Allograft harvested from human cadaveric donors is perhaps the most widely used example of a biologic temporary skin substitute. It can be refrigerated and used in a fresh state within the first week postharvest, resulting in its vascularization and adherence to the wound bed. However, this is rarely used because the cell viability deteriorates rapidly, and allograft is most commonly used in its cryopreserved state as a temporary skin substitute, ^, adhering to the wound bed until graft rejection occurs 3 to 4 weeks postapplication. As a temporizing measure, it is a highly effective method of wound closure and revolutionized practice in major burns, helping to decrease mortality. Furthermore, adherence for 3 to 4 weeks prevents the need for multiple and potentially painful dressing changes. Allograft is also available in a glycerol-preserved form. Glycerol preservation is less expensive and preserves allograft structure, although cellular components are destroyed. However, glycerol-preserved allograft can be distributed at refrigerated temperatures and is effective as a biologic dressing in partial-thickness burns, even though it is less adherent to wound beds when compared with cryopreserved allograft. Lastly, allograft can be used to create an acellular dermal matrix, either by its processing from human allograft or by debridement of the epithelial component, with the remaining dermal layer a permanent recipient for CEA or cultured composite skin substitute. Of note, as allograft recipients are not human leukocyte antigen (HLA) matched, they may develop anti-HLA antibodies via allosensitization that could have implications for future transplant compatibility.

Xenografts are another temporary skin substitute option and are animal-derived skin substitutes. Porcine-derived xenografts are commonly available, and these adhere to the wound bed, providing coverage for underlying dermal regeneration. However, there is some limited efficacy reported in burn healing potential when comparing porcine-derived substitutes with simple dressings. ^, Furthermore, some established porcine-derived substitutes (e.g., EZ Derm; Naples, FL) were eventually withdrawn from the market after a faulty product recall. Fish skin-derived alternatives are also present commercially, specifically Atlantic cod skin containing high amounts of omega-3 (Kerecis Omega-3 Burn; Isafjordur, Iceland). ^, This acts similarly to porcine xenograft and temporizes the underlying wound bed while reepithelialization occurs. Other recently developed xenografts include InnovaMatrix (Triad Life Sciences, Inc.; Memphis, TN), a decellularized extracellular matrix substitute procured from porcine placental tissue that acts as biodegradable wound coverage. The processing of InnovaMatrix removes cells while maintaining the porcine placental source material. This is thought to generate sheets of decellularized InnovaMatrix that may have enhanced regenerative potential and can be applied once as a biologic wound cover to facilitate healing without dressing changes.

Human amniotic membrane is another example of a biologic temporary skin substitute. It consists of a single epithelial layer, a basement membrane, and avascular stroma, all derived from the innermost placental layer. It has been used historically across the globe, with dehydrated forms such as EpiFix and EpiBurn containing decorin that is thought to promote healing and have antiscarring properties through their inactivation of transforming growth factor β ₁ . Amniotic membrane is also advantageous in that it is an immunologically privileged tissue type, so it does not elicit a host immune response when in situ as a skin substitute. However, it remains expensive, lacks some efficacy in barrier function compared with allograft, and its availability is limited by the need to consent donors peripartum when amnion harvest is not the priority of the clinician present.

Temporary skin substitutes also exist that are wholly or partially derived from synthetic components, including Biobrane, AWBAT, and Suprathel. Despite some parallels drawn between wound dressings and synthetic-containing temporary skin substitutes, temporary skin substitutes represent options that only require a single application to the wound bed. Not only does this distinguish them from wound dressings, but it also represents a significant advantage, especially in pediatric patients, because it avoids the pain and associated psychological trauma that may result from repeated wound dressing changes. ^, Epiprotect (S2Medical AB; Linköping, Sweden) is a biosynthetic cellulose temporary skin substitute that is also found to decrease pain and the total number of required dressing changes. ^, It is found to be equally effective in superficial burns as equivalent porcine xenograft without any immunologic or ethical/cultural issues.

One example of a bilayer acellular dermal substitute is Integra (Integra LifeSciences; Plainsboro, NJ), which has been used for decades in burns, trauma, and reconstructive surgery, with its use in major burns yielding favorable short- and long-term outcomes. The dermal bovine crosslinked collagen matrix is combined with chondroitin 6-sulfate glycosaminoglycan, and its vascularization and formation of neodermis occur over 3 to 4 weeks ( Fig. 50.1 ) under the protective cover of the silicone epithelial-equivalent layer. This allows for wound closure during the critical time of waiting for limited donor sites to heal and be ready for reharvesting ( Fig. 50.2 ). In fact, the fully matured vascularized matrix can be left in place, even for several further weeks, as long as the silicone layer remains adherent to it. The regenerated dermis has initially been noted as thicker than the normal dermis before thinning and becoming increasingly pliable, with positive outcomes recorded in terms of durable wound closure, minimal donor morbidity, and minimization of long-term contracture. More recently, Single-Layer Integra has also been utilized, ^, proving effective in single-stage reconstructive procedures where its structure facilitates the immediate application of SSG over the Integra. ^,

Stages of Integra vascularization. Matrix color is correlated with the stage of vascularization. Clinical (left) and histologic appearances (right) . (A and B) Appearance at first stage, day 0 with pale colored matrix. (C and D) Matrix developing a pinkish color at day 21, and (E and F) a peachy color at 4 weeks. (F) CD31-stained endothelial cells in the superficial layer of the neodermis.

