Implantable Ultra-low Power VO2 MEMS Scanner based Surface-enhanced Raman Spectroscope for Wide-field Tumor Imaging in Free Moving Small Animals

基于表面增强拉曼光谱仪的植入式超低功耗 VO2 MEMS 扫描仪，用于自由移动小动物的宽视场肿瘤成像

• 批准号: 1808436
• 负责人: Zhen Qiu
• 金额: $ 36万
• 依托单位: Michigan State University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1808436&HistoricalAwards=false
• 关键词: Implantable; Ultra; low; Power; VO2

Every year, over 200,000 women are diagnosed with breast cancer which causes more than 40,000 deaths per year in the US. Tumor-targeting surface enhanced Raman scattering nanoparticles based multiplexed Raman spectroscopy has recently demonstrated great potentials to promote early and accurate cancer detection, which significantly impact patient's survival rates. Spectral fingerprints of Raman nanoparticles make it possible to study multiple cell surface biomarkers and analyze targeted drug delivery in breast cancer rat models. With long scanning time in slow speed, conventional Raman spectroscopy can only image ex-vivo tissue specimens or monitor small animals under anesthesia, which behave differently from free moving ones. There is an unmet need for an implantable Raman system, which performs in-vivo multiplexed wide-field imaging and longitudinal study on tumor, monitoring the dynamic response after drug delivery, and quantitatively study targeted nanoparticles for multiple biomarkers. This project will be focused on implantable thermal micro-scanner based Raman spectroscope for wide-field tumor-imaging in free moving breast cancer rat model. Societal impact will be significant, not only on scientific communities (cancer biology), but also on broader communities of energy science (solar cell inspection), pharmaceutical industry (drug screening). The scientific impact is to generate knowledge that will be significance to researchers in the field of implantable micro-system. The outcomes will yield next generation transformative devices to enable a comprehensive understanding of tumor development and targeted drug delivery. This project will provide educational opportunities for students to learn different disciplines and develop multiple skill sets. Outreach events will transform state-of-the-art technologies to educational resources that are more accessible to local K-12 schools and broader communities in greater Lansing area. The goal of this project is to overcome the fundamental limitations in miniaturized ultra-low power surface-enhanced Raman spectroscopy aimed for in-vivo wide-field tumor imaging in free moving rat. The research plan will be focused on developing an implantable microelectromechanical system based Raman spectroscopy for in-vivo monitoring and longitudinal study of tumor growth and nanoparticles based targeted drug delivery. To achieve this goal, an ultra-low power vanadium dioxide based self-sensing thermal monolithic micro-scanner will be developed for fast beam steering with large mirror deflection in two-dimensional raster scan manner, which enables wide-field spectroscopic imaging with large field-of-view. Novel micro-scale electroplating and molding techniques based mass-producible integration process will be developed for ultra-thin opto-mechanical devices, including the implantable Raman scan-head. In addition, an ultra-compact ultra-low power micro-scanner based Raman spectrometer will be developed based on single element near infra-red photomultiplier tube and a vanadium dioxide micro-scanner with on-chip grating. For interconnecting the scan-head with spectrometer and providing physiological recording, a compact small animal backpack with integrated physiology sensors on conformal surface, will be developed using stereolithography three-dimensional printing process. Finally, the platform will be characterized on free moving breast cancer rat model for acquiring Raman spectra from nanoparticles conjugated with anti-bodies specifically targeting over-expressed biomarkers. Although significant progress has been made in the Raman spectroscopy on biological tissue samples, molecularly targeted wide-field in-vivo multiplexed Raman imaging of tumor in free moving rat has not been demonstrated yet. Miniaturization of the scan-head and spectrometer with ultra-low power consumption is critical to implantable Raman system. The proposed implantable ultra-low power thermal micro-scanner enabled Raman imaging strategy will overcome the fundamental limitation in current Raman imaging modality that has urgent and unmet needs, such as higher sensitivity, scalable resolution, deeper penetration, shorter integration time.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.

