Imaging on Lab-on-CMOS Systems

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Overview

Package cross-section

Lab-on-CMOS sensors have shown great promise in biological cell monitoring due to their potential for making label-free, high-throughput, and high-resolution measurements. However, validation of sensor data in real-time is vital in order to make sure signals originate from biological sources. This is a challenging task due to the difficulties in obtaining ground-truth and sensor data simultaneously.

  • CMOS chips are optically opaque so conventional transmitted light microscopy techniques used to image cells is not appropriate
  • Cell culture conditions must be maintained so imaging must be done within the incubator
  • Media evaporation in long experiments can cause images to go out of focus
We developed a real-time imaging platform that generates high-quality images of lab-on-CMOS sensors within the cell culture environment. We packaged sensors using a dual-well approach to alleviate the challenges of maintaining culture conditions and contending with media evaporation. A standard reflective microscope head unit along with a custom-machined assembly is used for imaging. The platform was used to validate a CMOS capacitance sensor that is used to monitor cell viability, proliferation, and death.

CMOS capacitance sensor

The platform was used to validate a CMOS capacitance sensor [1], [2], [3] that is used to monitor cell viability, proliferation, and death. The chip consists of a 4 × 4 array of sensor pixels, each with a set of interdigitated input electrodes that are insulated using the standard CMOS passivation layer. This layer acts as a substrate for adherent cells to grow on. Cells are initially round in shape when first seeded into the culture well. Over time, they will adhere to the substrate, flatten in shape, spread out across the substrate, and proliferate. These changes in cell morphology modulate the dielectric properties of the cell-substrate interface which can then then be measured as changes in surface capacitance.

CMOS capacitance sensor

Sample videos

Long-term cell monitoring

Morphological changes as cells first settle onto the CMOS chip, adhere, and proliferate.

Cell division

Multiple cells undergoing mitosis where the parent cell contracts and splits into two daughter cells.

Cell death

Cells deforming and shrinking in response to a cytotoxic agent.

Other experiments

# Cell Type Exp. Duration (hrs.) Media
1 A2780 59
2 A2780 58
3 A2780 66
4 CP70 63
5 CP70 63