Supraphysiologic Fluid Shear Stress as an Alternative Cause of Short-term Aseptic Loosening in Total Knee Replacements

 描述（由申请人提供）：骨水泥型全膝关节置换术（TKR）是一种成熟可靠的手术，旨在恢复关节活动度并缓解与类风湿或骨关节炎相关的疼痛。虽然每年有超过600，000例膝关节植入并取得巨大成功，但相当一部分（约15%）过早失效。大多数长期失效是由于无菌性松动的过程，其中骨小梁和骨水泥之间的机械联锁由于骨的侵蚀（骨质溶解）而减弱。这使得植入物移位并变得疼痛，需要进行翻修手术。无菌性松动最常归因于骨溶解，骨溶解是由身体对关节面聚乙烯（PE）磨损在植入物-骨界面处积聚的反应引起的。 重要的是，短期故障可能会发生，而且确实会发生，这些故障可能与PE碎片无关，因为产生的碎片量与使用时间成正比。最近对尸检取出的临床成功的人类TKR的研究指出了无菌性松动的另一个促成因素：在短期内，最初与骨水泥联锁的骨小梁吸收> 50%，但这对PE关节面没有太大磨损。这表明早期固定丢失是由另一种机制引起的。 在尸检研究中，观察到当对TKR施加关节载荷时，滑液和/或骨髓通过互锁小梁和骨水泥之间的小间隙泵出。由流体泵送产生的流体剪切应力（FSS）估计是超生理的，并且可能对排列在小梁骨表面的成骨细胞和破骨细胞产生影响。本研究的总体目标是证明这些超生理流体剪切应力足以导致与骨水泥联锁的骨小梁吸收，并且这可以在没有PE碎片的情况下发生。本项目的具体目的是证明：1）在不存在PE碎片的情况下发生界面处的小梁吸收，2）超生理性FSS可通过增加破骨细胞活性（矿物质吸收）同时降低成骨细胞活性（矿物质沉积）来影响吸收， 和3）PE碎片积聚和超生理FSS协同作用，产生比单独的任一过程更多的再吸收。 我们将首先确定在短期（<5年）和长期（> 10年）使用的临床成功的TKA死后取出的人类胫骨部件中骨水泥-骨处的PE碎片的位置和数量。我们预计短期器械在界面处几乎没有磨损，但有广泛的骨吸收。相比之下，我们预计长期器械会出现大量PE磨损和吸收。接下来，我们将阐明FSS的影响范围从亚超生理水平的破骨细胞和成骨细胞的体外细胞系，有或没有PE碎片。这些实验将使我们能够首先量化PE碎片与骨水泥-骨小梁界面的直接物理关系，其次区分高FSS与PE碎片的影响。总的来说，这项工作的目标是 以延长TKRs的长期成功。

 DESCRIPTION (provided by applicant): Cemented Total Knee Replacement (TKR) is an established and reliable procedure that seeks to restore joint mobility and relieve pain associated with rheumatoid or osteo-arthritis. While over 600,000 knees are implanted with great success annually, a substantial portion (~15%) fail prematurely. Most long-term failures are due to a process known as aseptic loosening, where the mechanical interlock between trabecular bone and cement weakens due to the erosion (osteolysis) of bone. This allows the implant to migrate and become painful, necessitating a revision surgery. Aseptic loosening is most often attributed to osteolysis caused by the body's response to articulating surface polyethylene (PE) wear accumulation at the implant-bone interface. Importantly, short-term failures can and do occur, and these may not be related to PE debris since the amount of debris created is proportional to time in service. Recent studies of postmortem retrieved, clinically- successful, human TKRs point to an additional, contributing factor in aseptic loosening: in the short-term, there is >50% resorption of the trabeculae that initially interlock with the bone cement, but this occurs without much wear to the PE articulating surface. This suggests early loss of fixation is caused by an alternate mechanism. In the postmortem studies, it was observed that when joint loads are applied to the TKRs, synovial fluid and/or marrow is pumped through small gaps between the interlocked trabeculae and cement. The fluid shear stresses (FSS) generated from the fluid pumping is estimated to be supraphysiologic, and will likely have an effect on the osteoblasts and osteoclasts that line the surface of trabecular bone. The overall goal of this study is to show that these supraphysiologic fluid shear stresses are sufficient to cause resorption of the trabeculae that interlock with cement, and that this can occur without PE debris. The Specific Aims of this project are to show: 1) trabecular resorption at the interface occurs in the absence of PE debris, 2) supraphysiologic FSS can affect resorption by increasing osteoclast activity (mineral resorption) while decreasing osteoblast activity (mineral deposition), and 3) PE debris accumulation and supraphysiologic FSS act in concert to produce more resorption than either process alone. We will first identify the location and amount of PE debris at the cement-bone in postmortem retrieved, clinically successful, human tibial components of TKA with short term (<5 years) and long term (>10 years) use. We expect short-term devices to contain little to no wear at the interface, but have extensive bone resorption. In contrast, we expect long-term devices to have both substantial PE wear and resorption. Next, we will elucidate the effects of FSS ranging from sub to supraphysiologic levels on in vitro cell lines of osteoclasts and osteoblasts, with or without PE debris. These experiments will allow us to first, quantify PE debris in direct, physical relation to the cement-trabeculae interface of retrievals, and second, differentiate the effects of high FSS from PE debris. Overall, the goal of this work is to extend the long-term success of TKRs.