Fluidics, the great shift in chemistry

A vision that breaks with traditional methods, aided by nanotechnologies, is bringing chemistry into the era of fluidics. Production of drugs à la carte, decentralization of factories and reduction of their size, more environmentally friendly, less expensive, more homogeneous and less dangerous exploitation... The promises of fluidics are numerous and are open to medicine, pharmacy, biomass valorization and other sectors. Researchers at ULiège have sensed this cross-disciplinary approach and are combining their strengths and tools. Between training, education, innovations and services, their platform is unique in the world.

MONBALIU Peptides Cycliques (c)ULiege


arburants, perfumes, solvents, medicines, textiles, wine, beer, plastics... We are surrounded by products resulting from chemical reactions. Traditionally, these mixtures are made in batch reactors, containing volumes of up to several thousand liters. With the help of nanotechnology, the early 2010s saw the birth of a revolution in the field: fluidics. In these micro- and meso-reactors, products no longer stagnate, but flow continuously and respond to different physical properties. These reactions, which are faster and require smaller quantities of products, open up a wide range of applications. But this cutting-edge technology requires a multidisciplinary approach. As an expert in this field, ULiège benefits from Corning equipment, which is not yet widely available in universities. Today, a laboratory organized as a platform that brings together skills that were previously isolated is becoming a unique place in the world. multidisciplinary centers around fluidics already exist," explains Jean-Christophe Monbaliu, an organic chemist and creator of CiTOS (Center for Integrated Technology and Organic Synthesis). But they don't offer as holistic an approach as ours." An opportunity for students, for research and innovation, and for the industrial sector.

Fine chemicals and drugs à la carte

Traditional chemistry is constrained by temperature, pressure and reaction time. Fluidics allows to obtain new chemical events. On the one hand, by using known reagents, but subject to new reaction conditions (they can, for example, be heated to very high temperatures without risk of being destroyed), and on the other hand, by using products that are forgotten or even forbidden in traditional methods. "These products are either toxic or carcinogenic, or have a powerful energy content. Their profile is interesting, especially because they can reduce the time of a reaction, but they are also expensive and explosive. A small and confined space offers increased possibilities of control, for very small quantities, moreover (from a hundred microliters to a few tens of milliliters). In such a device, a reaction runaway leading to an explosion is less likely and would have only a minor impact."

Fluidics remained initially exploited for military purposes. In 2012, Jean-Christophe Monbaliu, then engaged at MIT, contributed to the development of a mobile drug manufacturing unit (read about it in the article A portable drug manufacturing plant). This project, funded by the Defense Advanced Research Agency (DARPA), was intended to supply medicines to conflict zones. "We are talking about a few dozen grams of a product per day. That's enough to provide thousands of doses of an active ingredient. What works for conflict zones also works for epidemics, natural disasters, or to find cures for orphan diseases.

ULiège expands the horizon of fluidics

Inexpensive to use, requiring little product, transportable and of great analytical precision, fluidics applies to many fields beyond fine chemistry and drug production.

An alternative to petroleum: Most of the products we use are derived from petroleum (textiles, plastics, fuels, solvents...). These are called petroleum-based products. However, it is commonly accepted that oil is running out, and that its exploitation is particularly polluting. "We are experiencing a transition from petroleum-based to bio-based alternatives," says Jean-Christophe Monbaliu This is far from being unknown. What is less known is that microfluidics is helping this revolution considerably." Helping with this transition is one of the laboratory's major focuses, including research into how to transform and valorize molecules from biomass, such as forestry industry waste, grass clippings or algae, into more complex molecules."

One example that has been widely reported on the Internet is the industrial creation of algae turned into biofuel. "This is photochemistry. Light is used as a reagent. But using large pipes, light penetration is quickly stopped and remains superficial. The fine channels of fluidics offer optimal and intense penetration, which leads to reactions that are impossible in conventional productions."

Lifting the veil on fluid mechanics

At the macroscopic level, fluids are subject to non-linear turbulence phenomena, which disappear in microfluidics. another force appears, " says Tristan Gillet, assistant professor at the ULiège microfluidics laboratory, active in the technological development of fluidics. This force is the surface tension, which acts at the interface of two products, like a drop of water and a drop of oil, for example. This interface can be compared to a membrane, a balloon. It is also the tension coming from this force that explains why a drop is rounded. In reality, the behaviors generated by the surface tension are complex and little studied in microfluidics. We seek to better understand them in order to exploit them. We are working in this sense on a project of emulsion and manipulation of microdrops. In each microdrop, we will be able to confine a cell for independent testing." This technique has a big impact in the life sciences, as the next few points illustrate.

