Immunomodulation of juvenile femoral head osteonecrosis

项目摘要 莱格-卡尔维-珀斯病是一种儿童股骨头缺血性骨坏死(ONFH)，影响1/4 1200名2至14岁的儿童。这是影响儿童髋关节AS最严重的疾病之一 50%的患者会患上衰弱的骨关节炎，有些人在十几岁时就会患上。血液流动受阻 导致广泛的缺血细胞死亡，大量的坏死细胞碎片和损伤相关的分子 股骨头上的图案(湿气)。我们发现，坏死的微环境会激发慢性 炎症反应，损害骨再生并导致股骨头畸形。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。在……里面 幼年ONFH，巨噬细胞由于受潮和坏死性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。目前的治疗方法并没有解决负面的病理作用。 巨噬细胞在坏死骨修复中所起的作用。在这里，我们提出了一个新的概念来修复 坏死骨采用微创组织工程方法，从而将坏死性炎症转化为 从微环境到再生微环境。我们的长期目标是建立这些治疗方法 方法克服严重炎症障碍，迅速修复坏死骨。 目的：启动幼年型ONFH患者的骨再生。我们的中心假设是 骨骼微环境触发慢性炎性巨噬细胞反应，而组织工程 局部骨洗(即清除湿气和坏死性碎屑)的坏死性环境及其应用 巨噬细胞定向调节剂(如骨形态发生蛋白-2和白细胞介素4)将增加促肾上腺皮质激素释放。 治愈巨噬细胞，加速骨骼再生。我们将通过三个高度相关但 独立的具体目标。我们将1)确定冲洗湿气和坏死细胞的治疗效果 碎片对巨噬细胞反应的影响；2)确定局部控释对巨噬细胞反应的影响 使用水凝胶输送系统的骨形态发生蛋白-2(BMP2)治疗骨再生；以及3) 用仔猪模型确定白细胞介素4诱导的巨噬细胞对骨再生的调节作用 对缺血型股骨头坏死和体外实验的每一个目的。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治疗的反应。成功 该项目的完成将立即产生临床影响，为最低限度的 侵入性的，但可能非常有效的组织工程策略，以克服目前成功的障碍 ONFH的治疗。这项工作的结果将为临床试验奠定基础，并将极大地推进 我们使用免疫调节策略治疗ONFH的能力。

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.