Publications by authors named "Mathieu Odijk"

28 Publications

  • Page 1 of 1

Microfluidic Electrochemistry Meets Trapped Ion Mobility Spectrometry and High-Resolution Mass Spectrometry-In Situ Generation, Separation, and Detection of Isomeric Conjugates of Paracetamol and Ethoxyquin.

Anal Chem 2021 09 8;93(37):12740-12747. Epub 2021 Sep 8.

Institute of Inorganic and Analytical Chemistry, University of Münster, Corrensstr. 28/30, 48149 Münster, Germany.

Over the last 3 decades, electrochemistry (EC) has been successfully applied in phase I and phase II metabolism simulation studies. The electrochemically generated phase I metabolite-like oxidation products can react with selected reagents to form phase II conjugates. During conjugate formation, the generation of isomeric compounds is possible. Such isomeric conjugates are often separated by high-performance liquid chromatography (HPLC). Here, we demonstrate a powerful approach that combines EC with ion mobility spectrometry to separate possible isomeric conjugates. In detail, we present the hyphenation of a microfluidic electrochemical chip with an integrated mixer coupled online to trapped ion mobility spectrometry (TIMS) and time-of-flight high-resolution mass spectrometry (ToF-HRMS), briefly chipEC-TIMS-ToF-HRMS. This novel method achieves results in several minutes, which is much faster than traditional separation approaches like HPLC, and was applied to the drug paracetamol and the controversial feed preservative ethoxyquin. The analytes were oxidized in situ in the electrochemical microfluidic chip under formation of reactive intermediates and mixed with different thiol-containing reagents to form conjugates. These were analyzed by TIMS-ToF-HRMS to identify possible isomers. It was observed that the oxidation products of both paracetamol and ethoxyquin form two isomeric conjugates, which are characterized by different ion mobilities, with each reagent. Therefore, using this hyphenated technique, it is possible to not only form reactive oxidation products and their conjugates in situ but also separate and detect these isomeric conjugates within only a few minutes.
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http://dx.doi.org/10.1021/acs.analchem.1c02791DOI Listing
September 2021

Autonomous capillary microfluidic devices with constant flow rate and temperature-controlled valving.

Soft Matter 2021 Sep 5;17(33):7781-7791. Epub 2021 Aug 5.

National Center for International Research on Green Optoelectronics & South China Academy of Advanced Optoelectronics, South China Normal University, Guangzhou 510006, China.

In this paper, we report on a capillary microfluidic device with constant flow rate and temperature-triggered stop valve function. It contains a PDMS channel that was grafted by a thermo-responsive polymer poly(N-isopropylacrylamide) (PNIPAm). The channel exhibits a constant capillary filling speed. By locally increasing the temperature in the channel from 20 °C to 37 °C using a microfabricated heater, a change of the surface wettability from hydrophilic to hydrophobic is obtained creating a hydrophobic stop valve. The valve can be reopened by lowering the temperature. The device is simple to fabricate and can be used as an actuatable capillary pump operating around room temperature. To understand the constant capillary filling speed, we performed contact angle measurements, in which we found slow wetting kinetics of PNIPAm-g-PDMS surfaces at temperatures below the lower critical solution temperature (LCST) of PNIPAm and fast wetting kinetics above the LCST. We interpret this as the result of the diffusive hydration process of PNIPAm below the LCST and the absence of hydration on the hydrophobic PNIPAm thin layer above the LCST.
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http://dx.doi.org/10.1039/d1sm00625hDOI Listing
September 2021

Highly parallelized human embryonic stem cell differentiation to cardiac mesoderm in nanoliter chambers on a microfluidic chip.

Biomed Microdevices 2021 05 31;23(2):30. Epub 2021 May 31.

BIOS Lab On a Chip Group, MESA+ Institute for Nanotechnology, Max Planck - University of Twente Center for Complex Fluid Dynamics, University of Twente, Enschede, The Netherlands.

Human stem cell-derived cells and tissues hold considerable potential for applications in regenerative medicine, disease modeling and drug discovery. The generation, culture and differentiation of stem cells in low-volume, automated and parallelized microfluidic chips hold great promise to accelerate the research in this domain. Here, we show that we can differentiate human embryonic stem cells (hESCs) to early cardiac mesodermal cells in microfluidic chambers that have a volume of only 30 nanoliters, using discontinuous medium perfusion. 64 of these chambers were parallelized on a chip which contained integrated valves to spatiotemporally isolate the chambers and automate cell culture medium exchanges. To confirm cell pluripotency, we tracked hESC proliferation and immunostained the cells for pluripotency markers SOX2 and OCT3/4. During differentiation, we investigated the effect of different medium perfusion frequencies on cell reorganization and the expression of the early cardiac mesoderm reporter MESP1 by live-cell imaging. Our study demonstrates that microfluidic technology can be used to automatically culture, differentiate and study hESC in very low-volume culture chambers even without continuous medium perfusion. This result is an important step towards further automation and parallelization in stem cell technology.
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http://dx.doi.org/10.1007/s10544-021-00556-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166733PMC
May 2021

Measuring barrier function in organ-on-chips with cleanroom-free integration of multiplexable electrodes.

