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

描述（由申请人提供）：拟进行一系列实验，以确认和初步测试用于翻修全关节置换术的新小动物模型。在全关节置换术后出现无菌性松动，由于松动过程的后遗症，植入部位的成骨环境减少。目前，唯一的临床前体内筛选工具依赖于较大的动物模型，如犬，由于涉及的成本高，不可能研究多个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的大鼠模型，用于骨溶解抑制成骨潜力，这将为研究人员提供一种新的高影响力工具，用于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，该方法可在挑战性较小的模型中增强骨再生和植入物固定（植入物的转化生长因子-β治疗）。在新的小动物模型得到验证之后，后续研究可能处于经验水平，例如，确定各种骨移植替代物、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中是否可以成功。此外，后续研究还可以探索颗粒诱导的骨生成减少的分子机制，治疗骨质溶解而不进行翻修（例如，双膦酸盐治疗）和成功的翻修植入物固定增强策略。拟定的研究具有高风险，因为迄今为止还没有人使用大鼠模型来证明颗粒诱导骨质溶解后植入部位的成骨潜力实际上降低了。因此，没有在大鼠中进行研究来测试各种试剂在具有挑战性的翻修环境中增强骨再生和植入物固定的能力。尽管存在风险，但我们认为颗粒诱导的骨质溶解极有可能降低植入部位的成骨潜力，并且可以在大鼠模型中挽救环境。在美国每年进行的20万例全髋关节置换手术中，大约30，000例是翻修手术，300，000例全膝关节置换手术中有25，000例是翻修手术。本申请集中于解决翻修关节置换中的主要问题-骨再生的增强，使得可以实现植入物固定并且可以恢复丢失的骨量。

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.