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A microfluidic chip developed to study the effects of free-drug versus NPs-mediated drug delivery on cancer cells using their electromechanical biomarkers.

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Detection of a few cancer cells within a complex cellular mixture is a key challenge presented by clinical human biopsy samples. We have designed and tested a microfabricated bioimpedance device that can detect a few human MDA-MB-231 breast cancer cells in a mixed cell culture model of a breast tissue sample. The normal tissue components were modelled using non-cancerous MCF10A human breast epithelial cells and normal human HS68 fibroblasts. The sensor is a silicon chip 0.5 cm in diameter that contains one counter electrode and four 40 μm-wide multi-branched sensing electrodes. The cells' bioimpedances were characterized in pure monocultures and in mixed cell cultures following a brief cultivation on the sensor. After cell seeding, a stable bioimpedance signal was achieved indicative of cell attachment. A cancer-selective bioimpedance signal was elicited by addition of suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor with selective actions on the cytoskeleton in breast cancer cells. SAHA elicited a 50% rise in peak bioimpedance in MDA-MB-231 breast cancer cells by 15 h. In mixed cultures of MDA-MB-231, MCF10A, and HS68 cells, the contribution of cancer cells present in the mixture dominated impedance response to SAHA. A single adherent cancer cell on any one of four electrodes in a background of ∼100 normal cells resulted in ≥5% increase in bioimpedance. The estimated sensitivity of this device is therefore one cancer cell among a background of 400 normal cells or the equivalent of 25 cancer cells in a biopsy sample of 10 000 cells.

Triple negative breast cancer (TNBC) is highly aggressive and has a poor prognosis when compared to other molecular subtypes. In particular, the claudin-low subtype of TNBC exhibits tumor-initiating/cancer stem cell like properties. Here, we seek to find new biomarkers to discriminate different forms of TNBC by characterizing their bioimpedance. A customized bioimpedance sensor with four identical branched microelectrodes with branch widths adjusted to accommodate spreading of individual cells was fabricated on silicon and pyrex/glass substrates. Cell analyses were performed on the silicon devices which showed somewhat improved inter-electrode and intra-device reliability. We performed detailed analysis of the bioimpedance spectra of four TNBC cell lines, comparing the peak magnitude, peak frequency and peak phase angle between claudin-low TNBC subtype represented by MDA-MB-231 and Hs578T with that of two basal cells types, the TNBC MDA-MB-468, and an immortalized non-malignant basal breast cell line, MCF-10A. The claudin-low TNBC cell lines showed significantly higher peak frequencies and peak phase angles than the properties might be useful in distinguishing the clinically significant claudin-low subtype of TNBC.

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The relative sensitivity of standard gold microelectrodes for electric cell-substrate impedance sensing was compared with that of gold microelectrodes coated with gold nanoparticles, carbon nanotubes, or electroplated gold to introduce nano-scale roughness on the surface of the electrodes. For biological solutions, the electroplated gold coated electrodes had significantly higher sensitivity to changes in conductivity than electrodes with other coatings. In contrast, the carbon nanotube coated electrodes displayed the highest sensitivity to MDA-MB-231 metastatic breast cancer cells. There was also a significant shift in the peak frequency of the cancer cell bioimpedance signal based on the type of electrode coating. The results indicate that nano-scale coatings which introduce varying degrees of surface roughness can be used to modulate the frequency dependent sensitivity of the electrodes and optimize electrode sensitivity for different bioimpedance sensing applications.

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