Microfluidics is the science of manipulating very small amounts of fluids from microlitres (10-6 L) to picolitres (10-12 L) inside microchannels with typical lateral dimensions from ones to hundreds of micrometres (10-6 m). The discipline is an essential tool for the life sciences and biotechnologies. Both academic researchers and industrial groups develop more pertinent and less expensive applications by:
- Decreasing sample and reagent consumptions,
- Improving the measurement,
- Lowering limits of detection,
- Running multiple and parallel analysis,
- Shortening experiment time.
Electronics and computers evolution paved the way of the miniaturization. Smartphones are much more powerful, cheap and user-friendly than the first computers of the 60’s. Microfluidics pursue the same objectives.
HoliFAB, a holistic approach of microfluidics
Microfluidics is currently faced with 2 main difficulties:
- A considerable hindrance to fast prototyping and industrialisation, because system performances rely on complex selection and assembly of numerous fluidic, mechanic, optical, electronic (etc…) components,
- A complex process for setting the system requirements, because constraints and specifications of microfluidic systems cover a huge range in terms of complexity level, materials, dimensions, acceptable costs, without any standardisation and rationalisation of design and production.
The HoliFAB project aims at overcoming these difficulties with a holistic system-oriented and problem-solving approach, starting from the customer’s need, optimising the chip and addressing the question of its environment.
HoliFAB change of paradigm implies:
- A holistic approach at the instrument level: Providing new methods and production tools to instruments manufacturers and new generation of applications to users,
- A holistic approach for the chip production: Using a technology-agnostic strategy integrating both 3D printing and injection moulding technologies for the design of the microfluidic chip.
Applications to be tested within the HoliFAB project
HoliFAB has a broad range of potential impacts. The Consortium decided to focus on 3 specific applications, which will be tested to validate the developments in operational environment.
Application 1 (medical): Diagnosis and treatment orientation by circulating tumour cells (CTC) counting and typing
CTCs can provide information on the evolution of cancer during patient treatment. It was shown that CTC count is a good prognostic market of patient survival and can be used to assess treatment response during the course of therapy. However, CTCs are rare, especially at early stages of cancer, and the technologies for detecting them have a limited sensitivity and typing power.
Dozens of microfluidics technologies have been proposed to overcome this challenge but none made it to the clinic stage. The main bottleneck lies in the cost and complexity of use of the current microfluidic machines.
HoliFAB will offer significant improvements, setting the basis for the industrial development of an instrument cheaper to produce and easier to operate. Main expected advantages include:
- Unprecedented sensitivity: Detection of biological samples at a very low concentration,
- Multiplexing: Ability to detect various biomarkers during a single test,
- Industrialisation of the technology: Fast and repetitive testing of patients at a low cost and as a routine treatment follow-up.
Application 2 (medical): Organ-on-chips
Organ-on-chip is a new term corresponding to the creation of a cellular architecture in-vitro mimicking the organisation, structure and function of a real organ. This new field, at the crossing between microsystems, microfluidics and biology has the potential to revolutionise drug screening, personalised medicine and developmental biology.
The current kits commercially available mainly rely on the self-organisation power of cells and use conventional environment control. They are thus far from being able to reproduce the real-time spatio-temporal environment of tissues in real organs. Technologies for bio-printing start to appear, but they are mostly limited to equivalents of inkjet printing (limited resolution and low number of printable materials).
HoliFab will allow a change of paradigm, with at least 2 new features:
- Printing 3D architecture with tens of micrometres resolution and biocompatible multi-materials structure, allowing better biological reproducibility and functionality,
- Development of a fully integrated instrument compatible with environment control cabinets and allowing mechanical stimulation and programmable perfusion of different solutions and at a micrometre scale, allowing high throughput screening of complex systems currently reserved to only a few research laboratories worldwide.
Application 3 (environmental): Devices for environmental monitoring
There is a significant pull from the environmental market for lower cost sensors in water monitoring. Contaminated water is a serious concern in many aspects (drinking, waste, fresh, marine and coastal waters) and industries with often severe health and ecological consequences. However current methods for monitoring waterborne pathogens are time consuming, expensive and labour intensive.
