaffold derived from a xenographic source (e.g., Apligraf, OrCel). Some of these products may also consist of layers of synthetic materials like silicone, nylon, or polyglactin (e.g., Dermagraft).
Xenographic and Xenographic-Related or Derived Products
Many wound care and reconstructive products are made from materials derived from various animal sources including cow, horse, and pig tissues. Most of these products are created by harvesting living tissues (e.g., skin, intestines, tendons, etc.) from a donor animal, which are then processed to remove the cellular content and leave only the collagen protein scaffold. As with such allogeneic products, this scaffold is intended to act as a welcoming environment into which new autologous cells (e.g., skin, tendon, and cartilage) may grow. Most xenographic products are composed of the decellularized collagen scaffold alone (e.g., Collamend, Cuffpatch, Mediskin, Oasis, OrthoADAPT, Pelvicol, Pelvisoft, PriMatrix, Surgisis, Unite).
Xenographic materials have been proposed for many applications including reconstruction procedures of the breast, pelvic floor, abdominal wall, tendons, and others. These products are sewn onto the soft tissues where they are needed to provide support and strengthen the underlying structures. This occurs by the xenograft acting as a bed for new growth of autologous tissue.
Another type of product is a substance made by or derived from xenographic sources. One such product is honey, which has been proposed as a topical treatment for a wide variety of skin conditions.
Composite Products
Composite products are created from a variety of materials of combined origins. Such products usually combine a allogeneic or xenographic collagen-based product with a synthetic one (for example, Avaulta Plus, Integra Matrix, and Integra Bilayer Matrix). Additionally, the development of advanced in vitro culturing techniques has allowed the development of new products which combine human dermal cellular materials with those derived from animals (e.g., Epicel). These products involve the harvesting of human epidermal cells (either from the individual being treated or from donor tissue) which are then cultured with animal cells to produce sheets of biosynthetic skin which have been proposed for use in treating human skin conditions.
Bioengineered autologous skin-derived products
Bioengineered autologous skin-derived products (for example, MyOwn Skin, SkinTE) involve the harvesting of skin from an individual, which is then processed in a lab where it is altered in a manner that has been proposed to enhance it as a healing vector for wounds.
| Definitions |
Bullous keratopathy: A condition where small fluid-filled vesicles, or bullae, form within the cornea.
Conjunctiva: A clear, thin membrane that covers part of the front of the eye and lines the inside of the eyelids.
Corneal melt: Keratolysis, or sterile melting of the cornea, is a condition characterized by a progressing thinning of the cornea, leading to perforation.
Epidermolysis bullosa (EB): A disease characterized by the presence of extremely fragile skin and recurrent blister formation, resulting from minor mechanical friction or trauma.
Equine-derived decellularized collagen products (e.g., OrthADAPT and Unite): This is a type of product derived from purified tissues which are derived from horses. It has been proposed that this type of technology may be used for the repair and reinforcement of soft tissues such as tendons and ligaments, as well as the treatment of skin wounds.
Frey’s Syndrome: A condition occurring in some individuals after removal of the parotid salivary gland, in which nerve damage results in flushing and sweating on one side of the face when certain foods are consumed.
Limbal stem cell deficiency: A condition characterized by decreasing function of the stem cells within the epithelial layer of the cornea.
Neurotrophic keratitis: A degenerative disease of the eye due to a loss of corneal sensation leading to progressive damage to the top layer of the cornea.
Penetrating keratoplasty: A surgical procedure that is conducted during corneal transplantation.
Pterygium: A growth involving the conjunctiva of the eye that appears as a growth or bump on the side of the eye near the nose.
Stevens-Johnson syndrome: Also known as toxic epidermal necrolysis, is a rare, serious disorder of the skin and mucous membranes that is characterized by painful rash in its mild form and severe blisters and skin peeling in its more advanced form.
Wound infection: A wound with at least some clinical signs and symptoms of infections such as increased exudates, odor, redness, swelling, heat, pain, tenderness to touch, and purulent discharge; quantitative culture is not required.
| Coding |
The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.
Application of amniotic membrane-derived grafts or wound coverings for ophthalmologic conditions:
When services are Medically Necessary:
| CPT |
|
| 65778 | Placement of amniotic membrane on the ocular surface; without sutures |
| 65779 | Placement of amniotic membrane on the ocular surface; single layer, sutured |
| 65780 | Ocular surface reconstruction; amniotic membrane transplantation, multiple layers |
|
|
|
| HCPCS |
|
| V2790 | Amniotic membrane for surgical reconstruction, per procedure [vision services] |
|
|
|
| ICD-10 Diagnosis |
|
| C69.00-C69.02 | Malignant neoplasm of conjunctiva |
| C69.10-C69.12 | Malignant neoplasm of cornea |
| H11.001-H11.069 | Pterygium of eye |
| H16.001-H16.079 | Corneal ulcer |
| H16.231-H16.239 | Neurotrophic keratoconjunctivitis |
| H18.10-H18.13 | Bullous keratopathy |
| H18.40-H18.599 | Corneal degeneration, hereditary corneal dystrophies |
| H18.831-H18.839 | Recurrent erosion of cornea |
| H59.091-H59.099 | Other disorders of the eye following cataract surgery |
| L51.1 | Stevens-Johnson syndrome |
| T26.10XA-T26.12XS | Burn of cornea and conjunctival sac |
| T26.60XA-T26.62XS | Corrosion of cornea and conjunctival sac |
When services are Not Medically Necessary:
For the procedure codes listed above for all other diagnoses not listed.
