Combined Use of BMP-2 and Low Intensity Pulsed Ultrasound in Bone Regeneration

描述(申请人提供)：骨折是一种常见的肌肉骨骼损伤形式。虽然骨组织固有的修复能力会导致非危重损伤的恢复，但较大的节段性骨缺损更具挑战性。如果不进行治疗，这些节段性缺陷可能会导致骨不连。已知有许多刺激物可以促进骨再生，包括骨形态发生蛋白-2(BMP-2)和低强度脉冲超声(LIPUS)。目前尚不清楚大型节段性缺损区的再生过程将如何对这两种不同形式的组合做出反应。需要解决的假设是，用低强度脉冲超声和骨形态发生蛋白-2同时治疗节段性骨缺损将协同或相加地促进骨再生。这一假设是基于我们团队最近的观察，即LIPUS在大鼠异位骨形成模型中增强了重组人(Rh)BMP-2启动的新骨形成量。我们的目标是确定在一个特征良好的大鼠模型中，在rhBMP-2治疗节段性骨缺损的基础上加入LIPUS是否能加速愈合，从而开发出更好的治疗方案来改善骨愈合。在目标1中，我们将研究不同剂量的rhBMP-2(1-205G)负载到可吸收胶原海绵上对节段性骨缺损的反应，以确定最佳的rhBMP-2剂量。愈合情况将通过活体X光照片进行监测。主要终点是骨体积(微型计算机断层扫描和组织学)和机械强度(扭转测试)。在目标2中，我们将根据在目标1中获得的信息，测试在最佳和次佳剂量的情况下，LIPUS促进修复过程的能力。主要终点将与目标1相同。在目标3中，我们将确定在最佳综合治疗形式下，重组人骨形态发生蛋白-2诱导骨形成的最敏感时相(S)。主要终点将与目标1相同。这项研究的信息可以很容易地转化为临床情况，因为重组人骨形态发生蛋白-2和LIPUS都已被批准用于临床。这项拟议的研究还可能使接受关节置换、牵引成骨和牙种植体植入等手术的患者受益，在这些手术中，骨再生是成功结果不可或缺的一部分。这里提出的方法也可以作为治疗其他肌肉骨骼组织(例如肌肉、神经、韧带和肌腱)的模式。公共卫生相关性：该项目与公共卫生的相关性是，帮助骨骼固有的修复和再生能力将减少与非正常愈合和可能的骨不连相关的并发症的风险。骨折是肌肉骨骼损伤的一种常见形式；仅在美国，每年就有大约700万例骨折。这项研究将专注于通过联合应用FDA已经批准的两种治疗方法来增强骨再生，并可能迅速转化为临床应用。

DESCRIPTION (provided by applicant): Fractures are a common form of musculoskeletal injury. While the inherent repair capability of bone tissue results in recovery of non-critical injuries, larger segmental bone defects are more challenging. Left untreated, these segmental defects can lead to non-unions. A number of stimuli are known to enhance bone regeneration and include bone morphogenetic protein - 2 (BMP-2) and low intensity pulsed ultrasound (LIPUS). It is presently unknown how the regenerative process in a large segmental defect will respond to a combination of these two distinct modalities. The hypothesis to be addressed is that simultaneous treatment of segmental bone defects with low intensity pulsed ultrasound and bone morphogenetic protein-2 will act synergistically or additively to enhance bone regeneration. The hypothesis is based on recent observations by our group that LIPUS enhanced the amount of new bone formation initiated by recombinant human (rh)BMP-2 in an ectopic bone formation model in the rat. Our objective is to determine if addition of LIPUS to rhBMP-2 treatment of a segmental bone defect in a well-characterized rat model accelerates healing so that better treatment protocols can be developed for improved bone healing. In Aim 1, we will study the response of segmental bone defects to varying doses of rhBMP-2 (1 - 205g) loaded on to absorbable collagen sponges in order to determine the optimum dose of rhBMP-2. Healing will be monitored by in vivo radiographs. The primary endpoints will be bone volume (micro computed tomography and histology) and mechanical strength (torsional testing). In Aim 2, we will test the ability of LIPUS to enhance the repair process in the presence of optimum and sub-optimum doses of rhBMP-2 based on information obtained in Aim 1. The primary endpoints will be the same as for Aim 1. In Aim 3, we will identify the most responsive phase(s) of rhBMP-2-induced bone formation to LIPUS treatment in the best format of combined treatment. The primary endpoints will be the same as for Aim 1. Information from this study can be readily translated to clinical situation as both rhBMP-2 and LIPUS are already approved for clinical use. The proposed research also could benefit patients undergoing surgical procedures such as joint replacement, distraction osteogenesis and dental implant placement in which bone regeneration is integral to successful outcomes. The approach proposed here might also serve as a model for the treatment of other musculoskeletal tissues (e.g., muscles, nerves, ligaments and tendons). PUBLIC HEALTH RELEVANCE: The relevance of the project to Public Health is that aiding the inherent ability of bone to repair and regenerate will reduce the risk of complications associated with subnormal healing and possible non-union. Fractures are a common form of musculoskeletal injury; there are roughly 7 million fractures per year in the United States alone. This research will focus on enhancing bone regeneration by applying a combination of two already approved FDA treatments and could be rapidly translated into clinical use.