Synthetic lubricin biomaterial for osteoarthritis

用于治疗骨关节炎的合成润滑素生物材料

基本信息

批准号：
8904481
负责人：
DAVID A PUTNAM
金额：
$ 21.79万
依托单位：
ARTICULATE BIOMEDICAL, LLC
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-15 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8904481
关键词：
Acute Adhesions Animals Automobile Driving Biocompatible Materials Biomedical Engineering Bone Tissue Canis familiaris Cavia Cell Culture Techniques Clinical Clinical Sciences Clinical Trials Collaborations Complement Activation Counseling Data Degenerative polyarthritis Development Disease Progression Economic Burden Evaluation Exhibits Experimental Designs Fingers Foundations Grant Guidelines Hip region structure Human Hyaluronic Acid Implant In Vitro Industry Intra-Articular Injections Knee Knee Injuries Knee Osteoarthritis Laboratories Lubricants Lubrication Marketing Medical Device Modeling Orthopedic Surgery procedures Outcome Pathway interactions Phase Play Polyethylene Glycols Price Process Protocols documentation Quality of life Rattus Research Research Personnel Rodent Role Route Small Business Technology Transfer Research Spinal Structure Surface Surgeon Temporomandibular Joint Disorders Testing Toxic effect Translations United States Universities Vertebral column Veterinary Medicine Work acrylic acid analog articular cartilage base biomaterial compatibility clinical efficacy college copolymer cost cytotoxicity design economic impact experimental analysis eye dryness genotoxicity human morbidity human mortality implantable device implantation in vivo irritation long bone lubricin meetings palliative pre-clinical prevent product development programs public health relevance research study scale up success

项目摘要

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).

描述（由申请人提供）：骨关节炎 (OA) 是导致人类发病和死亡的一个重要因素，在美国每年造成的经济负担超过 300 亿美元。 Lubricin 是膝关节软骨的天然润滑剂，并且关节内给药。润滑素可预防膝关节损伤后 OA 的进展，然而，润滑素的生产成本超过 10,000 美元/毫克，使其成为一种经济上不切实际的产品。最近，康奈尔大学的一个生物医学工程师团队发现并减少了实践一种润滑素的合成类似物，它可以防止 OA 进展，并在大鼠膝盖的 ACL 横断模型中表现出优异的生物相容性。天然润滑素的结构和功能，以及成本模型表明随着进一步开发可预期商业上可行的定价的额外优势。 Lubrisynth(r) 走向临床应用以预防膝关节骨关节炎 (OA) 的进展定义了以下具体目标，以通过 1 期 STTR 机制推进 Lubrisynth(r) 的临床前开发，该机制是专家之间的综合合作。 Articulate Biomedical, LLC 和康奈尔大学具体目标 1：将 Lubrisynth(r) 的合成规模扩大到 100 g 试验规模。 Lubrisynth(r) 是一种由聚丙烯酸主链和聚乙二醇侧链组成的刷状共聚物，其合成路线旨在仅通过两个步骤即可实现轻松且受控的放大。具体目标 1 的目标是全面应用。阶乘实验设计和分析以确定可重复的 100 克规模合成 Lubrisynth(r) 所需的缩放工艺耐受性和驱动因子水平预期结果是合成 Lubrisynth(r) 的稳健的定量耐受性方案。 GMP 级生产。具体目标 2：建立 Lubrisynth(r) 的体外和体内生物相容性曲线。三级医疗 III 类医疗器械 PMA 开发路径的行业指南（即 ISO-10993）概述了与组织/骨骼接触超过 30 天的植入设备所需的具体生物相容性测试。生物相容性评估将按照 ISO 指南的定义完成。具体目标 2 的目标是根据 ISO 指南完成 Lubrisynth(r) 的体外和体内生物相容性评估。 FDA 接受的指南。预期结果是对 Lubrisynth(r) 的初始生物相容性概况进行彻底、成功的分析。总的来说，拟议工作的预期结果将为 Lubrisynth(r) 的商业开发奠定必要的基础。如果成功，将为 STTR 第 2 期具体目标（GMP 合成和临床功效研究）扫清道路。