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An In Situ Forming Dopamine-Functionalized Hydrogel System for Therapeutic Extracellular Vesicle Delivery

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title
An In Situ Forming Dopamine-Functionalized Hydrogel System for Therapeutic Extracellular Vesicle Delivery
author
Copus, Joshua
abstract
Osteo-derived extracellular vesicles (EVs) are nanovesicles that exhibit therapeutic potential for bone tissue engineering (BTE). Although EVs exhibit therapeutic potential, their low yield and delivery efficiency reduce their efficacy. Both systemic and locally delivered osteo-EVs are rapidly cleared from the target site before delivering their bioactive molecules. There is a need for a cell source capable of high EV yield and a hydrogel system which can sustain the release of EVs to native cells to improve their efficacy. To solve these issues we developed an injectable, dopamine-functionalized hydrogel for sustained delivery of EVs thereby allowing them to be internalized by target cells where they can then exhibit their therapeutic effect. Dopamine, the molecule responsible for marine mussel adhesion, is used to immobilize EVs within the click crosslinked hydrogel system. The click-chemistry molecules utilized in this study are non-toxic and have rapid crosslinking kinetics in physiological conditions. Next, we characterized the properties of our hydrogel system including dopamine functionalization percentage, rheological properties, degradation rates, and in vitro release kinetics with two model molecules. We analyzed cell viability and proliferation within the system before moving onto 3D in vitro differentiation experiments. The hydrogel system demonstrated good cell viability, and an improved osteogenic differentiation effect due to the retention of osteo-EVs. We tested the dopamine-functionalized hydrogel system in vivo in a rat calvarial defect model where we observed improved bone regeneration at the defect site. Biodistribution analysis of labeled EVs revealed that the hydrogel system could sustain delivery over 10 days. In conclusion, we’ve developed a novel, injectable hydrogel system capable of sustained release of EVs.
subject
Bone Tissue Engineering
Dopamine
Extracellular Vesicles
Hydrogels
Regenerative Medicine
Tissue Engineering
contributor
Lee, Sang Jin (advisor)
Whittington, Abby (committee member)
Almeida-Porada, Graça (committee member)
Chappell, John (committee member)
Soker, Shay (committee member)
date
2023-06-07T08:35:40Z (accessioned)
2023 (issued)
degree
Biomedical Engineering (discipline)
embargo
2024-06-06 (terms)
2024-06-06 (liftdate)
identifier
http://hdl.handle.net/10339/102108 (uri)
language
en (iso)
publisher
Wake Forest University
type
Dissertation

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