Lab Chip 2021 05;21(10):2040-2049

BIOS Lab on a Chip Group, MESA+ Institute for Nanotechnology, Technical Medical Center and Max Planck Institute for Complex Fluid Dynamics, University of Twente, The Netherlands.

Transepithelial/transendothelial electrical resistance (TEER) measurements can be applied in organ-on-chips (OoCs) to estimate the barrier properties of a tissue or cell layer in a continuous, non-invasive, and label-free manner. Assessing the barrier integrity in in vitro models is valuable for studying and developing barrier targeting drugs. Several systems for measuring the TEER have been shown, but each of them having their own drawbacks. This article presents a cleanroom-free fabrication method for the integration of platinum electrodes in a polydimethylsiloxane OoC, allowing the real-time assessment of the barrier function by employing impedance spectroscopy. The proposed method and electrode arrangement allow visual inspection of the cells cultured in the device at the site of the electrodes, and multiplexing of both the electrodes in one OoC and the number of OoCs in one device. The effectiveness of our system is demonstrated by lining the OoC with intestinal epithelial cells, creating a gut-on-chip, where we monitored the formation, as well as the disruption and recovery of the cell barrier during a 21 day culture period. The application is further expanded by creating a blood-brain-barrier, to show that the proposed fabrication method can be applied to monitor the barrier formation in the OoC for different types of biological barriers.
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http://dx.doi.org/10.1039/d0lc01289kDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130670PMC
May 2021

Single catalyst particle diagnostics in a microreactor for performing multiphase hydrogenation reactions.

Faraday Discuss 2021 May 5;229:267-280. Epub 2021 Mar 5.

Inorganic Chemistry and Catalysis, Debye Institute for Nanomaterials Science, Utrecht University, The Netherlands.

Since inter- and intra-particle heterogeneities in catalyst particles are more the rule than the exception, it is advantageous to perform high-throughput screening for the activity of single catalyst particles. A multiphase system (gas/liquid/solid) is developed, where droplet-based microfluidics and optical detection are combined for the analysis of single catalyst particles by safely performing a hydrogenation study on in-house synthesized hollow Pd/SiO catalyst microparticles, in a polydimethylsiloxane (PDMS) microreactor. A two-phase segmented flow system of particle-containing droplets is combined with a parallel gas-reactant channel separated from the flow channel by a 50 μm thick gas permeable PDMS wall. In this paper, the developed microreactor system is showcased by monitoring the Pd-catalyzed hydrogenation of methylene blue. A discoloration of blue to brown visualizes the hydrogenation activity happening in a high-throughput fashion on the single Pd/SiO spherical catalyst microparticles, which are encapsulated in 50 nL-sized droplets. By measuring the reagent concentration at various spots along the length of the channel the reaction time can be determined, which is proportional to the residence time in the channel. The developed experimental platform opens new possibilities for single catalyst particle diagnostics in a multiphase environment.
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http://dx.doi.org/10.1039/d0fd00006jDOI Listing
May 2021

Modular microreactor with integrated reflection element for online reaction monitoring using infrared spectroscopy.

Lab Chip 2020 11;20(22):4166-4174

BIOS Lab on a Chip Group, MESA+ Institute for Nanotechnology, University of Twente, Drienerlolaan 5, Enschede, The Netherlands.

We report on the fabrication of an internal reflection element (IRE) combined with a modular polymer microfluidic chip that can be used for attenuated total reflection (ATR) infrared spectroscopy. The IRE is fabricated from a silicon wafer. Two different polymers are used for the fabrication of the two types of modular microfluidic chips, namely polydimethylsiloxane (PDMS) and cyclic olefin copolymer (COC). The microfluidic chip is modular in the sense that several layers of mixing channels, using the herringbone mixer principle, and reactions chambers, can be stacked to facilitate the study of the desired reaction. A model Paal-Knorr reaction is carried out to prove that the chip works as intended. Furthermore, we highlight the strength of IR spectroscopy as a tool for reaction monitoring by identifying the peaks and showing the different reaction orders at the different steps of the Paal-Knorr reaction. The reduction of the aldehyde groups indicates a (pseudo) first order reaction whereas the vibrational modes associated with the ring formation indicate a zero order reaction. This zero order reaction can be explained with literature, where it is suggested that water acts as a catalyst during the dehydration step, which is the final step in the pyrrole ring formation.
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http://dx.doi.org/10.1039/d0lc00704hDOI Listing
November 2020

Spectroelectrochemistry, the future of visualizing electrode processes by hyphenating electrochemistry with spectroscopic techniques.

Analyst 2020 Apr 30;145(7):2482-2509. Epub 2020 Jan 30.

BIOS Lab-on-a-Chip Group, MESA+ Institute, University of Twente, 7522 NB Enschede, The Netherlands.

