|Subject:||Allogeneic, Xenographic, Synthetic and Composite Products for Wound Healing and Soft Tissue Grafting|
|Policy #:||SURG.00011||Current Effective Date:||01/01/2014|
|Status:||Revised||Last Review Date:||08/08/2013|
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. This document addresses the use of soft tissue (e.g., skin, ligament, cartilage, etc.) substitutes in wound healing and surgical procedures.
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: For additional information please see:
Alloderm® is considered medically necessary for either of the following uses:
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:
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.
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 few comparative studies available addressing the clinical outcomes for allographic, xenographic, and composite products, and the results are heterogeneous. 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 was 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. 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.
Meta-analyses and Systematic Reviews
In 2012 two well designed meta-analysis studies were published that evaluated the available peer-reviewed published evidence addressing the use of acellular dermal matrix (ADM) 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 3-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, 2.05; 95 percent confidence interval, 1.55 to 2.70), seroma (relative risk, 2.73; 95 percent confidence interval, 1.67 to 4.46), infection (relative risk, 2.47; 95 percent confidence interval, 1.71 to 3.57), and reconstructive failure (relative risk, 2.80; 95 percent confidence interval, 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.
Finally, a systematic review of ADM use for abdominal wall reconstruction was published by Zhong and others (2012). 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% recurrence to others reporting 80%. Out of the 30 studies reviewed, three used porcine ADM, one a synthetic composite mesh, and one a bovine-derived ADM. No separate data was provided for these studies. The remainder of the studies used allogeneic ADMs. Within the literature there was significant variation with regard to placement of ADMs within the surgical field, with ADM used as underlay/inlay, interposition, overlay/onlay or sandwiched (underlay and overlay) repairs. The type of fascial repair (bridged vs. reinforced) also had significant impact on outcomes. They state that in cases where fascial re-approximation was achieved, ADM used in a reinforced repair with fascial re-approximation was significantly better than that used in a bridged repair without fascial re-approximation. With the significant variation in selection criteria, ADM types, and surgical techniques, this pool of evidence should not be used to evaluate the use of ADM for abdominal reconstructions in a global manner, and each study should be weighted on its own merits.
Alloderm is a human derived decellularized grafting product. There are over a dozen small case series studies and non-randomized, controlled trials published in the peer-reviewed medical literature describing the use of Alloderm to partially or completely enclose an implanted breast prosthesis during post-mastectomy breast reconstruction (i.e., Becker, 2009; Bindingnavele, 2007; Breuing, 2005, 2007; Gamboa-Bobadilla, 2006; Preminger, 2008; Salzberg, 2006, 2011; Spear, 2008). The goal of using Alloderm for this type of procedure is to reduce complications related to contracture, periprosthetic atrophy, and development of thin capsules. The results provided in these case series studies indicate good symmetry, increased soft tissue padding, and decreased rippling and implant visibility. While the available data is limited regarding the long-term benefits and outcomes of this procedure, it has become a widely used and accepted method of breast reconstruction. Expert opinion of breast surgeons supports the use of Alloderm for this indication.
However, care must be taken when selecting Alloderm for use in breast reconstruction. A retrospective non-randomized 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 (n=442; 70.3%) or without Alloderm (n=186; n= 29.6%). The authors reported that major complications were significantly increased in the Alloderm group (15.3% vs. 5.4 %; p=0.001). Complications included infection requiring intravenous antibiotics (8.6% vs. 2.7%; p=0.001), flap necrosis requiring excision (6.7% vs. 2.7%; P=0.015), and explantation of the tissue expander (7.7% vs. 2.7%; p=0.004).
The treatment of infected or contaminated abdominal wall wounds and defects is difficult. Standard fascial prostheses such as polypropylene and polyester mesh, which are routinely used for non-complex cases, may exacerbate wound infection, fistula and adhesion formation, and erosion, leaving few real options for such individuals. The use of Alloderm for the treatment of complex abdominal wall wounds has been reported in over thirty peer-reviewed journal articles (i.e., Espinosa-de-los-Monteros 2007; Glasberg, 2006; Maurice 2009; Lee, 2009; Lin, 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 for breast reconstruction, Alloderm for complex abdominal wall wounds has been widely used and is an accepted treatment method, although data is limited regarding the long-term benefits and outcomes of this use. Expert opinion of surgeons who routinely treat these types of wounds supports the use of Alloderm for this indication.
