Synthesis, Characterization, and Evaluation of Polymeric Tissue Lubricants

描述(申请人提供)：Ru卡宾催化的开环歧化聚合(ROMP)是一种可靠和有效的方法来合成定义明确的聚合物，具有相对较低的多分散性。这些聚合物主要是由降冰片烯和环戊二烯合成的，由于可以制备不同的功能和结构，因此引起了广泛的兴趣。对于制药应用，化学药物或抗菌剂被捆绑在一起来产生生物活性聚合物。一个未开发的领域是基于这些聚合物的宏观或整体性质的功能医疗设备的设计。初步研究表明，水溶液中的大分子聚合物聚(7-氧代龙脑烯-2-羧酸酯)是有色的，可以润滑体外骨关节软骨表面(J.Am化学。SoC。2013、135、4930-4933)。重要的是，我们有初步数据表明，这些聚合物：1)与生理盐水或透明质酸黏度补充剂(例如Synvisc-One®)相比，可降低体外牛和人类关节软骨塞模型的摩擦系数，其性能与健康滑液相似；2)在体外或体内无毒性；3)抗透明质酸酶降解，可在关节内注射后延长滑膜关节停留时间。建立在这些基础上 结果，我们推测这些聚合物可能通过减少两个软骨表面之间的摩擦和磨损而具有合成生物润滑剂的功效。我们提出了以下三个特定目标来支持这一假说：目标1：使用金属对金属和体外牛软骨关节表面模型来确定聚合物的结构、相对分子质量、刚性和电荷对流变性和润滑性的依赖；目标2：确定生物润滑剂在体外健康和创伤/骨关节炎人类掌指关节(MCPJ；食指)中的性能和润滑机制，以评估离散的滑膜关节的功能；以及目标3：使用创伤诱导的兔骨关节炎模型确定生物润滑剂的性能和软骨保护能力。这些研究的成功完成将导致：1)开发用于软骨表面的高效生物润滑剂的结构-活性关系和设计要求；2)深入了解这些聚合物与关节软骨接触与传统金属表面接触的润滑机理；以及3)健康和骨关节炎软骨关节的体外和体内性能数据。将这项技术转化到临床的下一步将包括良好的制造实践合成，一种大型动物 创伤性骨关节炎的模型研究，FDA要求进行生物相容性测试和生物分布/药代动力学研究。首席PI拥有将聚合物医疗设备转化为临床设备的经验和成功。

DESCRIPTION (provided by applicant): Ruthenium carbene-catalyzed ring opening metathesis polymerization (ROMP) is a reliable and efficient method to synthesize well-defined polymers with relatively low polydispersities. These polymers, mostly synthesized from norbornenes and cyclopentadienes, are of wide-spread interest since diverse functionalities and architectures can be prepared. For pharmaceutical applications, chemotherapeutic or antibacterial agents are tethered to create bioactive polymers. An unexplored area is the design of functional medical devices based on the macroscopic or bulk properties of these polymers. Preliminary investigations revealed that large molecular weight polymers of poly(7-oxanorbornene-2 carboxylate) in aqueous solution were lubricious and can lubricate ex vivo osteoarthritic cartilage surfaces (J. Am. Chem. Soc. 2013, 135, 4930-4933). Importantly, we have preliminary data demonstrating that these polymers: 1) function to lower the coefficients of friction in ex vivo bovine and human articular cartilage plug models compared to saline or hyaluronic acid viscosupplements (e.g. Synvisc-One®), and perform similar to healthy synovial fluid; 2) exhibit no in vitro or in vivo toxicity; and 3) resist degradation by hyaluronidase, therby enabling prolonged synovial joint residence time after intra-articular injection. Building on these results, we hypothesized that these polymers may have efficacy as a synthetic bio lubricant by reducing the friction and minimizing the wear between two cartilage surfaces. We propose the following three specific aims to support this hypothesis: Aim 1: Determine the dependence of polymer architecture, molecular weight, rigidity, and charge on the rheological and lubricating properties using both metal-on-metal and ex vivo bovine cartilage plug models of articulating joint surfaces; Aim 2: Determine the performance and lubrication mechanism of the bio lubricant in ex vivo healthy and traumatized / osteoarthritic human metacarpal phalangeal joints (MCPJs; index finger) to evaluate function in a discrete synovial joint; and Aim 3: Determine the performance and chondroprotective capability of the biolubricant in vivo using a trauma-induced osteoarthritis rabbit model. Successful completion of these studies will result in: 1) the development of structure-activity relationships and design requirements for highly effective biolubricants for cartilage surfaces; 2) insight as to mechanism of lubrication for these polymers in contact with articular cartilage vs. conventional metal surface; and 3) ex vivo and in vivo performance data in healthy and osteoarthritic cartilage joints. The next steps in the translation of this technology to the clinic will involve good manufacturing practice synthesis, a large animal model study of traumatic osteoarthritis, FDA required biocompatibility testing, and biodistribution/pharmacokinetic studies. The lead PI has previous experience and success in translating a polymeric medical device to the clinic.