Histotripsy for collagenous tissues: a novel therapeutic approach to tendon injury

项目总结/摘要 高强度聚焦超声（HIFU）模式，如组织摧毁术，已成功地用于 心脏和肝脏等柔软的器官，但肌腱等高度胶原化的组织， 到机械乳化和组织破碎术最近，组织破坏术被证明可以启动免疫反应， 并释放生物标志物。如果组织摧毁术能成功地修复胶原组织， 通过诱导炎症并随后释放愈合因子来启动愈合反应。与高 肌腱损伤的临床患病率，确定组织粉碎术是否可以在胶原纤维中产生微损伤， 肌腱，以促进愈合具有长期影响的潜力。 肩袖撕裂是引起肩痛的一个非常普遍的原因，这也是患者寻求治疗的原因。 手术修复是肩袖撕裂的常见治疗方法，但高达90%的时间失败，可能是由于高 机械负荷旋转套在其关节活动性和稳定性方面具有双重作用。其他人已经 使用干针（DN），其中包括用细针反复穿刺肌腱，以诱导 微损伤和释放愈合因子，但这种方法的采用并不广泛。发展 可以非侵入性地促进愈合，同时保持肌肉肌腱的机械完整性的技术 单位急需。胶原组织乳化的组织摧毁疗法的证明将 提供临床上可转移的工具，以立即补充当代的当前治疗选择， 临床问题 在这里，我们建议建立非侵入性组织碎石协议，产生更好的肌腱指标 愈合相比DN，同时保持肌腱的机械性能。这些目标将是 通过以下方式完成：1）测试新的组织破坏方案以诱导胶原凝胶和离体大鼠中的微损伤 肌腱; 2）评估组织破坏和DN后肌腱的力学性能，并建立有限的 元件模型，以评估参数并进行预测分析;以及3）确定组织破坏是否 在大鼠的初步存活研究中，增强体内胶原组织愈合。这项创新工作旨在 证明组织破坏术可以成功地破坏胶原组织，并增强愈合的释放 因素一旦可行性得到证明，本项目中开发的方法和模型将 在较大的动物模型和人类中进行组织破坏试验。长期，结果将导致组织破坏 其他胶原组织的乳化以及肌腱愈合方案的临床转化， 可能会彻底改变对肩袖撕裂和其他胶原组织损伤的治疗。

PROJECT SUMMARY/ABSTRACT High intensity focused ultrasound (HIFU) modalities, such as histotripsy, have been used successfully to emulsify soft organs, like the heart and liver, but highly collagenous tissues, like tendons, have proven resistant to mechanical emulsification with histotripsy. Recently, histotripsy was shown to initiate an immune response and release biomarkers. If histotripsy can successfully emulsify collagenous tissues, it has the potential to initiate a healing response by inducing inflammation and subsequently release healing factors. With the high clinical prevalence of tendon injuries, establishing whether histotripsy can create microdamage in collagenous tendons to promote healing has the potential for long-term impact. Rotator cuff tear is a highly prevalent cause of shoulder pain, which is why patients seek medical treatment. Surgical repair is a common treatment for rotator cuff tear, but fails up to 90% of the time, likely from the high mechanical loading the rotator cuff experiences in its dual roles with joint mobility and stability. Others have used dry needling (DN), which involves repeated puncturing of the tendon with a fine-gauge needle to induce microdamage and release healing factors, but adoption of this approach is not wide-spread. Development of techniques that can noninvasively promote healing while maintaining mechanical integrity of the muscle-tendon units are desperately needed. Demonstration of histotripsy therapy for collagenous tissue emulsification would provide a clinically transferrable tool to immediately supplement current treatment options of a contemporary clinical problem. Here, we propose to establish non-invasive histotripsy protocols that produce better indicators of tendon healing compared to DN, while simultaneously maintaining tendon's mechanical properties. These goals will be accomplished by: 1) testing novel histotripsy protocols to induce microdamage in collagen gels and ex vivo rat tendons; 2) evaluating the mechanical properties of tendon following histotripsy and DN, and develop a finite element model to evaluate parameters and perform predictive analyses; and 3) determining whether histotripsy enhances collagenous tissue healing in vivo in a pilot survival study in rats. This innovative work seeks to demonstrate that histotripsy can successfully emulsify collagenous tissues, and enhance the release of healing factors. Once feasibility has been demonstrated, the methods and models developed in this project will be scaled to examine histotripsy in larger animal models and humans. Long term, outcomes will lead to histotripsy emulsification of other collagenous tissues as well as clinical translation of tendon healing protocols, which has the potential to revolutionize treatment for rotator cuff tear and other collagenous tissue injuries.