Application of skin substitutes and soft tissue grafts:
When services may be Medically Necessary when product criteria are met:
| CPT |
|
| 15150 | Tissue cultured skin autograft, trunk, arms, legs; first 25 sq cm or less |
| 15151 | Tissue cultured skin autograft, trunk, arms, legs; additional 1 sq cm to 75 sq cm |
| 15152 | Tissue cultured skin autograft, trunk, arms, legs; each additional 100 sq cm, or each additional 1% of body area of infants and children, or part thereof |
| 15155 | Tissue cultured skin autograft, face, scalp, eyelids, mouth, neck, ears, orbits, genitalia, hands, feet, and/or multiple digits; first 25 sq cm or less |
| 15156 | Tissue cultured skin autograft, face, scalp, eyelids, mouth, neck, ears, orbits, genitalia, hands, feet, and/or multiple digits; additional 1 sq cm to 75 sq cm |
| 15157 | Tissue cultured skin autograft, face, scalp, eyelids, mouth, neck, ears, orbits, genitalia, hands, feet, and/or multiple digits; each additional 100 sq cm, or each additional 1% of body area of infants and children, or part thereof |
| 15271 | Application of skin substitute graft to trunk, arms, legs, total wound surface area up to 100 sq cm; first 25 sq cm or less wound surface area |
| 15272 | Application of skin substitute graft to trunk, arms, legs, total wound surface area up to 100 sq cm; each additional 25 sq cm wound surface area, or part thereof |
| 15273 | Application of skin substitute graft to trunk, arms, legs, total wound surface area greater than or equal to 100 sq cm; first 100 sq cm wound surface area, or 1% of body area of infants and children |
| 15274 | Application of skin substitute graft to trunk, arms, legs, total wound surface area greater than or equal to 100 sq cm; each additional 100 sq cm wound surface area, or part thereof, or each additional 1% of body area of infants and children, or part thereof |
| 15275 | Application of skin substitute graft to face, scalp, eyelids, mouth, neck, ears, orbits, genitalia, hands, feet, and/or multiple digits, total wound surface area up to 100 sq cm; first 25 sq cm or less wound surface area |
| 15276 | Application of skin substitute graft to face, scalp, eyelids, mouth, neck, ears, orbits, genitalia, hands, feet, and/or multiple digits, total wound surface area up to 100 sq cm; each additional 25 sq cm wound surface area, or part thereof |
| 15277 | Application of skin substitute graft to face, scalp, eyelids, mouth, neck, ears, orbits, genitalia, hands, feet, and/or multiple digits, total wound surface area greater than or equal to 100 sq cm; first 100 sq cm wound surface area, or 1% of body area of infants and children |
| 15278 | Application of skin substitute graft to face, scalp, eyelids, mouth, neck, ears, orbits, genitalia, hands, feet, and/or multiple digits, total wound surface area greater than or equal to 100 sq cm; each additional 100 sq cm wound surface area, or part thereof, or each additional 1% of body area of infants and children, or part thereof |
| 15777 | Implantation of biologic implant (eg, acellular dermal matrix) for soft tissue reinforcement (ie, breast, trunk) |
| 17999 | Unlisted procedure, skin, mucous membrane and subcutaneous tissue [when specified as implantation of biologic implants for soft tissue reinforcement in tissues other than breast and trunk] |
|
|
|
| HCPCS |
|
| C5271 | Application of low cost skin substitute graft to trunk, arms, legs, total wound surface area up to 100 sq cm; first 25 sq cm or less wound surface area |
| C5272 | Application of low cost skin substitute graft to trunk, arms, legs, total wound surface area up to 100 sq cm; each additional 25 sq cm wound surface area, or part thereof |
| C5273 | Application of low cost skin substitute graft to trunk, arms, legs, total wound surface area greater than or equal to 100 sq cm; first 100 sq cm wound surface area, or 1% of body area of infants and children |
| C5274 | Application of low cost skin substitute graft to trunk, arms, legs, total wound surface area greater than or equal to 100 sq cm; each additional 100 sq cm wound surface area, or part thereof, or each additional 1% of body area of infants and children, or part thereof |
| C5275 | Application of low cost skin substitute graft to face, scalp, eyelids, mouth, neck, ears, orbits, genitalia, hands, feet, and/or multiple digits, total wound surface area up to 100 sq cm; first 25 sq cm or less wound surface area |
| C5276 | Application of low cost skin substitute graft to face, scalp, eyelids, mouth, neck, ears, orbits, genitalia, hands, feet, and/or multiple digits, total wound surface area up to 100 sq cm; each additional 25 sq cm wound surface area, or part thereof |
| C5277 | Application of low cost skin substitute graft to face, scalp, eyelids, mouth, neck, ears, orbits, genitalia, hands, feet, and/or multiple digits, total wound surface area greater than or equal to 100 sq cm; first 100 sq cm wound surface area, or 1% of body area of infants and children |
| C5278 | Application of low cost skin substitute graft to face, scalp, eyelids, mouth, neck, ears, orbits, genitalia, hands, feet, and/or multiple digits, total wound surface area greater than or equal to 100 sq cm; each additional 100 sq cm wound surface area, or part thereof, or each additional 1% of body area of infants and children, or part thereof |
|
|
|
| ICD-10 Diagnosis |
|
|
| All diagnoses |
When services are Not Medically Necessary:
For the procedure codes listed above when product criteria are not met.
When services are Investigational and Not Medically Necessary:
For the procedure codes listed above when the code describes application of a product indicated in the Position Statement section as investigational and not medically necessary.
