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Title: Faster, better, and cheaper: harnessing microfluidics and mass spectrometry for biotechnology

Abstract

High-throughput screening technologies are widely used for elucidating biological activities. These typically require trade-offs in assay specificity and sensitivity to achieve higher throughput. Microfluidic approaches enable rapid manipulation of small volumes and have found a wide range of applications in biotechnology providing improved control of reaction conditions, faster assays, and reduced reagent consumption. The integration of mass spectrometry with microfluidics has the potential to create high-throughput, sensitivity, and specificity assays. This review introduces the widely-used mass spectrometry ionization techniques that have been successfully integrated with microfluidics approaches such as continuous-flow system, microchip electrophoresis, droplet microfluidics, digital microfluidics, centrifugal microfluidics, and paper microfluidics. In addition, we discuss recent applications of microfluidics integrated with mass spectrometry in single-cell analysis, compound screening, and the study of microorganisms. Lastly, we provide future outlooks towards online coupling, improving the sensitivity and integration of multi-omics into a single platform.

Authors:
ORCiD logo [1]; ORCiD logo [2]; ORCiD logo [3];  [3]; ORCiD logo [1];  [4]
+ Show Author Affiliations
  1. Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, CA, USA, US Department of Energy Joint BioEnergy Institute, Emeryville, CA, USA
  2. Environmental Genomics and Systems Biology, Biosciences, Lawrence Berkeley National Laboratory, Berkeley, CA, USA
  3. Environmental Genomics and Systems Biology, Biosciences, Lawrence Berkeley National Laboratory, Berkeley, CA, USA, US Department of Energy Joint Genome Institute, Berkeley, CA, USA
  4. Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, CA, USA, US Department of Energy Joint BioEnergy Institute, Emeryville, CA, USA, Environmental Genomics and Systems Biology, Biosciences, Lawrence Berkeley National Laboratory, Berkeley, CA, USA, US Department of Energy Joint Genome Institute, Berkeley, CA, USA
Publication Date:
Research Org.:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Biological and Environmental Research (BER)
OSTI Identifier:
1809121
Alternate Identifier(s):
OSTI ID: 1826724
Grant/Contract Number:  
AC02-05CH11231
Resource Type:
Published Article
Journal Name:
RSC Chemical Biology
Additional Journal Information:
Journal Name: RSC Chemical Biology Journal Volume: 2 Journal Issue: 5; Journal ID: ISSN 2633-0679
Publisher:
Royal Society of Chemistry (RSC)
Country of Publication:
United Kingdom
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY

Citation Formats

Ha, Noel S., de Raad, Markus, Han, La Zhen, Golini, Amber, Petzold, Christopher J., and Northen, Trent R. Faster, better, and cheaper: harnessing microfluidics and mass spectrometry for biotechnology. United Kingdom: N. p., 2021. Web. doi:10.1039/D1CB00112D.
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Ha, Noel S., de Raad, Markus, Han, La Zhen, Golini, Amber, Petzold, Christopher J., & Northen, Trent R. Faster, better, and cheaper: harnessing microfluidics and mass spectrometry for biotechnology. United Kingdom. https://doi.org/10.1039/D1CB00112D
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Ha, Noel S., de Raad, Markus, Han, La Zhen, Golini, Amber, Petzold, Christopher J., and Northen, Trent R. Thu . "Faster, better, and cheaper: harnessing microfluidics and mass spectrometry for biotechnology". United Kingdom. https://doi.org/10.1039/D1CB00112D.
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@article{osti_1809121,
title = {Faster, better, and cheaper: harnessing microfluidics and mass spectrometry for biotechnology},
author = {Ha, Noel S. and de Raad, Markus and Han, La Zhen and Golini, Amber and Petzold, Christopher J. and Northen, Trent R.},
abstractNote = {High-throughput screening technologies are widely used for elucidating biological activities. These typically require trade-offs in assay specificity and sensitivity to achieve higher throughput. Microfluidic approaches enable rapid manipulation of small volumes and have found a wide range of applications in biotechnology providing improved control of reaction conditions, faster assays, and reduced reagent consumption. The integration of mass spectrometry with microfluidics has the potential to create high-throughput, sensitivity, and specificity assays. This review introduces the widely-used mass spectrometry ionization techniques that have been successfully integrated with microfluidics approaches such as continuous-flow system, microchip electrophoresis, droplet microfluidics, digital microfluidics, centrifugal microfluidics, and paper microfluidics. In addition, we discuss recent applications of microfluidics integrated with mass spectrometry in single-cell analysis, compound screening, and the study of microorganisms. Lastly, we provide future outlooks towards online coupling, improving the sensitivity and integration of multi-omics into a single platform.},
doi = {10.1039/D1CB00112D},
journal = {RSC Chemical Biology},
number = 5,
volume = 2,
place = {United Kingdom},
year = {Thu Oct 07 00:00:00 EDT 2021},
month = {Thu Oct 07 00:00:00 EDT 2021}
}
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https://doi.org/10.1039/D1CB00112D
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Utilizing Surface Acoustic Wave Nebulization (SAWN) for the Rapid and Sensitive Ambient Ionization Mass Spectrometric Analysis of Organic Explosives
journal, October 2019

