EURAMET 25NRM03 MFMET II
Establishing metrology standards in microfluidic devices
Overview
Advances in microfluidics and nanotechnology have enabled fast establishment of miniaturised and portable laboratories. Whilst academics and manufacturers have primarily focused on product development, novel approaches are needed to assess their performance and accuracy. Driven by the need for new testing approaches, recent work has already provided some refined approaches for harmonisation. Yet the qualification and characterisation of entire microfluidic systems still requires standards and regulations for democratisation. This project proposes to develop protocols and guidelines to eliminate the gaps in the microfluidics supply chain, including Organ-on-Chip applications. The output will directly support ISO/TC 48/WG 3 and other standardization committees.
Need
Microfluidics is a technology used to create various miniaturised products, ranging from microreactors for the chemical industry to Organs-on-Chips (OoC) and medical diagnostic devices. A microfluidic device contains microchannels, chambers, pumps, valves, sensors, and actuators to manipulate small volumes of fluid. Progress in microfabrication techniques and cost-effectiveness of microfluidics has enabled significant growth in this field. As a result, microfluidics is becoming a viable technology for improving the quality and sensitivity of critical processes within microsystems. Although initially envisioned for integrated chemical analysis (µTAS), microfluidics now finds applications in healthcare, supporting alternatives to animal testing (microphysiological systems, OoC) and medical diagnostics. Progress in OoC is driven by the demand to replace animal testing for disease modelling and drug development and is heavily supported by the Food and Drug Administration, FDA Modernization Act, 2.0. The field of Organ-on-Chip has grown rapidly with a compound annual growth rate (CAGR) of 70 % from 2015 to 2020 and will continue to do so with a projected CAGR of 31 % from 2020 until 2030, reaching a market size of 1.6B€. However, companies are commercialising OoC models and developing their own microfluidic systems without standard test methods for validation of basic manufacturing steps, performance, material compatibility, and safety of microfluidic devices. This problem is being addressed under the ISO/TC 276 Biotechnology, with several documents under preparation. Standardisation can help define common terminology, specifications, protocols, and criteria for microfluidic system design, fabrication, characterization, validation, operation, analysis, and reporting. Standardization can also enable the development of reference materials, quality control procedures, and regulatory frameworks. Harmonisation of performance testing is needed for the different classes of microfluidic components, including test conditions and quantity measurement protocols. Thus far, each microfluidic product is tested and validated according to its own protocol or using the few protocols developed under MFMET.
Objectives
The overall objective of the project is to enhance metrology research for standardization in biomedical, pharmaceutical, and chemical industries, with a focus on microfluidics and Organ-on-Chip. It aims to develop measurement protocols for various quantities, including: integration, materials, quality control and qualification, which will inform standards prepared or revised by ISO/TC48/WG3 and other standardization committees.
The specific objectives of the project are:
- Establish standard procedures to metrologically assess and characterize particle-laden flows (e.g., presence of droplets, bubbles, particles, cells), shear stress, pressure drop, flow resistivity, dead volume and total volume in microfluidic devices, including Organ-on-Chip.
- Investigate and develop protocols for the integration of sensors, actuators and fluidic components in microfluidics using scalable, cost-effective and sustainable manufacturing strategies (e.g., biodegradable materials) and supporting steps of sterilization (particularly important for Organ-on-Chip), characterization of the interface between material and medium (absorption, adsorption, coating quality: homogeneity, durability, and surface wettability modification efficiency) and preventing contamination. Study the integration of different materials and how that integration changes material shape.
- Define general standards and guidelines for quality control, validation and characterization regarding microfluidic system reliability/failure focusing on hydrostatic vs pneumatic testing, burst pressure, bonding strength, connector reliability and general safety precautions.
- Design (simulate, fabricate and mount) and characterize a setup of an integrated microfluidic system with several sensors and actuators to access the influence of different quantities in the system performance in order to qualify and validate a microfluidic system. This setup will act as a metrological transfer standard.
- Stimulate the development and implementation of microfluidic systems in applications that include, for example Organ-on-Chip standards by the dissemination of scientific outcomes and best practices through scientific publications, white papers, guidelines, protocols, recommendations reaching CEN/CENELEC and ISO committees, metrologists, developers, regulators and other decision makers, and the global Microfluidics Industry actors.
