Droplet based microfluidics
Microfluidics technology has seen a rapid growth over the past couple of decades, owing to its unique abilities to precisely handle fluidic operations at micro-scale. Being able to perform biochemical analyses on small chips in an automated way, microfluidics has redefined various fields revolving around biology and medicine, which conventionally required bulky apparatus and manual sample handling. Looking at the numbers, the microfluidics market has surpassed the 20-billion-dollar mark in 2024 and is expected to grow double in size by 2029. This remarkable growth is fueled by the need for having miniaturized fluidic systems that work on the “sample-in answer-out” principle, a concept only microfluidics can realize.
Initial efforts on microfluidics focused mostly on its biomedical applications, where it was considered merely as a “technique” to carry out biochemical analyses. However, the field has evolved significantly ever since, now maturing into a robust core technology with applications spanning various disciplines. Consequently, many use cases of microfluidics have recently started to surface that go well beyond biotechnology and healthcare e.g., microfluidics-based wearable devices, environmental sensing solutions, electronics cooling systems and so on.
In this article, we will discuss how microfluidics is evolving as a fundamental technology, as well as some of its emerging application areas that are set to reshape the future of various disciplines.
The way we fabricate and operate microfluidic systems has changed substantially over time. Traditional rigid silicon/glass-based chips that can handle only continuous fluid flow, although still preferred for many on-chip operations, are now considered outdated for more advanced applications such as single-cell analysis or high-throughput drug screening etc. These are also linked with higher cost and fabrication complexity, often making them infeasible for applications that require disposable microfluidic systems. Addressing these challenges, many technological advancements are underway that intend to transform microfluidics technology at a fundamental level. Some key emerging trends in this regard are as follows.
Historically, silicon was used as a substrate material to build microfluidic devices, since silicon micromachining techniques were already well established at that time due to significant progresses made by the semiconductor industry. Although silicon-based fabrication offered a readily available platform for realizing microfluidic concepts, the overall process is costly and complex making it infeasible for applications such as point-of-care testing that requires cheap, disposable devices. In addition, silicon as a material is rigid in nature and has limited biocompatibility, which further hinders the use of silicon microfluidics in emerging applications e.g., wearable devices. Considering these drawbacks, ongoing technological trends now focus on the transition towards fully polymer-based microfluidic chips (e.g., PDMS) that have excellent biocompatibility, low cost, and high structural flexibility.
More recently, a new class of microfluidic devices – “Paper Microfluidics” – has also emerged that utilizes paper as a substrate to handle fluid. Paper-based microfluidic devices are fabricated by modifying the paper surface such that it has hydrophobic barriers to repel fluid and hydrophilic channels to allow fluid flow via capillary forces. Paper microfluidics not only provides a significant reduction in chip cost making microfluidics technology easily accessible, but also has a much simpler fabrication process that can be carried out outside the cleanroom. This technology holds great future potential especially for point-of-care testing and environmental sensing applications, by promising cheap, easy-to-dispose devices. However, the commercialization of paper microfluidics is still in its infancy due to many different challenges e.g., high results compared to traditional devices, which are currently under investigation.
Early efforts on microfluidics primarily focused on analog fluid flow, in which a stream of fluid passes through microchannels in a continuous manner. This straightforward approach turned out very effective in transferring many fluidic operations onto a chip; however, with emerging needs for high throughput and multiplexing, continuous flow is no longer feasible. For instance, to increase the number of parallel assays on a continuous flow chip, the device size needs to be increased linearly to accommodate additional microchannels, making the overall system bulky.
To address these issues, ongoing research is now focusing on discretizing the fluid flow into a sequence of droplets, to achieve an independent control over each droplet serving as a microreactor (with volume in nanoliters). Individual manipulation of droplets passing through the same microchannel results in extreme parallelization, making the overall process much faster compared to continuous flow microfluidics. In addition, microdroplets also facilitate cell trapping due to the size similarity, thus bringing us one step closer to high-throughput single-cell analysis. Current research trends focus on bringing droplet microfluidics to mainstream, thus realizing high-throughput systems with extreme precision that are crucial for future drug discovery applications.
With the introduction of droplet microfluidics, another concept that has gained a lot of attention recently is the digitization of microfluidic chips by controlling each droplet individually using voltage electrodes. Digital microfluidics (DMF) works on the principle of electrowetting, where an array of electrodes drives pico- to micro-sized droplets to perform operations such as mixing, splitting, merging etc. Electronic control of droplets enables programmability and alleviates the need for any external pumping source as the droplet motion is fully digitized. With these advantages, droplet microfluidics nowadays is among the widely researched topics within the realm of microfluidics.
Inspired by typical semiconductor fabrication, manufacturing of microfluidics chips is inherently lengthy and complex. Lithographic processes are commonly needed along with relevant masks to produce a microfluidic chip. As an alternative, considering recent advancements in additive manufacturing, many reports are suggesting 3D print microfluidic chips. This would indeed bring down the chip cost, production time, and fabrication complexity.