Detection in a microfluidic platform offers many advantages such as portability, minimal use of instrumentation and easy integration with electronics.
HoliFAB will allow the combination of a strong reduction in production and operation costs, and an increase in the autonomy and reliability of these systems. New solutions with a strong expected impact on environment monitoring and control will be developed.
Pilot Line 3D Printing
- The prototyping, middle-scale series and complex 3D chips production, not amenable to being produced by injection moulding;
- The production of the mesofluidic bases for the whole instrument fabrication (see pilot line instruments).
- Sculpteo: Settings and overall operation of the pilot line,
- MRT/DCU: Development of new materials usable for printing (for example optically or magnetically active materials, hybrid polymer-ceramic materials, …),
- LAAS-CNRS: Development of innovative 3D printing technologies.
The equipment involved in the pilot line will be explained later on during the project (coming soon)
- New equipment: High resolution 3D printing equipment and bioprinting equipment,
- New materials: Innovative materials compatible for 3D printing, hydrogel materials for bioprinting and photosensitive hydrogel functional materials for post-hardening integration in a chip,
- New chips and casings: For pilot line instruments and markets
Pilot Line Injection Moulding
- The large-scale and low-cost production of chips with micro and nano-structures,
- The production of devices involving nanoscale features.
- MicroLiquid: Overall operation of the pilot line, support to microfluidic design stages, injection and bonding capabilities for the manufacturing of final microfluidic systems,
- EVG: Development of bonding equipment with alignment option,
- Mypa: Support design stages to guarantee the industrialisation capability of the microfluidic cartridges, providing its competences in high production rates of medical devices using injection moulding techniques.
The equipment involved in the pilot line will be explained later on during the project (coming soon)
- New equipment: Innovative bonding equipment,
- New chips: For pilot line instruments and markets.
Pilot Line Instruments
This pilot line is a production line for the construction of fully integrated microfluidic instrumentation. It will use mesofluidic bases produced in production line , and chips produced either in production lines 3D printing or injection moulding. It will also include bio-printing and post-fabrication processes to incorporate additional components (integrated valves for example).
- Fluigent: Overall set-up and operation of the pilot line, notably through the building of a library of components, the development of an assembly tool software and contribution to bio-printing instrument development and software development,
- DCU: Solutions for the modification of microfluidics post-fabrication (post-fabrication processes),
- LAAS-CNRS: Solutions for bioprinting.
HoliFAB Consortium includes 10 partners from 6 European countries.
Fluigent is a French SME which develops, manufactures and commercialises innovative flow control solutions and microfluidic instruments.
Fluigent (www.fluigent.com) is a French SME founded in 2005 by Institut Curie researchers. Fluigent develops, manufactures and commercialises innovative flow control solutions and instruments, both for researchers (end-user products) and industrials (OEM components to be integrated in global instruments). Pioneer company in introducing pressure-driven flow control to the market, as opposed to conventional syringe or peristaltic pumps, Fluigent is now the market world leader in this field. The products are based on patented technologies optimising stability and responsiveness of the flow inside microfluidic systems (chip, microarray, etc.).
As the leader of flow control and fluid handling solutions, Fluigent has been commercialising a range of pressure regulators, sensors, fluid handling instruments and integrated platforms for more than 11 years. The company products are widely used all over the world, and more than 500 peer-reviewed articles citing Fluigent products can be found in the literature.
Fluigent has thus strong experience and expertise in the design and production of complete microfluidic instruments (more than 3000 already sold worldwide). The SME is manufacturing its instruments in-house, on its own production line (assembly, tests, and quality control). Fluigent also has two subsidiaries for commercialisation, in Germany and in the US and a dense and trained distribution network for other areas.
All Fluigent products are EC-certified and the company also owns the ISO:9001 certification.
Sculpteo is a French SME which provides online 3D printing and laser cutting services for on-demand production of prototypes, individual products as well as short-run manufacturing.
Sculpteo (www.sculpteo.com) is a French digital manufacturing company founded in 2009. It provides professional online 3D printing and laser cutting services for on-demand production of prototypes, individual products as well as short-run manufacturing (400 000 individual parts produced in 2016). Sculpteo also provides access to a wide range of materials, finishes, and techniques, as well as superior optimisation tools for file analysis and repair.