The combination of electrochemistry and spectroscopy, known as spectroelectrochemistry (SEC), is an already established approach. By combining these two techniques, the relevance of the data obtained is greater than what it would be when using them independently. A number of review papers have been published on this subject, mostly written for experts in the field and focused on recent advances. In this review, written for both the novice in the field and the more experienced reader, the focus is not on the past but on the future. The scope is narrowed down to four techniques the authors claim to have the most potential for the future, namely: infrared spectroelectrochemistry (IR-SEC), Raman spectroelectrochemistry (Raman-SEC), nuclear magnetic resonance spectroelectrochemistry (NMR-SEC) and, perhaps slightly more controversial but certainly promising, electrochemistry mass-spectrometry (EC-MS).
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http://dx.doi.org/10.1039/c9an02105aDOI Listing
April 2020

Urea removal strategies for dialysate regeneration in a wearable artificial kidney.

Biomaterials 2020 03 6;234:119735. Epub 2020 Jan 6.

Department of Nephrology and Hypertension, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, the Netherlands. Electronic address:

The availability of a wearable artificial kidney (WAK) that provides dialysis outside the hospital would be an important advancement for dialysis patients. The concept of a WAK is based on regeneration of a small volume of dialysate in a closed-loop. Removal of urea, the primary waste product of nitrogen metabolism, is the major challenge for the realization of a WAK since it is a molecule with low reactivity that is difficult to adsorb while it is the waste solute with the highest daily molar production. Currently, no efficient urea removal technology is available that allows for miniaturization of the WAK to a size and weight that is acceptable for patients to carry. Several urea removal strategies have been explored, including enzymatic hydrolysis by urease, electro-oxidation and sorbent systems. However, thus far, these methods have toxic side effects, limited removal capacity or slow removal kinetics. This review discusses different urea removal strategies for application in a wearable dialysis device, from both a chemical and a medical perspective.
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http://dx.doi.org/10.1016/j.biomaterials.2019.119735DOI Listing
March 2020

Wafer-scale fabrication of high-quality tunable gold nanogap arrays for surface-enhanced Raman scattering.

Nanoscale 2019 Jul 13;11(25):12152-12160. Epub 2019 Jun 13.

BIOS Lab-on-a-Chip Group, MESA+ Institute, Max Planck Center for Complex Fluid Dynamics, University of Twente, 7522 NB Enschede, The Netherlands.

We report a robust and high-yield fabrication method for wafer-scale patterning of high-quality arrays of dense gold nanogaps, combining displacement Talbot lithography based shrink-etching with dry etching, wet etching, and thin film deposition techniques. By using the self-sharpening of <111>-oriented silicon crystal planes during the wet etching process, silicon structures with extremely smooth nanogaps are obtained. Subsequent conformal deposition of a silicon nitride layer and a gold layer results in dense arrays of narrow gold nanogaps. Using this method, we successfully fabricate high-quality Au nanogaps down to 10 nm over full wafer areas. Moreover, the gap spacing can be tuned by changing the thickness of deposited Au layers. Since the roughness of the template is minimized by the crystallographic etching of silicon, the roughness of the gold nanogaps depends almost exclusively on the roughness of the sputtered gold layers. Additionally, our fabricated Au nanogaps show a significant enhancement of surface-enhanced Raman scattering (SERS) signals of benzenethiol molecules chemisorbed on the structure surface, at an average enhancement factor up to 1.5 × 10.
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http://dx.doi.org/10.1039/c9nr02215eDOI Listing
July 2019

From chip-in-a-lab to lab-on-a-chip: a portable Coulter counter using a modular platform.

Microsyst Nanoeng 2018 19;4:34. Epub 2018 Nov 19.

BIOS Lab on Chip Group, MESA+ Institute for Nanotechnology, University of Twente, 7500 AE Enschede, Netherlands.

The field of microfluidics has been struggling to obtain widespread market penetration. In order to overcome this struggle, a standardized and modular platform is introduced and applied. By providing easy-to-fabricate modular building blocks which are compatible with mass manufacturing, we decrease the gap from lab-to-fab. These standardized blocks are used in combination with an application-specific fluidic circuit board. On this board, electrical and fluidic connections are demonstrated by implementing an alternating current Coulter counter. This multipurpose building block is reusable in many applications. In this study, it identifies and counts 6 and 11 μm beads. The system is kept in a credit card-sized footprint, as a result of in-house-developed electronics and standardized building blocks. We believe that this easy-to-fabricate, credit card-sized, modular, and standardized prototype brings us closer to clinical and veterinary applications, because it provides an essential stepping stone to fully integrated point -of -care devices.
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http://dx.doi.org/10.1038/s41378-018-0034-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6240576PMC
November 2018

A miniaturized push-pull-perfusion probe for few-second sampling of neurotransmitters in the mouse brain.

Lab Chip 2019 04;19(8):1332-1343

BIOS - Microdevices for Chemical Analysis group, MESA+ Institute for Nanotechnology, Techmed Centre, University of Twente, Hallenweg 15, 7522 NH Enschede, The Netherlands.

