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

Trinity University, San Antonio TX

Investigators

Abstract

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.