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 由于软骨的先天维修和再生能力差，可以解决早期软骨损伤的疗法 并防止进一步的骨关节炎恶化会产生巨大的临床影响。由于易于隔离 间充质基质细胞（MSC）的多条分分化潜力（MSC）依赖于 基质辅助间充质 - 基质细胞植入（MSCI）或微裂纹（MF）吸引了临床 注意力。当前，MSCI或MF的功能结果，包括提供增长因素的方法 体内的特征在于生物力学下纤维球杆菌，整合得分差。关节炎症 已确定以抑制MSC的软骨形成，从而有助于软骨修复的低疗效 结果。至关重要的是，通过减轻促进作用的分解代谢作用来提供软骨保护的方法 需要在促进原位软骨发生的同时进行炎症性关节环境。解决关键 提高功能性 - 牙齿修复结果的挑战，一种非侵入性辅助；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程序的增强的软骨修复。能力 Clius的改善软骨修复结果将通过三个特定目的证明：AIM 1：证明 在促炎环境中，Clius诱导的MSC的软骨发生。 RNA序列将是 用于收集深入的转录组分析和驱动MSC软骨发生的基础途径 在促炎环境中的克利乌斯之下。 AIM 2：开发经计算验证和优化的 Clius治疗方案。计算网格将由磁共振图像（MRI）构建 使用双相有限元模型用于关节中的波传播，以确定特定的clius方案 用于绵羊关节。模型将通过绵羊尾膝关节中的声学传播实验来验证。 AIM 3：证明Clius下软骨修复的功能结果改善。展示 使用MF和MSCI在绵羊关节软骨中使用MF和MSCI进行临界大小的软骨缺陷的卓越修复 优化了Clius的透皮传递，并在六个月内进行评估。再生软骨的分析将是 通过组织学，生物力学和生化方法。预计这项工作的成功完成 导致开发基于Clius的方案和交付系统，能够产生稳定的透明质 软骨表型通过微创程序，同时推进对MSC的基本理解 克利乌斯（Clius）的预处理。反过来，这将直接解决对4600万美国人的待遇 遭受OA的苦难，估计每年为1,280亿美元。