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.

该奖项是根据2021年《美国救援计划法》（公法117-2）全部或部分资助的。神经组织的炎症，神经炎症，已越来越被认为是神经元结构或功能逐渐丧失以及神经系统疾病的发作和进展的危险因素。几项研究已经确定了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，脑组织组成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和神经炎症的变化之间的关系。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触发的中枢神经系统组织中人类细胞的异常行为，称为星形胶质细胞。该项目的执行将为本科生提供动手经验，以发展解决问题，实验室和领导能力，并在高危中学生中促进STEM学科。几项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导致的组织损伤会导致ECM组成的变化。这些变化导致组织降解和重塑。分子（例如透明质酸）被降解为生物活性片段，而血浆（例如纤维蛋白原）的成分以纤维蛋白的形式沉积。与受伤的组织相邻的星形胶质细胞增殖并响应ECM变化而变得反应。目前，由于ECM的动态组成，脑组织ECM与神经炎症的变化之间的关系尚不清楚。为了研究CNS细胞炎症反应的ECM成分的分子机制，需要新的模型。该项目将为制造3D体外模型的制造提供原则证明，以研究人类星形胶质细胞中炎症信号的发作和进展。由纤维蛋白，透明质酸高分子量（HA-HMW），I型胶原蛋白和聚（乙二醇）二氯酸酯组成的多氨酸渗透聚合物网络（MIPN）将用作3D型糖浆，以模拟于MIMIM的关键变化（纤维蛋白和HAM-HMMW的含量），并研究甲壳度的重点和HAM-H-H-HMMW含量，并将其用于累累和研究，并研究了甲壳度和HAM-H-H-HMMW含量），并将其用于3D的关键变化，从提出的脚手架将使用网络制造方法制作。正交交联机制将用于动态和时间顺序地控制交联过程，从而调节脚手架刚度，物理稳定性和细胞形态。这项工作将表明，所提出的体外模型可用于发现连接ECM重塑的关键元素以及人类星形胶质细胞的反应性和炎症反应。从长远来看，提出的3D模型的开发和验证将进一步有助于对新的治疗分子的设计，测试和评估，以治疗CNS组织损害。该奖项反映了NSF的法定任务，并被认为是值得通过基金会的智力和更广泛影响的评估来通过评估来获得支持的。