When Services are also Investigational and Not Medically Necessary:
| CPT |
|
| 31574 | Laryngoscopy, flexible; with injection(s) for augmentation (eg, percutaneous, transoral), unilateral [when specified as using a skin/tissue substitute such as Cymetra] |
| 46707 | Repair of anorectal fistula with plug (eg, porcine small intestine submucosa [SIS]) |
| 0627T | Percutaneous injection of allogeneic cellular and/or tissue-based product, intervertebral disc, unilateral or bilateral injection, with fluoroscopic guidance, lumbar; first level [VAST, Via Disc] |
| 0628T | Percutaneous injection of allogeneic cellular and/or tissue-based product, intervertebral disc, unilateral or bilateral injection, with fluoroscopic guidance, lumbar; each additional level [VAST, Via Disc] |
| 0629T | Percutaneous injection of allogeneic cellular and/or tissue-based product, intervertebral disc, unilateral or bilateral injection, with CT guidance, lumbar; first level [VAST, Via Disc] |
| 0630T | Percutaneous injection of allogeneic cellular and/or tissue-based product, intervertebral disc, unilateral or bilateral injection, with CT guidance, lumbar; each additional level [VAST, Via Disc] |
|
|
|
| ICD-10 Diagnosis |
|
|
| All diagnoses |
Products
When services may be Medically Necessary when criteria are met [for AmnioBand, Apligraf, EpiCord, EpiFix (sheet or membrane form), Grafix PRIME, GraftJacket, mVASC, Oasis, OrCel, PriMatrix and Dermagraft]:
| HCPCS |
|
| A4100 | Skin substitute, FDA cleared as a device, not otherwise specified [when specified as OrCel for epidermolysis bullosa only; or when specified as mVASC for diabetic foot ulcers only] |
| C9399 | Unclassified drugs or biologicals [when specified as OrCel for epidermolysis bullosa only; or when specified as mVASC for diabetic foot ulcers only] |
| Q4100 | Skin substitute, not otherwise classified [when specified as OrCel for epidermolysis bullosa only; or when specified as mVASC for diabetic foot ulcers only] |
| Q4101 | Apligraf, per square centimeter |
| Q4102 | Oasis Wound Matrix, per square centimeter |
| Q4106 | Dermagraft, per square centimeter [for diabetic foot ulcers and epidermolysis bullosa only] |
| Q4107 | GraftJacket, per square centimeter |
| Q4110 | PriMatrix, per square centimeter |
| Q4124 | Oasis Ultra Tri-Layer Wound Matrix, per square centimeter |
| Q4133 | Grafix PRIME, GrafixPL PRIME, Stravix and StravixPL, per square centimeter [when specified as Grafix PRIME, for diabetic foot ulcers only] |
| Q4151 | AmnioBand or Guardian, per sq cm [for diabetic foot ulcers only]] |
| Q4186 | EpiFix, per square centimeter |
| Q4187 | EpiCord, per square centimeter [for diabetic foot ulcers only] |
|
|
|
| ICD-10 Diagnosis |
|
| E08.00-E13.9 | Diabetes mellitus |
| I83.001-I83.029 | Varicose veins of lower extremities with ulcer |
| I83.201-I83.229 | Varicose veins of lower extremities with both ulcer and inflammation |
| I87.011-I87.019 | Postthrombotic syndrome with ulcer |
| I87.031-I87.039 | Postthrombotic syndrome with ulcer and inflammation |
| I87.2 | Venous insufficiency (chronic) (peripheral) |
| I87.311-I87.319 | Chronic venous hypertension (idiopathic) with ulcer |
| I87.331-I87.339 | Chronic venous hypertension (idiopathic) with ulcer and inflammation |
| L12.30-L12.35 | Acquired epidermolysis bullosa [Dermagraft, OrCel] |
| L97.101-L97.929 | Non-pressure chronic ulcer of lower limb, not elsewhere classified |
| L98.411-L98.499 | Non-pressure chronic ulcer of skin, not elsewhere classified |
| Q81.0-Q81.9 | Epidermolysis bullosa [Dermagraft, OrCel] |
When services may be Medically Necessary when criteria are met [for AlloDerm Regenerative Tissue Matrix (aseptic or sterile), DermACELL, DermaMatrix, FlexHD, Strattice]:
| HCPCS |
|
| C9399 | Unclassified drugs or biologicals [when specified as DermaMatrix for breast reconstruction only] |
| Q4100 | Skin substitute, not otherwise specified [when specified as DermaMatrix for breast reconstruction only] |
| Q4116 | AlloDerm, per square centimeter [AlloDerm Regenerative Tissue Matrix (aseptic or sterile)for breast reconstruction and abdominal wall wounds] |
| Q4122 | Dermacell, Dermacell AWM or Dermacell AWM porous, per square centimeter [for breast reconstruction or diabetic foot ulcers only] |
| Q4128 | FlexHD, or Allopatch HD, per sq cm [when specified as FlexHD for breast reconstruction] |
| Q4130 | Strattice, per square centimeter [for breast reconstruction and abdominal wall wounds] |
|
|
|
| ICD-10 Diagnosis |
|
|
| All diagnoses |
When services may be Medically Necessary when criteria are met [for AlloSkin, Biobrane, EZ-Derm, Integra Bilayer Matrix Wound Dressing, StrataGraft]:
| HCPCS |
|
| A4100 | Skin substitute, FDA cleared as a device, not otherwise specified [when specified as Biobrane or StrataGraft] |
| C9363 | Skin substitute, Integra Meshed Bilayer Wound Matrix, per square centimeter |
| C9399 | Unclassified drugs or biologicals [when specified as Biobrane or StrataGraft] |
| Q4100 | Skin substitute, not otherwise specified [when specified as Biobrane or StrataGraft] |
| Q4104 | Integra Bilayer Matrix Wound Dressing (BMWD), per square centimeter |
| Q4115 | AlloSkin, per square centimeter |
| Q4136 | EZ-derm, per square centimeter |
|
|
|
| ICD-10 Diagnosis |
|
| T20.20XA-T20.39XS | Burn of second or third degree of head, face, and neck |
| T20.60XA-T20.79XS | Corrosion of second or third degree of head, face, and neck |
| T21.20XA-T21.39XS | Burn of second or third degree of trunk |
| T21.60XA-T21.79XS | Corrosion of second or third degree of trunk |
| T22.20XA-T22.399S | Burn of second or third degree of shoulder and upper limb, except wrist and hand] |
| T22.60XA-T22.799S | Corrosion of second or third degree of shoulder and upper limb, except wrist and hand |
| T23.201A-T23.399S | Burn of second or third degree of wrist and hand |
| T23.601A-T23.799S | Corrosion of second or third degree of wrist and hand |
| T24.201A-T24.399S | Burn of second or third degree of lower limb, except ankle and foot |
