Date of Award
Master of Science (MS)
Jeoung Soo Lee
Brian W. Booth
Traumatic brain injuries (TBIs) are a type of acquired head trauma that results from an external force to the head. The development and severity of the secondary injury increases the risk of neurodegeneration and reduced cognitive recovery. Glucocorticoids are potent antiinflammatory therapeutics that have been investigated for potential treatment of TBIs, strokes, and other neuroinflammatory pathologies. However, their clinical application has been limited due to their ability to induce a variety of side effects, including adrenal suppression, edema, and reduced plasticity of the hippocampus. The use of a localized drug delivery system would overcome these systemic concerns. In previous studies, semi-interpenetrating networks (semi- IPNs) incorporating dexamethasone-conjugated hyaluronic acid (HA-DXM) as a macromolecular prodrug were developed. These semi-IPNs reduced neuroinflammation and improved motor function when applied to the cortical surface following a TBI. A subtype of TBIs are penetrating brain injuries (PBIs), which occur when a foreign object, such as a bullet, strikes the cranial cavity creating an opened wound. Due to the irregular geometry of PBIs, there is a need for hydrogels to be fabricated in an injectable, or dispersible, microparticulate form. The previous studies utilized a photo-initiated, radical polymerization crosslinking method that was found not to be effective or scalable in this form. Therefore, the objective of this work was to develop a new hydrogel formulation compatible with fabrication of microgels. Thiolated gelatin (gelatin-SH) and poly(ethylene glycol) diacrylate (PEGdA) were synthesized, characterized, and then successfully crosslinked utilizing a Michael-type reaction to form hydrogels. Additionally, native hyaluronic acid (HA) was incorporated to model HA-based macromolecular prodrugs, such as HA-DXM. The effects of gelatin-SH concentration and HA (700 kDA and 1.5 MDa) on crosslinking time, storage modulus, swelling, and degradation were investigated using bulk hydrogel samples. Both the addition of HA and increasing gelatin-SH concentrations produced an increased hydrogel storage modulus. Hydrogel microparticles were then fabricated in a water-in-oil emulsion system, producing particles with an average diameter ranging from approximately 125 to 250 microns depending on composition and stir rate. These studies demonstrate that gelatin-SH/PEGdA can create microparticles capable of conforming to the irregular geometry of PBIs. Future work will focus on the incorporation of HA-DXM into the hydrogel microparticles and the evaluation of drug-release and therapeutic efficacy in an animal PBI model.
Foulger, Isabell, "Fabrication of Hydrogel Microparticles for Acute Treatment of Penetrating Brain Injuries" (2022). All Theses. 3762.