Comparison of Skin Substitutes for Acute and Chronic Wound Management

Abstract

Chronic and acute wounds, such as diabetic foot ulcers and burns, respectively, can be difficult to treat, especially when autologous skin transplantations are unavailable. Skin substitutes can be used as a treatment alternative by providing the structural elements and growth factors necessary for reepithelialization and revascularization from a nonautologous source. As of 2020, there are 76 commercially available skin substitute products; this article provides a review of the relevant literature related to the major categories of skin substitutes available.

Skin substitutes are temporary or permanent skin coverings utilized in treating acute and chronic wounds. Skin substitutes can be biologically, synthetically, or biosynthetically derived and are commonly indicated for chronic wounds, such as diabetic or venous ulcers, or acute wounds, such as burns. ¹ The use of skin substitutes can improve rates of wound healing, as well as cosmetic and functional outcomes. ¹ Bioengineered skin substitutes have now been around for several decades, beginning with the development of cultured epidermal autografts (CEAs) in the 1970s, Epicel (Vericel Corporation, Cambridge, MA), and the creation of the first dermal substitute, Integra (Integra Life Science Corporation, Plainsboro, NJ), in the early 1980s. ² Skin substitutes have widely diversified since then. A 2020 report from the Agency for Healthcare Research and Quality identified 76 commercially available skin substitute products. ³ With the wide variety of substitutes currently available and ongoing research into new substitutes, it is up to the clinician to fully understand the materials and their applications to ultimately decide the best skin substitute for their patient. Davison–Kotler et al proposed a classification system for skin substitutes based on cellularity, and therefore the substitute's immunogenic properties. Cellular and acellular skin substitutes are then further described according to layering, replaced region, materials used, and permanence. ⁴ As of 2020, all commercially available skin substitutes are considered biodegradable/temporary. ³ In this review, the skin substitutes presented are organized by the classification principles of Davison-Kotler et al. ⁴

Autologous skin transplantation is considered the gold-standard therapeutic option for wound coverage either as split-thickness or full-thickness skin grafts (STSG or FTSG, respectively). STSGs transfer epidermis and some of the underlying dermis from a donor site, such as the lateral thigh, to a well-vascularized wound bed for graft in-growth. ⁵ Since donor sites retain portions of the underlying dermis, skin can regrow in 2 to 3 weeks and subsequently be reharvested for another application. ⁵ However, STSGs are limited by fragility, abnormal pigmentation, lack of smooth texture, lack of hair, poor sensation of the recipient site, increased likelihood of secondary contracture, and prolonged need for wound care at the donor and recipient sites. ^{5 6} In contrast, FTSG consist of the epidermis and entire dermis; donor sites do not regrow and thus, must be closed primarily, limiting the size of the graft that can be harvested. Example donor sites for FTSGs include the pre- and postauricular areas, clavicular skin, and inner arm. ⁷ Given the thickness of FTSGs, they require a more robust wound bed for adequate graft take and are more likely to experience primary contracture. FTSGs are common choices to cover mechanically demanding areas of the body because the included dermis provides strength and viscoelastic properties. ⁵

CEAs are the precursor to skin substitutes. CEAs were developed in the 1970s and have been commercially available as Epicel since 1988. ⁸ Epicel is an aseptically processed wound dressing composed of autologous keratinocytes grown ex vivo in the presence of proliferation-arrested murine fibroblasts from biopsies of the patient's healthy skin. The CEA takes 16 to 21 days to culture, and the resulting graft sheet can range from 2 to 8 cells thick. Epicel is indicated for adult and pediatric patients with deep dermal or full-thickness burns comprising a total body surface area greater than or equal to 30%. It can be used in conjunction with STSGs or alone. ⁹ Epicel usage has remained limited due to its fragile nature, poor infection tolerance, variable take, and high manufacturing costs. ¹⁰

In cases of burn injuries where there is not sufficient donor skin to provide coverage, skin substitutes can be used as a dressing to facilitate healing and increase preservation of skin pliability and elasticity. ¹¹ In cases of diabetic foot ulcers (DFU), venous stasis ulcers, and other chronic wounds, skin substitutes can facilitate wound closure by providing the scaffolding, cells, cytokines, enzymes, and growth factors necessary for reepithelialization and revascularization. ^{1 3}

