Immunomodulation of juvenile femoral head osteonecrosis

青少年股骨头坏死的免疫调节

• 批准号: 10297658
• 负责人: HARRY K.W. KIM
• 金额: $ 63.48万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10297658
• 关键词: Adolescent; Affect; Age; BMP2 gene; Biocompatible Materials; Biological; Biology; Blood flow; Bone Regeneration; Bone necrosis; Cell Death; Cell Differentiation process; Cells; Child; Childhood; Chronic; Clinical; Clinical Trials; Cues; Deformity; Degenerative polyarthritis; Disease; Environment; Exhibits; Fibrosis; Goals; Head; Hip region structure; Hydrogels; IL4 gene; Immune; Impairment; In Vitro; Inflammatory; Inflammatory Response; Injectable; Injury; Interleukin-4; Legg-Perthes Disease; Liquid substance; Longevity; Methods; Microspheres; Molecular; Necrosis; Osteogenesis; Osteotomy; Outcome; Pathologic; Patients; Pattern; Phenotype; Play; Process; RNA; Role; Stimulus; System; Teenagers; Testing; Therapeutic Effect; Tissue Engineering; Tissues; Total Hip Replacement; Work; analytical method; base; bone; clinical application; controlled release; diabetic rat; effective therapy; experimental study; healing; immunomodulatory strategy; immunomodulatory therapies; immunoregulation; in vivo; insight; macrophage; mesenchymal stromal cell; minimally invasive; novel; optimal treatments; porcine model; prevent; recruit; regenerative; repaired; response

Project Summary Legg-Calvé-Perthes disease is a childhood ischemic osteonecrosis of the femoral head (ONFH) that affects 1 in 1200 children between the ages of 2 to 14. It is one of the most serious conditions affecting the pediatric hip as 50% of patients will develop debilitating osteoarthritis, some in their teenage years. A disruption of blood flow produces extensive ischemic cell death, abundance of necrotic cell debris, and damage-associated molecular patterns (DAMPs) in the femoral head. We discovered that the necrotic microenvironment incites a chronic inflammatory response, which impairs bone regeneration and produces femoral head deformity. Macrophages are the central innate immune cells that coordinate the repair process based on local environmental stimuli. In juvenile ONFH, macrophages exhibit chronic inflammatory response due to DAMPs and necrotic debris which leads to further tissue damage and fibrosis. Current treatments do not address the negative pathologic role played by macrophages in the necrotic bone repair. Here, we propose a new concept of reconditioning the necrotic bone using minimally invasive tissue engineering methods, thereby, converting a necrotic inflammatory microenvironment to a regenerative microenvironment. Our long-term goal is to establish these treatment methods to overcome the substantial inflammatory roadblock and to rapidly recondition the necrotic bone in order to jump start bone regeneration in patients with juvenile ONFH. Our central hypothesis is that the necrotic bone microenvironment triggers chronic inflammatory macrophage response, and that tissue engineering of the necrotic environment by local bone wash (i.e. clearance of DAMPs and necrotic debris) and application of macrophage-directional modulators (such as bone morphogenetic protein-2 and interleukin-4) will increase pro- healing macrophages and accelerate bone regeneration. We will attain our goal through three highly related but independent specific aims. We will 1) determine the therapeutic effects of washing out DAMPs and necrotic cell debris on macrophage response; 2) determine the effects of macrophage response to local controlled-release bone morphogenetic protein-2 (BMP2) therapy using a hydrogel delivery system on bone regeneration; and 3) determine the role of interleukin 4-induced macrophage modulation on bone regeneration, using the piglet model of ischemic ONFH and in vitro experiments in each Aim. We will determine the macrophage and bone repair responses to the immunomodulatory therapies using tissue, cell, and RNA analytic methods. Successful completion of this project will have immediate clinical impact by providing a proof-of-concept for the minimally invasive, yet potentially highly effective, tissue engineering strategies to overcome current barriers to successful treatment of ONFH. The outcome of this work will lay the groundwork for clinical trials and will greatly advance our ability to treat ONFH using immunomodulatory strategies.

项目概要 Legg-Calvé-Perthes 病是一种儿童期股骨头缺血性骨坏死 (ONFH)，影响 1 岁以下患者 1200 名 2 至 14 岁的儿童。这是影响儿童髋关节的最严重的疾病之一 50% 的患者会患上使人衰弱的骨关节炎，其中一些患者在青少年时期就会患上。血流中断 产生广泛的缺血性细胞死亡、大量坏死细胞碎片和损伤相关分子 股骨头中的模式（DAMP）。我们发现坏死的微环境会引发慢性 炎症反应会损害骨再生并导致股骨头畸形。巨噬细胞 是中央先天免疫细胞，根据局部环境刺激协调修复过程。在 幼年 ONFH 中，巨噬细胞因 DAMP 和坏死碎片而表现出慢性炎症反应， 导致进一步的组织损伤和纤维化。目前的治疗方法并未解决负面病理作用 由巨噬细胞参与坏死骨的修复。在此，我们提出了一个新的概念： 利用微创组织工程方法对坏死骨进行修复，从而将坏死的炎症转化为 微环境转变为再生微环境。我们的长期目标是建立这些治疗方法 克服实质性炎症障碍并快速修复坏死骨的方法 为了快速启动青少年 ONFH 患者的骨再生。我们的中心假设是坏死 骨微环境触发慢性炎症巨噬细胞反应，并且组织工程 通过局部骨冲洗（即清除 DAMP 和坏死碎片）和应用 巨噬细胞定向调节剂（例如骨形态发生蛋白 2 和白细胞介素 4）会增加促 治愈巨噬细胞并加速骨骼再生。我们将通过三个高度相关但又 独立的具体目标。我们将1）确定洗掉DAMPs和坏死细胞的治疗效果 巨噬细胞反应的碎片； 2) 确定巨噬细胞对局部控释反应的影响 使用水凝胶输送系统进行骨形态发生蛋白 2 (BMP2) 治疗以促进骨再生；和 3) 使用仔猪模型确定白细胞介素 4 诱导的巨噬细胞调节对骨再生的作用 每个目标的缺血性 ONFH 和体外实验。我们将确定巨噬细胞和骨修复 使用组织、细胞和 RNA 分析方法对免疫调节疗法的反应。成功的 该项目的完成将通过提供最低限度的概念验证来产生直接的临床影响 侵入性但可能非常有效的组织工程策略，以克服当前成功的障碍 ONFH 的治疗。这项工作的成果将为临床试验奠定基础，并将大大推进 我们有能力使用免疫调节策略治疗 ONFH。