This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections. / Thesis: Ph. D. in Medical Engineering and Medical Physics, Harvard-MIT Program in Health Sciences and Technology, 2019 / Cataloged from student-submitted PDF version of thesis. / Includes bibliographical references. / Spinal cord injury (SCI) is a devastating condition drastically reducing the quality of life that affects about 300,000 patients in the USA. As a result of the injury, sensory perception and motor functions are lost. Current treatments do not address the root cause - degeneration and loss of neural tissue. The overall goal of this pre-clinical work was to evaluate a novel gelatin-based conjugate (gelatin-hydroxyphenyl propionic acid; Gtn-HPA) capable of undergoing covalent cross-linking in vivo after being injected as a liquid. Gtn-HPA incorporating epidermal growth factor (EGF) and/or stromal cell-derived factor - 1ɑ (SDF-1ɑ) was evaluated for promoting tissue healing and functional recovery using a standardized 2-mm hemi-resection SCI rat model, four weeks after injection. Injection of Gtn-HPA/EGF immediately after the surgical excision injury significantly improved motor functional recovery, compared to gel alone and non-treated controls. / Bladder function was also improved in Gtn-HPA/EGF-treated animals. Functional improvement correlated with the amount of spared tissue. The volume of gel in the defects was quantified by a newly developed MRI-based method employing T1-weighted inversion recovery to unambiguously image Gtn-HPA in the injury site in a non-destructive manner. Histological analysis showed the presence of multiple islands of Gtn-HPA in the injury site after four weeks. There was a significantly greater number of cells migrating into the Gtn-HPA/EGF, compared to the gel alone, and these cells displayed neural progenitor cell markers: nestin, vimentin, and Musashi. The cells infiltrating Gtn- HPA were negative for glial fibrillary acidic protein (GFAP), a marker for astrocytes. Injection of the gel reduced the reactive astrocytic presence at the border outlining the injury site indicating the reduction of glial scar. / There was no notable inflammatory response to the Gtn-HPA gel, reflected in the number of CD68-positive cells, including macrophages. Of note was the demonstration by immunohistochemistry that the Gtn-HPA remaining at 4 weeks post-injection contained EGF. MMP2 was found to be playing a role in in vivo degradation of the Gtn-HPA gel. Additional behavioral and histological results were acquired injecting Gtn-HPA/EGF in 2-mm complete resection SCI rat model. Collectively, the findings signaled that injury sites injected with Gtn-HPA/EGF had greater potential for regeneration. In summary, this work commends an injectable, covalently cross-linkable formulation of Gtn-HPA incorporating EGF for further investigation in promoting functional recovery and potential regeneration for treatment of SCI and thereby improve the quality of life of SCI patients. / by Adhvait M. Shah. / Ph. D. in Medical Engineering and Medical Physics / Ph.D.inMedicalEngineeringandMedicalPhysics Harvard-MIT Program in Health Sciences and Technology
| Identifer | oai:union.ndltd.org:MIT/oai:dspace.mit.edu:1721.1/122195 |
| Date | January 2019 |
| Creators | Shah, Adhvait M. |
| Contributors | Myron Spector., 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 | 231 pages, application/pdf |
| Rights | MIT theses are protected by copyright. They may be viewed, downloaded, or printed from this source but further reproduction or distribution in any format is prohibited without written permission., http://dspace.mit.edu/handle/1721.1/7582 |
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