Skin substitutes

INTRODUCTION — Skin substitutes are a heterogeneous group of biologic, synthetic, or biosynthetic materials that can provide temporary or permanent coverage of open skin wounds. The aim of skin substitutes is to replicate the properties of the normal skin. Skin substitutes are an important adjunct in the management of acute or chronic wounds and can be used to cover defects following burns or other injuries, or for reconstruction, such as for release of extensive severe post-burn contractures [1].

Each skin substitute has its own unique set of advantages and disadvantages. Since wound healing tends to be unique to the individual, the use of skin substitutes is highly personalized with the choice of skin substitute depending upon the type of wound (ie, acute, chronic), its etiology (eg, trauma, chronic inflammation), and the skin component (ie, epidermis, dermis, or both) that requires replacement. In addition, the desired functional and aesthetic outcomes need to be considered. Other factors that determine the choice of skin substitute depend on whether wound coverage is temporary or permanent.

The types of skin substitutes, indications for use, general properties, and tips for application are reviewed here. Skin autografting is discussed in detail separately. (See "Skin autografting".)

AVAILABLE PRODUCTS — Skin substitutes are a heterogeneous group of biologic, synthetic, or biosynthetic materials that can provide temporary or permanent coverage of open skin wounds. Skin substitutes ideally possess the composition and function of skin or have the potential for autologous regenerative healing when applied to a wound [2]. When skin substitutes are applied in an optimized setting, they can provide a unique solution for difficult-to-treat wounds. Significant progress has been made in the past several decades in the production and engineering of these materials.

Prior to using a specific skin substitute, it is essential that the clinician has full understanding of the material being used and its properties. Each wound has a unique and variable microenvironment, and many products have been developed to try to accommodate the various needs. As an example, skin substitutes that contain a dermal component have added pliability [3-6]. Some of the available products and their efficacy are provided below and summarized in the table (table 1) [7]. A comprehensive listing of skin substitutes available for use in the United States and their properties can be found in the Agency for Healthcare Research and Quality (AHRQ) document [8].

Most commonly, human skin allografts, amnionic membrane products, and xenografts derived from a variety of animals (eg, pig, frog, fish) are used in specialized burn centers [8]. The earliest description of the use of xenograft as a form of skin substitute was from the 15^th century BC. Since then, a variety of skin substitutes have been developed. Skin allografts have proven to be effective in preventing insensible fluid, electrolytes, and protein loss and also act as a barrier to microbial contamination/infection. Allografts have also become indispensable in patients with large total body surface area burns with inadequate donor site availability. (See "Treatment of deep burns", section on 'Managing large burn wounds'.)

However, tissue engineering has significantly advanced the development of skin substitutes beyond allografts. There has been much focus on materials that can deliver all the cells and factors required for tissue healing. In the future, the focus will likely include incorporation of stem cells into scaffolds, as well as three-dimensional printing technology.

The general characteristics required when engineering functional skin substitutes include the ability to [6]:

●Protect the integument from loss of fluid and prevent infection

●Provide a stable, biodegradable scaffold that promotes the synthesis of new dermal tissue

●Allow the host or other cells to proliferate within the scaffold as functional dermal cells, rather than as scar tissue

●Resist shearing forces, while still being easy to handle

TERMINOLOGY AND CLASSIFICATION — There is no universally accepted classification system that allows for simple categorization of all the products that are commercially available. A technology assessment report from the Agency for Healthcare Research and Quality (AHRQ) from January 2019 listed 74 products classified as skin substitutes [8]. Regardless of the classification system used, the clinician needs to have an understanding of the materials used and their ultimate purpose. In the author's opinion, it is ideal to have knowledge of at least one product per category to enhance the ability to treat a variety of wounds.

