Microfluidic Cartridges and Active Flow Control for in vitro Diagnostics

Not long ago, molecular analyses were available only in central labs. For each medical test, the patient samples would be transported to the central laboratory. There, highly trained staff would carry out the sample analysis on large-scale laboratory instruments. In this way, the sample transport takes time and fuel, sample analysis requires expertise and considerable hands-on time, as well as dedicated lab space. And in the meanwhile, the patient waits to receive the right treatment.

Today, an increasing part of medical testing can be done at the general practitioner’s clinic because the analytical instruments are a lot more compact and fit on a benchtop. Moreover, automated testing devices reduce hands-on time and require much less training. This saves time to diagnosis and lowers the costs of running the molecular analyses. To take it even further, recent technological innovations allow building molecular testing devices so small and easily portable, that even in-the-field and at-home testing is possible for certain analysis. This means even more effective treatments thanks to quick diagnosis and timely health interventions.

In this article we will unpack microfluidic and fluid control technology innovations that make point-of-need testing (PoNT) and point-of-care testing (PoCT) a reality. We will further expand on the active flow control approaches and share two fluid control system examples based on memetis expertise. We will not cover the topic of microfabrication techniques but will be happy to direct you to our partners if needed.

Enabler Technology: Advanced Microfluidic Devices

The miniaturization and automatization of molecular testing have largely been driven by advancements in microfluidic technology. A sophistically designed microfluidic device can host many fluidic and molecular activities, thus allowing to miniaturize diagnostic assays and performing them on a single fluidic component. Such microfluidic devices are sometimes referred to as lab-on-chip devices. This is because all the chemical, biological and physical processes, that are typically performed in a laboratory, take place on a single integrated microfluidic system.

To bring all the diagnostic lab processes to the microfluidic format, a microfluidic device requires a network of microchannels, chambers and (in many cases) valves. Depending on the complexity of microfluidic structures and fluid transport principles, three main subtypes of microfluidic devices can be distinguished:

The increased complexity of microfluidic structures and the use of active fluid control elements allow performing complicated fluid manipulations that were not possible to automate before. Examples of these include timed reagent introduction, precise fluid control for mixing, fluid flow initiation and stopping at specific timepoints for a sensor measurement or imaging. The implementation of such fluidic functions within a microfluidic device allows miniaturizing and automating in vitro diagnostic (IVD) test assays like DNA-based COVID-19 detection.

Fluid Management Approach for IVD Cartridges

A typical IVD cartridge has reservoirs or blister pouches for reagent storage, a sample inlet, chambers for molecular assay reactions and microfluidic channels that connect all the structures. The exact type and count of microfluidic structures will vary depending on the specific test assay and on the processes that need to take place on the cartridge. Commonly the assays require chambers for reagent and sample mixing, molecule capture and/or amplification, result measurements and/or visualization. Sometimes cell culture chambers need to be integrated as well. None of these functions would happen without the active flow control enabled by on-cartridge and external actuation components.

The external actuation system components operate pumps and valves integrated within the microfluidic cartridge. The on-chip pumps and valves are formed by covering chambers and microchannels with an elastic membrane. The stretchable membrane is pulled or pressed, thus changing the volume of a chamber or the cross-section of a microfluidic channel. The membrane movement above a chamber pulls or pushes liquids to or from the chamber, transporting them to the right location on the cartridge. The pressure on the membrane above a channel can restrict or fully close the channel, to reduce or stop the flow. Exactly how the flow control is enabled by an external actuation system within the cartridge-handling instrument will be covered in a later section.

Advantages of Separating External Actuation from the Cartridge

Another positive aspect of the split fluidic and flow control modules is that the microfluidic cartridge can be designed as a one-time-use consumable. In other words, each cartridge is used just once and disposed of after the test is completed. In this way the sample and reagent interactions are always performed in a sterile environment, and cross-contamination between tests is safely prevented. Furthermore, such modular concept allows updating the cartridge design without having to make changes to the cartridge-handling instrument. In addition, cartridges with different reagent composition made for analyzing different disease biomarkers can be operated with the same instrument. These modularity advantages combined with miniaturization and automation make IVD testing feasible in a general physician’s clinic or in the field. One IVD cartridge instrument can perform assays for multiple types of diagnoses and the single-use cartridges provide a sterile environment outside the laboratory.

