Chemically cross-linked hydrogels (chemical gels) offer a number of enhanced properties over their physical counterparts, particularly in biomedical applications such as drug delivery, tissue engineering, and cell encapsulation. Conventional chemical gels are generally too elastic to be introduced into the body without requiring surgical implantation, making them challenging to use in a clinical context. In response, this thesis is focused on developing injectable analogues of conventional hydrogel-based biomaterials as well as advanced, engineered injectable hydrogels, enabling the facile use of these hydrogels in biomedical applications. Cross-linking is achieved using hydrazone chemistry, in which one precursor is functionalized with aldehyde groups and the other is functionalized with hydrazide groups. Following coextrusion of the reactive precursors, a stable hydrogel network spontaneously forms within seconds. By employing this chemistry as a standard in all of this work, a number of injectable hydrogel systems with well-defined properties (including swelling, drug loading and release, optical properties, gel formation and degradation kinetics, response to the temperature of the surrounding environment, and tissue response) have been generated that can be tuned by rationally varying the charge content in the precursor polymers, the number of cross-linking functional groups used, the reactivity of the electrophilic cross-linking units, and the length and number of hydrophobic affinity domains present within the gels. This work therefore presents a series of independent methods for customizing hydrogels so that they may be adapted to a number of different biomedical applications. / Dissertation / Doctor of Philosophy (PhD)

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Stem cell bioengineering and therapy require different model systems and materials in different stages of development. If a chemically defined biomatrix system can fulfill most tasks, it can minimize the discrepancy among various setups. By screening biomaterials synthesized through a coacervation-mediated self-assembling mechanism, a biomatrix system optimal for 2D human mesenchymal stromal cell (hMSC) culture and osteogenesis is identified. Its utility for hMSC bioengineering is further demonstrated in coating porous bioactive glass scaffolds and nanoparticle synthesis for esiRNA delivery to knock down the SOX-9 gene with high delivery efficiency. The self-assembled injectable system is further utilized for 3D cell culture, segregated co-culture of hMSC with human umbilical vein endothelial cells (HUVEC) as an angiogenesis model, and 3D bioprinting. Most interestingly, the coating of bioactive glass with the self-assembled biomatrix not only supports the proliferation and osteogenesis of hMSC in the 3D scaffold but also induces the amorphous bioactive glass (BG) scaffold surface to form new apatite crystals resembling bone-shaped plate structures. Thus, the self-assembled biomatrix system can be utilized in various dimensions, scales, and geometries for many different bioengineering applications.