Rodney K Chan Perry H Liu and Dennis P Orgill

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Department of Plastic Surgery, Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts


The healing of chronic wounds is a major health problem. Through studying the normal healing of acute wounds and the use of impaired wound healing models such as the genetically diabetic mouse, we have dissected the cell types and growth factors that are involved in this complex and collaborative process. This review discusses the classical phases of wound healing and the signals important for cell recruitment and proliferation, epithelialization, and angio-genesis. The complexity of this process is highlighted by numerous clinical trials performed to translate these growth factors into clinical use but only one currently approved drug recombinant human platelet derived growth factor-pp. There is a desperate need for therapies that are both efficacious and cost-effective.

Unlike amphibians, humans lack tissue regenerative abilities and generally respond to injury through scarring and contraction. Some exceptions, such as regeneration of liver tissue after partial hepatectomy, suggest that the capacity for regeneration exists. The skin also has the potential for repair and regeneration. In fact, wounds in the second trimester not only heal in utero with minimal scarring, but also achieve the strength of unwounded skin. Yet, in adults, chronic non-healing wounds are becoming a major problem, one made worse by our growing elderly population and a dramatic rise in the incidence of diabetes.

A wide variety of treatments for chronic wounds exist. These include surgical and enzymatic debridements, dress ings, topical and systemic antibiotics, moist environment, surgical revascularization, nutritional supplementation, skin grafts, tissue flaps, and tissue engineering products. These options have allowed many wounds to heal without the need to resort to amputations or radical reconstructions. Yet many chronic wounds persist, especially among diabetics, in areas of prior irradiation, as well as in areas under constant pressure or venous congestion.

In the past two decades, the mechanisms of normal wound healing have slowly been elucidated. The purpose of this chapter is to review our current understanding of wound healing biology and to provide a basis for devising new treatments, especially those involving the application of growth factors to poorly healing wounds.

Wound Healing Cascade

The creation of an acute wound initiates an overlapping sequence of events involving specific cells, chemokines, and cytokines directed at limiting the initial damage and restoring tissue integrity. The four classical phases of this process are coagulation, inflammation, proliferation, and maturation [1].

In the coagulation phase, traumatically exposed collagen IV and V initiate the coagulation cascade, which begins with platelet aggregation and plugging. Within seconds to minutes, the formation of a fibrin scaffold traps red blood cells and provides a lattice framework for endothelial cells, inflammatory cells, and fibroblasts to operate during wound healing.

This is followed by the inflammatory phase when activated platelets and endothelial cells release mediators that increase vascular permeability and recruit inflammatory cells such as neutrophils and, subsequently, macrophages and fibroblasts. The resulting inflammatory infiltrate clears the wound of contaminating debris and bacteria. Over the following 2 to 3 days, neutrophils are replaced by macrophages and mononuclear phagocytic cells. Aside from their phagocytic abilities, macrophages provide more than 30 different growth factors and cytokines that stimulate angio-genesis and extracellular matrix production.

The proliferative phase of wound healing is characterized by the replacement of the provisional fibrin matrix, established during the initial clot formation, with collagen and proteoglycans. Activated monocytes and platelets synthesize platelet-derived growth factor (PDGF) and transforming growth factor-b (TGF-b) to stimulate fibroblast proliferation and collagen synthesis. Type III collagen initially predominates but is gradually replaced by type I collagen as the wound matures. Endothelial cells also proliferate to form new capillaries to deliver the necessary oxygen and nutrients for wound repair.

During wound maturation, the final phase of wound healing, random collagen fibrils are replaced by organized fibrils with increasing numbers of intermolecular bonds. During the first 6 weeks, wound strength increases rapidly but then gradually levels off in an asymptotic fashion. Although healed wounds never achieve the strength or degree of collagen organization found in normal tissue, they do eventually reach 70 percent of the strength of nonwounded skin.

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Supplements For Diabetics

Supplements For Diabetics

All you need is a proper diet of fresh fruits and vegetables and get plenty of exercise and you'll be fine. Ever heard those words from your doctor? If that's all heshe recommends then you're missing out an important ingredient for health that he's not telling you. Fact is that you can adhere to the strictest diet, watch everything you eat and get the exercise of amarathon runner and still come down with diabetic complications. Diet, exercise and standard drug treatments simply aren't enough to help keep your diabetes under control.

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