|Subject:||Allogeneic, Xenographic, Synthetic and Composite Products for Wound Healing and Soft Tissue Grafting|
|Policy #:||SURG.00011||Current Effective Date:||05/12/2016|
|Status:||Revised||Last Review Date:||05/05/2016|
This document addresses the use of soft tissue (e.g., skin, ligament, cartilage, etc.) substitutes in wound healing and surgical procedures. 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. For more information regarding the treatment of osteochondral defects, please see:
Note: For additional information please see:
AlloDerm® Regenerative Tissue Matrix, also known as AlloDerm RTM, and AlloDerm® RTU, also known as AlloDerm Ready to Use, are considered medically necessary for either of the following uses:
FlexHD® is considered medically necessary for breast reconstruction surgery.
Apligraf® is considered medically necessary for a total of five (5) applications for either of the following indications:
Dermagraft® is considered medically necessary when used for either of the following indications:
Fresh frozen unprocessed allograft skin products (for example, AlloSkin™*, TheraSkin®) are considered medically necessary for the treatment of full-thickness or deep partial-thickness burns when the following criteria have been met:
Integra™ Bilayer Matrix Wound Dressing, an artificial skin substitute, is considered medically necessary in the post-excisional treatment of full-thickness or deep partial-thickness burns when autografting is not feasible due to the individual's weakened physiological condition or a lack of suitable healthy tissue.
The sheet or membrane form of EpiFix™, an allogeneic skin substitute, is considered medically necessary when used for either of the following indications:
OrCel™, a composite skin substitute, is considered medically necessary in children with recessive dystrophic epidermolysis bullosa who are undergoing reconstructive hand surgery.
TransCyte™, a biosynthetic skin substitute, is considered medically necessary as a temporary wound covering to treat second and third degree burns.
Investigational and Not Medically Necessary:
The following products are considered investigational and not medically necessary when criteria above are not met and for any use not listed above:
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:
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 that 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 safety and efficacy 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 too small to adequately demonstrate efficacy for a more general population.
Non-Product Specific Acellular Dermal Matrix (ADM) 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 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, 3 used porcine ADM, 1 a synthetic composite mesh, and 1 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 that 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.
Products addressed in the Medically Necessary statement
AlloDerm Regenerative Tissue Matrix
AlloDerm Regenerative Tissue Matrix, also known as AlloDerm RTM, is a 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. There are over a dozen small case series studies and nonrandomized controlled trials published in the peer-reviewed medical literature describing the use of AlloDerm RTM 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). The goal of using AlloDerm RTM 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 AlloDerm RTM for this indication.
However, care must be taken when selecting AlloDerm RTM 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 AlloDerm RTM (n=442, 70.3%) or without AlloDerm RTM (n=186, 29.6%). The authors reported that major complications were significantly increased in the AlloDerm RTM 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 AlloDerm RTM 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 AlloDerm RTM for breast reconstruction, AlloDerm RTM 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 AlloDerm RTM for this indication.
At this time, there is limited data addressing the use of AlloDerm RTM in treating chronic wounds. There is very limited evidence available regarding the use of AlloDerm RTM 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, AlloDerm RTM has been proposed for use in a wide variety of other surgical applications.
The use of AlloDerm RTM 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 small studies addressing this use in clinical trials (Helling, 2006; Steele, 2006). These studies show promising results, but are small and use weak study designs. Additional studies are needed to demonstrate the efficacy of this use of AlloDerm RTM.
In the one available clinical trial of AlloDerm RTM 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 AlloDerm RTM for treatment of burns. The first study involved 19 participants randomized to AlloDerm RTM with an autograft overgraft vs. AlloDerm RTM 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 AlloDerm RTM with thin autograft was associated with more healing than spilt thickness grafts. The second study involved 52 nonrandomized participants all of whom received AlloDerm RTM 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 AlloDerm RTM 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 AlloDerm RTM to treat Frey's syndrome. The first involved 64 participants randomly assigned to the use of AlloDerm RTM placement in the parotid bed following removal of the parotid gland vs. no AlloDerm RTM (Govindaraj, 2001). While the rate of gustatory sweating in the AlloDerm RTM group was found to be statistically lower than the control group, the AlloDerm RTM 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 AlloDerm RTM, (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.
