Between 15-25% of diabetic patients develop chronic foot ulcers within their lifetime. These ulcers are characterized by delayed wound healing, are highly susceptible to infection, and can lead to lower-limb/foot amputation. Impaired ulcer healing is most often due to ischemia and insufficient formation of new vessels in the wound bed, as well as rapid turnover of healing tissue by excessive matrix metalloproteinase (MMP) activity. To improve healing of chronic ischemic wounds, researchers have sought to increase angiogenesis at the wound site using growth factors such as vascular endothelial growth factor (VEGF). VEGF is a key angiogenic mediator and uniquely participates in multiple aspects of wound healing including revascularization, reepithelialization, and collagen deposition. However, the clinical success of growth factor therapies such as VEGF has been limited largely due to the overexpression MMPs in the wound environment that degrade or inactivate the growth factors. Furthermore, non-targeted angiogenic growth factor therapies raise significant concerns because they are not restricted to the wound site, but potentially diffuse into systemic circulation and cause malignancies. This thesis reviews current advances in understanding the pathogenesis and pathophysiology of the compromised wound healing environment leading to DFUs with particular emphasis on the roles of neovascularization and matrix remodeling. It also addresses recent progress in VEGF therapy for DFUs and the current limitations in clinical translation imposed by co-existing pathophysiological defects of diabetic wound healing. Given the current understanding of the impaired healing components suggesting a need to correct multiple derangements while maintaining efficacy in the complex and highly proteolytic environment, we propose multiple collagen-targeted, degradation resistant, proangiogenic therapies to activate and potentiate VEGF pathways and simultaneously protect existing collagen matrices. Specifically, we discuss the development of VEGF-loaded collagen-binding nanoparticles and two variants of engineered decorin mimetics functionalized with pro-angiogenic VEGF-mimicking or αvβ3 integrin-binding peptides to increase vascularization of the wound bed. Both the nanoparticles and the angiogenic proteoglycan mimics can be targeted to endogenous collagen or exogenous collagen dressings by a collagen-binding peptide and could be used in combination to exploit VEGF activation and potentiation. This project (i) develops a thermosensitive nanoparticle VEGF-delivery system, (ii) develops and characterizes pro-angiogenic peptide-functionalized decorin mimics, and (iii) assesses the in vitro and in vivo angiogenic potential of these pro-angiogenic decorin mimics as proof-of-concept supporting their potential to accelerate ischemic dermal wound healing in animal models
