Magnetic nanocomplexes-induced immunomodulation for fracture healing

磁性纳米复合物诱导的免疫调节促进骨折愈合

• 批准号: 10372632
• 负责人: Ramkumar Tiruvannamalai Annamalai
• 金额: $ 19.22万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-10 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10372632
• 关键词: Actins; Acute; Adopted; Area; Biochemical; Biocompatible Materials; Biomechanics; Bone Regeneration; Bone Resorption; Cells; Chromatin; Chronic; Cues; Cytoskeleton; Defect; Endothelium; Engineering; Exhibits; Exogenous Factors; Exposure to; F-Actin; Fostering; Fracture; Functional disorder; G Actin; Gene Expression; Genes; HDAC3 gene; Immune response; Infiltration; Inflammation; Inflammatory Response; Injury; Kinetics; Lead; Link; Macrophage Activation; Magnetism; Metabolic; Methodology; Methods; Modeling; Morphology; Multipotent Stem Cells; Mus; Natural regeneration; Nuclear; Nuclear Translocation; Organ failure; Osteogenesis; Pathogenesis; Pathology; Peptides; Pharmaceutical Preparations; Phenotype; Process; Quality of life; Regenerative Medicine; Research; Role; Signal Transduction; Site; Specificity; Surface; TLR4 gene; TNF gene; Testing; Therapeutic; Therapeutic Intervention; Tight Junctions; Time; Traction; Transcriptional Regulation; Trauma; Traumatic injury; Up-Regulation; Work; age related; base; bone; bone fracture repair; bone healing; cancer imaging; clinically translatable; cyclooxygenase 2; density; design; diagnostic value; disability; immunomodulatory therapies; immunoregulation; inflammatory modulation; insight; iron oxide; macrophage; magnetic field; nanocomplexes; nanomaterials; polymerization; prevent; regenerative therapy; success; systemic toxicity; tissue regeneration; transcription factor; uptake; wound 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. 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.

不愈合的骨折是导致严重残疾的原因，并对生活质量产生破坏性影响。 目前，还没有可靠的一线治疗方法来刺激健康的骨形成和预防骨不连。 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不愈合或愈合不良的发病机制中的关键组成部分 骨折应用生化因子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，由于其特异性、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复合物（MNC）的治疗方法， 骨折愈合巨噬细胞的细胞骨架动力学与它们的炎症反应密切相关。 反应我们的研究证实，巨噬细胞的细胞骨架动力学是由它们的 表型研究还表明，仅仅利用物理线索操纵细胞骨架动力学， 任何外源性因素，显示转化巨噬细胞表型。这种表型调节是由于 转录因子MRTF-A的核转位，以及 组蛋白去乙酰化酶-3（HDAC 3）的胞质到核的再分布。我们假设细胞内 磁力可以通过介导巨噬细胞表型的转录控制并促进骨折愈合 MRTF-A发布和HDAC 3重新分发。 在SA 1中，我们将设计磁性纳米复合物，用于靶向内化和机械化 阐明细胞内力诱导的细胞骨架调节和巨噬细胞中的相应变化 表型在SA 2中，我们将验证MNC的巨噬细胞靶向作用，并阐明其治疗潜力。 小鼠临界尺寸股骨缺损。拟议的研究将是伤口愈合的范式转变， 还提供了对巨噬细胞的机械生物学的重要见解，这对诊断和 治疗干预。