AlloDerm Regenerative Tissue Matrix (RTM) Ready To Use
LifeCell, Inc. has introduced another product, AlloDerm RTM Ready To Use (also referred to as AlloDerm Ready To Use or AlloDerm RTU) that is sterile and reportedly easier to use. This product is similar to their AlloDerm RTM 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 aspetic tissue processing. However, AlloDerm RTM is supplied as an aseptic product. The AlloDerm RTU product undergoes additional sterilizing with electron beam radiation. Additionally, whereas AlloDerm RTM is freeze-dried prior to packaging and requires rehydration prior to use, AlloDerm RTU 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 AlloDerm RTM (n=58; 90 breasts). At the 1 year point, subjects meeting the same criteria were all treated with AlloDerm RTU (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 RTM group was noted to have statistically significantly larger mean specimen weight and higher BMI vs. the RTU group (p=0.0485 and p=0.0376, respectively). The RTU group also had a higher incidence of nipple-sparing surgeries (p=0.0021). With regard to complications, the RTU group had significantly fewer overall infections vs. the RTM group (8.5% vs. 20%, p=0.0088). However, there were no significant differences between AlloDerm groups with regard to explantations (RTU=2 vs. RTM=6, p=0.147) or major infections requiring antibiotics (RTU=4.7% vs. RTM=12.2%, p=0.069). The incidence of seroma, hematoma, and skin flap necrosis were not different between AlloDerm groups. When comparing the RTU group vs. the submuscular coverage group, the RTU 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 RTM 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 RTU and tissue expander groups to be possible confounding factors in this study. The authors conclude that the use of AlloDerm RTU is acceptable and mitigates the risk of infectious complications compared to aseptic AlloDerm RTM.
In 2015, Lewis and others published the results of a retrospective case series study of subjects receiving AlloDerm RTM (n=93) or AlloDerm RTU (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 AlloDerm groups, the overall complication rate was significantly in favor of the RTU group (p=0.046). Based on aggregate complication rate on a per-breast basis the absolute risk reduction with RTU was reported to be 14.9%. The authors concluded that the use of the sterile AlloDerm RTU product resulted in fewer complications when compared to aseptic AlloDerm RTM.
The results of these studies, in conjunction with the previously reported evidence from AlloDerm RTM, have demonstrated a significant outcome benefit of the AlloDerm RTU product. This product is accepted as substantially equivalent to the AlloDerm RTM product. These products are sourced and processed in an identical manner, with the addition of a sterilization process in the case of the RTU 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.
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 Apigraft for the treatment of foot ulcers.
Apligraf has been investigated for the treatment of burns in only one peer-reviewed published study (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). Further study is needed to fully evaluate the use of Apligraf for the treatment of burns.
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 VLUs 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 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 diabetic foot ulcers 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. Additional clinical trials are needed to investigate the safety and effectiveness of this product for other applications.
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 small 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 smaller non-blinded RCT involving 25 subjects with diabetic foot ulcers 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.
The largest study currently available was reported by Serena in 2014. This unblinded RCT involved 84 subjects with VLUs randomized 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 diabetic foot ulcers 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.
Based on this evidence, specifically the data provided in the Serena (2014) and Zelen (2014b) studies, the use of EpiFix appears to provide significant clinical benefit when compared to standard compression therapy alone. 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.
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 small unblinded nonrandomized study need to be further investigated and a large well-controlled blinded trial is warranted.
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). Demographics between the two groups were smiliar, 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). 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 AlloDerm RTM (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). Another retrospective non-controlled study, also discussed in the DermaMatrix section below, involved 173 subjects receiving breast reconstruction and implantation with AlloDerm RTM (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 9 soft tissue infections, 8 partial flap necroses, and 2 seromas. Eleven subjects ultimately required explantation. Subjects undergoing radiation therapy (n=26) were significantly more likely to have complications (30.8% vs. 13.7%).
