BRAIN (Biomimetic Regenerative Angiogenic Immunomodulating Nanocomposite) materials for brain repair after stroke

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PROJECT SUMMARY Stroke is the leading cause of adult disability and one of the most common causes of death in the US. To date, no clinical trials have succeeded in alleviating patients' neurological impairment. The clinical and economical burden of this disease urges the need for a medical solution outside the confines of conventional practices in neurology. While the overwhelming majority of research on brain repair is centered on neurons, an increasing body of evidence suggests that angiogenesis and immunomodulation in the injured brain play a fundamental role in guiding post-stroke neuroplasticity and functional recovery. Recent advances in tissue engineering have led to the development of hydrogel materials that can be injected directly into the stroke lesion site to form cell- instructive scaffolds for tissue repair. However, these biomaterials have not been actively designed to promote angiogenesis and reduce inflammation in the lesion site, which significantly limits their reparative capability. We have recently shown that injection of hydrogels that are actively designed to promote angiogenesis or reduce inflammation enhance brain tissue repair, but do not lead to complete tissue regeneration or functional recovery. The studies in this grant investigate the development of a novel injectable material that is specifically designed to mimic the mechanical, structural, and biological properties of the brain extracellular matrix (ECM), while simultaneously inducing the formation of a mature and functional vascular network with a restored blood brain barrier, and modulating the immune response of reactive astrocytes and microglia in the injured brain. We propose to design, fabricate, characterize, and optimize the development of a “biomimetic regenerative angiogenic immunomodulating nanocomposite” (BRAIN) material that combines the synergic reparative potential of two distinct engineered systems previously developed by our team: 1) a microporous scaffold made of annealable microgel building blocks to target the post-stroke immune response, and 2) highly clustered vascular endothelial growth factor (hcV) immobilized onto heparin nanoparticles, to promote angiogenesis in the lesion site. We will follow a systematic multifactorial mathematical approach to simultaneously alter the mechanical, structural and biological hydrogel properties and screen for the optimal formulations that result in the highest degree of brain tissue regeneration and functional recovery. Successful completion of this proposal will pave the way for pioneering nanotechnology-based medical solutions to repair the injured brain and regain lost function after stroke.