The Role of Skin Substitutes in Acute Burn and Reconstructive Burn Surgery: An Updated Comprehensive Review

Abstract

Burns disrupt the protective skin barrier with consequent loss of cutaneous temperature regulation, infection prevention, evaporative losses, and other vital functions. Chronically, burns lead to scarring, contractures, pain, and impaired psychosocial well-being. Several skin substitutes are available and replace the skin and partially restore functional outcomes and improve cosmesis. We performed a literature review to update readers on biologic and synthetic skin substitutes to date applied in acute and reconstructive burn surgery. Improvement has been rapid in the development of skin substitutes in the last decade; however, no available skin substitute fulfills criteria as a perfect replacement for damaged skin.

General Introduction to Burns and Function of Skin

The skin serves many vital functions, mostly providing protection from the external environment to maintain the internal environment. It aids in homeostasis by preventing undue evaporative loss and regulating body temperature. ¹ It also protects from external factors such as pathogens, mechanical forces, and UV radiation. ² The skin accomplishes this by being composed of three layers:, epidermis, dermis, and hypodermis. The epidermis is further composed of five layers: the stratum corneum, lucidum, granulosum, spinosum, and basale. The stratum corneum is the true first line of defense against the outside environment. It is the thickest layer and consists of expired keratinocytes and keratin. The stratum basale houses the majority of stem cells to assure proper regeneration of sloughing keratinocytes. ¹ The dermis is composed of connective tissue (primarily type III collagen) and is responsible for the skin's elastic strength; it also houses the blood/lymph vessels and sweat/sebaceous glands and hair follicles. ³

Despite skin being so vital to our function, it is still rather fragile. This is highlighted by the fact that out of 27 million ED visits annually in the United States, 26% (7 million) are due to superficial and open wounds. ⁴ Of all the means to cause severe skin damage, burns are one of the most common and unfortunately most devastating culprits. Acutely, burns disrupt the protective skin barrier with consequential loss of temperature regulation, infection prevention, moisture retention, and various other vital functions. Chronically, burns lead to scarring, contractures, pain, and impaired psychosocial well-being. ⁵

The severity of burns is classified by the depth of injury as either superficial, superficial partial thickness, deep partial thickness, or full thickness. ⁶ Superficial burns do not penetrate through the epidermis, so the stratum basale is still intact. Therefore, in these types of burns, the skin retains its regenerative capacity without surgical intervention. The same can be said for superficial partial thickness burns as well, because even though they do penetrate through the stratum basale, residual follicular stem cells present in the deep dermis via hair follicles allow for regeneration of the epidermis. ^{3 7} In deep partial thickness and full thickness burns, the entire epidermis and much of the dermis is lost, dramatically limiting the ability to heal spontaneously. In these burns, surgical intervention is of benefit to not only remove devitalized tissue that impedes healing, but also to provide the skin a new source of epidermis to promote regeneration.

Acute Burns

The gold standard of surgical intervention for deep partial and full-thickness acute burns has been autologous split thickness skin grafting (STSG). ⁸ This involves harvesting the patient's own skin and grafting it to the burned site. Ideally, this option is utilized for every patient for all indicated burn wounds. However, some patients are burned so extensively that available donor sites cannot provide enough tissue, even when expanded, to provide wound coverage. Therefore, skin substitutes are used alone or as a supplement to STSG. ⁴

Many types of skin substitutes are available, and new options are continuously being developed. ⁹ Although allograft is still the most widely used substitute today, many other biologic and synthetic skin substitute are options. ^{4 9} Given the rapid pace of innovation in burn and wound care, it is important for surgeons to remain up to date on all therapeutic options. This poses a challenge given how many papers continue to be published surrounding this extensive and crucial topic. For this reason, updated reviews such as these are exceptionally valuable.