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 AlloDerm RTM. 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 RTM 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 RTM with regard to safety and efficacy since there is significant bias in the study design.
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 AlloDerm RTM (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 RTM 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 small nonrandomized or blinded study, the results of this study demonstrate that the use of FlexHD appears to be inferior to AlloDerm RTM 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.
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), AlloDerm RTM (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 RTM (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.
Cahan and colleagues (2011), evaluated a new surgical approach to breast reconstruction. This study involved 98 subjects undergoing 159 mastectomies using either FlexHD or AlloDerm RTM. 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.
Finall, a small 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 ocurred 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.
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 AlloDerm RTM 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 along side the AlloDerm products.
Fresh Frozen Unprocessed Allograft Skin (including AlloSkin and TheraSkin)
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 VLUs 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 VLUs 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 patient 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 a small RCT involving 23 subjects with diabetic foot ulcers 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, diabetic foot ulcers managed with Theraskin are approximately twice as likely to heal as diabetic foot ulcers 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."
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.
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). However, efficacy has not been demonstrated in the literature for other uses.
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.
TransCyte is a composite product composed of a polymer membrane impregnated with neonatal human fibroblast cells that has been approved through the FDA's PMA process. The available literature for TransCyte consists of three small randomized, controlled trials investigating its use for the treatment of burns (Demling, 1999; Kumar, 2004; Noordenbos, 1999). The study by Kumar involved 33 partial-thickness burn subjects with 58 wound sites, randomly assigned to treatment with TransCyte (n=20), Biobrane (n=17), or Silvazine cream (n=21). Mean time to re-epithelialization was 7.5 days for TransCyte, 9.5 days for Biobrane, and 11.2 days for Silvazine. The number of wounds requiring autografting were 5/21 (24%) for Silvazine, 3/17 (17%) for Biobrane, and 1/20 (5%) for TransCyte. The study by Noordenbos involved 14 subjects with partial-thickness burns assigned to receive treatment with either silver sulfadiazine (n=7) or TransCyte (n=7). The authors report that wounds treated with TransCyte healed more quickly (mean 11.14 days to 90% epithelialization vs. 18.14 days, p=0.002). There were no infections in the 32 wound sites treated with TransCyte. Late wound evaluations at 3, 6, and 12 months post-burn were performed with use of the Vancouver Scar Scale, which indicated that wound sites treated with TransCyte healed with less hypertrophic scarring than sites treated with silver sulfadiazine (p<0.001 at 3 and 6 months, p=0.006 at 12 months). Finally, the study by Demling and others involved 31 subjects assigned to receive treatment with either TransCyte (n=21) or open technique using bacitracin ointment applied 2-3 times daily (n=10). The findings include significant improvements in the TransCyte group compared to the antibiotics group in relation to wound care time (p<0.05), decrease in pain (p<0.05), and re-epithelialization time (p<0.05).
Products addressed in the Investigational and Not Medically Necessary statement
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).
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 small 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. Only a few of these studies are randomized controlled trials (Amer, 2010; Andonovska, 2008; Harvinder, 2005; Küçükerdönmez, 2007; Luanratanakorn, 2006; Paris, 2013). Unfortunately, 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.
Artelon CMC 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.
Artelon TMC is a synthetic grafting material made from degradable polyurethaneurea cleared through the FDA's 510K process. At this time, the available peer-reviewed published articles addressing this product are very small 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 was published by Brooks and others (2011). This case series study involved 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.
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 1 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. The results of this small uncontrolled case series are promising. Further data from more rigorously designed and executed studies is warranted.
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 AlloDerm RTM (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 RTM subjects, 9 Belladerm subjects, and 8 Repriza subjects. No AlloDerm RTM 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 small and the methodology too weak to sufficiently assess the safety or efficacy of any of these products for this procedure.
