Stable delivery of liquids to microfluidic systems is essential for their reproducible functioning, especially when supplying flows to organs-on-chips – delicate living models that recreate human physiology on the microscale and thus can be used to reduce the need for animal testing. Most flow control systems are unable to sustain a robust and stable flow in longer experiments (>1 week), particularly those based on the ubiquitous syringe pump. Though easy to use, syringe pumps have no mechanism for actually measuring flow, let alone flow regulation with sensor feedback. We have developed a liquid delivery system based on the generation of flow by applying a constant air pressure to liquids in sealed containers. A flow of liquid is monitored by accurate measurement of mass flows (mg/min) using downstream Coriolis-based mass flow sensors. Measured mass flows provide fast feedback to integrated valves, with valves opening or closing slightly to increase or decrease solution flows to the organs-on-chips as required. This mass flow sensing principle is not affected by changes in the density, temperature, and viscosity of the liquids being displaced. This is in contrast to systems that use volumetric flow sensors, which require recalibration when these parameters change. The rationale behind using this principle for organs-on-chips, is that the stability provided by this flow control system allows for more control over growth of these mini-organs. We demonstrate the functionality of this system with three examples: 1) Fast stabilization (within seconds) under changing physical conditions; 2) Short-term stability (minutes to hours) of delivered flows in a microreactor with interconnected inlets; and 3) Long-term stability (>1 week) of cell medium flows to a living organ-on-a-chip. Two categories of organs-on-chips (OOCs) can be distinguished: 1) solid OOC are designed for three-dimensional cell or tissue constructs that interact with each other and their surroundings, and 2) barrier-type OOC contain a selective cellular barrier between two compartments as do many barriers in the body. The latter of these two types is the most challenging to culture and maintain as they are very sensitive to variations in flow and pressure surges. The flow control system presented in this work provides a great improvement compared to the use of syringe pumps and volumetric flow sensors in OOC studies. The novelty of this work lies in the long-term stability use of this system for organs-on-chips, maintaining stability for short to very long periods of time without compromising the barrier function of the organ-on-chip by pressure surges, bacterial contamination, or other undesired effects from the flow delivery system.

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Reciprocating piezoelectric micropumps enable miniaturization in microfluidics for lab-on-a-chip applications such as organs-on-chips (OoC). However, achieving a steady flow when using these micropumps is a significant challenge because of flow ripples in the displaced liquid, especially at low frequencies or low flow rates (<50 µL/min). Although dampers are widely used for reducing ripples in a flow, their efficiency depends on the driving frequency of the pump. Here, we investigated multi-phase rectification as an approach to minimize ripples at low flow rates by connecting piezoelectric micropumps in parallel. The efficiency in ripple reduction was evaluated with an increasing number (n) of pumps connected in parallel, each actuated by an alternating voltage waveform with a phase difference of 2π/n (called multi-phase rectification) at a chosen frequency. We introduce a fluidic ripple factor ((Formula presented.)), which is the ratio of the root mean square ((Formula presented.)) value of the fluctuations present in the rectified output to the average fluctuation-free value of the discharge flow, as a metric to express the quality of the flow. The fluidic ripple factor was reduced by more than 90% by using three-phase rectification when compared to one-phase rectification in the 2–60 μL/min flow rate range. Analytical equations to estimate the fluidic ripple factor for a chosen number of pumps connected in parallel are presented, and we experimentally confirmed up to four pumps. The analysis shown can be used to design a frequency-independent multi-phase fluid rectifier to the desired ripple level in a flow for reciprocating pumps.

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Organ-on-a-chip (OoC) devices require the precise control of various media. This is mostly done using several fluid control components, which are much larger than the typical OoC device and connected through fluidic tubing, i.e., the fluidic system is not integrated, which inhibits the system’s portability. Here, we explore the limits of fluidic system integration using off-the-shelf fluidic control components. A flow control configuration is proposed that uses a vacuum to generate a fluctuation-free flow and minimizes the number of components used in the system. 3D printing is used to fabricate a custom-designed platform box for mounting the chosen smallest footprint components. It provides flexibility in arranging the various components to create experiment-specific systems. A demonstrator system is realized for lung-on-a-chip experiments. The 3D-printed platform box is 290 mm long, 240 mm wide and 37 mm tall. After integrating all the components, it weighs 4.8 kg. The system comprises of a switch valve, flow and pressure controllers, and a vacuum pump to control the diverse media flows. The system generates liquid flow rates ranging from 1.5 μ Lmin ^{- 1} to 68 μ Lmin ^{- 1} in the cell chambers, and a cyclic vacuum of 280 mbar below atmospheric pressure with 0.5 Hz frequency in the side channels to induce mechanical strain on the cells-substrate. The components are modular for easy exchange. The battery operated platform box can be mounted on either upright or inverted microscopes and fits in a standard incubator. Overall, it is shown that a compact integrated and portable fluidic system for OoC experiments can be constructed using off-the-shelf components. For further down-scaling, the fluidic control components, like the pump, switch valves, and flow controllers, require significant miniaturization while having a wide flow rate range with high resolution.

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Microfluidic organs-on-chips (OoCs) technology has emerged as the trend for in vitro functional modeling of organs in recent years. Simplifying the complexities of the human organs under controlled perfusion of required fluids paves the way for accurate prediction of human organ functionalities and their response to interventions like exposure to drugs. However, in the state-of-the-art OoC, the existing methods to control fluids use external bulky peripheral components and systems much larger than the chips used in experiments. A new generation of compact microfluidic flow control systems is needed to overcome this challenge. This study first presents a structured classification of OoC devices according to their types and microfluidic complexities. Next, we suggest three fundamental fluid flow control mechanisms and define component configurations for different levels of OoC complexity for each respective mechanism. Finally, we propose an architecture integrating modular microfluidic flow control components and OoC devices on a single platform. We emphasize the need for miniaturization of flow control components to achieve portability, minimize sample usage, minimize dead volume, improve the flowing time of fluids to the OoC cell chamber, and enable long-duration experiments.

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Piezoelectric micropumps enable miniaturization in microfluidics for lab-on-a-chip applications such as Organs-on-chips (OoC). However, achieving a steady flow with these micropumps is a significant challenge because of the reciprocating motion of the displacing component. Although dampers are widely preferred for reducing ripples, they are not efficient at low flow rates. Here, we propose a phased-actuation of piezoelectric micropumps connected in parallel and a damper to minimize ripples at low flow rates. We are able to reduce ripples by 80% with our proposed configuration compared to a micropump-only configuration between 10-50 μl/min flow rate range.@en