Similar to autologous skin grafts, the ideal skin substitute should be nontoxic, immunologically compatible, nondisease transmitting, and minimally or nonantigenic. Furthermore, it needs to protect against bacteria and be able to maintain an appropriate wound healing environment: moist, oxygenated, and sterile. ¹²

Acellular Skin Substitutes

Acellular skin substitutes are the most common commercially available type of product. These products are sourced from donated human dermis, human placental membranes, or animal tissues. ³ They are decellularized to leave behind a scaffold for recipient cells to infiltrate but retain cytokines and growth factors to facilitate healing. By virtue of these processing methods, acellular skin substitutes are immunologically inert and thus do not cause a strong immune response ( Table 1 ).

Table 1. Acellular skin substitutes.

Product	Manufacturer	Replaced region
Human-derived acellular dermal matrices
AlloPatch	Musculoskeletal Transplant Foundation (dba MTF Biologics) Edison, NJ	Dermal
AlloPatch Pliable	Musculoskeletal Transplant Foundation (dba MTF Biologics) Edison, NJ	Dermal
Alloskin AC Acellular Dermal Matrix	AlloSource, Centennial, CO	Dermal
AlloSkin RT	AlloSource, Centennial, CO	Dermal
Coll-e-derm	Parametrics Medical, Leander, TX	Dermal
DermACELL Human Acellular Dermal Matrix and DermACELL AWM	LifeNet Health, Virginia Beach, VA	Dermal
Dermapure	Tissue Regenix Group, San Antonio, TX	Dermal
DermaSpan Acellular Dermal Matrix	Zimmer Biomet (manufactured by Biomet Orthopedics, Warsaw, IN)	Dermal
FlowerDerm	Flower Orthopedics, Horsham, PA	Dermal
GammaGraft	Promethean LifeSciences, Inc., Pittsburgh, PA	Dermal
GraftJacket RTM	Wright Medical Group N.V., Memphis, TN	Dermal
hMatrix ADM	Bacterin International, Inc., Belgrade, MT	Dermal
InteguPly	Aziyo Biologics, Silver Spring, MD	Dermal
Matrix HD Allograft	RTI Surgical, Alachua, FL	Dermal
Human amnion chorion membrane grafts
AlloWrap	AlloSource, Centennial, CO	Dermal
AltiPlast	Aziyo Biologics, Silver Spring, MD	Dermal
AltiPly	Aziyo Biologics, Silver Spring, MD	Epidermal / Dermal
AmnioBand	Musculoskeletal Transplant Foundation (dba MTF Biologics), Edison, NJ	Dermal
Amnioexcel	Integra LifeSciences Corp. acquired Derma Sciences, Plainsboro, NJ	Dermal
AmnioFill Human Placental Tissue Allograft	MiMedx Group, Inc., Marietta, GA	Dermal
AmnioFix Amnion/Chorion Membrane Allograft	MiMedx Group, Inc., Marietta, GA	Dermal
Amniomatrix Human Amniotic Suspension Allograft	Integra LifeSciences Corp. acquired Derma Sciences, Plainsboro, NJ	Dermal
Artacent Wound	Tides Medical, Lafayette, LA	Dermal
BioDFactor Viable Tissue Matrix	Integra LifeSciences, originally BioD, LLC	Dermal
Biodfence	Integra LifeSciences, originally BioD	Dermal
Biovance Amniotic Membrane Allograft	Alliqua Biomedical, Langhorne, PA	Dermal
Cellesta Amniotic Membrane	Ventris Medical, Newport Beach, CA	Dermal
Cygnus Amnion Patch Allografts	Vivex Biomedical, Atlanta, GA	Dermal
Dermavest and Plurivest Human Placental Connective Tissue Matrix	Aedicell, Inc., Honeoye Falls, NY	Dermal
EpiCord	MiMedx, Marietta, GA	Dermal
Epifix	MiMedx, Marietta, GA	Dermal
