Efficacy of kynurenic acid and methotrexate in prevention of fibrosis

In postnatal life, tissue injuries with sufficient intensity, such as surgical procedures, elicit a repair process rather than regeneration. Hypertrophic scaring, capsular contracture around implants and peritendinous adhesions are common fibroproliferative reactions observed following surgery. These complications not only adversely affect the patients’ quality of life but also impose a significant economic burden on health care system. Despite recent advances in knowledge, refinements of techniques, and various therapeutic methods, the management of post- surgical fibrosis remains a challenge. Recently, Kynurenic acid (KynA), an end product of tryptophan metabolism, has been found to have an anti-fibrotic effect both in vitro and in vivo through suppression of type 1 collagen and enhancement of the matrix metalloproteinase 1 (MMP-1) expression in dermal fibroblasts. Another potential anti-fibrotic molecule is methotrexate (MTX). Systemic low dose MTX, which is a popular first line drug in the management of early and established rheumatoid arthritis (RA), has also been reported to be effective in prevention and treatment of keloid in few case reports. Since fibroproliferative disorders usually appear after the wound is healed, the intact skin can be an obstacle to effective delivery of topical KynA or MTX, and serious side effects limit the systemic use of MTX. In this dissertation, it is hypothesized that localized controlled release of anti-fibrosis agents from biodegradable, biocompatible polymer microspheres, embedded within the wound bed before skin closure, will reduce fibrotic scar formation following surgical procedures. To test this hypothesis, three specific objectives were employed: (1) Developing and validating a suitable animal model for in vivo studies, (2) Fabricating controlled release microspheres loaded with KynA and evaluating the efficacy of fabricated microspheres in vivo and (3) Determining the anti-fibrotic effect of MTX in vitro and evaluating the efficacy of fabricated MTX microspheres in vivo. The findings of these specific objectives demonstrated that the implantation of the controlled release polymer microspheres containing MTX and/or KynA efficiently reduces the fibrotic tissue formation in the PVA sponge-implant model of fibrosis, supporting our hypothesis that controlled local delivery of small anti-fibrosis agents to the wound bed is a feasible method for prevention of post surgical fibrosis.Medicine, Faculty ofExperimental Medicine, Division ofMedicine, Department ofGraduat