| T24.601A-T24.799S | Corrosion of second or third degree of lower limb, except ankle and foot |
| T25.211A-T25.399S | Burn of second or third degree of ankle and foot |
| T25.611A-T25.799S | Corrosion of second or third degree of ankle and foot |
| T31.0-T31.99 | Burns classified according to extent of body surface involved |
| T32.0-T32.99 | Corrosions classified according to extent of body surface involved |
When services may be Medically Necessary when criteria are met [for TheraSkin]:
| HCPCS |
|
| Q4121 | TheraSkin, per square centimeter |
|
|
|
| ICD-10 Diagnosis |
|
| E08.00-E13.9 | Diabetes mellitus |
| I83.001-I83.029 | Varicose veins of lower extremities with ulcer |
| I83.201-I83.229 | Varicose veins of lower extremities with both ulcer and inflammation |
| I87.011-I87.019 | Postthrombotic syndrome with ulcer |
| I87.031-I87.039 | Postthrombotic syndrome with ulcer and inflammation |
| I87.2 | Venous insufficiency (chronic) (peripheral) |
| I87.311-I87.319 | Chronic venous hypertension (idiopathic) with ulcer |
| I87.331-I87.339 | Chronic venous hypertension (idiopathic) with ulcer and inflammation |
| L97.101-L97.929 | Non-pressure chronic ulcer of lower limb, not elsewhere classified |
| L98.411-L98.499 | Non-pressure chronic ulcer of skin, not elsewhere classified |
| T20.20XA-T20.39XS | Burn of second or third degree of head, face, and neck |
| T20.60XA-T20.79XS | Corrosion of second or third degree of head, face, and neck |
| T21.20XA-T21.39XS | Burn of second or third degree of trunk |
| T21.60XA-T21.79XS | Corrosion of second or third degree of trunk |
| T22.20XA-T22.399S | Burn of second or third degree of shoulder and upper limb, except wrist and hand] |
| T22.60XA-T22.799S | Corrosion of second or third degree of shoulder and upper limb, except wrist and hand |
| T23.201A-T23.399S | Burn of second or third degree of wrist and hand |
| T23.601A-T23.799S | Corrosion of second or third degree of wrist and hand |
| T24.201A-T24.399S | Burn of second or third degree of lower limb, except ankle and foot |
| T24.601A-T24.799S | Corrosion of second or third degree of lower limb, except ankle and foot |
| T25.211A-T25.399S | Burn of second or third degree of ankle and foot |
| T25.611A-T25.799S | Corrosion of second or third degree of ankle and foot |
| T31.0-T31.99 | Burns classified according to extent of body surface involved |
| T32.0-T32.99 | Corrosions classified according to extent of body surface involved |
When services are Not Medically Necessary:
For the product codes listed above when criteria are not met or for all other diagnoses not listed, or when the code describes a procedure indicated in the Position Statement section as not medically necessary.
When Services are also Investigational and Not Medically Necessary:
| HCPCS |
|
| A2001 | Innovamatrix AC, per square centimeter |
| A2002 | Mirragen advanced wound matrix, per square centimeter |
| A2004 | Xcellistem, 1mg |
| A2005 | Microlyte matrix, per square centimeter |
| A2006 | Novosorb synpath dermal matrix, per square centimeter |
| A2007 | Restrata, per square centimeter |
| A2008 | TheraGenesis, per square centimeter |
| A2009 | Symphony, per square centimeter |
| A2010 | Apis, per square centimeter |
| A2011 | Supra SDRM, per square centimeter |
| A2012 | Suprathel, per square centimeter |
| A2013 | InnovaMatrix FS, per square centimeter |
| A2014 | Omeza Collagen Matrix, per 100 mg |
| A2015 | Phoenix Wound Matrix, per sq cm |
| A2016 | PermeaDerm B, per sq cm |
| A2017 | PermeaDerm Glove, each |
| A2018 | PermeaDerm C, per sq cm |
| C9352 | Microporous collagen implantable tube (NeuraGen Nerve Guide), per centimeter length |
| C9353 | Microporous collagen implantable slit tube (NeuraWrap Nerve Protector), per centimeter length |
| C9354 | Acellular pericardial tissue matrix of non-human origin (Veritas), per square centimeter |
| C9355 | Collagen nerve cuff (NeuroMatrix), per 0.5 centimeter length |
| C9356 | Tendon, porous matrix of cross-linked collagen and glycosaminoglycan matrix (TenoGlide Tendon Protector Sheet), per square centimeter |
| C9358 | Dermal substitute, native, non-denatured collagen, fetal bovine origin (SurgiMend Collagen Matrix), per 0.5 square centimeters |
| C9360 | Dermal substitute, native, non-denatured collagen, neonatal bovine origin (SurgiMend Collagen Matrix), per 0.5 square centimeters |
| C9361 | Collagen matrix nerve wrap (NeuroMend Collagen Nerve Wrap), per 0.5 centimeter length |
| C9364 | Porcine implant, Permacol, per square centimeter |
| C9399 | Unclassified drugs or biologicals [when describing a product with no specific code indicated as investigational and not medically necessary] |
| G0428 | Collagen meniscus implant procedure for filling meniscal defects (e.g., CMI, collagen scaffold, Menaflex) |
| Q4100 | Skin substitute, not otherwise specified [when describing a product with no specific code indicated as investigational and not medically necessary] |
| Q4103 | Oasis Burn Matrix, per square centimeter |
| Q4105 | Integra Dermal Regeneration Template (DRT) or Integra Omnigraft dermal regeneration matrix, per square centimeter |
| Q4108 | Integra Matrix, per square centimeter |
| Q4111 | Gammagraft, per square centimeter |
| Q4112 | Cymetra, injectable, 1 cc |
| Q4113 | Graftjacket Xpress, injectable, 1 cc |
| Q4114 | Integra Flowable Wound Matrix, injectable, 1 cc |
| Q4117 | Hyalomatrix, per square centimeter |
| Q4118 | Matristem micromatrix, 1 mg |
| Q4123 | AlloSkin RT, per square centimeter |
| Q4125 | ArthroFlex, per square centimeter |
| Q4126 | Memoderm, dermaspan, tranzgraft or integuply, per square centimeter |
| Q4127 | Talymed, per square centimeter |
| Q4128 | FlexHD, or AlloPatch HD, per sq cm [when specified as AlloPatch HD] |
| Q4132 | Grafix CORE and GrafixPL CORE, per square centimeter |
| Q4133 | Grafix PRIME, GrafixPL PRIME, Stravix and StravixPL, per square centimeter [when specified as GrafixPL PRIME, Stravix, StravixPL] |
| Q4134 | hMatrix, per square centimeter |
