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Recent Advances in Microfluidic Technology for Bioanalysis and Diagnostics Research Collection Review Article Recent Advances in Microfluidic Technology for Bioanalysis and Diagnostics Author(s): Berlanda, Simon F.; Breitfeld, Maximilian; Dietsche, Claudius L.; Dittrich, Petra S. Publication Date: 2021-01-12 Permanent Link: https://doi.org/10.3929/ethz-b-000468393 Originally published in: Analytical Chemistry 93(1), http://doi.org/10.1021/acs.analchem.0c04366 Rights / License: In Copyright - Non-Commercial Use Permitted This page was generated automatically upon download from the ETH Zurich Research Collection. For more information please consult the Terms of use. ETH Library This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes. pubs.acs.org/ac Review Recent Advances in Microfluidic Technology for Bioanalysis and Diagnostics Simon F. Berlanda,† Maximilian Breitfeld,† Claudius L. Dietsche,† and Petra S. Dittrich* Cite This: Anal. Chem. 2021, 93, 311−331 Read Online ACCESS Metrics & More Article Recommendations ■ CONTENTS Extracellular Vesicles (EV) 324 Identification of Pathogens and Antibiotic Materials and Fabrication 312 Susceptibility Testing 325 Materials 312 Virus Detection 326 Polymers 312 Conclusion and Outlook 326 Silicon-Glass Devices 312 Author Information 327 Alternative Materials 312 Corresponding Author 327 Fabrication 313 Authors 327 Lithography 313 Author Contributions 327 Direct Laser Writing 313 Notes 327 3D Printing 313 Biographies 327 3D Channel Fabrication 313 Acknowledgments 327 Well Plate Insert 314 References 327 Coating 314 Antifouling 314 Cell Adherence 314 fl Operational Units 314 icro uidics has become a mature technology, providing Pumping 314 M an excellent toolbox for the handling and manipulation of fluid samples, suspended cells, and particles. About 30 years Valves 315 fi fl Gradient Formation 316 ago, the rst micro uidic devices aimed mainly at miniaturizing Mixing 316 analytical methods, particularly for improving the separation of Filtration and Separation 316 analytes. Since then, fabrication protocols and operation of the Filtration 316 devices have become more and more facile. The improved Separation 316 accessibility allowed increasing numbers of researchers to fl Droplet Microfluidics and Digital Microfluidics 317 design, manufacture, and use micro uidic systems, which Downloaded via ETH ZURICH on February 18, 2021 at 10:28:21 (UTC). Droplet Generation 317 rapidly revealed the potential for widespread applications fl Droplet Sorting 317 across the life sciences. Numerous novel micro uidic methods Droplet Storage 317 are reported every year for observation and manipulation of Droplet Interfaces 317 cells, mimicking organs, detection of biomarkers, and many See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles. fi In-Droplet Manipulation 318 other elds of study. fl fi Digital Microfluidics 318 Micro uidic technology has multiple bene ts for bioanalyt- Detection 319 ical procedures. Obviously, the miniaturized devices facilitate Electroanalytical Methods 319 processing and analyzing of small sample volumes, in the range μ Raman Spectroscopy 320 of L to pL. Correspondingly, the consumption of assay Optical Methods 321 compounds is low, thereby reducing the cost of the analysis. In fl Mass Spectrometry (MS) 321 digital and droplet micro uidics, the sample is further Other Methods 321 segmented into droplets. In this way, thousands of discrete Selected Applications in Bioanalysis and Diagnos- reaction compartments are created, which can be utilized for fi tics 322 high-throughput screenings in the elds of drug discovery, drug Cell Manipulation 322 Cytometry and Cell Sorting 322 Special Issue: Fundamental and Applied Reviews in Analysis of Secreted Compounds 324 Analytical Chemistry 2021 Diagnostic Applications 324 Blood Cell Separation 324 Published: November 10, 2020 Point-of-Care Devices for the Detection of Biomarkers 324 © 2020 American Chemical Society https://dx.doi.org/10.1021/acs.analchem.0c04366 311 Anal. Chem. 2021, 93, 311−331 Analytical Chemistry pubs.acs.org/ac Review testing, directed evolution, or single-cell analysis. Owing to the a hydrophilic-in-hydrophobic well array. This commercially ease of use, droplet microfluidic platforms have been added to appealing fabrication procedure generates surface properties, biologists’ routine methods for single-cell sequencing, also which are long-term stable.7 referred to as droplet sequencing, which we do not further Potential commercialization of microfluidic devices is often cover in this review. hindered by the limited capabilities for mass production. Hot Microfluidic devices made it possible to integrate different embossing, the imprinting of the microfluidic structure under functional