FlowerAmnioPatch and FlowerAmnioFlo	Flower Orthopedics, Horsham, PA	Dermal
Genesis Amniotic Membrane	Genesis Biologics, Anaheim, CA	Dermal
Integra BioFix Amniotic Membrane Allograft	Integra LifeSciences Corp., Plainsboro, NJ	Dermal
Integra BioFix Flow Placental Tissue Matrix Allograft	Integra LifeSciences Corp., Plainsboro, NJ	Dermal
Interfyl Human Connective Tissue Matrix	Alliqua Biomedical, Langhorne, PA	Dermal
Neox Wound Allografts	Amniox Medical, Inc., Miami, FL	Dermal
NuShield	Organogenesis, Inc., Canton, MA	Dermal
PalinGen Membrane & Hydromembrane	Amnio Technology LLC, Phoenix, AZ	Dermal
Restorigin Amniotic Tissue Patches	Parametrics Medical, Leander, TX	Dermal
Revita	StimLabs, LLC, Roswell, GA	Dermal
WoundEx Membrane and WoundEx Flow	Skye Biologics, Inc., El Segundo, CA	Dermal
Xwrap Amniotic Membrane-Derived Allograft	Applied Biologics, Scottsdale, AZ	Dermal
Architect stabilized collagen matrix	Harbor MedTech, Inc., Irvine, CA	Dermal
Bio-ConneKt Wound Matrix	MLM Biologics, Inc., Alachua, FL	Dermal
CollaWound collagen sponge	Collamatrix Co., Ltd., Miaoli County, Taiwan	Dermal
Xenografts
Cytal wound matrix	Acell, Inc., Columbia, MD	Dermal
Endoform dermal template	Hollister Wound Care, Libertyville, IL	Dermal
Excellagen	Taxus Cardium Pharmaceuticals Group, San Diego, CA	Dermal
EZ Derm	Mölnlycke Health Care, Norcross, GA	Dermal
Geistlich Derma-Gide	Geistlich Pharma North America Inc., Princeton, NJ	Dermal
Helicoll	EnColl Corp., Fremont, CA	Dermal
Integra Matrix Wound Dressing; originally Avagen wound dressing.	Integra LifeSciences Corp., Plainsboro, NJ	Dermal
Integra Flowable Wound Matrix	Integra LifeSciences Corp., Plainsboro, NJ	Dermal
MicroMatrix	Acell, Inc., Columbia, MD	Dermal
Miroderm	Miromatrix Medical, Inc., Eden Prairie, MN	Dermal
Ologen Collagen Matrix	Aeon Astron, Europe B.V.	Dermal
Kerecis Omega3 Wound (originally Merigen wound dressing)	Kerecis, Arlington, VA	Dermal
Oasis Wound Matrix	Smith & Nephew, Inc., Fort Worth, TX	Dermal
PriMatrix Dermal Repair Scaffold	Integra LifeSciences Corp., Plainsboro, NJ	Dermal
Puracol and Puracol Plus Collagen Wound Dressings	Medline Industries, Northfield, IL	Dermal
PuraPly Antimicrobial (PuraPly AM) Wound Matrix (formally called FortaDerm)	Organogenesis, Inc., Canton, MA	Dermal
Talymed	Marine Polymer Technologies, Inc., Burlington, MA	Dermal
TheraForm Standard/Sheet Absorbable Collagen Membrane	Sewon Cellontech Co., Seoul, Korea	Dermal
Synthetic grafts
Hyalomatrix tissue reconstruction matrix	Anika Therapeutics, Bedford, MA	Dermal
Restrata	Acera Surgical, Inc., St. Louis, MO	Dermal
Combined natural and synthetic grafts
Integra Bilayer Matrix Wound Dressing	Integra LifeSciences Corp., Plainsboro, NJ	Dermal
Integra Dermal Regeneration Template and Integra Omnigraft Regeneration Template	Integra LifeSciences Corp., Plainsboro, NJ	Dermal

Source: Adapted from Snyder D, Sullivan N, Margolis D, et al. Skin Substitutes for Treating Chronic Wounds [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); Published February 2, 2020. Findings. Accessed April 10, 2021. https://www.ncbi.nlm.nih.gov/books/NBK554222/ .