Biobrane is a synthetic product composed of a silicone film bonded to a nylon fabric base that 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). While all of these studies found that in comparison to their various control groups the use of Biobrane significantly improved pain scores and healing times, unfortunately all of these studies involved small numbers of participants and were not conducted in a blind fashion. Further data are required to allow a thorough assessment of the efficacy of this technology.
Please see 'Surgisis' section below.
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.
Cymetra, an injectable micronized particulate form of AlloDerm RTM (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 month 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 small (n=10) case series study. 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.
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 AlloDerm RTM (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. Further study is warranted to evaluate the safety and efficacy of DermaMatrix for breast reconstruction. A larger retrospective non-controlled study was done which involved 173 subjects receiving breast reconstruction and implantation of either AlloDerm RTM (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 AlloDerm RTM (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 RTM 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.
This study does not support the use of DermaMatrix for parotid reconstruction surgery. Additional studies are warranted to determine the safety and efficacy of this product for this indication.
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 AlloDerm RTM (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 RTM 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 small nonrandomized or blinded study, the results of this study demonstrate that the use of DermaMatrix appears to be similar to AlloDerm RTM with regard to the occurrence of postoperative seromas, and significantly better that 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 AlloDerm RTM to DermaMatrix for immediate breast reconstruction procedures. The planned follow-up time was 2.5 years. Argarwal randomized 128 subjects to undergo reconstruction with either AlloDerm RTM (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 RTM 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 RTM group it was 33.6% vs. 38.8% in the DermaMatrix group (p=0.52). The only complications that were significantly different between group were early loss of the implant defined as less than 45 days (1.0% for AlloDerm RTM vs. 6.1% for DermaMatrix; p=0.049) and loss due to skin necrosis (1.0% for AlloDerm RTM vs. 47.1% for DermaMatrix; p=0.027). The authors also reported that less time was needed in the AlloDerm RTM group for complete expansion vs. DermaMatrix (42 days vs. 70 days; p<0.001). The results from Phase II and Phase III of the BREASTrial are forthcoming.
Enduragen is a product composed of porcine acellular dermal matrix and has been cleared through the FDA's 510K process. McCord and others 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.
E-Z Derm is a product composed of porcine acellular dermis that has been cleared through the FDA's 510K process. The available evidence addressing the use of the E-Z Derm brand porcine-derived decellularized fetal skin is limited to two small trials from over a decade ago (Healy, 1989; Vanstraelen, 1992). While both of these studies are controlled trials, they are hampered by small numbers of participants (20 and 32 respectively). The Vanstraelen study concluded that hypertrophic scarring occurred in 25% of xenograft-dressed sites, but none was seen in the comparison group. In addition, 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 E-Z 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. Data from more recent trials is not available but is needed.
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 1 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.
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.
Grafix is a grafting product derived from allogeneic chorionic membrane. It is treated as human tissue for transplantation under the FDA's HCT/P process. A small number of peer-reviewed published articles addressing the use of Grafix are available, but only one RCT has been reported. Lavery and others (2014) conducted a RCT involving 97 subjects with diabetic foot ulcers (DFU) who were randomized to receive treatment with either Grafix (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.
The only other reasonably sized published study currently available addressing the use of Grafix included 67 wounds in 66 subjects with either diabetic foot ulcers (n=27), VLUs (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%) VLUs and 23 of 27 (85.2%) diabetic foot ulcers 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.
Further study is warranted regarding the safety and efficacy of this product.
GraftJacket is an acellularized human skin-derived product and is treated as human tissue for transplantation under the FDA's HCT/P process. The current body of evidence available in the peer-reviewed medical literature addressing the use of GraftJacket for the treatment of diabetic skin lesions is limited to a few small studies. 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 diabetic foot ulcers 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). A third RCT involved 85 subjects with diabetic foot ulcers assigned to receive treatment with either GraftJacket (n=46) or standard care (n=39) (Reyzelman, 2009). 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. These studies do not provide sufficient data to allow full evaluation of GraftJacket. Further investigation is warranted.