(From Moiemen NS, Vlachou E, Staiano JJ, et al. Reconstructive surgery with Integra dermal regeneration template: histologic study. Clinical evaluation and current practice. Plast Reconstruct Surg. 2006;117[7]:S160-S174.)

Acute early burn excision and Integra application with 7-year follow-up. Top row : (A) Patient with 60% total body surface area flame burn; (B) Postexcision of burn on back and (C) legs. Middle row : (D) Day 9 postexcision appearance of burn wound and application of Integra on back. (E) Day 18 appearance of abdominal and (F) leg burn wounds postexcision and application of Integra. Bottom row : (G) Appearance of the healed wounds 7 years postburn of the back, (H) abdomen, and (I) lower limbs.

The advantage of using Integra over a prolonged period is that clinicians have been able to evaluate the long-term outcomes of Integra more fully. One landmark paper documented the long-term outcomes of a burn patient cohort in which two-stage reconstruction of scars using Integra had been performed more than 2 years before assessment. This work detailed clinical outcomes using subjective (Vancouver Scar Scale [VSS]) and objective (Cutometer) scar assessment measures and histologically analyzing dermal substitute punch biopsy specimens. Improvements were found in a range of patient-reported scar measures, with the most marked improvements recorded in the range of motion achieved postreconstruction and in both scar softness and visual appearance. VSS was decreased from prereconstructive measures, with a progressive decrease recorded at annual measures taken postoperatively. Cutometer analysis showed persistent differences to normal skin, with viscoelasticity of Integra found to resemble normal skin measures most closely. Histology showed elastin and collagen present in all samples, although with abnormal arrangement. Collagen arrangement patterns were most akin to that of normal dermis and/or relatively immature scars. Nodular collagen arrangements, which are more typical of hypertrophic scars, were not found to span the full thickness of the reticular dermis. Nerve fibers were also identified in the reconstructed dermis sampled, suggesting a mechanism for patient-reported improvements in sensation and possibly also indicating the ongoing slow reinnervation of Integra with its continued long-term maturation.

Matriderm (MedSkin Solutions Dr. Suwelack AG; Billerbeck, Germany) was the first recorded acellular dermal substitute used in single-stage operations. It consists of a thin matrix of bovine collagen and elastin. ^, Matriderm is formed from non-crosslinked collagen, so it is vascularized more rapidly than Integra and resorbs more quickly, gaining CE certification in 2005 and FDA approval in 2021. This early angiogenic activity is shown histologically, with matrix resorption completed by the second month postoperatively. It has applications in burns where function and aesthetics are essential (e.g., in the hand overlying joints and/or on the face), possibly because of the positive clinical findings regarding scar quality and pliability postoperatively. ^, Initial postoperative improvement in scar assessment measures was absent 1 year postoperatively, ^, although there was identified improvement in scar quality over a decade later compared with SSG alone. This may result from the improved scar pliability identified and the effects of longer-term scar remodeling and maturation. Furthermore, like Single-Layer Integra, the requirement for immediate grafting is a limitation in major burns when donor sites are sparse. However, longitudinal studies have shown long-lasting efficacy in both acute burn and reconstructive settings.

A more recently produced fully synthetic permanent skin substitute is NovoSorb Biodegradable Temporizing Matrix (BTM) (PolyNovo; Melbourne, Australia), which was granted CE mark approval in 2019 and FDA approval in 2017 for use in full-thickness wounds and partial thickness burns ( Fig. 50.3 ). It is made up entirely of polyurethane in a layered structure, where a biodegradable polyurethane open-cell foam is adhered to a nonbiodegradable polyurethane membrane using a polyurethane adhesive. Like Integra, a staged operative approach with BTM is used, and maturation is allowed over 2 to 3 weeks. The polyurethane membrane is then removed, and SSG is applied in the second stage of operation. Initial results show promise regarding potentially lowered costs and lack of antigenicity from its fully synthetic structure, ^, with its efficacy reported in wound coverage in large TBSA burns. ^, In animal studies, the vascularization achieved using BTM is thought to exceed that in Integra, with potentially decreased contraction and scarring. The synthetic structure may also underlie its observed resilience to infection, with successful matrix salvage demonstrated; however, no longitudinal data as yet indicate BTM is superior to existing dermal substitutes.

Acute early burn excision and biodegradable temporizing matrix (BTM) application in a 37-year-old female with 35% total body surface area flame burn. (A) Preexcision and (B) postexcision images of abdominal/trunk burns. (C) BTM was applied as wound coverage at the time of excision and is (D) shown 2 weeks postapplication during a change of dressing. (E) Second-stage procedure with application of split-thickness skin graft was performed, and graft take was reviewed at 1 week and (F) 2 weeks postprocedure.

