Collaborative Research: Glial scar morphology informed tunable biomimetic platforms toward spinal cord injury repair

脊髓损伤（SCI）导致细胞和血液供应的丧失，大脑与各种组织的连接中断，并在损伤部位周围形成致密的疤痕，最终导致永久性的行动能力丧失。目前还没有经过证实的临床解决方案或药物干预来逆转脊髓损伤。为了制定成功的脊髓损伤治疗方案，首先了解受伤组织随时间发生的物理、化学和生物学变化是很重要的。这些信息反过来将有助于开发这种损伤组织的改进模拟物（结合重要的结构，机械和炎症方面），以测试驻留在脊髓的各种细胞的反应，以及评估药物在促进组织再生方面的功效，最终提高下游临床应用的成功。这些目标的成功实施将导致生理学相关综合系统的开发和验证，从而提高我们对SCI的基本理解，同时也使新的测试平台成为可能。这项工作的广泛影响将包括对神经细胞生长和靶向如何在炎症性脊髓损伤组织中被抑制的新见解，以及如何克服修复效益，特别是在脊髓损伤的背景下。除了向科学界传播研究成果的机会外，该项目还将通过开发研究/教育模块以及在研究人员各自的机构主持已建立的暑期实习/外展计划，培养不同类型的本科生和研究生。中枢神经系统（CNS）的损伤具有深远的、长期的生理后果，因为组织的先天再生能力较低，并且在损伤部位周围形成胶质疤痕。这种疤痕有很大的软区，抑制轴突/神经突的生长，提供一个抗再生的环境，并以胶质瘤和产生抑制性硫酸软骨素蛋白聚糖为特征。这种损伤部位特征改变的潜在机制尚不清楚。本研究的目的是：(1)阐明和关联中枢神经系统损伤后关键阶段脊髓组织尺度的力学特性、结构和机械化学信号；(2)通过定义的信号通路、改变的膜张力和张力调节行为，确定中枢神经系统细胞对疤痕样物理特性的机械化学反应。这种多学科、综合的策略建立了迄今未定义的神经胶质疤痕结构、微力学特性、ECM成分和中枢神经系统细胞力学化学反应之间的多尺度关系。新发现的胶质疤痕特征将用于开发可调节的仿生水凝胶，用于分离中枢神经系统细胞功能、机械化学特征、膜张力和调节行为，从而在人源化的体外平台上模拟急性损伤阶段。该项目更广泛的研究影响包括产生新的机制见解，了解细胞功能如何在炎症环境中失调，同时为再生提供新的靶点。通过强调神经胶质疤痕仿生支架的机械生物学知识驱动配方，该项目代表了中枢神经系统修复和再生策略的范式转变。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Spinal cord injury (SCI) results in loss of cells and blood supply, disruption of brain connectivity to various tissues, and formation of a dense scar around the injury site, ultimately resulting in permanent loss of mobility. There are no proven clinical solutions or pharmaceutical interventions to reverse SCI. To develop successful treatment options for SCI, it is important to first understand the physical, chemical, and biological changes occurring over time in the injured tissues. This information would in turn help in developing improved mimics of such injured tissues (combining important structural, mechanical, and inflammatory aspects) to test the response of various cells resident to the spinal cord, as well as to evaluate the efficacy of pharmaceutical drugs in promoting tissue regeneration to ultimately improve the success of downstream clinical applications. Successful implementation of these objectives will lead to the development and validation of physiologically-relevant integrated systems that improve our fundamental understanding of SCI, while also enabling new testing platforms. The broader impact of this work will include the generation of new insights into how nerve cell outgrowth and targeting is inhibited in an inflammatory SCI tissue, and may be overcome for reparative benefit, specifically in the context of SCI. Besides opportunities for research dissemination to the scientific community, this project will lead to training of diverse undergraduate and graduate students through development of research/educational modules and through the auspices of established summer internship/outreach programs at the investigators’ respective institutions.Injury to the central nervous system (CNS) has profound, long-term physiological consequences due to the tissue’s low innate regenerative ability and formation of a glial scar around the injury site. This scar has large soft regions, is inhibitive to axonal/neurite outgrowth, confers an anti-regenerative environment, and is marked by gliosis and production of inhibitory chondroitin sulfate proteoglycans. The underlying mechanisms for such altered characteristics at the injury site are unclear. The goals of this study are to (1) elucidate and correlate spinal cord tissue-scale mechanical properties, architecture, and mechanochemical signaling at key phases following CNS injury, and (2) identify the mechanochemical response of CNS cells to scar-like physical properties measurable via defined signaling pathways, altered membrane tension, and tension-regulated behaviors. This multi-disciplinary, comprehensive strategy establishes hitherto undefined multi-scale relationships between glial scar structure, micromechanical properties, ECM composition, and CNS cell mechanochemical responses. The newly identified glial scar characteristics will be utilized to develop tunable biomimetic hydrogels for the isolation of CNS cell function, mechano-chemical profiles, membrane tension, and regulated behaviors, towards mimicking the acute injury phase in a humanized in vitro platform. The broader research impacts of this project include generation of new mechanistic insights into how cell functions are dysregulated in an inflammatory milieu, while offering new targets for regeneration. By emphasizing mechanobiological knowledge-driven formulation of glial scar-biomimetic scaffolds, this project represents a paradigm shift in CNS repair and regeneration strategies.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.