Skin Substitutes in Burn Care

Large surface area burns continue to be one of the most difficult and deadly problems the medical community faces today. Although major strides have been made in burn care throughout the years, many difficulties remain. Historically, some rather bizarre and egregious concoctions, at least by modern standards, have been applied to burns to promote healing. Barbara Ravage, author of Burn Unit, records and describes fascinating unguents and emollients that include using calf dung and black mud as topical burn treatments, as recorded in the Ebers Papyrus from the 1500s BC.¹
While partial-thickness burns have the ability to heal on their own while restoring relatively normal skin architecture, full-thickness burns do not. Full-thickness burn injuries that destroy both the epidermis and dermis produce irretrievable skin loss, since completely destroyed dermis does not regenerate. Although a full-thickness burn wound may heal with a contracting scar tissue base and an overgrowth of thin epidermis, it lacks many of the normal structures and basic functions of skin. Temperature regulation, sensory perception, excretory function (through sweating), and metabolic activities such as the formation of Vitamin D, to mention but a few, are either severely compromised or completely lost.² Some skin barrier function may be maintained; however, the resilience and elasticity of normal skin are never recovered. Thick, even hypertrophied scarring is often the hallmark of burn healing.
Although partial-thickness burns may heal spontaneously, skin grafting provides the best results for deep partial- to full-thickness burns. Most burn surgeons would agree that the best replacement for a full-thickness burn is a full-thickness skin graft. Unfortunately, the amount of full-thickness skin that can be donated willingly from other parts of the body for transplantation is limited, and the old principle of “robbing Peter to pay Paul” rapidly comes into play. Therefore, large burns requiring excision are treated with split-thickness grafts of varying thickness. Split-thickness donor sites heal and can be re-harvested. This allows for multiple cropping from the same site, although the process is not without limits.
While split-thickness skin grafts are satisfactory they are not perfect, as only a small portion of dermis is transplanted with each split-thickness graft. The ideal skin replacement product is one that is readily available off the shelf, is dependable, easy to use, infection resistant, has a low profile of side effects, demonstrates an acceptable appearance, is reasonably priced, and restores both the dermal and epidermal layers of the skin to its original state. While this chimerical creature does not exist, strides have been made in reaching that goal and the search is ongoing.
Skin substitutes are often categorized as either temporary or permanent and are also thought of as products that provide temporary wound coverage or wound closure.^3,4 In actuality, few (if any) of the products used to treat burns today are permanent skin substitutes. Deciding whether a product is a temporary or permanent covering and whether or not it produces formal wound closure as opposed to simple coverage is somewhat arbitrary and can be confusing.⁵
Temporary skin substitutes, as a group, include a collection of varied, topically applied agents that are thought to offer more than a simple protective covering to a healing burn. Such skin substitutes include products that have inherent healing properties of their own or have added biologically active substances, presumably able to advance wound healing.⁶ Products can be constructed of either intact human skin, animal skin, or a combination of biological and man made materials. One of the most widely used temporary skin substitutes is frozen cadaver skin. This allograft skin will heal and be incorporated into the patient’s tissues when applied to a raw or otherwise prepared burn surface. Unfortunately, the fate of the allograft is sealed at the moment of application. Being antigenic, allograft eventually succumbs to rejection by the patient’s system when immune competence is restored. Xenografts from various animals have been tested and tried over the centuries; frozen pig skin is used today. Pig skin functions only as a temporary substitute or burn cover, as it is not incorporated into the patient’s tissues. It merely adheres to the skin and provides protection to the healing burn wound. Although not defined in detail perhaps some contribution to healing may occur from the deposition of growth factors, collagen, and perhaps other proteins, from the raw undersurface of the porcine dermis. The same may be said of human allograft.
The search for a true skin substitute is an ongoing process because of the inherent difficulties with allograft and xenograft. The term “skin substitute” entered the burn vernacular in the 1980s. A giant leap forward in the development of skin substitutes came from Burke et al⁷ and the development of Integra® (Integra Life Sciences, Plainsboro, NJ). Their historic and groundbreaking work was presented in 1981.⁷ According to Ravage, the development of Integra was the result of a collaborative effort by these two pioneers that dates back nearly 30 years.¹