External Flow Control

So far, we have covered the advancements of microfluidic devices and the concept of separating microfluidic cartridges from the external flow control. Both aspects are crucial for miniaturizing sophisticated laboratory analyses on a microfluidic cartridge. Now it is time to have a look at the external actuation part which enables active flow control and automation of the IVD tests.

There are several approaches for controlling fluid flow on cartridges covered with an elastic membrane. Two common ones are by using pneumatic and mechanical actuation systems:

Pneumatic actuation means that the active force applied on the cartridge comes from compressed air or vacuum generated by a pump or another air pressure source. The control module applies over- or under- pressure on the cartridge membrane to operate the on-chip valves and pumps. Applying over-pressure to the on-chip valve membrane deflects it and closes the microfluidic channel that it is situated on. Doing the same for a membrane on top of an on-chip pump reduces the volume of the pump chamber, thus pushing the liquid out of the chamber and further along the functional path of the assay. When under-pressure is applied to the elastic membranes covering the cartridge, the respective channel width or the respective chamber size increases, pulling the fluid inside the microchannel or chamber. With a single multichannel pneumatic actuation module, several on-chip valves and pumps can be operated in a coordinated manner.

On-cartridge fluid control can alternatively be operated by mechanical actuation. With this approach it is the physical force of a moving plunger that deflects the elastic membrane. One can compare the mechanical flow control principle to a pinch valve, with the difference that - instead of squeezing a soft tube with circular cross-section - a soft cover membrane is pressed into an on-chip channel profile. A fluid control system based on mechanical actuation can be built simpler than a pneumatic system because no additional components like a pump are needed to close microfluidic channels or press fluids out of blister pouches or pumping chambers. With the mechanical actuation, however, it is more difficult to pull liquids into a chamber, because the mechanical plunger cannot actively pull on the membrane. On the other hand, the mechanical control components can provide more force than a pneumatic solution and thus are capable of compressing blister packs to introduce liquid reagents.

Overcoming Hurdles in Flow Control Miniaturization

Advanced microfluidics and active fluid control on cartridges make IVD test automatization and miniaturization possible. However, the size of the external flow control components is the one defining how small and portable the lab-on-chip operating instruments can become. The more compact the pumps, valves, sensors and electronics that power and coordinate the flow control, the higher level of miniaturization can be achieved.

Until lately, miniaturizing flow control systems was limited by the bulkiness and weight of the traditionally used electromagnetic (solenoid) valves and pumps. This is why the introduction of piezoelectric ceramics and shape memory alloy (SMA) actuation has been a game changer for increasing miniaturization and portability of microfluidic testing instruments. Both of these new technologies are characterized by much lower power consumption, lower weight and smaller size.

Among the two fluid control technologies, flat-foil SMA actuation-based components offer the smallest size and the lightest weight with the drawback of reduced switching speed (see SMA vs solenoid valve comparison). Commonly solenoid, piezoelectric and SMA-based components are combined to optimize for performance, compactness and cost of a fluidic system. The optimal solution depends on the fluidic schematic and how many on-chip valves and pumps need to be operated to enable the fluidic functions of the assay.

Highly Miniaturized Flow Control Examples

Don't hesitate to contact memetis if you need a customized pneumatic solution! It can be adapted to a different port number, other pressure ranges or custom microfluidic manifolds for interfacing your cartridge.

These two example flow control systems are representations of pneumatic and mechanical actuation solutions for microfluidic cartridges and chips. Each approach has its strengths and disadvantages, as we discussed earlier. Depending on the complexity of the cartridge and forces required from the external control system, one of the approaches might be more beneficial - or even a combination of approaches might be the way to go. memetis is happy to provide our expertise to find the optimal solution for each specific case.

Summary and memetis Intro

Since the introduction of the first microfluidic devices many technology advancements have been made to enable miniaturization of IVD assays and perform them at the point-of-need. Thanks to intelligent microfluidic cartridge design combined with highly miniaturized active flow control systems, molecular testing is becoming more accessible and cost-effective in providing quality healthcare.

memetis has been part of the miniaturization movement since 2017 by providing flat-foil SMA based components. Our team has built numerous sub-systems for fluid control since and is continuously pushing the boundaries of miniaturization. We are experienced with integrating SMA, piezo and solenoid based components into pneumatic and mechanical flow control systems. Get in touch with us if you would like to discuss how memetis can help your miniaturization goals!

Last edited Feb 27, 2025

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