  • Pintabona, Lauren; Astefanei, Alina; Corthals, Garry L.
  • Journal of the American Society for Mass Spectrometry, Vol. 30, Issue 12
  • DOI: 10.1007/s13361-019-02335-y

SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor
journal, April 2020

Recent advances in SALDI-MS techniques and their chemical and bioanalytical applications
journal, August 2010

Surface acoustic wave (SAW) directed droplet flow in microfluidics for PDMS devices
journal, January 2009

  • Franke, Thomas; Abate, Adam R.; Weitz, David A.
  • Lab on a Chip, Vol. 9, Issue 18
  • DOI: 10.1039/b906819h

Droplet Barcoding for Single-Cell Transcriptomics Applied to Embryonic Stem Cells
journal, May 2015

Microfluidic Large-Scale Integration
journal, September 2002

Improved Sensitivity in Low-Input Proteomics Using Micropillar Array-Based Chromatography
journal, October 2019

Uncovering the Formation of Color Gradients for Glucose Colorimetric Assays on Microfluidic Paper-Based Analytical Devices by Mass Spectrometry Imaging
journal, September 2018

  • de Freitas, Soraia V.; de Souza, Fabrício R.; Rodrigues Neto, Jorge C.
  • Analytical Chemistry, Vol. 90, Issue 20
  • DOI: 10.1021/acs.analchem.8b02384

Highly Integrated Microfluidic Chip Coupled to Mass Spectrometry for Online Analysis of Residual Quinolones in Milk
journal, September 2019

An integrated chip-mass spectrometry and epifluorescence approach for online monitoring of bioactive metabolites from incubated Actinobacteria in picoliter droplets
journal, September 2018

  • Wink, Konstantin; Mahler, Lisa; Beulig, Julia R.
  • Analytical and Bioanalytical Chemistry, Vol. 410, Issue 29
  • DOI: 10.1007/s00216-018-1383-1

MALDI MS Guided Liquid Microjunction Extraction for Capillary Electrophoresis–Electrospray Ionization MS Analysis of Single Pancreatic Islet Cells
journal, July 2017

Integrated Microfluidic Platform with Multiple Functions To Probe Tumor–Endothelial Cell Interaction
journal, August 2017

Mass Spectrometry Imaging of Lipids in Human Skin Disease Model Hidradenitis Suppurativa by Laser Desorption Ionization from Silicon Nanopost Arrays
journal, November 2019

On-Chip Mesoporous Functionalized Magnetic Microspheres for Protein Sequencing by Extended Bottom-up Mass Spectrometry
journal, January 2016

A perspective on paper-based microfluidics: Current status and future trends
journal, March 2012

  • Li, Xu; Ballerini, David R.; Shen, Wei
  • Biomicrofluidics, Vol. 6, Issue 1
  • DOI: 10.1063/1.3687398

Strong Anion Determination in Biological Fluids by Capillary Electrophoresis for Clinical Diagnostics
journal, October 2013

