LTCC Packaged Ring Oscillator Based Sensor for Evaluation of Cell Proliferation.

Joni Kilpijärvi,Niina Halonen,Elisabeth Smela,Bathiya Senevirathna,Pamela Abshire,Anita Lloyd Spetz,Jari Juuti,Kajsa Uvdal,Antti Hassinen,Sakari Kellokumpu,Maciej Sobocinski

doi:10.3390/s18103346

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.

Highlights

Health effect evaluation of chemicals and medicines begins with cytotoxicity assays including cell cultures which are followed by animal testing
We present an low temperature co-fired ceramic (LTCC) packaged complementary metal-oxide-semiconductor (CMOS) biosensor chip, which is utilized in measuring the proliferation of a cell population
This work has examined and produced a biosensor applied to adherent cell viability monitoring

Summary

Introduction

Health effect evaluation of chemicals and medicines begins with cytotoxicity assays including cell cultures which are followed by animal testing. Proliferation of cells is evaluated after exposure to the assessed substance and usually includes laborious handwork required in the staining and fixing of cells for visual inspection under the microscope. This is an end-point measurement method, which lacks real-time information on the health status of the cell population and is vulnerable to various sources of human error. There is a true demand for a cost-effective, real-time, label-free cell viability evaluation method with a high degree of automation, which highlights the need for intensive development in this technology [1]

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