Inappropriate healing is associated with an imbalance in growth factors and cytokines — proteins that cells use to communicate with one another. The discovery of these signals and their mode of action has led to major pharmaceutical development in recent years. Locally applied natural or recombinant growth factors are experimentally effective in accelerating wound repair, and a few have overcome the clinical challenge of functioning in the hostile environment of the chronic wound.
It is a greater challenge to block the pathological effects of growth factors and cytokines, since this requires neutralizing the signal molecule or inactivating the cell machinery that drives the healing process. Several anti-scarring strategies are in clinical development. In addition to the cosmetic implications of excess healing, scarring is prominent in diseases of many internal organs such as the heart, kidney and lung.Research targets pathway
The principal therapeutic target is the transforming growth factor-beta signal pathway. This system is very important in repair and restoration of the extracellular matrix, but it is overactive in many scarring situations. As we understand the biochemistry of these healing processes, small, synthetic drugs and peptides may replace the need for complex proteins.
The skin has remarkable repair properties because of self-renewing stem cells in the epidermis. These cells have the potential to regenerate not only skin but also hair follicles and other specialized epidermal structures. Likewise, we know that fibroblasts in the underlying dermis are involved in restoring the connective tissue, while endothelial cells form new capillaries.
However, now it is evident that this process is supplemented by bone marrow stem cells that arrive from the circulation to rebuild new connective tissue and blood vessels. We may be able to improve the regenerative capacity of skin by boosting the activity of stem cells.
Gene therapy of wounds holds the promise of temporarily reprogramming wound tissue into a local drug production system. DNA, usually in the form of a virus, can be used to deliver genes for growth factors or other proteins. Clinical progress with this technique shows it can be safe and effective. Further safeguards can be added to the gene delivery system by adding drug-responsive switches to the system.
Living skin equivalents are one of the key advances in tissue engineering. Simple, delicate sheets of epidermal cells have been in extensive use in burn applications, and current devices are composites with a durable, synthetic dermis containing fibroblasts. Artificial skin acts as a temporary, biological source of growth factors and other protective substances while the host tissue undergoes repair.
Currently, scientists are engineering more complete skin by incorporating capillaries and other structures to make a longer-lived equivalent. Purely synthetic skin substitutes can also improve repair by creating a more optimal wound healing environment. Tissue engineering and gene transfer can also be partnered by introducing therapeutic genes into the skin equivalent during laboratory production, thus turning the device into a drug delivery system.
These advances will develop into practical solutions for the challenges facing the cosmetic surgeon.
Disclosure: Jeffrey M. Davidson, Ph.D., is president of the Wound Healing Society; professor of pathology, Vanderbilt University School of Medicine; and senior research career scientist, Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville (Tenn.) campus.