Publications by authors named "Jan C T Eijkel"

84 Publications

A CRISPR/Cas12a-assisted in vitro diagnostic tool for identification and quantification of single CpG methylation sites.

Biosens Bioelectron 2021 Dec 11;194:113624. Epub 2021 Sep 11.

BIOS Lab on a Chip Group, MESA+ Institute for Nanotechnology, Technical Medical Centre, Max Planck Institute for Complex Fluid Dynamics, University of Twente, P.O. box 217 7500 AE Enschede, the Netherlands.

The excellent specificity and selectivity of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/associated nuclease (Cas) is determined by CRISPR RNA's (crRNA's) interchangeable spacer sequence, as well as the position and number of mismatches between target sequence and the crRNA sequence. Some diseases are characterized by epigenetic alterations rather than nucleotide changes, and are therefore unsuitable for CRISPR-assisted sensing methods. Here we demonstrate an in vitro diagnostic tool to discriminate single CpG site methylation in DNA by the use of methylation-sensitive restriction enzymes (MSREs) followed by Cas12a-assisted sensing. Non-methylated sequences are digested by MSREs, resulting in fragmentation of the target sequence that influences the R-loop formation between crRNA and target DNA. We show that fragment size, fragmentation position and number of fragments influence the subsequent collateral trans-cleavage activity towards single stranded DNA (ssDNA), enabling deducting the methylation position from the cleavage activity. Utilizing MSREs in combination with Cas12a, single CpG site methylation levels of a cancer gene are determined. The modularity of both Cas12a and MSREs provides a high level of versatility to the Cas12a-MSRE combined sensing method, which opens the possibility to easily and rapidly study single CpG methylation sites for disease detection.
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http://dx.doi.org/10.1016/j.bios.2021.113624DOI Listing
December 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

Inducing AC-electroosmotic flow using electric field manipulation with insulators.

Lab Chip 2021 Aug 13;21(16):3105-3111. Epub 2021 Jul 13.

μFlow group, Department of Chemical Engineering, Vrije Universiteit Brussel, Pleinlaan 2, 1050, Brussels, Belgium.

Classically, the configuration of electrodes (conductors) is used as a means to determine AC-electroosmotic flow patterns. In this paper, we use the configuration of insulator materials to achieve AC-electroosmotic flow patterning in a novel approach. We apply AC electric fields between parallel electrodes situated on the top and bottom of a microfluidic channel and separated by an insulating material. Channels of various cross-sectional shapes (e.g. rectangular and parallelogram) were fabricated by shaping the insulating material between the electrodes. We found that vortex flow patterns are induced depending on the cross-sectional shape of the channel. A bell-shaped design with non-orthogonal corners gave rise to 2 vortices, whereas in a channel with a parallelogram shaped cross-section, only a single vortex was observed. The vortices were experimentally observed by analysing the 3D trajectories of fluorescent microparticles. From a theoretical analysis, we conclude that flow shaping is primarily caused by shaping the electrical field lines in the channel.
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http://dx.doi.org/10.1039/d1lc00393cDOI Listing
August 2021

Bottom-Up Assembled Photonic Crystals for Structure-Enabled Label-Free Sensing.

ACS Nano 2021 06 24;15(6):9299-9327. Epub 2021 May 24.

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

Photonic crystals (PhCs) display photonic stop bands (PSBs) and at the edges of these PSBs transport light with reduced velocity, enabling the PhCs to confine and manipulate incident light with enhanced light-matter interaction. Intense research has been devoted to leveraging the optical properties of PhCs for the development of optical sensors for bioassays, diagnosis, and environmental monitoring. These applications have furthermore benefited from the inherently large surface area of PhCs, giving rise to high analyte adsorption and the wide range of options for structural variations of the PhCs leading to enhanced light-matter interaction. Here, we focus on bottom-up assembled PhCs and review the significant advances that have been made in their use as label-free sensors. We describe their potential for point-of-care devices and in the review include their structural design, constituent materials, fabrication strategy, and sensing working principles. We thereby classify them according to five sensing principles: sensing of refractive index variations, sensing by lattice spacing variations, enhanced fluorescence spectroscopy, surface-enhanced Raman spectroscopy, and configuration transitions.
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http://dx.doi.org/10.1021/acsnano.1c02495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8291770PMC
June 2021

Patterning Biological Gels for 3D Cell Culture inside Microfluidic Devices by Local Surface Modification through Laminar Flow Patterning.

