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丧失，大脑与各种组织的连接中断，损伤部位周围形成致密的疤痕，最终导致永久性丧失活动能力。目前还没有经过验证的临床解决方案或药物干预来逆转脊髓损伤。为了开发成功的脊髓损伤治疗方案，重要的是首先了解损伤组织中随时间发生的物理、化学和生物变化。这些信息反过来将有助于开发这种损伤组织的改进模拟(结合重要的结构、机械和炎症方面)，以测试驻留在脊髓上的各种细胞的反应，以及评估药物促进组织再生的有效性，最终提高下游临床应用的成功。这些目标的成功实现将导致与生理相关的集成系统的开发和验证，这些系统将改善我们对SCI的基本理解，同时也使新的测试平台成为可能。这项工作的更广泛影响将包括产生新的见解，了解神经细胞在炎症性脊髓损伤组织中如何生长和靶向受到抑制，并可能被克服以获得修复益处，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/教育模块以及通过各自研究机构既定的暑期实习/外展计划来培训不同的本科生和研究生。由于组织的先天再生能力较低，并在损伤部位周围形成胶质疤痕，因此对中枢神经系统(CNS)的损伤具有深远的、长期的生理后果。这种疤痕有很大的软组织区域，对轴突/轴突生长有抑制作用，提供了一个抗再生的环境，以胶质增生和抑制硫酸软骨素蛋白多糖的产生为标志。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)阐明和关联脊髓组织尺度的力学特性、结构和中枢神经系统损伤后关键阶段的机械力化学信号；(2)确定中枢神经系统细胞对疤痕样物理特性的机械力化学反应，这些特性可以通过确定的信号通路、改变的膜张力和张力调节行为来测量。这一多学科、综合的策略建立了迄今为止尚未明确的胶质瘢痕结构、微机械特性、细胞外基质成分和中枢神经系统细胞机械力化学反应之间的多尺度关系。新发现的胶质瘢痕特性将被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的功能、力化学特征、膜张力和调节行为，从而在人性化的体外平台上模拟急性损伤阶段。该项目的更广泛的研究影响包括对炎症环境中细胞功能如何失调产生新的机械性见解，同时为再生提供新的靶点。通过强调机械生物学知识驱动的神经胶质疤痕-仿生支架的配方，该项目代表了中枢神经系统修复和再生战略的范式转变。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势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.