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R2R Biofluidics Report Summary

Project ID: 646260
Funded under: H2020-EU.

Periodic Reporting for period 1 - R2R Biofluidics (Large scale micro-and nanofabrication technologies for bioanalytical devices based on R2R imprinting)

Reporting period: 2015-02-01 to 2016-07-31

Summary of the context and overall objectives of the project

The importance of sensors and miniaturized analytical systems to determine chemical and biochemical parameters increases steadily. Such so called labs-on-chip or micro-total-analysis-systems (µTAS) find applications in diagnostics, patient monitoring, biotechnology, and environmental monitoring.
Driven by global trends towards personalized medicine and decentralized healthcare, more than ever, rapid, accurate and low-cost tests are needed. Also in pharmaceutical research, the tremendous increase of costs for drug development and testing, drives the advancement of in-vitro cell based test assays. For both fields, consumables with additional and more complex functionalities are required. By offering innovative solutions, microfluidic technologies have partially filled this gap. For high volume applications like point-of-care diagnostics and life science consumables, requirements such as simple operation and low-cost production become crucial factors. A total adoption of the technology by industry is massively dependent on the implementation of new, cost-efficient, high-throughput production technologies. An important step towards the low-cost fabrication of monolithically integrated bioanalytical systems can be expected from the fast progress in roll-to-roll processing technology.
Roll-to-roll (R2R) technologies are mature core processes in manufacturing lines for graphical printing industry. In several other areas (e.g. electronics or optics) R2R techniques are emerging, in particular relying on recently developed roller-based nanoimprinting methods. They enable manufacturing of highly cost-effective and large-scale sheets of flexible polymer film with extremely precise structures on a micro- and nanoscale. Micro- and nanofabrication technologies such as nanoimprint lithography (NIL) are suitable for the production of microfluidic and microoptic structures in flexible polymer foils. In combination with printing of functional materials this opens new opportunities for the integration of e.g. microfluidic structures and sensors on flexible substrates. The current trends to miniaturize, automatize and parallelize assays while simultaneously increasing resolution and accuracy are directly addressed by such approaches.

Areas that will benefit strongly from adopting such R2R imprinting technologies are microfluidics, biosensors, and lab-on-chip products for point of care diagnostics, drug discovery and food control. Here R2R fabrication will greatly reduce production costs and increase manufacturing capacity with respect to currently used products.

As the overall objective, the “R2R Biofluidics” aims on the realization of a complete high-volume process chain for industrial fabrication of bioanalytical lab-on-chip devices based on setting–up a roll-to-roll (R2R) production line. Fabrication of two types of demonstrator devices (an in-vitro diagnostics device and a microstructured cell-culture dish) shall be shown by developing high-throughput R2R nanoimprinting processes in combination with complementary printing and manufacturing technologies.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

The capabilities of the R2R production technology and pilot line are demonstrated based on the development of two different application demonstrators:

• Demonstrator 1: In-vitro diagnostic chip with imprinted microfluidic channels based on optical chemiluminescence detection using photodetectors; containing imprinted optical nanostructures for light coupling and thus improving device performance.

• Demonstrator 2: Neuron-culture plates containing imprinted cavities and channels for controlled culturing and fluorescence imaging of neurons, to be applied in high throughput drug screening.

These types of demonstrators target application areas, which will clearly benefit from technology advancement in high volume manufacturing, show large potential for commercial exploitation and adopt standard formats (microtiter plate and microscope slides) currently used in the Life Sciences.

Within the first project period, the R2R-Biofluidics project made already very good progress towards the objectives: Innovative designs for both demonstrator devices being compatible with R2R imprinting technologies have been developed. These multistep design processes were facilitated by intensive use of optical and fluid dynamics simulation methods. Concomitantly to the design phase, master structures for the demonstrator designs were successfully fabricated and first imprints for tests of device functionalities were prepared using batch fabrication processes. The fabrication of optical microstructures for the diagnostics device was even already demonstrated on a R2R pilot line. In parallel, special UV-curable imprinting materials were developed, allowing efficient R2R processing and providing additional properties, such as refractive index tuning, biocompatibility, hydrophilic surface properties and bio-functionalization capabilities. Especially for these bio-functionalization steps, a broad range of possible biomolecules and immobilization methods have been screened in order to select suitable processes for fabrication of the demonstrators. Different protein coatings on the used UV-curable resist materials were found that ensured good viability of model cell lines and are further refined by applying peptidomimetic approaches. In addition to those activities towards the two application demonstrators, the R2R fabrication pilot line setup was significantly advanced. This comprised the planning and construction of imprinting modules and complimentary equipment and integration of additional processing steps for complete device fabrication in a microfluidic assembly pilot line. The testing of processes and materials on the existing R2R imprinting modules and subsequent improvements and advancements of this equipment played also a key role in establishing the R2R pilot line concept so far.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Based on the results achieved so far, R2R Biofluidics is well on track to reach one of its main objectives: to change the manufacturing paradigm within the microfluidic industry and establish R2R micro/nanopatterning methods as an industrially viable fabrication technology for microfluidic and bioanalytical consumables. This will be a disruptive advancement compared to the current state of the art in manufacturing. R2R manufacturing will easily allow for throughputs > 5.000 chips/h and hence could lead to reduction of production costs by a factor of 5-10.
R2R Biofluidics is currently working towards integrated production concepts for R2R manufacturing lines combining all relevant processing steps (imprinting, printing, etc.) for microfluidic, bioanalytical consumables based on plastic foils. This is far beyond current approaches that usually comprise just single R2R patterning steps.
Regarding the design and functionality of selected demonstrator applications themselves, a number of innovations could already be realized in the first project period.
Novel optical outcoupling structures could be integrated into a microfluidic chip for chemiluminescence based detection of that significantly improve optical detection efficiency. A novel method for patterned functionalization of microchannels by selective wetting contrast has been established. A new class of directly biofunctionalizable R2R UV-imprinting resist was developed, and the integration of actuators (pumps/valves) to microtiterpaltes has been shown, anabling cell culture device with higher degree of automation (autonomous, controlled perfusion and buffer exchange) without requiring complete robotic lab automation systems .

All those advancements will further contribute to significant future impact on society and public health.
For example, bacteria that are resistant to any class of antibiotics are a very real and close threat. R2R fabricated diagnostic chips will allow to rapidly screen for such pathogens in patients entering a hospital and thus allow to isolate infected or colonized patients. Such technology will prevent superbugs from spreading throughout hospitals causing catastrophic outbreaks. Such outbreaks not only cause many deaths but also a great amount of costs that public health systems have to bear.
As another example, the project will provide a device that would allow more reliable and robust cell based assays for drug screening. Using such devices, will speed up the drug production pipeline and accelerate introduction to the market. This will have a positive influence in the availability of new promising treatments for patients.

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