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 who were 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.
While the data reviewed shows some benefit of GraftJacket use, further studies with larger populations are warranted to better evaluate the safety and efficacy of this product.
The currently available evidence addressing the use of Hyalomatrix is limited mostly to small, uncontrolled, unblinded case series studies. The largest studies available involve 300, 262, and 57 subjects (Gravante 2007; Caravaggi, 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 small 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 Matrix Wound Dressing
Integra matrix wound dressing is derived from bovine tendon collagen and glycosaminoglycan. It has been cleared through the FDA's 510K process. It is a type of wound care device comprised of a porous matrix of cross-linked bovine tendon collagen and glycosaminoglycan. At this time, there are no peer-reviewed published studies regarding the efficacy of this device in the clinical setting. Such data is needed for an appropriate evaluation of this technology.
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 small 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.
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 2 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. 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).
A much smaller 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.
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 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, only two studies have been published in peer-reviewed journals describing this use (Farole, 2008; Wangensteen, 2010). The study by Wangensteen and colleagues was a retrospective analysis of 96 subjects with various nerve injuries who underwent 126 nerve repairs with Neruogen conduits. Only 64 (66.7%) subjects were seen at follow-up. Twenty-six of 126 repairs had quantitative testing of nerve recovery, with 35% reporting improvement and 31% going on to additional surgery. Sixty of 126 repairs underwent qualitative testing, with 45% reporting improvement and 5% going on to additional surgery. Overall, sensory recovery was between 35-45%.
The Farole study is a small case series study involving only 8 subjects with facial nerve damage followed for at least 1 year. The authors report 4 subjects had good improvement. Using the criteria described by another author, 4 cases were found to have good improvement, 4 with some improvement, and 1 had no improvement. None of the cases had worsening of symptoms.
Further study is needed to fully evaluate the safety and efficacy of this product.
Oasis is a grafting product composed of decellularized intestinal mucosa of porcine origin and has been cleared through the FDA's 510K process. At this time, there are only a limited number of peer-reviewed published studies addressing the use of this product. The first was published by Mostow and colleagues (2005). They described a randomized controlled trial (RCT) involving 62 participants who received Oasis and compression therapy for venous stasis leg ulcers 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 diabetic foot ulcers (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 study 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.
In summary, the available evidence addressing the use of Oasis is limited to small unblinded studies with limited generalizability. At this time, the available data addressing the use of Oasis is insufficient to allow conclusions to be drawn regarding its efficacy and safety. Data from larger, randomized blinded trials is warranted to fully understand these aspects of Oasis use in the clinical setting.
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 is a product derived from decellularized bovine pericardium and cleared through the FDA's 510K process. At this time there is only one 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.
Perlane - See Restylane
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 to a single retrospective, nonrandomized controlled study of 37 subjects undergoing congenital diaphragmatic hernia repair. 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. Further investigation into the safety and efficacy of Permacol is needed.
Primatrix is a product derived from acellular bovine dermis 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 venous stasis ulcers (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 venous stasis wounds 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 venous stasis ulcers, 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. No data addressing statistical significance of these findings was provided, making the relevance of this data unclear.
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."
Neither of these small controlled studies were randomized, and it is unclear what the criteria were for group selection. Additionally, the retrospective nature, small sample size and lack of blinding significantly impair the usefulness of this data in understanding the comparative efficacy of PriMatrix.
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 diabetic foot ulcers 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 et al. involved 73 subjects with VLUs 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.
