Current Concepts In Managing The Wound Microenvironment

By Amy Jelinek, DPM, and Vickie Driver, DPM, FACFAS

   Wound healing is a process that involves the stages of coagulation, inflammation, cell proliferation and repair of the matrix, epithelialization and remodeling of the scar tissue. These stages overlap and the entire process can last for months.1

   During the post-injury coagulation phase, platelets initiate the wound healing process by releasing a number of soluble mediators including platelet-derived growth factor (PDGF), insulin-like growth factor-1 (IGF-1), epidermal growth factor (EGF), fibroblast growth factor (FGF), and transforming growth factor-beta (TGF-beta). These growth factors rapidly diffuse from the wound and inflammatory cells are drawn to the area of the injury.1

   The inflammatory phase is initiated by the blood clotting and platelet degranulation process. During this phase, there is significant vasodilatation, increased capillary permeability, complement activation as well as migration of polymorphonuclear leukocytes (PMN) and macrophages to the site of the wound. The neutrophils and macrophages engulf and destroy bacteria. They also release proteases, including elastase and collagenase, which degrade damaged extracellular matrix (ECM) components. Inflammation is largely regulated by a class of molecules called cytokines, which have powerful stimulatory and inhibitory actions on inflammatory cells.1

   The final phase of wound healing involves a balanced process that degrades old ECM and synthesizes new ECM in order to remodel the scar that was formed during proliferation and repair. Among the most important cells are the fibroblasts, which, among other cells, produce matrix metalloproteinases (MMPs) that degrade the matrix and tissue inhibitors of metalloproteinases (TIMPs) that regulate the activity of the MMPs.2

   In short, normal wound healing is a complex and finely tuned process that is mediated by growth factors and cytokines.2 In the chronic, non-healing wound, these factors change the environment so the normal phases of healing cannot be completed or regulated. This includes decreased amounts of growth factors; increased bacteria, decreased oxygen and senescent cells, which are unable to respond to growth factors.3,4 This upset in the balance of the wound bed causes an increase or decrease in the cellular expression of wound bed factors. This results in delayed healing.

What About The Role Of MMPs?

   Much of the tissue degradation required in wound healing is performed by a specific group of proteolytic enzymes called matrix metalloproteinases (MMPs). The MMPs are a family of structurally related, protein degrading enzymes that require calcium ions for structural conformation and zinc ions in their active site for function. The MMP family of enzymes is capable of digesting almost all of the components of the ECM, including needed growth factors.5 These enzymes function optimally at neutral pH. They are usually produced in response to tissue injury and are not normally present in detectable levels in healing, non-injured tissue.6,7

   In regard to MMP activity during the inflammatory phase of repair, one should not confuse this activity with the release of MMPs during the remodeling phase of healing. During the inflammatory phase, MMP activity assists with debridement and preparation for the migratory phase of healing. During the final phase of healing, MMPs assist with the remodeling of scar and tissue after wound closure. Macrophages, keratinocytes and fibroblasts may produce MMPs in the inflammatory phase.4

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