Abstract
BackgroundThe influence of skin substitutes upon angiogenesis during wound healing is unclear.ObjectivesTo compare the angiogenic response in acute cutaneous human wounds treated with autogenic, allogenic and xenogenic skin substitutes to those left to heal by secondary intention.MethodsOn day 0, four 5mm full-thickness punch biopsies were harvested from fifty healthy volunteers (sites 1-4). In all cases, site 1 healed by secondary intention (control), site 2 was treated with collagen-GAG scaffold (CG), cadaveric decellularised dermis (DCD) was applied to site 3, whilst excised tissue was re-inserted into site 4 (autograft). Depending on study group allocation, healing tissue from sites 1-4 was excised on day 7, 14, 21 or 28. All specimens were bisected, with half used in histological and immunohistochemical evaluation whilst extracted RNA from the remainder enabled whole genome microarrays and qRT-PCR of highlighted angiogenesis-related genes. All wounds were serially imaged over 6 weeks using laser-doppler imaging and spectrophotometric intracutaneous analysis.ResultsInherent structural differences between skin substitutes influenced the distribution and organisation of capillary networks within regenerating dermis. Haemoglobin flux (p = 0.0035), oxyhaemoglobin concentration (p = 0.0005), and vessel number derived from CD31-based immunohistochemistry (p = 0.046) were significantly greater in DCD wounds at later time points. This correlated with time-matched increases in mRNA expression of membrane-type 6 matrix metalloproteinase (MT6-MMP) (p = 0.021) and prokineticin 2 (PROK2) (p = 0.004).ConclusionCorroborating evidence from invasive and non-invasive modalities demonstrated that treatment with DCD resulted in increased angiogenesis after wounding. Significantly elevated mRNA expression of pro-angiogenic PROK2 and extracellular matrix protease MT6-MMP seen only in the DCD group may contribute to observed responses.
Highlights
Angiogenesis is a crucial mechanism during wound healing involving the dynamic co-ordinated interaction of structural, cellular and molecular components [1]
Site 1 healed by secondary intention, site 2 was treated with collagen-GAG scaffold (CG), cadaveric decellularised dermis (DCD) was applied to site 3, whilst excised tissue was re-inserted into site 4
Angiogenesis in Wounds Treated with Skin Substitutes
Summary
Angiogenesis is a crucial mechanism during wound healing involving the dynamic co-ordinated interaction of structural, cellular and molecular components [1]. Defined as formation of new capillaries from pre-existing blood vessels, this key component of the proliferative phase gives rise to vasculature forming up to 60% of granulation tissue [2, 3]. Subsequent extravasation of plasma proteins forms a provisional scaffold for endothelial cell migration, facilitated by secretion of matrix metalloproteinases and angiopoietin-2 which degrade the extracellular matrix (ECM) and liberate further growth factors [3, 4]. Formed vessels are stabilised by recruitment of smooth muscle cells, pericytes, fibroblasts and secretion of ECM proteins whilst lumen formation is dependent upon VEGF, angiopoietin-1 and integrins [3, 4]. The influence of skin substitutes upon angiogenesis during wound healing is unclear
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