Within its two factories (France and the US) producing over a thousand objects a day, and in addition to the 3D printers, Sculpteo production lines include diverse sanding, cleaning, polishing and curing equipment to adapt the various post-processing needs of each material, as well as multiple chemical baths.
Sculpteo R&D department handles the development of the company offer (new materials, new manufacturing techniques and new finishes) as well as quality control and characterisation. Concerning 3D printing, each material comes with its specificities, and industrial production adds strong constraints on the processes. The wide variety of objects also tends to reduce economies of scale, requiring sometimes a different approach than traditional manufacturing. By creating and developing a technology-agnostic production line using a wide range of 3D printing techniques, Sculpteo has acquired the necessary experience for integrating new 3D printing techniques into industrial production.
CNRS (Centre National de la Recherche Scientifique) is the largest governmental research organisation in France and the largest fundamental science agency in Europe. Two CNRS entities are involved in HoliFAB: CNRS-LAAS and CNRS-Curie.
- LAAS (www.laas.fr): the Laboratory of Analysis and Architecture of Systems is a research unit among the largest academic research labs in France covering a wide spectrum of the fields of micro- and nano-systems and technologies, signal optimisation, command and treatment, critical informatics systems, robotics an artificial intelligence. The LAAS shields one of the largest micro- and nano-fabrication facilities in France and delivers enabling micro- and nano-technologies for biology and environment applications. The ELiA team (involved in HoliFAB.) is part of the Micro and Nano Bio Technologies department and develops cutting edge technologies for the nanoscale characterisation and 2D/3D structuration of biomolecules and cells with a resolution at the nanoscale level. Applications cover the study of sub-cellular mechanisms, the development of micro-devices for the detection and analysis of circulating biomarkers, and the fabrication of cell microenvironments and tissue models.
- Institut Curie (curie.fr): the Curie Institute is an interdisciplinary, non-profit foundation dedicated to cancer research and treatment. It was founded with the aim of applying the progress of science to human health. Recognised as one of Europe’s best places for interdisciplinary research and translational medicine, it is strongly involved in the development of innovative technologies for medicine. Two departments are involved in HoliFAB: the “Macromolecules and Microsystems in Biology and Medicine” team, dedicated to the development of microfluidic tools for fundamental biology and clinics, and the Institut Curie hospital, for clinical validations.
Mypa is a Spanish SME specialised in mould design, manufacturing and injection moulding for various sectors.
Mypa (www.gemypa.com) is a Spanish company specialised in mould design, manufacturing and injection moulding for the automotive and home appliances sector. Mypa has been diversifying its activities since 2012 towards the health sector.
Already collaborating with MicroLiquid on microfluidic cartridges projects, Mypa also has experience in setting-up highly automated manufacturing plants with important companies in the IVD (In-Vitro Diagnostics) field. Furthermore, the company is involved with several R&D centres (for example the University of Zaragoza) and start-ups in the development of biomedical devices for cell culture application.
Finally, Mypa has experience in optical monitoring in their injection moulding lines for automotive and home appliances companies.
MicroLiquid, a Spanish SME, provides custom development and mass production of microfluidic devices and biochip.
Microliquid (www.microliquid.com) is a Spanish SME founded in 2008, that provides custom development and mass production of microfluidic devices and biochips for the health, pharmaceutical, agro-alimentary, veterinarian and petrochemical industries. Developments go from the design and moulding to encapsulation (capping), including sensing integration by standard external fluidic and electrical connections. Microliquid provides integration of microfluidic drug delivery components and reagents directly in their facilities, providing a full service to customers.
As such, Microliquid main goal is the manufacturing of OEM drug delivery & diagnostic/analysis devices, helping its customers to move forward from lab services to deliver microfluidic-based products. The company capacities range from the device and disposable prototyping to the clinical validation stages, including the disposable mass manufacturing.
Finally, Microliquid benefits from a fully equipped 400 m2 clean room, with state-of-the-art equipment for micro-manufacturing.
DCU is an Irish University with skills in microfluidic fabrication and integration into functioning analytical systems.
