Development and Initial Application of a Rat Model for Revision Joint Replacement

描述(由申请人提供)：建议进行一系列实验来验证和初步测试用于翻修全关节置换术的新的小动物模型。在全关节置换术无菌松动后，由于松动过程的后遗症，植入部位的成骨环境被削弱。目前，唯一的临床前活体筛查工具依赖于较大的动物模型，如犬，由于成本较高，无法研究多变量和时间点或分子终点。该项目的第一个具体目标是开发一种新型的大鼠溶骨抑制成骨潜能的模型，这将为研究人员提供一种新的高影响力的工具，以开发解决这一重要临床问题的策略。第二个具体目标是在新开发的模型中测试一种已知的方法，该方法可以在挑战性较小的模型(种植体的转化生长因子-β治疗)中增强骨再生和种植体固定。在新的小动物模型得到验证后，后续的研究可能处于经验水平，例如，确定各种骨移植替代品、植入物表面处理、外源性生长因子或基因治疗方法在这种环境下是否可以成功。此外，后续研究还可以探索颗粒诱导的成骨减少的分子机制、无翻修的骨溶解治疗(例如，双膦酸盐疗法)和成功的翻修种植体固定增强策略。拟议的研究是高风险的，因为到目前为止还没有人使用大鼠模型来证明颗粒诱导的骨溶解后种植部位的成骨潜力实际上是减弱的。因此，在具有挑战性的翻修环境中，没有在大鼠身上测试各种试剂促进骨再生和种植体固定的能力的研究。尽管存在风险，但我们认为，颗粒诱导的骨溶解很可能会降低种植部位的成骨潜力，环境可以在大鼠模型中得到拯救。在美国每年进行的20万例髋关节置换手术中，约有3万例是翻修手术，30万例膝关节置换手术中有2.5万例是翻修手术。本申请致力于解决翻修关节置换术中的一个主要问题--促进骨再生，从而实现种植体固定，恢复丢失的骨量。

DESCRIPTION (provided by applicant): A series of experiments is proposed to validate and initially test a new small animal model for revision total joint replacement. Following aseptic loosening of total joint replacements, the osteogenic environment of the implantation site is diminished because of the sequelae of the loosening process. Currently, the only pre-clinical in vivo screening tools rely on larger animal models such as the canine in which it is not possible to study multiple variables and time points or molecular endpoints because of the high costs involved. The first specific aim of the project is to develop a novel rat model for osteolysis-inhibited osteogenic potential that will provide researchers with a new high impact tool for developing strategies to attack this important clinical problem. The second specific aim is to test an approach known to enhance bone regeneration and implant fixation in less challenging models (transforming growth factor-beta treatment of the implant) in the newly developed model. Following validation of the new small animal model, subsequent research could be at the empirical level, e.g., determining if various bone graft substitutes, implant surface treatments, exogenous growth factors, or gene therapy approaches can be successful in this environment. In addition, follow-on studies could also explore molecular mechanisms of particle-induced diminution of osteogenesis, treatment of osteolysis without revision (e.g., bisphosphonate therapy) and successful revision implant fixation enhancement strategies. The proposed studies are high risk because no one to date has used a rat model to show that the osteogenic potential of the implantation site following particle-induced osteolysis is actually diminished. Consequently, there are no studies in the rat to test the ability of various agents to enhance bone regeneration and implant fixation in the challenging revision environment. Despite the risk, we believe that there is a strong likelihood that particle-induced osteolysis will reduce the osteogenic potential of the implantation site and that the environment can be rescued in the rat model. Of the 200,000 total hip replacements performed annually in the U.S., approximately 30,000 are revisions and of the 300,000 total knee replacements 25,000 are revisions. The present application focuses on resolving a major problem in revision joint replacement - enhancement of bone regeneration so that implant fixation can be achieved and lost bone stock can be restored.