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Author ORCID Identifier

https://orcid.org/0000-0003-4745-1784

Date Available

8-11-2026

Year of Publication

2026

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

College

Pharmacy

Department/School/Program

Pharmaceutical Sciences

Faculty

Jonghyuck Park

Faculty

Daniel Pack

Abstract

Spinal cord injury is a severe and debilitating condition that often results in lifelong complications, including paralysis. Many of these chronic outcomes are driven by a sustained inflammatory response at the injury site, which limits tissue regeneration and functional recovery. As a result, therapeutic strategies that modulate this immune response have gained significant interest. Polymer based nanoparticle therapies have emerged as a promising approach due to their ability to interact with and influence immune cell behavior. Importantly, the physicochemical properties of nanoparticles can be precisely tuned to optimize these effects. Among these properties, size has been shown to influence key parameters such as cellular interactions, metabolic activity, and biodistribution. This dissertation investigates how the size of poly(lactic-co-glycolic acid) nanoparticles influences these factors and, in turn, modulates the innate immune response following spinal cord injury.

Initially, in vitro macrophage studies were conducted to evaluate size dependent effects on cellular association, viability, and metabolism. Following these studies, ex vivo immune profiling of murine blood derived innate immune cells was performed using RT-qPCR after nanoparticle treatment. Finally, in vivo biodistribution, tissue level responses, and functional recovery were assessed using in vivo imaging, immunohistochemistry, Basso Mouse Scale scoring, and CatWalk XT analysis.

In vitro studies demonstrated high cellular association for both nanoparticle sizes, with no significant differences in cell viability. However, nanoparticle size produced distinct metabolic profiles in murine macrophages. Gene expression analysis of innate immune cells isolated following spinal cord injury revealed size dependent differences in immune polarization. In vivo imaging demonstrated distinct biodistribution patterns between nanoparticle sizes, while spinal cord tissue analysis showed differences in the polarization of infiltrating innate immune cells, growth factor expression, and myelination patterns. Finally, functional assessments revealed significant differences in hindlimb recovery and coordination.

Overall, these findings demonstrate that nanoparticle size is a critical design parameter for modulating post-injury inflammation and improving therapeutic outcomes.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2026.394

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Funding Information

This study was supported by the National Institutes of Health Centers of Biomedical Research Excellence (COBRE) Grant (no.:P20GM130456) (allocated through the research laboratory, 2022–2026), the University of Kentucky Neuroscience Research Priority Area Grant (no.:NRPA017) (2022–2026), and the National Institutes of Health National Institute of Neurological Disorders and Stroke Grant (no.: R01NS136272) (allocated through the research laboratory, 2024–2026).

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