| Q4135 | Mediskin, per square centimeter |
| Q4137 | AmnioExCel, AmnioExCel plus or BioDExCel, per square centimeter |
| Q4138 | BioDfence Dryflex, per square centimeter |
| Q4139 | AmnioMatrix or BioDMatrix, injectable, 1 cc |
| Q4140 | BioDfence, per square centimeter |
| Q4141 | Alloskin AC, per square centimeter |
| Q4142 | XCM Biologic Tissue Matrix, per square centimeter |
| Q4143 | Repriza, per square centimeter |
| Q4145 | Epifix, injectable, 1 mg |
| Q4146 | TenSIX, per square centimeter |
| Q4147 | Architect, Architect PX, or Architect FX, extracellular matrix, per square centimeter |
| Q4148 | NEOX Cord 1k, NEOX Cord RT, or Clarix Cord 1k, per square centimeter |
| Q4149 | Excellagen, 0.1 cc |
| Q4150 | Allowrap DS or Dry, per square centimeter |
| Q4152 | DermaPure, per square centimeter |
| Q4153 | Dermavest and Plurivest, per square centimeter |
| Q4154 | Biovance, per square centimeter |
| Q4155 | NeoxFlo or ClarixFlo, 1 mg |
| Q4156 | NEOX 100 or Clarix 100, per square centimeter |
| Q4157 | Revitalon, per square centimeter |
| Q4158 | Kerecis Omega3, per square centimeter |
| Q4159 | Affinity, per square centimeter |
| Q4160 | NuShield, per square centimeter |
| Q4161 | Bio-connekt wound matrix, per square centimeter |
| Q4162 | WoundEx Flow, BioSkin Flow, 0.5 cc |
| Q4163 | WoundEx, BioSkin, per square centimeter |
| Q4164 | Helicoll, per square centimeter |
| Q4165 | Keramatrix or Kerasorb, per square centimeter |
| Q4166 | Cytal, per square centimeter [formerly Matristem wound/burn matrix] |
| Q4167 | TruSkin, per square centimeter |
| Q4168 | AmnioBand, 1 mg |
| Q4169 | Artacent Wound, per square centimeter |
| Q4170 | CYGNUS, per square centimeter |
| Q4171 | Interfyl, 1 mg |
| Q4173 | PalinGen or PalinGen Xplus, per square centimeter |
| Q4174 | PalinGen or ProMatrX, 0.36 mg per 0.25 cc |
| Q4175 | Miroderm, per square centimeter |
| Q4176 | NeoPatch or Therion, per square centimeter |
| Q4177 | FlowerAmnioflo, 0.1 cc |
| Q4178 | FlowerAmniopatch, per square centimeter |
| Q4179 | FlowerDerm, per square centimeter |
| Q4180 | Revita, per square centimeter |
| Q4181 | Amnio Wound, per square centimeter |
| Q4183 | Surgigraft, per square centimeter |
| Q4184 | Cellesta or Cellesta Duo, per square centimeter |
| Q4185 | Cellesta flowable amnion (25 mg per cc); per 0.5 cc |
| Q4188 | Amnioarmor, per square centimeter |
| Q4189 | Artacent AC, 1 mg |
| Q4190 | Artacent AC, per square centimeter |
| Q4191 | Restorigin, per square centimeter |
| Q4192 | Restorigin, 1 cc |
| Q4193 | Coll-e-derm, per square centimeter |
| Q4194 | Novachor, per square centimeter |
| Q4195 | Puraply, per square centimeter |
| Q4196 | PuraPly AM, per square centimeter |
| Q4197 | PuraPly XT, per square centimeter |
| Q4198 | Genesis amniotic membrane, per square centimeter |
| Q4199 | Cygnus matrix, per square centimeter |
| Q4200 | Skin TE, per square centimeter |
| Q4201 | Matrion, per square centimeter |
| Q4202 | Keroxx (2.5g/cc), 1cc |
| Q4203 | Derma-gide, per square centimeter |
| Q4204 | Xwrap, per square centimeter |
| Q4205 | Membrane graft or Membrane wrap, per square centimeter |
| Q4206 | Fluid flow or Fluid GF, 1 cc |
| Q4208 | Novafix, per square cenitmeter |
| Q4209 | Surgraft, per square centimeter |
| Q4210 | Axolotl graft or Axolotl dualgraft, per square centimeter |
| Q4211 | Amnion bio or AxoBioMembrane, per square centimeter |
| Q4212 | AlloGen, per cc |
| Q4213 | Ascent, 0.5 mg |
| Q4214 | Cellesta cord, per square centimeter |
| Q4215 | Axolotl Ambient or Axolotl Cryo, 0.1 mg |
| Q4216 | Artacent cord, per square centimeter |
| Q4217 | Woundfix, BioWound, Woundfix Plus, BioWound Plus, Woundfix Xplus or BioWound Xplus, per square centimeter |
| Q4218 | Surgicord, per square centimeter |
| Q4219 | SurgiGRAFT-Dual, per square centimeter |
| Q4220 | BellaCell HD or Surederm, per square centimeter |
| Q4221 | Amniowrap2, per square centimeter |
| Q4222 | Progenamatrix, per square centimeter |
| Q4224 | Human health factor 10 amniotic patch (hhf10-p), per square centimeter |
| Q4225 | Amniobind, per square centimeter |
| Q4226 | MyOwn Skin, includes harvesting and preparation procedures, per square centimeter |
| Q4227 | AmnioCore, per square centimeter |
| Q4229 | Cogenex amniotic membrane, per square centimeter |
| Q4230 | Cogenex flowable amnion, per 0.5 cc |
| Q4231 | Corplex P, per cc |
| Q4232 | Corplex, per square centimeter |
| Q4233 | SurFactor or NuDyn, per 0.5 cc |
| Q4234 | XCellerate, per square centimeter |
| Q4235 | Amniorepair or AltiPly, per square centimeter |
| Q4237 | Cryo-cord, per square centimeter |
| Q4238 | Derm-Maxx, per square centimeter |
| Q4239 | Amnio-Maxx or Amnio-Maxx Lite, per square centimeter |
| Q4240 | CoreCyte, for topical use only, per 0.5 cc |
| Q4241 | PolyCyte, for topical use only, per 0.5 cc |
| Q4242 | AmnioCyte Plus, per 0.5 cc |
| Q4244 | Procenta, per 200 mg |
| Q4245 | Amniotext, per cc |
| Q4246 | Coretext or Protext, per cc |
| Q4247 | Amniotext patch, per square centimeter |
| Q4248 | Dermacyte Amniotic Membrane Allograft, per square centimeter |
| Q4249 | Amniply, for topical use only, per square centimeter |
| Q4250 | AmnioAMP-MP, per square centimeter |
| Q4251 | Vim, per sq cm |
| Q4252 | Vendaje, per sq cm |
| Q4253 | Zenith Amniotic Membrane, per sq cm |
| Q4254 | Novafix DL, per square centimeter |
| Q4255 | REGUaRD, for topical use only, per square centimeter |
| Q4256 | MLG-complete, per square centimeter |
| Q4257 | Relese, per square centimeter |
| Q4258 | Enverse, per square centimeter |
| Q4259 | Celera dual layer or celera dual membrane, per square centimeter |
| Q4260 | Signature Apatch, per square centimeter |
| Q4261 | TAG, per square centimeter |
|
|
|
| ICD-10 Diagnosis |
|
|
| All diagnoses |
| References |
Peer Reviewed Publications:
Non-Product Specific Acellular Dermal Matrix (ADM) Studies, Multiple Product Studies, Meta-analyses, and Systematic Reviews
Allogeneic amniotic membrane-derived grafts or wound coverings used for ophthalmologic indications.
