Elsevier

Clinics in Dermatology

Volume 23, Issue 4, July–August 2005, Pages 403-412
Clinics in Dermatology

Engineered skin substitutes: practices and potentials

https://doi.org/10.1016/j.clindermatol.2004.07.023Get rights and content

Abstract

Wound healing can be problematic in several clinical settings because of massive tissue injury (burns), wound healing deficiencies (chronic wounds), or congenital conditions and diseases. Engineered skin substitutes have been developed to address the medical need for wound coverage and tissue repair. Currently, no engineered skin substitute can replace all of the functions of intact human skin. A variety of biologic dressings and skin substitutes have however contributed to improved outcomes for patients suffering from acute and chronic wounds. These include acellular biomaterials and composite cultured skin analogs containing allogeneic or autologous cultured skin cells.

Introduction

Wound coverage can be problematic in several different clinical settings. In one extreme example, massive burn injuries can require replacement of skin covering nearly the entire body surface area. Burns are an important medical problem in the United States, where greater than 1 million burn injuries occur each year.1 Fires and burns result in 45,000 hospitalizations and 4500 deaths annually. Many advances in burn care have however caused a decline in burn mortality rates. In 1952, only half of all pediatric patients with greater than 50% total body surface area (TBSA) burns survived. Currently, most survive a 50% TBSA burn, and half of children who receive 98% TBSA burns survive.2 Advances in burn care contributing to the decline in mortality include early excision, improved fluid resuscitation, infection control, nutritional support, and aggressive physical therapy.2, 3, 4 Because most patients survive the initial resuscitation phase, even after very severe burns affecting a large percentage of TBSA, wound management is critical for recovery. Autografting with split-thickness skin, either meshed or unmeshed, has been considered the preferred treatment for coverage of excised burn wounds, but donor sites for autograft are limited in patients with very large burns. In these patients, wound coverage requires repeated harvesting of available donor sites, which is associated with pain and scarring at the donor site and lengthy hospital stays.

Chronic wounds represent a different kind of challenge for wound healing. These wounds do not usually involve a large surface area, but they have a high incidence in the general population and thus have enormous medical and economic impacts. The most common chronic wounds include pressure ulcers and leg ulcers.5 In the United States alone, these wounds are estimated to affect more than 2 million people6 with total treatment costs as high as $1 billion annually.5 These figures may be expected to rise as the average age of the population increases. Pressure ulcers, characterized by tissue ischemia and necrosis,7 are common among patients in long-term care settings, but patients hospitalized for short-term care or in home settings are also at risk if mobility is impaired.5 Leg ulcers can have a variety of etiologies. Venous ulcers are the most common, often resulting from dysfunction of valves in veins of the lower leg that normally prevent the backflow of venous blood. Venous congestion leads to leakage of blood and macromolecules into the dermis, which can act as physical barriers to diffusion of oxygen and nutrients from the vasculature into the skin.7 Arterial insufficiency and diabetes also contribute to the development of leg ulcers. Arterial blockage can lead to tissue ischemia, causing ulcers or necrosis. Patients with diabetes are prone to leg ulcers because of several aspects of their disease, including neuropathy, poor circulation, and reduced response to infection. Diabetic foot ulcers can lead to complications that result in as many as 50,000 amputations annually in the United States,6 accounting for 45% to 70% of all lower-extremity amputations performed.5 Historically, treatment of relatively small chronic wounds has included the use of topical agents and occlusive dressings, and grafting of split- or full-thickness skin.8 Skin grafts can provide timely wound coverage, but may lead to painful donor sites which are slow to heal and may be unsuccessful because of underlying deficiencies in wound healing.

Though they affect a relatively small fraction of the population, congenital skin conditions and diseases represent significant challenges for wound coverage. For example, giant congenital nevi can cover more than 50% TBSA and when untreated can significantly increase a patient's lifetime risk for development of melanoma.9 Traditional treatment has involved serial excision and skin autografting, but donor site morbidity, including hypertrophic scarring, can result. Another example is epidermolysis bullosa (EB), an inherited mechanobullous disorder that is characterized by erosions and blistering of the epidermis.10 The genetic causes are heterogeneous but primarily affect proteins of the basement membrane zone of the skin, leading to mechanical fragility. Wounds in patients with EB are difficult to avoid and tend to heal slowly or progress to chronic wounds. Because EB results from genetic mutations in proteins of the patient's own skin, autografting is not a viable treatment. Clinical management has focused on protection from damage and topical therapy, including sterile dressings, antibiotics, and analgesics.11, 12 Currently, treatment is supportive at best, and there is no known cure.

There are clearly many medical needs for safe and effective therapeutic options for wound coverage in these diverse patient populations. Skin substitutes have been developed in response to these needs, providing new alternatives for temporary coverage and permanent wound closure with stable skin tissue.

Section snippets

Available skin substitutes

Human skin performs a wide range of protective, perceptive, and regulatory functions, but its role in providing a protective barrier is most critical for survival. The barrier function of skin is performed by the epidermis, which is comprised mainly of keratinocytes. The keratinocytes form a stratified epithelium, with proliferating basal cells at the innermost layer and the keratinized, relatively impermeable outer stratum corneum layer at the surface. Other cells of the epidermis include

On the horizon

Despite favorable results with skin substitutes, limitations in anatomy remain which can influence engraftment and functional and cosmetic outcome. Because skin substitutes currently available contain at most only 2 cell types, fibroblasts and keratinocytes, they cannot replace all of the functions of native skin. Recent and ongoing studies are addressing the preparation of engineered skin containing additional cell types to increase homology to native human skin and improve functional outcome.

Conclusions

Technological advances in the fabrication of biomaterials and the culture of skin cells have permitted the production of engineered skin substitutes. The variety of products currently available has contributed to improved treatment of burns, chronic wounds, and congenital skin disorders. Continued research will focus on improving the anatomy and physiology of skin substitutes, working toward better homology to native human skin. In addition, evaluation of the use of genetically modified cells

Acknowledgment

Supported in part by the Shriners Hospitals for Children, the National Institutes of Health, and the US Food and Drug Administration.

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      Citation Excerpt :

      Epidermis, the outermost layer mainly composed of keratinocytes and some other cell types such as melanocytes, langerhans and Merkel cells, is very thin and contributes to a little part of mechanical behavior of the skin [2]. Dermis, the internal layer that offers the structural and the nutritional support, and elasticity for this tissue, is mainly composed of fibroblasts and extracellular matrix (ECM) enriched in collagen, and it also contains blood and lymphatic vessels, nerves, keratinizing structures, excretory and secretory glands, immune cells and sensory nerve receptors [3–5]. Once the skin is wounded, diverse cell types within the layers cooperate at precise stages involving hemostasis, growth, inflammation, angiogenesis, re-epithelialization, and remodeling to bring about healing [6,7].

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