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

ERI：网络通过仿生支架的网络制造方法研究纤维蛋白和透明质酸对人星形胶质细胞反应和炎症反应的影响

• 批准号: 2138684
• 负责人: Dany Munoz Pinto
• 金额: $ 20万
• 依托单位: Trinity University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2138684&HistoricalAwards=false
• 关键词: ERI; Network; network; fabrication; approach

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.

该奖项的全部或部分资金根据《2021 年美国救援计划法案》（公法 117-2）提供。神经组织炎症（神经炎症）已越来越被认为是神经元结构或功能进行性丧失以及神经系统疾病发生和进展的危险因素。多项研究已确定脑组织成分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，脑组织成分的变化与神经炎症之间的关系仍不清楚。 该工程研究启动 (ERI) 奖将研究脑组织成分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中枢神经系统组织中由组织成分变化引发的人类细胞（称为星形胶质细胞）的异常行为。该项目的执行将为本科生提供实践经验，以培养解决问题、实验室和领导技能，并在高危中学生中推广 STEM 学科。多项研究已确定细胞外基质（ECM）是调节中枢神经系统（CNS）急性和慢性炎症的关键因素。衰老、创伤性脑损伤和神经退行性疾病导致的组织损伤会导致 ECM 成分发生变化。这些变化导致组织退化和重塑。透明质酸等分子被降解为生物活性片段，而纤维蛋白原等血浆成分以纤维蛋白的形式沉积。邻近受损组织的星形胶质细胞会增殖，并对 ECM 变化做出反应。目前，由于 ECM 的动态组成，脑组织 ECM 变化与神经炎症之间的关系仍不清楚。为了研究ECM成分对CNS细胞炎症反应的分子机制，需要新的模型。该项目将为 3D 体外模型的制作提供原理验证，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重互穿聚合物网络 (mIPN) 将用作 3D 支架，以模拟基质成分（纤维蛋白）的关键变化和HA-HMW含量）并研究它们对星形胶质细胞反应性和炎症反应的影响。拟议的支架将使用逐个网络的制造方法来制造。正交交联机制将用于动态和按时间顺序控制交联过程，从而调节支架刚性、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 ECM 重塑与人类星形胶质细胞的反应和炎症反应之间的关键要素。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治疗中枢神经系统组织损伤的新治疗分子的设计、测试和评估。该奖项反映了NSF的法定使命，并通过评估被认为值得支持利用基金会的智力优势和更广泛的影响审查标准。