Skin Substitutes and Wound Healing: Current Status and Challenges

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


Wounds. 2004;16(1) 

In This Article

Continuing Issues in the Design of Cellular Skin Substitutes

There remain many controversies and unanswered questions associated with the design of cell-based wound therapies and cellular skin substitutes. For example, to what extent does addition of a neodermis improve results, especially in chronic wounds, compared with application of more simple cultured keratinocyte sheets? Fibroblasts are already plentiful in the beds of many chronic nonhealing wounds. Epidermal sheets seem to help regenerate dermis over time, and their engraftment requires attachment but no in-growth of blood vessels. Conversely do keratinocytes add anything to the action of a cultured fibroblast-containing matrix? Dermal replacement products ultimately become covered with a new epidermis. There is much evidence that dermal components may be effective in preventing wound contracture, which may be helpful in the cosmetic and functional outcome of healing in some circumstances. While the bilayered products (LSE, BCM) are elegant in design, in that, as co-cultures, they mimic skin more closely than a simple monolayer of keratinocytes, the relative importance of the artificial epidermis and dermis included in these devices is not yet fully established. Nevertheless, there are compelling in-vitro data, such as quantitative cytokine expression profiles (Figure 2), that imply a potentially broader capability for these products. Both LSE and BCM, for example, have shown significant efficacy in a wide range of acute and chronic wounds of varying etiology.[42]

The matrix has been appreciated as important in providing a scaffold for cellular proliferation and migration, but its potential problems have been under-recognized. The poor durability of matrix collagen exposed to the enzyme-rich wound environment may limit the longevity and effectiveness of certain cell-based wound therapies and cellular skin substitutes. Once the matrix begins to disintegrate, the cells may wash away from the wound surface and their effect may be lost. BCM uses a cross-linked, partially protease-resistant collagen matrix to reduce this effect. The matrix also physically separates the epidermis from the wound bed; if keratinocyte-derived cytokines, for example, are of primary importance in the therapeutic effect of cellular skin substitutes, maintaining this diffusion distance may be less effective than applying the cells directly to the wound surface. Both LSE and BCM are relatively thin (<1mm) to attempt to minimize this effect.

Insofar as the actual mechanism of action of cell-based wound therapies is not completely known, the value of maintaining live cells that are capable of proliferating has actually not been demonstrated conclusively.[60] What has been shown is that metabolic activity, as distinct from proliferative capacity, is associated with wound healing efficacy.[21] Conversely, since the donor cells in a bilayered skin substitute applied to a venous ulcer appear to have very limited longevity,[15] there appears to be no safety concern regarding replicative competence of the cells.

Severe limitations on shelf life have led to various cryopreservation techniques that improve the logistics of product distribution and use. The extent to which the cryopreservation process and the thawing and rinsing procedures may damage cells within the product or wash away potentially beneficial growth factors remains an incompletely resolved question.[28] In the case of BCM, product recovered after thawing and rinsing has been shown capable of resuming apparently normal cell growth (not shown) and cytokine secretion (Figure 2) (Prajapati R, Silberklang M, manuscript in preparation), consistent with the absence of irreversible cell damage.


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