Polyurethane Bone Cements for Total Hip Implants

描述（由申请人提供）：自20世纪60年代以来，聚甲基丙烯酸甲酯（PMMA）一直被用作全髋关节置换术（THA）的骨水泥，今天在全球每年150万例THA手术中仍有很大比例使用。尽管PMMA具有悠久的临床历史，但骨科界承认其缺点，包括放热性、未反应单体的毒性、纤维组织的包被性以及水泥-植入物界面强度[1][2]。本建议将侧重于后一点，水泥-种植体（或水泥-金属）界面强度。此接口的本地去绑定将启动一系列事件；微动、颗粒碎片产生、巨噬细胞活性、骨吸收，最后是种植体的无菌松动。人们已经尝试提高PMMA的界面强度，但收效甚微，这使得研究人员得出结论，这不是界面是否失效的问题，而是何时失效的问题。使用聚氨酯（PUR）基水泥为解决这一临床问题提供了一种完全不同的方法。PURs的生物稳定性和生物相容性可追溯到几十年前。最近，原位固化PUR胶粘剂配方已被引入欧洲市场，并被用作骨空隙填充物和稳定骨折的临床应用。这些PUR基水泥已被证明可以为骨和金属提供牢固的粘结。随着这些材料的临床经验的增长，PUR骨水泥用于全关节置换术装置的固定有了很大的兴趣。本研究提出开发一种PUR骨水泥，专门用于THA的生物力学需求。该项目的第一阶段将包括使用聚合物化学的基本结构-性能原理来制定新的pur，以提供一个反应性的两部分系统，混合后在24小时内达到完全的承载性能，与骨和金属植入物的强附着力，以及长期的生物稳定性。然后将对这些配方进行机械测试，以充分了解其性能。第一阶段的重点将是它们与THA设备和骨骼的粘附性。这些材料将受到静态和动态测试协议的影响，在实验室模型中再现体内负荷。同时，新材料将进行体外生物稳定性测试，以确定原位氧化降解的风险，这将限制其临床可行性。此外，将评估开发的pur的可提取单体水平，并与PMMA进行比较。这些试验的总体目标是评估每种材料在THA中作为PMMA替代品的潜力。项目的后期阶段将包括进一步改进主要候选材料，以提高承载能力、粘附性和生物稳定性，并完成生物相容性测试、更复杂载荷下的机械评估，最终用于人类临床。

DESCRIPTION (provided by applicant): Polymethylmethacrylate (PMMA) has been used as a bone cement in total hip arthroplasty (THA) since the 1960's and today is still used in a significant percentage of the 1.5 million THA procedures performed worldwide each year. Despite its long clinical history the orthopaedic community acknowledges shortcomings with PMMA including among other things its exotherm, the toxicity of any unreacted monomer, its encapsulation by fibrous tissue and its cement-implant interface strength [1][2]. This proposal will focus on the later point, the cement-implant (or cement-metal) interface strength. Local debonding at this interface initiates a cascade of events; micromotion, particulate debris generation, macrophage activity, bone resorption and finally aseptic loosening of the implant. Attempts have been made to improve the interface strength of PMMA, but gains have been marginal, leading researchers to conclude that it's not an issue of if the interface should fail but when [3]. The use of polyurethane (PUR) based cement provides a completely different approach to addressing this clinical problem. PURs have a proven record of biostability and biocompatibility going back several decades [4]. More recently, in situ curing PUR adhesive formulations have been introduced to European markets and are seeing clinical use as bone void fillers and in stabilizing fractures. These PUR based cements have been shown to provide strong bond to bone and metal. As clinical experience with these materials grows, there is significant interest in development of PUR bone cement for affixation of total joint replacement devices. This research proposes development of a PUR bone cement specifically engineered for the biomechanical demands of THA. Phase 1 of the project will include formulation of new PURs using fundamental structure- property principles of polymer chemistry to provide a reactive two part system that upon mixing achieves full load bearing properties within 24 hour, strong adhesion to bone and metal implants, and long-term biostability. These formulations will then undergo mechanical testing to gain a full understanding of their capabilities. Of specific interest in Phase 1 will be their adhesion to THA devices and bone. The materials will be subjected to both static and dynamic test protocols, reproducing in vivo loads in a laboratory model. In parallel, the new materials will undergo in vitro biostability testing to characterize the risk of in situ oxidative degradation that would limit its clinical viability. Furthermore, level of extractable monomers will be evaluated for developed PURs and compared to PMMA. The overarching objective of these tests is to assess each material's potential as a replacement for PMMA in THA. Later phases of the project would include further refinement of the leading candidate material to improve load bearing capability, adhesion, and biostability, and to complete biocompatibility testing, mechanical assessment under more complex loading, and ultimately human clinical use. PUBLIC HEALTH RELEVANCE: The overall goal of this project is to develop a polyurethane adhesive bone cement for use in total hip replacement surgery. This alternative to polymethylmethacrylate will have superior bond strength between the cement and the metal device, significantly reducing the risk of failure due to loosening at this interface. The technology developed in this study has the potential to improve the lives of over 1.5 million new patients each year who undergo hip replacement surgeries.