Measuring biomolecule concentrations in the brain of living animals, in real time, is a challenging task, especially when detailed information at high temporal resolution is also required. Traditionally, microdialysis probes are used that generally have sampling areas in the order of about 1 mm2, and provide information on concentrations with a temporal resolution of at least several minutes. In this paper, we present a novel miniaturized push-pull perfusion sampling probe that uses an array of small 3 μm-wide sampling channels to sample neurotransmitters at a typical recovery rate of 61%, with a reduced risk of clogging. The added feature to segment the dialysate inside the probe into small water-in-decane droplets enables the detection of concentrations with a temporal resolution of a few seconds. Here we used the probe for in vivo recordings of neurotransmitter glutamate released upon electrical stimulation in the brain of a mouse to demonstrate the feasibility of the probe for real-time neurochemical brain analysis.
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http://dx.doi.org/10.1039/c8lc01137kDOI Listing
April 2019

Luminescence thermometry for in situ temperature measurements in microfluidic devices.

Lab Chip 2019 03;19(7):1236-1246

Condensed Matter and Interfaces, Debye Institute for Nanomaterials Science, Utrecht University, Princetonplein 1, 3584 CC Utrecht, The Netherlands.

Temperature control for lab-on-a-chip devices has resulted in the broad applicability of microfluidics to, e.g., polymerase chain reaction (PCR), temperature gradient focusing for electrophoresis, and colloidal particle synthesis. However, currently temperature sensors on microfluidic chips either probe temperatures outside the channel (resistance temperature detector, RTD) or are limited in both the temperature range and sensitivity in the case of organic dyes. In this work, we introduce ratiometric bandshape luminescence thermometry in which thermally coupled levels of Er3+ in NaYF4 nanoparticles are used as a promising method for in situ temperature mapping in microfluidic systems. The results, obtained with three types of microfluidic devices, demonstrate that temperature can be monitored inside a microfluidic channel accurately (0.34 °C) up to at least 120 °C with a spot size of ca. 1 mm using simple fiber optics. Higher spatial resolution can be realized by combining luminescence thermometry with confocal microscopy, resulting in a spot size of ca. 9 μm. Further improvement is anticipated to enhance the spatial resolution and allow for 3D temperature profiling.
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http://dx.doi.org/10.1039/c8lc01292jDOI Listing
March 2019

Non-invasive sensing of transepithelial barrier function and tissue differentiation in organs-on-chips using impedance spectroscopy.

Lab Chip 2019 01;19(3):452-463

BIOS Lab on a Chip group, MESA+ Institute for Nanotechnology, MIRA Institute for Biomedical Technology and Technical Medicine and Max Planck Center for Complex Fluid Dynamics, University of Twente, P. O. Box 217, 7500 AE Enschede, The Netherlands.

Here, we describe methods for combining impedance spectroscopy measurements with electrical simulation to reveal transepithelial barrier function and tissue structure of human intestinal epithelium cultured inside an organ-on-chip microfluidic culture device. When performing impedance spectroscopy measurements, electrical simulation enabled normalization of cell layer resistance of epithelium cultured statically in a gut-on-a-chip, which enabled determination of transepithelial electrical resistance (TEER) values that can be compared across device platforms. During culture under dynamic flow, the formation of intestinal villi was accompanied by characteristic changes in impedance spectra both measured experimentally and verified with simulation, and we demonstrate that changes in cell layer capacitance may serve as measures of villi differentiation. This method for combining impedance spectroscopy with simulation can be adapted to better monitor cell layer characteristics within any organ-on-chip in vitro and to enable direct quantitative TEER comparisons between organ-on-chip platforms which should help to advance research on organ function.
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http://dx.doi.org/10.1039/c8lc00129dDOI Listing
January 2019

Engulfment control of platinum nanoparticles into oxidized silicon substrates for fabrication of dense solid-state nanopore arrays.

Nanotechnology 2019 Feb;30(6):065301

BIOS Lab-on-a-Chip Group, MESA+ Institute for Nanotechnology, Max Planck Center for Complex Fluid Dynamics, University of Twente, The Netherlands.

We found that platinum (Pt) nanoparticles, upon annealing at high temperature of 1000 °C, are engulfed into amorphous fused-silica or thermal oxide silicon substrates. The same phenomenon was previously published for gold (Au) nanoparticles. Similar to the Au nanoparticles, the engulfed Pt nanoparticles connect to the surface of the substrates through conical nanopores, and the size of the Pt nanoparticles decreases with increasing depth of the nanopores. We explain the phenomena as driven by the formation of platinum oxide by reaction of the platinum with atmospheric oxygen, with platinum oxide evaporating to the environment. We found that the use of Pt provides much better controllability than the use of Au. Due to the high vapor pressure of platinum oxide, the engulfment of the Pt nanoparticles into oxidized silicon (SiO) substrates is faster than of Au nanoparticles. At high temperature annealing we also find that the aggregation of Pt nanoparticles on the substrate surface is insignificant. As a result, the Pt nanoparticles are uniformly engulfed into the substrates, leading to an opportunity for patterning dense nanopore arrays. Moreover, the use of oxidized Si substrates enables us to precisely control the depth of the nanopores since the engulfment of Pt nanoparticles stops at a short distance above the SiO /Si interface. After subsequent etching steps, a membrane with dense nanopore through-holes with diameters down to sub-30 nm is obtained. With its simple operation and high controllability, this fabrication method provides an alternative for rapid patterning of dense arrays of solid-state nanopores at low-cost.
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http://dx.doi.org/10.1088/1361-6528/aaf114DOI Listing
February 2019

Lab-on-a-Chip: Frontier Science in the Classroom.