DCU (www.dcu.ie) is a young, dynamic and ambitious university with a distinctive mission to transform lives and societies through education, research and innovation. Located just north of Dublin City in Glasnevin, in the last nine years, DCU has twice been named Sunday Times “Irish University of the Year” and is a member of the European Consortium of Innovative Universities (ECIU). DCU regularly features among the top young universities globally as measured by the Times Higher Education Top 100 under 50 and the QS Top 50 under 50.
The University has extensive expertise in microfluidic fabrication and integration into functioning analytical systems, including addition of pumps, valves, detectors, system design, method development and validation, through to ruggedized fully functional prototype autonomous analysers for water quality monitoring. This includes electronics, power, and wireless communications, organisation and delivery of deployments in real scenarios (rivers/lakes, waste water treatment plants, estuary and marine environments). DCU also has developed futuristic concepts for flow control in microfluidics using stimuli-responsive (biomimetic) soft polymer gel actuators.
TelLab is an Irish SME specialising in water analysis.
Established in 1991, TelLab (www.tellab.ie) is a privately-owned SME based in Ireland, which employs 48 people including 6 full time researchers in its R&D Department. TelLab is ISO:9001 compliant and has an independent INAB/ISO 17025 accredited testing laboratory specialising in water analysis and chemical manufacturing laboratories, as well as a newly established Engineering Department, comprising of an oil analysis laboratory and research/engineering workshop.
The SME has a strong domestic and international client base and has been active in the environmental analysis market since 1995, with its environmental laboratory processing in excess of 5,000 environmental samples per year. This is carried out by environmental analysts which consist of a team of third level chemists in a fully equipped laboratory. TE Lab-manufactured chemicals, standards and reagent products are currently exported to a large number of export territories supplying most European countries including the United Kingdom, Germany, France, Italy and Spain.
Within TelLab, the Trend Institute activities include providing R&D solutions to companies for a range of services which includes bringing a laboratory research idea to productization. In addition, the company has been active in the research area for the past 6 years and has strong expertise in the areas of dissemination and project exploitation.
T2M is a Polish consulting firm specialised in technological innovation.
Tech2Market Polska ( tech2market.pl) is a Polish strategy consulting firm specialised in technological innovation. The company provides support to their clients from their early work of research to marketing and selling of their innovations.
Tech2Market is a key player in innovation projects, providing support and expertise in marketing studies, corporate strategy, and technology transfer and funding. In particular, Tech2Market consultants have developed a strong experience in 3D Printing, having studied many potential applications as a business point of view considering limits of the technologies.
Micro Resist Technology (MRT), a German SME, manufactures, develops and sells innovative photoresists, specialty photopolymers and ancillary materials for micro- and nanolithography and micro-optical applications.
Micro Resist Technology GmbH (www.microresist.com) is a German SME located in Berlin and leading company for the development and production of innovative photoresists, special polymers as well as ancillaries for micro- and nanolithography and micro-optical applications. Its products are applied in key technologies like microsystems technologies, microelectronics, micro and nano photonics, micro and nano engineering as well as in life sciences. Serving the global high-tech markets MRT’s products enable processes like UV, laser, X-ray, and e-beam lithography, nanoimprint lithography as well as associated micro-/nanopatterning technologies.
TMRT has been involved in various interdisciplinary research programmes both from academia and industry being in charge of the development of novel resists and photopolymers for next generation lithography applications. MRT is committed to advance its product portfolio by continuously innovating new products as well as preparing tailored solutions for customer’s technological demands in highest quality. Since 1997 MRT has been certified according to DIN EN ISO 9001 (Quality Management System) and since 2011 according to DIN EN ISO 14001 (Environment Management System).
MRT’s worldwide customers are innovative manufacturing companies whose value creation is significantly based on micro and nano fabrication. Leading research institutes and top level universities are clients which are supported already in the early phase of their technology development. All customers appreciate MRT’s expertise for photoresists, polymers, photo polymers as well as our comprehensive technological consultations with a holistically view on the lithographic interaction between material and processes.
