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201293 https://hdl.handle.net/2286/R.2.N.201293 http://rightsstatements.org/vocab/InC/1.0/ All Rights Reserved 2025 2027-05-01T17:44:57 175 pages Doctoral Dissertation Academic theses en Jensen, Gregory Holloway, Julianne Stabenfeldt, Sarah D'arcy, Richard Newbern, Jason Green, Matthew Acharya, Abhinav Arizona State University Partial requirement for: Ph.D., Arizona State University, 2025 Field of study: Chemical Engineering Traumatic brain injury (TBI) occurs when an impact to the head damages the brain, disrupting normal brain function. Primary injury causes cell death within the damaged region. Afterwards, a secondary injury sequence ensues that exacerbates the initial injury. One consequence is the loss of parvalbumin expressing interneurons following TBI that regulate the excitatory:inhibitory balance in the brain during physiological conditions. The loss of excitatory:inhibitory balance can exacerbate the initial injury and contribute to the development of post-traumatic epilepsy. However, the neuroprotective growth factor neuregulin-1 (NRG1) can selectively target parvalbumin interneurons through ErbB4 receptors expressed primarily on parvalbumin interneurons in the cortex. To harness the potential of NRG1, I have designed and characterized the components of a combinatorial hydrogel/microgel system that can be used for the controlled delivery of NRG1 following TBI. An injectable hyaluronic acid hydrogel was developed that was crosslinked via guest-host interactions between cyclodextrin and adamantane. Rheological characterization verified the shear-thinning and self-healing properties of the hydrogel, as well as confirmed its similar stiffness to endogenous neural tissue. The guest-host hydrogel was also non-toxic in vitro. Importantly, in vivo biocompatibility testing using a mouse model of intracortical injections indicated the guest-host hydrogel had comparable biocompatibility to poly(lactic-co-glycolic acid (PLGA), a commonly used material in neural tissue engineering. Sulfate-containing microgels were similarly based on hyaluronic acid and were formedvia bulk extrusion of a ultraviolet (UV) light crosslinked hydrogel. Sulfate groups were utilized to control the loading and release of NRG1 via its heparin binding domain. Design of experiments (DOE) was used to determine the design parameters that had the greatest impact on microgel size and NRG1 loading efficiency. The needle gauge used for bulk hydrogel extrusion had the greatest impact on microgel size, while the NRG1 loading efficiency was mostly impacted by the NRG1 loading method. Although sulfate groups within microgels did not have a significant impact on the release rate/profile of NRG1 compared to non-sulfated microgels, sulfate inclusion increased the amount of NRG1 loaded. This work supports the utility of guest-host hydrogel usage for neural tissue engineering and highlights vital parameters for biomaterial design and characterization. Chemical Engineering Materials Science Bioengineering Central Nervous System Hydrogel injectable neuregulin-1 Tissue Engineering Traumatic Brain Injury Development and Characterization of a Shear-thinning Hydrogel and NRG1 Presenting Microgel for Neural Tissue Engineering Applications