Monolithic integration of a smart temperature sensor on a modular silicon-based organ-on-a-chip device

Ronaldo Martins Da Ponte,Nikolas Gaio,Henk Van Zeijl,Sten Vollebregt,Paul Dijkstra,Ronald Dekker,Wouter A Serdijn,Vasiliki Giagka

doi:10.1016/j.sna.2020.112439

Abstract

One of the many applications of organ-on-a-chip (OOC) technology is the study of biological processes in human induced pluripotent stem cells (iPSCs) during pharmacological drug screening. It is of paramount importance to construct OOCs equipped with highly compact in situ sensors that can accurately monitor, in real time, the extracellular fluid environment and anticipate any vital physiological changes of the culture. In this paper, we report the co-fabrication of a CMOS smart sensor on the same substrate as our silicon-based OOC for real-time in situ temperature measurement of the cell culture. The proposed CMOS circuit is developed to provide the first monolithically integrated in situ smart temperature-sensing system on a micromachined silicon-based OOC device. Measurement results on wafer reveal a resolution of less than ±0.2 °C and a nonlinearity error of less than 0.05% across a temperature range from 30 to 40 °C. The sensor's time response is more than 10 times faster than the time constant of the convection-cooling mechanism found for a medium containing 0.4 ml of PBS solution. All in all, this work is the first step towards realizing OOCs with seamless integrated CMOS-based sensors capable to measure, in real time, multiple physical quantities found in cell culture experiments. It is expected that the use of commercial foundry CMOS processes may enable OOCs with very large scale of multi-sensing integration and actuation in a closed-loop system manner.

Highlights

Organ-on-a-chip (OOC) is an emergent technology in which a microfluidic perfusion platform for culturing human induced pluripotent stem cells (iPSCs) is used to mimic a minituarized version of an explicit organ anatomy and physiology
This work is the first step towards realizing OOCs with seamless integrated CMOS-based sensors capable to measure, in real time, multiple physical quantities found in cell culture experiments
The chips include a pneumatically-activated freestanding dog-bone-shaped PDMS membrane to accommodate the cell culture while delivering mechanical stimuli to the cells in various in-vitro studies, additional features, such as throughmembrane micro-pores for biological signal exchange, on-membrane grooves for cell alignment, in-membrane titanium nitride (TiN) microelectrodes for monitoring activity from electrically active cells, and titanium (Ti) strain gauges to measure the deformation of the PDMS membrane during inflation

Summary

Introduction

Organ-on-a-chip (OOC) is an emergent technology in which a microfluidic perfusion platform for culturing human iPSCs is used to mimic a minituarized version of an explicit organ anatomy and physiology. This technology has been developed to substitute traditional in vitro and animal models that are often inaccurate to predict the human physiology [1,2]. The simplicity, fast turnaround time, and relatively low cost of this technique affords quick experimentation of new designs Examples of such designs include OOCs for the heart [4], the liver [5], the kidney [6], the lung [7], and tumours [8,29]. Shortcomings of such methods include limited device throughput which is a crucial feature for high-volume manufacturing

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Results

Conclusion