At this time there is limited data addressing the use of Alloderm in treating chronic wounds. There is very limited evidence available regarding the use of Alloderm in the treatment of burns or for surgical reconstruction procedures such as in the treatment of lid retraction in individuals with Graves' disease or in the prevention of Frey's Syndrome. Additionally, Alloderm has been proposed for use in a wide variety of other surgical applications.
The use of Alloderm has been proposed for the treatment of various nasal and oral surgical 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.
In the one available clinical trial of Alloderm in people with lid retraction due to Graves' disease, only 14 participants were studied in a non-blinded fashion (Sullivan, 2003). While the findings of this study were promising, further controlled studies with larger numbers of participants are needed to confirm the efficacy of this procedure.
There are currently two studies available in the peer-reviewed literature addressing the use of Alloderm for treatment of burns. The first study involved 19 participants randomized to Alloderm with an autograft overgraft vs. Alloderm with an allograft overgraft which was replaced with an autograft overgraft after one week (Munster, 2001). Graft uptake was not different between groups. Immediate use of Alloderm with thin autograft was associated with more healing than spilt thickness grafts. The second study involved 52 non-randomized participants all of whom received Alloderm covering to radial arm free flap donor sites (Sinha, 2003). The results of this study indicated that there were minimal contractures or restrictions to the healed graft. While these studies suggest some benefit from the use of Alloderm for burns, larger randomized trials are needed to confirm efficacy of this procedure.
At this time there are two available studies in the peer-reviewed literature regarding the use of Alloderm to treat Frey's syndrome. The first involved 64 participants randomly assigned to the use of Alloderm placement in the parotid bed following removal of the parotid gland vs. no Alloderm (Govindaraj, 2001). While the rate of gustatory sweating in the Alloderm group was found to be statistically lower than the control group, the Alloderm group also had an almost 3-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 three groups; 1) superficial parotidectomy with placement of Alloderm, 2) superficial parotidectomy without placement, and 3) deep-plane rhytidectomy (Sinha, 2003). The incidence of both subjective and objective Frey's syndrome was significantly higher in group 2 when compared to both groups 1 and 3. However, given the small numbers of subjects in each group, the results of this study do not allow strong conclusions to be drawn as to the effectiveness of this procedure.
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 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 randomized, controlled trial (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 study 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 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. 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 an RCT 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, respectfully (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 eight pieces and eight applications (n=12); 2) two pieces of Dermagraft applied every 2 weeks for a total of eight pieces and four applications (n=14); and 3) one piece of Dermagraft applied every 2 weeks for a total of four pieces and four 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= .03), and those 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.
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. 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. This product was granted an FDA Humanitarian Device Exemption (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. 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 = .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 < .001 at 3 and 6 months, P = .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. The currently available evidence in the peer-reviewed published literature addressing the use of AlloMax consists of a single case series study involving 65 subjects undergoing tissue expander breast reconstruction (Venturi, 2013). The results of this study are limited, but include a complication rate of 4.6% (three subjects). These included 1 case of cellulitis and 2 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.
Avaulta is a composite product composed of polypropylene mesh with acellular cross linked collagen of bovine origin. The use of Avaulta Plus and Avaulta Biosynthetic Support System for the treatment of vaginal prolapse has been described in one prospective case series study involving 40 subjects (Bondili, 2012). Subjects were followed for up to three years (median 27 months (range 20-36). The primary outcome was 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 one 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 likewise 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.
Biobrane is a synthetic product composed of a silicone film bonded to a nylon fabric base. 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 (Lal, 2000; Barret, 2000; Feldman, 1991; Gerding, 1990). 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.