Nevertheless, it should be noted that 3D printing is an emerging technology and achieving design resolution in printed structures similar to what standard microfabrication offers is quite challenging. Furthermore, since 3D printing is a serial process where chips (or sets of chips) are printed sequentially using a single printing nozzle, scaling up production beyond a certain level becomes simply infeasible with 3D printers. In contrast, 3D printing can be an excellent choice at the prototyping stages, since changing chip designs with 3D printing is quite straightforward, compared to conventional microfabrication that requires unique lithography masks for each design. Leveraging these benefits, many researchers are attempting to shift from conventional soft lithography to 3D printing during the R&D and prototyping phase of the microfluidic devices.
Artificial intelligence, as one of the most powerful modern technologies, is reshaping various fields including microfluidics. In any typical microfluidic process, there is plenty of data that needs to be collected for analysis. These datasets become even larger when conducting high-throughput assays (e.g., using droplet microfluidics), which are extremely difficult to process if not fully impossible. With AI’s unprecedented capabilities to efficiently process large datasets, we can unveil intricate patterns embedded in data and gain insights that would otherwise stay hidden, essentially indicating a natural synergy between microfluidics and AI. Currently, integration of AI with microfluidics is at its initial stages with plenty of room for development.
Healthcare and life sciences are among the earliest application areas of microfluidics, where the technology has made many substantial breakthroughs. Simply put, microfluidics technology has successfully transferred various biochemical analyses to miniaturized chips, providing us with microscale total analysis systems (µTAS) that can work autonomously without human intervention. Since then, the fields of microfluidics and healthcare are evolving side by side, with focus on emerging concepts including:
Drug discovery is a lengthy process where initially tens of thousands of samples need to be processed, while only a few of those progress towards the clinical trials. Such applications demand high speed systems that can handle parallel assays and are able to dispense very small volumes (below µL range), which is almost impossible with conventional well-plate-based methods. In addition, typical screening processes are often carried out in static conditions, thus not accurately simulating the true in vivo conditions. Microfluidics technology, as an alternative, provides fully automated systems that can handle sample volumes down to nanoliters. In addition, dynamic nature of fluid flow in microfluidics devices strongly mimics the in vivo cell conditions, making them ideal for drug screening.
Considering these advantages, current industry trends focus on standardizing microfluidic platforms for high-throughput screening applications. The invention of droplet microfluidics is yet another fundamental technological advancement facilitating us in achieving this goal. Droplet microfluidics provide us with microbioreactors capable of isolating single cells, which results in efficient evaluation of candidate drugs, thus streamlining the overall drug discovery process.
Personalizing treatments for certain diseases including cancer, diabetes, and autoimmune diseases, is among the cutting-edge research topics, as personalized medicine promises a better prevention and treatment of diseases tailored to a patient’s genetics. Developing personalized medicine requires a sophisticated system that can fully unfold the complexities in a sample, and this goes beyond the capabilities of traditional methods e.g., petri dish-based analysis of tumor cells, where many patterns get overlooked. In contrast, microfluidics technology offers unique benefits that makes it an ideal candidate for developing precision medicine, including a precise control and monitoring of fluids at micro/nanoscale, ability to work with low sample quantities (e.g., coming from a patient’s biopsies), and extreme automation.
Recently surfaced organ-on-a-chip systems, as a microfluidics marvel, are now also playing a pivotal role in the advancement of precision medicine. These are miniaturized 3D organ models built on microfluidic chips that mimic human organs, allowing us to test and formulate patient-specific medicine. Currently, many efforts are being made to develop different organs (including gut, liver, lung etc.) on microfluidic chips, and this technology is expected to grow rapidly in the coming years.
Microfluidics technology has seen significant success in various point of care applications such as blood glucose monitoring, pregnancy tests, and even detection of infectious diseases such as covid-19. The dominance of microfluidics is expected to grow further in this domain, as the salient features of microfluidics technology align perfectly with the requirements of next generation point of care devices i.e., rapid, cost effective, miniaturized, and portable etc. There is an ongoing effort to cover more and more diseases using microfluidics while bringing down the test costs, to make this technology readily accessible.
On-chip diagnosis can also benefit from the availability of single-cell analysis options enabled by microfluidics, to refine the diagnosis. Another key benefit that makes microfluidic-based testing stand out among others is its ability to parallelize operations by employing multiple analysis channels, thereby improving the statistical depth of the results. Paper-based microfluidic devices are also becoming a popular substrate choice to build point of care testing kits, in an effort to slash down test costs and improve the technology accessibility. All in all, the overall point of care diagnostic industry relies heavily on microfluidics, and the technology will play a crucial role in reshaping the future of diagnostic systems.