Micromachines (Basel) 2020 Dec 16;11(12). Epub 2020 Dec 16.

Applied Stem Cell Technologies, University of Twente, 7500-AE Enschede, The Netherlands.

Microfluidic devices are used extensively in the development of new in vitro cell culture models like organs-on-chips. A typical feature of such devices is the patterning of biological hydrogels to offer cultured cells and tissues a controlled three-dimensional microenvironment. A key challenge of hydrogel patterning is ensuring geometrical confinement of the gel, which is generally solved by inclusion of micropillars or phaseguides in the channels. Both of these methods often require costly cleanroom fabrication, which needs to be repeated even when only small changes need be made to the gel geometry, and inadvertently expose cultured cells to non-physiological and mechanically stiff structures. Here, we present a technique for facile patterning of hydrogel geometries in microfluidic chips, but without the need for any confining geometry built into the channel. Core to the technique is the use of laminar flow patterning to create a hydrophilic path through an otherwise hydrophobic microfluidic channel. When a liquid hydrogel is injected into the hydrophilic region, it is confined to this path by the surrounding hydrophobic regions. The various surface patterns that are enabled by laminar flow patterning can thereby be rendered into three-dimensional hydrogel structures. We demonstrate that the technique can be used in many different channel geometries while still giving the user control of key geometric parameters of the final hydrogel. Moreover, we show that human umbilical vein endothelial cells can be cultured for multiple days inside the devices with the patterned hydrogels and that they can be stimulated to migrate into the gel under the influence of trans-gel flows. Finally, we demonstrate that the patterned gels can withstand trans-gel flow velocities in excess of physiological interstitial flow velocities without rupturing or detaching. This novel hydrogel-patterning technique addresses fundamental challenges of existing methods for hydrogel patterning inside microfluidic chips, and can therefore be applied to improve design time and the physiological realism of microfluidic cell culture assays and organs-on-chips.
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http://dx.doi.org/10.3390/mi11121112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765499PMC
December 2020

Reduction of Taylor-Aris dispersion by lateral mixing for chromatographic applications.

Lab Chip 2020 11 25;20(21):3938-3947. Epub 2020 Sep 25.

μFlow Group, Department of Chemical Engineering, Vrije Universiteit Brussel, Pleinlaan 2, 1050, Brussels, Belgium.

Chromatographic columns are suffering from Taylor-Aris dispersion, especially for slowly diffusing molecules such as proteins. Since downscaling the channel size to reduce Taylor-Aris dispersion meets fundamental pressure limitations, new strategies are needed to further improve chromatography beyond its current limits. In this work we demonstrate a method to reduce Taylor-Aris dispersion by lateral mixing in a newly designed silicon AC-electroosmotic flow mixer. We obtained a reduction in κ by a factor of three in a 40 μm × 20 μm microchannel, corresponding to a plate height gain of 2 to 3 under unretained conditions at low to high Pe values. We also demonstrate an improvement of a reverse-phase chromatographic separation of coumarins.
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http://dx.doi.org/10.1039/d0lc00773kDOI Listing
November 2020

Plasmonic Nanocrystal Arrays on Photonic Crystals with Tailored Optical Resonances.

ACS Appl Mater Interfaces 2020 Aug 5;12(33):37657-37669. Epub 2020 Aug 5.

BIOS Lab-on-a-Chip Group, MESA+ Institute for Nanotechnology, Technical Medical Centre & Max Planck Center for Complex Fluid Dynamics, University of Twente, 7522 NB Enschede, the Netherlands.