在美国，每年有超过20万名女性被诊断患有乳腺癌，导致4万多人死亡。基于肿瘤靶向表面增强拉曼散射纳米粒子的多路拉曼光谱最近显示出促进早期和准确癌症检测的巨大潜力，这显着影响患者的生存率。拉曼纳米粒子的光谱指纹图谱使得研究多种细胞表面生物标志物和分析乳腺癌大鼠模型中的靶向药物递送成为可能。传统的拉曼光谱扫描时间长，速度慢，只能成像离体组织标本或监测麻醉状态下的小动物，其行为与自由运动的小动物不同。目前对植入式拉曼系统的需求尚未得到满足，该系统可以对肿瘤进行体内多路宽视场成像和纵向研究，监测药物传递后的动态反应，并定量研究多种生物标志物的靶向纳米颗粒。本课题将重点研究基于热微扫描仪的植入式拉曼光谱仪在自由运动乳腺癌大鼠模型中的宽视场肿瘤成像。社会影响将是显著的，不仅在科学界（癌症生物学），而且在更广泛的社区能源科学（太阳能电池检查），制药工业（药物筛选）。科学影响是产生对植入式微系统领域的研究人员有意义的知识。这些成果将产生下一代变革性设备，使人们能够全面了解肿瘤发展和靶向药物输送。该项目将为学生提供学习不同学科和发展多种技能的教育机会。外展活动将把最先进的技术转化为教育资源，使当地K-12学校和大兰辛地区更广泛的社区更容易获得这些资源。本项目的目标是克服小型化超低功率表面增强拉曼光谱在自由运动大鼠体内宽视场肿瘤成像的基本限制。该研究计划将侧重于开发一种基于拉曼光谱的植入式微机电系统，用于肿瘤生长的体内监测和纵向研究，以及基于纳米颗粒的靶向药物输送。为了实现这一目标，将开发一种基于超低功耗二氧化钒的自传感热单片微扫描仪，以二维光栅扫描方式实现大反射镜偏转的快速光束转向，从而实现大视场的宽视场光谱成像。基于可植入拉曼扫描头的超薄光机械器件将开发基于微尺度电镀和成型技术的可批量生产集成工艺。此外，还将研制基于单元件近红外光电倍增管的超小型超低功耗微扫描仪拉曼光谱仪和带有片上光栅的二氧化钒微扫描仪。为了实现扫描头与光谱仪的互连，提供生理记录，将采用立体光刻三维打印工艺开发一种紧凑的小动物背包，该背包在保形表面集成了生理传感器。最后，该平台将在自由移动的乳腺癌大鼠模型上进行表征，以获取纳米颗粒与特异性靶向过表达生物标志物的抗体结合的拉曼光谱。尽管拉曼光谱在生物组织样品上取得了重大进展，但分子靶向的大鼠肿瘤体内宽视场多路拉曼成像尚未得到证实。扫描头和光谱仪的小型化和超低功耗是实现可植入拉曼系统的关键。提出的可植入的超低功耗热微扫描仪拉曼成像策略将克服当前拉曼成像方式的根本限制，如更高的灵敏度、可扩展的分辨率、更深的穿透、更短的集成时间等迫切需要。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。

项目成果

2D Au-Coated Resonant MEMS Scanner for NIR Fluorescence Intraoperative Confocal Microscope

用于近红外荧光术中共焦显微镜的二维镀金谐振 MEMS 扫描仪

• DOI: 10.3390/mi10050295
• 发表时间: 2019
• 期刊: Micromachines
• 影响因子: 3.4
• 作者: Yao, Cheng-You;Li, Bo;Qiu, Zhen
• 通讯作者: Qiu, Zhen

MEMS Actuators for Optical Microendoscopy

• DOI: 10.3390/mi10020085
• 发表时间: 2019-01
• 期刊: Micromachines
• 影响因子: 3.4
• 作者: Z. Qiu;W. Piyawattanametha

Editorial for the Special Issue on Implantable Microdevices

• DOI: 10.3390/mi10090603
• 发表时间: 2019-09
• 期刊: Micromachines
• 影响因子: 3.4
• 作者: Wen Li;Z. Qiu