Synthesis, Characterization, and Evaluation of Polymeric Tissue Lubricants

聚合物组织润滑剂的合成、表征和评估

• 批准号: 8886944
• 负责人: MARK W. GRINSTAFF
• 金额: $ 36.47万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-08 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8886944
• 关键词: Adrenal Cortex Hormones; Affect; Animal Model; Anti-Bacterial Agents; Anti-Inflammatory Agents; Anti-inflammatory; Architecture; Area; Arthralgia; Biodistribution; Biological Preservation; Body Weight decreased; Bovine Cartilage; Braces-Orthopedic appliances; CCL4 gene; Cadaver; Cartilage; Cattle; Charge; Chondrocytes; Chronic Disease; Clinic; Clinical Research; Contusions; Cyclopentadienes; Cyst; Data; Deformity; Degenerative polyarthritis; Dependence; Development; Drug Kinetics; Equilibrium; Evaluation; Exhibits; Fingers; Friction; Glycosaminoglycans; Human; Hyaline Cartilage; Hyaluronic Acid; Hyaluronidase; In Vitro; Individual; Injection of therapeutic agent; Injury; Intervention; Intra-Articular Injections; Investigation; Joint Instability; Joints; Knee; Lead; Lesion; Lubricants; Lubrication; Maintenance; Medical Device; Metacarpal bone; Metals; Methods; Modeling; Modification; Molecular Weight; Motion; Needles; Operative Surgical Procedures; Oryctolagus cuniculus; Pain; Patients; Performance; Pharmaceutical Preparations; Pharmacologic Substance; Physical therapy; Physical therapy exercises; Polymers; Procedures; Property; Randomized; Replacement Arthroplasty; Resistance; Ruthenium; Saline; Sclerosis; Series; Solutions; Structure-Activity Relationship; Surface; Synovial Fluid; Synovial joint; Synvisc; Technology; Testing; Thick; Time; Tissues; Toxic effect; Translating; Translations; Trauma; Viscosity; aqueous; articular cartilage; base; biomaterial compatibility; bone; carbene; carboxylate; chemotherapeutic agent; design; experience; improved; in vivo; indexing; innovation; insight; interest; knee replacement arthroplasty; novel; polymerization; prevent; public health relevance; reconstitution; residence; success; translational study; treatment strategy

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(R)), 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.

描述（由申请人提供）：钌卡宾催化的开环复分解聚合（ROMP）是一种可靠且有效的合成具有相对低多分散性的明确聚合物的方法。这些聚合物，主要是从环己烯和环戊二烯合成的，是广泛的兴趣，因为不同的功能和结构可以制备。对于药物应用，化学治疗剂或抗菌剂被束缚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性质的功能性医疗器械的设计。初步研究显示，水溶液中的聚（7-氧杂降冰片烯-2羧酸酯）的大分子量聚合物是润滑的，并且可以润滑离体骨关节炎软骨表面（J. Am. 2013，135，4930-4933）。重要的是，我们有初步的数据表明，这些聚合物：1）功能，以降低摩擦系数，在离体牛和人类关节软骨塞模型相比，盐水或透明质酸粘度补充剂（例如Synvisc-One（R）），并且表现类似于健康滑液; 2）不表现出体外或体内毒性;和3）抵抗透明质酸酶的降解，因此能够延长关节内注射后的滑膜关节停留时间。根据这些 结果，我们假设这些聚合物可以通过减少两个软骨表面之间的摩擦和最小化磨损而具有合成生物润滑剂的功效。我们提出了以下三个具体目标来支持这一假设：目标1：使用关节表面的金属对金属和离体牛软骨塞模型，确定聚合物结构、分子量、刚度和电荷对流变学和润滑性能的依赖性;目标2：确定生物润滑剂在离体健康和创伤/骨关节炎人掌指关节中的性能和润滑机制目标3：使用创伤诱导的骨关节炎兔模型确定生物润滑剂的体内性能和软骨保护能力。这些研究的成功完成将导致：1）开发软骨表面高效生物润滑剂的结构-活性关系和设计要求; 2）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制; 3）健康和骨关节炎软骨关节的离体和体内性能数据。下一步在翻译这项技术的临床将涉及良好的生产实践的合成，一个大的动物 创伤性骨关节炎模型研究、FDA要求的生物相容性试验和生物分布/药代动力学研究。主要研究者之前在将聚合物医疗器械转移到临床方面具有经验和成功经验。