VEGF ligand presentation and therapeutic angiogenesis

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Summary Stroke is the leading cause of disability in the US, and, apart from physical therapy, therapeutic options to reduce this burden are non-existent. Following a stroke, cell death and glial scarring leads to the formation of a non- regenerative stroke cavity surrounded by the regenerative peri-infarct region. We are interested in understanding how bioengineered therapeutics can synergize with pro-repair programs active in the peri-infarct region to promote tissue regeneration in the stroke cavity and thereby improve neurological recovery. We have previously engineered a dual-acting angiogenic hydrogel that, when injected into the stroke cavity, can reduce glial scarring and promote vascularization to allow axonal infiltration. Although achieving brain repair in the stroke cavity is remarkable, these results were achieved in young mice with un-impaired neuroplasticity. We believe that to bring this technology closer to clinical translation, we must be able to show similar brain repair and behavioral improvement in more clinically relevant animal models, like aged mice with decreased neuroplasticity. In this application, we aim to identify our angiogenic hydrogel’s mechanism of action and optimize its formulation and to utilize this new formulation in a stroke models with decreased neuroplasticity. The hydrogel is composed of hyaluronic acid functionalized with cell-binding integrins and loaded with clustered vascular endothelial growth factor (VEGF) and heparin nanoparticles. Heparin is a known anti-inflammatory agent that potentially acts by breaking the inflammatory cycle between macrophages and astrocytes following stroke. We will use design of experiment methodology to determine the composition of these three factors (integrins, clustered VEGF, and heparin nanoparticles) that leads to substantial brain repair (Aim 1) and assess how the hydrogel components modulate the pro-repair environment by analyzing temporal changes in proteins, mRNA, and immune cell populations following stroke (Aim 2). Using the improved formulation, we will also evaluate the angiogenic hydrogel’s ability to promote neurological regeneration and functional recovery in more rigorous animal models, specifically aged mice treated immediately following cerebral ischemia and young mice with cerebral ischemia treated as the plasticity window is closing (Aim 3). Overall, we aim to deepen our understanding of how bioengineered therapeutics synergize with endogenous pro-regenerative programs and thereby improve behavioral outcomes following stoke in more difficult-to-treat cases.