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Dissertation_TRH_FINAL.pdf (158.94 MB)

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Covalent Growth Factor Tethering to Guide Neural Stem Cell Behavior

Ham, Trevor Richard
http://rave.ohiolink.edu/etdc/view?acc_num=akron1555347467862553

Abstract Details

2019, Doctor of Philosophy, University of Akron, Biomedical Engineering.
Spinal cord injury (SCI) results in permanent motor and sensory deficits, primarily caused by localized cell death. Treatment strategies which focus on guiding cell behavior (exogenous or endogenous) are attractive. Neural stem cells (NSCs) can contribute to recovery indirectly (secreted neurotrophic factors) or directly (by differentiating into functional cell types). Their efficacy is also clearly enhanced with an active biomaterial carrier to keep them within the site of injury and guide their behavior. Here, a biomaterial-based approach for treating SCI was investigated, consisting of NSCs seeded within a biomimetic scaffold made from methacrylamide chitosan (MAC). The scaffold contained tethered, biotinylated recombinant growth factors to specify the lineage of the encapsulated NSCs. This scaffold showed promising tissue-level improvements but failed to restore locomotor function. Next, a new approach for covalently immobilizing azide-tagged recombinant proteins was developed. This approach was tested on interferon-gamma (IFN-gamma, which induces neuronal differentiation from NSCs) and found to enable immobilization to multiple materials while retaining its bioactivity. A new, open-source gait analysis technique was then adapted to include SCI-specific parameters. This technique was tested on a treatment which is known to be effective, intracellular sigma peptide (ISP, which reduces inhibitory cues from the microenvironment) and found to sensitively measure benefits. The NSC-seeded scaffolds were tested again, with two major improvements: they were primed in subcutaneous tissue prior to transplantation into the spinal cord and ISP was co-administered. This approach was based on a finding that NSC-seeded scaffolds with immobilized IFN-gamma increased the expression of developmental markers after subcutaneous maturation. Ultimately, subcutaneous maturation with ISP was found to improve function. The tissue-level analysis suggested that this was due to an indirect pro-regenerative effect of the NSCs within the scaffolds, which is enhanced by both subcutaneous priming and ISP administration. Finally, a method for enabling the controlled release of soluble proteins from this system was developed. Methacrylated heparin was introduced into MAC hydrogel scaffolds with immobilized IFN-gamma and observed to slow the release of soluble stromal cell-derived factor-1alpha (SDF-1alpha), which enabled NSC recruitment to the scaffold in vitro where they then differentiated into neurons following exposure to immobilized IFN-gamma. In general, this work sought to develop and test new approaches to improve NSC-seeded biomaterials for treating SCI.
Nic Leipzig, PhD (Committee Chair)
Rebecca Willits, PhD (Committee Member)
Hossein Tavana, PhD (Committee Member)
Bi-Min Zhang Newby, PhD (Committee Member)
Adam Smith, PhD (Committee Member)
320 p.
Biomedical Engineering
Tissue engineering; spinal cord injury; protein engineering; neural stem cells; biomaterials; cell scaffolds; gait analysis

Recommended Citations

Citations

  • Ham, T. R. (2019). Covalent Growth Factor Tethering to Guide Neural Stem Cell Behavior [Doctoral dissertation, University of Akron]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=akron1555347467862553

    APA Style (7th edition)

  • Ham, Trevor. Covalent Growth Factor Tethering to Guide Neural Stem Cell Behavior. 2019. University of Akron, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=akron1555347467862553.

    MLA Style (8th edition)

  • Ham, Trevor. "Covalent Growth Factor Tethering to Guide Neural Stem Cell Behavior." Doctoral dissertation, University of Akron, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=akron1555347467862553

    Chicago Manual of Style (17th edition)

akron1555347467862553
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© 2019, all rights reserved.
This open access ETD is published by University of Akron and OhioLINK.