Title: Immunomodulatory Microribbon Hydrogels for Bone Regeneration: From Soluble Signals to ECM Modulation

Abstract: Critical-sized bone defects do not heal, and can be caused by trauma, diseases, or tumor resection. Current standard treatments rely on tissue grafts or metal implants, which are limited by insufficient donor tissue supply or lacking biological functions. There remains a critical need for regenerative therapies to heal critical-sized bone defects. Biomaterial scaffolds have been widely used for bone regeneration by providing structural support and an artificial cellular niche to promote desirable cell fates. Majority of previous biomaterials research focus on targeting stem cell differentiation or promoting vascularization. However, emerging studies suggest biomaterials can also modulate tissue regeneration via modulating immune cells, yet most previous work focus on soft tissues. It has also been shown that naturally-derived biomaterials induce a more regenerative immune response, compared to synthetic biomaterials. There remains a need for engineering immunomodulatory biomaterials for repairing critical-sized bone defects.

To address this, the goal of this thesis is to develop immunomodulatory microribbon (µRB) hydrogels for bone regeneration, via modulating the soluble signals and incorporating tissue-derived ECM cues. In my presentation, I will first discuss one project to incorporate Asprin (Asp), a widely used anti-inflammatory drug, into µRB hydrogels for enhancing bone regeneration.  We demonstrate Asp and mineral particle-coated µRB scaffolds provide a promising therapy for repairing critical-sized cranial bone defects via immunomodulation. The leading formulation supports rapid endogenous bone regeneration without the need for exogenous cells or growth factors, making it attractive for translation. Our results also highlight the importance of optimizing mineral particles and Asp dosage to achieve robust bone healing while avoiding bone resorption by targeting macrophage and osteoclasts.

I will also share a second project on incorporating tissue-derived ECM (tdECM) cues into µRB hydrogels for bone regeneration. tdECM have been shown to favor pro-regenerative immune response. However, previous studies were limited to soft tissue regeneration using nanoporous hydrogels. To addresses this gap, we developed various techniques that allow incorporation of tdECM into µRB scaffolds with tunable dosage and tissue types. Using tdECM-modified µRB hydrogels, we demonstrated enhanced MSC osteogenesis and accelerated bone regeneration, associated with decreased M1 macrophage polarization and enhanced vascularization.  The findings from this work establish immunomodulatory µRB hydrogels as promising biomaterials-based therapy for repairing critical-sized bone defects. The biomaterials tools developed from this thesis work can be broadly applied for regenerating other tissue types and treating osteolytic diseases by targeting immune cells.