Development of Multifunctional Microgels for Complex Bone Defects

Complex bone defects are often caused by trauma, tumor resection, and infection. Characterized by infection, compromised osteogenesis, inadequate osteogenesis-angiogenesis coupling, or aberrant callus mineralization, these defects have served as a significant challenge in orthopedic practice for many years. Conventional surgical and drug treatments are inadequate for addressing the dynamic and multifaceted pathological microenvironment of these defects. Although existing biomaterials applied in clinical practice offer essential structural support, their passive nature and lack of bio-instructive cues hinder the regeneration of bone tissue and the integration of biomaterials with bone tissue. Microgels can load drugs, nanoparticles, and cells, be injected into defected sites, and act as micro-scaffolds for cell adherence and differentiation within the defect sites. Thus, in recent years, various microgels have been developed to address these pathological challenges in the regeneration of complex bone defects.

This thesis work developed microgels loaded with different types of actives for drug delivery (antimicrobial peptides, a carbon monoxide donor compound, siRNA-loaded calcium phosphate nanoparticles, stromal cell-derived factor-1α protein, bone morphogenetic protein-2 mRNA, β-catenin mRNA, L-arginine, and an EPLQLKM peptide) to address various pathological challenges at different stages of bone regeneration. Utilizing nano-co-precipitation, interface reaction, and microfluidic technology, these bioactives can be integrated within the microgel. This work systematically characterized the material properties of these microgels and evaluated their functional performance in vitro and in complex bone defects.

The microgels consisting of antimicrobial peptides and a carbon monoxide donor compound were capable of eliminating drug-resistant free bacteria and removing biofilms. The microgels co-loaded with siRNA-encapsulated calcium phosphate nanoparticles and stromal cell-derived factor-1α were able to recruit bone marrow-derived mesenchymal stem cells (BMSCs) for the regulation of epigenetic modifications in BMSCs. The third kind of microgels, integrated with bone morphogenetic protein-2 mRNA, L-arginine, and an EPLQLKM peptide, restored nitric oxide (NO) metabolism in BMSCs, thereby promoting osteogenesis-angiogenesis coupling. Finally, a microgel-based β-catenin-activated osteo-callus organoid precursor was proposed to enhance the mineralization of bone callus under osteoporotic conditions. In summary, this work is expected to make a substantial contribution to microgel-based strategies for the regeneration of complex bone defects.