Date of Award
Steven B. Nicoll
Biomaterials, Tissue Engineering, Cellulose, Growth Factor Delivery, Intervertebral Disc
Low back pain is the most common cause of disability in the world and is often caused by degeneration or injury of the intervertebral disc (IVD). The IVD is a complex, fibrocartilaginous tissue that allows for the wide range of spinal mobility. Disc degeneration is a progressive condition believed to begin in the central, gelatinous nucleus pulposus (NP) region of the tissue, for which there are few preventative therapies. Current therapeutic strategies include pain management and exercise, or surgical intervention such as spinal fusion, none of which address the underlying cause of degeneration. With an increasingly aging population, the socioeconomic impact of disability associated with low back pain and disc degeneration cannot be understated. Tissue engineering strategies are increasingly being investigated as an alternative therapy by which early-stage degeneration may be halted and reversed, thus restoring disc mechanics and inducing biological repair to prevent more painful long-term degeneration and disability. In order to prevent further injury to the IVD, an ideal therapeutic should be injectable via small gauge needle, be retained within the high-pressure intradiscal space, restore biomechanical properties, and deliver therapeutic agents and/or cells to drive tissue regeneration. Therefore, the overall objective of this thesis was to develop and characterize an injectable, bioactive, cellulose-based hydrogel system for NP replacement and repair. Methylcellulose (MC) is cellulose derivative that forms physically crosslinked gels at increasing temperatures. Methacrylation of MC allows for the formation of more robust, chemically crosslinked hydrogels with lower effective macromer concentration. The first aim of this thesis investigated the influence of methacrylation on the thermoresponsive behavior of MC with implications for injectability and in situ retention. Results showed that increasing methacrylation percentage increased hydrophobic interactions that drive thermogelation, lowering the thermogelation onset temperature to within physiologic range, and produced robust, rapidly gelling, dual-crosslinked hydrogels when formed at physiologic temperature versus room temperature with redox initiators. The addition of anionic groups to MC would allow the polymer to mimic the sulfated glycosaminoglycan-rich matrix of the NP, enhancing water retention and sequestration of cationic proteins such as TGF-b3 that are critical for regenerative repair. Thus, the second aim was to develop an injectable, sulfonated MC hydrogel capable of forming stable gels in situ and electrostatically sequestering TGF-b3 to improve bioavailability of the therapeutic molecule. Findings showed that using sulfonated methacrylate monomers, negatively charged moieties could be incorporated into the MC hydrogels without sacrificing thermoresponsiveness below 37°C. Sulfonation was easily tunable by increasing monomer concentration, and TGF-b3 sequestration was closely correlated with sulfonate concentration, resulting in a viable bioactive acellular biomaterial for NP replacement. Factorial design of macromer and sulfonate concentration allowed for selection of a sulfonated MC (sMC) formulation with optimal chemical and mechanical properties for injection into the NP. The third aim evaluated the bioactivity of the sMC hydrogels by encapsulating human bone-marrow derived mesenchymal stromal cells (hMSCs) with and without TGF-b3. Results demonstrated that sMC hydrogels with TGF-b3 were able to support NP-like matrix elaboration and maintained relevant mechanical properties. Overall, this work advanced the development of injectable cellulose-based hydrogels as potential bioactive NP replacements for IVD repair and regeneration.
Haq-Siddiqi, Nada A., "Development of an Injectable Methylcellulose Hydrogel System for Nucleus Pulposus Repair and Regeneration" (2021). CUNY Academic Works.
Biology and Biomimetic Materials Commons, Biomaterials Commons, Mechanics of Materials Commons, Molecular, Cellular, and Tissue Engineering Commons, Orthopedics Commons, Polymer and Organic Materials Commons, Polymer Science Commons