Peer Reviewed Publications:
Government Agency, Medical Society, and Other Authoritative Publications:
KeraSys
Prokera
Allograft (unspecified)
AlloDerm Regenerative Tissue Matrix (Aseptic)
AlloDerm Regenerative Tissue Matrix (Sterile)
Affinity
Allomax
AlloPatch
AmnioBand
AMNIOEXCEL
Snyder RJ, Shimozaki K, Tallis A, et al. A prospective, randomized, multicenter, controlled evaluation of the use of dehydrated amniotic membrane allograft compared to standard of care for the closure of chronic diabetic foot ulcer. Wounds. 2016; 28(3):70-77.
Amniofix
Amniotic Allografts – Not specified
Apligraf
Artacent Wound
Artelon CMC
Artelon TMC
Avance Nerve Graft
Avaulta
Belladerm:
Biobrane
Biodesign (See Surgisis section below)
Cardiocel:
Clarix
Conexa
CorMatrix
Cortiva
Cymetra
DermACELL
Dermagraft
DermaMatrix
Enduragen
EpiCord
EpiFix
E-Z Derm
FlexHD
Fortiva
GalaFLEX
Gentrix
Gore BioA
Gore® Acuseal Cardiovascular Patch
Grafix CORE
Grafix PRIME
GrafixPL PRIME
GraftJacket
Hyalomatrix
Integra Bilayer Matrix Wound Dressing
Integra Omnigraft Dermal Regeneration Template
Integra Flowable Wound Matrix
Keramatrix
Kerecis
MatrACELL
Matriderm
Medihoney
Menaflex
mVASC
Neuragen
NeuraWrap
Novosorb Biodegradable Temporizing Matrix (BMT)
Ologen Collagen Matrix
Oasis
Pelvicol
Peri-Strips Dry
Permacol
PriMatrix
Phasix-ST
Promogran
PuraPly
Regeneten
Repriza
See Solomon (2013) in the Belladerm section above.
Seamguard
StrataGraft
Strattice
Suprathel
SurgiMend
Surgisis
Talymed
TheraSkin
Tutomesh
Vascu-Guard
VIA Disc NP
Veritas
Xelma
XenoGrafts (unspecified) for Burns
Government Agency, Medical Society, and Other Authoritative Publications:
| Websites for Additional Information |
| Index |
Bilaminate Skin Substitute
Culture-Derived Human Skin Equivalent
Frey’s Syndrome
Graves’ Disease
Human Skin Equivalent
Wound Healing
Xenograft
The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.
| Document History |
| Status | Date | Action |
|
| 09/28/2022 | Updated Coding section with 10/01/2022 HCPCS changes; revised descriptor for Q4128 and added A2014, A2015, A2016, A2017, A2018. |
| Revised | 05/12/2022 | Medical Policy & Technology Assessment Committee (MPTAC) review. Revised INV and NMN statement for products with MN indications. Updated Rationale and References sections. Updated Coding section, including 07/01/2022 HCPCS changes; added Q4259, Q4260, Q4261 and revised A2004 descriptor. |
| Revised | 02/17/2022 | MPTAC review. Moved StrataGraft from INV and NMN section to MN section for burns. Added mVASC to MN section for treatment of DUFs. Clarified product terminology regarding AlloDerm products. Added new products to INV and NMN statement. Updated Rationale and References sections. Updated Coding section to include MN indications for StrataGraft and mVASC (NOC codes) and 04/01/2022 HCPCS updates to add A2011, A2012, A2013, A4100, Q4224, Q4225, Q4256, Q4257, Q4258. |
| Revised | 11/11/2021 | MPTAC review. Updated title and scope to include bioengineered products. Reorganized MN section by indication. Simplified criteria for treatment of DFUs and venous stasis ulcers. Incorporated position statement addressing bioengineered autologous skin-derived products from MED.00110. Added new products to INV and NMN statement. Updated Description/Scope, Rationale, Background, and References sections. Updated Coding section with 01/01/2022 HCPCS changes to add A2001-A2002, A2004-A2010 and Q4199 effective 01/01/2022, also added Q4200, Q4226 previously addressed in MED.00110. |
|
| 10/01/2021 | Updated Coding section with 10/01/2021 HCPCS changes; added Q4251, Q4252, Q4253 effective 10/01/2021 and removed Q4228, Q4236 deleted 09/30/2021. |
| Revised | 11/05/2020 | MPTAC review. Added new MN statement for TheraSkin for treatment of lower extremity dermal wounds. Revised note addressing fresh frozen unprocessed allograft skin products. Revised several statements to begin with the name of the product. Revised IVN and NMN statement for products which have MN indications. Added new products to INV and NMN statement. Updated Scope, Rationale, and References sections. Updated Coding section to include 01/01/2021 CPT changes adding 0627T-0630T. |
|
| 10/01/2020 | Updated Coding section with 10/01/2020 HCPCS changes to add Q4249, Q4250, Q4254, Q4255, and also 10/01/2020 ICD-10-CM changes adding H18.599 replacing H18.59 deleted 09/30/2020. |
|
| 07/01/2020 | Updated Coding section with 07/01/2020 HCPCS changes to add Q4227-Q4242, Q4244-Q4248 and revised descriptor for Q4176; also removed C1878, L8607 now addressed in MED.00132. |
| Revised | 11/07/2019 | MPTAC review. Moved AmbioDisk from INV and NMN statement to the MN statement addressing of allogeneic amniotic membrane-derived grafts or wound coverings. Added Artacent Ocular to MN statement addressing of allogeneic amniotic membrane-derived grafts or wound coverings. Added new products to INV and NMN statement. Updated Rationale and References sections. |
|
| 10/01/2019 | Updated Coding section with 10/01/2019 HCPCS changes; added Q4205-Q4206, Q4208-Q4222, revised descriptors for Q4122, Q4165, Q4184; also added C1878. |
|
| 06/18/2019 | Correction to MN statement addressing amniotic membrane-derived products for conjunctival and corneal indications made. Kerasys removed and replaced by AmnioGraft. |
| Revised | 06/06/2019 | MPTAC review. Added new MN and INV and NMN statements addressing amniotic membrane-derived products for conjunctival and corneal indications. Added new products to INV and NMN statement. Updated Rationale, Coding and References sections. |