Reconstructive Burn Surgery

Reconstructive burn surgery is a burgeoning field thanks to several factors. Chiefly, given advancements in burn care management and skin graft options, survival rates have never been higher. This has dramatically increased the population benefitting from reconstructive procedures for function and cosmesis purposes. ^{4 10} Previously, mortality was predicted to be roughly equivalent to the total body surface area (TBSA) plus the patient's age, and a 70% TBSA burn was a death sentence at any age. Currently, a patient with a 70% TBSA burn has a mortality rate far lower than what would be predicted by the Baux score. Numerous updates to the prediction of mortality in burn patients are now outdated due to rapid advances in burn care. ¹¹ So, whereas the primary intention of acute burn management was previously and justifiably focused solely on patient survival, it now also involves the management of chronic scarring in severe burn survivors. ⁹

Conventionally the treatment for burn reconstruction has been autologous with skin grafting following contracture release. ^{12 13} Much like the care of acute burns has evolved, so has the management of burn reconstruction with the development of novel options of dermal and composite skin substitutes. ¹³ Therefore, we review the wide range of products in the skin substitute market with emphasis on their roles in the management of acute burns and burn reconstruction.

The Ideal Skin Substitute

As previously stated, skin is the largest organ in the body and plays several roles, including thermoregulation, fluid loss prevention, and a barrier to bacteria entry. Burns often damage substantial portions of the skin, leaving patients vulnerable to the environment. If a patient survives, scarring results leaving the patient not only with a permanent mark, but also frequently functional limitations in the form of contractures or chronic wounds. ^{14 15 16}

Rapid wound coverage in burns is lifesaving and improves the quality of scarring, thus influencing further reconstructive procedures later in life. When a full-thickness burn occurs, the skin is deprived of its cache of regenerative elements and will need a substitution. STSG from an unaffected location provides the surgeon with a reliable tissue bank. Still, STSG ultimately falls short when replacing full-thickness skin loss. Additionally, sufficient quantities of unburnt skin may not be present to provide adequate coverage. Thus, skin substitutes are lifesaving in these situations. Dedicated management of graft donor sites allows for not only rapid reepithelization and regeneration of tissue for further grafting but also minimizes patient discomfort. The ideal skin substitute would reliably replicate the functions of native skin and be economically feasible in even the poorest settings.

Every product has limitations in how it compares to the theoretical ideal skin substitute. Experts suggest the ideal substitute has the following attributes: (1) inexpensive, (2) long shelf life, (3) available off the shelf, (4) non-antigenic, (5) durable, (6) flexible, (7) prevents water loss, (8) bacterial barrier, (9) drapes well, (10) easy to secure, (11) grows with the development of children, (12) applied in one operation, and (13) does not become hypertrophic. Such a skin substitute does not exist. ^{17 18}

Temporary Skin Substitutes

Temporary skin substitutes are most frequently used in the setting of partial-thickness wounds, where elements of the lost epidermis retained in the dermis serve to regenerate the denuded skin. The purpose, therefore, of temporary skin substitutes is to augment the natural healing process, improve the resulting scarring, and reduce pain. Temporary dressings provide a moist environment, promoting the migration of cells, and reestablish the barrier function of normal skin, reducing evaporative fluid losses and impeding bacterial invasion. ¹⁶

The composition and applications of temporary dressing are varied, but products can be superficially divided into the biologic and synthetic type. Each product has advantages and drawbacks regarding shelf life, affordability, availability, and efficacy. Modern synthetic dressings have largely replaced biologic dressings in many settings, and there are many hydrocolloids and hydrofiber products on the market for the temporary dressing of partial-thickness wounds. ^{8 14 16 19 20}

Biologics

Allografts

Allografts retrieved from cadaveric human donors are currently the gold standard of wound coverage when a patient's skin is not available or sufficient. ^{21 22 23} Allografts may be used in their fresh state after being refrigerated shortly after harvesting and retain viability. Fresh allografts undergo vascularization into the underlying wound bed just as an autograft. If a graft is not used in the first 7 days, it may be cryopreserved, extending its shelf life and increasing tissue availability. However, the graft is rendered nonviable and loses the ability to vascularize into the wound bed. Despite this loss of function, a nonviable allograft is still an excellent temporary dressing and admirably performs many functions of the ideal wound dressing.