Bioengineering and bacterial resistance

At the Faculty of Gembloux Agro-Bio Tech, Frank Delvigne, Professor of Microbial Biotechnology, is involved in many European projects on fluidics. His two main research fields are analytical and applicative. The first aims to study microbial behavior on an individual scale. "We observe that single-celled microorganisms with identical genomes tend to diversify over time. This heterogeneity, the mechanisms of which we are beginning to identify, is not without impact. For example, some pathogenic bacteria will survive a treatment with antibiotics and give rise to a new population. With microfluidics, we can study individual cells and quantify this heterogeneity. At the application level, cellular heterogeneity makes it difficult to control the production of biochemical reactions. I would like to use microfluidics to extrapolate these bioprocesses. By starting with small quantities, which are easier to control, and paralleling them to other reactors, we can achieve a higher level of productivity."

Miniaturization of diagnostic tests

Microfluidics allows faster, more precise and less invasive treatment of blood samples. we are using it in particular to measure antibiotics of the penicillin family," says Professor Bernard Joris of the ULiège Protein Engineering Center. The curative dose of antibiotics that patients need varies according to their profile. In some cases, they are given at high doses, which flirt with significant toxicity. Diagnostic tests will allow the doctor to measure their concentration in the blood and adapt the treatment to the patient's needs One can imagine that such miniaturization of blood diagnostics will more broadly facilitate the advent of more personalized medicine. Doctors will be able to have their own reactor. From a single drop of blood, they will obtain the results of their patients, without necessarily having to go through clinical biology laboratories. The time saved, often precious in diagnosis, will be considerable!

In partnership with the Giga, Tristan Gillet is also working on studies of isolated cells, to penetrate the heterogeneity of biological tissues. "A typical example of the interest of cellular diagnostics is the search for the beginnings of cancer development in a blood sample. What fluidics allows is to find a needle in a haystack. The challenge is twofold: to detect a cancer that has not yet developed, when only a few cancerous cells are present out of millions of blood cells, using a simple blood test. In other words, a process that is accessible and can be generalized to the greatest number of people. To go beyond medicine, diagnostic studies can also be conducted in the agri-food sector, to detect contaminants of all kinds

The ethics of fluidics

Special attention is paid to the negative aspects of the technology, as Jean-Christophe Monbaliu testifies. "It is so compact and democratized that it can fit in a suitcase, for example, and produce several kilograms of amphetamines per day, or create combat gases. With this in mind, we used a mesofluidic photochemical reactor to neutralize mustard gas. We were able to neutralize it extremely effectively with only light and air. That's just one example. And since almost everything around us is derived from chemistry, there's a lot to invent or reinvent."

"In a fluidic reactor, a pump feeds reagents into a very thin diameter pipe," explains Jean-Christophe Monbaliu. The submillimeter dimension of the pipe generates new fluid dynamics phenomena. In the macroscopic world, it is gravity and density that separate two fluids. Other forces characterize the microscopic world. They allow a more homogeneous, faster mixing and a better heat management. As they flow, the reaction progresses. The products are then harvested for conditioning or for a new reaction. Depending on the size of the reactors, this is called microfluidics or mesofluidics. But in both cases, the process remains the same This way of conceiving chemistry is unprecedented. From a static approach to the reaction, defined in time, we are moving towards spatially resolved processes. The flow is continuous and the length of the pipe determines the reaction time.

An industrial opportunity

The flexibility of fluidics allows for decentralized thinking, but does not preclude high production capacity. Mesofluidic reactors can indeed produce several hundred tons per year. What used to be a one-off operation is now a continuous and systematic production process. "The most influential regulatory bodies are suggesting that it be integrated into production lines. With fluidics, it is no longer a question of producing "on the spot", but of ensuring generalized production of active ingredients or molecules with high added value This decentralization will enable local production, in reduced infrastructures, and offers advantages in terms of risk management, reaction time, transport, logistics and storage of sometimes dangerous products. The environmental and economic benefits are undeniable.