| Revised | 01/24/2019 | MPTAC review. Added new MN statements for EpiCord, Grafix PRIME, and the sheet or membrane form of AmnioBand. Revised INV and NMN statements regarding those products. Added EpiBurn to INV and NMN statement. Updated Coding, Rationale, and References sections. |
|
| 12/27/2018 | Updated Coding section with 01/01/2019 HCPCS changes; removed Q4131, Q4172 deleted 12/31/2018. |
| Revised | 09/13/2018 | MPTAC review. Added several products to the INV and NMN section. Updated Rationale, Coding and References sections. |
| Revised | 01/25/2018 | MPTAC review. Revised criteria for EpiFix and Integra Bilayer Matrix Wound Dressing. Deleted statement regarding TransCyte. Moved several products from the INV and NMN section to the MN section. Updated Rationale and References sections. Updated Coding section to include removing Q4182 no longer addressed. |
|
| 12/27/2017 | The document header wording updated from “Current Effective Date” to “Publish Date.” Updated Coding section with 01/01/2018 HCPCS changes; added codes Q4176-Q4182, descriptor revisions for Q4132, Q4133, Q4148, Q4156, Q4158, Q4162, Q4163. |
| Revised | 08/03/2017 | MPTAC review. Added new products to INV and NMN list. Removed Perlane and Restylane from Inv and NMN list. Updated Rationale, Coding and References sections. |
| Revised | 02/02/2017 | MPTAC review. Made minor typographical revisions to Position Statement. Added new products to INV and NMN list. Updated Rationale and References sections. |
|
| 01/01/2017 | Updated Coding section with 01/01/2017 CPT and HCPCS changes; removed codes C9349, Q4119, Q4120, Q4129 deleted 12/31/2016. |
| Revised | 05/05/2016 | MPTAC review. Added AlloDerm Ready to Use as MN for the same indications as AlloDerm Regenerative Tissue Matrix. Added FlexHD as MN for breast reconstruction surgery. Clarified INV and NMN statement regarding fresh frozen allograft products. Added new products to the INV and NMN list. Updated Rationale, Coding, and References sections. |
| Revised | 11/05/2015 | MPTAC review. Added Restlyane and Perlane to investigational and not medically necessary list. Updated Rationale and References sections. Updated Coding section with 01/01/2016 HCPCS changes; also removed ICD-9 codes. |
|
| 07/01/2015 | Updated Coding section with 07/01/2015 HCPCS change to descriptor for C9349. |
| Revised | 05/07/2015 | MPTAC review. Added new medically necessary position statement regarding the use of fresh, frozen, unprocessed skin allograft products for the treatment of full-thickness or deep partial-thickness burns when criteria are met. Added new products to investigational and not medically necessary section. Updated Rationale, Coding, and References sections. |
| Revised | 02/05/2015 | MPTAC review. Added new medically necessary position statement regarding the use the sheet or membrane form of EpiFix. Revised investigational and not medically necessary statement to differentiate between the sheet or membrane form of EpiFix and the particulate or injectable form of EpiFix. Added new products to investigational and not medically necessary section. Updated Rationale, Background, Coding, and References sections. Revised position statements were finalized in a follow-up vote on 03/04/2015. |
|
| 01/01/2015 | Updated Coding section with 01/01/2015 HCPCS changes. |
| Revised | 02/13/2014 | MPTAC review. Clarified nomenclature of AlloDerm product in medically necessary section. Added new products to investigational and not medically necessary section. Updated Rationale, Background, and References sections. |
|
| 01/01/2014 | Updated Coding section with 01/01/2014 CPT and HCPCS changes. |
| Revised | 08/08/2013 | MPTAC review. Added new products to Investigational and Not Medically Necessary list. Updated Rationale and References sections. |
| Revised | 05/09/2013 | MPTAC review. Added new products to Investigational and Not Medically Necessary list. Updated Rationale, Coding, and Reference sections. |
|
| 01/01/2013 | Updated Coding section with 01/01/2013 HCPCS changes; removed C9366, C9368, C9369 deleted 12/31/2012. |
| Revised | 05/10/2012 | MPTAC review. Deleted “autologous” from title. Split off growth factors, silver-based products and autologous tissues for wound treatment and soft tissue to a new policy (MED.00110). Reorganized position statement section. Clarified Medically necessary statement for Apligraf regarding number of applications and deleted corresponding investigational and not medically necessary statement. Added new products to investigational and not medically necessary position statement. Revised Rationale, Background, References, and Index sections. Updated Coding section to include 07/01/2012 HCPCS changes. |
|
| 01/19/2012 | Updated Coding section with correct diagnosis coding for Apligraf; removed HCPCS codes G0440, G0441 deleted 12/31/2011. |
|
| 01/01/2012 | Updated Coding section with 01/01/2012 CPT and HCPCS changes; removed codes 15170, 15171, 15175, 15176, 15330, 15331, 15335, 15336, 15340, 15341, 15360, 15361, 15365, 15366, 15400, 15401, 15420, 15421, 15430, 15431, C9365 deleted 12/31/2011; also removed CPT 15150, 15151, 15152, 15155, 15156, 15157. |
| Revised | 05/19/2011 | MPTAC review. Added synthetic soft-tissue grafting materials as investigational and not medically necessary to Section I. Added xenographic-related or derived products as investigational and not medically necessary to Section IV. Updated Rationale, References, and Index sections. Updated Coding section with 07/01/2011 HCPCS changes. |
