Date of Award

5-2015

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Legacy Department

Bioengineering

Committee Member

Dr. Ken Webb, Committee Chair

Committee Member

Dr. Martine LaBerge

Committee Member

Dr. Jeoung Soo Lee

Committee Member

Dr. Ying Mei

Abstract

Hydrogels have been widely investigated for their versatility in biomedical applications such as tissue engineering scaffolds and minimally invasive vehicles for site-specific delivery of bioactive molecules. Hybrid hydrogels combine the strengths of intrinsic bioactivity from naturally derived materials and superior control over network physical and chemical properties from synthetic materials. The most prominent approach in three-dimensional (3D) hybrid matrices is the use of MMP-sensitive peptides derived from native extracellular matrix molecules to crosslink synthetic polymers. These peptide-based techniques have several limitations such as high cost, limited mechanical properties, and reduced degradation kinetics that limit the network crosslinking density and mechanical properties. This led us to develop a novel hydrid hydrogel system, in situphotopolymerizable, degradable, poly(ethylene glycol) (PEG) diacrylate / hyaluronic acid (HA) semi-interpenetrating networks (semi-IPNs). In the first set of studies, we determined the effects of network composition (PEGdA and HA molecular weight and concentration) on 3D cell spreading and identified polymerization-induced phase separation as the underlying mechanism responsible for the ability of PEGdA/HA semi-IPNs to support 3D cell spreading. Semi-IPNs with optimal network composition including a blend of three different PEGdA providing improved degradation kinetics demonstrated the ability to support long-term fibroblast cell spreading, migration, and network formation. In addition, the selected semi-IPNs were also found to possess elastic moduli significantly higher than most alternative hybrid hydrogels and within the range reported as optimal for osteogenic differentiation of mesenchymal stem cells. In second study, we investigated the ability of the semi-IPNs to support hMSC differentiation as a preliminary study towards bone tissue engineering application. Gene expression, alkaline phosphatase activity, histological analysis, and calcium quantification demonstrated the semi-IPN’s ability to support osteogenic differentiation over 35 days of culture. In the final study, we incorporated poly-L-lactic acid (PLLA) nanospheres in semi-IPNs to test the hypothesis that provision of hydrophobic domains capable of supporting higher protein adsorption than the PEG network could increase extracellular matrix accumulation. Significantly increased collagen deposition was observed in histological sections and by quantitative analysis. Overall, the results of this work suggest that PEGdA / HA semi-IPNs and their composite derivatives offer potential as a hybrid matrices for therapeutic cell transplantation. In the future, the biofunctionality of these hybrid networks can be further enhanced by inclusion of growth factors or biochemicals.

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