Collaborative Research: An implantable intracranial ultrasound stimulation for treating neurodiseases

合作研究：用于治疗神经疾病的植入式颅内超声刺激

• 批准号: 2053591
• 负责人: Srinivas Tadigadapa
• 金额: $ 25万
• 依托单位: Northeastern University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2053591&HistoricalAwards=false
• 关键词: Collaborative; Research; implantable; intracranial; ultrasound

Ultrasound stimulation has been demonstrated to be an effective therapeutic tool for treating several brain related disorders in humans. Reducing the symptoms of chronic disorders such as migraine, epilepsy, neuropathic pain due to spinal cord damage, essential tremors and Parkinson’s disease can be accomplished through neuromodulation and targeted delivery of drugs to specific regions of the brain via temporary disruption of the blood- brain-barrier (BBB). However, current ultrasound neuromodulation technology uses a bulky arrangement of several single element ultrasonic transducers inside a helmet shaped device that require high voltage for operation. This limits its use to only clinical settings in hospitals. In contrast, minimally invasive, implantable intracranial ultrasonic stimulation microchips can help treat neurodiseases that require intermittent and chronic stimulation over prolonged periods. Towards this goal, this project will design, fabricate, and validate a low power and biocompatible intracranial micromachined ultrasound chip for temporary opening of the BBB. Such a chip will consume minimal power, operate at safe low voltage, and has the potential to treat chronic neural diseases requiring intermittent on-demand stimulation over periods of months to years. Beyond the application proposed here, successful demonstration of miniaturized ultrasonic chips could also find applications for non-invasive wearable imaging of arterial blood flow for diagnosing vascular diseases and inspection of critical fractures and material failures in aircraft and infrastructural constructions like bridges and pipelines. The multidisciplinary research will enable integration of new pedagogical materials on ultrasound neuromodulation and piezoelectric micromachined ultrasound transduces (PMUTs) design and development, into both undergraduate and graduate engineering curriculum and Senior Capstone Design projects. Outreach activities will target diverse middle and high school students, underrepresented in engineering, with the goal of raising interest and curiosity in ultrasound transduction and imaging methods.This project addresses the current need in implantable focused ultrasound (fUS) technology by leveraging microelectromechanical systems (MEMS) approach to fabricate miniaturized curved 3D transducers in single and array formats and demonstrate their use for trans-BBB drug delivery. To suit implantable and wearable applications, low-voltage, scandium-doped aluminum nitride (Sc-AlN) MEMS approach will be used to realize the PMUTs. To achieve ultra-high electromechanical coupling coefficient, unique curved PMUT membrane shapes will be developed using chip-scale glass-blowing fabrication. The proposed curved PMUT arrays will use optimized Sc-AlN thin films for piezoelectric material, thus ensuring lead-free and biocompatible implants. Inherently curved 3D PMUTs are expected reduce beam width in elevational direction and thus deliver ultrasound energy more efficiently to the neural target of interest. Overall, by using a set of innovations at material, structure, and system level, 8 x 8 PMUT arrays will be demonstrated to generate steerable focused ultrasound output at up to 2 cm depth in the brain tissue with 1 MPa pressure at the focal spot and 0.5 mm resolution. This approach will offer unique flexibility to cover a large region of interest in brain with high resolution for ultrasound stimulation applications. Further, the pressure output of the fabricated curved PMUT array device will be validated using experiments on brain tissue. BBB-opening capabilities will be tested using in vitro cell culture experiments.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

超声波刺激已被证明是治疗人类多种脑部相关疾病的有效治疗工具。减轻偏头痛、癫痫、脊髓损伤引起的神经性疼痛、原发性震颤和帕金森病等慢性疾病的症状可以通过神经调节和通过暂时破坏血脑屏障（BBB）将药物定向输送到大脑的特定区域来实现。然而，当前的超声神经调节技术在头盔状装置内使用了多个单元件超声换能器的笨重布置，需要高电压才能运行。这限制了其只能在医院的临床环境中使用。相比之下，微创、植入式颅内超声刺激微芯片可以帮助治疗需要长时间间歇性和慢性刺激的神经疾病。为了实现这一目标，该项目将设计、制造和验证一种低功耗且生物相容性的颅内微机械超声芯片，用于暂时打开血脑屏障。这种芯片消耗的功率最小，在安全低电压下运行，并且有潜力治疗需要数月至数年间歇性按需刺激的慢性神经疾病。除了这里提出的应用之外，微型超声波芯片的成功演示还可以用于动脉血流的非侵入性可穿戴成像，用于诊断血管疾病以及检查飞机和桥梁和管道等基础设施中的严重断裂和材料故障。多学科研究将使关于超声神经调节和压电微机械超声换能器（PMUT）设计和开发的新教学材料整合到本科生和研究生工程课程以及高级顶点设计项目中。外展活动将针对工程学领域代表性不足的不同中学生和高中生，目的是提高对超声转导和成像方法的兴趣和好奇心。该项目通过利用微机电系统 (MEMS) 方法来制造单一和阵列格式的微型弯曲 3D 换能器，并演示其在跨 BBB 中的用途，从而满足当前对植入式聚焦超声 (fUS) 技术的需求 药物输送。为了适应植入式和可穿戴式应用，低压掺钪氮化铝 (Sc-AlN) MEMS 方法将用于实现 PMUT。为了实现超高机电耦合系数，将使用芯片级玻璃吹制制造技术开发独特的弯曲 PMUT 膜形状。拟议的弯曲 PMUT 阵列将使用优化的 Sc-AlN 薄膜作为压电材料，从而确保植入物的无铅和生物相容性。固有弯曲的 3D PMUT 有望减少高度方向上的波束宽度，从而更有效地将超声能量传递到感兴趣的神经目标。总体而言，通过使用一系列材料、结构和系统级别的创新，8 x 8 PMUT 阵列将被证明能够在脑组织深度达 2 厘米处产生可操纵的聚焦超声输出，焦点处压力为 1 MPa，分辨率为 0.5 毫米。这种方法将提供独特的灵活性，以高分辨率覆盖大脑中的大片感兴趣区域，用于超声刺激应用。此外，所制造的弯曲 PMUT 阵列装置的压力输出将通过脑组织实验进行验证。 BBB 开放能力将使用体外细胞培养实验进行测试。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。