Among all acellular substitutes, dermal substitutes from biologic materials (allograft or xenograft) are the most common commercially available products. ³ Human-derived acellular dermal matrices (ADM) are sterilized and decellularized to remove immunogenic cellular material such as major histocompatibility complex (MHC) proteins, thereby diminishing host immune response and improving incorporation into the wound. ¹³ AlloDerm (Allergan Inc., Madison, NJ), DermACELL (LifeNet Health, Virginia Beach, VA), and Graftjacket (Wright Medical Group N.V., Memphis, TN) are three popular human-derived ADMs that provide nonliving dermal scaffolding of collagen, elastin, and glycosaminoglycans to open wound beds to promote healing. ¹⁴ The long shelf lives and increased supply compared with skin grafting have made these acellular dermal allografts a popular choice for wound coverage. Further, they provide a barrier against infection, help decrease fluid losses, and provide a more favorable wound bed for future skin grafting. ¹⁵ Unfortunately, as human-derived substitutes, there is the possibility of disease transmission if improperly sterilized. ¹⁶

AlloDerm (developed in 1994) is a freeze-dried matrix derived from donated cadaveric human skin with an intact basement membrane complex, collagen fibers and bundles, elastin filaments, and biochemical components necessary for initiating angiogenesis and cellular migration. It can be stored for 2 years. ¹⁷ AlloDerm requires 10 to 14 minutes of rehydration prior to application; however, the Ready-To-Use product only requires 2 minutes of rehydration. ¹⁴ AlloDerm grafts have been shown to be tolerant to infection and revascularize quickly. ¹⁴ DermACELL, in comparison, can also be stored at room temperature, but it is ready to use directly out of the package. ¹³ A randomized controlled trial comparing DermACELL use for venous leg ulcers (VLU) with conventional wound care management demonstrated significant reduction in wound size (59.6 vs. 8.1%) at 24 weeks from one application of DermACELL ( p  < 0.01). ¹⁸ AlloDerm, DermACELL, and Graftjacket grafts have been shown to fully integrate into tissue without complication. ¹⁹ Graftjacket, a newer acellular cadaveric dermal scaffold, has a shelf life of 2 years and requires 10 to 40 minutes for rehydration depending on the thickness. ²⁰ Graftjacket has been shown to have a higher rate of complete wound healing (100% reepithelialization) at 12 weeks after application compared with conventional wound management for DFU (70 vs. 46%, p  = 0.03). ²¹ More recently, a systematic review by Guo et al evaluated six randomized controlled trials from 2004 to 2015 that compared ADMs with standard of care therapy (debridement, offloading, daily dressing changes, and glucose/infection control) in 632 patients with DFU. There were three studies comparing Graftjacket to standard of care and one that compared Graftjacket and DermACELL. This review showed that ADMs increased the relative risk of wound healing at 12 and 16 weeks by 2.31 and 1.57, respectively. ²²

These same human-derived ADMs have gained considerable use in expander-based breast reconstruction and abdominal wall reconstruction. ^{13 14 23 24} They are indicated for reinforcing soft-tissue repairs and facilitating wound healing, especially in hostile environments such as irradiated or infected tissue. ²⁵ A recent randomized controlled trial comparing AlloDerm Ready-To-Use with DermACELL in immediate subpectoral implant-based breast reconstruction demonstrated no statistically significant differences in complication incidences, although AlloDerm Ready-To-Use was 35% more expensive at the research site. ¹⁴ A 2019 retrospective chart review also found no significant differences in complication rates of seroma, hematoma, mastectomy flap necrosis, or infection between AlloDerm and DermACELL grafts for immediate alloplastic breast reconstruction. ²⁶

Acellular skin substitutes are products derived from human placental membrane, also known as human amnion chorion membrane (HACM) allografts. Those products that are commercially available include EpiFix (MiMedx Group Inc., Marietta, GA) and AmnioRepair (Zimmer Biomet, Warsaw, IN). The human placental membranes are composed of amnion and chorion which are rich in extracellular matrix proteins, growth factors, and cytokines for angiogenesis, dermal fibroblast proliferation, and mesenchymal stem cell recruitment. ²⁷ These membranes are obtained from the placenta of screened donors after cesarean deliveries. ^{3 28} Grafts are processed and decellularized to remove blood-borne pathogens and to stabilize for storage and off-the-shelf use, usually via cryopreservation and dehydration. ²⁷ Notably, AmnioRepair is a freeze-dried acellular epidermal and dermal replacement, as opposed to just a dermal replacement. The product has distinct epithelial and stromal sides; the outer basement membrane is maintained in addition to an epithelial layer scaffold. ³ AmnioRepair is indicated for use as a biological barrier or wound cover. No hydration is necessary; the graft absorbs moisture directly from the wound. ²⁹

