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Engineering Modular Self-Assembling Biomaterials for Multifunctionality

Jung, Jangwook Philip

Abstract Details

2010, PhD, University of Cincinnati, Engineering and Applied Science: Biomedical Engineering.
The objective of this thesis was to design self-assembling biomaterials whose physical and biological properties can be systematically adjusted to modulate cell growth and differentiation. The intended applications of these biomaterials include defined 3D cell culture scaffolds as well as coatings for existing prosthetics. The complex and dynamic nature of extracellular matrices necessitates the precise integration and adjustment of multiple physical, chemical, and biological features within engineered biomaterials, but this has been challenging for previous scaffolds owing to the fact that these features tend not to be adjustable independently. Instead, these properties tend to be conflated and entangled, limiting the ability to systematically engineer scaffolds with multiple components. As a step towards addressing this issue, this thesis describes the development of a modular self-assembling biomaterial system capable of incorporating multiple physical or biological functions into precisely defined biomaterials without affecting other material properties. Three families of different biological and physical functionalities were designed, synthesized, and investigated: those that modulate matrix mechanics, those that mediate cell-matrix binding, and those that can release soluble effector molecules. All materials were based on a short, synthetic, self-assembling peptide sequence, Q11, which formed self-supporting hydrogels in physiological conditions. To independently modulate matrix mechanics, Q11 derivatives were developed possessing chemoselective functional groups that could be polymerized via native chemical ligation. This method produced significantly stiffened gels, which also significantly enhanced endothelial cell proliferation in an independent manner. To develop modular self-assembling ligand-bearing peptides, endothelial cell-interactive ligands, RGDS, REDV, IKVAV, and YIGSR amino acid sequences were added to the N-terminus of Q11 (X-Q11). The incorporation of X-Q11 into hydrogels was quantitative and did not significantly alter stiffness when different ligands were included in the hydrogels. The ligands were physically presented on the surface of fibrils, retained their biological activities, and interacted with cell surface receptors to modulate endothelial cell behaviors. To develop Q11 derivatives capable of releasing soluble effectors, Q11 peptides were synthesized containing a nitric oxide (NO) donor compound. The conjugation efficiency was about 88%, and fibril morphologies were not significantly altered by the NO donor compound, allowing quantitative incorporation of this peptide into Q11 hydrogels. The last stage of the project employed a statistical method, design of experiments, to capitalize upon the modularity of the developed co-assembling matrices, with the purpose of maximizing the growth of endothelial cells on the materials. Through several rounds of multifactorial experimentation, an optimal formulation of multiple peptides was determined, resulting in endothelial cell attachment and proliferation comparable to the native matrix protein, fibronectin. Such a calculation of an optimal formulation would be prohibitively costly, both in terms of time and materials, for conventional biomaterials not constructed in a modular fashion. These results suggested that modular Q11-based self-assembling systems enable facile manipulation of multiple factors, allowing the efficient targeting of a desired response, in this case endothelial cell growth. This approach should allow for the systematic design of biomaterials for a wide range of applications, without relying on ad hoc strategies.
Daria Narmoneva, PhD (Committee Chair)
Joel Collier, PhD (Committee Member)
Marepalli Rao, PhD (Committee Member)
Jason Shearn, PhD (Committee Member)
232 p.

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Citations

  • Jung, J. P. (2010). Engineering Modular Self-Assembling Biomaterials for Multifunctionality [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1291150805

    APA Style (7th edition)

  • Jung, Jangwook. Engineering Modular Self-Assembling Biomaterials for Multifunctionality. 2010. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1291150805.

    MLA Style (8th edition)

  • Jung, Jangwook. "Engineering Modular Self-Assembling Biomaterials for Multifunctionality." Doctoral dissertation, University of Cincinnati, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1291150805

    Chicago Manual of Style (17th edition)