In contrast to dermal skin substitutes, some permanent skin substitutes aim to restore only the epidermal components of the skin. Autologous epithelial autografts (i.e., CEA) have long been used as permanent skin substitutes alongside SSGs. ^{, ,} CEA production and preparation involve the harvesting of patient tissue, which is then cultured in a lab to grow sufficient skin for reapplication operatively. Epicel (Vericel; Cambridge, MA) is FDA approved and is the most well-known form of CEA, consisting of autologous keratinocytes cultured ex vivo in the presence of proliferation-arrested murine fibroblasts. It can be used for wound coverage alone or in combination with SSG. ^, However, in reality, it is infrequently used as a first-line treatment because of concerns over its lack of ability to withstand shearing forces, graft loss, and the intensive and costly nature of its production. ^{, ,}

Alternative epidermal skin substitutes include autologous noncultured cell therapy, most notably ReCell (Avita Medical; Woburn, MA). ReCell is prepared intraoperatively and consists of a relatively small partial-thickness skin biopsy that contains the full range of epidermal cells, eliminating the need for culture. It has been shown to provide effective wound coverage in burns when used alone or when supplementing SSGs, with some comparability to SSGs in deeper burns also reported.

Rapid healing of skin graft donor sites is critical to patients with major burns. Expanded preconfluent autologous epidermal cells (ReCell) or sprayed CEA may accelerate epithelization and allow more frequent harvesting from the limited donor sites in these situations. ^{, ,} However, wider use is prohibited by cost and efficacy. ReCell has also accelerated the healing of partial-thickness burn wounds when covered with widely meshed skin grafts. Other autologous options similar to ReCell include SkinGun (RenovaCare, Inc.; NY, USA) ^, and MySkin (Regenerys; Sheffield, UK), but their improved efficacy has yet to be reported.

Some permanent skin substitutes aim to reconstitute both epidermal and dermal skin layers. They are developed as composite skin substitutes, including bilaminar cellular substitutes, such as Apligraf and Orcel. Apligraf (Organogenesis; Canton, MA) was the first available composite substitute but has recorded efficacy more so in chronic wounds than deep partial-thickness or full-thickness burns. ^, Another permanent skin substitute produced from harvested autologous epithelial cells and fibroblasts is engineered skin substitute, PermaDerm (Reginicin Inc.; Little Falls, NJ). It is advantageous in that it only requires a very limited skin biopsy from the patient and can facilitate complete wound coverage in a bilayer structure, showing promising utility in major burns.

Zurich Skin (denovoSkin, Cutiss AG) is the latest in dermoepidermal skin substitutes, representing a laboratory-grown autologous dermoepidermal skin analog developed by the Tissue Biology Research Unit (Department of Surgery, University Children’s Hospital; Zurich, Switzerland) for use in massive skin loss. It differs from other cultured skin substitutes in that it also contains a dermal component, with numerous preclinical and animal studies finding it effective in wound coverage. To date, a phase 1 clinical trial has been completed, and a phase 2 clinical trial comparing it to SSGs is in progress. It has even been used in extensive pediatric burns on a compassionate basis because of the favorable phase 1 trial results, with it reportedly providing remarkable similarities to natural skin coverage ( Fig. 50.4 ).

Use of Zurich Skin in wound coverage in a 5-year-old child. (A) Trunk shown 35 days postburn with previously applied autologous graft using Meek micrografting (circumscribed in green ) and Integra (circumscribed in blue ). (B) Intraoperative view immediately postapplication of Zurich Skin to the previously applied Integra. (C) Trunk outcomes 70 days postapplication of Zurich Skin (circumscribed in blue ). (D) Both legs shown postapplication of Zurich Skin; before application of Zurich Skin the wound beds were covered with allograft alone. (E) Zurich Skin outcomes 49 days postapplication; total of 105 days postburn.

(From Moiemen N, Schiestl C, Hartmann-Fritsch F, et al. First time compassionate use of laboratory engineered autologous Zurich skin in a massively burned child. Burns Open. 2021;5[3]:113-117.)

StrataGraft (StrataTech, A Mallinckrodt Company; Madison, WI) is another more recently developed product, bioengineered to be a full-thickness skin substitute consisting of human fibroblasts and an epithelial layer overlying a collagen dermal layer. Alongside the fibroblasts embedded into the collagen gel are neonatal immortalized keratinocytes generated from a single-source human cell line, capable of providing a stable source of human keratinocytes. It is not an acutely immunogenic skin substitute in traumatic wounds and maintains barrier function effectively. ^, Surgically, it is handled similarly to other permanent skin substitutes because it can be meshed and subsequently stapled or sutured into place. Its use in multicenter randomized controlled trials has shown promising wound closure results in deep partial-thickness burns in the absence of autograft use, ^, with comparable safety profiles and wound closure rates to autograft. ^, Further registered clinical trials are active, comparing the postburn scarring outcomes of StrataGraft to autograft, its efficacy in pediatric burn patients, and the concurrent use of StrataGraft in major burn wound coverage when used alongside SSGs.