HACM allografts are commonly used for treatment and management of DFU but may also have applications for burns and VLUs. ^{30 31} A randomized controlled trial comparing EpiFix to standard of care dressings (alginate dressings, absorbent nonadhesive hydropolymer secondary dressings, and gauze) found that DFUs treated with EpiFix were more than twice as likely to heal completely (complete reepithelialization of the wound without drainage or need for dressing) within 12 weeks ( p  = 0.0338). ³² Several studies have suggested that wounds treated with HACM grafts heal at an expedited rate. ^{27 30 33 34} A randomized controlled trial comparing AmnioBand (MTF Biologics, Edison, NJ)—an acellular dermal matrix– to Apligraf (Organogenesis, Canton, MA)—a cellular bilayered composite of neonatal foreskin fibroblasts, and keratinocytes cultured onto bovine collagen matrix—found that at 12 weeks, 90% of DFUs closed and healed in the HACM group versus 40% of DFUs in the non-HACM group. ³³ A pediatric burn case series showed that the time to healing for dehydrated HACM (dHACM)-treated burns on average was less than those treated with STSG; dHACM burns took 15 to 21 days to heal while STSG took, on average, greater than 21 days. ³⁰ It should be noted that while there have been several comparative randomized controlled studies evaluating dHACM grafts to Apligraf, ^{33 35} these studies are often funded by product manufacturers and publication of positive outcomes should be assessed with this in mind. For example, a retrospective cohort study funded by Organogenesis, the manufacturer of Apligraf, found contrary results that at 24 weeks, 72% DFUs treated with Apligraf were healed versus 47% DFUs treated with EpiFix ( p  = 0.01). ³⁶ More comparative research is needed in this area to determine the best protocols for application of HACM grafts.

Integra's Dermal Regeneration Template (Integra Template) is perhaps the best known acellular skin substitute. One of many products offered by Integra, it is a bilayered matrix of bovine tendon collagen cross-linked with shark glycosaminoglycans and a thin semipermeable silicone layer that can be stored at room temperature with a 24-month shelf life. ³ The outer silicone barrier is meant to control fluid loss and provide flexibility and strength to the dressing. The collagen matrix functions as an extracellular matrix to provide a scaffold for reepithelization and revascularization of a neodermis by 10 to 14 days. ³⁷ While the collagen matrix is biodegradable, the silicone layer must be removed, usually after 3 weeks, for application of a thin STSG. Integra Template is indicated for postexcisional treatment of full-thickness or deep partial-thickness burns where sufficient autograft is unavailable and for the repair of scar contractures. ³⁸ Use of Integra can provide a vascularized bed over exposed bone, tendon, or joint and necessitates a thinner STSG than without treatment because it establishes a vascularized dermal matrix. ³⁹ Further, Integra Template is indicated for postexcisional treatment of full-thickness burns when insufficient skin graft is available or when reconstruction of scar contractures is needed. ^{40 41 42 43} A prospective trial of bilateral acute full-thickness dorsal hand burns where one hand was randomized to STSG and one to Integra with STSG demonstrated no difference in graft take on either hand, but did show superior range of motion when Integra was used. ⁴⁴ Integra Template, however, is expensive and treatment of the wound usually requires a staged procedure. Additionally, Integra tends to have a higher rate of infection compared with other products. ⁴⁵

Biobrane (Smith and Nephew, Largo, FL) is another bilayered acellular skin substitute that is used for temporary coverage of postexcisional burn wounds. The bilayer structure consists of a semipermeable silicone outer layer over a nylon mesh embedded with porcine collagen. Although susceptible to contaminated wound beds, Biobrane has gained use as temporary coverage for partial-thickness wounds allowing for a single-stage procedure. ⁴⁶ More recently, there have been reports of Biobrane coverage of toxic epidermal necrolysis (TEN), chronic wounds, and skin resurfacing. ⁴⁷

