From: The Diabetic Foot, Second Edition Edited by: A. Veves, J. M. Giurini, and F . W. LoGerfo © Humana Press Inc., Totowa, NJ 83 5 Induced Regeneration of Skin and Peripheral Nerves Eric C. Soller, MSME and Ioannis V. Yannas, PhD INTRODUCTION Acute or chronic injury to an organ is followed by a spontaneous healing process. Injury to the mammalian fetus is reversible during early stages of gestation; the sponta- neous wound response is capable of restoring the structure and function of the original organ (regeneration). In contrast, the unimpaired response of adults to severe injury is an irreversible process leading to closure of the injured site by contraction and formation of scar, a nonphysiological tissue (repair). The consequences of irreversible healing at the organ scale are far reaching: they often result in an essentially nonfunctional organ. Numerous approaches have been investigated to restore the loss of organ function in adults following irreversible injury . These strategies include transplantation, autograft- ing, implantation of permanent prostheses, use of stem cells, in vitro synthesis, and regenerative medicine (1). The last of these strategies is also referred to as induced organ regeneration, or the recovery of physiological structure and function of non- regenerati ve tissues in an organ (de novo synthesis) by use of elementary reactants, such as biologically active scaffolds, either unseeded or seeded with cells. There is accumulating evidence that the spontaneous healing process of an injured organ in the adult mammal can be modified to yield a partially or completely regenerated organ. Regenerati ve medicine is an emerging field of study involving the implantation of biomaterials to facilitate formation (regeneration) of tissue in vi vo. This f ield is under going rapid growth at this time, as evidenced by observation of regeneration or reported progress in on-going research efforts in a wide range of organs including skin (2), conjunctiva (3), peripheral nerves (4), bone (5), heart valves (6) articular cartilage (7), urological organs (8), and the spinal cord (9). The basic outline of a hypothetical mechanism for induced organ regeneration has become clear . It relies on regenerati ve studies in three organs (skin, conjuncti va, and peripheral nerves), which started much earlier and have progressed much further than research in other organs. From these studies a pattern has emerged, based on two obser- vations: (1) regeneration was successfully induced, at least partially, when contraction was blocked, following grafting with a class of scaffolds that were characterized by a very highly specif ic structure (collecti vely referred to as “regeneration templates”) and (2) when a class of “inacti ve scaffolds” with slightly different properties than their biologically