When an allograft is placed on a prepared wound bed, whether fresh or frozen, it quickly forms a fibrin seal, adhering it to the wound bed. Fibroblast proliferation and collagen synthesis slowly incorporate the graft. If the tissue is viable, vascular ingrowth from the wound bed occurs, providing nutrients to the graft and increasing its viability. Over time though, regardless of vascularization, rejection of the graft occurs in immunocompetent individuals. Because the time until rejection depends on the constitution of the host's immune system, those with the most severe injuries are expected to reject allograft the slowest, given the immunosuppressing nature of their condition. Grafts typically do not survive longer than 3 to 4 weeks, though, and the use of antirejection medications to prolong their adherence is not recommended given the fear of infection. While in place, the epidermis of the allograft serves as an effective vapor barrier to reduce fluid losses and maintain a moist environment for cellular migration and proliferation. Allograft is also effective at reducing pain by protecting exposed nerve endings and decreasing the frequency of dressing changes. Further, allograft may also be used in conjunction with widely meshed autograft (4:1 to 9:1) to maximize coverage known as the Alexander technique. ²⁴

The use of allograft is not without limitations and potential risks. As with any transplanted human tissue, a risk of transmitting a communicable disease must be considered, even adhering to stringent screening and preservation protocols. Donors are carefully screened and tested for pathogens and high-risk behaviors. Fresh tissue has a short shelf life, and skin banks cannot always guarantee that tissue supply meets patient demands. Cryopreservation extends the shelf life and increases availability, but grafts are often rendered nonviable or some forms are glycerolized with the same effect. Allograft is the costliest wound coverage option given its limited availability and strict regulation. Still, the value of allograft cannot be overstated in the setting of extensive burns.

Human Amnion

Human amnionic membrane is used worldwide as a cheap dressing for superficial wounds, in use for at least 100 years. The inner layer surrounding the developing fetus differs from epidermal allografts in critical aspects. First, amnion appears to be an immunologically privileged tissue and does not elicit a host immunological response leading to rejection. Amnion also forms an effective vapor barrier but is inferior when compared with allograft epidermis, which naturally is specialized for this task. ^{25 26 27}

Like allograft, amnion can be used in its fresh, refrigerated state or preserved for later use in a nonviable state. Amnion is more commonly used outside the United States, in resource-poor settings given its cheap cost, particularly when used fresh. Its availability is limited given the donor pool, the time-sensitive nature in which donors must be consented and need to test the tissue for communicable diseases. Given its scarcity in the United States, it most commonly finds use in covering corneal injuries or partial-thickness burns to the face. ^{28 29}

Xenograft

Sheep were the first source of xenograft used to cover wounds. Today most xenografts are composed of different preparations of porcine epidermis and dermis. These products have typically been processed to hide them from the host immune system more effectively and increase the time until they are ultimately rejected. Products may be impregnated with silver to impede bacterial colonization. Xenograft adheres to the underlying wound but does not vascularize. While in place, it provides an excellent scaffold for dermal regeneration. It is best used in clean, superficial wounds and has explicitly demonstrated excellent results when used to cover split-thickness skin graft donor sites and in patients with toxic epidermal necrolysis. ³⁰ While inferior to allograft as it does not engraft, xenograft is more widely available and cheaper, making it an essential tool for temporarily covering partial-thickness wounds. ^{31 32 33}