The portfolio of in-house manufactured products is complemented by a strategic distributorship of associated products from supplementary international manufacturers. MRT operates as a high service distributor to the European small and medium sized businesses and offer a wide range of materials from one source which can be used for conventional technologies as well as for advanced processes in micro and nano patterning.
EV Group (EVG) is a leading supplier of equipment and process solutions for the manufacture of semiconductors, microelectromechanical systems (MEMS), compound semiconductors, power devices, photonic as well as microfluidic devices.
EV Group (EVG) is a leading supplier of equipment and process solutions for the manufacture of semiconductors, microelectromechanical systems (MEMS), compound semiconductors, power devices, photonic as well as microfluidic devices. Key products include wafer bonding, thin-wafer processing, lithography/nanoimprint lithography (NIL) and metrology equipment, as well as photoresist coaters, cleaners and inspection systems. Founded in 1980, EV Group services and supports an elaborate network of global customers and partners all over the world. More information about EVG is available at www.EVGroup.com.
- Accardo, A.; Blatché, M.-C.; Courson, R.; Loubinoux, I.; Vieu, C.; Malaquin, L. Direct Laser Fabrication of Free-Standing PEGDA-Hydrogel Scaffolds for Neuronal Cell Growth: Engineering 3D Biocompatible Microenvironments. Mater. Today 2018, 21, 315–316. DOI :10.1016/j.mattod.2018.02.004
- Accardo, A.; Courson, R.; Riesco, R.; Raimbault, V.; Malaquin, L. Direct Laser Fabrication of Meso-Scale 2D and 3D Architectures with Micrometric Feature Resolution. Addit. Manuf. 2018, 22, 440–446. DOI:10.1016/j.addma.2018.04.027
- Murray E., Li Y., Currivan S., Moore, B., Morrin A., Diamond D., Macka M. and Paull B. (2018) ‘Miniaturised capillary ion chromatograph with indirect UV LED based detection for anion analysis in potable and environmental waters’, Journal of Separation Science, 16, Journal Cover.
- Donohoe A, Lacour G, McCluskey P, Diamond D, McCaul M. Development of a Cost-Effective Sensing Platform for Monitoring Phosphate in Natural Waters. Chemosensors. 2018. DOI link
Conferences / Workshops
- 4th microfluidics workshop @ METAS (Bern, Switzerland), MakeFluidics, 11-12 July 2018, link 1, link 2
- 5th Workshop on Microfluidics Standards@ INESC-MN.(Lisbon, Portugal), MakeFluidics, 2019, link
- Spectra Biologie, « L'Europe investit 7,1 M € pour créer la Silicon Valley de la microfluidique », 01/04/2019
- Communiqué de presse Fluigent / Sculpteo, « L’Europe investit 7,1 M € pour créer la Silicon Valley de la microfluidique » , 05/04/2018, link
- Les Echos, Fluigent veut accélérer la révolution industrielle avec la microfluidique, 13/04/2018 link
- Actu365, Fluigent veut accélérer la révolution industrielle avec la microfluidique, 13/04/2018 link
- Boursier.com, L'Europe investit 7,1 ME pour créer la Silicon Valley de la microfluidique, 13/04/2018 link
- Les Echos, Fluigent veut accélérer la révolution industrielle avec la microfluidique, 13/04/2018
- Maddyness, Les startups françaises ont levé 39 millions d’euros du 7 au 13 avril 2018, 13/04/2018 link
- Industrie Mag, L’Europe investit 7,1 M € pour créer la Silicon Valley de la microfluidique, 15/04/2018 link
- Yahoo Finance France, Fluigent, champion européen d'une nouvelle filière industrielle de pointe, la microfluidique, 16/04/2018 link
- Challenges.fr, Fluigent, champion européen d'une nouvelle filière industrielle de pointe, la microfluidique, 16/04/2018 link
- ITRNews.com, Pourquoi la Commission européenne investit dans la microfluidique, 16/04/2018 link
- Info DSI, Pourquoi la Commission européenne investit dans la microfluidique, 16/04/2018 link
- ITR Mobiles.com, Pourquoi la Commission européenne investit dans la microfluidique, 16/04/2018 link
- L'Usine Nouvelle, Fluigent veut industrialiser la microfluidique à l’aide de l’impression 3D, 16/04/2018 link
- IT Channel.info, Pourquoi la Commission européenne investit dans la microfluidique, 16/04/2018 link
- 3Dprint Sculpteo, Partnering with Fluigent on Horizon 2020-Funded 3D Printing Microfluidics Research Project, 19/04/2018 link
- Flash Infos Economie Paris Ile-De-France Centre Val-De Loire 94, R&D : Fluigent obtient 7,1 M€ de financements européens, 20/04/2018
- Classe-Export.Com, Fluigent, champion européen d’une nouvelle filière : la microfluidique, 01/05/2018 link
- CNRS, Fluigent industrialise la microfluidique, 21/06/2018 link
- Oral presentation: Presentation to Sanofi, 01/10/2018
- Participation to a workshop: Workshop - Summer school IPGG, 28/08/2018
- Mesoscale 3D printing with micrometric resolution, Angelo Accardo, Rémi Courson, Roberto Riesco, Vincent Raimbault, Laurent Malaquin.
