Immunomodulation of juvenile femoral head osteonecrosis

青少年股骨头坏死的免疫调节

• 批准号: 10595649
• 负责人: HARRY K.W. KIM
• 金额: $ 59.56万
• 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/10595649
• 关键词: Acceleration; Adolescent; Affect; Age; BMP2 gene; Biocompatible Materials; Biological Products; 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; Hip region structure; Hydrogels; IL4 gene; Immune; Impairment; In Vitro; Inflammatory; Inflammatory Response; Injectable; Injury; Interleukin-4; Ischemia; Legg-Perthes Disease; Liquid substance; Longevity; Macrophage; 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; bone; bone repair; clinical application; conditioning; controlled release; diabetic rat; effective therapy; experimental study; femur head; healing; immunomodulatory strategy; immunomodulatory therapies; immunoregulation; in vivo; insight; 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.

项目摘要 legg-calvé-perthes疾病是一种影响股骨头（ONFH）的童年缺血性骨质症，影响1 1200名2至14岁之间的儿童。这是影响小儿髋关节的最严重疾病之一 50％的患者会出现使人衰弱的骨关节炎，其中一些在青少年时期。血流中断 产生广泛的缺血细胞死亡，坏死细胞碎片的抽象和损伤相关的分子 股骨头中的图案（湿）。我们发现坏死微环境促使慢性 炎症反应，会损害骨骼再生并产生股骨头畸形。巨噬细胞 是基于局部环境刺激协调修复过程的中央先天免疫细胞。 青少年，巨噬细胞暴露了由于潮湿和坏死碎片而导致的慢性炎症反应 导致进一步的组织损伤和纤维化。当前治疗没有解决负面病理作用 由巨噬细胞在坏死骨修复中扮演。在这里，我们提出了一个重新调解的新概念 坏死骨使用微创组织工程方法，从而转化坏死性炎症 微环境至再生微环境。我们的长期目标是建立这些治疗 克服实质性炎症障碍并快速重新修复坏死骨的方法 为了在少年ONFH患者中开始骨骼再生。我们的中心假设是坏死 骨微环境触发慢性炎症性巨噬细胞反应，并触发该组织工程 局部骨洗涤的坏死环境（即潮湿和坏死碎片的清除率）和应用 巨噬细胞方向调节剂（例如骨形态发生蛋白-2和白介素-4）将增加促序 治愈巨噬细胞和加速骨再生。我们将通过三个高度相关，但 独立的特定目的。我们将1）确定洗涤潮湿和坏死细胞的治疗作用 巨噬细胞反应的碎片； 2）确定巨噬细胞对局部受控释放的影响 骨形态发生蛋白-2（BMP2）疗法使用水凝胶递送系统在骨骼再生上； 3） 使用小猪模型，确定白介素4诱导的巨噬细胞调制在骨再生上的作用 在每个目标中的缺血性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 该项目的完成将立即产生临床影响，通过提供最小的概念验证证明 具有侵入性但潜在有效的组织工程策略，以克服当前成功的障碍 ONFH的处理。这项工作的结果将为临床试验奠定基础，并将大大进步 我们使用免疫调节策略治疗ONFH的能力。