Restylane and Perlane are injectable synthetic hyaluronic acid products that received PMA approval from the FDA in 2003 for the treatment of facial wrinkles. Use of these products has also been proposed for the treatment of vocal cord paralysis through injection laryngoplasty. There are currently only two studies published in the peer-reviewed literature addressing this use. The first study, by Lau and colleagues, was intended to determine if particle size affects durability of medialization in individuals undergoing injection laryngoplasty for unilateral vocal cord paralysis. This prospective randomized controlled single-blind trial compared 6month outcomes between subjects injected with Restylane, which has a small particle size, and those injected with Perlane, which has a large particle size. Data for 17 subjects were reported. The authors stated that Normalized Voice Handicap Index scores at 6 months after injection laryngoplasty were significantly lower in the Perlane group vs. the Restylane group when not adjusted for age and sex (p=0.027). After adjustment, the difference was not significant (p=0.053). They concluded that their findings support the hypothesis that the larger particle-size of hyaluronic acid results in more durable outcomes for injection laryngoplasty. The second study by Wang et al. investigated the feasibility of using an injectable needle electrode to guide injection of Restylane or Perlane during laryngeal electromyography for unilateral vocal fold paralysis. Only 16 subjects were enrolled. The authors reported that at 6 month follow-up there were significant improvements in the normalized glottal gap area, maximal phonation time, Voice Handicap Index, and other measures.
The data from these two studies show that, at least in the limited study polulations evaluated, the use of Restylane and Perlane for injection laryngoplasty is safe and effective. However, due to the small number of subjects and short follow-up times, the value of these findings is limited. Additional evidence is needed to better understand the safety and efficacy of injection laryngoplasty with these products in the general population.
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 small studies with significant methodological flaws. Further investigation with robust trials is warranted.
Strattice is an acellular dermal collagen product of porcine origin and is 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. AlloDerm RTM (n=90) for tissue expander breast reconstruction (Glasberg, 2012). The authors reported a significantly higher complication rate in the AlloDerm RTM 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 RTM and 2.8% for Strattice). This study was not prospective, randomized, or blinded. Further study with more rigorous study designs would be welcome.
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. Nine subjects had concomitant panniculectomy (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), AlloDerm RTM (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. The authors concluded that although biologic mesh in these situations is safe, the long-term durability seems to be less favorable. Additionally, it should be noted that no data was presented separating outcomes by product used, so no conclusions can be made on the benefit of any individual product alone.
The results of these studies are an interesting beginning into the understanding of the clinical performance of Strattice. Further investigation with larger, more robust randomized controlled methodology is needed to better understand the safety and efficacy of this product.
Also see Clemens, 2013 in the SurgiMend section below for an additional study involving Strattice.
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 to two small studies. The first was a small RCT involving 22 subjects with burn injuries treated with split-thickness skin grafts (Schwarze, 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 Omiderm 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). Unfortunately, this small sample of subjects in these studies is not sufficient to allow generalization of the findings.
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 was done using SurgiMend and the other 59 used AlloDerm RTM. 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 RTM 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 RTM 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 RTM; 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), a product not available in the U.S. 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 Subjects 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 subjects pool, lack of blinding and randomization, and retrospective nature of the study limit the utility of these findings.
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 provide 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.
Overall, the available evidence for SurgMend 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.
Surgisis is a product composed of decellularized intestinal mucosa of porcine origin and is cleared under the FDA's 510k process. At this time, there are a large number of case series studies published on the use of the Surgisis anal fistula plug (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.
Two 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.
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 1of 7 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 4 different hospitals. After a median of 13 months, 30 (24%) of fistulae had closed with no discomfort or secretion reported. The outcomes in the 4 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 [hazard ratio (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.
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.
Surgisis is a product composed of decellularized intestinal mucosa of porcine origin and is cleared under the FDA's 510k process. Unlike the product discussed above, Surgisis Gold is provided in larger sheets and proposed for the closure of fascial layers following abdominal surgery procedures. At this time, only one published study addresses this product. Sarr and others (2014) conducted a 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.
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 venous stasis leg ulcers 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.
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.
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 VLUs (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.
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: http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/DeviceApprovalsandClearances/PMAApprovals/default.htm.
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: http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/DeviceApprovalsandClearances/510kClearances/default.htm.
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: http://www.fda.gov/medicaldevices/deviceregulationandguidance/howtomarketyourdevice/premarketsubmissions/humanitariandeviceexemption/default.htm.
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.
