Magnetic nanocomplexes-induced immunomodulation for fracture healing

无法愈合的骨折是导致严重残疾的原因之一，并对生活质量产生破坏性影响。 目前，还没有可靠的一线疗法来刺激健康的骨形成和防止骨不连。 越来越多的证据支持巨噬细胞在骨折愈合中不可或缺的作用。 此外，巨噬细胞功能障碍是无法愈合或愈合不良的发病机制中的重要组成部分。 骨折。应用生化因素的免疫调节策略正在获得牵引力以调节 巨噬细胞表型。然而，由于并发症的特异性，有效性， 和全身毒性。 在这里，我们建议开发一种基于磁性氧化铁纳米络合物(MNC)的治疗方法，以促进 骨折愈合。巨噬细胞的细胞骨架动力学与其炎症密切相关。 回应。我们的研究证实，巨噬细胞的细胞骨架动力学是由它们的 表型。研究还表明，仅仅使用物理线索来操纵细胞骨架动力学，而不是 任何外源性因素都会改变巨噬细胞的表型。这种表型调节是由于 转录因子MRTF-A的核移位及其引起的染色质压缩的变化 组蛋白脱乙酰酶-3(HDAC3)胞浆到胞核的重分布。我们假设细胞内 磁力可诱导巨噬细胞表型的转录调控并通过以下途径促进骨折愈合 MRTF-A释放和HDAC3重分布。 在SA1中，我们将设计磁性纳米复合体，以实现定向内化和机械化 阐明细胞内力诱导的细胞骨架的调节和巨噬细胞的相应变化 表型。在SA2中，我们将验证MNC的巨噬细胞靶向，并阐明其在 小鼠临界大小的股骨缺损。这项拟议的研究将是伤口愈合的范式转变，并将 还提供了对巨噬细胞的机械生物学的重要见解，这些机械生物学对诊断和 治疗性干预。

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.