Measuring and modeling macrophage proliferation in a lab-on-CMOS capacitance sensing microsystem.

We report on the use of a lab-on-CMOS biosensor platform for quantitatively tracking the proliferation of RAW 264.7 murine Balb/c macrophages. We show that macrophage proliferation correlates linearly with an average capacitance growth factor resulting from capacitance measurements at a plurality of electrodes dispersed in a sensing area of interest. We further show a temporal model that captures the cell number evolution in the area over long periods (e.g., 30 h). The model links the cell numbers and the average capacitance growth factor to describe the observed cell proliferation.

Measuring and Modeling Macrophage Growth using a Lab-on-CMOS Capacitance Sensing Microsystem.

We report on the use of a lab-on-CMOS biosensor platform for quantitatively tracking the growth of RAW 264.7 murine Balb/c macrophages. We show that macrophage growth over a wide sensing area correlates linearly with an average capacitance growth factor resulting from capacitance measurements at a plurality of electrodes dispersed in the sensing area. We further show a temporal model that captures the cell evolution in the area of interest over long periods (e.g., 30 hours). The model links the cell numbers and the average capacitance growth factor associated with the sensing area to describe the observed growth kinetics.

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.

High resolution monitoring of chemotherapeutic agent potency in cancer cells using a CMOS capacitance biosensor.

Monitoring cell viability and proliferation in real-time provides a more comprehensive picture of the changes cells undergo during their lifecycle than can be achieved using traditional end-point assays. Particularly for drug screening applications, high-temporal resolution cell viability data could inform decisions on drug application protocols that might lead to better treatment outcomes. We describe a CMOS biosensor that monitors cell viability through high-resolution capacitance measurements of cell adhesion quality. The system consists of a 3 × 3 mm2 chip with an array of 16 sensors, on-chip digitization, and serial data output that can be interfaced with inexpensive off-the-shelf components. An imaging system was developed to provide ground-truth data of cell coverage concurrently with data recordings. Results showed the sensor's ability to detect single-cell binding events, track cell morphology changes, and monitor cell motility. A chemotherapeutic assay was conducted to examine dose-dependent cytotoxic effects on drug-resistant and drug-sensitive cancer cell lines. Concentrations higher than 5 µM elicited cytotoxic effects on both cell lines, while a dose of 1 µM allowed discrimination of the two cell types. The system demonstrates the use of real-time capacitance measurements as a proof-of-concept tool that has potential to hasten the drug development process.

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.

Optical filtering technologies for integrated fluorescence sensors.

Numerous approaches have been taken to miniaturizing fluorescence sensing, which is a key capability for micro-total-analysis systems. This critical, comprehensive review focuses on the optical hardware required to attenuate excitation light while transmitting fluorescence. It summarizes, evaluates, and compares the various technologies, including filtering approaches such as interference filters and absorption filters and filterless approaches such as multicolor sensors and light-guiding elements. It presents the physical principles behind the different architectures, the state-of-the-art micro-fluorometers and how they were microfabricated, and their performance metrics. Promising technologies that have not yet been integrated are also described. This information will permit the identification of methods that meet particular design requirements, from both performance and integration perspectives, and the recognition of the remaining technological challenges. Finally, a set of performance metrics are proposed for evaluating and reporting spectral discrimination characteristics of integrated devices in order to promote side-by-side comparisons among diverse technologies and, ultimately, to facilitate optimized designs of micro-fluorometers for specific applications.