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Sensors 2018, 18(10), 3346; https://doi.org/10.3390/s18103346

LTCC Packaged Ring Oscillator Based Sensor for Evaluation of Cell Proliferation

1
Microelectronics Research Unit, University of Oulu, P.O. Box 4500, FI-90014 Oulu, Finland.
2
Faculty of Biochemistry and Molecular Medicine, University of Oulu, P.O. Box 5400, FI-90014 Oulu, Finland
3
Department of Electrical & Computer Engineering and the Institute for Systems Research, University of Maryland, College Park, MD 20742, USA
4
Division of Molecular Surface Physics and Nanoscience, Department of Physics, Chemistry and Biology, Linköping University, SE-58183 Linköping, Sweden
5
Department of Mechanical Engineering and the Institute for Systems Research, University of Maryland, College Park, MD 20742, USA
6
Division of Sensor and Actuator Systems, Department of Physics, Chemistry and Biology, Linköping University, SE-58183 Linköping, Sweden
*
Author to whom correspondence should be addressed.
Received: 29 August 2018 / Revised: 27 September 2018 / Accepted: 2 October 2018 / Published: 7 October 2018
(This article belongs to the Special Issue Non-Invasive Biomedical Sensors)
Full-Text   |   PDF [3971 KB, uploaded 7 October 2018]   |  

Abstract

A complementary metal-oxide-semiconductor (CMOS) chip biosensor was developed for cell viability monitoring based on an array of capacitance sensors utilizing a ring oscillator. The chip was packaged in a low temperature co-fired ceramic (LTCC) module with a flip chip bonding technique. A microcontroller operates the chip, while the whole measurement system was controlled by PC. The developed biosensor was applied for measurement of the proliferation stage of adherent cells where the sensor response depends on the ratio between healthy, viable and multiplying cells, which adhere onto the chip surface, and necrotic or apoptotic cells, which detach from the chip surface. This change in cellular adhesion caused a change in the effective permittivity in the vicinity of the sensor element, which was sensed as a change in oscillation frequency of the ring oscillator. The sensor was tested with human lung epithelial cells (BEAS-2B) during cell addition, proliferation and migration, and finally detachment induced by trypsin protease treatment. The difference in sensor response with and without cells was measured as a frequency shift in the scale of 1.1 MHz from the base frequency of 57.2 MHz. Moreover, the number of cells in the sensor vicinity was directly proportional to the frequency shift. View Full-Text
Keywords: capacitive sensing; cell proliferation assay; CMOS; lab-on-a-chip; low temperature co-fired ceramic; ring oscillator capacitive sensing; cell proliferation assay; CMOS; lab-on-a-chip; low temperature co-fired ceramic; ring oscillator
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Kilpijärvi, J.; Halonen, N.; Sobocinski, M.; Hassinen, A.; Senevirathna, B.; Uvdal, K.; Abshire, P.; Smela, E.; Kellokumpu, S.; Juuti, J.; Lloyd Spetz, A. LTCC Packaged Ring Oscillator Based Sensor for Evaluation of Cell Proliferation. Sensors 2018, 18, 3346.

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