modules (or operational units) on a single platform pressure and heat, is a promising manufacturing approach for and construct a micro total analysis system, as it was the commercialization of microfluidic devices. Sun et al. envisioned in the early days of microfluidics.1 Excellent utilized hot embossing to fabricate polypropylene (PP) examples of integrated systems are reported for digital and microfluidic chips. These chips have superior chemical droplet microfluidics, where several process steps were resistance and exceptional antifouling properties, which successfully realized on a single platform. Serial coupling of increases the consistency of bioassay readout compared to different separation methods before analysis, e.g., of cell PDMS.8 suspensions, was likewise achieved. Silicon-Glass Devices. Si-glass chips are expensive to The detection method is integral to the microfluidic fabricate but exhibit excellent pressure and chemical resistance platform to acquire a meaningful readout for the desired quality. Qi et al. presented a manifold for small Si-chips, which application. Microdevices can have either an integrated reduces the footprint of single devices to 50 mm2.Ona detection module or are coupled to an external instrument. common 4 in. wafer, up to 80 single microfluidic chips can be While optical and fluorescence microscopy are commonly produced. This reduces the cost per chip by 2 orders of employed, interfaces to many other analytical methods were magnitude, paving the way for single-use Si-glass micro- further advanced, opening multiple options for assays, with or fluidics.9 Si-glass devices are generally fabricated by wet or dry without the need of (fluorescent) labels. etching processes, which limit the microfluidic channel design This review covers recent advances and developments in the to open 2D structures. Kotz et al. succeeded in producing field of microfluidic technology and selected articles published complex 3D structures in fused silica glass. This is achieved by between August 2018 and September 2020. In tradition of a sacrificial template, which leaves a cavity, the microfluidic previous review articles on micro total analysis systems,2,3 we channel, inside of the fused silica.10 highlight new developments in manufacturing techniques and Alternative Materials. In contrast to rigid materials, materials for microfluidic devices, operational units including hydrogels are soft and, due to their similarity with the droplet microfluidics, and detection methods. The field of extracellular matrix, are far better suited for long-term on-chip applications are continuously growing. We selected here cell culture experiments. One major drawback of hydrogel- interesting studies for bioanalysis and diagnostics, with the based chips is the intrinsic swelling of the hydrogel, making it focus on extracellular vesicles, detection of biomarkers, and cell difficult to design and fabricate complex structures. Shen et al. studies. In the light of the pandemic in 2020 caused by the overcame this problem by fabricating microfluidic devices with virus SARS-CoV-2, we also emphasize microfluidic methods the nonswelling diacrylated Pluronic F127 (F127-DA). This for viral detection and related studies. copolymer is covalently cross-linked and retains its structure and mechanical properties after an equilibrium is established at ■ MATERIALS AND FABRICATION 37 °C in aqueous solution.11 Zhang et al. used a biodegradable Materials. Polymers. Many materials are suitable to build polymer to fabricate a scaffold for a branched network of microfluidic devices. Most often, polymers are chosen due to seeded cells. This multimaterial system is fabricated by a 3D their low price and established fabrication protocols. Among stamping technique and it allows the integration of a complex them, poly(dimethylsiloxane) (PDMS) is very common, since 3D network.12 the production of prototypes by soft lithography is facile, and A remarkable alternative material is wood, which is PDMS is biocompatible, gas permeable, and transparent. renewable and biodegradable. Point-of-care (POC) devices, However, PDMS is not amenable for mass fabrication, suffers which are generally single-use devices, could benefit from this from alteration of surface properties over time, and absorbs environmentally friendly material. Andar et al. fabricated hydrophobic substances at its surface. Auner et al. investigated wooden microfluidic devices and showed rapid and sensitive the binding of 19 chemicals to the surface of PDMS. Based on protein detection with a POC device, which was fabricated by the chemical affinity for PDMS, they implicate that the laser engraving plywood. This inexpensive method of effective concentration of certain chemicals
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