  • de Macedo, Adriana Nori; Irfan Yasin Jiwa, Muhammad; Macri, Joseph
  • Analytical Chemistry, Vol. 85, Issue 22
  • DOI: 10.1021/ac402975q

Ambient Sampling/Ionization Mass Spectrometry: Applications and Current Trends
journal, June 2011

  • Harris, Glenn A.; Galhena, Asiri S.; Fernández, Facundo M.
  • Analytical Chemistry, Vol. 83, Issue 12, p. 4508-4538
  • DOI: 10.1021/ac200918u

Challenges and recent advances in mass spectrometric imaging of neurotransmitters
journal, February 2014

  • Gemperline, Erin; Chen, Bingming; Li, Lingjun
  • Bioanalysis, Vol. 6, Issue 4
  • DOI: 10.4155/bio.13.341

Application of capillary electrophoresis for the early diagnosis of cancer
journal, March 2014

  • Yang, Zhiyong; Sweedler, Jonathan V.
  • Analytical and Bioanalytical Chemistry, Vol. 406, Issue 17
  • DOI: 10.1007/s00216-014-7722-y

Novel volumetric method for highly repeatable injection in microchip electrophoresis
journal, September 2017

Miniature and Fieldable Mass Spectrometers: Recent Advances
journal, October 2015

Forensic determination of pesticides in human serum using metal ferrites nanoparticles and SALDI-MS
journal, January 2021

Sheathless coupling of microchip electrophoresis to ESI-MS utilising an integrated photo polymerised membrane for electric contacting
journal, July 2018

  • Scholl, T.; Dietze, C.; Schmidt, M.
  • Analytical and Bioanalytical Chemistry, Vol. 410, Issue 23
  • DOI: 10.1007/s00216-018-1226-0

Miniature Mass Spectrometers
journal, July 2009

On-chip integration of droplet microfluidics and nanostructure-initiator mass spectrometry for enzyme screening
journal, January 2017

  • Heinemann, Joshua; Deng, Kai; Shih, Steve C. C.
  • Lab on a Chip, Vol. 17, Issue 2
  • DOI: 10.1039/C6LC01182A

Rapid separation and identification of beer spoilage bacteria by inertial microfluidics and MALDI-TOF mass spectrometry
journal, January 2019

  • Condina, Mark R.; Dilmetz, Brooke A.; Razavi Bazaz, Sajad
  • Lab on a Chip, Vol. 19, Issue 11
  • DOI: 10.1039/C9LC00152B

Present state of microchip electrophoresis: State of the art and routine applications
journal, February 2015

Diagnostics for the Developing World: Microfluidic Paper-Based Analytical Devices
journal, January 2010

  • Martinez, Andres W.; Phillips, Scott T.; Whitesides, George M.
  • Analytical Chemistry, Vol. 82, Issue 1
  • DOI: 10.1021/ac9013989

High sensitive matrix-free mass spectrometry analysis of peptides using silicon nanowires-based digital microfluidic device
journal, January 2011

  • Lapierre, Florian; Piret, Gaëlle; Drobecq, Hervé
  • Lab on a Chip, Vol. 11, Issue 9
  • DOI: 10.1039/c0lc00716a

High-Throughput Enzyme Kinetics with 3D Microfluidics and Imaging SAMDI Mass Spectrometry
journal, September 2018

Combinatorial drug discovery in nanoliter droplets
journal, June 2018

  • Kulesa, Anthony; Kehe, Jared; Hurtado, Juan E.
  • Proceedings of the National Academy of Sciences, Vol. 115, Issue 26
  • DOI: 10.1073/pnas.1802233115

Linked optical and gene expression profiling of single cells at high-throughput
journal, February 2020

Ion-mobility spectrometry as a fast monitor of chemical composition
journal, April 2002

Microfluidics: Fluid physics at the nanoliter scale
journal, October 2005

Microfluidic Platform for Next-Generation Sequencing Library Preparation with Low-Input Samples
journal, January 2020

