PhD Thesis Proposal: John H. Molinski

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"Patterned Magnetic and Plasmonic Nanostructures in Microfluidics for Extracellular Vesicle Screening and Drug Loading"

Extracellular vesicles (EVs), once dismissed as shuttles for cellular waste, have emerged as vital nanoscale biomolecules, facilitating intercellular communication through transfer of host-cell specific molecular cargo. Tumor-derived EVs, released by cancer cells, hold potential as diagnostic biomolecules due to their links to cancer cells, abundance within biofluids, and potential for direct extraction and detection. Alternatively, EVs from various cellular origins have been explored as therapeutic carriers, stemming from their innate function as cargo carriers, high biocompatibility, and their ability to evade immune detection. Utilizing EVs for diagnostic or therapeutic applications, however, necessitates efficient isolation, purification, and manipulation directly from biofluids, which presents challenges given their minuscule size and micro-nano scale physics. Consequently, the tangible use of EVs in clinical settings has remained limited, with technological progress primarily constrained to research pursuits.

This thesis proposal outlines the development of three pivotal technologies: (1) magnetic microchips for rapid EV isolation from complex biofluids, (2) plasmonic nanostructures for EV detection via plasmon-enhanced fluorescence, and (3) a photothermal engineering system for engineering of EVs as therapeutic carriers. Firstly, we describe a novel magnetic microchip architecture with patterned flow-invasive micromagnets, enhancing traditional immunomagnetic sorting while enabling precise profiling of EVs directly from undiluted biofluids. Secondly, we detail the development progress of an exosome assay that utilizes patterned plasmonic nanostructures to enhance fluroscence and facilitate exosome detection within the standard well-plate format. Thirdly, we introduce a novel photothermal engineering system that enables cargo loading within patient derived EVs and highlight promising proof-of-concept results concerning loading of the chemotherapeutic drug doxorubicin. Technology development within each contribution spans from enabling micro/nanoscale phenomena, through material and device engineering, and concludes with application driven technology validation. Performance is evaluated in terms of capture (throughput and efficiency), detection (limit of detection and dynamic range), and loading (quantity and efficiency) metrics, respectively, and results are benchmarked against the current state-of-the-art. Collectively, this thesis presents a step towards the realization of EV-centered diagnostic and therapeutic clinical workflows, whereby we can harness the innate biological properties and functions of EVs within molecular diagnostics and personalized medicine.

Thesis Committee

• Prof. John X.J. Zhang
• Prof. William Scheideler
• Dr. Gregory J. Tsongalis
• Prof. Steven Jay (University of Maryland)

Contact

For more information, contact Julia Abraham at julia.s.abraham@dartmouth.edu.