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Flow control for organ-on-a-chip application

March 30, 2021 Joost Lötters

In my role as Science Officer at Bronkhorst I am always looking for emerging fields of application for flow control systems. As part-time professor of Microfluidic Handling Systems at both the University of Twente and Delft University of Technology I am involved in the development of miniaturized flow meters and controllers for micro flow rates. In this blog I want to share my insights about the role of flow control in organ-on-a-chip applications, where both aspects come together.

Organ-on-a-chip technology can potentially play an important role in research for new biomedical treatment methods [1]. The control of gas flow, liquid flow [2] and pressure are 3 important functionalities to consider when working with these kinds of applications, as I will further explain in this blog.

Joost Lotters about flow control for organ-on-a-chip application

What is organ-on-a-chip? 

An organ-on-a-chip can be described as a small microfluidic device on which living tissue of a specific organ has been grown while mimicking real life conditions. The development of organ-on-a-chip systems is quite known in the field of biomedical research, it enables research towards new treatment methods. 

There are many examples of organ-on-a-chip applications. In this blog I will focus on lung-on-a-chip devices as they have recently been used in COVID-19 research: minuscule models of the lungs were created, to understand how COVID-19 invades the human body and does its damage [3].

Lung-on-a-chip system

In 2010, the first lung-on-a-chip system was presented by D. Huh et al. [4]. In 2013, the same group presented a follow-up paper [5]. We reproduces some results from their 2013 follow-up paper [5] in figure 1. The lung cells on the chip are grown on flexible, stretchable membranes which are a realistic imitation of the alveoli.

lung-on-a-chip principle
Picture 1: Microfluidic chip, reproduced after [5]

By applying pressure differences to the side chambers, the artificial alveoli can be expanded, thus mimicking the breathing process. By means of flowing liquid through the lower channel, and gas through the upper channel, the blood and oxygen circulation can be simulated, respectively.

A microfluidic chip suitable for growing lung-on-a-chip cell cultures, with an upper channel used for air flow, a lower channel used for liquid flow, and side chambers to apply different pressures; 
Below; A mechanical stretching of the lung cells when a vacuum is applied in the side chambers.

Flow and pressure control

The control of gas flow, liquid flow and pressure are 3 important functionalities to consider when working with lung-on-a-chip applications:

  • Pressure control, where (sub-atmospheric) pressure differences (“vacuum”) can be applied to the side chambers to mimic the stretching of the lung cells when breathing; pressure range is -100 .. -600 mbarg (with respect to atmospheric pressure)
  • Gas flow control, which nimics the oxygen supply to the lung cells; flow range is 1 – 20 mln/min of air
  • Liquid flow control, where the blood-like liquids and nutrition can be provided to the lung cells, and where the blood circulation can be mimicked; flow range is 1 - 50 µl/min
Bronkhorst has an extensive product line with instruments for flow and pressure control that are a perfect fit for these flow and pressure rates.

iMicrofluidics; Microfluidic sensor & actuators platform

In my role as Science Officer at Bronkhorst, I am also involved in the iMicrofluidics project [6] together with the NERI initiative of Delft University of Technology. Our goal is to support and speed up the development and optimization of organ-on-a-chip systems by providing researchers with an integrated, compact and modular microfluidic sensor and actuator platform to which they can effortlessly connect their different types of organs on-a-chip, and real-time monitor and control the quality of the output of their process.

More about iMicrofluidics
lung-on-a-chip flow controller setup
Picture 2: [7] Schematic connection of flow and pressure controllers used for a lung-on-a-chip application
iMicrofluidics Flow control platform
Picture 3: Preliminary version of the flow control platform with mini CORI-FLOWs

A preliminary version of the platform was recently fabricated [7], comprising among others two Bronkhorst ML120 Coriolis mass flow controllers – to control the liquid and gas flow – and an IQ+PRESS pressure controller – to regulate the vacuum. Of course, it would also be possible to control the gas flow with a thermal gas mass flow controller from the EL-FLOW Select or EL-FLOW Prestige series and the liquid flow with a liquid flow controller for ultra-low flow rates from the µ-FLOW series.

Initial measurement results show a good performance of the platform. Future research will involve improvement and optimisation of the platform, and application of the platform in organ-on-a-chip research. Among others, scientists of Erasmus Medical Centre in Rotterdam have expressed their interest in using the platform for their research on lung-on-a-chip [8].

Picture 3: Preliminary version of the flow control platform, with two Bronkhorst ML120 mini CORI-FLOWs for fluid control in the upper and lower channel and an IQ+PRESS instrument for pressure control to stretch the membrane.

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