Micro Nano Engineering (MNE 2018), Sep 2018, Copenhagen, Denmark.
- Multi-Photon Direct Laser Writing and 3D Imaging of Nano-scale Resolution 3D Architectures for Cell Colonization, A. Accardo, M.C. Blatche, R. Courson, I. Loubinoux, C. Thibault, C. Vieu, L. Malaquin.
5th Nano Today Conference, Hawaï, December 6-10, 2017
- 3D free-standing neuronal microenvironments fabricated by two-photon lithography of PEGDAhydrogels, Angelo Accardo, Isabelle Loubinoux, Christophe Vieu, Laurent Malaquin
e-MRS Fall Meeting, Warsaw, Poland, September 17-19, 2018
- Lab-on-a-Chip World Congress, Oct 03, 2018 – San Diego, USA (CA)
- MicroTAS, Nov 12, 2018 – Kaohsiung, Taiwan
- MEDICA congress 2018, Dusseldorf, Germany
- AACC congress 2018, Chicago, USA
- BioSpain 2018, Seville, Spain
- MEDICA congress 2019, Dusseldorf, Germany
- Tech2Market. EPPN meetings, Brussels, Belgium. November 2017
- Tech2Market. EPPN meetings, Brussels, Belgium. November 2018
- NIL Industrial Day 2018,
- MNE 2018,
- Nano Science & Technlogy 2018,
- European Coating Show 2019
- 32nd International Symposium on Chromatography, Cannes-Mandelieu, France, Oral Presentation by Eoin Murray, PhD student: ‘Monitoring of nitrate and nitrite in aquatic environments using ion chromatography with low-cost, portable UV optical detection’, 23-27 September 2018
- ICE-AQUA workshop, Toulouse, France, Oral Presentation by Eoin Murray, PhD student: ‘Planning for the successful commercialisation of the first low-cost, deployable nitrate analyser’, 26-27 November 2018
- WET Networks, Enterprise Ireland, Ireland, A water and wastewater innovation seminar in Dublin where MD Mark Bowkett was one of the Innovation Presentations, 27 February 2019
- International Conference on Water, Wastewater and Environmental Monitoring (WEMM) 2018, Telford, UK, Tellab attended this event and were one of the exhibitors, 21–22 November 2018
- US EPA Market Research Workshops, USA, This workshop took place in New York and Cape Cod where technology developers could engage with stakeholders(including regulators) and end users in the water sector regarding their sensor needs ,25-27 November 2018
- Dermot Diamond, Shinde, Akshay, Donohoe, Andrew, Barret, Ruairi and McCaul, Margaret (2019) Microfluidic platforms with bioinspired functionalities: new concepts for future devices. In: SelectBIO “Lab-on-a-Chip & Microfluidics Europe 2019 Congress, 18-19 June 2019, Rotterdam, The Netherlands
- Margaret McCaul, Shinde, Akshay, Donohoe, Andrew, Barret, Ruairi and McCaul, Margaret (2019) 3D Printed Chips for Environmental Applications. In: SelectBIO “Lab-on-a-Chip & Microfluidics Europe 2019 Congress, 18-19 June 2019, Rotterdam, The Netherlands.