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 (e.g., Biobrane) are composed of man-made materials to form a complex multilayer covering for wounds. This type of product may consist of a wide array of materials including silicone, nylon, and others, as well as collagen or other biologic materials.
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 RTM, 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, TransCyte).
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 Autologous / Allogeneic / Xenographic Products
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.
Xenographic products may be combined with synthetic materials to create a composite product (e.g. Avaulta Plus, Integra Matrix, Integra Bilayer Matrix).
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.
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.
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 skin substitutes and soft tissue grafts:
When services may be Medically Necessary when criteria are met:
|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]|
|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|
When services are Investigational and Not Medically Necessary:
For the procedure codes listed above when criteria are not met, or 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:
|31599||Unlisted procedure, larynx [when specified as injection laryngoplasty]|
|46707||Repair of anorectal fistula with plug (eg, porcine small intestine submucosa [SIS])|
When services may be Medically Necessary when criteria are met [for Apligraf, EpiFix (sheet or membrane form), OrCel, and Dermagraft]:
|Q4100||Skin substitute, not otherwise classified [when specified as OrCel]|
|Q4101||Apligraf, per square centimeter|
|Q4106||Dermagraft, per square centimeter|
|Q4131||EpiFix, per square centimeter|
|E08.00-E13.9||Diabetes mellitus [Apligraf, Dermagraft, EpiFix]|
|I83.001-I83.029||Varicose veins of lower extremities with ulcer [Apligraf, EpiFix]|
|I83.201-I83.229||Varicose veins of lower extremities with both ulcer and inflammation [Apligraf, EpiFix]|
|I87.011-I87.019||Postthrombotic syndrome with ulcer [Apligraf, EpiFix]|
|I87.031-I87.039||Postthrombotic syndrome with ulcer and inflammation [Apligraf, EpiFix]|
|I87.2||Venous insufficiency (chronic) (peripheral) [Apligraf, EpiFix]|
|I87.311-I87.319||Chronic venous hypertension (idiopathic) with ulcer [Apligraf. EpiFix]|
|I87.331-I87.339||Chronic venous hypertension (idiopathic) with ulcer and inflammation [Apligraf, EpiFix]|
|L12.30-L12.35||Acquired epidermolysis bullosa [Dermagraft, OrCel]|
|L97.101-L97.929||Non-pressure chronic ulcer of lower limb, not elsewhere classified [Apligraf, Dermagraft, EpiFix]|
|L98.411-L98.499||Non-pressure chronic ulcer of skin, not elsewhere classified [Apligraf, Dermagraft, EpiFix]|
|Q81.0-Q81.9||Epidermolysis bullosa [Dermagraft, OrCel]|
When services may be Medically Necessary when criteria are met [for AlloDerm RTM, AlloDerm RTU]:
|Q4116||AlloDerm, per square centimeter [AlloDerm RTM, AlloDerm RTU]|
|All diagnoses including, but not limited to, the following:|
|C50.011-C50.929||Malignant neoplasm of breast|
|C79.81||Secondary malignant neoplasm of breast|
|D05.01-D05.99||Carcinoma in situ of breast|
|N65.1||Disproportion of reconstructed breast|
|Z42.1||Encounter for breast reconstruction following mastectomy|
|Z85.3||Personal history of malignant neoplasm of breast|
|Z90.10-Z90.13||Acquired absence of breast and nipple|
When services may be Medically Necessary when criteria are met [for FlexHD]:
|Q4128||FlexHD, Allopatch HD, or Matrix HD, per square centimeter [when specified as FlexHD]|
When services may be Medically Necessary when criteria are met [for AlloSkin, Integra Bilayer Matrix Wound Dressing, TheraSkin, TransCyte]:
|C9363||Skin substitute, Integra Meshed Bilayer Wound Matrix, per square centimeter|
|Q4100||Skin substitute, not otherwise classified [when specified as TransCyte]|
|Q4104||Integra Bilayer Matrix Wound Dressing (BMWD), per square centimeter|
|Q4115||AlloSkin, per square centimeter|
|Q4121||TheraSkin, per square centimeter|
|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 Investigational and 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 investigational and not medically necessary.