Integra was approved by the United States FDA for use in the treatment of burns in 1996. It is a bilayered skin substitute composed of an outer layer of silicone covering a bioengineered collagen matrix. The product is marketed as a “dermal regeneration template” that allows the ingrowth of fibroblasts, vascular tissues, and cells in a more organized fashion. While the bovine collagen in the dermal template is ultimately replaced by the patient’s collagen and cell ingrowth, the reformed “neodermis” has an architecture that more closely resembles normal dermis than that of simple scar tissue. The outer semipermeable silicone membrane functions as a protective barrier while revascularization and remodeling occur, much like normal epidermis. After maturation of the framework, this neodermis is covered by thin sheets of the patient’s autograft skin to complete the reconstruction. Following the advent of Integra, many similar products burst forth into the market place.
The dermal replacement product AlloDerm® (LifeCell Corp., Branchburg, NJ) consists of specially treated cadaver skin. The epidermis and antigenic dermal cells are removed (by proprietary processes) and leave an acellular, nonantigenic, dermal matrix. This matrix is then applied to the burn bed. Some of this dermal matrix may remain permanently incorporated into the patient’s tissue as healing and remodeling occur. As with Integra, AlloDerm must also be covered with thin skin autografts to restore any missing epidermis. Dermal replacement products offer many advantages. When healing is complete, the amount of scar tissue formation in the wound is markedly decreased. This results in a measured improvement in elasticity and flexibility of the healed burn. Scar contracture is lessened and leads to a reduction in the number of scar contracture procedures and plastic surgical reconstructions required long term. Dermal replacement has therefore been a major advancement in the treatment of burns.
Another at least semipermanent skin substitute is the patient’s epidermal cells that are grown in tissue cultures. This technique allows the in-vitro cultivation of the patient’s epidermal cells by modifications of the innovatory techniques described by Rheinwald and Green in 1975.⁸ The matured sheets of cultured keratinocytes are subsequently reapplied to the burn surface, or applied along with a dermal replacement product, such as Integra or AlloDerm. Epicel® (Genzyme Biosurgery, Cambridge, Mass), which is an ingenious product, has had difficulty gaining widespread use. Epicel cannot be thought of as a total skin substitute, unless used in combination with some form of dermal reconstruction, since it only restores epidermis.
The field of skin substitutes has been bombarded with almost Messianic zeal in an effort to develop the next generation of newer and better skin replacements. These dressings are made with varied combinations of synthetic and/or biologic substances. Although all may have some utility and each has its champions, they appear to find more application in the larger and therefore more lucrative wound market. One earlier product is Biobrane™ (Smith & Nephew, Largo, Fla), which is still used throughout the burn community often as a temporary cover for burn and perhaps equally as often as skin donor site coverage. It is composed of two layers of silicone and a nylon mesh to which collagen is bonded (Voigt DW, Hao Z, Paul CN, Wiebelhaus P, personal communication, March 2007). Transcyte™ (Smith & Nephew, Largo, Fla) is another product with great utility in the treatment of burns. It combined Biobrane with growth factors derived from neonatal foreskin fibroblasts and showed significantly improved healing rates in partial-thickness burns. Transcyte increased the percentage of patients with burns who could be treated in the outpatient setting, but unfortunately was removed from the marketplace because of financial considerations; a significant loss to the armamentarium of the burn physician.⁹ Apligraf® (Organogenesis, Canton, Mass) and Dermagraft® (Advanced BioHealing, Westport, Conn) are two synthetic products that can be used as temporary skin substitutes, although their major utility appears to be in treating wounds other than burns. Apligraf is a man-made biological construct combining neonatal keratinocytes, fibroblasts, and collagen. Dermagraft uses either polygalactic or polyglycolic acid meshes combined with neonatal fibroblast to enhance wound healing. Multiple other products are, or are on the way to the burn and wound care markets. What role these existing and newer products will play is still not clearly defined.

Conclusion

While numerous advances have been made in the science of biological tissue engineering in the past few decades, the ideal skin replacement remains elusive. None of the currently available products fulfill all the criteria of a “perfect” skin replacement. Currently, the patient’s skin remains the best alternative to replace burned tissues. The addition of dermal replacement alternatives has improved the long-term success of split-thickness skin grafts. Further progress will undoubtedly be made in the years to come. Unfortunately, ideal skin replacement remains an ephemeral goal that must be diligently pursued. Hopefully this replacement will be found sooner rather than later.