J Chem Educ 2018 Feb 15;95(2):267-275. Epub 2017 Dec 15.

BIOS Research Group, University of Twente, P.O. Box 217, 7500 AE Enschede, The Netherlands.

Lab-on-a-chip technology is brought into the classroom through development of a lesson series with hands-on practicals. Students can discover the principles of microfluidics with different practicals covering laminar flow, micromixing, and droplet generation, as well as trapping and counting beads. A quite affordable novel production technique using scissor-cut and laser-cut lamination sheets is presented, which provides good insight into how scientific lab-on-a-chip devices are produced. In this way high school students can now produce lab-on-a-chip devices using lamination sheets and their own lab-on-a-chip design. We begin with a review of previous reports on the use of lab-on-a-chip technology in classrooms, followed by an overview of the practicals and projects we have developed with student safety in mind. We conclude with an educational scenario and some initial promising results for student learning outcomes.
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http://dx.doi.org/10.1021/acs.jchemed.7b00506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6150665PMC
February 2018

Barriers-on-chips: Measurement of barrier function of tissues in organs-on-chips.

Biomicrofluidics 2018 Jul 26;12(4):042218. Epub 2018 Jun 26.

Department of Applied Stem Cell Technologies, University of Twente, 7522 NB Enschede, The Netherlands.

Disruption of tissue barriers formed by cells is an integral part of the pathophysiology of many diseases. Therefore, a thorough understanding of tissue barrier function is essential when studying the causes and mechanisms of disease as well as when developing novel treatments. methods play an integral role in understanding tissue barrier function, and several techniques have been developed in order to evaluate barrier integrity of cultured cell layers, from microscopy imaging of cell-cell adhesion proteins to measuring ionic currents, to flux of water or transport of molecules across cellular barriers. Unfortunately, many of the current methods suffer from not fully recapitulating the microenvironment of tissues and organs. Recently, organ-on-chip devices have emerged to overcome this challenge. Organs-on-chips are microfluidic cell culture devices with continuously perfused microchannels inhabited by living cells. Freedom of changing the design of device architecture offers the opportunity of recapitulating the physiological environment while measuring barrier function. Assessment of barriers in organs-on-chips can be challenging as they may require dedicated setups and have smaller volumes that are more sensitive to environmental conditions. But they do provide the option of continuous, non-invasive sensing of barrier quality, which enables better investigation of important aspects of pathophysiology, biological processes, and development of therapies that target barrier tissues. Here, we discuss several techniques to assess barrier function of tissues in organs-on-chips, highlighting advantages and technical challenges.
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http://dx.doi.org/10.1063/1.5023041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6019329PMC
July 2018

Magnetophoretic Sorting of Single Catalyst Particles.

Angew Chem Int Ed Engl 2018 Aug 13;57(33):10589-10594. Epub 2018 Jul 13.

BIOS lab on a chip group, MESA+ Institute for Nanotechnology, University of Twente, Drienerlolaan 5, Enschede, The Netherlands.

A better understanding of the deactivation processes taking place within solid catalysts is vital to design better ones. However, since inter-particle heterogeneities are more a rule than an exception, particle sorting is crucial to analyse single catalyst particles in detail. Microfluidics offers new possibilities to sort catalysts at the single particle level. Herein, we report a first-of-its-kind 3D printed magnetophoretic chip able to sort catalyst particles by their magnetic moment. Fluid catalytic cracking (FCC) particles were separated based on their Fe content. Magnetophoretic sorting shows that large Fe aggregates exist within 20 % of the FCC particles with the highest Fe content. The availability of Brønsted acid sites decreases with increasing Fe content. This work paves the way towards a high-throughput catalyst diagnostics platform to determine why specific catalyst particles perform better than others.
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http://dx.doi.org/10.1002/anie.201804942DOI Listing
August 2018

Nanoscale Electrochemical Sensing and Processing in Microreactors.

Annu Rev Anal Chem (Palo Alto Calif) 2018 06 8;11(1):421-440. Epub 2018 Mar 8.

MESA+ Institute for Nanotechnology, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede 7500 AE, The Netherlands; email:

In this review, we summarize recent advances in nanoscale electrochemistry, including the use of nanoparticles, carbon nanomaterials, and nanowires. Exciting developments are reported for nanoscale redox cycling devices, which can chemically amplify signal readout. We also discuss promising high-frequency techniques such as nanocapacitive CMOS sensor arrays or heterodyning. In addition, we review electrochemical microreactors for use in (drug) synthesis, biocatalysis, water treatment, or to electrochemically degrade urea for use in a portable artificial kidney. Electrochemical microreactors are also used in combination with mass spectrometry, e.g., to study the mimicry of drug metabolism or to allow electrochemical protein digestion. The review concludes with an outlook on future perspectives in both nanoscale electrochemical sensing and electrochemical microreactors. For sensors, we see a future in wearables and the Internet of Things. In microreactors, a future goal is to monitor the electrochemical conversions more precisely or ultimately in situ by combining other spectroscopic techniques.
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http://dx.doi.org/10.1146/annurev-anchem-061417-125642DOI Listing
June 2018

Fabrication and Validation of an Organ-on-chip System with Integrated Electrodes to Directly Quantify Transendothelial Electrical Resistance.

