Non-Thermal Pulsed FUS for Treatment of Intervertebral Disc Degeneration

项目摘要： 这笔赠款的总体目标是开发通过体外治疗轴性背痛的改进方法。 非热或机械脉冲聚焦超声(p-FUS)的应用 研究表明，低强度脉冲超声(LIPUS)刺激可以诱导大鼠的疾病修饰活动 间盘细胞。这些观察表明，LIPUS或p-FUS可能是一种有价值的非侵入性 估计300万保守治疗失败的下腰痛患者的治疗策略 他唯一的其他选择是有风险的，脊柱手术。然而，可行的p-fus剂量设置可优化 尚未建立理想的椎间盘细胞行为和组织再生；此外，提供 基于应用于脊柱的超声成像方案，将超声能量提供给盘似乎是可行的， 但将LIPUS的能量输送到椎间盘的实用方法仍有待评估。 该R21应用程序的目标是：1)使用已建立的3D人类退行性变椎间盘细胞培养 用于表征和优化细胞行为以响应不同的LIPUS或p-FUS方案的系统，使用 定制校准超声暴露仪系统专为提供靶向超声而设计 强度，同时防止细胞培养板内的加热、反射和驻波；2)建立 使用p-FUS系统建立的鼠尾损伤模型在体内的Lipus疾病修改活性 专为目标盘的隔离校准曝光而设计；以及3)应用现有的诊断数据 建立和使用复杂的3D声学和热模拟来确定临床应用的可行性和局限性。 FUS送货。创新点包括一种新的体外研究方法，以提供可量化的LIPUS 在没有样品加热或驻波的情况下，LIPUS的频率和能量效应的广泛优化 考虑脊柱中的深层靶点所需的受损的椎间盘细胞，并调查和 描述体内愈合和重塑反应的成分。 这个研究团队在开发、表征和活体评估方面拥有丰富的经验 超声系统以及体外和体内的椎间盘退变和再生模型。 因此，这些具有重要临床意义和意义的研究具有很高的实用价值。 成功完成的概率。这项拟议研究的完成有可能导致一部小说 并改进了治疗背部损伤及相关疼痛的非侵入性方法。

PROJECT ABSTRACT: The overall goal of this grant is to develop improved methods of treating axial back pain via extracorporeal application of non-thermal or mechanical pulsed focused ultrasound (p-FUS) Recent in vitro studies have shown that low intensity pulsed ultrasound (LIPUS) stimulation can induce disease-modifying activities in intervertebral disc cells. These observations suggest that LIPUS or p-FUS may be a valuable non-invasive therapeutic strategy for the estimated 3 million low back pain sufferers who have failed conservative therapy and whose only other option is risky, spinal surgery. However, practicable p-FUS dose settings that optimize desirable disc cell behaviors and tissue regeneration have not been established; further, methods to deliver ultrasound energy to the disc appear feasible based upon ultrasound imaging protocols applied to the spine, but practical methods to deliver the energy for LIPUS to the disc remain to be evaluated. The goals of this R21 application are to: 1) use an established 3D human degenerative disc cell culture system to characterize and optimize cell behaviors in response to varying LIPUS or p-FUS regimens, using a custom calibrated ultrasound exposimetry system specifically designed to deliver a targeted ultrasound intensity while preventing heating, reflections, and standing waves within cell culture plates; 2) establish the LIPUS disease-modifying activity in vivo using an established rat-tail injury model, using a p-FUS system designed specifically for isolated calibrated exposure of the targeted disc; and 3) apply existing diagnostic data sets and employ complex 3D acoustic and thermal modeling to define feasibility and limitations of clinical p- FUS delivery. Points of innovation include a novel approach for in vitro studies to deliver quantifiable LIPUS without sample heating or standing waves, a broad optimization of frequency and energy effects of LIPUS on damaged disc cells as required for consideration of deep targets in the spine, and to also investigate and characterize components of the healing and remodeling response in vivo. This research team has significant experience with developing, characterizing, and the in vivo evaluation of ultrasound systems as well as in vitro and in vivo models of intervertebral disc degeneration and regeneration. Consequently, these proposed studies with important clinical implications and significance have high probability of being completed successfully. Completion of this proposed study has potential to lead to a novel and improved non-invasive method for treating back injury and related pain.