| Revised | 02/17/2011 | MPTAC review. Added use of cryopreserved allogeneic human skin to the Allogeneic section as investigational and not medically necessary. Updated Rationale, Coding, References, and Index sections. |
|
| 01/01/2011 | Updated Coding section with 01/01/2011 HCPCS changes; removed Q4109 deleted 12/31/2010. |
| Revised | 08/19/2010 | MPTAC review. Added use of synthetic fistula plugs to synthetic products section as investigational and not medically necessary. Expanded investigational and not medically necessary statement for Dermagraft to cover all indications not listed as medically necessary. Revised language in xenographic investigational and not medically necessary statement. Updated list of xenographic products, including Menaflex™ Collagen Meniscus Implant. Added new section addressing composite autologous / allogeneic / xenographic products. Updated Rationale, Background, Coding, and References sections. |
|
| 07/01/2010 | Updated Coding section with 07/01/2010 CPT and HCPCS changes. |
|
| 01/01/2010 | Updated Coding section with 01/01/2010 CPT changes; removed CPT 0170T deleted 12/31/2009. |
| Revised | 08/27/2009 | MPTAC review. Added Platelet Rich Plasma as investigational and not medically necessary. Updated coding and Index sections. |
| Reviewed | 05/21/2009 | MPTAC review. Added note stating that this document does not address the use of meshes or patches of non-biologic origin when used for standard hernia repair procedures. Updated Index section. Updated coding section with 07/01/2009 HCPCS changes. |
| Revised | 02/26/2009 | MPTAC review. Added Investigational and Not Medically Necessary statements for C-QUR and Strattice. |
| Revised | 11/20/2008 | MPTAC review. Added AlloDerm as medically necessary for breast reconstruction and complex abdominal wall wound closure. Updated Rationale and Reference sections. Updated coding section with 01/01/2009 HCPCS changes; removed C9357, J7340, J7341, J7342, J7343, J7344, J7346, J7347, J7348, J7349 deleted 12/31/2008. |
| Revised | 08/28/2008 | MPTAC review. Added Vitagel to Investigational and Not Medically Necessary statement of Section II Autologous Products. Added Cymetra to Investigational and Not Medically Necessary statement of Section III Allogeneic Products. Updated Background. Coding section updated to include 10/01/2008 ICD-9 changes. |
| Revised | 05/15/2008 | MPTAC review. Changed title from “Wound Healing: Skin Substitutes and Blood-Derived Growth Factors” to “Autogous, Allogeneic, Xenographic, Synthetic and Composite Products for Wound Healing and Soft Tissue Grafting.” Reorganized Position Statement section. Added position statements regarding the following products: Actisorb, Avaulta Plus, Collamend, CuffPatch, Mediskin, Neoform Dermis, Pelcvicol, Pelvisoft, Silversorb, and Unite. Revised Rationale, Coding, Background, Definitions, References, and Index sections. Deleted information regarding Procuren®. Updated Coding section with 07/01/2008 HCPCS changes. |
| Revised | 02/21/2008 | MPTAC review. Added position statements for Integra™ Matrix Wound Dressing, Primatrix, and TissueMend. Expanded investigational and not medically necessary statement for Surgisis, Autogel and Safeblood to include all indications. Updated Rationale, Background, Definitions, and References sections. |
|
| 01/01/2008 | Updated Coding section with 01/01/2008 HCPCS changes; removed HCPCS C9351, J7345 deleted 12/31/2007. The phrase “investigational/not medically necessary” was clarified to read “investigational and not medically necessary.” This change was approved at the November 29, 2007 MPTAC meeting. |
| Revised | 05/17/2007 | MPTAC review. Added the use of AlloDerm for breast reconstruction or augmentation to investigational/not medically necessary statement. Updated Rationale and References sections. |
|
| 01/01/2007 | Updated Coding section with 01/01/2007 CPT/HCPCS changes. |
| Revised | 09/14/2006 | MPTAC review. Added position statement for Surgisis®; updated rationale, background and reference sections. Coding updated; removed CPT 15342, 15343 deleted 12/31/05, HCPCS Q0182, Q0183 deleted 12/31/04. |
| Revised | 03/23/2006 | MPTAC review. Added position statement for AlloDerm® and GraftJacket™. |
|
| 01/01/2006 | Updated Coding section with 01/01/2006 CPT/HCPCS changes |
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| 11/22/2005 | Added reference for Centers for Medicare and Medicaid Services (CMS) – National Coverage Determination (NCD). |
| Revised | 07/14/2005 | MPTAC review. Revision based on Pre-merger Anthem and Pre-merger Wellpoint Harmonization. |
| Pre-Merger Organizations | Last Review Date | Document Number | Title |
| Anthem, Inc. | 04/28/2005 | SURG.00011 | Wound Healing: Tissue Engineered Skin Substitutes and Growth Factors |
| WellPoint Health Networks, Inc. | 04/28/2005 | 3.02.03 | Human Skin Equivalent Grafts |
|
| 09/23/2004 | 8.01.08 | Autologous Blood Derived Preparations for Wound Healing |
Federal and State law, as well as contract language, including definitions and specific contract provisions/exclusions, take precedence over Medical Policy and must be considered first in determining eligibility for coverage. The member’s contract benefits in effect on the date that services are rendered must be used. Medical Policy, which addresses medical efficacy, should be considered before utilizing medical opinion in adjudication. Medical technology is constantly evolving, and we reserve the right to review and update Medical Policy periodically.
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