Kumar classification — The most commonly used system proposes three classes (table 2) [9]:

●Class I – Temporary, impervious dressing material

•Mechanical traits of epidermis but no cells

•Subcategorized as single layer or bilayer

●Class II – Single-layer durable skin substitutes

•Epidermal substitutes – Functionally similar to the epidermis

•Dermal substitute – Including collagen sheets, dermal matrices, and porcine collagen sheets

●Class III – Composite skin substitutes

•Replaces both the dermal and epidermal component

•Includes allograft, xenograft, and tissue-engineered skin

Davison-Kotler classification — In a later publication, a potentially universal classification system classifies skin substitutes based upon the following factors (figure 1) [10]:

●Cellularity – Acellular, cellular

●Layering – Single or bilayer

●Replaced region – Epidermis, dermis, or both

●Material used – Natural, synthetic, or both

●Permanence – Temporary (biodegradable), permanent (nonbiodegradable)

Other clinical classifications — In addition to the above classification systems, a more clinically inclined system classifies skin substitutes and scaffolds based on material (synthetic, biological, biosynthetic), permanence (temporary or permanent), and location (epidermis, dermis, or both) [11].

INDICATIONS FOR USE AND EFFICACY — Wound healing is a complex process involving multiple cell types and mediators such as growth factors and cytokines. (See "Basic principles of wound healing".)

Skin substitutes were initially introduced to manage extensive burns, but their use has extended to include the management of a variety of other acute and chronic wounds such as traumatic wounds, diabetic ulcers, pressure-related skin injuries, venous ulcers, and others [12-15].

The use of skin substitutes for acute burn wound management and other common chronic wounds is discussed briefly below. The general management of these conditions is discussed in detail in the linked topic reviews.

Burn wounds — Skin substitutes improve the long-term functional and cosmetic outcomes in burn patients and increase quality of life [16-21]. During the acute phase of burn treatment, skin substitutes can be used as temporary dressings and are particularly useful for large surface area burns where donor skin availability is limited. In the chronic phase, dermal substitutes are also used to reconstruct and improve burn scars and other defects. (See "Treatment of deep burns", section on 'Managing large burn wounds' and "Overview of surgical procedures used in the management of burn injuries", section on 'Burn scar revision and timing'.)

A systematic review identified 20 trials of skin substitutes [16]. For the management of partial-thickness burns, bioengineered skin substitutes and allogeneic cultured skin were at least as effective as topical agents/wound dressings or allograft. In two trials, a bilayered living cell construct (BLCC) had a significantly faster time to healing (11 versus 14 days) compared with autografts, allografts, or xenografts; however, the proportion of patients with ≥75 percent of wound closure was significantly lower. In a separate review, a skin substitute (Biobrane) significantly reduced pain during the treatment of superficial and partial-thickness burn wounds compared with topical agents [18].

One drawback of skin substitutes in the treatment of burns may be the potential for infection. In a multicenter trial that included 216 burn patients, the rate of invasive infection at sites treated with BLCC was 3 percent (consistent with 1 to 3 percent rate for autografting) and the superficial wound infection rate was 13 percent [22]. In a later systematic review of studies that compared dermal substitutes and split-thickness skin grafts for the treatment of burn wounds, three trials reported either low rates of infection or no significant difference in infection rates between dermal substitutes and skin grafts, and four of the seven trials reported no significant differences in scar quality [19]. Statistical pooling of data was not performed due to heterogeneity of the studies. (See "Burn wound infection and sepsis", section on 'Epidemiology and risk factors'.)

Chronic wounds — Chronic wounds have derangements of the healing process, including impaired fibroblast replication and keratinocyte migration [23-25]. Skin substitutes can provide cells, growth factors, and other elements that promote reepithelialization and revascularization of the wound. (See "Clinical assessment of chronic wounds".)

Diabetic foot ulcers — Among chronic wounds, skin substitutes are most studied for promoting healing of diabetic foot ulcers [26-30]. Wound healing in diabetic ulcers is impaired through of lack of response to growth factors and reduced collagen accumulation [31-33]. (See "Management of diabetic foot ulcers", section on 'Local care'.)

Many types of skin substitutes have been used in the treatment of diabetic foot ulcers, including epidermal, dermal, and bilayer substitutes [26,34-44]. A systematic review identified 17 trials using various skin substitutes (eg, Graftjacket, Hyalograft, Dermagraft, Apligraf, OrCel, Kaloderm) for the treatment of diabetic foot ulcers [26]. Completed closure of diabetic foot ulcers was significantly improved for skin substitutes compared with standard care (risk ratio [RR] 1.55, 95% CI 1.30-1.85). In two trials, there were no significant differences for ulcer recurrence. Among two trials that reported the incidence of lower limb amputations, skin grafts and substitutes were also associated with significantly lower risk for amputation, although the absolute risk reduction for amputation was small. Based upon four trials that directly compared products, no specific type of skin graft or skin substitute was superior to another.

