Investigating the role of acellular skin substitutes in wound healing

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Abstract

After cutaneous injury, wound healing is an essential process that restores barrier and homeostatic function to the skin. Tissue restoration is classically grouped into four phases, involving the dynamic, regulated and sequential interaction of multiple cells types, effector molecules and extracellular matrix components. While most wounds heal in a timely fashion, local and systemic factors can prevent wound resolution resulting in chronic wound formation. Examples include diabetic and venous ulcers, which are costly, prone to recurrence and associated with reduced quality of life for sufferers. Poor therapeutic efficacy has driven the development of new treatment modalities including bioengineered skin substitutes. First developed in the 1980’s, these biomaterials have become increasingly diverse in their structure, cellular content and biomechanical properties. Their evidence base in chronic wound management has increased, though their exact mode of action remains elusive. Furthermore, skin substitute use in acute human wounds has never been studied and it is unclear whether they have a role in this setting. This thesis evaluates a novel acellular dermal skin substitute, known as Decellularised Dermis (DCD), through 2 large human studies involving clinical and laboratory components. In the first phase, a pilot study utilising DCD as part of a management strategy for treatment-resistant chronic wounds resulted in healing rates of 60% after six months with average wound surface area reduction of 87%. Additionally, there was significantly increased angiogenesis 6 weeks after treatment and a statistical association between ulcer duration pre-therapy and likelihood of successful treatment. In the second phase, a prospective cohort study was undertaken involving acute wounds in fifty healthy volunteers. DCD was compared to controls, autografts and collagen-GAG scaffolds. Whole genome micorarrays demonstrated that treatments exerted differential effects upon the type, magnitude and temporality of gene expression with resultant variation in key processes during wound healing including angiogenesis, fibroplasia and scar formation. Concurrently, skin substitute architecture strongly influenced the influx of host cells into biomaterials and dictated reformation of the dermis and vasculature. These data reveal that DCD has significant pro-angiogenic effects in both acute and chronic wound settings. Moreover, there was reduced fibrosis 6 weeks after wounding in DCD-treated wounds compared to controls. A number of potentially significant genes were identified including prokineticin 2 and membrane type-6 matrix metalloproteinase that may underlie these findings and represent potential therapeutic targets. In conclusion, these studies effectively evaluate DCD, demonstrating potential therapeutic roles in chronic wounds and scar reduction through genetic and translational modification of angiogenesis and fibroplasia during wound healing. Furthermore, optical coherence tomography was shown to be an effective diagnostic tool with potential use in assessment of cutaneous morphology and quantitation of tissue fibrosis.

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