Manipulating liquids on a micrometric scale is recent, but the applications are already numerous, in particular in the medical field.
It started with… molecular cuisine. “A culinary idea was how the idea to encapsulate cells in microspheres of alginate was born: saving pearls” reveals Pierre Nassoy, researcher at the Phonics, Digital and Nanosciences Laboratory (LP2N – CNRS/Optics Institute Graduate School/Université de Bordeaux). These 3 mm of diameter balls are formed of sodium alginate, jellified in a calcium chloride bath, and used to decorate dishes. Food is encapsulated within, using a microfluidic devise.
Micro-tumours in drops
The same extrusion principle - enabling these multilayer structures to be achieved – applied to a submillimetric scale, results in a microfluidic devise, that gives shape to porous alginate spheres, in which cells are encapsulated and multiplied. “We, thus created micro-tumours, at Institut Curie”, reveals Pierre Nassoy. The tumour cells deform the alginate capsule as they multiply. The capsule applies, in return, a mechanical force. The spheroids show a necrotic heart surrounded by hypermobile cells. “The compression could limit tumour growth, but it could also increase appearance of metastasis”, explains the researcher.
When in vitro comes close to the living
On another note, “between in vitro tests in Petri dishes and those performed on animal models, there is no correlation in efficiency”, Pierre Nassoy reminds us. “The 3D architecture of the tumour must be rebuilt to discover its behaviour in relation to the treatment”. These 3D models enable us a better preselection of the treatment candidates. Bonus: as up to 5,000 little drops are generated per second, it is possible to proceed to drug screening.
This optimisation is also possible in cellular therapy, for neurodegenerative diseases, as the Treefrog start-up demonstrates (created by two post-doctoral students of the laboratory). “The culture of stem cells in Petri dishes takes a long time and is not productive. Amplification is multiplied by 100 when the pluripotent cells are encapsulated in the spheroids”, appraises Pierre Nassoy. Stem cells thus cultivated, differentiated from dopaminergic neurons, have been injected into Parkinson rat models, that recovered their initial capacities within four weeks.
Grafting a CD instead of a lung
Microfluidic tools can be used for other purposes. The 2020 Bioart-Lung project, involving the Marie-Lannelongue surgical Centre, Université Paris-Sud and Université Paris-Saclay, CEA, Inserm, CNRS and manufacturers, aims to manage pulmonary arterial hypertension at a terminal stage, when a lung transplant becomes necessary. While awaiting a transplant, oxygenators are necessary to perform gas exchange, in place of the lungs. These big boxes, however, connected to the patient “prevent the patient from moving. Furthermore, thrombosis occurs at some point so their use is limited to three weeks”, explains Anne-Marie Haghiri-Gosnet, researcher at the Centre for Nanoscience and Nanotechnology (CNRS/Université Paris-Sud). A three-layer microfluidic system has been designed to offset the drawbacks: it consists in a network of micro-capillaries where the blood flows, a fine membrane that is permeable to gas, and a layer filled with air. It takes the form of a 10 cm diameter disk, a few millimetres thick, and looks like a CD. “It is very light and comprised of PDMS, a biocompatible material that is transparent and used to make soft contact lenses”, adds the researcher. “It takes several hours to make in a laboratory today, but when we can produce it with a supply chain process, rapid industrial techniques will reduce the time period to an hour or less”.
Increasing the debit
This system has been tested with a pig’s venous blood. “We have scheduled a similar experience on a rat where the Pr. Olaf Mercier (who is running the 2020 Bioart-Lung programme) will have grafted an extra-corporal three-layer system. The debit is still too low for the system to be tested on larger animals, but oxygenation is of good quality”, Anne-Marie Haghiri-Gosnet explains. We will then, in the future, consider hooking a patient up to this device in order to enable him to sit and move around. Microfluidic will then be a “pearl”… for patients.
∙ K. Alessandri et al. A 3D printed microfluidic device for production of functionalized hydrogel microcapsules for culture and differentiation of human Neuronal Stem Cells (hNSC). Lab Chip, 2016.
∙ Zhang Q. et al. Logic digital fluidic in miniaturized functional devices: Perspective to the next generation of microfluidic lab-on-chips. Electrophoresis. 2017 Apr;38(7):953-976.
“We don’t claim to outdo lung transplants, but to find a temporary alternative.”
Anne-Marie Haghiri-Gosnet co-heads the Microsystems and Nanobiofluidic department of the Centre for Nanoscience and Nanotechnology (CNRS/Université Paris-Sud). She graduated from Chimie ParisTech and has, throughout her career, used her physics and chemistry training to contribute to expanding micro and nano-manufacturing development. In the field of micro/nanofluidics, her research work is focused on soft lithograph (a technique that enables patterns to appear on thin films) and associated processes to format biocompatible materials, developing microfluidic platforms for biochemical analysis on chips and developing organs of chips.