CorMatrix is a product produced from acellular porcine small intestinal submucosa. 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, non-randomized, 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 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 (decellularized human dermis), has been proposed as a minimally invasive tissue graft product. At this time, there are only three peer-reviewed published articles addressing the use of this product. All these studies involve participants with vocal cord paralysis. One study by Morgan and colleagues (2007) was a retrospective, non-randomized, 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 eight 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. Below are discussions of several of the most recent controlled studies.
The use of DermaMatrix was evaluated in a retrospective, non-randomized, controlled trial involving 30 subjects who were assigned to undergo breast reconstruction with DermaMatrix (n=25) or Alloderm (n=25) (Becker, 2009). The authors reported that there were no significant differences between groups with regard to complication rates. Both groups exhibited good incorporation, with evidence of neovascularization. Further study is warranted to evaluate the safety and efficacy of DermaMatrix for breast reconstruction. A larger study was done which involved 173 subjects receiving breast reconstruction and implantation of either Alloderm (n=49), DermaMatrix (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 (n=69) or DermaMatrix (n=31) (2012). Sixty-nine Alloderm implants were associated with a total of 5 complications (7%), whereas 31 DermaMatrix implants were associated with a total of 8 complications (26%) (p=0.0107). Subgroup analyses found that for subtotal parotidectomies, the incidence of complications was found to be 8% for the AlloDerm group and 37% for the DermaMatrix group (p=0.004). The authors conclude that, "…this study suggests that DermaMatrix was associated with increased postoperative complications compared with AlloDerm when used for reconstruction of parotidectomy defects. To better define the complication profile of AlloDerm versus DermaMatrix in the postoperative parotid bed, a prospective study should be considered to determine implant performance following parotidectomy reconstruction." This study does not support the use of DermMatrix for parotid reconstruction surgery. Additional studies are warranted to determine the safety and efficacy of this product for this indication.
Enduragen is a product composed of porcine acellular dermal matrix. 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 percent. 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.
Epifix is a product composed of allogeneic amniotic membrane. The use 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, at this time only two specifically use Epifix (Forbes, 2012; Sheik, 2013). Both of these reports involved very small numbers of subjects, 5 and 4 respectively, and provide limited data demonstrating the safely and efficacy of this product. The remainder of the available peer-reviewed published evidence involves the use products that are not specified by the authors. Aside from Epifix, there are several other commercially available products made from amniotic membrane tissue , including Amniofix and Amniomatrix. Each of these products is harvested and processed using different methods that affect the product's physical properties. Until such time as evidence is available for a specific product, the use of such amniotic tissue-derived materials cannot be fully evaluated.
E-Z Derm is a product composed of porcine acellular dermis. The available evidence addressing the use of E-Z Derm brand porcine-derived decellularized fetal skin is limited to two small trials from over a decade ago (Vanstraelen, 1992; Healy, 1989). 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, and time for spontaneous healing, analgesic requirements or frequency of dressing changes. Data from more recent trials is not available but is needed.
Flex HD is an acellular hydrated dermis product. For the most part, the data addressing the use of Flex HD is from retrospective, non-randomized, controlled studies. The largest of these 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 Flex HD and 280 underwent standard reconstruction without implantation. The authors noted significant differences in the baseline characteristics between groups, with the Flex HD group having a larger body mass (p=0.0001) and more nipple-sparing mastectomies (p=0.04). Postoperatively, the Flex HD 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 Flex HD 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 Flex HD (n=159; 233 breasts) to Alloderm (n=96; 136 breasts). This study found no significant differences between groups with regard to total complication rate including flap necrosis (p=0.849), IV antibiotic use (p=0.09), hematoma (p=0.431), seroma (p=1.0), and dehiscence (p=1.0). A third study, already discussed in the DermaMatrix section, involved 173 subjects receiving breast reconstruction and implantation with Alloderm (n=49), DermaMatrix (110), Flex HD (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 conducted the largest published study investigating FlexHD (2011). This case series study describes 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%).
