The Impact of Bioactive Collagen Peptides on Promoting Cutaneous Wound Healing

Ph. D. Thesis.Chronic wounds continue to be a major clinical and financial burden to healthcare providers worldwide with increased prevalence associated with an ageing population and systemic diseases such as diabetes. An acute unmet need for innovative therapies for effective wound repair thus remains. Recent studies using bioactive collagen peptides report their ability to promote cellular differentiation, proliferation and migration in animal models of cutaneous wound healing, leading to the present study aimed at defining the potential for and the mechanistic action of porcine-derived collagen peptides (Peptan P) to increase cutaneous healing in primary human keratinocytes and dermal fibroblasts in vitro and in wounded full thickness ex vivo skin equivalents, in an age dependent context. Results demonstrated Peptan P significantly promoted wound closure of both dermal fibroblasts and keratinocytes derived from young or aged individuals by enhancing cellular proliferation, with additional studies demonstrating the ability for Peptan P to also promote keratinocyte and dermal fibroblast wound closure in a hyperglycaemic environment. Mechanistic studies revealed Peptan P induced significant increase of both integrin α2 and β1 subunit expression by both keratinocytes and dermal fibroblasts, promoting activation of an ERK-FAK signalling cascade during keratinocyte wound closure, whilst integrin ligation most likely activates other downstream signalling pathways to promote dermal fibroblast wound closure. These observations were further supported by studies showing diminished Peptan P-induced wound closure of keratinocytes and fibroblasts following siRNAmediated knockdown of the integrin β1 subunit. Studies in optimised 3D human skin equivalent models subjected to punch biopsy-induced wounding further revealed Peptan P promoted wound closure through enhanced re-epithelialisation. Collectively, these data highlight the translational and clinical potential for Peptan P as a viable topical therapeutic to promote re-epithelialisation of superficial cutaneous wounds