Development and application of anti-fibrogenic dressings

It is well established that more than 15 million patients develop pathological scarring each year following elective operations, surgical procedures, deep trauma, thermal and electrical injuries. These scars, that cause major functional, cosmetic, psychological, and social consequences for the patients, impose a significant financial burden on health care systems. The current treatment modalities for these pathological conditions vary from topical application and intralesional injection of anti-scarring agents to surgical revisions and radiotherapy. The limited efficacy of these therapeutics for prevention of scar formation raised a great need for innovation within the wound care industry. Recently Kynurenine (Kyn), a tryptophan metabolite, has been identified as a potent anti-fibrotic agent. Kyn prevents scar formation by enhancing the expression of ECM degrading enzymes, matrix metalloproteinases (MMPs), and suppressing the expression of collagen. Although daily topical application of Kyn-cream improved the wound healing outcome in animal models, this method of drug delivery is not clinically practical in situations where dressings need to be kept on for 3-5 days. In this dissertation, it is hypothesized that topical application of a slow and controlled releasing Kyn or its metabolites from nanofiber dressing at the wound site improves and/or prevents dermal fibrosis by modulating the expression of the key ECM components involved in dermal fibrotic conditions. To test this hypothesis, three specific objectives were employed: (1) Evaluating and comparing the anti-fibrotic effects of Kynurenic acid (KynA) and Kyn, (2) Developing, characterizing and optimizing the nanofibrous dressings as a slow releasing drug delivery system for Kyn and KynA, (3) Examining the functionality of the developed anti-fibrotic dressings in open wounds in animal models. The findings of these specific objectives of this work demonstrated that topical application of the developed polymeric dressings, which slowly release Kyn/KynA over the course of 4 days, effectively reduces dermal fibrosis by modulating the key ECM components such as MMPs, collagen and fibronectin. The findings of this study support our hypothesis that development of an anti-fibrogenic dressing is feasible and as such its application would overcome the difficulties associated with development of hypertrophic scarring frequently seen in millions of patients worldwide.Medicine, Faculty ofMedicine, Department ofExperimental Medicine, Division ofGraduat