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Author ORCID Identifier

https://orcid.org/0009-0007-3888-1420

Date Available

4-24-2027

Year of Publication

2026

Document Type

Doctoral Dissertation

Degree Name

Doctor of Philosophy (PhD)

College

Engineering

Department/School/Program

Biomedical Engineering

Faculty

Caigang Zhu

Faculty

Sridhar Sunderam

Abstract

Radioresistance (RR) remains a major obstacle to effective radiotherapy (RT) in solid tumors. Although hypoxia diminishes RT efficacy by weakening oxygen-dependent DNA damage, it alone cannot fully explain RR. Metabolic reprogramming, closely linked to oxygen availability, also contributes to RR. Understanding metabolic adaptation alongside hypoxia is therefore essential for improving RT personalization. However, current metabolic techniques have their limitations, restricting long-term monitoring during fractionated RT. Optical methods offer a sensitive, non-destructive, and cost-effective alternative for probing tumor energetics. This dissertation advances optical techniques for RR research through three projects. Project 1 developed a portable optical spectroscopic assay using a dual-color LED illuminator, compact spectrometer, and fiber probe to quantify glucose uptake and mitochondrial membrane potential (MMP). Validated in MCF-7 and MDA-MB-231 breast cancer cells, our optical assay showed consistent trends with flow cytometry and published Seahorse data. When applied to fresh tumor slices, it non-destructively distinguished tumor from normal tissue metabolism. This portable optical assay offers a more cost-effective and accessible platform, enabling a translational spectrum from basic mechanism study to clinical relevance. It allows future longitudinal monitoring of RT through the lens of tumor energetics, significantly advancing RT cancer research. Project 2 advanced multi-parametric optical spectroscopy to characterize vascular and metabolic responses to fractionated radiation and distinguish radiosensitivity in head and neck squamous cell carcinoma (HNSCC). Using matched radioresistant HNSCC models, we captured distinct radiation-induced metabolic and vascular changes: radioresistant rSCC-61 tumors showed increased oxygen saturation, total and oxygenated hemoglobin, decreased glucose uptake, and elevated MMP, while SCC-61 tumors had minimal changes after radiation. Our multi-parametric optical spectroscopy holds strong potential for monitoring vascular and metabolic responses in RT research. Although optical spectroscopy provides non-destructive, region-averaged metabolic assessments, it lacks single-cell resolution and may overlook metabolic heterogeneity relevant to RR. To address this, project 3 presented an optical imaging strategy integrating CellProfiler with standard fluorescence microscopy for single-cell metabolic analysis. This approach captured radiation-induced metabolic changes at the single-cell level in a more efficient and cost-effective manner. It revealed distinct metabolic responses under radiation and underscored the contribution of radiation-induced HIF-1α in metabolic modulation and RR. Overall, these three projects demonstrate that optical spectroscopy and a single-cell imaging strategy are powerful, non-destructive tools for monitoring metabolic dynamics across cancer models under radiation. These methods have strong potential for prognosis and RT decision-making in future cancer RR studies.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2026.114

Archival?

Archival

Funding Information

This study supported by the National Institute of Dental and Craniofacial Research (NIDCR) and the National Institute of General Medical Sciences (NIGMS) [National Institutes of Health (NIH), R01 DE031998 (2023-2028)], the National Institute of Biomedical Imaging and Bioengineering [NIBIB, R21 EB032515 (2022-2025)], and the University of Kentucky Startup (2019-2024).

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Available for download on Saturday, April 24, 2027

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