Achieving Integrative Cartilage Repair Success Under Low Intensity Ultrasound

项目摘要 骨软骨移植或基质辅助细胞植入（MACI）是治疗软骨炎的有前途的策略 关节软骨损伤不能自行愈合。内在修复的一个共同特征是 修复或移植组织与宿主的横向整合明显缺乏 软骨，可导致预后不良。本R 03项目的目标是证明 采用相对非侵入性的辅助手段，例如连续低强度超声（cLIUS）， 一体化先前的治疗在脉冲LIUS（pLIUS@1.5 MHz）方面取得了不同程度的成功，但 使用了一种任意的治疗方法，没有考虑膝关节组织的特性或组织对LIUS的反应。到 超越采用经验推导的pLIUS在1.5 MHz用于体内应用的现状的进展， 首先，我们的方法采用cLIUS，因为与pLIUS相比，cLIUS耦合更多的能量。重要的是，我们正在 创新研究代表了一种新的和实质性的脱离现状，将重点转移到 以下：（1）识别3.8 ± 0.3 MHz的临床相关组织共振频率范围，其中cLIUS 通过考虑组织特性，使诱导的生物效应最大化，以及（2）了解 cLIUS在关节间隙和缺损附近以这些较高频率传播， 最佳cLIUS方案和递送途径。总之，这些创新使我们能够提供治疗 剂量的cLIUS以使软骨修复。基于我们有希望的体外研究结果，表明cLIUS 为了保护软骨和诱导软骨，我们的中心假设是cLIUS将有助于软骨- 在兔软骨下损伤模型中通过促进迁移和 将软骨形成增强到比没有cLIUS处理的方法更高的程度。为了验证这一点，一 将进行具体目标：1：证明LIUS下增强的软骨整合。我们的目标是 表明cLIUS将实现可再现的软骨整合修复，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性。家兔将 在cLIUS处理4周和12周后安乐死，此时将进行软骨再生和整合。 评估。除非刺激对照外，还将与标准US方案进行组比较 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 涉及能够促进移植物处整合的基于cLIUS的方案和递送系统的开发 接口.这为骨科医生试图治疗 有这种临床难题的患者。这将直接解决4600万美国人的需求 据估计，仅在美国，每年就有1280亿美元的患者患有骨关节炎。

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.