ERI:Network by network fabrication approach of bioinspired scaffolds to study the effect of fibrin and hyaluronic acid on the reactive and inflammatory response of human astrocytes

该奖项全部或部分由《2021年美国救援计划法案》（公法117-2）资助。神经组织的炎症，即神经炎症，已被越来越多地认为是神经元结构或功能的进行性丧失以及神经系统疾病的发生和发展的一个危险因素。一些研究已经确定脑组织组成的变化是调节中枢神经系统（CNS）急性和慢性炎症的关键因素。由于动态变化，脑组织成分变化与神经炎症之间的关系尚不清楚。该工程研究启动（ERI）奖将研究脑组织组成变化与神经炎症之间的关系。为了实现这项研究，将开发一个生物材料平台来研究由组织组成变化引发的中枢神经系统组织中被称为星形胶质细胞的人类细胞的异常行为。该项目的实施将为本科生提供实践经验，以培养解决问题的能力、实验室能力和领导能力，并在有风险的初高中学生中推广STEM学科。一些研究已经确定细胞外基质（ECM）是调节中枢神经系统（CNS）急性和慢性炎症的关键因素。由于衰老、创伤性脑损伤和神经退行性变引起的组织损伤导致ECM成分的改变。这些变化导致组织退化和重塑。分子，如透明质酸，被降解成生物活性片段，而血浆成分，如纤维蛋白原，以纤维蛋白的形式沉积。损伤组织附近的星形胶质细胞增生并对ECM变化作出反应。目前，脑组织ECM的变化与神经炎症之间的关系由于ECM的动态组成尚不清楚。为了研究ECM成分对中枢神经系统细胞炎症反应的分子机制，需要建立新的模型。该项目将为3D体外模型的制造提供原理证明，以研究人类星形胶质细胞炎症信号的发生和进展。由纤维蛋白、高分子量透明质酸（HA-HMW）、I型胶原蛋白和聚乙二醇二丙烯酸酯组成的多互穿聚合物网络（mipn）将被用作3D支架，模拟基质组成（纤维蛋白和HA-HMW含量）的关键变化，并研究它们对星形胶质细胞反应性和炎症反应的影响。所建议的支架将使用网络对网络的制造方法。正交交联机制将用于动态和按时间顺序控制交联过程，允许调节支架刚度，物理稳定性和细胞形态。这项工作将证明，所提出的体外模型可用于揭示连接ECM重塑和人类星形胶质细胞的反应性和炎症反应的关键因素。从长远来看，所提出的3D模型的开发和验证将进一步有助于设计、测试和评估治疗中枢神经系统组织损伤的新治疗分子。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。

This award is funded in whole or in part under the American Rescue Plan Act of 2021 (Public Law 117-2). Inflammation of the nervous tissue, neuroinflammation, has been increasingly recognized as a risk factor for the progressive loss of structure or function of neurons and the onset and progression of neurological disorders. Several studies have identified changes in brain tissue composition as key factors in regulating acute and chronic inflammation in the central nervous system (CNS). Due to the dynamic changes, the relationship between changes in brain tissue composition and neuroinflammation remains unclear. This Engineering Research Initiation (ERI) award will investigate the relationship between changes in brain tissue composition and neuroinflammation. To enable this study, a biomaterial platform will be developed to study the abnormal behavior of human cells, called astrocytes, in CNS tissue triggered by changes in tissue composition. The execution of this project will provide undergraduate students with hands-on experience to develop problem-solving, laboratory, and leadership skills and to promote the STEM disciplines among at-risk middle/high school students. Several studies have identified the extracellular matrix (ECM) as a key factor in regulating acute and chronic inflammation in the central nervous system (CNS). Tissue damage due to aging, traumatic brain injury, and neurodegeneration causes changes in the composition of the ECM. These changes result in tissue degradation and remodeling. Molecules, such as hyaluronic acid, are degraded into bioactive fragments, while components of blood plasma, such as fibrinogen, are deposited in the form of fibrin. Astrocytes adjacent to injured tissue proliferate and become reactive in response to ECM changes. Currently, the relationship between changes in brain tissue ECM and neuroinflammation remains unclear due to dynamic composition of the ECM. To study the molecular mechanism of ECM components on the inflammatory response of CNS cells, new models are needed. This project will provide a proof-of-principle for the fabrication of a 3D in vitro model to study the onset and progression of inflammatory signaling in human astrocytes. Multi-interpenetrating polymer networks (mIPNs), comprised of fibrin, hyaluronic acid high molecular weight (HA-HMW), collagen type I, and poly(ethylene glycol) diacrylate will be used as 3D scaffolds to mimic key changes in matrix composition (fibrin and HA-HMW content) and to study their effect on astrocyte reactivity and inflammatory response. The proposed scaffolds will be made using a network-by-network fabrication approach. Orthogonal crosslinking mechanisms will be used to control the crosslinking process dynamically and chronologically, allowing for the modulation of scaffold rigidity, physical stability, and cell morphology. This work will demonstrate that the proposed in vitro model can be used to uncover key elements connecting ECM remodeling and the reactive and inflammatory response of human astrocytes. In the long term, the development and validation of the proposed 3D model will further contribute to the design, testing, and evaluation of new therapeutic molecules to treat CNS tissue damage.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.