Efficient Development of Integrated Lab-On-A-Chip Systems Featuring Operational Robustness and Manufacturability

The majority of commercially oriented microfluidic technologies provide novel point-of-use solutions for laboratory automation with important areas in the context of the life sciences such as health care, biopharma, veterinary medicine and agrifood as well as for monitoring of the environment, infrastructures and industrial processes. Such systems are often composed of a modular setup exhibiting an instrument accommodating rather conventional actuation, detection and control units which interfaces with a fluidically integrated “Lab-on-a-Chip” device handling (bio-)sample(s) and reagents. As the complex network of tiny channels, chambers and surface-functionalised zones can typically not be properly cleaned and regenerated, these microfluidic chips are mostly devised as single-use disposables. The availability of cost-efficient materials and associated structuring, functionalisation and assembly schemes thus represents a key ingredient along the commercialisation pipeline and will be a first focus of this work. Furthermore, and owing to their innate variability, investigations on biosamples mostly require the acquisition of statistically relevant datasets. Consequently, intermediate numbers of consistently performing chips are already needed during application development; to mitigate the potential pitfalls of technology migration and to facilitate regulatory compliance of the end products, manufacture of such pilot series should widely follow larger-scale production schemes. To expedite and de-risk the development of commercially relevant microfluidic systems towards high Technology Readiness Levels (TRLs), we illustrate a streamlined, manufacturing-centric platform approach employing the paradigms of tolerance-forgiving Design-for-Manufacture (DfM) and Readiness for Scale-up (RfS) from prototyping to intermediate pilot series and eventual mass fabrication. Learning from mature industries, we further propose pursuing a platform approach incorporating aspects of standardisation in terms of specification, design rules and testing methods for materials, components, interfaces, and operational procedures; this coherent strategy will foster the emergence of dedicated commercial supply chains and also improve the economic viability of Lab-on-a-Chip systems often targeting smaller niche markets by synergistically bundling technology development.

[1]  Stavros Stavrakis,et al.  High‐throughput droplet‐based microfluidics for directed evolution of enzymes , 2019, Electrophoresis.

[2]  H. vanHeeren,et al.  Standards for connecting microfluidic devices , 2012 .

[3]  A. Boisen,et al.  Combined detection of C-reactive protein and PBMC quantification from whole blood in an integrated lab-on-a-disc microfluidic platform , 2018, Sensors and Actuators B: Chemical.

[4]  C. Kim,et al.  Electrowetting and electrowetting-on-dielectric for microscale liquid handling , 2002 .

[5]  Roland Zengerle,et al.  The centrifugal microfluidic Bio-Disk platform , 2007 .

[6]  Achim Wixforth,et al.  Acoustic manipulation of small droplets , 2004, Analytical and bioanalytical chemistry.

[7]  P. Andersson,et al.  Simultaneous multiple immunoassays in a compact disc-shaped microfluidic device based on centrifugal force. , 2005, Clinical chemistry.

[8]  R. Fair,et al.  Electrowetting-based actuation of droplets for integrated microfluidics. , 2002, Lab on a chip.

[9]  Holger Becker,et al.  Chips, money, industry, education and the "killer application". , 2009, Lab on a chip.

[10]  T. Laurell,et al.  Free flow acoustophoresis: microfluidic-based mode of particle and cell separation. , 2007, Analytical chemistry.

[11]  Jens Anders Branebjerg,et al.  Microfluidics-a review , 1993 .

[12]  Holger Becker,et al.  Polymer microfabrication technologies for microfluidic systems , 2008, Analytical and bioanalytical chemistry.

[13]  Ratna Tantra,et al.  Role of standard documents in advancing the standardization of microfluidics connectors , 2016 .

[14]  Richard B Fair,et al.  Sensors and Actuators B: Chemical Low Voltage Picoliter Droplet Manipulation Utilizing Electrowetting-on-dielectric Platforms , 2022 .

[15]  Joel Voldman,et al.  An active bubble trap and debubbler for microfluidic systems. , 2008, Lab on a chip.

[16]  S. Terry,et al.  A gas chromatographic air analyzer fabricated on a silicon wafer , 1979, IEEE Transactions on Electron Devices.

[17]  Subra Suresh,et al.  Isolation of exosomes from whole blood by integrating acoustics and microfluidics , 2017, Proceedings of the National Academy of Sciences.

[18]  Holger Becker,et al.  One size fits all? , 2010, Lab on a chip.

[19]  Tom Quirk,et al.  There’s Plenty of Room at the Bottom , 2006, Size Really Does Matter.

[20]  Jens Ducrée,et al.  Event-triggered logical flow control for comprehensive process integration of multi-step assays on centrifugal microfluidic platforms. , 2014, Lab on a chip.

[21]  Pieter Roux,et al.  Blister pouches for effective reagent storage and release for low cost point-of-care diagnostic applications , 2016, SPIE BiOS.

[22]  Akkapol Suea-Ngam,et al.  Droplet microfluidics: from proof-of-concept to real-world utility? , 2019, Chemical communications.

[23]  Claudia Gärtner,et al.  Microfluidics-Enabled Diagnostic Systems: Markets, Challenges, and Examples. , 2017, Methods in molecular biology.

[24]  M. Madou,et al.  Elastic reversible valves on centrifugal microfluidic platforms. , 2019, Lab on a chip.

[25]  Xiongying Ye,et al.  A bubble- and clogging-free microfluidic particle separation platform with multi-filtration. , 2016, Lab on a chip.

[26]  Teodor Veres,et al.  Active pneumatic control of centrifugal microfluidic flows for lab-on-a-chip applications. , 2015, Lab on a chip.

[27]  Jens Ducrée,et al.  Fully automated chemiluminescence detection using an electrified-Lab-on-a-Disc (eLoaD) platform. , 2016, Lab on a chip.

[28]  G.E. Moore,et al.  Cramming More Components Onto Integrated Circuits , 1998, Proceedings of the IEEE.

[29]  H. Lilja,et al.  Microfluidic, label-free enrichment of prostate cancer cells in blood based on acoustophoresis. , 2012, Analytical chemistry.

[30]  A. Manz,et al.  Miniaturized total chemical analysis systems: A novel concept for chemical sensing , 1990 .

[31]  C. Klapperich,et al.  Microfluidic diagnostics: time for industry standards , 2009, Expert review of medical devices.

[33]  S N Buhl,et al.  Portable simultaneous multiple analyte whole-blood analyzer for point-of-care testing. , 1992, Clinical chemistry.

[34]  Friedrich Schuler,et al.  A technology platform for digital nucleic acid diagnostics at the point of care , 2017 .

[35]  Sung Kwon Cho,et al.  Concentration and binary separation of micro particles for droplet-based digital microfluidics. , 2007, Lab on a chip.

[36]  T. Laurell,et al.  Label-free separation of leukocyte subpopulations using high throughput multiplex acoustophoresis. , 2019, Lab on a chip.

[37]  Holger Becker,et al.  It's the economy... , 2009, Lab on a chip.

[38]  S. Jacobson,et al.  Counting single chromophore molecules for ultrasensitive analysis and separations on microchip devices. , 1998, Analytical chemistry.

[39]  R. Ismagilov,et al.  Screening of protein crystallization conditions on a microfluidic chip using nanoliter-size droplets. , 2003, Journal of the American Chemical Society.

[40]  R. Fair,et al.  Electrowetting-based actuation of liquid droplets for microfluidic applications , 2000 .

[41]  R.B. Fair,et al.  Digital microfluidic chips for chemical and biological applications , 2009, 2009 Annual International Conference of the IEEE Engineering in Medicine and Biology Society.