When Services are also Investigational and Not Medically Necessary:
|C9349||PuraPly, and PuraPly Antimicrobial, any type, per square centimeter [change to trade name, formerly Fortaderm, Fortaderm Antimicrobial]|
|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|
|G0428||Collagen meniscus implant procedure for filling meniscal defects (e.g., CMI, collagen scaffold, Menaflex)|
|L8607||Injectable bulking agent for vocal cord medialization, 0.1 ml, includes shipping and necessary supplies|
|Q4100||Skin substitute, not otherwise specified [when describing a product with no specific code indicated as investigational and not medically necessary]|
|Q4102||Oasis Wound Matrix, per square centimeter|
|Q4103||Oasis Burn Matrix, per square centimeter|
|Q4105||Integra Dermal Regeneration Template (DRT), per square centimeter|
|Q4107||Graftjacket, per square centimeter|
|Q4108||Integra Matrix, per square centimeter|
|Q4110||PriMatrix, 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|
|Q4119||Matristem wound matrix, per square centimeter|
|Q4120||Matristem burn matrix, per square centimeter|
|Q4122||Dermacell, per square centimeter|
|Q4123||AlloSkin RT, per square centimeter|
|Q4124||Oasis Ultra Tri-Layer Wound Matrix, per square centimeter|
|Q4125||ArthroFlex, per square centimeter|
|Q4126||Memoderm, dermaspan, tranzgraft or integuply, per square centimeter|
|Q4127||Talymed, per square centimeter|
|Q4128||FlexHD, AlloPatch HD, or Matrix HD, per square centimeter [when specified as AlloPatch HD or Matrix HD]|
|Q4129||Unite Biomatrix, per square centimeter|
|Q4130||Strattice, per square centimeter|
|Q4132||Grafix CORE, per square centimeter|
|Q4133||Grafix PRIME, per square centimeter|
|Q4134||hMatrix, per square centimeter|
|Q4135||Mediskin, per square centimeter|
|Q4136||EZ-derm, per square centimeter|
|Q4137||AmnioExCel 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 1K, per square centimeter|
|Q4149||Excellagen, 0.1 cc|
|Q4150||Allowrap DS or Dry, per square centimeter|
|Q4151||AmnioBand or Guardian, 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, per square centimeter|
|Q4157||Revitalon, per square centimeter|
|Q4158||MariGen, per square centimeter|
|Q4159||Affinity, per square centimeter|
|Q4160||NuShield, per square centimeter|
|Q4161||Bio-connekt wound matrix, per square centimeter|
|Q4162||Amniopro flow, Bioskin flow, Biorenew flow, Woundex flow, Amniogen-A, Amniogen-C, 0.5 cc|
|Q4163||Amniopro, Bioskin, Biorenew, Woundex, Amniogen-45, Amniogen-200, per square centimeter|
|Q4164||Helicoll, per square centimeter|
|Q4165||Keramatrix, per square centimeter|
Peer Reviewed Publications:
Meta-Analyses and Systematic Reviews
AlloDerm RTM Ready To Use
Amniotic Allografts –Not specified
Avance Nerve Graft
Biodesign (See Surgisis section below)
Perlane- See Restylane.
See Solomon (2013) in the Belladerm section above.
XenoGrafts (unspecified) for Burns
Government Agency, Medical Society, and Other Authoritative Publications:
|Websites for Additional Information|
Bilaminate Skin Substitute
Culture-Derived Human Skin Equivalent
Human Skin Equivalent
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.
|Revised||05/05/2016||Medical Policy & Technology Assessment Committee (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 Reference sections.|
|Revised||11/05/2015||MPTAC review. Added Restlyane and Perlane to investigational and not medically necessary list. Updated Rationale, and Reference 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, Reference, and Background 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 Reference 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, Reference 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, Reference 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, Reference 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 Reference 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.|
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, Reference, 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 Reference 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, Reference 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|
|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|
|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|