Ramos Rivera, Carolina; (2020) Development of HIF-mimicking materials for chronic wound healing. Doctoral thesis (Ph.D), University College London.

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Abstract

Non-healing (chronic) wounds are a major health problem; they are painful, cause considerable morbidity and costs the NHS between £4.5 and £5.1 billion annually. New approaches to wound healing that target tissue regeneration, rather than infection management, are urgently needed. The cellular response to oxygen via the Hypoxia Inducible Factor (HIF) pathway is vital for healthy wound repair and activates a number of processes important for wound regeneration including; the recruitment of inflammatory cells, metabolic adaptation, cell survival and a plethora of pro-angiogenic factors. Considering that patients with increased chance of developing chronic wounds (e.g. diabetic and elderly patients) have an impaired response to hypoxia, wound dressings that artificially targets the HIF pathway may offer some promise in restoring chronic wound healing. Here we investigate if HIF mimetics (DMOG, DFO and cobalt) and HIF mimicking bioactive glasses as a possible strategy for chronic wound repair. To test the effect of these HIF mimetics an in vitro hyperglycaemic model, that mimics the impaired HIF response observed in diabetic patients, was developed. HaCaT preconditioned with high glucose levels for 28 days, resulted in an impaired response to hypoxia (reduced VEGF expression and reduced HIF stabilisation, p<0.5). By comparing a range of glucose levels and pre-conditioning periods, this study provides a comprehensive guide to in vitro modelling of wound healing responses, not currently present in the literature. In the hyperglycaemic model, HIF mimetics (DFO and cobalt), restored HIF-1α stabilisation and VEGF expression to a similar (DFO) or greater level (cobalt) to that observed in the normal glucose response to hypoxia (p<0.0001). DMOG also increased VEGF expression, but in mechanism that appeared to be independent to HIF-1α stabilisation. Considering that topical oxygen therapy of chronic wounds is a current treatment modality with some evidence of success, despite the inevitable oxidative stress caused, it was investigated if HIF mimetics would enhance cell survival and activate the regenerative approaches associated with HIF stabilisation (regardless of the local oxygen pressure). HaCaTs were subjected to 100% O2 which caused cell death within 48 hours. Interestingly, HIF stabilisation levels were higher under hyperoxygen conditions in the hyperglycaemic conditions, when compared to normal levels of glucose (p=0.003). This is in line with the increased cell survival observed in hyperglycaemic cells at a prolonged exposure to 85% O2 (p>0.001). Silica-based bioactive glasses containing cobalt (and other ions that may enhance wound healing, Mg & Zn) were prepared via the melt-derived route. Controlled Co release from the glasses was observed in the physiological range of HIF stabilisation. Zinc ions promoted cell proliferation under hypoxic conditions but not normoxic conditions (p<0.01). The dissolution products from the Cobalt-containing glasses stimulated VEGF secretion linearly to the percentage of cobalt molarity in the glass compositions. Cobalt and zinc-releasing glasses demonstrated the potential use in advanced wound dressings for chronic wounds.

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