Optimizing Ultrasound Regimens for Achieving Cartilage Repair

优化超声治疗方案以实现软骨修复

• 批准号: 10366768
• 负责人: Anuradha Subramanian
• 金额: $ 49.39万
• 依托单位: UNIVERSITY OF ALABAMA IN HUNTSVILLE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-11 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10366768
• 关键词: Acoustics; Address; American; Attention; Biochemical; Biological Response Modifier Therapy; Biomechanics; Cadaver; Cartilage; Cartilage injury; Chondrocytes; Chondrogenesis; Clinical; Contralateral; Coupled; Data; Data Aggregation; Defect; Degenerative polyarthritis; Deterioration; Development; Elements; Engineering; Environment; Fibrocartilages; Frequencies; Growth Factor; Histologic; Human; Hyaline Cartilage; Impairment; In Situ; In Vitro; Inferior; Inflammatory; Joints; Knee joint; Lead; Magnetic Resonance Imaging; Methods; Modality; Modeling; Morbidity - disease rate; Natural regeneration; Non-linear Models; Oryctolagus cuniculus; Outcome; Pathway interactions; Phenotype; Phosphorylation; Procedures; Property; Publishing; Regenerative capacity; Regimen; Sheep; Site; System; Tissues; Translations; Ultrasonic Therapy; Ultrasonic Transducer; Work; articular cartilage; attenuation; base; cartilage regeneration; cartilage repair; clinical application; clinically relevant; computer grid; conditioning; cost estimate; cytokine; experimental study; functional outcomes; implantation; improved; improved outcome; in vivo; inflammatory milieu; innovation; joint function; joint inflammation; mesenchymal stromal cell; minimally invasive; preconditioning; prevent; regeneration function; repaired; response; restoration; sheep model; therapy development; transcriptome sequencing; transcriptomics; treatment group; ultrasound

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.

抽象的 由于软骨的先天修复和再生能力较差，因此可以解决早期软骨损伤的治疗方法 并防止骨关节炎进一步恶化将产生巨大的临床影响。由于隔离方便 间充质基质细胞（MSC）的多谱系分化潜力，方法依赖于 基质辅助间充质基质细胞植入（MSCI）或微骨折（MF）已吸引了临床 注意力。目前，MSCI 或 MF 的功能成果，包括在中提供生长因子的方法 体内，其特点是生物力学较差的纤维软骨和较差的整合分数。关节炎症 已被鉴定可抑制间充质干细胞的软骨形成，从而导致软骨修复效率低下 结果。至关重要的是，通过减轻亲细胞的分解代谢作用来提供软骨保护的方法 需要炎症性关节环境，同时促进原位软骨形成。为了解决关键问题 改善功能性软骨修复结果的挑战，一种非侵入性辅助手段；连续低 强度超声 (cLIUS) 具有最近发表的软骨诱导和软骨保护特性 为了证明 MACI 和 MF 手术的软骨修复能力得到增强。能力 cLIUS 改善软骨修复结果的作用将通过三个具体目标来证明： 目标 1：展示 cLIUS 在促炎环境中诱导 MSC 软骨形成。 RNA测序将是 用于收集深入的转录组分析和驱动 MSC 软骨形成的潜在途径 在促炎环境中的 cLIUS 下。目标 2：开发经过计算验证和优化的 cLIUS治疗方案。计算网格将由磁共振图像（MRI）耦合构建 使用关节中波传播的双相有限元模型来确定特定的 cLIUS 方案 用于羊关节。模型将通过绵羊尸体膝关节的声传播实验进行验证。 目标 3：展示 cLIUS 下软骨修复功能效果的改善。展示 使用 MF 和 MSCI 对绵羊关节软骨中的临界尺寸软骨缺损进行卓越修复 优化 cLIUS 的透皮给药并在六个月时进行评估。再生软骨的分析将是 通过组织学、生物力学和生化方法。预计这项工作的顺利完成 导致开发基于 cLIUS 的治疗方案和递送系统，能够产生稳定的透明质 通过微创手术研究软骨表型，同时增进对 MSC 的基本了解 cLIUS 下的预处理。反过来，这将直接解决 4600 万美国人的待遇问题。 每年因 OA 造成的损失估计为 1,280 亿美元。