Optimizing Ultrasound Regimens for Achieving Cartilage Repair

摘要 由于软骨的先天修复和再生能力较差，可以治疗早期软骨损伤的治疗方法 而防止骨关节炎进一步恶化将对临床产生很大的影响。由于容易与外界隔绝 和间充质基质细胞(MSCs)的多向分化潜能，依赖于 基质辅助间充质-基质细胞植入(MSCI)或微骨折(MF)已引起临床的广泛关注 请注意。目前，MSCI或MF的功能结果，包括在 活体，其特点是纤维软骨生物力学较差，综合评分较差。关节炎症 已被发现抑制骨髓间充质干细胞的软骨生成，从而导致软骨修复的低效率 结果。关键的是，通过减轻促进剂的分解代谢影响来提供软骨保护的方法- 在促进原位软骨形成的同时，需要炎性关节环境。要解决关键问题 改善功能性软骨修复结果的挑战，一种非侵入性附件；持续低... 强度超声(CLIUS)及其最新发表的软骨诱导和软骨保护特性 为了证明MACI和MF的强化软骨修复，将采用MACI和MF手术。一种能力 CLIUS改善软骨修复的效果将通过三个具体目标来演示：目标1：演示 激光诱导骨髓间充质干细胞在促炎环境中的软骨形成。RNA测序将是 用来收集深入的转录图谱和驱动MSC软骨形成的潜在途径 在cLIUS下，在促炎的环境中。目标2：开发一个经过计算验证和优化的 CLIUS治疗方案。计算网格将由磁共振成像(MRI)耦合而成 关节内波传播的双相有限元模型确定具体的cLIUS方案 对于绵羊关节来说。模型将通过在绵羊身体膝关节中的声传播实验进行验证。 目的3：展示cLIUS下软骨修复功能的改善结果。演示 微创和MSCI联合应用修复绵羊关节软骨大小缺损 优化cLIUS的经皮给药，并在6个月内进行评估。对再生软骨的分析将是 通过组织学、生物力学和生化方法。这项工作的圆满完成预计将 导致基于cLIUS的方案和能够产生稳定的透明膜的输送系统的开发 通过微创程序进行软骨表型，同时促进对MSC的基本理解 CLIUS下的预适应。反过来，这将直接解决4600万美国人的待遇 每年估计花费1280亿美元患上骨质疏松症。

ABSTRACT As cartilage has poor innate repair and regeneration capacity, therapies that can address early cartilage injury and prevent further osteoarthritic deterioration would have a large clinical impact. Due to the ease of isolation and multi-lineage differentiation potential of mesenchymal stromal cells (MSCs), methods that rely either on matrix assisted mesenchymal-stromal-cell-implantation (MSCI) or microfracture (MF) have attracted clinical attention. Currently, the functional outcomes of MSCI or MF, including approaches that deliver growth factors in vivo, are characterized by biomechanically inferior fibrocartilage, and poor integration scores. Joint inflammation has been identified to inhibit chondrogenesis of MSCs, thus contributing to the low efficacy of cartilage repair outcomes. Critically, approaches that offer chondroprotection by the mitigating the catabolic effects of the pro- inflammatory joint environment while promoting in situ chondrogenesis are required. To address the critical challenge of improving functional-cartilage-repair outcomes, a non-invasive adjunct; continuous low- intensity ultrasound (cLIUS) with recently published chondroinductive and chondroprotective properties to demonstrate enhanced chondral repair for both MACI and MF procedures will be employed. The ability of cLIUS to improve cartilage repair outcomes will be demonstrated via three specific aims: AIM 1: Demonstrate cLIUS-induced chondrogenesis of MSCs in a pro-inflammatory environment. RNA-sequencing will be employed to gather an in-depth transcriptomic profiling and underlying pathways that drive MSC chondrogenesis under cLIUS in a pro-inflammatory environment. AIM 2: Develop a computationally validated and optimized regimen of cLIUS therapy. Computational grids will be built from magnetic resonance images (MRIs) coupled with a biphasic finite element model for wave propagation in the joints to determine the specific cLIUS regimen for sheep joints. Models will be validated with acoustic propagation experiments in sheep-cadaver knee joints. AIM 3: Demonstrate Improved Functional Outcomes of Cartilage Repair Under cLIUS. Demonstrate the superior repair of critically sized chondral defects via MF and MSCI in the articular cartilage of sheep using an optimized transdermal delivery of cLIUS and evaluate at six months. Analysis of regenerated cartilage will be through histological, biomechanical and biochemical methods. Successful completion of this work is expected to lead to the development of a cLIUS-based regimen and delivery system capable of generating a stable hyaline cartilage phenotype via minimally invasive procedures, while advancing the fundamental understanding of MSC preconditioning under cLIUS. This would, in turn, directly address the treatment of 46 million Americans who suffer from OA at an estimated cost of $128 billion annually.