脑衰老过程中小生境的改变是导致神经干细胞功能衰退的重要原因，如何恢复老年大脑神经干细胞的活力是改善大脑衰老需要解决的首要问题。申请人前期研究表明，通过优化微/纳米纤维的拓扑结构、粗糙度和生物功能可有效调控胶质细胞行为并促进神经轴突生长。据此推测，具有特定结构、物理性能和生物功能的微/纳米纤维能够调控老年大脑神经干细胞及其小生境的活力。本研究利用创新的光焊交联技术制备一类负载静电喷微粒的可注射微/纳米纤维微球，研究微球的尺寸、多级结构以及硬度和粗糙度等物理性能对老年大脑神经干细胞增殖、神经元分化以及髓鞘再生的调控作用。将干扰素-γ抗体和PIEZO1机械敏感性离子通道的抑制剂负载到静电喷微粒中，明确两种生物分子的不同释放行为对细胞信号通路和离子通道的调节作用，揭示对老年大脑神经干细胞及其小生境的调控规律，从而构建功能一体化的可注射微/纳米纤维微球，为改善大脑衰老提供新策略和思路。

The age-dependent changes in the niche cause dysfunction of neural stem cells with brain aging. How to restore the activity of aged neural stem cells is the primary problem to be solved in terms of rejuvenating aged brains. Previously we have showed that both glial cell behavior and neurite outgrowth can be manipulated by optimizing the topographic structures and roughness of electrospun micro/nanofibers, together with the bio-functional modification. As such, we hypothesize that electrospun micro/nanofibers with expected structures, physical features, and biological functions can rejuvenate aged neural stem cells and the stem cell niche. In this project, we fabricate a novel class of injectable, photothermal-welded microspheres made of a blend of electrospun micro/nanofiber segments and electrosprayed microparticles. We will study the proliferation of aged stem cells, neuronal differentiation, and remyelination by harnessing the physical features (i.e., size, hierarchical structure, stiffness, and roughness) coming from the microspheres. Post optimization, we will further incorporate payloads (i.e., IFN-γ antibody and an inhibitor of PIEZO1 mechanosensitive ion channel) into the electrosprayed microparticles for localized release in the stem cell niche. By varying the biodegradability of the microparticles, we will clarify how the different release profiles of payloads affect the cell signaling pathway and/or ion channel and reveal the rules involving the manipulation of aged neural stem cells and the stem cell niche. Taken together, we aim to pave the way to the rejuvenation of aged brain by developing useful biomaterials with integrated functions involving stem cell proliferation, neuronal differentiation, and remyelination.