Development of Chondroinductive Hydrogel Pastes from Naturally Derived Cartilage Matrix

Abstract

The main focus of hydrogel technology is on hydrogels in their crosslinked form. Although hydrogels are promising materials for cartilage tissue engineering, the clinical translation of these materials are hindered because they lack the ability to be molded into a defect site by a surgeon due to hydrogel precursors being liquid solutions that are prone to leaking from the implantation site during placement. Therefore, the current thesis work focuses on the hydrogels in their precursor form prior to crosslinking and describes the development of creating hydrogel pastes that have the potential to be clinically translatable. The current thesis first developed a platform hydrogel paste composed of methacrylated hyaluronic acid (MeHA), which is a more traditional hydrogel material, and hyaluronic acid nanoparticles. The hyaluronic acid nanoparticles were shown to impart a yield stress on the hydrogel precursors, allowing the precursors to be molded and shaped prior to crosslinking. Furthermore, the mixtures containing hyaluronic acid nanoparticles were able to be crosslinked and further characterized as solids and they could encapsulate bone marrow-derived stem cells that remained viable. The next major focus of the thesis was tailoring the platform system for cartilage tissue specifically, by gradually replacing each of the two components of the platform system with naturally derived cartilage extracellular matrix, to create a chondroinductive material. Devitalized (DVC) and decellularized cartilage (DCC) particles were found to impart paste-like behavior in MeHA gels, where DVC significantly upregulated chondrogenic gene expression. DCC that was solubilized and methacrylated (MeSDCC) was created and crosslinked, which formed hydrogels with a compressive modulus in the range of native cartilage tissue. Finally, DVC particles mixed in with solubilized and methacrylated DVC created pastes that significantly upregulated chondrogenic gene expression compared to gels without DVC particles. The important next steps will be to further evaluate these MeSDVC and DVC particle pastes in an in vivo model, and further explore whether decellularization of the tissue is necessary. Ultimately, this thesis successfully developed a hydrogel paste that is inherently chondroinductive and promising for future cartilage tissue engineering applications.