Molecular engineering of HA-based lubricants for articular cartilage

用于关节软骨的 HA 基润滑剂的分子工程

• 批准号: 10712721
• 负责人: Shyni Varghese
• 金额: $ 61.19万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-21 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10712721
• 关键词: Acute; Adhesions; Adhesives; Animal Model; Architecture; Atomic Force Microscopy; Bone Tissue; Cartilage; Cartilage injury; Charge; Clinic; Clinical; Degenerative polyarthritis; Deterioration; Development; Electrostatics; Engineering; Ensure; Exhibits; Extracellular Matrix; Family suidae; Formulation; Friction; Goals; Histologic; Hyaluronic Acid; Image; Individual; Injury; Intervention; Intra-Articular Injections; Joints; Liquid substance; Lubricants; Lubrication; Lysine; Measurement; Mechanics; Modeling; Molecular; Molecular Weight; Monitor; Movement; Operative Surgical Procedures; Outcome; Pain; Property; Pyrimidinones; Research; Role; Saline; Slide; Surface; Synovial Fluid; Synovial Membrane; Time; Tissues; Trauma; Traumatic Arthropathy; United States; Weight-Bearing state; anterior cruciate ligament injury; anterior cruciate ligament reconstruction; articular cartilage; cartilage degradation; chondroprotection; design; healing; improved; improved outcome; in vivo; inflammatory marker; joint injury; lubricin; novel; novel therapeutic intervention; prevent; repaired; success

ABSTRACT Altered lubrication of articular cartilage following joint injury increases friction between the sliding cartilage surfaces, leads to deterioration of cartilage, and hastens the development of osteoarthritis (OA). OA due to joint injury, termed as post-traumatic osteoarthritis (PTOA), is estimated to account for at least 12% of all OA cases in the United States and approximately half of the individuals with an anterior cruciate ligament (ACL) injury develop PTOA regardless of the ACL reconstruction. Replenishing the synovial fluid and thereby restoring the articular cartilage lubrication has been demonstrated to benefit the joint. The overarching goal of the proposed study is to investigate the potential of cartilage-adhering, self-healing hyaluronic acid molecules to prevent or delay the degeneration of articular cartilage, and thereby osteoarthritis, following injury or trauma. The molecularly engineered HA-based lubricants are designed to integrate the function of both hyaluronic acid and lubricin, two key components of the synovial fluid, while exhibiting self-repairing ability. The self-healing properties are incorporated to ensure both long-term retention and adaptability of the lubricant within the mechanically active joint, while the cartilage adhering properties are expected to improve boundary lubrication. We hypothesize that the dynamic cartilage-adhering molecules that integrate the molecular features of HA and lubricin and simultaneously exhibit self-healing properties will protect the articular cartilage and prevent or slow down the progression of PTOA. Towards this, we will: (i) develop cartilage-adhering, self-healing HA molecules and determine the effect of molecular architecture-lubrication function relationship, (ii) determine the effect of the molecular architecture of the proposed novel HA-based lubricants on chondroprotection by using a joint-on-chip platform, and (iii) determine the effect of these lubricants on mitigating the development of post-traumatic osteoarthrits. The proposed studies will enable a new paradigm in which intra-articular injection of self-healing HA-bottle brush molecules could be an important treatment following acute injury to ameliorate or delay PTOA, or they could be used as an adjunct after surgical repair to improve the outcome.

摘要 关节损伤后关节软骨的润滑改变增加了滑动软骨之间的摩擦 表面，导致软骨退化，加速骨性关节炎(OA)的发展。由关节引起的骨性关节炎 损伤，被称为创伤后骨关节炎(PTOA)，估计至少占所有OA病例的12% 在美国，前交叉韧带(ACL)损伤的个人中约有一半 无论前交叉韧带重建如何，都要发展PTOA。补充滑液，从而恢复 关节软骨润滑已被证明有益于关节。建议的总体目标是 这项研究是为了研究软骨黏附、自我修复的透明质酸分子预防或 延缓损伤或创伤后关节软骨的退化，从而延缓骨关节炎。这个 分子工程HA润滑剂旨在整合透明质酸和透明质酸的功能 润滑剂，滑液的两个关键成分，同时显示出自我修复能力。自我疗愈 将各种性能结合在一起，以确保润滑油在 关节具有机械活性，而软骨的粘附性有望改善边界润滑。 我们假设，整合了HA和HA的分子特征的动态软骨黏附分子 润滑剂同时表现出自我修复性能，将保护关节软骨，防止或减缓 延缓了PTOA的进展。为此，我们将：(I)开发软骨粘连、自我修复的HA分子 确定了分子构型-润滑功能关系的影响，(Ii)确定了分子构型-润滑功能关系的影响 基于片上关节的新型HA基软骨保护润滑剂的分子结构 平台，以及(3)确定这些润滑剂在减轻创伤后发展方面的作用 骨关节。拟议的研究将使一种新的范式成为可能，在这种范式中，关节内注射自我修复 HA-瓶刷分子可能是急性损伤后改善或延迟PTOA的重要治疗方法， 或者，它们可以作为手术修复后的辅助工具，以改善结果。