Hierarchical plasmonic-photonic microspheres (PPMs) with high controllability in their structures and optical properties have been explored toward surface-enhanced Raman spectroscopy. The PPMs consist of gold nanocrystal (AuNC) arrays (3rd-tier) anchored on a hexagonal nanopattern (2nd-tier) assembled from silica nanoparticles (SiONPs) where the uniform microsphere backbone is termed the 1st-tier. The PPMs sustain both photonic stop band (PSB) properties, resulting from periodic SiONP arrangements of the 2nd-tier, and a surface plasmon resonance (SPR), resulting from AuNC arrays of the 3rd-tier. Thanks to the synergistic effects of the photonic crystal (PC) structure and the AuNC array, the electromagnetic (EM) field in such a multiscale composite structure can tremendously be enhanced at certain wavelengths. These effects are demonstrated by experimentally evaluating the Raman enhancement of benzenethiol (BT) as a probe molecule and are confirmed via numerical simulations. We achieve a maximum SERS enhancement factor of up to ∼10 when the resonances are tailored to coincide with the excitation wavelength by suitable structural modifications.
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http://dx.doi.org/10.1021/acsami.0c05596DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7441488PMC
August 2020

Point-of-care CRISPR/Cas nucleic acid detection: Recent advances, challenges and opportunities.

Biosens Bioelectron 2020 Oct 26;166:112445. Epub 2020 Jul 26.

BIOS Lab on a Chip group, Technical Medical Centre, MESA+ Institute for Nanotechnology, University of Twente, P.O. box 217, 7500, AE, Enschede, the Netherlands.

With the trend of moving molecular tests from clinical laboratories to on-site testing, there is a need for nucleic acid based diagnostic tools combining the sensitivity, specificity and flexibility of established diagnostics with the ease, cost effectiveness and speed of isothermal amplification and detection methods. A promising new nucleic acid detection method is Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-associated nuclease (Cas)-based sensing. In this method Cas effector proteins are used as highly specific sequence recognition elements that can be combined with many different read-out methods for on-site point-of-care testing. This review covers the technical aspects of integrating CRISPR/Cas technology in miniaturized sensors for analysis on-site. We start with a short introduction to CRISPR/Cas systems and the different effector proteins and continue with reviewing the recent developments of integrating CRISPR sensing in miniaturized sensors for point-of-care applications. Finally, we discuss the challenges of point-of-care CRISPR sensing and describe future research perspectives.
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http://dx.doi.org/10.1016/j.bios.2020.112445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7382963PMC
October 2020

Droplet encapsulation of electrokinetically-focused analytes without loss of resolution.

Lab Chip 2020 06 20;20(12):2209-2217. Epub 2020 May 20.

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

Lab-on-chip electrokinetic focusing and separation techniques are widely used in several scientific fields. In a number of cases, these techniques have been combined with a selective analyte extraction for off-chip analysis. Nevertheless, the usability of the extracts is limited by diffusion which reduces the separation resolution. In this paper we propose the integration of a droplet generator capable of continuous or on-demand generation and extraction of electrokinetically separated and focused analytes. We demonstrate the selective droplet extraction of model analytes separated and concentrated via ion concentration polarization focusing (ICPF). We report extracted droplets with 1000-fold increased concentration. Importantly, the droplet generator does not interrupt the ICPF process making it suitable for integration with the majority of electrokinetic separation techniques.
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http://dx.doi.org/10.1039/d0lc00191kDOI Listing
June 2020

Mass Transport Determined Silica Nanowires Growth on Spherical Photonic Crystals with Nanostructure-Enabled Functionalities.

Small 2020 Jun 13;16(24):e2001026. Epub 2020 May 13.

BIOS Lab on a Chip Group, Technical Medical Centre, MESA+ Institute for Nanotechnology & Max Planck Centre for Complex Fluid Dynamics, University of Twente, Enschede, 7500 AE, the Netherlands.

A robust and facile method has been developed to obtain directional growth of silica nanowires (SiO NWs) by regulating mass transport of silicon monoxide (SiO) vapor. SiO NWs are grown by vapor-liquid-solid (VLS) process on a surface of gold-covered spherical photonic crystals (SPCs) annealed at high temperature in an inert gas atmosphere in the vicinity of a SiO source. The SPCs are prepared from droplet confined colloidal self-assembly. SiO NW morphology is governed by diffusion-reaction process of SiO vapor, whereby directional growth of SiO NWs toward the low SiO concentration is obtained at locations with a high SiO concentration gradient, while random growth is observed at locations with a low SiO concentration gradient. Growth of NWs parallel to the supporting substrate surface is of great importance for various applications, and this is the first demonstration of surface-parallel growth by controlling mass transport. This controllable NW morphology enables production of SPCs covered with a large number of NWs, showing multilevel micro-nano feature and high specific surface area for potential applications in superwetting surfaces, oil/water separation, microreactors, and scaffolds. In addition, the controllable photonic stop band properties of this hybrid structure of SPCs enable the potential applications in photocatalysis, sensing, and light harvesting.
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http://dx.doi.org/10.1002/smll.202001026DOI Listing
June 2020

Free Flow Ion Concentration Polarization Focusing (FF-ICPF).