Acellular xenografts, like Integra, are commonly sourced from bovine or porcine sources. In recent years, xenografts from acellularized fish skin have also become a widely available alternative. ⁴⁸ Fish skin, in particular, is rich in omega-3 polyunsaturated fatty acids, eicosapentaenoic acid, and docosahexaenoic acid which are natural antimicrobial agents. ⁴⁹ Tilapia skin has been identified as having noninfectious microbiota, high amounts of type-I collagen, and similar morphological structure to human skin. ⁵⁰ One study showed that tilapia collagen could induce collagen synthesis, exhibits good biocompatibility for degradation and absorption at the wound site, and could significantly promote proliferation and differentiation of fibroblasts and keratinocytes through epidermal growth factor and fibroblast growth factor expression. ⁵¹ Fish skin has also demonstrated good adherence to wound beds, limiting or eliminating the need for dressing changes and thus raising its potential for cost effectiveness, reducing patient pain, and reducing health care team workload. ⁵⁰ Unlike porcine or bovine products, fish skin products do not carry the risk of prion transmission. ⁵² Currently, Kerecis Omega3 Wound (Kerecis Limited, Isafjordur, Iceland) is commercially available as a freeze-dried fish skin–based acellular skin substitute harvested from North Atlantic cod. It is indicated for partial- and full-thickness wounds, including diabetic ulcers, chronic vascular ulcers, trauma wounds, and surgical wounds, but should not be used in patients with known fish allergies or sensitivities. ⁵³ Kerecis retains fat, protein, elastin, glycans, and other natural skin elements, has a shelf life of 3 years, and can be stored at room temperature. ⁵⁴

Several studies have suggested that wounds treated with fish skin heal faster. One double-blind randomized controlled trial found that full-thickness wounds treated with Kerecis Omega3 Wound healed significantly faster than wounds treated with EpiFix (MiMedx Group Inc., Marietta, GA), a dHACM skin substitute product ( p  = 0.0014). Furthermore, on average, the calculated cost of fish skin treated wounds was $80 USD/square cm, or 50% cheaper than dHACM treated wounds. ⁵⁵ Another study found that compared with a standard dressing of paraffin gauze, patients treated with Kerecis Omega3 Wound reported significantly lower levels of donor site pain 5 days post–free flap harvest ( p  = 0.034). Application of Kerecis also halved the average healing time of the donor site, although this difference was not significant ( p  = 0.126). ⁵² Researchers have further been exploring other applications of fish skin substitutes. In one case series, Nile tilapia skin was successfully used as a scaffold for neovaginoplasty in three patients with an absent vaginal canal due to Mayer–Rokitansky–Kuster–Hauser syndrome. Histopathologic analysis 180 days after surgery showed the presence of stratified squamous epithelium with five cell layers, ectasic blood vessels, and occasional desquamated epithelial cells. Macroscopically and microscopically, the neoepithelium was reported as indistinguishable from normal vaginal epithelium. No complications were reported. ⁵⁶ Nile tilapia skin has also been successfully used as a biodressing to facilitate reepithelialization for superficial and deep partial thickness burns. ⁵⁰ A retrospective study found that at 16 weeks, DFU patients treated with Kerecis grafts showed a wound surface area reduction by a mean 87.57%, with complete healing found in over half. ⁵⁷

Cellular Skin Substitutes

Unlike acellular skin substitutes, cellular skin substitutes preserve viable cells that manufacturers believe provide a unique benefit toward wound healing. As of 2020, there are eight commercially available cellular skin substitutes ( Table 2 ).

Table 2. Cellular skin substitutes.

Product	Manufacturer	Replaced region
Human-derived grafts
SkinTE	PolarityTE, Salt Lake City, UT	Epidermal/dermal
TheraSkin	LifeNet Health, Virginia Beach, VA (procurement and processing) Solsys Medical, Newport News, VA (distribution)	Epidermal/dermal
Human amnion chorion membrane grafts
Affinity Human Amniotic Allograft	Organogenesis, Inc., Canton, MA	Dermal
FlōGraft Amniotic Fluid-Derived Allograft	Applied Biologics, Scottsdale, AZ	Dermal
Grafix	Osiris Therapeutics, Inc., Columbia, MD	Dermal
GrafixPL Prime	Osiris Therapeutics, Inc., Columbia, MD	Dermal
Combined human and animal grafts
Apligraf	Organogenesis, Inc., Canton, MA	Epidermal/dermal
Synthetic grafts
Hyalomatrix tissue reconstruction matrix	Anika Therapeutics, Bedford, MA	Dermal
Restrata	Acera Surgical, Inc., St. Louis, MO	Dermal
Combined natural and synthetic grafts
Dermagraft	Organogenesis, Inc., Canton, MA	Dermal

