Flexible and Wireless Bioelectronics for Continuous Monitoring of Intracranial Pressure

项目概述：本提案描述了一个为期五年的研究和职业发展计划，以准备 Razieh Khalifehzadeh博士作为独立调查员的职业生涯。这一计划将建立在Dr。 Khalifehzadeh作为生物工程科学家的多学科背景，接受过生物电子学、生物材料方面的培训 和基础癌症研究，通过提供设计灵活和高灵敏度的压力传感器的专业知识 持续无线监测与脑肿瘤相关的颅内压(ICP)。PI将会是 在斯坦福大学工程和医学院由包振南博士指导(主要导师，灵活和 可穿戴生物电子)，Sanjiv S.Gambhir(癌症诊断、癌症生物工程和癌症联合导师 纳米技术)，Heike Daldrup-Link(脑癌成像和治疗的共同导师，促进 多样性)、Ada Poon(无线生物电子合作者)、Melanie Hayden(神经外科和 神经学)和Eric Appl(合作者，生物材料和生物兼容性)。 脑肿瘤通常与颅内压升高有关。高血压病的延迟诊断和治疗 妊娠期肝内胆汁淤积症常常导致不可逆转的神经损害，甚至死亡。建议的总体目标是 研究是设计高灵敏度和大脑兼容的压力传感器，可以无线检测颅内压 变异，作为脑肿瘤患者普遍被忽视的神经标记物。最近，我开发了超小型 (3×3×0.1mm3)、灵活且可植入的压力传感器，可有效地无线监测颅内压 小鼠U87脑肿瘤生长模型在其30天存活期内的变化。的关键组件 这些压力传感器是具有特定压力响应微图案的中间弹性体层， 定义了这些设备对大脑中长期准确测量的一致灵敏度。在目标1中 在本项目中，我将研究这种弹性体层的新设计，以进一步提高灵敏度和耐久性能。 我的压力传感器的机电稳定性。此外，我将使用实验和模拟来 寻找替代设计，以实现更高效的无线信号传输(即更高的信噪比) 传感器。我还将开发一个手持无线信号记录设置，以实现记录和快速分析 使用智能手机的无线压力数据，以便更轻松地进行活体测量和未来的护理 申请。目标2的重点是延长植入后的寿命和传感器的大脑兼容性 通过在它们表面涂上对二甲苯(厚度约1-4微米)。对二甲苯已被广泛用作防护层 神经接口和心脏辅助装置，以延长其植入后的寿命。最后，我将使用这些 传感器用于连续无线监测不同脑瘤模型小鼠的颅内压变化，不同 生存期，取决于肿瘤的侵袭性(目标3)。将使用核磁共振成像、模拟和组织学 以核实颅内压测量结果。临床上需要这些传感器来监测不同脑部疾病的颅内压， 包括肿瘤，我们设想它们的多功能性设计将促进它们的临床应用。

Project Summary: This proposal describes a five-year research and career development program to prepare Dr. Razieh Khalifehzadeh for a career as an independent investigator. This program will build upon Dr. Khalifehzadeh’s multidisciplinary background as a bioengineer scientist, trained in bioelectronics, biomaterials and basic cancer research, by providing expertise in designing flexible and highly sensitive pressure sensors for continuous wireless monitoring of intracranial pressure (ICP) associated with brain tumors. The PI will be mentored at Stanford Schools of Engineering and Medicine by Drs. Zhenan Bao (Main mentor, flexible and wearable bioelectronics), Sanjiv S. Gambhir (co-mentor, cancer diagnosis, cancer bioengineering and cancer nanotechnology), Heike Daldrup-Link (co-mentor, brain cancer imaging and therapy, and a leader in promoting diversity), Ada Poon (collaborator, wireless bioelectronics), Melanie Hayden (collaborator, neurosurgery and neurology) and Eric Appel (collaborator, biomaterials and biocompatibility). Brain tumors are usually associated with increased ICP. Delayed diagnosis and treatment of the elevated ICP often results in irreversible neurological damage and even death. The overall goal of the proposed research is to design highly sensitive and brain compatible pressure sensors that can wirelessly detect ICP variations, as a generally neglected neurological marker in brain tumor patients. Recently, I developed ultrasmall (3×3×0.1 mm3), flexible, and implantable pressure sensors that were effective for wireless monitoring of the ICP variations in mice models of growing U87 brain tumor over their 30 day survival period. The key component of these pressure sensors is an intermediate elastomer layer with a specific pressure-responsive micropattern that defines the consistent sensitivity of these devices for long-term accurate measurements in the brain. In Aim 1 of this project, I will study new designs for this elastomer layer, in order to further improve the sensitivity and long- term electro-mechanical stability of my pressure sensors. Additionally, I will use experiments and simulations to find alternative designs for more efficient wireless signal transfer (i.e., higher signal-to-noise ratios) from these sensors. I will also develop a handheld wireless signal recording setup to enable recording and rapid analysis of the wireless pressure data using a smartphone, for easier in vivo measurements and future point-of-care applications. Aim 2 is focused on extending the post-implantation lifetime and brain compatibility of the sensors by coating them with parylene (thickness ~ 1-4 µm). Parylene has been broadly used as a protective coating for neuro-interface and cardiac assist devices to enhance their post-implantation lifetime. Finally, I will use these sensors for continuous wireless monitoring of ICP variations in different mice models of brain tumors, with various survival periods, depending on invasiveness of the tumor (Aim 3). MRI, simulations and histology will be used to verify ICP measurements. These sensors are clinically needed for monitoring ICP in different brain diseases, including tumors, and we envision that their versatile design will facilitate their clinical applications.