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wound healing research

Wound Healing is a complex and dynamic process involving numerous cell types (epithelial and endothelial cells, lymphocytes, fibroblasts, etc.) and an array of soluble factors (e.g. growth factors, cytokines, etc.). This tightly orchestrated process involves various cellular events that often overlap one another, including:

  • the establishment of a fibrin clot, which serves as a temporary hemostatic plug, a provisonal matirx for cells to migration on and over (e.g. re-epithelialization phase), and a reservoir of soluble factors for subsequent cell activation events (e.g. chemotaxis, wound angiogenesis, cell proliferation, etc.)
  • the recruitment of inflammatory cells (inflammation phase), including neutrophils, macrophages and monocytes, that eradicate potential pathogenic microorganisms (both neutrophils and macrophages engulf or phagocytize bacteria), clean up the wound site (e.g. macrophages engulf spent neutrophils), and, upon activation, release important chemotactic and growth factors that help propagate the tissue repair processes
  • re-epithelialization of the wound site by neighbouring epidermal cells restores the protective epithelial barrier of the skin that allows proper tissue remodelling events to occur (i.e. formation of wound granulation tissue)
  • Wound granulation tissue (collagen-rich stroma engineered by infiltrating fibroblasts and stimulated by macrophage secreted factors) forms below the new epithelial barrier. Neovasculization of the newly synthesized stroma is vital, and triggered by the release of several angiogenic factors by resident fibroblasts, epithelial cells, macrophages and endothelial cells themselves
  • Finally, wound contraction occurs. This dynamic process involves stromal fibroblasts and myofibroblasts re-organizing and contracting the collagen-rich granulation tissue.

Chronic Wounds

The skin is the body's largest organ and serves as the primary protective barrier to the outside world. Any disruption (i.e. wound) in this organ must therefore be quickly and efficiently repaired in order to restore tissue integrity and function. Quite often proper wound healing is impaired (e.g. diabetics, paraplegics, elderly), with devastating consequences (severe morbidity - amputations, or death).

In North America alone, the cost of care for patients with chronic wounds is presently estimated to exceed $10 billion dollars per annum. It is known that 16% of all hospital admissions and 23% of all patient hospital days are attributable to wound care problems in lower extremity wounds of diabetics. These figures are expected to rise as the demographics of society evolve towards an increase in the number of people (e.g. immunocompromised, diabetics and elderly) who are prone to developing wound healing problems.

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Pathogenesis of Wound Infections

In spite of the great advances made in infection control and treatment, wound infections remain the principal cause of prolonged and debilitating complications of surgery, leading to morbidity and death.Clinical studies have shown that, under optimal circumstances, the surgical infection rate in clean wounds (Class 1 wounds) may be as low as 0.01 %. This percentage however, rapidly increases in direct proportion to contamination of the surgical site and the duration of operations (>2 hours). In the absence of appropriate autogenous materials to achieve the surgical goal of restoring normal anatomical relationships and physiologic functioning, surgeons are increasingly forced to use alloplastic implant material to support increasingly complicated organism trauma. However, high infection rates occur when the surgical site is complicated by the implantation of medical devises, such as osteosynthesis plate or soft tissue alloplast augmentation.

Staphylococcus aureus and S. epidermidis, among other Gram-positive microorganisms, are commonly found in the skin and are frequent causes of infections associated with surgical implants. Indeed, staphylococcal wound infections can cause severe local and systemic complications. Wound dehiscence, failure of the operation, hernia formation, septic thrombophlebitis, pain, and scars can occur at the incision site. Systemic complications include bacteremia, metastatic infection, hypotension, organ failure, and death. Chronic wounds and burn wounds are prone to infection by staphylococci as well as the Gram-negative opportunistic pathogen Pseudomonas aeruginosa. P. aeruginosa wound infections are also associated with ulcer enlargement and/or healing delay.

Several strategies have been employed to combat the significant infectious complication rates associated with wounds. However, to-date, these strategies have been mainly limited to improved surgical asepsis, surgical technique, and regimens of administration of peri-operative systemic antibiotics, local antibiotic irrigation procedures, modification of surface characteristics of surgical implants, and impregnation of surgical implants with antibiotic compounds. Newer approaches are emerging in the clinic, including vacuum-sealed dressings, transparent film dressings, irrigation with antimicrobial agents, use of the port and cap, use of new agents such as deuteroporphyrin, gamma interferon (IFN-g), silver sulfadiazone water soluble gel, geomagnetic therapy, and natural remedies such as milliacynic oil and lysozyme. Unfortunately, few of these innovations have made a major impact on infection and fatality rates. Indeed, most new approaches involve delivery of an antimicrobial compound, provided in the form of liposomes or in collagen dressings, to which many wound pathogens are resistant.

New therapeutic strategies are required to counter infections by multidrug resistant bacteria, since they cause the vast majority of hospital acquired wound infections. The importance of microbial factors in the pathogenesis of surgical wound infection is clearly highlighted by the fact that despite the complexity of the human microflora, only a few bacterial species, including the staphylococci and pseudomonads, are reproducibly associated with wound infection and abscesses. Thus a detailed understanding of both bacteria and host wound factors is essential in order to develop novel and rational therapies for wound infections.

One novel approach that we have been exploring is the natural anti-infective and anti-microbial activity of probiotic strains of Lactobacillus.

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