Dissertations and Theses
Development of Cellulose-Based, Semi-Interpenetrating Network Hydrogels as Tissue-Adhesive, Thermoresponsive, Injectable Implants
Date of Award
tissue adhesive, injectable, thermogelation, hydrogel, implant, cellulose
Abstract Development of Cellulose-Based, Semi-Interpenetrating Network Hydrogels as Tissue-Adhesive, Thermoresponsive, Injectable Implants
Hydrogels are three-dimensional polymer networks with high water content and tunable mechanical properties, which have been widely investigated as replacements for soft tissues, such as the intervertebral disc (IVD). Various derivatives of the plant polysaccharide, cellulose, have been explored for use as injectable hydrogel implants. Methylcellulose (MC), which exhibits thermogelation at temperatures above 32°C, and relatively hydrophilic carboxymethyl-cellulose (CMC), are versatile cellulosic polymers that have shown promise as base materials for such applications. In prior work, functionalization with methacrylate groups allowed for the formation of stable, covalently crosslinked MC/CMC dual-polymer network hydrogels in situ via reduction/oxidation (redox)-initiated polymerization. Thermogelation prevented extravasation while curing, but when used for IVD repair in an explant injury model, implants reherniated under bending loads, underscoring the need to improve hydrogel implant stabilization and retention. Biological adhesives (i.e., fibrin glue) have been used for internal fixation of implants (e.g., hernia meshes) but lack long-term stability due to enzymatic degradation. A potential strategy may involve controlled oxidation of cellulosic polysaccharides (which are not enzymatically degradable in humans) to introduce aldehyde functional groups along the backbone capable of binding to tissue proteins. Since oxidation can be destructive to methacrylate moieties necessary for covalent crosslinking, a viable approach may be to engineer stable, semi-interpenetrating polymer network (sIPN) hydrogels comprised of oxidized and methacrylated cellulosic polymers, with the oxidized macromers physically entangled within, but not chemically coupled to, the crosslinked network of methacrylated macromers. Hence, the overarching goal of this thesis was to vi develop proof-of-concept for a tissue-adhesive, injectable, cellulosic sIPN hydrogel implant platform. Methacrylated MC (mMC) was chosen as the structural network, with the adhesive components comprised of oxidized MC (oMC) or oxidized CMC (oCMC). Aim 1 confirmed that oxidation results in aldehyde substitution while retaining thermosensitivity of oMC. Aim 2 refined sIPN formulations produced when combining MC with oMC (MoMC) and mMC with oCMC (MoCMC) by varying the degree of oxidation, macromer concentration and ratio of oxidized to methacrylated polymer. The composite gels were characterized in terms of thermal and redox-initiated gelation and for adhesion strength to porcine skin. Thermosensitivity and redox-mediated gelation were consistently robust. Tissue adhesivity improved once specific formulation parameters were established but MoCMC achieved average tissue adhesive strength superior to that of MoMC, and comparable to fibrin glue. Refined formulations of both composites were selected for further study based on adhesive performance and ease of handling. Aim 3 characterized hydrolytic stability under physiologic conditions and evaluated cytotoxicity in the presence of bovine IVD cells. The composites displayed limited degradation, remaining stable after two weeks. Although both sIPNs exhibited comparable properties by the end of the study, MoCMC was more stable throughout. All materials demonstrated negligible cytotoxic effects but seemed to disrupt cell adhesion. Still, the effect was significantly less pronounced for cells cultured with MoCMC gels. Overall, these results indicate that MoCMC sIPNs show the most promise as surgical adhesives. Moreover, this work has established the feasibility of the platform as a viable biomedical product, prescribing methods for future refinement necessary for clinical translation.
Martin, Jesse, "Development of Cellulose-Based, Semi-Interpenetrating Network Hydrogels as Tissue-Adhesive, Thermoresponsive, Injectable Implants" (2022). CUNY Academic Works.