J Vis Exp 2017 09 26(127). Epub 2017 Sep 26.

BIOS Lab on a Chip group, MIRA Institute for Biomedical Technology and Technical Medicine, MESA+ Institute for Nanotechnology and Max Planck Center for Complex Fluid Dynamics, University of Twente.

Organs-on-chips, in vitro models involving the culture of (human) tissues inside microfluidic devices, are rapidly emerging and promise to provide useful research tools for studying human health and disease. To characterize the barrier function of cell layers cultured inside organ-on-chip devices, often transendothelial or transepithelial electrical resistance (TEER) is measured. To this end, electrodes are usually integrated into the chip by micromachining methods to provide more stable measurements than is achieved with manual insertion of electrodes into the inlets of the chip. However, these electrodes frequently hamper visual inspection of the studied cell layer or require expensive cleanroom processes for fabrication. To overcome these limitations, the device described here contains four easily integrated electrodes that are placed and fixed outside of the culture area, making visual inspection possible. Using these four electrodes the resistance of six measurement paths can be quantified, from which the TEER can be directly isolated, independent of the resistance of culture medium-filled microchannels. The blood-brain barrier was replicated in this device and its TEER was monitored to show the device applicability. This chip, the integrated electrodes and the TEER determination method are generally applicable in organs-on-chips, both to mimic other organs or to be incorporated into existing organ-on-chip systems.
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http://dx.doi.org/10.3791/56334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5752338PMC
September 2017

In-situ Raman spectroscopy to elucidate the influence of adsorption in graphene electrochemistry.

Sci Rep 2017 03 24;7:45080. Epub 2017 Mar 24.

BIOS - Lab on a Chip group, MESA+ Institute for Nanotechnology and MIRA Institute for Biomedical Engineering and Technical Medicine, University of Twente, Enschede, P.O. box 217 7500AE, The Netherlands.

Electrochemistry on graphene is of particular interest due to graphene's high surface area, high electrical conductivity and low interfacial capacitance. Because the graphene Fermi level can be probed by its strong Raman signal, information on the graphene doping can be obtained which in turn can provide information on adsorbed atoms or molecules. For this paper, the adsorption analysis was successfully performed using three electroactive substances with different electrode interaction mechanisms: hexaammineruthenium(III) chloride (RuHex), ferrocenemethanol (FcMeOH) and potassium ferricyanide/potassium ferrocyanide (Fe(CN)). The adsorption state was probed by analysing the G-peak position in the measured in-situ Raman spectrum during electrochemical experiments. We conclude that electrochemical Raman spectroscopy on graphene is a valuable tool to obtain in-situ information on adsorbed species on graphene, isolated from the rest of the electrochemical behaviour.
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http://dx.doi.org/10.1038/srep45080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5364475PMC
March 2017

Oxidation and adduct formation of xenobiotics in a microfluidic electrochemical cell with boron doped diamond electrodes and an integrated passive gradient rotation mixer.

Lab Chip 2016 10;16(20):3990-4001

BIOS - Lab on a Chip group, MESA+ Institute for Nanotechnology and MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede, The Netherlands.

Reactive xenobiotic metabolites and their adduct formation with biomolecules such as proteins are important to study as they can be detrimental to human health. Here, we present a microfluidic electrochemical cell with integrated micromixer to study phase I and phase II metabolism as well as protein adduct formation of xenobiotics in a purely instrumental approach. The newly developed microfluidic device enables both the generation of reactive metabolites through electrochemical oxidation and subsequent adduct formation with biomolecules in a chemical microreactor. This allows us to study the detoxification of reactive species with glutathione and to predict potential toxicity of xenobiotics as a result of protein modification. Efficient mixing in microfluidic systems is a slow process due to the typically laminar flow conditions in shallow channels. Therefore, a passive gradient rotation micromixer has been designed that is capable of mixing liquids efficiently in a 790 pL volume within tens of milliseconds. The mixing principle relies on turning the concentration gradient that is initially established by bringing together two streams of liquid, to take advantage of the short diffusion distances in the shallow microchannels of thin-layer flow cells. The mixer is located immediately downstream of the working electrode of an electrochemical cell with integrated boron doped diamond electrodes. In conjunction with mass spectrometry, the two microreactors integrated in a single device provide a powerful tool to study the metabolism and toxicity of xenobiotics, which was demonstrated by the investigation of the model compound 1-hydroxypyrene.
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http://dx.doi.org/10.1039/c6lc00708bDOI Listing
October 2016

Electrochemical Protein Cleavage in a Microfluidic Cell with Integrated Boron Doped Diamond Electrodes.

Anal Chem 2016 09 26;88(18):9190-8. Epub 2016 Aug 26.

BIOS-Lab on a Chip Group, MESA+ Institute for Nanotechnology and MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente , 7500 AE Enschede, The Netherlands.