EURAMET 20NRM02 MFMET
Establishing metrology standards in microfluidic devices
Overview
Microfluidics, concerned with fluid-handling in the nano-to-millilitre scale, has major applications in biomedical and chemical analysis however global standards are lacking. ISO/TC48/WG3 has been set up to develop microfluidic standards covering metrology for the methodologies and fabrication processes that are essential to ensure measurement accuracy and traceability of devices. The goal of this project is to contribute to the development of globally accepted standards for microfluidics and disseminate them to end users in industry (health, pharmaceutical) and academia.
Need
The increased technical capability required to miniaturise devices along with the growing need for faster, more accessible and cost-effective solutions for precision analytical tools has led to the rapid growth of microfluidics in diverse sectors (e.g. pharmaceutical and biomedical industries). However, due to this rapid growth, microfluidics and specifically the control of fluids in microfluidic devices still lacks universal solutions and standards. Stakeholders from industry, academia and government have recognised these needs [1] and as a result ISO/TC48/WG3 has been set up to develop microfluidic standards covering metrology for the methodologies and fabrication processes that are essential to ensure measurement accuracy and traceability of devices.
Standardisation of performance characteristics is needed for the different classes of components, including test conditions, measurement protocols and guidelines. The increasing demand for passive flow devices has already led NMIs to establish protocols and calibrations services for the small flow rates [2,3]. Traceability to National Standards has been available since 2012 down to 0.1 μL/min through facilities developed under EMRP JRP HLT07 MeDD. Also, in 2018 a new EMPIR JRP 18HLT08 MeDDII, related to microflow measurements down to 5 nL/min, was set up and the new facilities are now under implementation. This new technology can now be used to develop microfluidic measurement protocols, and the new microflow pump devised in MeDDII can be used as a traceable flow generator.
In 2016, a first step towards microfluidic standardisation was made through ISO IWA23 [4]. The document was created to facilitate the uptake of microfluidic devices by making them easier to use, reducing the cost for assembling and enabling plug and play functionality. Recently a new standard, ISO/CD 22916 [5], is being established based on the information from ISO IWA 23 and it will replace this document; however, this new standard still lacks the metrological specifications required for accurate and reproducible manufacturing.
[1] D.R. Reyes and H. Van Heeren, Proceedings of the First Workshop on Standards for Microfluidics, Journal of Research of the National Institute of Standards and Technology, Volume 124, Article No. 124001 (2019). https://doi.org/10.6028/jres.124.001
[2] Metrology for Drug Delivery, EURAMET EMRP JRP HLT07, www.drugmetrology.com
[3] E. Batista, A. Furtado, J. Pereira M. Ferreira, H. Bissig , E. Graham , A. Niemann , A. Timmerman, J. Alves e Sousa , F. Ogheard , A. W. Boudaoud, New EMPIR project – Metrology for Drug Delivery, Flow Measurement and Instrumentation, Volume 72, April 2020, 101716. https://doi.org/10.1016/j.flowmeasinst.2020.101716
[4] ISO IWA 23:2016 – Interoperability of microfluidic devices – Guidelines for pitch spacing dimensions and initial device classification. https://www.iso.org/standard/70603.html
[5] ISO / CD 22916 – Laboratory equipment — Interoperability of microfluidic devices. https://www.iso.org/standard/74157.html
Objectives
The overall objective of this project is to contribute to the development of globally accepted standards for microfluidic devices used particularly in the health and pharmaceutical industry.
The specific objectives are:
1. To investigate, evaluate and formulate consensus-based flow control specifications, guidelines and protocols to enhance the manufacturing capability of the microfluidics industry supply chain through voluntary compliance.
2. To develop measurement protocols for different flow quantities and liquid properties, in different microfluidics devices to be used in pharmaceuticals, biomedical and mechanobiology applications. A EURAMET guide and a technical report on these measurement protocols will be developed.
3. To define consensus-based standards and guidelines for interfaces and connectivity between fluidic passages and optical/electrical connections of microfluidics components and corresponding measurement standards, from micro to macro size scales.
4. To define guidelines for the standardisation of dimensions and accuracy for modularity (either module-to-module or module-to-world) and sensor integration (combination of sensing elements/materials with microfluidic modules), in accordance with good practices in microfluidic component design and manufacturing.
5. To collaborate with ISO/TC48/WG3 and end users of the standards (e.g. health and pharmaceutical industry) to ensure that the outputs of the project are aligned with their needs and in a form that can be incorporated into standards (e.g. new technical guides, ISO 10991 and ISO/CD 22916) at the earliest opportunity