Modulation of Insertional Achilles Tendinopathy by Multiaxial Mechanical Strains

项目总结 附着性跟腱病(IAT)是一种衰弱的疾病，对保守的(非 外科)治疗。对这种疾病的有效保守治疗必须针对以下根本原因 病理组织改变，并导致畸形，促进其逆转。因此，这一行动的目标是 该项目旨在阐明在体外引起和逆转IAT的机械应变(即变形)的模式， 并确定在以运动为基础的物理治疗期间如何在体内诱导这些应变模式。在……里面 前期工作中，我们已经使用超声弹性成像来证明IAT相关的变化是 在深部肌腱中较大，其中横向压缩应变|𝜀2𝐺|-沿短轴的压缩应变 肌腱的位置--由于与脚后跟的骨头接触而达到最高。此外，我们已经确定了肌腱 在体外横向加压下的外植体表现出类似于IAT的变化。重要的是 先前的研究表明，横向压迫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)。这些发现支持我们的中心 假设横向压缩应变与轴向拉伸应变之比|𝜀𝐺|/|𝜀𝐺|较高的变形 21岁 低应变比的变形|𝜀𝐺|/|𝜀𝐺|可以逆转这种疾病。为了检验这一假设， 21岁 在目标1中，我们建议调查高水平的|𝜀𝐺|/|𝜀𝐺|是否会在猪体内产生类似IAT的变化 21岁 跟腱植入组织块的体外培养。在目标2中，我们将调查低水平的|𝜀𝐺|/|𝜀𝐺|是否可以 21岁 体外逆转人IAT肌腱移植的IAT相关改变。在AIMS 1-2中，我们还将测试 第二个假设是肌腱对|εG|和|εG|的不同反应是由于它们的显著不同 21岁 对肌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。这些影响 可能导致介导基因的核染色质组织或核运输的明显变化 表达和组织成分。最后，在目标3中，我们将描述机械应变模式 通过不同的运动在体内诱导，并确定如何调整运动来调节 |𝜀𝐺|/|𝜀𝐺|在跟腱插入中。这项研究将朝着建立有效的、 21岁 IAT患者的靶向保守治疗。此外，在中建立的调查结果和方法 这一建议也适用于其他重要的肌腱和韧带疾病，包括肩袖 疾病、腕管综合征和髌腱病。

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.