Engineering Dynamic Granular Composites for the Repair of Cartilage Tissue
In recent years, mesenchymal stromal cell (MSC) cellular aggregates, known as MSC spheroids, are being used as ‘building blocks’ to generate engineered tissues. MSC spheroids can fuse together to produce high cell density, macroscopic tissues with enhanced functional properties; however, their potential is hindered by challenges in the stabilization of and control over fusion. Hydrogel microparticles, known as microgels, are being jammed together into granular hydrogels, that are injectable, stabilizing via inter-particle crosslinking, and guiding tissue formation through microporosity and microgel properties. This thesis developed granular composites, which are mixtures of MSC spheroids and engineered hyaluronic acid (HA) microgels, to address the limitations in the use of MSC spheroids for biomedical applications. Granular composites were investigated for injectable cartilage tissue repair, dynamic tissue shape morphing, and 4D bioprinting, where features such as microgel micromechanical properties, volume ratios of spheroids and microgels, rate of microgel degradation, and overall spatial positioning of granular composites were controlled. First, the micromechanical properties of HA microgels were explored via building a micropipette aspiration device and validated through nanoindentation to understand differences between microgel and bulk properties. Next, granular composites are introduced and the volume ratio of spheroids and microgels were tailored in silico and in vitro to produce an interconnected network of MSC or chondrocyte mixed spheroids that were structurally supported by HA microgels and produced engineered cartilage with native cartilage mechanics and deposition of cartilage-specific extracellular matrix (ECM). After, HA microgels with variable degradation rates were introduced into granular composites, where degradation rate controlled compaction and ECM deposition. Altering spatial location, volume ratio, and degradation rate of HA microgels demonstrated control over curvature within engineered tissues in vitro and in silico. Lastly, 4D bioprinting was implemented to spatiotemporally control granular composites, where a cylinder to hemisphere shape transition was demonstrated as a physiologically relevant shape transformation reminiscent of a cartilage cap. The use of MSC spheroids for biomedical applications will increase and this work will further advance of spheroid use in engineering cartilage.
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