Thesis: Ph. D., Harvard-MIT Program in Health Sciences and Technology, June 2015. / Cataloged from PDF version of thesis. / Includes bibliographical references (pages 170-192). / Spinal cord injury (SCI) results in sudden life-altering paralysis with chronic medical consequences. Although no clinical therapy is currently available to reverse paralysis, a number of biomacromolecule drug candidates in the form of proteins, enzymes and monoclonal antibodies have demonstrated restoration of function in studies with SC animal models. However, the inability to address drug formulation stability issues and overcome delivery barriers has limited the clinical translation of these promising drugs. To address this inadequacy, we designed a versatile injectable hydrogel platform and investigated its utility for local delivery of biomacromolecules to SCI contusion lesions. To develop this hydrogel platform we synthesized a library of different tri-thiol-functionalized ethoxylated polyol esters (TEPE) and combined these entities with PEG diacrylates (PEGDA) of various molecular weights to form crosslinked materials with diverse physiochemical properties using Michael addition thiol-ene chemistry. This hydrogel platform afforded unprecedented temporal control over both material degradation and the triphasic release of model biomacromolecule drugs over a 5 to 35 day period. Favorably, these materials display fast and controllable gelation kinetics under physiological conditions as well as non-swelling hydrolytic degradation profiles making them amendable for use in volume constrained anatomical sites within the spinal cord. Many of the biomacromolecule drugs of interest for SCI are complex and fragile making them susceptible to aggregation, denaturation and loss of activity during biomaterial encapsulation and controlled release. We devised a strategy to improve the long-term functional stability of biomacromolecules within hydrogels by covalently incorporating trehalose, a non-reducing disaccharide, into hydrogel networks by reacting trehalose diacrylate monomers with TEPEs and PEGDA. The covalent incorporation of trehalose within hydrogels afforded prolonged stabilization and controlled release of model enzymes in vitro and in vivo via a proposed mechanism of strong and ordered hydrogen bonding interactions. There is currently limited information pertaining to the performance of hydrogel therapies in non-penetrating contusive SCI, which represents the dominant injury mode observed clinically. Therefore, in the final part of this thesis we evaluated biomacromolecule drug delivery outcomes following intrathecal and intraparenchymal injection of hydrogel within rat thoracic SCI contusion lesions. Intraparenchymal hydrogel injection but not intrathecal administration afforded prolonged release of biomacromolecules locally within spinal cord parenchymal tissue over a two week period. Using a fluorescently labeled model drug, FITC-Dextran, we observed localized diffusion of drug within the neuropil as well as evenly distributed punctated deposits within the extracellular space that appeared to drain into local perivascular spaces. Overall, this work validates novel strategies for improved localization, temporal delivery and long term functional stability of promising biomacromolecule drug candidates in SCI. / by Timothy Mark O'Shea. / Ph. D.
| Identifer | oai:union.ndltd.org:MIT/oai:dspace.mit.edu:1721.1/98723 |
| Date | January 2015 |
| Creators | O'shea, Timothy Mark |
| Contributors | Robert S. Langer., Harvard--MIT Program in Health Sciences and Technology., Harvard--MIT Program in Health Sciences and Technology. |
| Publisher | Massachusetts Institute of Technology |
| Source Sets | M.I.T. Theses and Dissertation |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | pages, application/pdf |
| Rights | M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission., http://dspace.mit.edu/handle/1721.1/7582 |
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