Achieving Integrative Cartilage Repair Success Under Low Intensity Ultrasound

在低强度超声下实现综合软骨修复成功

• 批准号: 9917692
• 负责人: Anuradha Subramanian
• 金额: $ 7.4万
• 依托单位: UNIVERSITY OF ALABAMA IN HUNTSVILLE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9917692
• 关键词: Accounting; Address; American; Anabolism; Animal Model; Biological; Biomechanics; Cartilage; Cells; Characteristics; Chondrocytes; Chondrogenesis; Clinical; Collagen; Collagen Fibril; Control Groups; Couples; Data; Defect; Degenerative polyarthritis; Deterioration; Development; Extracellular Matrix; Frequencies; Future; Goals; Histologic; Impairment; In Vitro; Injury; Joints; Knee; Knowledge; Lateral; Lead; Lesion; Methodology; Methods; Modality; Modeling; Modification; Natural regeneration; Nature; Operative Surgical Procedures; Orthopedics; Oryctolagus cuniculus; Outcome; Pathway interactions; Patients; Persons; Phase; Physiologic pulse; Process; Property; Proteins; Proteoglycan; Protocols documentation; Publishing; Regimen; Rehabilitation therapy; Reproducibility; Research; Route; Signal Transduction; Surface; Surgeon; System; Techniques; Testing; Therapeutic; Time; Tissue Engineering; Tissue Grafts; Tissues; Transducers; Translations; Ultrasonography; Work; articular cartilage; base; cartilage degradation; cartilage regeneration; cartilage repair; cell motility; clinically relevant; comparison group; cost estimate; dosage; experimental study; healing; implantation; improved; improved outcome; in vivo; inflammatory milieu; innovation; interfacial; joint function; mechanotransduction; migration; osteochondral tissue; osteogenic; outcome forecast; prevent; reconstitution; recruit; repaired; response; restoration; stem cells; success; therapy development; tissue repair; tool; wound

PROJECT ABSTRACT Osteochondral grafts or Matrix-Assisted-Cell-Implantation (MACI) are promising strategies to treat chondral lesions as articular cartilage does not heal spontaneously. One characteristic shared by intrinsic reparative processes and surgical therapies is an apparent lack of lateral integration of repair or graft tissue with the host cartilage that can lead to poor prognosis. The goal of this R03 project is to demonstrate the feasibility of employing a relatively non-invasive adjunct such as continuous low-intensity ultrasound (cLIUS) to enhance integration. Previous therapies have had varied levels of success with pulsed LIUS (pLIUS @ 1.5 MHz), but have used an arbitrary treatment that doesn't take into account knee tissue properties or tissue response to LIUS. To progress beyond the status quo that employs an empirically derived pLIUS at 1.5 MHz for in vivo applications, first, our approach employs cLIUS as it couples more energy when compared to pLIUS. Importantly, our ongoing innovative research represents a new and substantive departure from the status quo by shifting the focus to the following: (1) identification of a clinically relevant tissue resonant frequency range of 3.8 ± 0.3 MHz, where cLIUS induced bioeffects are maximized by accounting for the tissue properties, and (2) understanding of the propagation of cLIUS at these higher frequencies in the joint space and in the vicinity of the defect to permit optimal cLIUS regimens and route of delivery. Taken together, these innovations enable us to deliver therapeutic dosages of cLIUS to enable cartilage repair. Based on our promising in vitro findings that demonstrate the cLIUS to be chondroprotective and chondrpoinductive, our central hypothesis is that cLIUS will aid in the cartilage-to- cartilage integration of critical sized defects in a rabbit model of subchondral injury by promoting migration and enhancing chondrogenesis to a degree greater than approaches without cLIUS treatment. To test this, one specific aim will be undertaken: 1: Demonstrate enhanced cartilage integration under LIUS. Our objective is to demonstrate that cLIUS will achieve reproducible integrative cartilage repair and maintain normal articular cartilage histologic and biomechanical characteristics in a rabbit model of chondral repair. Rabbits will be euthanized after 4 and 12 weeks of cLIUS treatment, at which time cartilage regeneration and integration will be assessed. In addition to non-stimulated controls, group comparison will be made with the standard US regimen that uses pulsed US signal at 1.5 MHz with 1 kHz repeat. Successful completion of this work is expected to lead to the development of a cLIUS-based regimen and delivery system capable of promoting integration at the graft interface. This presents an exciting potential treatment modality for orthopedic surgeons attempting to treat patients with this difficult clinical problem. This would, in turn, directly address the needs of 46 million Americans who suffer from osteoarthritis at an estimated cost of $128 billion annually in the U.S. alone.

项目摘要 骨软骨移植或基质辅助细胞植入（MACI）是治疗软骨病的有前途的策略 关节软骨损伤不会自然愈合。内在修复共有的一个特征 过程和手术治疗明显缺乏修复或移植组织与宿主的横向整合 软骨可能导致预后不良。这个 R03 项目的目标是证明 采用相对无创的辅助手段，例如连续低强度超声 (cLIUS) 来增强 一体化。以前的治疗方法使用脉冲 LIUS (pLIUS @ 1.5 MHz) 取得了不同程度的成功，但 使用任意治疗方法，未考虑膝关节组织特性或组织对 LIUS 的反应。到 超越采用基于经验的 1.5 MHz pLIUS 进行体内应用的现状， 首先，我们的方法采用 cLIUS，因为与 pLIUS 相比，它耦合了更多能量。重要的是，我们正在进行的 创新研究代表着对现状的新的实质性偏离，将重点转移到 (1) 确定临床相关组织共振频率范围 3.8 ± 0.3 MHz，其中 cLIUS 通过考虑组织特性来最大化诱导的生物效应，以及（2）了解 cLIUS 在关节空间和缺陷附近以这些较高频率传播，以允许 最佳 cLIUS 方案和给药途径。总而言之，这些创新使我们能够提供治疗 cLIUS 剂量可实现软骨修复。基于我们有前景的体外研究结果，证明了 cLIUS 为了起到软骨保护和软骨诱导作用，我们的中心假设是 CLIUS 将有助于软骨- 通过促进迁移和软骨下损伤兔模型中临界尺寸缺损的软骨整合 与未经 cLIUS 治疗的方法相比，在更大程度上增强软骨形成。为了测试这一点，一个 将实现的具体目标： 1：展示 LIUS 下增强的软骨整合。我们的目标是 证明 cLIUS 将实现可重复的综合软骨修复并维持正常的关节 兔软骨修复模型的软骨组织学和生物力学特征。兔子将会 cLIUS 治疗 4 周和 12 周后实施安乐死，此时软骨再生和整合将发生 评估。除了非刺激对照外，还将与标准美国方案进行分组比较 使用 1.5 MHz 的脉冲 US 信号，重复频率为 1 kHz。这项工作的顺利完成预计将导致 开发基于 cLIUS 的治疗方案和输送系统，能够促进移植物整合 界面。这为试图治疗的骨科医生提供了一种令人兴奋的潜在治疗方式 患有这一棘手临床问题的患者。反过来，这将直接满足 4600 万美国人的需求 据估计，仅在美国，每年因骨关节炎造成的损失就达 1280 亿美元。