Author ORCID Identifier

https://orcid.org/0000-0001-5573-5985

Date of Award

Spring 6-15-2025

Document Type

Thesis (Ph.D.)

Department or Program

Engineering Sciences

First Advisor

Scott C. Davis

Abstract

Fluorescence guided surgery (FGS) is an emerging surgical technique that aims to help surgeons identify tissue types to assist in surgical decision making - ideally providing “cut-by-color” guidance. A primary application for this approach is the identification of tumor tissue to achieve more accurate and complete tumor removal while simultaneously minimizing damage to surrounding normal tissue. The cornerstone of tumor visualization for FGS is the administration of fluorescent contrast agents, or in some cases metabolic precursors, designed to accumulate specifically in tumor tissue, and a wide range of agents that use different targeting mechanisms are currently under investigation. Although these fluorescent contrast agents often provide elevated tumor contrast, many require long incubation times, which complicate their clinical use and/or exhibit imperfect tumor specificity which may confound the surgeon’s ability to accurately distinguish cancerous from healthy tissue.

This project aims to improve FGS techniques for tumor resection by advancing new fluorescent contrast agents with more favorable properties. These properties include a short administration-to-imaging time, which eases the use of these agents in the clinic, and significant improvements in diagnostic performance. To achieve these aims, we used whole-body fluorescence cryotomography with co-registered contrast-enhanced MRI and histopathology to evaluate a panel of candidate fluorescent contrast agents. Specifically, we focused on applications in neurosurgical fluorescence guidance and identified a lead candidate agent which displayed rapid, diagnostically accurate and persistent contrast that closely correlated to contrast-enhanced MRI and ground-truth tumor as early as 10 minutes after administration. The lead candidate agent was also directly compared with two clinically established fluorescent contrast agents—each requiring administration schedules of 3 to 24 hours—in both small and large animal models, including an inducible glioma model in genetically modified pigs. In these studies, the candidate agent either outperformed or displayed equivalent performance metrics while offering a significantly shorter administration-to-imaging time. The fluorescence cryotomography system is further leveraged in this thesis to investigate region of interest impact on fluorescent contrast agent performance metrics, the delivery of genetic medicines, metastatic spread of tumor models and biodistribution of fluorescent reporters.

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