Collaborative Research: An implantable intracranial ultrasound stimulation for treating neurodiseases

超声刺激已被证明是治疗人类几种脑相关疾病的有效治疗工具。减轻慢性疾病的症状，如偏头痛、癫痫、脊髓损伤引起的神经性疼痛、原发性震颤和帕金森病，可以通过神经调节和通过暂时破坏血脑屏障（BBB）将药物靶向递送到大脑的特定区域来实现。然而，目前的超声神经调节技术使用了一个头盔形状的装置，里面有几个单元件超声换能器，需要高电压来操作。这限制了它的使用，仅在医院的临床设置。相比之下，微创、可植入的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，本项目将设计、制造和验证一种低功耗和生物相容性的颅内微机械超声芯片，用于临时打开血脑屏障。这种芯片将消耗最小的功率，在安全的低电压下工作，并且有可能治疗需要数月至数年间歇性按需刺激的慢性神经疾病。除了本文提出的应用之外，小型化超声芯片的成功演示还可以在动脉血流的无创可穿戴成像中找到应用，用于诊断血管疾病，检查飞机和桥梁、管道等基础设施的关键骨折和材料故障。多学科研究将使超声神经调节和压电微机械超声换能器（PMUTs）设计和开发的新教学材料整合到本科和研究生工程课程和高级顶点设计项目中。外展活动将针对不同的初中和高中学生，在工程方面代表性不足，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）方法制造单个和阵列格式的小型化弯曲3D换能器，解决了当前对植入式聚焦超声（fUS）技术的需求，并展示了它们在跨血脑动脉药物输送中的应用。为了适应可植入和可穿戴的应用，将采用低电压、掺钪氮化铝（Sc-AlN） MEMS方法来实现pmut。为了实现超高机电耦合系数，将采用芯片级玻璃吹制技术开发独特的弯曲PMUT膜形状。提出的弯曲PMUT阵列将使用优化的Sc-AlN薄膜作为压电材料，从而确保无铅和生物相容性植入物。固有弯曲的3D pmut有望在高度方向上减小波束宽度，从而更有效地将超声能量传递到感兴趣的神经目标。总的来说，通过在材料、结构和系统层面上的一系列创新，8 x 8 PMUT阵列将被证明能够在脑组织中产生可操纵的聚焦超声输出，深度可达2厘米，焦点处压力为1 MPa，分辨率为0.5 mm。这种方法将提供独特的灵活性，以高分辨率覆盖大脑的大区域，用于超声刺激应用。此外，制备的弯曲PMUT阵列装置的压力输出将通过脑组织实验进行验证。打开血脑屏障的能力将通过体外细胞培养实验进行测试。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

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 for implantable focused ultrasound (fUS) technology by leveraging a 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 to 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.