半导体芯片集成的循环肿瘤细胞捕获、检测方法研究

Cancer is one of the malignant diseases with the highest incidence and mortality worldwide. Most of the cancer patients died due to the tumor recurrence and metastasis. Circulating tumor cells (CTCs) in peripheral blood have been proven valuable for cancer diagnosis, prognostic evaluation, and metastasis monitoring. Due to the extremely low concentration and high heterogeneity of CTCs, the current techniques based on CTCs’ biomarkers or physical properties for CTCs capture and detection have some limitations. This project proposes a new concept to use a semiconductor-chip integrated device for CTCs capture and detection. By monolithic integration of the micro through via, microelectrodes, and integrated circuits on a single chip, a new multidimensional CTCs capture and detection method can be realized, such as CTCs sized-based filtering, electrical detection and microfluidic separation with high throughput, high specificity, and high resolution (single cell level). Firstly, we will theoretically study the interactions between cell and external voltage (electric field), and their mechanisms. Then, the effects of electric stimulation on CTCs will be evaluated theoretically and experimentally to establish a safe and effective CTCs detection condition. The integrated device will be designed and fabricated using micro/nano fabrication facilities. Finally, the application of the developed method for highly efficient CTCs capture and detection will be studied with cultured cell lines and clinical samples. This project will pave the way for developing the next-generation cancer diagnostics technique, high throughput single cell analysis by providing theoretical supports and basic experimental data.

血液中的循环肿瘤细胞（Circulating Tumor Cells, CTCs）被证实可用于癌症检测、预后评价、及转移监测。由于CTCs含量极少，异质性高，现有基于CTCs肿瘤标志物、或其自身物理性质的捕获、检测方法均存在一定局限性。本项目提出了一种半导体芯片集成的CTCs捕获、检测新方法。通过将筛分微孔、检测微电极、及集成电路进行片上垂直集成，并结合微流控芯片，来实现多维度、高特异性、高通量、单细胞级别的CTCs捕获与检测。本项目首先建立物理模型，系统研究细胞与电压（电场）相互作用及物理机制，评估电压（电场）对CTCs的影响，建立安全、高效的CTCs捕获、检测实验条件。然后，利用微纳加工技术、分步骤地设计与制备半导体芯片集成的微器件。最后，利用制作的集成式器件，实现CTCs的高效捕获与检测。研究成果将为新一代癌症早期检测技术、高通量单细胞分析研究提供理论依据、基础实验数据和技术储备。

癌症是当今发病率和死亡率最高的恶性疾病之一，大部分患者死于癌症的复发和转移。血液中的循环肿瘤细胞（Circulating Tumor Cells, CTCs）被证实可用于癌症检测、预后评价、及转移的监测。由于CTCs含量极少，异质性高，现有基于CTCs肿瘤标志物、或其自身物理性质的捕获、检测方法均存在一定局限性。本项目引入融合微电子技术与微流技术，研制了多款硅基和聚合物基的CTC筛选器件用于CTC的捕获和筛选，对于硅基CTC筛选芯片，在硅基通孔阵列结构的基础上，进一步研制了微孔与微电极垂直集成的CTC检测芯片，实现了基于细胞尺寸及电学特性的多参数捕获。另外，鉴于硅基芯片成本较高的不足，进一步开发了基于聚合物微孔膜的二维，及三维CTC筛选器件，并搭建了实验平台，对不同肿瘤细胞系、全血中的CTC细胞以及临床样品进行了细胞筛选实验，取得了了较好的效果。项目成果发表期刊学术论文10篇，其中SCI论文7篇，申请中国发明专利2项目，美国发明专利2项。