An emerging alternative to porcine xenografts is derived from fish, specifically Atlantic cod whose skin is rich in Omega-3 fatty acids. Advantages of fish-derived skin grafts include minimal processing to generate a product safe for human use, given no known pathogens transmitted from these fish to humans. Grafts are also reportedly easy to handle and Kerecis Omega-3 Burn (Kerecis, Reykjavik, Iceland) is marketed as a shelf stable product with a life span of 3 years. These properties make it attractive in areas where cold supply chain storage is infeasible. One small trial enrolled 10 patients receiving Kerecsis to their split thickness graft donor site; no adverse events or infections were reported. The same authors report successful application in two superficial burns resulting in complete epithelization at 14 days. ³⁴ Another preclinical trial compared fish-derived skin grafts to fetal bovine dermis in the management of deep partial thickness wounds in a porcine model. The authors report fish xenograft produced granulation tissue 7 days faster with more extensive reepithelization at day 14. ³⁵

Synthetics

Synthetic skin substitutes target drawbacks associated with biological dressings, including scarcity, potential for disease transmission, and cost. These products frequently contain synthetic materials that mimic the function of native skin, reducing evaporative fluid losses, and promote the migration of cells into the wound bed. Increasingly, human and animal materials are incorporated into these products. Antimicrobials may be incorporated into synthetic materials to reduce the risk of infection. Modern wound dressings showed excellent clinical outcomes and offer a consistent, readily available means for temporary partial-thickness wound closure. ^{8 16 18 36 37}

Biobrane (Smith & Nephew, Andover, MA) is a biosynthetic bilaminar temporary dressing composed of an outer silicone layer in conjunction with an inner nylon mesh bonded to dermal collagen. The occlusive silicone layer provides a protective barrier from bacterial invasion and creates a moist wound healing environment. ³⁸ The dermal collagen structure promotes strong adherence to the underlying clean wound and minimizes the number of required dressing changes, a key consideration in pediatric populations. Biobrane is most frequently used to cover clean superficial wounds and dress skin graft donor sites, promoting more rapid reepithelization. Biobrane has no intrinsic antimicrobial activity and should not be placed over contaminated wounds. Rarely, toxic shock syndrome has been reported. As with all synthetics, particularly ones that stay in place for extended periods, careful attention should be paid to possible infections developing under the dressing. ^{39 40} Unfortunately, Biobrane production has been discontinued due to safety issues arising during the manufacturing. A similar bilayer dermal substitute, PermeaDerm, has appeared on the market. Early studies show similar efficacy to Biobrane, further investigation is needed to determine the safety and utility of this new product. ⁴¹

Mepitel and Mepilex (Mölnlycke, Göteborg, Sweden) are two additional silicone-based dressings commonly used for superficial partial-thickness burns and donor sites. Mepitel is a non-adhesive net that allows wound exudate to drain to a more absorptive top dressing and for the top dressing to be changed without painfully disrupting re-epithelization in the wound bed. Mepilex is a bilaminar dressing composed of polyurethane foam and a silicone-based surface that interfaces with the wound. ^{42 43} The foam is imbued with antimicrobial silver and may be left in place for up to 5 days. Mepilex is a cost-effective option for managing partial-thickness burns compared with Biobrane and other commonly used dressings such as Acticoat. A randomized control trial found Mepilex to promote the quickest re-epithelization of the products assessed. ⁴⁴

Acticoat (Smith & Nephew, St. Petersburg, FL) is a trilaminate silver-containing dressing that must be hydrated with sterile water to begin the process of liberating silver from nanocrystals into the wound. The adherent layer is composed of a polyethylene net. The antimicrobial effect has been reported to occur for 3days following application. ³²

Aquacel-Ag (ConvaTec, Princeton, NJ) is a hydrofiber dressing composed of cellulose impregnated with silver for antimicrobial effect. Wound exudate causes the dressing to form a gel and conform to the wound. This dressing can stay in place for the duration of partial-thickness burn healing, thus minimizing the discomfort of dressing changes. Compared with Acticoat, patients have reported better pain control with Aquacel. The same trial also found Aquacel to be a more cost-effective option. ⁴⁵

