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Holistic digital-to-physical prototyping and production pilot for microfluidic MEMS

Periodic Reporting for period 1 - HoliFAB (Holistic digital-to-physical prototyping and production pilot for microfluidic MEMS)

Reporting period: 2017-11-01 to 2019-04-30

Numerous key study systems in the domains of Science and Health have to deal with very small size of dynamic elements, particularly to mimic living systems, with actors on a scale of micro- to pico-meters. Among the most known applications with a significant impact one can cite DNA sequencing or tumoral cell detections.
The HoliFAB project aims at a holistic new design strategy, coordinated by 3 pilot lines and business model for prototyping, fabrication and commercialization of microfluidic systems. It stems from the recognition that a microfluidic chip, where most, if not all, of the key observations and data are produced, is a key part of a future microfluidic instrument. Moreover, standard fabrication processes do not allow, as of today, fast prototyping and large-scale production. Finally, the chip is only a part of the overall instrument, and many limitations to development, industrialization and ultimate performances do not lie in the chip itself, but in the world-to-chip connections and integration of external instrumentation.
We shall address in a single strategy the streamlined construction of whole microfluidic systems, starting from existing pilot lines in injection moulding, 3D printing and instrument construction.
At the end, partners jointly hold the production lines onto which the project’s innovation will be readily integrated during the project, helping microfluidics to become a major component of the 4th industrial revolution.
Materials for 3D printing : A specification table for resins to be developed was established under the coordination of Micro resist technology GmbH. Micro resist and the CNRS-LAAS investigated new resins that achieved 3D printing of microfluidic chips with 1μm features and fit the final applications requirements. Bioprinting with flexible hydrogel-based material produced substrates and scaffolds for biological cell cultures, and cell survival was demonstrated (CNRS-LAAS). Finally, the partner Dublin City University integrated valves for controlling liquids with new photo-sensitive hydrogels that expand and retract inside the chip.

3D printing : Sculpteo partner completed the software tool that manages the chip 3D printing. It allows to set, layer per layer, the resolution and the speed, check the feasibility of the structures, determine the cost and the time of the process. CNRS-LAAS obtained, in cooperation with CNRS-Curie and Fluigent, microfluidic structures with 1μm features, by continuing developments around the new very high-resolution 3D printer DILASE 3D from the company Kloé. They also demonstrated the production of fluidic connectors with no leaks, using an established printer with industrial standard from the company DWS Systems.

Injection moulding : MYPA and MicroLiquid partners developed a new injection equipment with a variotherm module, which rises and lowers the temperature of the mould for the plastic to reach all the parts of the moulds. EVG partner is about to achieve the bonding machine that will bond moulded parts together. MicroLiquid explored the quality control strategy for the pilot line, developed the equipment for chip functionalization with reagents and fluidic control valves integration for moulded chips. Some specifications initially defined by the end-users appeared technologically unreachable, which required back and forth exchanges to find the best compromises that led to a significant delay. For the midterm evaluation (May 2018), an intermediate production step has been decided involving hot embossing (at Microliquid) and micromachined templates (made by CNRS-Curie) to provide thermoplastic chips and proceed without delay with tests and validations.

Instrument integration : Fluigent produced the first version of the computer-aided design (CAD) software tool for microfluidic systems. It allows to build in a few minutes only a microfluidic circuit (like an electronic circuit), place components in the 3D space and optimize the final layout. Mathematical routine has also been coded for the optimization of the instrument layout. Moreover, Fluigent investigated, in cooperation with Sculpteo and CNRS-LAAS, strategies for integration of connectors and capillaries. It was then observed that the standard industrial scale-production 3D printers did not have the resolution to achieve these connectors, suggesting a partial reorganization of the pilot line in which these connectors will be addressed by MultiFAB, the fablab of CNRS-LAAS with the potential for production.

Market analysis: Based on specialized reports and interviews of experts in microtechnology and life sciences, Tech2Market defined the economical context of microfluidics and its evolution for the next few years. Thanks to the data collected and the cross-comparisons of the different microfluidics applications, a set of 6 applications could have been chosen as the best ROI and the choices for HoliFAB developments.
The project results are more easily understood under the scope of the 3 pilot lines. Pilot line 1 will involve enhanced 3D printing technology for prototyping and small series fabrication (less than 100 samples) of microfluidic chips. Pilot line 2 will adapt and improve injection moulding technology for large series production of microfluidic chips. Finally, pilot line 3 aims at the development and production of next generation full microfluidic based instruments, taking advantage of the above two technologies and of new integration methods.
More precisely, this will involve the specific innovations listed below:
- The pilot line 1 proposes 3D printing and bio-printed solutions for prototyping and small series production of chip. The resolution of 3D printing will be increased by a factor of at least 10, down to 1~3μm, with a throughput of 10 to 100x higher than the current high-resolution 3D printing machines. This will support the flexible production of chips with complex 3D architectures. New soft, bio-, environment-friendly and/ or active materials will be integrated in the production chain using a technology patented by the partners.
- The pilot line 2 addresses large-scale markets requiring mass production at the lowest cost with a fully integrated pilot line, streamlining injection moulding of raw chips, reagents and components integration, sealing and quality control. Inter-compatibility between 3D printing and injection moulding, regarding architectures and materials, will be developed to accelerate the prototype to product value chain.
- The pilot line 3 follows the previous development and upscaling to demonstrate and qualify the technology in operational environment by end-users with lab-on-chip applications in health (cancer diagnosis, organ-on-chip) and environment (water control).
At the end of the project, those 3 pilot lines would have to be able to handle a customer request, custom or not, from the very beginning of the needs definition to the delivery of a final product, passing by the design of a custom instrument and the creation of a large-scale production line (when needed) dedicated to a project.
This should pave the way for another approach when it comes to create and sell custom instruments and/or solutions dedicated to particular applications. The time between a scientific idea and its realization thanks to a microfluidic instrument will significantly decrease while the quality will, on the contrary, increase.
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