Chronic venous ulcers — While the mainstay of treatment of chronic venous ulcers is compression therapy, difficult or large ulcers may require additional measures to achieve wound healing. (See "Evaluation and management of chronic venous insufficiency including venous leg ulcer", section on 'Ulcer care'.)

A variety of skin substitutes have been used in the treatment of chronic venous ulcers [45-52]. In a systematic review, pooled rates of wound healing were significantly improved in two studies using bilayered human skin equivalents compared with standard care (RR 1.51, 95% CI 1.22-1.88) [48]. Allografts (fresh or frozen; five studies) also significantly increased healing compared with standard care (RR 2.0, 95% CI 1.04-3.84). Single-layered dermal skin replacements were not associated with any significant improvements in wound healing.

Pressure-related injury — A single trial has evaluated a skin substitute (Oasis wound matrix) for the treatment of pressure-induced skin injury [53]. In this trial, wound healing was significantly improved in 130 adults with stage IV pressure ulcers who received standard care plus the skin substitute compared with standard care alone (proportion with complete wound healing: 40 versus 29 percent; 90 percent reduction in ulcer surface area: 55 versus 38 percent). (See "Clinical staging and general management of pressure-induced skin and soft tissue injury".)

Other types of wounds — Other studies have demonstrated positive outcomes for a variety of complex wounds [41,54-61].

●Abdominal wall reconstruction (see "Management of the open abdomen in adults" and "Management of ventral hernias")

●Breast reconstruction (see "Overview of breast reconstruction")

●Extremity reconstruction (see "Surgical reconstruction of the upper extremity" and "Surgical reconstruction of the lower extremity")

●Epidermolysis bullosa (see "Overview of the management of epidermolysis bullosa", section on 'Skin and wound care')

●Pyoderma gangrenosum (PG) (see "Pyoderma gangrenosum: Treatment and prognosis", section on 'Wound management')

Cost considerations — In the era of increasing health care costs associated with new technologies, several cost analysis studies suggest that despite the high initial costs, skin substitutes can shorten time to wound closure and result in an overall cost reduction [62,63].

GENERAL PROPERTIES AND APPLICATION — The successful use of skin substitutes is ultimately predicated on the basic principles of wound management. (See "Overview of treatment of chronic wounds", section on 'Wound bed preparation' and "Treatment of deep burns", section on 'Early burn excision'.)

●The underlying causes of poor wound healing must be addressed. Underlying patient comorbidities need to be addressed to optimize the wound healing environment. As with skin grafting, impaired perfusion needs to be corrected before using skin substitutes. (See "Risk factors for impaired wound healing and wound complications".)

●Prior to placement of a skin substitute, the wound bed should be debrided of all necrotic tissue so that the wound margins contain only healthy cells. Skin substitutes do not replace an inadequately debrided wound bed. (See "Basic principles of wound management".)

●The recipient wound bed must be free of infection. Skin substitutes are not effective in infected wounds that have not been adequately treated.

It is essential to have full understanding of the material being used and its indications. (See 'Terminology and classification' above and 'Indications for use and efficacy' above.)

Dehydrated human amniotic/chorion membrane — Naturally occurring membrane materials, such as human amniotic membrane, have been successfully used for treating partial-thickness or full-thickness wounds [64-67].

Sterilized, dehydrated human amnion/chorion membrane (DHACM) is composed of a single layer of epithelial cells, a basement membrane, and an avascular connective tissue matrix. DHACM contains growth factors that promote wound healing, including platelet-derived growth factor A and B, basic fibroblastic growth factor, and transforming growth factor beta 1 [68,69]. DHACM is stable at ambient temperatures for up to five years.

DHACM has been used for managing burn wounds, diabetic foot ulcers, venous leg ulcers, pressure ulcers, surgical wounds, and traumatic wounds.

