Focused ultrasound-induced cavitation in elastic, anisotropic tissues: a treatment for tendinopathies

项目概要/摘要 据报道，美国每年有近3000万例肌腱损伤，估计费用为114美元 亿即使经过治疗，这些肌腱损伤中的一些也会变成慢性的，伴随疼痛和功能丧失 持续3个月以上。保守的治疗技术，诱导微损伤，以促进 治疗，如干针（DN）和体外冲击波治疗（ESWT），产生混合的结果 0 - 85%的患者表现出改善。加强参数报告、校准、给药 协议和实时监测有助于广泛的患者结果。 我们试图克服现有肌腱病治疗的许多局限性，通过开发一种新的 集成被动空化和组织多普勒的肌腱病聚焦超声（fUS）治疗 用于fUS治疗的对准和定量监测的成像。最近，我们发现一个狭窄的 一系列fUS参数导致离体大鼠肌腱局部胶原纤维分离和磨损， 空化气泡的产生、振荡和破裂。当在体内大鼠肌腱病模型中测试时， fUS保留肌腱的机械性能以及或优于传统的DN治疗; IGF 1和TGF β在DN和fUS之间的愈合因子相似。然而，慢性肌腱病会影响 肌腱的力学性能，这将影响导致胶原纤维的fUS参数 破坏这提示需要在与人类相似大小的肌腱病变肌腱中进行测试， 开发定量被动空化和组织多普勒成像，用于实时监测 肌腱治疗进展。 在这里，我们建议使用实验和建模：1）评估新的fUS诱导机械范围 在健康和肌腱病离体大型动物肌腱中的分离; 2）整合PCI和组织多普勒 成像，用于fUS治疗的定量、实时评估;以及3）评价fUS治疗慢性 肌腱病创新包括确定fUS参数如何受到 健康肌腱与损伤肌腱的力学特性以及集成被动空化的发展 和组织多普勒成像用于fUS治疗进展的定量分析。额外的新颖性产生 通过在大型动物慢性肌腱病模型中测试fUS治疗并与传统DN进行比较， 和ESWT疗法。这些实验结果将用于大型动物生物力学模型， 治疗计划和基于愈合的个性化治疗计划框架的开发， 以及fUS治疗后的细胞和机械性质。从长远来看，我们将寻求翻译成人类 基于体内实验结果和为治疗计划开发的模型。

PROJECT SUMMARY/ABSTRACT Almost 30 million tendon injuries are reported annually in the United States, with estimated costs of $114 billion. Even with treatment, some of these tendon injuries become chronic, with pain and loss of function persisting for more than 3 months. Conservative therapeutic techniques that induce microdamage to promote healing, such as dry needling (DN) and extracorporeal shock wave therapy (ESWT), produce mixed results with 0-85% of patients showing improvement. Inconsistencies in parameter reporting, alignment, dosing protocols, and real-time monitoring contribute to the wide range in patient outcomes. We seek to overcome many of the limitations of existing tendinopathy treatments by developing a novel focused ultrasound (fUS) therapy for tendinopathies with integrated passive cavitation and tissue Doppler imaging for alignment and quantitative monitoring of the fUS therapy. Recently, we showed that a narrow range of fUS parameters caused localized collagen fiber separation and fraying in ex vivo rat tendons through the creation, oscillation, and collapse of cavitation bubbles. When tested in an in vivo rat tendinopathy model, fUS preserved tendon mechanical properties as well as or better than the traditional DN therapy; the release of IGF1 and TGFβ healing factors was similar between DN and fUS. However, chronic tendinopathy will influence the mechanical properties of tendon, which will influence the fUS parameters that result in collagen fiber disruption. This prompts the need for testing in tendinopathic tendons of similar size to humans and the development of quantitative passive cavitation and tissue Doppler imaging for real-time monitoring of the tendon treatment progression. Here, we propose to use experiments and modeling to: 1) assess novel fUS to induce ranges of mechanical fractionation in healthy and tendinopathic ex vivo large animal tendons; 2) integrate PCI and tissue Doppler imaging for quantitative, real-time assessment of the fUS therapy; and 3) evaluate fUS to treat chronic tendinopathy. Innovations include a determination of how fUS parameters are affected by the change in mechanical properties of healthy versus injured tendons and the development of integrated passive cavitation and tissue Doppler imaging for quantitative analysis of fUS treatment progression. Additional novelty arises from testing the fUS therapy in a large-animal chronic tendinopathy model and comparing to conventional DN and ESWT therapies. These experimental results will feed into a large animal biomechanical model for treatment planning and the development of a framework for personalized treatment planning based on healing, and cellular and mechanical properties after fUS therapy. Long-term, we will seek translation into humans based on the in vivo experimental results and the models developed for treatment planning.