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

描述（由申请人提供）：骨折是一种常见的肌肉骨骼损伤。虽然骨组织固有的修复能力导致非关键损伤的恢复，但较大的节段性骨缺损更具挑战性。如果不及时治疗，这些节段性缺陷会导致骨不连。已知许多刺激可以促进骨再生，包括骨形态发生蛋白-2 （BMP-2）和低强度脉冲超声（LIPUS）。目前尚不清楚大节段性缺损的再生过程将如何对这两种不同方式的组合作出反应。我们的假设是，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加增作用，以促进骨再生。该假设是基于我们小组最近的观察，LIPUS在大鼠异位骨形成模型中增加了重组人（rh）BMP-2引发的新骨形成的数量。我们的目的是确定在具有良好特征的大鼠模型中，将LIPUS加入rhBMP-2治疗节段性骨缺损是否会加速愈合，以便开发更好的治疗方案来改善骨愈合。在Aim 1中，我们将研究不同剂量的rhBMP-2 （1 - 205g）加载到可吸收胶原海绵上对节段性骨缺损的反应，以确定rhBMP-2的最佳剂量。愈合情况将由体内x光片监测。主要终点将是骨体积（显微计算机断层扫描和组织学）和机械强度（扭转测试）。在Aim 2中，我们将根据Aim 1中获得的信息，测试LIPUS在最佳和次最佳剂量的rhBMP-2存在下增强修复过程的能力。主要终点与目的1相同。在Aim 3中，我们将以最佳的联合治疗形式确定rhbmp -2诱导的骨形成对LIPUS治疗反应最灵敏的阶段。主要终点与目的1相同。由于rhBMP-2和LIPUS已经被批准用于临床，因此本研究的信息可以很容易地转化为临床情况。拟议的研究也可以使接受外科手术的患者受益，如关节置换术、牵张成骨术和牙科种植体置入术，在这些手术中，骨再生是成功结果的组成部分。本文提出的方法也可以作为治疗其他肌肉骨骼组织（如肌肉、神经、韧带和肌腱）的模型。公共卫生相关性：该项目与公共卫生的相关性在于，帮助骨骼修复和再生的固有能力将减少与愈合不正常和可能的不愈合相关的并发症的风险。骨折是一种常见的肌肉骨骼损伤；仅在美国，每年就有大约700万例骨折。这项研究将集中于通过应用两种已经批准的FDA治疗方法的组合来增强骨再生，并可以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.