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

项目总结 中风是导致成人残疾的主要原因，也是美国最常见的死亡原因之一。到目前为止， 目前还没有临床试验能成功缓解患者的神经损伤。临床和经济 这种疾病的负担促使人们需要一种超越传统做法的医学解决方案 神经学。虽然绝大多数关于大脑修复的研究都集中在神经元上，但越来越多的人 大量证据表明，损伤脑中的血管生成和免疫调节起着基础性作用 对卒中后神经可塑性和功能恢复的指导作用。组织工程学的最新进展 导致了水凝胶材料的发展，这种材料可以直接注射到中风病变部位形成细胞- 用于组织修复的指导性支架。然而，这些生物材料并没有被积极地设计来促进 血管生成和减少病变部位的炎症，这显著限制了它们的修复能力。我们 最近有研究表明，注射水凝胶可以促进血管生成或减少 炎症可促进脑组织修复，但不会导致完全的组织再生或功能恢复。 这项资助的研究调查了一种专门设计的新型注射材料的开发。 模拟脑细胞外基质(ECM)的机械、结构和生物学特性，同时 同时诱导形成成熟的、有功能的血管网络和恢复的血脑 并调节损伤脑内反应性星形胶质细胞和小胶质细胞的免疫反应。我们 建议设计、制造、表征和优化一种“仿生再生”的开发 具有协同修复潜能的血管生成免疫调节纳米复合材料(脑) 我们团队之前开发的两种不同的工程系统：1)由以下材料制成的微孔支架 用于靶向中风后免疫反应的可退火微凝胶构建块，以及2)高度聚集的血管 肝素纳米粒固定的血管内皮细胞生长因子(丙型肝炎病毒)促进病变血管生成 地点。我们将遵循系统的多因素数学方法来同时改变机械的， 结构和生物水凝胶特性以及筛选最佳配方以获得最高的 脑组织再生和功能恢复的程度。这项提案的成功完成将为 首创基于纳米技术的医疗解决方案来修复受伤的大脑并恢复失去的功能 中风后。

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.