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

在美国，每年有超过20万名妇女被诊断出患有乳腺癌，每年导致超过4万人死亡。肿瘤靶向表面增强拉曼散射纳米粒子复合拉曼光谱技术在癌症的早期和准确检测方面显示出巨大的潜力，这对患者的生存率有很大的影响。拉曼纳米颗粒的光谱指纹图谱使研究多个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输送成为可能。传统的拉曼光谱扫描速度慢，扫描时间长，只能对体外组织标本成像或监测麻醉下的小动物，其行为与自由运动的动物不同。植入式拉曼系统是一种尚未得到满足的需求，它可以对肿瘤进行体内多路复用的广域成像和纵向研究，监测药物输送后的动态反应，并定量研究多个生物标志物的靶向纳米颗粒。本项目将专注于基于植入式热显微扫描仪的拉曼光谱仪，用于在自由活动的乳腺癌大鼠模型中进行广域肿瘤成像。社会影响将是巨大的，不仅对科学界(癌症生物学)，而且对更广泛的能源科学界(太阳能电池检查)、制药业(药物筛选)。科学的影响是产生对可植入微系统领域的研究人员具有重要意义的知识。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的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，使当地的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野肿瘤成像中的根本局限性。该研究计划将专注于开发一种基于拉曼光谱的可植入微电子机械系统，用于体内监测和纵向研究肿瘤生长和基于纳米颗粒的靶向药物输送。为了实现这一目标，将研制一种超低功耗的基于二氧化钒的自感热单片微型扫描器，用于以二维光栅扫描的方式实现大镜面偏转的快速波控，从而实现大视场的广视场光谱成像。基于微细电镀和模塑技术的新型可大规模集成工艺将被开发用于超薄光学机械器件，包括可植入的拉曼扫描头。此外，还将基于红外光电倍增管附近的单元件和带有片上光栅的二氧化钒微扫描器，开发一种基于超小型超低功耗微扫描器的拉曼光谱仪。为了实现扫描头与光谱仪的互连，并提供生理记录，将利用立体光刻三维打印工艺开发一种紧凑的小动物背包，在保形表面集成生理传感器。最后，该平台将在自由运动的乳腺癌大鼠模型上进行表征，以获取与特定针对过度表达的生物标志物的抗体结合的纳米颗粒的拉曼光谱。虽然生物组织样品的拉曼光谱已经取得了重大进展，但分子靶向的大鼠自由运动肿瘤的体内广域多路拉曼成像尚未得到证实。超低功耗的扫描头和光谱仪的小型化是植入式拉曼系统的关键。建议的植入式超低功率热显微扫描仪启用的拉曼成像策略将克服当前拉曼成像模式的基本限制，这些模式具有更高的灵敏度、可扩展的分辨率、更深的渗透、更短的集成时间等迫切和未满足的需求。该奖项反映了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。

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.