The chronic wound: impaired healing and solutions in the context of wound bed preparation

Abstract

In the past few years, a different paradigm for the understanding and treatment of chronic wounds has emerged. The term used to describe this new context in which failure to heal is viewed is “wound bed preparation”. This term is revolutionizing the way we approach chronic wounds, and has allowed chronic wounds to gain independence from established models of acute injury. Within the context of wound bed preparation, impaired healing and solutions to it are being addressed in novel ways. In this report, we make use of the diabetic ulcer as an example of a chronic wound, and emphasize the pathophysiological principles, the cellular and molecular abnormalities, and the solutions offered by the new approaches of gene therapy and stem cells. The emerging view is that chronic wounds are characterized by resident cells that have undergone phenotypic changes that need to be corrected for optimal healing to occur. We have established in animal models and in humans that stem cells have the potential to bring about fundamental changes in the repair process and, ultimately, a “quantum” jump in our therapeutic success.

Introduction

In the field of wound healing, most of the emphasis has been on the mechanisms underlying the normal repair process. Much has been learned about wound healing even in the last few years, given the technical opportunities brought about by molecular science. For example, numerous growth factors, thought to play a role in wound healing, have been isolated, cloned, produced as recombinant molecules, and tested for their ability to accelerate wound closure [1], [2]. Another dramatic example is our ability to grow cells in vitro, including what were previously rather fastidious cells such as keratinocytes and microvascular endothelial cells [3], [4]. These tissue culture techniques, together with increased understanding and more effective manipulation of extracellular matrix components, have helped spawn the field of tissue engineering in wound repair [5], [6]. We have also learned some important lessons from fetal wound healing, where scarring is noticeably downregulated or absent [7], [8], [9], [10]. In addition, our understanding of the mechanisms underlying tissue repair is benefiting from transgenic and knockout animal models, which are beginning to point to particular proteins that are critical to healing [11].

The above advances have also brought to the field a rather sophisticated array of new therapeutic products. However, in chronic wounds, the efficacy of many advanced therapeutic agents has been less than what had been predicted from in vitro studies or from animal models and human acute wounds. Several reasons for this discrepancy become apparent when one examines the underlying pathophysiology and complicating features of chronic wounds. In this discussion, we will discuss the phenomenon of impaired healing, its scientific and clinical underpinnings, and how the field of wound healing can benefit from greater recognition of these issues. The clinical emphasis will be on the diabetic ulcer and how these advances in our understanding of barriers to healing can benefit this type of chronic wound. The cellular and molecular abnormalities of chronic wounds will be discussed in the context of wound bed preparation, a new paradigm for our understanding of impaired healing.