Suprathel (PolyMedics Innovations GmbH, Denkendorf, Germany) is a synthetic polylactic acid membrane designed to be easily applied to a prepared wound bed and remain in place until reepithelization is complete. The ultrastructure of Suprathel allows for wound exudate to drain through its perforations. Over time the dressing becomes translucent, allowing for inspection of the underlying wound without repeated dressing changes. ^{46 47 48 49} It is recommended that a single layer of paraffin gauze is placed directly over the Suprathel followed by an absorbent gauze. These top dressings may be easily changed while allowing Suprathel to remain in place until epithelization occurs. Unlike other dressings, Suprathel detaches from completely epithelized skin, allowing for sections of the dressing to be trimmed off over time without disrupting the remainder of the wound. A randomized trial compared Suprathel to Mepilex in managing partial-thickness burns in the outpatient setting. Both dressings did not differ in time to reepithelization, and Mepilex was found to be significantly cheaper. The primary advantage of Suprathel was decreased pain scores in the first 5 days after burn, particularly in the pediatric subgroup. ⁴⁹

Permanent Skin Substitutes

Unlike superficial burns, deep partial and full thickness burns should undergo surgical intervention by means of early excision and autologous split-thickness grafting. The goal of surgical autologous grafting is to augment wound closure by bringing epidermal cells to the wound. Unfortunately, in major burns donor sites may be limited. Different techniques for expanding grafts are used to cover the burn wound, but frequently suffer unsatisfying functional and cosmetic results. ⁵⁰ With advancements in the management of acute burn care, the majority of severely burned patients (to 90% TBSA) survive. Consequently, the need for skin coverage for severely burned patients has led to advancements in the field of tissue engineering.

In deep burns, simply replacing the epidermis is insufficient; dermal elements must be incorporated as well for optimal outcomes. The involvement of the remaining dermis in deep partial-thickness burns is commonly accompanied with hypertrophic scarring. Fortunately, recently studies showed long-term benefits of dermal equivalents on scar outcomes by reducing scar formation. ⁵¹

As previously discussed, in some burns temporary wound dressings are sufficient for healing and re-epithelization. However, some burns benefit from a permanent substitute as the patient's wound are not amenable to autologous STSG alone. Skin substitutes now come into play and the burn surgeon aims to replace all layers of the skin or either dermal and/or epidermal components to not only physiologically close the wound but also minimize further reconstruction due to poor functional or cosmetic limitations.

Over the last few decades, researchers developed several products such as cultured epithelial sheets, sprays, or epithelial skin substitutes ( Table 1 ). ^{52 53} Research into permanent dermal/or epidermal skin coverage is expanding. The objective is to enhance wound healing, ideally with minimal or no scar formation. In the following we will provide insights and an update into permanent skin substitutes for burns.

Table 1. This table shows different temporary and permanent skin substitutes, their composition, indication, and disadvantages.