Apligraf (Organogenesis Inc., Canton, MA), formerly known as Graftskin, is unique in that it is an epidermal and dermal replacement derived from a combination of human and animal sources. Apligraf is bilayered and composed of neonatal foreskin-derived keratinocyte stem cells constituting an epidermis and a bovine type-1 collagen with human fibroblasts constituting a dermal matrix. Given that it is a living, cellular product, Apligraf must be applied clinically within 5 days of delivery. It must be stored sealed under a controlled temperature of 20 to 23°C. Apligraf is approved by the Food and Drug Administration (FDA) to treat VLUs and DFUs. There is current research investigating the mechanisms through which a bilayered living cellular construct, such as Apligraf, promotes healing. ⁵⁸ With earlier research having established the utility of Apligraf for treatment of DFUs and VLUs, ^{59 60 61 62} recent research has been evaluating the economic outcomes of Apligraf. Martinson & Martinson conducted a comparative analysis of Apligraf, Dermagraft (Organogenesis Inc., Canton, MA), OASIS (Smith & Nephew, Inc., Fort Worth, TX), and MatriStem (ACell, Columbia, MD) and found that Apligraf healed 58% of DFUs at 90 days with a Medicare reimbursement of $5,364 per episode. Apligraf was less costly than Dermagraft but equivalent in healing. ⁶³ In another study, Apligraf-treated DFU patients saw lower amputation rates, fewer days hospitalized, and fewer emergency department visits ( p  < 0.05) at a per-patient average cost that was $5,253 less than conventional care. ⁶⁴ Some studies, however, suggest that Apligraf may not be the most cost-effective skin substitute available. ^{64 65 66 67}

TheraSkin (LifeNet Health, Virginia Beach, VA [procurement and processing] and Solsys Medical, Newport News, VA [distribution]) is a cadaveric-derived epidermal and dermal replacement. Tissue is harvested within 24 hours postmortem from an organ donor who cleared standard safety screenings for organ procurement. TheraSkin is washed with antibiotics and then cryopreserved up to 5 years until it is delivered on dry ice. It is thawed to room temperature just before application. ⁶⁷ A retrospective clinical study found that by week 12, 60.38% of DFUs and 60.77% of VLUs treated with TheraSkin were closed and healed. Furthermore, no adverse events were found to be attributable to use of the graft. ⁶⁸ Gurtner et al demonstrated similar results. Notably, wounds with exposed deep structures (e.g., muscle, tendon, and bone) were 13.6% more likely to close when treated with TheraSkin versus standard of care alone ( p  < 0.0001). ⁶⁹ An independent randomized comparative trial that, although there was no statistical difference in healing rates between TheraSkin and Apligraf, there was a statistically significant 42.2% decrease in cost for patients treated with TheraSkin ($2,495.33 vs. 4,316.67/patient). ⁶⁷

Dermagraft is a dermal replacement derived from human and synthetic sources. It is composed of human fibroblast cells derived from donated newborn foreskin tissues that are seeded onto a bioabsorbable polyglactin mesh scaffold. The end product is a developed extracellular matrix with living fibroblasts which is then cryopreserved. ³ Marston et al concluded that Dermagraft is a safe and effective treatment for chronic DFUs, however, the difference in wound closure rates at 12 weeks was not statistically significant when compared with the control. ⁷⁰ Similarly, a randomized controlled study did not find a statistically significant difference between VLU wound healing rates treated with Dermagraft versus compression therapy alone. ⁷¹ Per Martinson & Martinson, the mean Medicare reimbursement for Dermagraft-treated wounds was $14,424 with a 58% healing rate at 90 days. This was significantly higher than the other mean reimbursements compared: Apligraf, for example, had a mean reimbursement of $5,364. Both Dermagraft and Apligraf, however, were determined to cost over $5,000 to heal a DFU. ⁶³ Perhaps in contrast, one study found that average Dermagraft-treated per patient care was $6,991 less than conventional care. ⁶⁴

