Date of Award


Document Type

Open Access Dissertation


Chemistry and Biochemistry


College of Arts and Sciences

First Advisor

Qian Wang


This thesis is focused on the development of novel hybridized biomaterials for applications in tissue engineering and controlled drug delivery. Two types of materials used in my research are biopolymers and nanomaterials. Hyaluronic acid (HA), a natural polymer commonly found in extracellular matrix (ECM), was the primary polymer used in my research due to biocompatibility, biodegradability and the ease of manipulation to offer a wide range of physical and mechanical properties. Meanwhile, the nanomaterials, including Tobacco mosaic virus (TMV), gold nanorods and graphene, provide attractive properties, such as a nanoscale topography, biochemistry, high surface area, and special chemical and electrical properties. These properties could promote cell response, and allow the nanomaterials to react with a myriad of biological small molecules. Hence, in this thesis, we aimed to integrate these two types of materials to create a new type of biomaterials, and provide ideal properties that can leverage the tissue regeneration and targeted drug delivery for various treatment applications.

Previously, our research group has found the intriguing effect of TMV on bone differentiation of mesenchymal stem cells (MSCs). We demonstrated that TMV could promote MSC osteogenesis via upregulating bone morphogenetic protein-2 (BMP-2) gene expression, a common gene used to enhance cartilage differentiation. This discovery combined with the clinical demand for cartilage tissue repair, which is limited by the minimum self-healing capacity of cartilage, inspired us to design a hybrid TMV scaffold in a simple injectable form, using thiol-ene “click” chemistry, to promote the MSC differentiation to cartilage. We demonstrated that cysteine-inserted TMV mutants (TMV1cys), containing thiol functional groups, could successfully crosslink to methacrylated hyaluronic acid (MeHA) polymers by thiol–ene “click” chemistry and form hydrogels under physiological conditions. The resulting hydrogels promoted in vitro chondrogenesis of MSCs by upregulating BMP-2 and enhancing collagen accumulation. In addition, incorporation of RGD-inserted TMV mutants (TMV-RGD1) in the HA hydrogels further promoted the in vitro chondrogenesis of BMSCs. Meanwhile, incorporation of gold nanorods, which provide similar size and shape as TMV, HA hydrogels showed no impact on the in vitro chondrogenesis. These results implied that the influences of nanoscale topography and biochemistry provided by TMV and TMV-RGD play critical roles in directing encapsulated MSC chondrogenesis.

To better mediate new cartilage tissue formation, the physical and mechanical properties of the HA hydrogels were further optimized by varying the structures of thiol-tailored crosslinker molecules using dithiothreitol (DTT), 4-arm polyethylene glycol (PEG), and a multi-arm polyamidoamine (PAMAM) dendrimer. Chondrogenesis and osteogenesis of MSCs were highly enhanced in 4-arm PEG-crosslinked HA hydrogels, as measured by chondrogenic markers, glycosaminoglycan (GAG) and collagen accumulation, and osteogenic markers, alkaline phosphatase activity, and calcium deposition. It implied that the differentiation performance of MSCs directly correlated to the mechanical stiffness, permeability, pore size, porosity and chemistry of crosslinkers. The 4-arm PEG-crosslinked HA hydrogels seemingly mimicked the architecture of real cartilage and bone closer than other hydrogels. Aside from the application in tissue engineering, we developed a graphene oxide (GO)-hybridized HA-based hydrogel for perivascular drug delivery. The nanoscale GO was used as a novel nanocarrier for controlled drug delivery, owing to its high loading capacity of drugs resulting from the aromatic structure. HA serves as a biodegradable macroscale polymeric scaffold, making the prepared GO nanocarriers localized and stable in different microenvironments. The nanocarrier was firstly synthesized by attaching Senexin A (SNX), a kinase inhibitor and a possible anti-tumor drug, to GO via strong π–π interaction, followed by the in situ encapsulation of GO-SNX with HA-based hydrogel. The results of in vitro testing indicate high loading of SNX onto GO, and subsequent slow release of SNX within the therapeutic window. The slow release of SNX closed correlates to the loading-ratio of GO to SNX. With the in vitro results, we have demonstrated that the SNX loaded-GO hybridized HA hydrogel could be successfully attached to the decellularized scaffolds and form hydrogels under physiological condition. The hybridized materials provided a good biocompatibility and no impact on the proliferation and migration of vessel smooth muscle cells (VSMCs). More importantly, it could inhibit the dedifferentiation of VSMCs in the same manner as the SNX treatment.

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Chemistry Commons