Category and skin substitute	Composition	Indication	Risks/Disadvantages	References
Temporary coverage
Biologics
Allograft	Cadaveric human donors	Temporary wound coverage when patient's skin is not available or sufficient	Nonzero risk of transmitting a communicable disease	21 22 23
Human Amnion	Semi-permeable tissue derived from innermost layer of fetal membrane	Partial thickness burns	Poor mechanical stability	25 26 27 28 29
Kerecis Omega-3 Burn (Kerecis, Reykjavik, Iceland)	Processed fish skin from Atlantic cod (Gadus morhua)	Deep partial thickness burns	No randomized controlled trials data	34 35
Synthetic
PermeaDerm	Bilaminate matrix made of nylon mesh and silicone that contains gelatin and Aloe Vera extract	Superficial burns	No randomized controlled trials data	41
Mepitel and Mepilex (Mölnycke, Göteborg, Sweden)	Two silicone-based dressings	Cost-effective option for partial-thickness burns	Limited to superficial and minor partial thickness burns	43 44
Acticoat (Smith & Nephew, St. Petersburg, FL)	Trilaminate silver-containing dressing	Partial-thickness burns	Limited to superficial burns	32
Aquacel Ag (ConvaTec, Princeton, NJ)	Hydrofiber dressing composed of cellulose impregnated with silver	Partial-thickness burns	Limited to more superficial and minor partial thickness burns	45
Suprathel (PolyMedics Innovations GmbH, Denkendorf, Germany)	Synthetic copolymer >70% d-lactide polymerized with ε-caprolactone and methylenecarbonate	Partial-thickness burns; decreased pain scores reported	More expensive compared with Mepilex	46 47 48 49
Permanent coverage
Cultured epidermal autografts (CEA)
Epicel (Genzyme Biosurgery, Cambridge, MA)	Human keratinocytes embedded in fibrin mesh	Severe full-thickness burns covering >30% TBSA	High cost; fragility; delayed closure due to cell replication time increased susceptibility to infections; tendency for blistering; poor healing; pruritis and itching; wound contractures	58 60
Autologous skin suspension
ReCell (Avita Medical, Woburn, MA)	Autologous skin suspension produced using minimal donor skin; applied as spray	Deep partial-thickness burns	High cost; no dermal substitute; limited to more superficial burns	61 62 63
SkinGun (RenovaCare, Inc., NY)	Epidermal cells and stem cells	Partial-thickness burns	No randomized controlled trials data	64 65
MySkin (Regenerys, Cambridge, UK)	Suspended CEA delivered as spray s spray	Partial-thickness burns	No randomized controlled trials	64 65
Dermal substitutes
Integra (Integra LifeSciences, Plainsboro, NJ)	Acellular and bovine collagen matrix with a silicone layer	Deep and full-thickness burns	High costs, the potential for infection, and the need for reoperation to replace the silicone layer	67 68 69 70 71 72 73
MatriDerm (MedSkin Solutions DR. Suwelack AG, Billerbeck, Germany)	Bovine collagen (types I, III, IV) and elastin.	Deep and full-thickness burns; reconstruction	Risk of rejection and infection	51 76 77
AlloDerm (LifeCell Corporation, Branchburg, NJ)	Acellular dermal matrix with intact basement membrane derived from human cadaver	Deep and full-thickness burns	Antigenicity, infection, availability, and shelf life	78 79 80
Synthetic dermal substitutes
NovoSorb Biodegradable Temporizing Matrix, BTM (PolyNovo, Melbourne Australia)	Fully synthetic biodegradable polyurethane foam plus a temporary nonbiodegradable polyurethane seal	Deep and full-thickness burns	More extensive vascular network and a greater inflammatory response compared with Integra.	81 82 83
Composite substitutes
EpiFix (MiMedx Group Inc., Marietta, GA)	Bioactive cellular tissue matrix allograft composed of human amnion/chorion membrane containing a single layer of epithelial cells	Improves wound healing and regeneration	Applied more in chronic wounds.	4
StrataGraft (StrataTech, A Mallinckrodt Company, Madison, WI)	Cultured composite autograft derived from neonatal keratinocytes used to generate biologically functional epidermis over a dermal component	Deep and full-thickness burns	Reported pruritus (15%)	90

Autologous Cultured Epithelial Autografts

In cases of major burns involving extensive TBSA, autologous epithelial autografts, also known as cultured epidermal autografts (CEA) have been widely used for coverage for the past 30 years. ^{54 55} CEAs are prepared as sheets using the patient's own skin cells. Several studies showed benefits in wound closure when applied in conjunction with STSG. ^{56 57} A study by Chrapusta et al confirmed benefits when CEA combined with STSG. Their findings suggested that wound closure is achieved faster when meshed STSG are combined with cultured autologous keratinocytes (CAK) compared with STSG or CAK alone. ⁵⁷ Currently, CEA is rarely used as it takes more than 2 weeks to harvest a patient's tissue, grow sufficient amounts in the laboratory, and reapply them. Other disadvantages include the high costs and studies highlighting fragility compared with STSG. ⁸ Epicel ( Genzyme Biosurgery, Cambridge, MA ) is the most known form of CEA and has been widely used in the burn community. ⁵⁸ It is cultured from full-thickness biopsies from the patient's skin and usually applied in combination with STSG or alone in severe burns involving an extensive amount of the TBSA. Studies have pointed out its limitations including the high costs, fragility, and long preparation time. ⁵⁹ Studies have also reported complications such as early blistering and shearing, pruritis and itching, graft loss, wound contractures. Furthermore, squamous cell carcinoma has been reported in patients with burn injury after being grafted with Epicel, making it an infrequent first line treatment. ⁶⁰

