Collaborative Research: An implantable intracranial ultrasound stimulation for treating neurodiseases

超声刺激已被证明是一种有效的治疗工具，用于治疗人类的几种脑相关疾病。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、特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)将药物定向输送到大脑特定区域来实现。然而，目前的超声神经调节技术在头盔形状的设备内使用几个单元件超声换能器的笨重布置，这需要高电压才能操作。这限制了它只能在医院的临床环境中使用。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刺激和慢性刺激的神经疾病。为了实现这一目标，本项目将设计、制造和验证一种用于暂时打开血脑屏障的低功耗和生物兼容的颅内微机械超声芯片。这种芯片将消耗最低的功率，在安全的低电压下运行，并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。除了这里提出的应用，微型超声波芯片的成功展示还可以应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建设中的严重骨折和材料故障。这项多学科研究将使有关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能够整合到本科和研究生工程课程以及高级Capstone设计项目中。推广活动将面向不同的初中生和高中生，他们在工程学中的比例较低，目的是提高人们对超声传输和成像方法的兴趣和好奇心。该项目通过利用微电子机械系统(MEMS)方法制造单一和阵列格式的微型曲面3D换能器，满足了植入式聚焦超声(FUS)技术的当前需求，并展示了它们在跨血脑屏障药物输送中的用途。为了适应可植入和可穿戴的应用，将使用低电压、钪掺杂氮化铝(SC-AlN)MEMS方法来实现PMUT。为了实现超高的机电耦合系数，将利用芯片级玻璃吹制技术开发出独特的曲面PMUT薄膜形状。建议的弯曲PMUT阵列将使用优化的SC-AlN薄膜作为压电材料，从而确保无铅和生物兼容的植入物。自然弯曲的三维PMUT有望减小垂直方向的波束宽度，从而将超声能量更有效地传递到感兴趣的神经靶。总体而言，通过在材料、结构和系统层面的一系列创新，将展示8 x 8 PMUT阵列将在脑组织中产生可控制的聚焦超声输出，焦点压力为1兆帕，分辨率为0.5毫米。这种方法将提供独特的灵活性，以高分辨率覆盖大范围的大脑感兴趣区域，用于超声刺激应用。此外，制作的曲面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。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势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 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.