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

BRAIN（仿生再生血管生成免疫调节纳米复合材料）用于中风后大脑修复的材料

• 批准号: 10545034
• 负责人: Lina R. Nih
• 金额: $ 46.09万
• 依托单位: LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10545034
• 关键词: Adhesions; Adult; Astrocytes; Biocompatible Materials; Biological; Biomimetics; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain Injuries; Cause of Death; Cells; Cicatrix; Clinical; Clinical Trials; Data; Development; Diameter; Disadvantaged; Economic Burden; Engineering; Extracellular Matrix; Formulation; Gel; Gelatin; Grant; Heparin; Hydrogels; Immobilization; Immune response; Impairment; In Situ; In Vitro; Individual; Infiltration; Inflammation; Inflammatory; Injectable; Injections; Injury; Journals; Lesion; Long-Term Effects; Mechanics; Medical; Methodology; Microglia; Microspheres; Motor; Nanoporous; Nanotechnology; Nature; Neurologic; Neurologic Deficit; Neurology; Neuronal Plasticity; Neurons; Patients; Phenotype; Play; Porosity; Property; Publishing; Recovery; Recovery of Function; Research; Role; Site; Solid; Stroke; System; Technology; Testing; Therapeutic; Thick; Tissue Engineering; Tissues; Transplantation; Vascular Endothelial Growth Factors; angiogenesis; axonal sprouting; brain repair; brain tissue; burden of illness; cell motility; cortex mapping; design; disability; fabrication; functional outcomes; immunoregulation; improved; in vitro Assay; in vivo; injury and repair; innovation; mathematical methods; mimetics; minimally invasive; motor function recovery; nanocomposite; nanoparticle; nanoscale; neurogenesis; novel; porous hydrogel; post stroke; post-stroke angiogenesis; regenerative; repaired; reparative capacity; scaffold; stroke survivor; tissue regeneration; tissue repair; tissue support frame

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.

项目总结