Integrated microdevice with a windmill-like hole array for the clog-free, efficient, and self-mixing enrichment of circulating tumor cells

Hao Li; Jinze Li; Zhiqi Zhang; Zhen Guo; Changsong Zhang; Zixu Wang; Qiuquan Guo; Chao Li; Chuanyu Li; Jia Yao; Anran Zheng; Jingyi Xu; Qingxue Gao; Wei Zhang; Lianqun Zhou

doi:10.1038/s41378-021-00346-y

Integrated microdevice with a windmill-like hole array for the clog-free, efficient, and self-mixing enrichment of circulating tumor cells

Microsyst Nanoeng. 2022 Feb 15:8:23. doi: 10.1038/s41378-021-00346-y. eCollection 2022.

Authors

Hao Li^{1

2}, Jinze Li², Zhiqi Zhang², Zhen Guo^{1

2

3}, Changsong Zhang⁴, Zixu Wang², Qiuquan Guo⁵, Chao Li², Chuanyu Li^{2

6}, Jia Yao², Anran Zheng^{1

2}, Jingyi Xu², Qingxue Gao^{1

2}, Wei Zhang^{1

2}, Lianqun Zhou^{1

2

6

7}

Affiliations

¹ School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, 260026 Hefei, China.
² CAS Key Lab of Bio-Medical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, 215163 Suzhou, China.
³ Ji Hua Laboratory, 528000 Foshan, China.
⁴ Department of Laboratory Medicine, The Affiliated Suzhou Science and Technology Town Hospital, Nanjing Medical University, 215153 Suzhou, China.
⁵ Shenzhen Institute for Advanced Study, University of Electronic Science and Technology of China, 518000 Shenzhen, China.
⁶ Suzhou CASENS Co., Ltd, 215163 Suzhou, China.
⁷ Jinan Guoke Medical Technology Development Co., Ltd, 250001 Jinan, China.

Abstract

Circulating tumor cells (CTCs) have tremendous potential to indicate disease progression and monitor therapeutic response using minimally invasive approaches. Considering the limitations of affinity strategies based on their cost, effectiveness, and simplicity, size-based enrichment methods that involve low-cost, label-free, and relatively simple protocols have been further promoted. Nevertheless, the key challenges of these methods are clogging issues and cell aggregation, which reduce the recovery rates and purity. Inspired by the natural phenomenon that the airflow around a windmill is disturbed, in this study, a windmill-like hole array on the SU-8 membrane was designed to perturb the fluid such that cells in a fluid would be able to self-mix and that the pressure acting on cells or the membrane would be dispersed to allow a greater velocity. In addition, based on the advantages of fluid coatings, a lipid coating was used to modify the membrane surface to prevent cell aggregation and clogging of the holes. Under the optimal conditions, recovery rates of 93% and 90% were found for A549 and HeLa cells in a clinical simulation test of our platform with a CTC concentration of 20-100 cells per milliliter of blood. The white blood cell (WBC) depletion rate was 98.7% (n = 15), and the CTC detection limit was less than 10 cells per milliliter of blood (n = 6). Moreover, compared with conventional membrane filtration, the advantages of the proposed device for the rapid (2 mL/min) and efficient enrichment of CTCs without clogging were shown both experimentally and theoretically. Due to its advantages in the efficient, rapid, uniform, and clog-free enrichment of CTCs, our platform offers great potential for metastatic detection and therapy analyses.

Keywords: Biosensors; Environmental, health and safety issues; Microfluidics; NEMS.