Noninvasive histotripsy ablation of fibrotic tissue in benign prostatic hyperplasia

项目摘要 良性前列腺增生（BPH）是最常见的原因，令人烦恼的下尿路症状 （LUTS）在50岁的男性中影响一半，在80岁的男性中影响约90%。BPH的特征是增生性 腺上皮细胞和纤维肌性基质细胞生长，导致中位和 前列腺外侧叶由此产生的膀胱出口梗阻阻碍了尿液通过前列腺的流动 尿道，导致LUTS的发展（紧迫性，频率，弱流，紧张，犹豫， 夜间排尿和排尿）。虽然目前的手术治疗BPH是有效的，但越来越多的患者， 这一患者群体的年龄和发病率导致了相当大的临床需求， 侵入性更小和病态程度更低的手术。组织摧毁术是一种新兴的非侵入性技术， 高振幅聚焦超声脉冲以机械地分解组织。正在调查组织解剖学 用于各种疾病，包括良性前列腺增生、血栓形成、肿瘤治疗、先天性 缺陷该技术的研究主要集中在主要是细胞的软组织上; 组织分解的生物效应、成像和大体特征、组织学分析、暴露参数，以及 治疗的其它方面基于软的、腺体的 组织中然而，包括BPH在内的许多疾病都含有关键的纤维成分。初步数据 表明不同的组织破坏暴露可以实现纤维组织保留或消融。在这 建议，我们的目的是表征组织破坏对纤维化组织的物理和生物学效应，评估 有希望的治疗策略来治疗这样的组织，并将这些方法专门应用于改善组织破坏 前列腺我们建议开发气泡-纤维基质相互作用的物理和数值模型， 使用超声和光学表征组织破坏暴露对纤维结构的物理影响 成像方法将测试新的暴露策略，以促进纤维组织的分解， 通过超声成像反馈识别组织破裂。先进的策略将在体外进行测试 人类前列腺标本，以确认改进的消融。急性和慢性生物效应将在 BPH犬模型。我们还将测量治疗之间排尿模式和尿动力学的变化 以证明症状改善。该项目的成功实施将克服 对BPH组织碎石术的临床实施存在障碍，并有助于其他组织碎石术的发展 应用.

PROJECT SUMMARY Benign prostatic hyperplasia (BPH) is the most common cause of bothersome lower urinary tract symptoms (LUTS) in men affecting half by age 50 and about 90% of men by age 80. BPH is characterized by hyperplastic growth of glandular epithelial cells and fibromuscular stromal cells, leading to enlargement of the median and lateral lobes of prostate. The resulting bladder outlet obstruction impedes the flow of urine through the prostatic urethra, accounting for the development of LUTS (urgency, frequency, weak stream, straining, hesitancy, intermittency and night time voiding). Although current surgical management of BPH is efficacious, the increasing age and morbidity of this patient population has resulted in considerable clinical need for equally effective but less invasive and less morbid procedures. Histotripsy is an emerging noninvasive technology that applies short, high-amplitude focused ultrasound pulses to mechanically disintegrate tissue. Histotripsy is being investigated for a variety of diseases, including benign prostate hyperplasia, thrombosis, tumor treatment, and congenital defects. Investigations of the technology have strongly focused on soft tissues that are primarily cellular; the bioeffects, imaging and gross signatures of tissue breakdown, histological analysis, exposure parameters, and other aspects of the treatment are characterized and progressed based on the response of soft, glandular tissues. However, many of these diseases including BPH contain a critical fibrous component. Preliminary data indicates that different histotripsy exposures can achieve either fibrous tissue sparing or ablation. In this proposal, we aim to characterize the physical and biological effects of histotripsy on fibrotic tissue, evaluate promising treatment strategies to treat such tissue, and apply these methods specifically to improve histotripsy of the prostate. We propose to develop physical and numerical models for bubble-fibrous matrix interaction and characterize the physical effects of histotripsy exposures on fibrous structures using ultrasound and optical imaging methods. New exposure strategies will be tested to promote disintegration of fibrous tissue and identification of tissue disruption via ultrasound imaging feedback. Advanced strategies will be tested in ex vivo human prostate specimens to confirm improved ablation. Acute and chronic bioeffects will be assessed in a canine model of BPH. We will also measure changes in voiding patterns and urodynamics between treatment groups to demonstrate symptomatic improvement. The successful implementation of this project will overcome existing obstacles to clinical implementation of histotripsy for BPH and aid development of histotripsy for other applications.