Microfluidics, once known for its use in biotechnology and biomedical science, has now grown into a mainstream technology, unraveling many new application areas. Below, we highlight some key use cases of microfluidics that go well beyond the domain of life sciences and are considered to have a significant future potential.
Wearable technology providing cost-effective flexible devices that can attach onto skin for constant body fluids monitoring, has revolutionized the healthcare and wellness industries. The convenience of wearable devices, along with their ability to perform real-time patient monitoring in a minimally invasive way, has made them ideal for various healthcare applications. Microfluidics technology, with its abilities to effectively handle small volumes of body fluids in a precise way, is a natural fit for wearable technology. By integrating microfluidic circuitry on wearable devices, we can monitor a person’s health by measuring electrolyte levels, extracting biomarkers, and processing other body fluids etc.
For instance, sweat analysis using microfluidics-based epidermal patches has gained a lot of attention recently. Typically, these devices absorb sweat, that contains a wealth of information, into tiny microfludic channels. Through the micro canals, the fluid is then transferred towards flexible electronic circuitry to carry out the sensing and generate output signals. Sweat analysis allows monitoring of various important biomarkers, including blood glucose, which is crucial for the overall well-being of patients, especially diabetics.
With ever-increasing demands for high data rates, electronic devices are becoming denser each day. Continuous efforts are being made to fit the same (or more) number of electronic components in a smaller area. While this is advancing the state of electronics like never before, increased power density is leading to difficulties in efficient thermal management. Existing thermal management techniques design cooling systems separately away from the electronics, leading to a large waste in energy as the coolant dissipates energy while traveling from its source to the hotspots. To address these cooling issues of future electronic systems, integrated cooling systems built on the same electronics chip using microfluidics channels have been proposed recently [6]. Microscale dimensions of microfluidic channels make them ideal to be embedded directly onto the electronic chips, leading to highly efficient cooling systems.
The concept of co-designing microfluidics and electronic circuits is quite new but has great prospects, as electronic systems will continue to get denser with increasingly stringent thermal management requirements.
Another promising application area for microfluidics that has emerged recently is monitoring the quality of food products. Foodborne pathogenic bacteria can be dangerous and can cause more than 200 different types of diseases. While many reliable laboratory-based methods exist to detect food bacteria, they often become infeasible in practical applications as food can be infected at any stage from its initial production and packaging to final consumption. Thus, there is a need for having miniaturized equipment that can detect foodborne bacteria in situ, while matching the detection accuracy of laboratory-dependent analyses e.g., gas chromatography-based mass spectrometry.
Microfluidics-based biosensing has surfaced as a potential candidate to monitor food quality in situ, as such biosensors can perform pretreatment, sensing, and output signal generation all on a single miniaturized chip. In particular, microfluidic paper-based analytical devices (µPAD) are gaining significant popularity in food safety applications, owing to their low cost, rapid response and excellent biocompatibility.
However, it must also be noted that application of microfluidics in food safety is relatively new, where many unsolved challenges remain in the way of widespread commercialization. For example, on-chip sample pretreatment methods vary from one food type to the other, calling for the development of more generalized chips. In addition, cross contamination when parallelizing assays is yet another factor that sometimes affects the sensing performance.
In general, microfluidics technology provides a promising technological platform to tackle food safety issues, where many breakthroughs are expected to appear in the near future.
Microfluidics has matured significantly over time, now transforming into a well-established technology that attracts applications from many fields including biology, electronics, material science, food and nutrition etc. Current industry trends are multi-faceted, where on one hand, many fundamental technological advancements are underway to make the future microfluidic devices portable, faster, cheaper, and readily accessible. While on the other hand, the application spectrum of microfluidics is expanding rapidly each day, thanks to the broad range of capabilities of microfluidic devices.
While microfluidics has been a huge success, there remain challenges that need to be addressed for further improvement of the technology. For instance, PDMS-based microfluidic devices are widely used and make up a large portion of the microfluidics market, due to their benefits including optical transparency, biocompatibility, and flexible nature etc. However, they do suffer from fabrication complexity, channel sealing issues, incompatibility towards hydrophobic chemicals, and so on, calling researchers to investigate alternative affordable materials outperforming PDMS. Ongoing trends, in this regard, include exploring options such as thermoplastics, polycarbonate and 3D printed structures. Advancing paper-based microfluidics technology is another prime focus of the industry in search of better materials.
An additional issue facing microfluidics is that despite the extreme technology miniaturization, current state-of-the-art microfluidic devices still often require external equipment for operation. Therefore, researchers are now attempting to build the microfluidic counterparts of these equipment on the same chip, to improve the portability, cost, and scalability of microfluidic devices. Another area for improvement in microfluidic chips is their lack of programmability, making these devices application-specific that are directly associated with the cost as a different chip is needed for each task. To overcome these limitations, there is an ongoing trend of introducing programmability in microfluidic devices to improve their generalization ability, with technologies such as digital microfluidics.
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