Impact of high-throughput screening in biomedical research
journal, March 2011

  • Macarron, Ricardo; Banks, Martyn N.; Bojanic, Dejan
  • Nature Reviews Drug Discovery, Vol. 10, Issue 3
  • DOI: 10.1038/nrd3368

Ror2 signaling regulates Golgi structure and transport through IFT20 for tumor invasiveness
journal, January 2017

Ionic-surfactant-mediated electro-dewetting for digital microfluidics
journal, August 2019

Scaling and the design of miniaturized chemical-analysis systems
journal, July 2006

  • Janasek, Dirk; Franzke, Joachim; Manz, Andreas
  • Nature, Vol. 442, Issue 7101
  • DOI: 10.1038/nature05059

Droplet microfluidics for high-throughput biological assays
journal, January 2012

  • Guo, Mira T.; Rotem, Assaf; Heyman, John A.
  • Lab on a Chip, Vol. 12, Issue 12
  • DOI: 10.1039/c2lc21147e

A High‐Throughput Mass Spectrometric Enzyme Activity Assay Enabling the Discovery of Cytochrome P450 Biocatalysts
journal, July 2019

  • de Rond, Tristan; Gao, Jian; Zargar, Amin
  • Angewandte Chemie International Edition, Vol. 58, Issue 30
  • DOI: 10.1002/anie.201901782

Acoustic Microfluidics
journal, June 2020

Simultaneous analysis of enzyme structure and activity by kinetic capillary electrophoresis–MS
journal, September 2016

  • Mironov, Gleb G.; Clouthier, Christopher M.; Akbar, Abdullah
  • Nature Chemical Biology, Vol. 12, Issue 11
  • DOI: 10.1038/nchembio.2170

Quantifying a Biocatalytic Product from a Few Living Microbial Cells Using Microfluidic Cultivation Coupled to FT-ICR-MS
journal, May 2019

High Throughput Complementary Analysis and Quantitation of Metabolites by MALDI- and Silicon Nanopost Array-Laser Desorption/Ionization-Mass Spectrometry
journal, February 2019

Surface Acoustic Wave Nebulization of Peptides As a Microfluidic Interface for Mass Spectrometry
journal, May 2010

  • Heron, Scott R.; Wilson, Rab; Shaffer, Scott A.
  • Analytical Chemistry, Vol. 82, Issue 10
  • DOI: 10.1021/ac100372c

Microfluidic Capillary Electrophoresis–Mass Spectrometry for Analysis of Monosaccharides, Oligosaccharides, and Glycopeptides
journal, June 2017

Development, Characterization, and Application of Paper Spray Ionization
journal, March 2010

  • Liu, Jiangjiang; Wang, He; Manicke, Nicholas E.
  • Analytical Chemistry, Vol. 82, Issue 6, p. 2463-2471
  • DOI: 10.1021/ac902854g

Microfluidics for single cell analysis
journal, February 2012

Mass Spectrometry, Review of the Basics: Electrospray, MALDI, and Commonly Used Mass Analyzers
journal, April 2009

  • El-Aneed, Anas; Cohen, Aljandro; Banoub, Joseph
  • Applied Spectroscopy Reviews, Vol. 44, Issue 3
  • DOI: 10.1080/05704920902717872

MALDI-TOF mass spectrometry: an emerging technology for microbial identification and diagnosis
journal, August 2015

Large-Scale Metabolite Analysis of Standards and Human Serum by Laser Desorption Ionization Mass Spectrometry from Silicon Nanopost Arrays
journal, July 2016

Ambient mass spectrometry in metabolomics
journal, January 2017

  • Clendinen, Chaevien S.; Monge, María Eugenia; Fernández, Facundo M.
  • The Analyst, Vol. 142, Issue 17
  • DOI: 10.1039/C7AN00700K

Applications of microfluidics in chemical biology
journal, December 2006

A Microfluidic DNA Library Preparation Platform for Next-Generation Sequencing
journal, July 2013

High-Throughput Nanoelectrospray Ionization-Mass Spectrometry Analysis of Microfluidic Droplet Samples
journal, April 2019

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