Autologous Non-Cultured Cell Therapy

In recent years, new developments in autologous cell therapy were added to the burn surgeon's armamentarium as an alternative treatment approach. ReCell ( Avita Medical, Woburn, MA) is a system that uses small sheets of partial thickness skin from the patient and processes it to an autologous epidermal suspension in the form of a spray application. In contrast to Epicel, these are prepared intraoperatively with no need for off-site culturing of the samples. Furthermore, it is a complete complement of epidermal cells including keratinocytes, Langerhans cells, melanocytes, and fibroblasts. ReCell has shown promising results as an effective adjunct or alternative to meshed STSG in deep partial-thickness burns. ^{61 62 63} A randomized clinical trial by Holmes et al highlighted the benefits of the ReCell system. Authors demonstrated increased wound healing, decreased pain, and less scarring in donor sites. Furthermore they report that wound healing in deep burns using the ReCell system was comparable to STSG. ⁶³ However, disadvantages of the ReCell system include costs and limited applications given that it provides only epidermal elements. ^{62 63} Other epithelial autologous skin suspensions are available including SkinGun (RenovaCare, Inc., NY) and MySkin (Regenerys, Cambridge, UK). ^{64 65} However, to date no randomized clinical trials are extant showing clinical evidence of these suspensions.

Dermal Substitutes

As previously discussed, the restoration of the dermis plays a crucial part in the management of deep burn wounds. The goal is to enhance wound healing and improve the quality of future scarring. A wide range of different dermal substitutes are commercially available today. They range from acellular dermal scaffolds to complex cellular matrices. Products may be divided into biologic and synthetic categories but a majority will contain both elements.

Acellular Dermal Substitutes

Integra (Integra LifeSciences, Plainsboro, NJ) is the most studied dermal substitute on the market. ⁶⁶ It consists of a dermal bovine collagen matrix, a chondroitin-6-sulfate glycos-aminoglycan (GAG) and an epithelial silicon layer. ⁶⁷ Integra is typically applied in two stages. First, it is applied on a sterile debrided full thickness burn. The inner dermal layer allows for neovascularization and the epidermal silicon layer functions as a neoepidermis and stays temporarily for 2 to 3 weeks. Next, the silicon layer is removed after 2 to 3 weeks, and the wound can be closed with a thin STSG. Several studies have shown benefits regarding functional and esthetic outcomes in both acute and reconstructive burn surgery. ^{67 68 69 70 71} Disadvantages include high costs, potential for infection, and an additional operation to replace the silicone layer. ^{70 71 72 73} To avoid this, Integra has developed a monolayer product. ¹⁰ Without the outer epidermal silicon layer, it is applied in full-thickness burns with immediate application of STSG in a single-stage operation. ^{69 74} Although still in development, case reports showed promising functional and aesthetic results applying a single layer Integra with immediate application of STSG. ⁷⁵

MatriDerm (MedSkin Solutions DR. Suwelack AG, Billerbeck, Germany ) was the first commercially available single-operation acellular dermal substitute. It has a thin (1 mm) layer consisting of a bovine collagen (types I, III, IV) and elastin. ^{8 76} It can be applied in a one stage operation with immediate application of STSG and several clinical studies have reported acceptable outcomes regarding the quality of scar tissue and improvement of elasticity. ^{76 77} A 12-year clinical follow-up by Bloemen et al demonstrated the long-lasting effects of MatriDerm and its impact on scar improvement in both acute and reconstructive burn setting. ⁵¹