The prospective data for Flex HD is limited to several small case series studies. The largest, by Cahan and colleagues, was intended to evaluate a new surgical approach to breast reconstruction. This study involved 98 subjects undergoing 159 mastectomies using either Flex HD or Alloderm. The authors report that successful reconstruction was achieved in 93% of cases. Complications were seen in 23% of subjects, including dehiscence, seroma, full thickness necrosis and infection. Removal of the implant was needed in 5 cases as a result of persistent infection (5%). Unfortunately, no data was provided enumerating the numbers of subjects receiving each product nor was any data provided comparing outcomes between product groups. The relative performance of Flex HD in this setting is unclear. Another prospective study included 50 subjects undergoing single-stage breast reconstruction with Flex HD (Rosenberg, 2011). The authors report that at 6 months, histologic samples demonstrated vascular and cellular ingrowth in the Flex HD graft. Removal of the implant was required in 6 subjects (12%), seroma requiring drainage occurred in 10 subjects (20%), and infection was reported in 6 subjects (12%). Dehiscence of the implant occurred in one subject.
Overall the data addressing the use of Flex HD is of poor quality. Additional data from prospective randomized studies would assist in better understanding the safety and efficacy of this product.
Gore BioA is a completely synthetic, bioabsorbable product composed of 67% polyglycolic acid and 33% trimethyl chitosan. 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 two 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 depending on the number of previous interventions. In individuals having had only drainage of the abscess, success occurred in 63.6% (14/22) whereas in those having had one or more flap fistula reconstructions the healing rate decreased slightly to 50% (9/18). Further study is warranted to better understand the impact of surgeon experience as well as optimal patient selection criteria for individuals requiring treatment for anal fistulas.
Graftjacket is an acellularized human skin-derived product. 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) vs. 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 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). Another study by Gupta and others involved 24 subjects with rotator cuff tears who were followed for 3 years postoperatively (2012). 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.
Integra Matrix Wound Dressing
Integra matrix wound dressing is derived from bovine tendon collagen and glycosaminoglycan. 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.
There is limited peer-reviewed literature addressing the use of MatriDerm, a decellularized dermis allograft product. The largest available study involves 30 subjects undergoing nasal tip skin grafts non-randomly assigned to receive conventional full-thickness skin grafting, retroauricular perichondrodermal composite grafts, and skin transplantation supplemented with MatriDerm (Riml, 2011). Ten subjects were assigned to each group. This retrospective study was conducted in a randomized and blind manner by assigned reviewers using the Manchester scale. The authors report that two (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 (e.g., MediHoney®) 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, most addressing the treatment of venous leg and foot ulcers. Jull and colleagues published the largest of these trials, which included 368 subjects randomized to receive treatment with either calcium alginate dressing impregnated with manuka honey or standard care with whatever dressings were appropriate for the individual at that time (2008). After following the participants for a total of 12 weeks of follow-up, the authors concluded that there was no significant difference in outcomes between the two groups. It was noted that the honey-treated group experienced significantly greater numbers of adverse events (p = 0.013). Contradicting these findings is a study by Gethin and Cowman (2008). In this study 108 subjects with venous ulcers were randomized to receive treatment with either honey dressing or standard hydrogel therapy. The findings were that the honey treated group had significantly better results in terms of median reduction in wound size at 12 weeks (44% vs. 33% , p=0.037), but no significant differences between groups in other primary endpoints were reported.
The other most studied condition addressed in the literature is the treatment of burns. The largest study currently available addressing burns involved 150 subjects randomized to receive treatment with either silver sulphadiazine (SSD) or honey (Malik, 2010). Each subject acted as his or her own control, with one burn site randomly treated with SSD and the other with honey. The authors report that the honey treated sites had significantly faster re-epithelialization and healing of superficial and partial thickness burns than the SSD sites (13.47 days vs. 15.62 days, p < 0.0001). Additionally, the honey treated sites achieved complete healing significantly faster than SSD sites (21 days vs. 24 days, p < 0.0001).
Lund and colleagues compared the use of honey-coated dressing for breast malignant wounds. In this study 67 subjects, 79% of whom had breast cancer, were randomized to receive treatment with either honey-coated dressing (n=34) or silver dressing (n=33). The authors report no significant differences between groups, and they concluded that the possible antibacterial effect of either treatment "could not be confirmed in these malignant wounds".
