Magnetic Nanocomplexes-Induced Immunomodulation for Fracture Healing

Non-healing fractures are a cause of severe disability and have devastating effects on the quality of life. Currently, there are no reliable first-line therapies that stimulate healthy bone formation and prevent nonunion. There is a growing body of evidence supporting the indispensable role of macrophages in fracture healing. Also, macrophage dysfunction is a critical component in the pathogenesis of non-healing or poorly healing fractures. Immunomodulatory strategies that apply biochemical factors are gaining traction to regulate macrophage phenotypes. However, they have limited success due to complications with specificity, efficacy, and systemic toxicity. Here we propose to develop a magnetic iron-oxide nanocomplexes (MNC)-based therapy for promoting fracture healing. The cytoskeletal dynamics of macrophages are intricately linked to their inflammatory response. During proinflammatory activation, the macrophage starts to spread through actin polymerization accompanied by a concomitant decrease in the G-actin levels and subsequent upregulation of several proinflammatory genes. Our central hypothesis is that the intracellular MNC coupled with an external magnetic field, can modulate the macrophage actin cytoskeleton and promote the proinflammatory to prohelaing phenotype switch, which in turn promotes fracture healing. In SA1, we will design MNC with a macrophage targeting tuftsin peptide for targeted internalization by macrophages. In SA2, we will examine the magnetic field-induced changes in actin polymerization and its downstream effects on the phenotype modulation of macrophages in both in vitro (3D collagen matrix) and in vivo (murine segmental defect) models. The proposed research will be a paradigm shift in wound healing and will also provide crucial insights into the mechanobiology of macrophages that are valuable for diagnostic and therapeutic interventions.