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

项目摘要 中风是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成功地减轻病人的神经损伤。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范围的医疗解决方案， 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，但越来越多的研究表明， 大量证据表明，受损大脑中的血管生成和免疫调节在脑损伤中起着重要作用。 在指导中风后神经可塑性和功能恢复中的作用。组织工程学的最新进展 导致了可以直接注射到中风损伤部位以形成细胞的水凝胶材料的发展， 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 这可能导致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 最近表明，注射被积极设计为促进血管生成或减少血管生成的水凝胶， 炎症促进脑组织修复，但不导致完全组织再生或功能恢复。 这项研究的目的是开发一种新的注射材料， 模拟脑细胞外基质（ECM）的机械、结构和生物学特性， 同时诱导成熟和功能性血管网络的形成以及恢复的血脑 屏障，以及调节受损脑中反应性星形胶质细胞和小胶质细胞的免疫应答。我们 建议设计，制造，表征和优化“仿生再生”的发展 血管生成免疫调节纳米复合材料”（BRAIN），结合了协同修复潜力， 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 靶向中风后免疫应答的可退火微凝胶构建块，和2）高度聚集的血管 将内皮生长因子（hcV）固定在肝素纳米颗粒上，以促进病变中的血管生成 绝佳的价钱我们将遵循一个系统的多因素数学方法，同时改变机械， 结构和生物水凝胶特性，并筛选最佳配方， 脑组织再生和功能恢复的程度。成功完成这一提案将为 开创基于纳米技术的医疗解决方案，以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.