Synthesis, Characterization, and Evaluation of Polymeric Tissue Lubricants

描述（由申请人提供）：钌催化开环复分解聚合（ROMP）是一种可靠、高效的方法来合成具有良好定义的聚合物，具有相对低的多分散性。这些聚合物主要由降冰片烯和环戊二烯合成，由于可以制备不同的功能和结构，因此受到广泛关注。对于制药应用，化学治疗剂或抗菌剂被拴在一起以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特性的功能性医疗设备的设计。初步研究表明，水溶液中的大分子量聚合物聚（7-氧生冰片烯-2羧酸酯）具有润滑性，可以润滑离体骨关节炎软骨表面（J. m.）。化学。Soc. 2013, 35(1), 4930-4933。重要的是，我们有初步的数据表明，这些聚合物：1)与生理盐水或透明质酸黏液补充剂（例如Synvisc-One®）相比，在离体牛和人关节软骨塞模型中具有降低摩擦系数的功能，并具有与健康滑液相似的功能；2)在体内或体外均无毒性；3)抗透明质酸酶降解，从而延长关节内注射后滑膜关节停留时间。以此为基础

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.