At this time, the evidence addressing the use of honey for skin wounds is lacking. The current studies are mostly unblinded, controlled studies, and a large variety of controls have been used. These factors make comparison study outocomes 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 fifty-nine months (range, sixteen to ninety-two months). Repeat arthroscopies done in the experimental group at one 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 non-randomized 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 and 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.
Neuragen collagen tube conduits are composed of bovine-derived acellular collagen, and have been 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. 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), and they describe 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 of the OASIS group over the control group at 12 weeks. Another publication described an 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 describes 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. 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 three months follow-up, there were significantly more surgical failures and recurrences in the Pelvicol group, but by the three-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".
Peri-Strips Dry is a product derived from decellularized bovine pericardium. 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.
Permacol is an acellular dermal collagen product of porcine origin. Currently, the peer-reviewed published data addressing the use of Permacol is limited to a single retrospective non-randomized, 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 the 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. To date, there are only a limited number of small studies addressing its use in humans. One retrospective non-randomized 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 the 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 non-randomized 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 (87.9mm3/wk) compared with control (59.0mm3/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 was 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. 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, in 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 venous leg ulcers 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.
Seamguard is a synthetic product composed of polyglycolic acid: and trimethylene carbonate. 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, 84 who were assigned to the Seamguard group and 42 to 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.
Strattice is an acellular dermal collagen product of porcine origin. 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 (n=90) for tissue expander breast reconstruction (Glasberg, 2012). The authors reported a significantly higher complication rate in the Alloderm group (21.4% vs. 6.3%; p=0.0003), caused by the incidence of seromas (12.7% vs. 1.4%; p=0.0003). No other significant differences were reported, including capsule formation (2.4% for Alloderm and 2.8% for Strattice). This study was not prospective, randomized, or blinded. 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 unanticipated adverse events occurred, and 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 OR. Wound dehiscence and seroma were noted in 3 subjects respectively. One subjects required skin grafting for wound closure.
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.
SurgiMend is a product made from acellular fetal bovine dermis. The available peer-reviewed published literature addressing its use in humans is limited to a few studies. The largest of these was a non-randomized 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. The investigators reported no significant differences in complication rates between the two products in the incidence of hematoma, infection, major skin necrosis, or breast implant removal. However, the incidence of seroma was significantly more common in the Alloderm subjects (15.7%) than in the SurgiMend group (8.3%) (p<0.05). However, this finding must be considered in light of the fact that the Alloderm group was followed up, on average for over twice the length of time (15.6±8.79 months for SurgiMend vs. 32.8±15.87 for Alloderm; p<0.0001). The SurgiMend group had a significantly higher rate of any necrosis (11.0% [39/351] for the SurgiMend vs. 3.4% [3/89]; p<0.0265). In a multivariate analysis, it was found that both a BMI > 30kg/m2 and previous radiation therapy significantly increased the rate for complications and expander loss.
The only other article found was another retrospective non-randomized case series of 28 subjects who underwent 49 breast reconstructions with SurgiMend compared to 91 subjects who underwent 123 breast reconstructions with no additional grafting materials (Endress, 2012). The mean immediate fill volume in group A was 181.2±148.3 mL and 117.7±66.3 mL in group B (p<0.001). The results show that the duration of drainage was significantly shorter in the SurgiMend group vs. controls (8.51±3.4 days vs. 11.07±5.1 days; p<0.015). No significant differences in the overall complication rate were noted (20.8% in group A, 13.0% in group B). 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. At this time, there are a large number of case series studies published on the use of the Surgisis anal fistula plug (Ellis, 2010; Champagne, 2006; 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 one 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 non-randomized, controlled, retrospective trials. Ellis and colleagues described the results of a study that involved 95 control subjects who had transsphincteric or rectovaginal fistulas repaired via advancement flap repair (2007). The experimental group included only 18 subjects who received treatment with Surgisis. The results indicated a significant benefit to the Surgisis procedure. Another study included 80 subjects who received treatment with either anal fistula plug or endorectal advancement flap (Christoforidis, 2009). The results of this trial demonstrated that treatment success was close to over twice as likely with the flap procedure compared to treatment with a fistula plug after a mean follow-up period of 56 months. Chung and colleagues (2009) reported on the results of a retrospective study that involved 245 subjects who underwent anal fistula repair surgery with either Surgisis (n=27), fibrin glue (n=23), Seton drain (n=86), or an endorectal advancement flap procedure (n=96). The results indicate that the rate of success was similar between the Surgisis group and the endorectal advancement flap group. Hyman and others conducted a study that involved 245 subjects who received one of seven procedures, including the Surgisis plug (n=43), endorectal advancement flap (n=4), Seton drain (n=34), fibrin glue (n=5), fistulotomy (n=156), and other unspecified procedures (n=3) (2009). In contrast to the findings of the Chung study, the authors reported that the Surgisis plug demonstrated the lowest success rate, with only 32% healed at 3 months vs. 87% for the fistulotomy group.
