Immunomodulation of juvenile femoral head osteonecrosis

青少年股骨头坏死的免疫调节

基本信息

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
项目类别：
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

项目摘要

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% 的患者会出现使人衰弱的骨关节炎，其中一些患者在青少年时期就会出现血流中断。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我们发现股骨头坏死的微环境会引发慢性疾病。炎症反应，损害骨再生并产生巨噬细胞畸形。是中央先天免疫细胞，根据局部环境刺激协调修复过程。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，目前的治疗方法并不能解决负面的病理作用。在这里，我们提出了修复骨的新概念。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）会增加促我们将通过三个高度相关但加速骨骼再生来实现我们的目标。我们将 1) 确定洗掉 DAMP 和坏死细胞的治疗效果。碎片对巨噬细胞反应的影响；2)确定巨噬细胞反应对局部控释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，促进骨再生；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缺血性 ONFH 和体外实验的每个目标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。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这项工作的结果将为临床试验奠定基础，并将大大推进。我们使用免疫调节策略治疗 ONFH 的能力。