Towards High Throughput Cell Growth Screening: A New CMOS 8 <inline-formula> <tex-math notation="LaTeX">$\times$</tex-math> </inline-formula> 8 Biosensor Array for Life Science Applications

Abstract

In this paper we present a CMOS capacitive sensor array as a compact and low-cost platform for high-throughput cell growth monitoring. The proposed biosensor, consists of an array of 8 × 8 CMOS fully differential charge-based capacitive measurement sensors. A DC-input Σ∆ modulator is used to convert the sensors' signals to digital values for reading out the biological/chemical data and further signal processing. To compensate the mismatch variations between the current mirror transistors, a calibration circuitry is proposed which removes the output voltage offset with less than 8.2% error. We validate the chip functionality using various organic solvents with different dielectric constants. Moreover, we show the response of the chip to different concentrations of Polystyrene beads that have the same electrical properties as the living cells. The experimental results show that the chip allows the detection of a wide range of Polystyrene beads concentrations from as low as 10 beads/ml to 100 k beads/ml. In addition, we present the experimental results from H1299 (human lung carcinoma) cell line where we show that the chip successfully allows the detection of cell attachment and growth over capacitive electrodes in a 30 h measurement time and the results are in consistency with the standard cell-based assays. The capability of proposed device for label-free and real-time detection of cell growth with very high sensitivity opens up the important opportunity for utilizing the device in rapid screening of living cells.

A CMOS Pixelated Nanocapacitor Biosensor Platform for High-Frequency Impedance Spectroscopy and Imaging

“…LECTROCHEMICAL impedance spectroscopy (EIS) is a popular sensing technique, thanks to its capability to investigate different sample properties at different frequencies [1]. Miniaturization and monolithic integration of EIS sensors in CMOS technology is possible, enabling highly parallel sensing and readout [2] [13]. Within the field of capacitance biosensors [14], high sensitivity realizations have been presented, that enable the implementation of CMOS DNA sensor arrays [4] [15], and even F. Widdershoven is with NXP Semiconductors, Eindhoven, The Netherlands (e-mail: frans.widdershoven@nxp.com).…”

Transistors for Chemical Monitoring of Living Cells

“…Besides ISFET devices, classical MOSFETs have been described for the monitoring of cell detachment. For example, Nabovati et al [ 3 ] reported a capacitive sensor array using the CMOS technology for in-situ cell growth monitoring. They constructed an array of 8 × 8 CMOS that measured capacitance at the interface between the sensor and the cell culture medium.…”

“…Complex biological interactions or cellular stress responses difficult to highlight using conventional biosensors, can be identified because of the changes in cellular physiology. These changes are, typically, local changes in pH [ 1 , 2 ], in surface coverage of cells [ 3 , 4 , 5 , 6 ], in protein expression, or in cellular metabolism that induce local changes in the concentration of metabolites or biochemicals, such as glucose, lactate [ 7 , 8 ], dopamine [ 9 ], glutamate, acetylcholine, etc. Cell culture monitoring may also be applied to monitor cancer cells’ metabolism, for example.…”

Toward High Throughput Core-CBCM CMOS Capacitive Sensors for Life Science Applications: A Novel Current-Mode for High Dynamic Range Circuitry

“…In spite of microelectromechanical systems (MEMS)-based capacitive sensors such as accelerometers [ 1 , 2 ], position sensors [ 3 , 4 ], pressure sensors [ 5 , 6 , 7 , 8 ], and moisture sensors [ 9 ], a growing body of literature has studied capacitive sensors for Laboratory on a Chip (LoC) applications. These applications include DNA hybridization detection [ 10 ], protein interactions quantification [ 11 ], cellular monitoring [ 12 , 13 , 14 ], bio-particle detection [ 15 ], microRNA detection [ 16 ], organic solvent monitoring [ 17 ], sensing of droplet parameters [ 18 ], and bacteria detection [ 19 , 20 ].…”

“…A capacitive sensor consists of sensing electrodes that are connected to an interface readout circuit, as shown in Figure 1 a,b for both MEMS-based and LoC applications, respectively. The capacitive electrodes convert the physical [ 3 , 4 ], biological [ 10 , 11 , 12 ], and/or chemical parameters [ 21 , 22 ] in proximity of the electrodes into electrical signals. As illustrated in Figure 1 a, the capacitive electrodes in MEMS-based applications such as accelerometers are used as an off-chip device wire-bonded (or flip-chip bonded) to the CMOS chip.…”