Correlation of Capacitance and Microscopy Measurements Using Image Processing for a Lab-on-CMOS Microsystem.

We present a capacitance sensor chip developed in a 0.35-µm complementary metal-oxide-semiconductor process for monitoring biological cell viability and proliferation. The chip measures the cell-to-substrate binding through capacitance-to-frequency conversion with a sensitivity of 590 kHz/fF. In vitro experiments with two human ovarian cancer cell lines (CP70 and A2780) were performed and showed the ability to track cell viability in realtime over three days. An imaging platform was developed to provide time-lapse images of the sensor surface, which allowed for concurrent visual and capacitance observation of the cells. The results showed the ability to detect single-cell binding events and changes in cell morphology. Image processing was performed to estimate the cell coverage of sensor electrodes, showing good linear correlation and providing a sensor gain of 1.28 ± 0.29 aF/µm2, which agrees with values reported in the literature. The device is designed for unsupervised operation with minimal packaging requirements. Only a microcontroller is required for readout, making it suitable for applications outside the traditional laboratory setting.

Real-Time Measurements of Cell Proliferation Using a Lab-on-CMOS Capacitance Sensor Array.

We describe a capacitance sensor array that has been incorporated into a lab-on-CMOS system for applications in monitoring cell viability. This paper presents analytical models, calibration results, and measured experimental results of the biosensor. The sensor has been characterized and exhibits a sensitivity of 590 kHz/fF. We report results from benchtop tests and in vitro experiments demonstrating on-chip tracking of cell adhesion as well as monitoring of cell viability. Human ovarian cancer cells were cultured on chip, and measured capacitance responses were validated by comparison with images from photomicrographs of the chip surface. Analysis was performed to quantify cell proliferation and adhesion, and responses to live cells were estimated to be 100 aF/cell.

System-on-Chip Considerations for Heterogeneous Integration of CMOS and Fluidic Bio-Interfaces.

CMOS chips are increasingly used for direct sensing and interfacing with fluidic and biological systems. While many biosensing systems have successfully combined CMOS chips for readout and signal processing with passive sensing arrays, systems that co-locate sensing with active circuits on a single chip offer significant advantages in size and performance but increase the complexity of multi-domain design and heterogeneous integration. This emerging class of lab-on-CMOS systems also poses distinct and vexing technical challenges that arise from the disparate requirements of biosensors and integrated circuits (ICs). Modeling these systems must address not only circuit design, but also the behavior of biological components on the surface of the IC and any physical structures. Existing tools do not support the cross-domain simulation of heterogeneous lab-on-CMOS systems, so we recommend a two-step modeling approach: using circuit simulation to inform physics-based simulation, and vice versa. We review the primary lab-on-CMOS implementation challenges and discuss practical approaches to overcome them. Issues include new versions of classical challenges in system-on-chip integration, such as thermal effects, floor-planning, and signal coupling, as well as new challenges that are specifically attributable to biological and fluidic domains, such as electrochemical effects, non-standard packaging, surface treatments, sterilization, microfabrication of surface structures, and microfluidic integration. We describe these concerns as they arise in lab-on-CMOS systems and discuss solutions that have been experimentally demonstrated.