AlloDerm (LifeCell Corporation, Branchburg, NJ ) is another acellular dermal substitute in the burn surgeons tool box. It has been widely used in burn care as well as in other fields of surgery. It is produced by using cadaveric allograft skin and goes through a process where epidermal and dermal cells are chemically removed. The basement membrane and collagen fibers (laminin and type IV and VII collagen) are then preserved. It is commonly applied in a one-stage approach with a 1:1 ratio meshed AlloDerm and immediate application of a thin meshed STSG. ^{78 79} Some, within the burn community, have questioned whether a two-stage approach would be more appropriate. ⁷⁹ A prospective randomized study suggested no difference in the graft take and scar quality when comparing immediate versus delayed grafting. ⁸⁰

Synthetic Dermal Substitutes

In contrast to the acellular matrices, Biodegradable Temporizing Matrix (BTM) (PolyNovo, Melbourne Australia) is a fully synthetic product and contains no human or animal products. It consists of a 2-mm thin synthetic dermal template, composed of a biodegradable polyurethane open-cell foam bonded via a polyurethane adhesive layer to a superficial transparent non-biodegradable polyurethane sealing membrane 150 mm in thickness. Initial clinical studies showed promising outcomes and due to its synthetic nature it has low costs. ^{81 82} In contrast to other dermal substitutes it eliminates any risk of cross-species residual antigenicity. Like Integra, it is applied in a two-stage approach. First, the dermal scaffold is applied and after its integration into the wound, the membrane is peeled off and STSG can be applied. ⁸¹ A comparative study by Cheshire et al found that BTM had a more extensive vascular network and a greater inflammatory response compared with Integra. ⁸³ To date no randomized trials are in the literature showing superiority of BTM over other dermal substitutes.

Composite Substitutes

Previously described substitutes replace either epidermal or dermal components. New products have been developed with the aim to replace both layers following a burn. ⁸⁴ One of the first of this kind commercially available on the market was Apligraf (Organogenesis, Canton, MA). Although clinical studies exist, this tissue-engineered bilaminar skin analog has its use more in chronic wounds, rather than in full-thickness burns. ^{85 86} Another approach in this field is the use of dehydrated human amnion/chorion membrane allografts or also often referred as EpiFix, AmnioFix, EpiBurn; (MiMedx Group Inc., Marietta, GA). These products contain collagen, cytokines, growth factors and facilitate wound healing; several randomized trials reported its benefits in chronic wounds. ^{87 88} However, to date, no randomized controlled trials in the literature show evidence of dehydrated human amnion/chorion membrane allografts in the application for burn wounds. Only case series exist, which show promising results. ⁸⁹ One of the newest substitutes is StrataGraft (StrataTech, A Mallinckrodt Company, Madison, WI). StrataGraft is a bioengineered full-thickness skin substitute and consists of a dermal layer with human fibroblasts and an epithelial layer; and is indicated for deep-partial and full thickness burns. A recent published phase 3, open-label, controlled, randomized, multicenter trial evaluated the efficacy and safety of StrataGraft in patients with deep partial-thickness thermal burns. In this trial the authors demonstrated that treatment of deep partial thickness burns with StrataGraft resulted in wound closure without autografting in 92% of the patient population. The most common StrataGraft-related adverse event was pruritus (15%). ⁹⁰

Conclusion

This literature review provides an update on temporary and permanent skin substitutes applied in acute and reconstructive burn surgery. Rapid improvement in the development of skin substitutes has occurred in the last decade. However, to date no skin substitute fulfills all the criteria of a perfect replacement for autologous STSG. Skin substitutes either have epidermal or dermal components, which help in the management of burn wounds. Lately, improvement has been made in the development of full-thickness substitutes but are still lacking the complex dermal appendages. We expect engineered tissue substitutes to continue to advance and improve wound closure times and reduce scarring.

Funding Statement

Funding This study was funded by Remembering the 15 Burn Research and Education Endowment.