Just as there are acellular human placental-derived skin substitutes, there are also cellular ones. Grafix (Osiris Therapeutics, Inc., Columbia, MD) is one such product; it is a cryopreserved aseptically processed placental allograft indicated for treatment of both acute and chronic wounds as a dermal replacement wound cover. Grafix must be stored at −80°C before use and has a 3-year shelf life. ^{72 73} Given the cryopreservation, Grafix preserves the structural and cellular integrity of the amnion and chorion and is a true alternative to fresh placental membranes. ⁷⁴ A multicenter, blinded randomized control trial found that by week 12, 62% of Grafix-treated DFU patients closed their wounds versus 21% of standard-of-care patients treated with surgical debridement and nonadherent dressings ( p  = 0.0001). A median healing time of 42 days was observed compared with 69.5 days among the control group ( p  = 0.019). ⁷⁵ These results were further supported by a retrospective analysis of data from a wound care registry, reporting closure of 59.4% of wounds with a median treatment duration of 42 days and four applications of Grafix. Among the 360 patients treated, 13 amputations (2.9%) and 9 patients with wound infection (2.0%) were recorded. ⁷⁶ An obvious downside to cryopreserved products is the ultralow temperature equipment that is required for shipment and storage. However, new preservation techniques are being introduced: GrafixPL PRIME is a lyopreserved placental membrane that can be stored at room temperature with a shelf life of 1 year and still retain an extracellular matrix structure with similar levels of growth factors and endogenous viable cells. A recent study found that patients treated with lyopreserved grafts averaged a wound closure rate of 59.2%, suggesting clinical equivalency to the cyropreserved counterpart. ⁷³

Cost Effectiveness of Skin Substitutes

The cost effectiveness of skin substitutes is an obvious and necessary question, given the shift of the United States toward value-based care and general increasing concern for rising medical costs. This review has shown that there is significant evidence supporting that the usage of skin substitutes is superior to conventional care. The task now is to distinguish the best, cost-effective performers from the plethora of options available. More research, however, is necessary to understand the intersections between the economic benefit of skin substitutes, applications needed, product wastage, and wound healing rates to further help providers choose the best skin substitute for their patients' needs. Several comparative economic analyses have been conducted examining these factors. A 2020 analysis of Medicare claims data determined that wound-related costs and product wastage were lower for TheraSkin patients relative to both Dermagraft and Apligraf patients at 60, 90, and 180 days ( p  < 0.05). At 90 days, Apligraf waste (units) was nearly twice and Dermagraft waste was nearly three times more than TheraSkin waste. ⁷⁷ A cost-effectiveness analysis examining Apligraf, Dermagraft, and OASIS (an acellular dermal replacement from donated human dermis) estimated that OASIS, representing decellularized extracellular matrix products, was the most cost-effective treatment in the management of VLUs. This estimation was based on a three-state Markov model the authors derived from medical literature. ⁷⁸ In Martinson & Martinson's four product analysis, the authors concluded that each product offers benefits to DFU patients and to payers in regards to DFU episode length, payer reimbursement, and cost. ⁶³

New Frontiers in Research

The realm of skin substitutes has grown significantly in the past few decades and is continuing to grow with new advancements and technologies in the field. Alternative matrix sources, electrospun nanofibers, stem cells, and three-dimensional (3D) printing are on the horizon. Decellularized extracellular matrix from ovine forestomach tissue is in development to address the disease risk associated with porcine, bovine, and human sources, as well as the cultural and religious objections to collagens sourced from these sources. ⁷⁹ A recent 29 participants' study found that 73% of wounds treated with ovine forestomach matrix had closed at 12 weeks. ⁸⁰ Electrospun nanofibers are being investigated for their ability to potentially more precisely create an ECM that is superior in compositional, mechanical, and structural mimicry to current available products. Antimicrobial agents may even be able to be spun into scaffolds or be delivered on-demand via nanoparticles. ^{81 82} Researchers are also interested in combining the regenerative potential of stem cells and 3D bioprinting to construct vascularized skin grafts which would ensure the perfusion necessary for the rapid take and long-term survival of grafts. ^{83 84}

Conclusion

Currently, there are at least 76 commercially available skin substitutes and many more in development. This review has sought to introduce and distinguish the major types of skin substitutes as categorized by the classification system of Davison-Kotler et al. While there is strong evidence supporting the clinical superiority of skin substitutes over conventional care to treat acute and chronic wounds, more independent comparative research is needed to determine the cost effectiveness of these grafts.