| Popis: |
The objective of this research was to study and engineer the signals that promote angiogenesis in the wound healing process. These signals include but are not limited to growth factors and integrin ligands. Extracellular matrix (ECM) molecules such as fibronectin, growth factors such as VEGF (vascular endothelial growth factors), and their receptors have been shown to be key regulators of angiogenesis and neovascularization, with embryos lacking these genes dying due to defects in angiogenesis1, 2. Currently, efforts to optimize angiogenic biomaterials have been focused dominantly on (1) controlling angiogenic factor release or presentation (the binding methods) and (2) modulating the material’s bulk physical properties and integrin ligand density. The controlled growth factor release and presentations have also been thoroughly studied. For example, the design of therapeutic angiogenic materials to treat cardiovascular diseases, such as deficient blood supply to the heart, limbs, and brain, has primarily been driven by the delivery of growth factors within a scaffold. Out of the entire library of growth factors, we selected VEGF as our model molecule, since it has been described as the master regulator of angiogenesis. Methods such as repeated low dosing of soluble VEGF, protease-responsive VEGF nanocapsules and covalently-bound VEGF in hydrogels have shown to promote regeneration of functional healthy vessels. However, there are still many questions remaining to be answered in the field of growth factors. My dissertation focuses on answering three major ones: (1) How can we monitor the delivery of a growth factor in a signal-response cargo system, such as protease-degradable VEGF nanocapules? (2) Is there another presentation form of VEGF that can effectively promote therapeutic wound healing? (3) Besides the presentation method, does the distribution of growth factors across a substrate or within a matrix affect cellular response? Can we develop a screening system for it? Aside from growth factors, integrins also play an important role in the process of angiogenesis. However, even though adhesive ligands that promote integrin binding are generally incorporated within therapeutic angiogenic materials, the subsequent cell-material interactions have not been explored as an angiogenic signal. As there are many different types of integrin pairs which exist in nature, we still do not fully understand the function of each one of them in the process of angiogenesis. In this dissertation, I hope to answer the question: Aside from bulk physical properties and integrin ligand density, does the integrin-specific design of biomaterials play a role in biomaterial-mediated angiogenesis? If so, then what type of role? I deeply investigated how integrins affect vessel morphogenesis and therapeutic outcomes using both the subcutaneous mouse and ischemic stroke mouse models. We discovered that integrin specificity can significantly impact the vascular outcomes. This work shows for the first time that precisely controlled integrin activation from a biomaterial can be harnessed to direct therapeutic vessel regeneration and reduce VEGF induced vascular permeability in vivo. |