Specific electrochemical cleavage of peptide bonds at the C-terminal side of tyrosine and tryptophan generates peptides amenable to liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis for protein identification. To this end we developed a microfluidic electrochemical cell of 160 nL volume that combines a cell geometry optimized for a high electrochemical conversion efficiency (>95%) with an integrated boron doped diamond (BDD) working electrode offering a wide potential window in aqueous solution and reduced adsorption of peptides and proteins. Efficient cleavage of the proteins bovine insulin and chicken egg white lysozyme was observed at 4 out of 4 and 7 out of 9 of the predicted cleavage sites, respectively. Chicken egg white lysozyme was identified based on 5 electrochemically generated peptides using a proteomics database searching algorithm. These results show that electrochemical peptide bond cleavage in a microfluidic cell is a novel, fully instrumental approach toward protein analysis and eventually proteomics studies in conjunction with mass spectrometry.
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http://dx.doi.org/10.1021/acs.analchem.6b02413DOI Listing
September 2016

Direct quantification of transendothelial electrical resistance in organs-on-chips.

Biosens Bioelectron 2016 Nov 8;85:924-929. Epub 2016 Jun 8.

BIOS Lab on a Chip group, MIRA Institute for Biomedical Technology and Technical Medicine & MESA, Institute for Nanotechnology, University of Twente, P.O. box 217, 7500 AE Enschede, The Netherlands.

Measuring transendothelial or transepithelial electrical resistance (TEER) is a widely used method to monitor cellular barrier tightness in organs-on-chips. Unfortunately, integrated electrodes close to the cellular barrier hamper visual inspection of the cells or require specialized cleanroom processes to fabricate see-through electrodes. Out-of-view electrodes inserted into the chip's outlets are influenced by the fluid-filled microchannels with relatively high resistance. In this case, small changes in temperature or medium composition strongly affect the apparent TEER. To solve this, we propose a simple and universally applicable method to directly determine the TEER in microfluidic organs-on-chips without the need for integrated electrodes close to the cellular barrier. Using four electrodes inserted into two channels - two on each side of the porous membrane - and six different measurement configurations we can directly derive the isolated TEER independent of channel properties. We show that this method removes large variation of non-biological origin in chips filled with culture medium. Furthermore, we demonstrate the use of our method by quantifying the TEER of a monolayer of human hCMEC/D3 cerebral endothelial cells, mimicking the blood-brain barrier inside our microfluidic organ-on-chip device. We found stable TEER values of 22 Ω cm(2)±1.3 Ω cm(2) (average ± standard error of the mean of 4 chips), comparable to other TEER values reported for hCMEC/D3 cells in well-established Transwell systems. In conclusion, we demonstrate a simple and robust way to directly determine TEER that is applicable to any organ-on-chip device with two channels separated by a membrane. This enables stable and easily applicable TEER measurements without the need for specialized cleanroom processes and with visibility on the measured cell layer.
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http://dx.doi.org/10.1016/j.bios.2016.06.014DOI Listing
November 2016

In situ surface-enhanced Raman spectroelectrochemical analysis system with a hemin modified nanostructured gold surface.

Anal Chem 2015 Mar 13;87(5):2588-92. Epub 2015 Feb 13.

Analytical Biochemistry and Department of Pharmacy, University of Groningen , Deusinglaan 1, 9713 AV, Groningen, The Netherlands.

An integrated surface-enhanced Raman scattering (SERS) spectroelectrochemical (SEC) analysis system is presented that combines a small volume microfluidic sample chamber (<100 μL) with a compact three-electrode configuration for in situ surface-enhanced Raman spectroelectrochemistry. The SEC system includes a nanostructured Au surface that serves dual roles as the electrochemical working electrode (WE) and SERS substrate, a microfabricated Pt counter electrode (CE), and an external Ag/AgCl reference electrode (RE). The nanostructured Au WE enables highly sensitive in situ SERS spectroscopy through large and reproducible SERS enhancements, which eliminates the need for resonant wavelength matching of the laser excitation source with the electronic absorption of the target molecule. The new SEC analysis system has the merits of wide applicability to target molecules, small sample volume, and a low detection limit. We demonstrate in situ SERS spectroelectrochemistry measurements of the metalloporphyrin hemin showing shifts of the iron oxidation marker band ν4 with the nanostructured Au working electrode under precise potential control.
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http://dx.doi.org/10.1021/ac504136jDOI Listing
March 2015

Capacitive deionization on-chip as a method for microfluidic sample preparation.

Lab Chip 2015 Mar;15(6):1458-64

BIOS - the Lab-on-a-Chip group, Mesa+ Institute for Nanotechnology, MIRA Institute, University of Twente, P.O. box 217, 7500 AE Enschede, The Netherlands.

