title: Two-stage microfluidic chip for selective isolation of circulating tumor cells (CTCs).
abstract: Over the past few decades, circulating tumor cells (CTCs) have been studied as a means of overcoming cancer. However, the rarity and heterogeneity of CTCs have been the most significant hurdles in CTC research. Many techniques for CTC isolation have been developed and can be classified into positive enrichment (i.e., specifically isolating target cells using cell size, surface protein expression, and so on) and negative enrichment (i.e., specifically eluting non-target cells). Positive enrichment methods lead to high purity, but could be biased by their selection criteria, while the negative enrichment methods have relatively low purity, but can isolate heterogeneous CTCs. To compensate for the known disadvantages of the positive and negative enrichments, in this study we introduced a two-stage microfluidic chip. The first stage involves a microfluidic magnetic activated cell sorting (μ-MACS) chip to elute white blood cells (WBCs). The second stage involves a geometrically activated surface interaction (GASI) chip for the selective isolation of CTCs. We observed up to 763-fold enrichment in cancer cells spiked into 5 mL of blood sample using the μ-MACS chip at 400 μL/min flow rate. Cancer cells were successfully separated with separation efficiencies ranging from 10.19% to 22.91% based on their EpCAM or HER2 surface protein expression using the GASI chip at a 100 μL/min flow rate. Our two-stage microfluidic chips not only isolated CTCs from blood cells, but also classified heterogeneous CTCs based on their characteristics. Therefore, our chips can contribute to research on CTC heterogeneity of CTCs, and, by extension, personalized cancer treatment.
authors: School of Mechanical Engineering, Yonsei University, 262 Seongsan-no, Seodaemun-gu, Seoul 120-749, Republic of Korea.
authors: Kyung-A
authors: KA
authors: Hyun
authors: Materials & Components R&D Laboratory, LG Advanced Research Institute, Seoul 137-724, Republic of Korea.
authors: Tae Yoon
authors: TY
authors: Lee
authors: Nano Medical National Core Research Center, Yonsei University, 262 Seongsan-no, Seodaemun-gu, Seoul 120-749, Republic of Korea.
authors: Su Hyun
authors: SH
authors: Lee
authors: School of Mechanical Engineering, Yonsei University, 262 Seongsan-no, Seodaemun-gu, Seoul 120-749, Republic of Korea; Nano Medical National Core Research Center, Yonsei University, 262 Seongsan-no, Seodaemun-gu, Seoul 120-749, Republic of Korea. Electronic address: uridle7@yonsei.ac.kr.
authors: Hyo-Il
authors: HI
authors: Jung
mesh_terms: D000951:Antigens, Neoplasm / Q000096:biosynthesis; D015374:Biosensing Techniques; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D045744:Cell Line, Tumor; D002469:Cell Separation; D000071858:Epithelial Cell Adhesion Molecule; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007962:Leukocytes / Q000473:pathology; D046210:Microfluidic Analytical Techniques; D009360:Neoplastic Cells, Circulating / Q000737:chemistry* / Q000473:pathology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis
chemical_list: D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; D000071858:Epithelial Cell Adhesion Molecule; D018719:Erb-b2 Receptor Tyrosine Kinases; C499379:EPCAM protein, human; C508053:ERBB2 protein, human
keywords: Circulating tumor cell (CTC); Epithelial cell adhesion molecule (EpCAM); Geometrically activated surface interaction (GASI); Human epidermal growth factor receptor 2 (HER2); Microfluidic magnetic activated cell sorting (micro-MACS); Selective isolation