Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095-1763, USA.
Department of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, CA, 90095-1600, USA.
Nat Commun. 2020 Dec 4;11(1):6203. doi: 10.1038/s41467-020-19906-3.
Biomaterials hold promise for therapeutic applications in the central nervous system (CNS). Little is known about molecular factors that determine CNS foreign body responses (FBRs) in vivo, or about how such responses influence biomaterial function. Here, we probed these factors in mice using a platform of injectable hydrogels readily modified to present interfaces with different physiochemical properties to host cells. We found that biomaterial FBRs mimic specialized multicellular CNS wound responses not present in peripheral tissues, which serve to isolate damaged neural tissue and restore barrier functions. We show that the nature and intensity of CNS FBRs are determined by definable properties that significantly influence hydrogel functions, including resorption and molecular delivery when injected into healthy brain or stroke injuries. Cationic interfaces elicit stromal cell infiltration, peripherally derived inflammation, neural damage and amyloid production. Nonionic and anionic formulations show minimal levels of these responses, which contributes to superior bioactive molecular delivery. Our results identify specific molecular mechanisms that drive FBRs in the CNS and have important implications for developing effective biomaterials for CNS applications.
生物材料在中枢神经系统（CNS）的治疗应用中具有广阔的前景。目前，人们对于决定中枢神经系统内异物反应（FBR）的分子因素知之甚少，也不了解这些反应如何影响生物材料的功能。在这里，我们使用一种可注射水凝胶平台来研究这些因素，该平台可轻松修改以呈现具有不同物理化学特性的界面，以适应宿主细胞。我们发现，生物材料 FBR 模拟了特化的多细胞中枢神经系统创伤反应，而这些反应不存在于周围组织中，其作用是隔离受损的神经组织并恢复屏障功能。我们表明，中枢神经系统 FBR 的性质和强度取决于可定义的特性，这些特性显著影响水凝胶的功能，包括在注射到健康大脑或中风损伤时的吸收和分子传递。阳离子界面会引起基质细胞浸润、外周炎症、神经损伤和淀粉样蛋白产生。非离子和阴离子制剂表现出这些反应的最低水平，这有助于实现更好的生物活性分子传递。我们的研究结果确定了驱动中枢神经系统 FBR 的特定分子机制，这对开发用于中枢神经系统应用的有效生物材料具有重要意义。