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.
Talymed is a synthetic product composed of poly-N-acetyl glucosamine (pGIcNAc) isolated from microalgae. 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 one of 3 groups that received standard treatment combined with different treatment frequencies with talymed: 1) applied only once, 2) once every other week, or 3) once every third week. Seven subjects were lost to follow-up, 5 from the one application group and 2 from the every three weeks group. Additionally, another 4 subjects were withdrawn from the study, 3 from the one application group and 1 from the every three 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.
The use of Theraskin cryopreserved human skin allograft has only been described in 2 studies (DiDomenico, 2011; Landsman, 2010). Landsman and colleagues conducted a single-center, retrospective, uncontrolled case series study of 188 subjects with venous leg ulcers 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 only 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 venous leg ulcer and diabetic foot ulcers. No superiority was found, and in the absence of the desired outcome, the authors proffer that Theraskin as 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 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 conclude that Theraskin was more efficacious in healing diabetic foot ulcers. Again, this conclusion is flawed, in that this small study was not properly powered to determine whether or not Theraskin was more effective than Apligraf. In order to properly test for their hypothesis of superiority, the authors would have had to include a much larger study population.
At this time, given the data available, no solid conclusions can be made regarding the superiority, equivalency, or inferiority of Theraskin in relation to other treatment options. The results of these studies demonstrate the need for better quality data from large, long term controlled trials in order to properly assess the safety and efficacy of Theraskin.
Veritas is a decellularized product derived from bovine pericardium. 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.
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, from 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 hernia 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, 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 is 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 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|
|ICD-9 Diagnosis||[For dates of service prior to 10/01/2014]|
|ICD-10 Diagnosis||[For dates of service on or after 10/01/2014]|
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 (e.g., porcine small intestine submucosa [SIS])|
|ICD-9 Diagnosis||[For dates of service prior to 10/01/2014]|
|ICD-10 Diagnosis||[For dates of service on or after 10/01/2014]|
When services may be Medically Necessary when criteria are met [for Apligraf, OrCel, and Dermagraft]:
|Q4100||Skin substitute, not otherwise classified [when specified as OrCel]|
|Q4101||Apligraf, per square centimeter|
|Q4106||Dermagraft, per square centimeter|
|ICD-9 Diagnosis||[For dates of service prior to 10/01/2014]|
|250.00-250.93||Diabetes mellitus [Apligraf, Dermagraft]|
|454.0-454.2||Varicose veins of lower extremities with ulcer/inflammation [Apligraf]|
|459.11-459.13||Postphlebitic syndrome with ulcer/inflammation [Apligraf]|
|459.31-459.33||Chronic venous hypertension with ulcer/inflammation [Apligraf]|
|459.81||Venous (peripheral) insufficiency, unspecified [Apligraf]|
|707.10-707.9||Ulcer of lower limbs, chronic ulcer of other or unspecified site [Apligraf, Dermagraft]|
|757.39||Other specified anomalies of skin (epidermolysis bullosa) [Dermagraft, OrCel]|
|ICD-10 Diagnosis||[For dates of service on or after 10/01/2014]|
|E08.00-E13.9||Diabetes mellitus [Apligraf, Dermagraft]|
|I83.001-I83.029||Varicose veins of lower extremities with ulcer [Apligraf]|
