Wound Bed Preparation: The Science Behind the Removal of Barriers to Healing

Stuart Enoch, MBBS, MRCSEd, MRCS (Eng), Keith Harding, MB ChB, MRCGP, FRCS


Wounds. 2003;15(7) 

In This Article

Normal Wound Healing

Vasoconstriction in combination with clot formation and platelet aggregation occurs in response to initial injury. Once aggregated, the platelets degranulate and release mediators that help form the fibrin clot together with growth factors and chemo-attractants. During this initial hemostatic phase, platelets release several growth factors, including platelet-derived growth factor (PDGF), insulin-like growth factor-1 (IGF-1), epidermal growth factor (EGF), and transforming growth factor-beta (TGF-b) into the wound bed. Neutrophils and macrophages migrate into the wound and secrete additional growth factors, such as transforming growth factor-alpha (TGF-a), heparin-binding epidermal growth factor (HB-EGF), and basic fibroblast growth factor (bFGF), which further stimulate the inflammatory process. These various growth factors are mitogenic and chemotactic for endothelial cells, macrophages, keratinocytes, and fibroblasts, which migrate to the site of the wound to form the "granulation tissue" or provisional matrix.[3]

During the earliest stages of repair, neutrophil proteases participate in antimicrobial defense and in the debridement of devitalized tissue at the wound site.[4] Macrophages, activated by CD4+ T helper cells and by the cytokine interferon-g (produced by T-lymphocytes and NK cells), stimulate acute inflammation through the secretion of cytokines, mainly tumor necrosis factor (TNF), IL-1 and chemokines, and short-lived lipid mediators, such as platelet-activating factor, prostaglandins, and leukotrienes. Their collective action is to further enhance local inflammation that is rich in neutrophils, which helps to phagocytose and destroy infectious organisms.[5] The cytokines play a further role in tissue repair: IL-1b stimulates the proliferation of fibroblasts, and TNF-a and IL-1b stimulate fibroblasts to synthesize MMPs.

Activated macrophages, along with neutrophils, remove dead tissues to facilitate repair after the infection is controlled. In addition, they induce the formation of repair tissue by secreting growth factors that stimulate fibroblast proliferation (PDGF), collagen synthesis (TGF-b), and new blood vessel formation (FGF). Though many different growth factors contribute in their own way to wound repair, FGF plays a pivotal role in this process, as it is a potent mitogen for endothelial cells, accelerates granulation tissue formation by increasing fibroblast proliferation and collagen accumulation,[6] and provides the initial angiogenic stimulus.[7]

Fibroblasts, epithelial cells, and vascular endothelial cells begin to multiply freely as the wound enters the proliferative phase of repair. During the proliferative phase, the number of inflammatory cells in the wound decreases, and fibroblasts, endothelial cells, and keratinocytes secrete further growth factors that are required to mediate the process of wound healing.

The development of granulation tissue during wound healing requires the formation of new capillaries. New vessel formation or sprouting of capillaries from pre-existing ones is called angiogenesis, and this plays a pivotal role in the complex process of wound healing. Angiogenesis is tightly regulated by factors that act by either stimulating or inhibiting vessel growth.[8] During wound healing, angiogenic capillary sprouts invade the fibrin/fibronectin-rich wound clot and within a few days organize into a microvascular network throughout the granulation tissue.[9] As collagen accumulates in the granulation tissue to produce scar, the density of blood vessels diminishes. Disturbance of this dynamic process may influence the development of chronic wounds.[10]

The rapid onset and predominance of proangiogenic factors optimizes healing in damaged tissues.[11] Among all proangiogenic factors, the one that has been extensively studied in wound vessel angiogenesis is the vascular endothelial growth factor (VEGF). Experimental evidence suggests that a defect in VEGF regulation might be associated with wound healing disorders,[12] and healing-impaired diabetic mice show decreased VEGF expression levels.[13] Initial angiogenic stimulus in wound healing might be provided by FGF-2, followed by a subsequent and more prolonged angiogenic stimulus mediated by VEGF.[7]

During the phases of inflammation and proliferation, proteolytic enzymes, such as MMPs and serine proteases, play an essential role in tissue repair and remodeling. Once in the tissue, the inflammatory cells and fibroblasts stimulate the production of MMP-1, -2, -3, and -9 so that they can degrade the damaged ECM in preparation for macrophage phagocytosis of the ECM debris. Cytokines, growth factors, and tissue inhibitors of metalloproteinases (TIMPs) tightly regulate the production and activity of MMPs.

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 during this phase are the fibroblasts, as they synthesize matrix molecules, such as collagen, elastin, and proteoglycans. They also produce MMPs that degrade the matrix and TIMPs, which regulate the activity of MMPs. This phase can take several months and results in a mature scar.

In summary, normal wound healing is a complex and finely tuned process that is mediated by growth factors, cytokines including angiogenic mediators, and MMPs.[14] Although the phases involved in normal wound healing overlap, they occur in a timely manner and are tightly regulated.