DHACM should be prepared using aseptic technique before applying to a clean wound bed that has been debrided as necessary. DHACM can be applied to a wet or dry wound bed. Any number of methods can be used to secure DHACM to the wound, followed by the appropriate wound dressing. DHACM can be changed weekly or biweekly depending on the needs of the patient [70].

Dermal replacement template — Dermal replacement template (DRT) is composed of a cross-linked bovine collagen and glycosaminoglycan dermal layer and a silicone epidermal layer.

DRT (eg, Matriderm, Integra dermal regeneration template [IDRT]) can be used for partial-thickness or full-thickness wounds, including burn wounds, pressure ulcers, venous leg ulcers, diabetic foot ulcers, and other surgical wounds [36,41]. A commonly used DRT is Matriderm. This product is available outside the United States and is widely used in Western European countries such as the United Kingdom, Germany, and Spain, among others. Matriderm is a highly porous dermal scaffold comprised of bovine collagen (collagen type I, III, and V) cross-linked to an elastin hydrolysate. The matrices (1 or 2 mm thick sheets) are irradiated (approximately 1000 Gy) and the product is stored at room temperature. Matriderm can be used as a one-stage procedure with a split-thickness skin graft, and its use may minimize loss in pliability and elasticity of the skin [71].

The application of DRT is a straightforward process. The DRT product is cut to the size of the wound and placed in the wound bed. One option is to moisten the DRT with normal saline prior to applying it to the wound. Another option that seems useful is to apply the dry template to the wound, then wet it with saline. This reduces difficulty in handling the material. After ensuring there are no air bubbles beneath the DRT, the edges are then secured to the wound edges. (See "Skin autografting", section on 'Graft placement and fixation'.)

Appropriate dressings are used to secure it in place and protect the wound area. The outer dressing can be changed as needed depending on the volume of exudate. Once the template has become vascularized (usually by 14 days), any silicone layer can be removed and an autograft applied [72]. (See "Skin autografting", section on 'Recipient site dressings and care'.)

In one trial, the combination of DRT and postoperative negative-pressure therapy compared with DRT alone significantly increased the take rate (98 versus 78 percent) [41]. The interval between DRT and subsequent autografting also decreased from 24 to 10 days. (See "Skin autografting", section on 'Graft immobilization' and "Negative pressure wound therapy".)

Acellular dermal matrix — Acellular dermal matrix (ADM) is an allograft (also called homograft) product created from skin from a nongenetically identical deceased human donor that has been processed to remove the epidermis using a sequential decellularization process [73,74]. ADM (eg, Alloderm) can be distributed fresh or cryopreserved after glycerol preservation from cadavers. These decellularized matrices fully integrate into the wound bed after application, replacing lost dermal tissue and providing a scaffold into which the recipient's cells can grow and become vascularized, ultimately regenerating into normal skin.

ADMs are used in the reconstruction of skin defects, including burn wounds and abdominal wall defects, as well as for breast reconstruction. The application of ADM over superficial partial-thickness wounds can minimize pain and facilitate reepithelialization.

Before application, preserved ADM must be rehydrated in warm sterile saline solution. It should be applied within four hours of rehydration with the dermal side down and the basement membrane side facing up.

Following placement and fixation, we dress the ADM in three layers. We use an inner layer of petrolatum-based antimicrobial impregnated gauze, a middle layer of damp saline gauze, and an outer layer of a dry gauze covered by an elastic bandage. The inner layer is not changed for the first seven days, but the outer two layers can be changed as often as necessary [75].

Synthetic dermal substitutes — In contrast to ADM or IDRT, Biodegradable Temporizing Matrix (BTM) is a fully synthetic product. It consists of a 2-mm thin biodegradable polyurethane bonded to a nonbiodegradable polyurethane sealing membrane which is 150 mm thick. Like IDRT, it is applied in a two-stage approach. In an animal model, BTM had a more extensive vascular network and a greater inflammatory response compared with IDRT [76]. In a study of 30 patients, the authors described the potential advantage of the polyurethane origin of BTM against metalloproteinases from bacterial and lysosomal enzymes, which otherwise degrade collagen in collagen-based matrices [77]. No randomized trials have demonstrated superiority of BTM over other dermal substitutes [76-78]. Given the potential protective nature of BTM against infectious complications and its ability to remain in place for longer periods without the need for delamination and application of split-thickness skin graft, BTM might prove to be beneficial in coverage of wound in those with extensively large percentage total body surface area burns.

