Modulation of Insertional Achilles Tendinopathy by Multiaxial Mechanical Strains

项目摘要 插入性跟腱病（IAT）是一种使人衰弱的疾病，对保守（非保守）治疗反应不佳。 外科）治疗。有效的保守治疗这种疾病必须针对根本原因， 病理性组织改变并诱导促进其逆转的变形。因此，这一目标 项目是阐明机械应变的模式（即，在体外引起和逆转IAT， 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 初步工作，我们已经使用超声弹性成像来证明IAT相关的变化是 更大的深层肌腱，其中横向压缩应变|𝜀2𝐺|- 沿短轴沿着的压缩应变 由于与跟骨接触，肌腱的应力最高。此外，我们已经确定肌腱 在体外横向压缩下加载的外植体表现出类似于IAT的改变。重要的是， 先前的研究已经证明，横向压缩引起的肌腱改变可以逆转， 通过轴向拉伸应变|𝜀1𝐺|（沿肌腱的长轴沿着拉紧）。这些发现支持了我们的核心观点。 假设高比率变形|𝜀𝐺|横向压缩应变与轴向拉伸应变之比|𝜀𝐺| of transverse compressive strain to axial tensile strain 21 低应变比变形引起IAT|𝜀𝐺|可以逆转这种疾病。|𝜀𝐺| can reverse this disease.为了验证这个假设， 21 在目标1中，我们建议研究高水平的|𝜀𝐺|在猪中产生IAT样变化|𝜀𝐺| generate IAT-like changes in porcine 21 跟腱止点离体植块。在目标2中，我们将研究低水平的|𝜀𝐺|可以|𝜀𝐺| can 21 逆转体外人IAT肌腱外植体中的IAT相关变化。在目标1-2中，我们还将测试 第二个假设，肌腱的差异反应|εG|和|εG|是因为它们的显著不同 21 肌腱细胞核体积和形状的影响，初步研究支持的概念。这些影响 可能导致核染色质组织或核转运的明显改变， 表达和组织组成。最后，在目标3中，我们将描述机械应变模式 诱导不同的运动在体内，并建立如何运动可以调整，以调节水平， |𝜀𝐺|跟腱止点|𝜀𝐺| in the Achilles tendon insertion.这项研究将朝着建立有效的、 21 针对性保守治疗IAT患者。此外， 这一建议也可应用于其他重要的肌腱和韧带疾病 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.