Chapter 2: Healing Response in Acute and Chronic Wounds

INTRODUCTION

Perhaps the hamartia, or the flaw, in the study of wound healing is the tendency to oversimplify the truly elegant system that ensures healing, both anatomically and functionally. The multitude of processes that ensure wound closure and the commensurate return of function are equally marvelous.

The illustrations in this chapter introduce the interplay of cellular and molecular signaling in conjunction with vascular events that occur during the healing process. The figures demonstrate how cells involved in the repair process are directed, based upon global and local stimuli that may be cytokine, chemokine, pH, or galvanically driven.^1,2 If invaders or pathogens (eg, bacteria, fungi, viruses, or debris) are present, innate immune cells migrate and proliferate to the site of injury.³ These cells include macrophages, neutrophils, natural killer (NK) cells, and gamma delta T cells. If the invader is a repeat offender that the host has successfully fended off previously, adaptive immune responses (B cell clonal expansion) are triggered.^3–5 Simultaneously, debris (necrotic and/or injured cells) is removed and a new wound bed excavated via proteases and extracellular matrix (ECM) degradation. This serves two purposes: (1) the clearance of cell and invader refuse and (2) the provision of pathways for cellular migration and proliferation, which constitute repair.²

The signaling in wound healing, renewal, and regeneration is a product of many factors, including the concentration and timing of chemical signal delivery, target cell receptor availability, active form after cleavage, degradation rate, messenger half-life, pH and presence of enzymes (eg, proteases) in the wound milieu, hydrophobicity, and hydrophilicity. Scaffold-binding (via heparin activation or other mechanisms), fiber type (whether fibrin or collagen), cell shape, adhesion interfaces (via integrins), and storage of growth factors all contribute to the timing and intensity of cell signaling during wound healing. These factors work together to drive growth factor, cytokine, and chemokine bioavailability, thus resulting in wound healing.

Vascular changes occur as a result of endothelial cell activation, migration, and capillary expansion in response to tissue hypoxia and increased lactic acid concentration.^6–8 Phenotypical changes in prominent cells (platelets, macrophages, and fibroblasts) are important in directing healing through the influence and production of many of the chemical messengers. The macrophages have a pronounced cellular functional metamorphosis ...