Modulation of Insertional Achilles Tendinopathy by Multiaxial Mechanical Strains

多轴机械应变调节插入性跟腱病

• 批准号: 9380380
• 负责人: Mark Raymond Buckley
• 金额: $ 30.36万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9380380
• 关键词: Affect; Ankle; Bioreactors; Caring; Carpal Tunnel Syndrome; Cells; Chromatin; Clinical; Data; Disease; Exercise; Exhibits; Family suidae; Funding; Gene Expression; General Population; Goals; Human; In Vitro; Individual; Intervention; Isometric Exercise; Lead; Ligaments; Measures; Mechanics; Mediating; Methods; Modification; Modulus; Morphology; Nuclear; Operative Surgical Procedures; Outcome; Pain; Pathogenesis; Pathologic; Pathology; Patients; Pattern; Physical therapy; Play; Posterior Tibial Tendon Dysfunction; Procedures; Publications; Reporting; Resistance; Role; Rotator Cuff; Shapes; Techniques; Tendinopathy; Tendon structure; Testing; Tissues; Ultrasonography; United States National Institutes of Health; Walking; Weight-Bearing state; Work; achilles tendon; base; calcaneum; elastography; experience; improved; improved outcome; in vivo; lifetime risk; mechanical properties; nucleocytoplasmic transport; operation; response

PROJECT SUMMARY Insertional Achilles tendinopathy (IAT) is a debilitating disorder that responds poorly to conservative (non- surgical) therapies. An effective conservative treatment for this disease must target the fundamental causes of pathological tissue alterations and induce deformations that promote their reversal. Thus, the objective of this project is to elucidate the patterns of mechanical strain (i.e., deformation) that cause and reverse IAT in vitro, and determine how to induce these strain patterns in vivo during exercise-based physical therapy. In preliminary work, we have used ultrasound elastography to demonstrate that IAT-associated changes are greater in the deep tendon, where transverse compressive strain |𝜀2𝐺| – compressive strain along the short-axis of the tendon – is highest due to contact with the heel bone. Moreover, we have determined that tendon explants loaded under transverse compression in vitro exhibit alterations that resemble IAT. Importantly, previous studies have demonstrated that transverse compression-induced tendon alterations can be reversed by axial tensile strain |𝜀1𝐺| (strain along the long axis of the tendon). These findings support our central hypothesis that deformations with high ratios |𝜀𝐺|/|𝜀𝐺| of transverse compressive strain to axial tensile strain 21 cause IAT while deformations with low strain ratios |𝜀𝐺|/|𝜀𝐺| can reverse this disease. To test this hypothesis, 21 in Aim 1 we propose to investigate whether high levels of |𝜀𝐺|/|𝜀𝐺| generate IAT-like changes in porcine 21 Achilles tendon insertion explants in vitro. In Aim 2, we will investigate whether low levels of |𝜀𝐺|/|𝜀𝐺| can 21 reverse IAT-associated changes in human IAT tendon explants in vitro. In Aims 1-2, we will also test the secondary hypothesis that the differential response of tendon to |εG| and |εG| is due to their markedly different 21 effects on tendon cell nuclear volume and shape, a concept supported by preliminary studies. These effects could lead to distinct alterations in nuclear chromatin organization or nuclear transport that mediate gene expression and tissue composition. Finally, in Aim 3, we will characterize the mechanical strain patterns induced by different exercises in vivo and establish how exercises can be adjusted to modulate levels of |𝜀𝐺|/|𝜀𝐺| in the Achilles tendon insertion. This study will take a significant step towards establishing effective, 21 targeted conservative treatment for patients with IAT. Moreover, the findings and approaches established in this proposal could also be applicable to other important tendon and ligament diseases including rotator cuff disease, carpal tunnel syndrome and patellar tendinopathy.

项目概要 插入性跟腱病 (IAT) 是一种使人衰弱的疾病，保守治疗（非治疗）效果不佳。 对于这种疾病的有效保守治疗必须针对其根本原因。 病理组织改变并引起变形，从而促进其逆转。 该项目旨在阐明在体外引起和逆转 IAT 的机械应变（即变形）模式， 并确定如何在基于运动的物理治疗期间在体内诱导这些应变模式。 在前期工作中，我们使用超声弹性成像来证明 IAT 相关的变化 深层肌腱更大，其中横向压缩应变 |𝜀2𝐺| – 沿短轴的压缩应变 肌腱的高度 – 由于与脚跟骨接触而最高，此外，我们还确定了肌腱。 体外横向压缩下加载的外植体表现出类似于 IAT 的变化。 先前的研究表明，横向压缩引起的肌腱改变是可以逆转的 通过轴向拉伸应变|𝜀1𝐺|（沿肌腱长轴的应变）这些发现支持了我们的中枢。 假设横向压缩应变与轴向拉伸应变具有高比率 |𝜀𝐺|/|𝜀𝐺| 的变形 21 导致 IAT，而低应变比 |𝜀𝐺|/|𝜀𝐺| 的变形可以逆转这种疾病。 21 在目标 1 中，我们建议研究高水平的 |𝜀𝐺|/|𝜀𝐺| 是否会在猪体内产生类似 IAT 的变化 21 在目标 2 中，我们将研究低水平的 |𝜀𝐺|/|𝜀𝐺| 是否可以进行体外跟腱插入。 21 在体外逆转人 IAT 肌腱外植体中与 IAT 相关的变化。在目标 1-2 中，我们还将测试 第二假设：肌腱对 |εG| 和 |εG| 的不同反应是由于它们的显着不同 21 对腱细胞核体积和形状的影响，这一概念得到了初步研究的支持。 可能导致介导基因的核染色质组织或核运输的明显改变 最后，在目标 3 中，我们将表征机械应变模式。 由体内不同的运动引起，并确定如何调整运动以调节 |𝜀𝐺|/|𝜀𝐺| 在跟腱插入方面将迈出重要一步， 21 此外，针对 IAT 患者的针对性保守治疗也确立了。 该提议也适用于其他重要的肌腱和韧带疾病，包括肩袖 疾病，腕管综合症和髌腱病。