Desalination as a sample preparation step is essential for noise reduction and reproducibility of mass spectrometry measurements. A specific example is the analysis of proteins for medical research and clinical applications. Salts and buffers that are present in samples need to be removed before analysis to improve the signal-to-noise ratio. Capacitive deionization is an electrostatic desalination (CDI) technique which uses two porous electrodes facing each other to remove ions from a solution. Upon the application of a potential of 0.5 V ions migrate to the electrodes and are stored in the electrical double layer. In this article we demonstrate CDI on a chip, and desalinate a solution by the removal of 23% of Na(+) and Cl(-) ions, while the concentration of a larger molecule (FITC-dextran) remains unchanged. For the first time impedance spectroscopy is introduced to monitor the salt concentration in situ in real-time in between the two desalination electrodes.
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http://dx.doi.org/10.1039/c4lc01410cDOI Listing
March 2015

Mass spectrometric detection of short-lived drug metabolites generated in an electrochemical microfluidic chip.

Anal Chem 2015 Feb 13;87(3):1527-35. Epub 2015 Jan 13.

BIOS - Lab on a Chip group, MESA+ Institute for Nanotechnology and MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente , Enschede, The Netherlands.

The costs of drug development have been rising exponentially over the last six decades, making it essential to select drug candidates in the early drug discovery phases before proceeding to expensive clinical trials. Here, we present novel screening methods using an electrochemical chip coupled online to mass spectrometry (MS) or liquid chromatography (LC) and MS, to generate phase I and phase II drug metabolites and to demonstrate protein modification by reactive metabolites. The short transit time (∼4.5 s) between electrochemical oxidation and mass spectrometric detection, enabled by an integrated electrospray emitter, allows us to detect a short-lived radical metabolite of chlorpromazine which is too unstable to be detected using established test routines. In addition, a fast way to screen candidate drugs is established by recording real-time mass voltammograms, which allows one to identify the drug metabolites that are expected to be formed upon oxidation by applying a linear potential sweep and simultaneously detect oxidation products. Furthermore, detoxification of electrochemically generated reactive metabolites of paracetamol was mimicked by their adduct formation with the antioxidant glutathione. Finally, the potential toxicity of reactive metabolites can be investigated by the modification of proteins, which was demonstrated by modification of carbonic anhydrase I with electrochemically generated reactive metabolites of paracetamol. With this series of experiments, we demonstrate the potential of this electrochemical chip as a complementary tool for a variety of drug metabolism studies in the early stages of drug discovery.
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http://dx.doi.org/10.1021/ac503384eDOI Listing
February 2015

Measuring direct current trans-epithelial electrical resistance in organ-on-a-chip microsystems.

Lab Chip 2015 Feb;15(3):745-52

BIOS/Lab-on-Chip Group, MESA+ Institute for Nanotechnology & MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, P. O. Box 217, 7500 AE Enschede, The Netherlands.

Trans-epithelial electrical resistance (TEER) measurements are widely used as real-time, non-destructive, and label-free measurements of epithelial and endothelial barrier function. TEER measurements are ideal for characterizing tissue barrier function in organs-on-chip studies for drug testing and investigation of human disease models; however, published reports using this technique have reported highly conflicting results even with identical cell lines and experimental setups. The differences are even more dramatic when comparing measurements in conventional Transwell systems with those obtained in microfluidic systems. Our goal in this work was therefore to enhance the fidelity of TEER measurements in microfluidic organs-on-chips, specifically using direct current (DC) measurements of TEER, as this is the most widely used method reported in the literature. Here we present a mathematical model that accounts for differences measured in TEER between microfluidic chips and Transwell systems, which arise from differences in device geometry. The model is validated by comparing TEER measurements obtained in a microfluidic gut-on-a-chip device versus in a Transwell culture system. Moreover, we show that even small gaps in cell coverage (e.g., 0.4%) are sufficient to cause a significant (~80%) drop in TEER. Importantly, these findings demonstrate that TEER measurements obtained in microfluidic systems, such as organs-on-chips, require special consideration, specifically when results are to be compared with measurements obtained from Transwell systems.
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http://dx.doi.org/10.1039/c4lc01219dDOI Listing
February 2015

Improved conversion rates in drug screening applications using miniaturized electrochemical cells with frit channels.

Anal Chem 2012 Nov 22;84(21):9176-83. Epub 2012 Oct 22.

BIOS Lab-on-a-Chip Group, MESA+ Institute for Nanotechnology, University of Twente, Enschede, The Netherlands.

This paper reports a novel design of a miniaturized three-electrode electrochemical cell, the purpose of which is aimed at generating drug metabolites with a high conversion efficiency. The working electrode and the counter electrode are placed in two separate channels to isolate the reaction products generated at both electrodes. The novel design includes connecting channels between these two electrode channels to provide a uniform distribution of the current density over the entire working electrode. In addition, the effect of ohmic drop is decreased. Moreover, two flow resistors are included to ensure an equal flow of analyte through both electrode channels. Total conversion of fast reacting ions is achieved at flow rates up to at least 8 μL/min, while the internal chip volume is only 175 nL. Using this electrochemical chip, the metabolism of mitoxantrone is studied by microchip electrospray ionization-mass spectrometry. At an oxidation potential of 700 mV, all known metabolites from direct oxidation are observed. The electrochemical chip performs equally well, compared to a commercially available cell, but at a 30-fold lower flow of reagents.
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http://dx.doi.org/10.1021/ac301888gDOI Listing
November 2012
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