|I83.201-I83.229||Varicose veins of lower extremities with both ulcer and inflammation [Apligraf]|
|I87.011-I87.019||Postthrombotic syndrome with ulcer [Apligraf]|
|I87.031-I87.039||Postthrombotic syndrome with ulcer and inflammation [Apligraf]|
|I87.2||Venous insufficiency (chronic) (peripheral) [Apligraf]|
|I87.311-I87.319||Chronic venous hypertension (idiopathic) with ulcer [Apligraf]|
|I87.331-I87.339||Chronic venous hypertension (idiopathic) with ulcer and inflammation [Apligraf]|
|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]|
|L98.411-L98.499||Non-pressure chronic ulcer of skin, not elsewhere classified [Apligraf, Dermagraft]|
|Q81.0-Q81.9||Epidermolysis bullosa [Dermagraft, OrCel]|
When services may be Medically Necessary when criteria are met [for Alloderm]:
|Q4116||Alloderm, per square centimeter|
|ICD-9 Diagnosis||[For dates of service prior to 10/01/2014]|
|Including, but not limited to, the following:|
|174.0-174.9||Malignant neoplasm of female breast|
|175.0||Malignant neoplasm of male breast|
|175.9||Malignant neoplasm of male breast|
|198.81||Secondary malignant neoplasm, breast|
|233.0||Carcinoma in situ, breast|
|612.1||Disproportion of reconstructed breast|
|V10.3||Personal history of malignant neoplasm, breast|
|V45.71||Acquired absence of breast and nipple|
|V51.0||Encounter for breast reconstruction following mastectomy|
|ICD-10 Diagnosis||[For dates of service on or after 10/01/2014]|
|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 TransCyte and Integra Bilayer Matrix Wound Dressing]:
|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|
|ICD-9 Diagnosis||[For dates of service prior to 10/01/2014]|
|941.20-941.59||Burn of face, head, and neck, second or third degree|
|942.20-942.59||Burn of trunk, second or third degree|
|943.20-943.59||Burn of upper limb, second or third degree|
|944.20-944.58||Burn of wrist(s) and hand(s), second or third degree|
|945.20-945.59||Burn of lower limb(s), second or third degree|
|946.2-946.5||Burns of multiple specified sites, second or third degree|
|948.00-948.99||Burn classified according to extent of body surface involved (specified as second or third degree)|
|949.2-949.5||Burn, unspecified, second or third degree|
|ICD-10 Diagnosis||[For dates of service on or after 10/01/2014]|
|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:
|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|
|C9367||Skin substitute, Endoform Dermal Template, per square centimeter|
|G0428||Collagen meniscus implant procedure for filling meniscal defects (e.g., CMI, collagen scaffold, Menaflex)|
|Q4100||Skin substitute, not otherwise specified [when describing a product with no specific code indicated as investigational and not medically necessary]|
|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|
|Q4115||Alloskin, per square centimeter|
|Q4117||Hyalomatrix, per square centimeter|
|Q4118||Matristem micromatrix, 1 mg|
|Q4119||Matristem wound matrix, PSMX, RS, or PSM per square centimeter|
|Q4120||Matristem burn matrix, per square centimeter|
|Q4121||Theraskin, 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|
|Q4129||Unite Biomatrix, per square centimeter|
|Q4130||Strattice, per square centimeter|
|Q4131||EpiFix, 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 Extracellular Matrix, per square centimeter|
|Q4148||NEOX 1K, per square centimeter|
|Q4149||Excellagen, 0.1 cc|
|ICD-9 Diagnosis||[For dates of service prior to 10/01/2014]|
|ICD-10 Diagnosis||[For dates of service on or after 10/01/2014]|
Peer Reviewed Publications:
Meta-Analyses and Systematic Reviews.
XenoGrafts (unspecified) for Burns
Government Agency, Medical Society, and Other Authoritative Publications:
|Web Sites 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.
|01/01/2014||Updated Coding section with 01/01/2014 CPT and HCPCS changes.|
|Revised||08/08/2013||Medical Policy & Technology Assessment Committee (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|