Bilayered living cellular construct — The bilayered living cellular construct (BLCC) has two components:

●Dermal part – Bovine type I collagen with human neonatal foreskin fibroblasts

●Epidermal part – Keratinocytes

BLCC (eg, IDRT, Apligraf) can be used to treat burn wounds, venous leg ulcers, diabetic foot ulcers, pyoderma granulosum, acute wounds, epidermolysis bullosa, and post-radiation ulcers. In the author's practice, BLCC is more often in the acute burn setting, but its use has been gradually extended to become a versatile additional tool for burn reconstruction.

A commonly used BLCC is IDRT [79]. The BLCC template serves as a scaffold for neovascular and cellular infiltration from the wound bed. It can be used as a standard two-stage dermal template or as a single stage. In the two-stage procedure, the BLCC scaffold is gradually replaced with the patient's own collagen, forming a neo-dermis. After two to three weeks, the silicone epidermal layer is removed and the wound is covered with a thin split-thickness skin graft.

BLCC should be handled with aseptic technique and applied directly to a clean wound base after proper debridement and hemostasis. As with autografts, BLCC can be meshed or slit before application to allow for drainage of exudate. The product can be secured in place using any one of a variety of techniques. (See "Skin autografting", section on 'Graft meshing' and "Skin autografting", section on 'Graft placement and fixation'.)

A nonadherent dressing should be placed over the BLCC followed by the appropriate wound dressing. (See "Skin autografting", section on 'Recipient site dressings and care'.)

The wound should be evaluated and dressings changed at least once per week. Reapplication may be necessary. Outer dressings can be changed more frequently, as needed [80]. Evidence of neovascularization occurs in a minimum of 10 days but usually within two to three weeks. When this has occurred, any silicone layer can be removed and a split-thickness skin graft applied.

Xenografts — Skin xenografts (heterografts) are obtained from an unrelated species and can be used as temporary skin coverage, particularly for large burn wounds. Porcine grafts have been the most commonly used xenograft [81,82], however, there’s been research into the use of tilapia fish skin as xenograft [83-85]. Xenografts are generally readily available but may not be as effective as allografts and are not generally used in resource-rich environments; however, xenografts do have an ongoing role in resource-limited countries where access to allograft and advanced technologies is limited or nonexistent. Xenografts are handled and applied in a manner similar to autografts. (See "Skin autografting".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic wound management".)

SUMMARY AND RECOMMENDATIONS

●Skin substitutes – Skin substitutes are a heterogeneous group of biologic, synthetic, or biosynthetic materials that can provide temporary or permanent coverage of open skin wounds. The aim of skin substitutes is to replicate the properties of the normal skin. Skin substitutes are an important adjunct in the management of acute or chronic wounds. (See 'Introduction' above and 'Available products' above.)

●Classification – There is no universally accepted classification system that allows for simple categorization of all the products that are commercially available (table 2 and figure 1). Skin substitutes can be classified based on clinical features, including replaced skin component (epidermis, dermis, or both) or required permanence (temporary, permanent), or by composition, including material used (biologic, synthetic, or both), layering (single layer, bilayer), and cellularity (acellular, cellular). (See 'Terminology and classification' above.)

●Indications – Skin substitutes can be used to cover acute burn wounds or other injuries, or for burn wound reconstruction, such as for release of extensive severe post-burn contractures, or other forms of reconstruction, such as for abdominal wall or breast reconstruction. (See 'Indications for use and efficacy' above.)

●General properties and application – Each skin substitute has unique advantages and disadvantages (table 1). The type of skin substitute chosen depends upon the type of wound (ie, acute, chronic), its etiology (eg, trauma, chronic inflammation), the skin component that requires replacement (ie, epidermis, dermis, or both), and need for permanence. In addition, the desired functional and aesthetic outcomes need to be considered. Commonly used skin substitutes, their usage, and efficacy are reviewed above. (See 'General properties and application' above.)