Inkjet-Print Micromagnet Array on Glass Slides for Immunomagnetic Enrichment of Circulating Tumor Cells

Abstract

We report an inkjet-printed microscale magnetic structure that can be integrated on regular glass slides for the immunomagnetic screening of rare circulating tumor cells (CTCs). CTCs detach from the primary tumor site, circulate with the bloodstream, and initiate the cancer metastasis process. Therefore, a liquid biopsy in the form of capturing and analyzing CTCs may provide key information for cancer prognosis and diagnosis. Inkjet printing technology provides a non-contact, layer-by-layer and mask-less approach to deposit defined magnetic patterns on an arbitrary substrate. Such thin film patterns, when placed in an external magnetic field, significantly enhance the attractive force in the near-field close to the CTCs to facilitate the separation. We demonstrated the efficacy of the inkjet-print micromagnet array integrated immunomagnetic assay in separating COLO205 (human colorectal cancer cell line) from whole blood samples. The micromagnets increased the capture efficiency by 26% compared with using plain glass slide as the substrate.

Keywords: Circulating tumor cells; Immunomagnetic cell separation; Inkjet printing; Microfluidic; Micromagnets.

Figures

Figure 1

Inkjet-printed micromagnet integrated immunomagnetic microchip for the detection of rare circulating tumor cells. (a) Principle of the immunomagnetic CTC separation and the micromagnet integration. (b) 3-dimensional illustration of the assembled microchip device.

Figure 2

Fabrication of the micromagnet array. (a) Fabrication process of the micromagnet array using inkjet printing technology. (b) Printing waveform used to control the ink ejection from the inkjet printer.

Figure 3

Theoretical analyses of the magnetic field generated by the pixel permanent magnets array. (a) Schematic of the permanent magnet array and the spacers. (b) Magnetic field at the bottom of the microchannel. (c) Magnetic potential energy distribution at the bottom of the microchannel.

Figure 4

Design of the microchannel and the micromagnet array. Blue solid line – geometry and dimensions of the microchannel. Orange dash line – position and layout of the permanent magnet array. Black dot array – layout and distribution of the inkjet micromagnets. Inset: zoom-in view of the micromagnet array and the array periodicity.

Figure 5

Inkjet-printed micromagnets. (a) SEM of the inkjet- printed micromagets, and zoom-in view of a single micromanget element. (b) AFM profile of a single micromagnet element. (c) Cross-section profile of a single micromagnet element showing the maximum height at the edge of the micromagnet is 300 nm.

Figure 6

Magnetic screening of fluorescent magnetic microbeads. (a) Fluorescent image of substrate showing regular distribution of the fluorescent magnetic beads. (b) Relative fluorescent intensity profile of the substrate. The peak-to-peak distance is 75 μm, equals to the periodicity of the micromagnet array.

Figure 7

COLO 205 screening experiment results using the inkjet-printed micromagnet integrated immunomagnetic assay. The arrows point to the locations of the micromagnets. Bright-field and fluorescent panel show the interactions between the COLO205 cells and the micromagnet elements.

Figure 8

Locations and distributions of the captured COLO 205 cells on (a) inkjet-print micromagnet integrated slides and (b) plain slide respectively. In (a), blue dots represent the cells that are attached to the micromagnets, while the orange dots are the cells that are found not attached to any micromagnet.