Friday, April 19, 2024
4/19/2024
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. Our studies confirmed that the cytoskeletal dynamics of macrophages are determined by their phenotype. Studies also show that mere manipulation of cytoskeletal dynamics using physical cues, without any exogenous factors, is shown to transform macrophage phenotype. This phenotype modulation is due to the nuclear translocation of the transcription factor MRTF-A, and changes in chromatin compaction caused by cytoplasmic-to-nuclear redistribution of histone deacetylase-3 (HDAC3). We hypothesize that intracellular magnetic force can elicit transcriptional control of macrophage phenotype and promote fracture healing via MRTF-A release and HDAC3 redistribution. In SA1, we will engineer magnetic nanocomplexes for targeted internalization and mechanistically elucidate intracellular force-induced modulation of the cytoskeleton and corresponding change in macrophage phenotype. In SA2, we will validate macrophage targeting of MNC and elucidate their therapeutic potential in a murine critical-sized femoral defect. 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.
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