Synthetic lubricin biomaterial for osteoarthritis

 描述(由申请人提供)：骨关节炎(OA)是导致人类发病率和死亡率的重要因素，在美国每年造成超过300亿美元的经济负担。润滑剂是膝关节软骨的天然润滑剂，关节内注射润滑剂可防止膝关节损伤后的骨性关节炎进展。然而，润滑油的制造价格超过10,000美元/毫克，使其成为经济上不切实际的候选产品。最近，康奈尔大学的一个生物医学工程师团队发现并实践了一种合成的润滑剂类似物，它可以防止OA的进展，并在大鼠膝关节ACL横断模型中表现出极好的生物相容性。这种润滑剂类似物Lubrisynth(R)模仿了本地润滑剂的结构和功能，另外一个优势是，成本模型表明，随着进一步的发展，商业上可行的定价是可以预期的。这项拟议研究的目的是将Lubrisynth(R)的转化转化为临床使用，以防止膝关节骨关节炎(OA)的发展。以下具体目标是为了通过第一阶段STTR机制推动Lubrisynth(R)的临床前开发，该机制是Articate Biomedical、LLC和康奈尔大学的专家之间的综合合作。具体目标1：放大合成Lubrisynth(R)至100g中试 比例。Lubrisynth(R)是一种刷式共聚物，由聚丙烯酸主链和聚乙二醇侧链组成。合成路线的设计允许在只需两步的情况下进行简单和可控的放大。具体目标1的目标是应用完全析因实验 设计和分析以确定可重现的100克规模的Lubrisynth(R)合成所需的规模化工艺耐受性和驱动因素水平。预期的结果是为符合GMP级生产的Lubrisynth(R)的合成制定一个可靠的定量容差协议。具体目标2：建立Lubrisynth(R)的体外和体内生物相容性。Lubrisynth(R)将被开发为III级医疗 设备。第三类医疗设备的聚甲基丙烯酸甲酯开发路径行业指南(即ISO-10993)概述了植入性设备与组织/骨骼接触超过30天所需的具体生物兼容性测试。体外生物相容性评价和体内生物相容性评价将按照ISO指南的定义进行。具体目标2的目标是根据FDA接受的指南完成Lubrisynth(R)的体外和体内生物兼容性评估。预期的结果是对Lubrisynth(R)的初始生物兼容性概况进行彻底和成功的分析。总的来说，拟议工作的预期结果将为开始Lubrisynth(R)的商业开发奠定必要的基础，如果成功，将为STTR第二阶段的具体目标(GMP合成和临床疗效研究)扫清道路。

 DESCRIPTION (provided by applicant): Osteoarthritis (OA) is a significant contributor to human morbidity and mortality with an economic burden exceeding $30 billion annually in the United States. Lubricin is a natural lubricant of the articular cartilage of the knee, and the intraarticular administration of lubricin prevents OA progression following knee injury. However, the manufacture of lubricin exceeds $10,000/mg, making it an economically impractical product candidate. Recently, a team of biomedical engineers at Cornell University discovered and reduced to practice a synthetic analog of lubricin that prevents OA progression and exhibits excellent biocompatibility in the ACL transection model in rat knees. This lubricin analog, Lubrisynth(r), mimics the structure and function of native lubricin, with the added advantage that cost models indicate commercially viable pricing can be expected with further development. The objective of the proposed research is to advance the translation of Lubrisynth(r) toward clinical use to prevent the progression of osteoarthritis (OA) in the knee. The following Specific Aims are defined to advance the preclinical development of Lubrisynth(r) through the Phase 1 STTR mechanism which is an integrated collaboration between experts at Articulate Biomedical, LLC and Cornell University. Specific Aim 1: Scale-up synthesis of Lubrisynth(r) to the 100 g pilot scale. Lubrisynth(r) is a brush copolymer consisting of a poly acrylic acid backbone with polyethylene glycol sidechains. The synthetic route was designed to allow facile and controlled scale-up in only two steps. The objective of Specific Aim 1 is to apply full factorial experimental design and analysis to establish the scaled process tolerability and the driving factor levels necessary for the reproducible 100 gram-scale synthesis of Lubrisynth(r). The anticipated outcome is a robust quantitated tolerance protocol for the synthesis of Lubrisynth(r) that is amenable to GMP grade manufacture. Specific Aim 2: Establish the in vitro and in vivo biocompatibility profiles of Lubrisynth(r). Lubrisynth(r) will be developed as a Class III medical device. The Industry Guidance for the PMA development pathway of Class III medical devices (i.e., ISO-10993) outlines the specific biocompatibility tests required for implanted devices in contact with tissue/bone for longer than 30 days. In vitro biocompatibility evaluation and in vivo biocompatibility evaluation will be completed as defined by the ISO Guidance. The objective of Specific Aim 2 is to complete both the in vitro and in vivo biocompatibility evaluations of Lubrisynth(r) in accordance with the FDA-accepted guidelines. The anticipated outcome is a thorough and successful analysis of the initial biocompatibility profile of Lubrisynth(r). Collectively, the anticipated outcomes of the proposed work will establish the necessary foundation to begin the commercial development of Lubrisynth(r), and if successful, will clear the way for the STTR Phase 2 Specific Aims (GMP synthesis and clinical efficacy studies).