Skin Substitutes and Wound Healing: Current Status and Challenges

David Eisenbud, MD, CWS; Ngan F. Huang, BS; Sunny Luke, DSc; Melvin Silberklang, PhD

Disclosures

Wounds. 2004;16(1) 

In This Article

Rationale for the Use of Cell-Based Skin Substitutes in Chronic Wound Therapy

While autologous tissue transfers can be highly effective in securing wound healing, such procedures (e.g., grafts and flaps) are invasive, painful, and expensive, and are not within the purview of many wound care practitioners. In practical terms, skin substitutes represent artificial, off-the-shelf alternatives to skin grafts that avoid the pain and potential complications of harvesting, are always available in any quantity needed, and can be applied in an office setting. The ideal skin substitute would adhere quickly to the wound and would, during its residence in the wound bed, mimic the physiology and some of the mechanics of normal skin. It would be inexpensive, not subject to immune rejection by the host, and would be highly effective in accelerating tissue regeneration and wound repair.

Unfortunately, this ideal skin substitute has not yet been achieved, and expectations for such a product may be unrealistic. Nevertheless, some very useful products have been developed that do provide many of the desired clinical characteristics. In order to be available off-the-shelf, these products rely on the use of donor allogeneic cells. Allogeneic skin substitutes do not provide cells that persist on the recipient site long term. Deoxyribonucleic acid (DNA) analyses of biopsies of healed wounds after application of a living skin equivalent (LSE) (Apligraf®, Organogenesis Inc., Canton, Massachusetts), for example, have demonstrated one-month persistence of allogeneic cells in only a minority of venous ulcer patients, and the complete disappearance of these cells by two months post-application.[15] In the case of chronic wounds, therefore, the goals of skin substitute therapy have evolved away from providing an immediate new skin towards the more reasonable goal of providing a temporary biologic dressing that accelerates skin tissue regeneration and wound healing by stimulating the recipient's own wound bed-derived skin cells.[16]

The mechanisms by which bioengineered skin substitutes aid wound repair are not completely understood, but may range from maintenance of a biochemically balanced moist wound environment to structural support for tissue regeneration and/or the provision of beneficial cytokines and growth factors to the wound bed. The FDA has regulated skin substitute products as medical devices and has not required extensive elucidation of their therapeutic mechanisms. As knowledge of the myriad cellular events involved in the wound healing cascade increases, dozens of molecular mediators (growth factors) have been found to be involved in wound repair.[17,18] One hope implicit in the use of any cell-based wound therapy, as opposed to exogenous growth factor therapy, is that cells applied to the wound surface are "smart" and will bathe the wound bed with balanced cocktails of such mediators appropriate for the particular physiology of the wound environment that is sensed. For example, incubation of cells derived from biopsies of venous ulcers in conditioned medium supernatant from human fibroblast cell culture induces a highly significant increase in skin cell proliferation, and this effect has been correlated with levels of several cytokines.[19] There is mounting evidence that a bioengineered skin substitute is indeed acting as an interactive "drug" delivery system.[20] Mansbridge, et al., for example, have reported that the viability and metabolic activity of the cellular component of a cellular skin substitute is essential for therapeutic efficacy and have proposed that this is due to the need for ongoing cytokine expression in the wound bed following application.[21] Osborne and Schmid[22] have used measurements of matrix metalloproteinases (MMPs) secreted by the epidermis and dermis of LSE to show that the individual layers of bioengineered skin sense their environment and secrete MMPs in different quantities and ratios depending upon their environment.

While the end point of wound closure is the most intensely studied, there is also increasing focus upon the quality of the healed wound. Cell-based wound therapies, such as cellular skin substitutes, have the potential to reduce wound contraction and to influence the nature of the final healed tissue; indeed, there are reports to indicate an additional benefit of skin substitute therapy in leading to a healed wound with properties that more closely resemble those of normal uninjured skin.[23]

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