Anal Chem 2020 04 30;92(7):4866-4874. Epub 2020 Mar 30.

BIOS Lab on a Chip group, MESA+ Institute for Nanotechnology, Max Planck Centre for Complex Fluid Dynamics and Technical Medical Centre, University of Twente, Enschede 7500 AE, The Netherlands.

Electrokinetic separation techniques in microfluidics are a powerful analytical chemistry tool, although an inherent limitation of microfluidics is their low sample throughput. In this article we report a free-flow variant of an electrokinetic focusing method, namely ion concentration polarization focusing (ICPF). The analytes flow continuously through the system via pressure driven flow while they separate and concentrate perpendicularly to the flow by ICPF. We demonstrate free flow ion concentration polarization focusing (FF-ICPF) in two operating modes, namely peak and plateau modes. Additionally, we showed the separation resolution could be improved by the use of an electrophoretic spacer. We report a concentration factor of 10 in human blood plasma in continuous flow at a flow rate of 15 μL min.
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http://dx.doi.org/10.1021/acs.analchem.9b04526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7143306PMC
April 2020

Dimension-reconfigurable bubble film nanochannel for wetting based sensing.

Nat Commun 2020 02 10;11(1):814. Epub 2020 Feb 10.

International Joint Laboratory of Nanofluidics and Interfaces, School of Physical Science and Technology, Northwestern Polytechnical University, 710100, Xi'an, China.

Dimensions and surface properties are the predominant factors for the applications of nanofluidic devices. Here we use a thin liquid film as a nanochannel by inserting a gas bubble in a glass capillary, a technique we name bubble-based film nanofluidics. The height of the film nanochannel can be regulated by the Debye length and wettability, while the length independently changed by applied pressure. The film nanochannel behaves functionally identically to classical solid state nanochannels, as ion concentration polarizations. Furthermore, the film nanochannels can be used for label-free immunosensing, by principle of wettability change at the solid interface. The optimal sensitivity for the biotin-streptavidin reaction is two orders of magnitude higher than for the solid state nanochannel, suitable for a full range of electrolyte concentrations. We believe that the film nanochannel represents a class of nanofluidic devices that is of interest for fundamental studies and also can be widely applied, due to its reconfigurable dimensions, low cost, ease of fabrication and multiphase interfaces.
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http://dx.doi.org/10.1038/s41467-020-14580-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010761PMC
February 2020

Plasmonic Bubble Nucleation and Growth in Water: Effect of Dissolved Air.

J Phys Chem C Nanomater Interfaces 2019 Sep 28;123(38):23586-23593. Epub 2019 Aug 28.

Physics of Fluids, Max Planck Center Twente for Complex Fluid Dynamics and J.M. Burgers Centre for Fluid Mechanics, MESA+ Institute, Physics of Interfaces and Nanomaterials, MESA+ Institute, TechMed Centre, and BIOS Lab-on-a-Chip, MESA+ Institute, University of Twente, P.O. Box 217, 7500AE Enschede, The Netherlands.

Under continuous laser irradiation, noble metal nanoparticles immersed in water can quickly heat up, leading to the nucleation of so-called plasmonic bubbles. In this work, we want to further understand the bubble nucleation and growth mechanism. In particular, we quantitatively study the effect of the amount of dissolved air on the bubble nucleation and growth dynamics, both for the initial giant bubble, which forms shortly after switching on the laser and is mainly composed of vapor, and for the final life phase of the bubble, during which it mainly contains air expelled from water. We found that the bubble nucleation temperature depends on the gas concentration: the higher the gas concentration, the lower the bubble nucleation temperature. Also, the long-term diffusion-dominated bubble growth is governed by the gas concentration. The radius of the bubbles grows as () ∝ for air-equilibrated and air-oversaturated water. In contrast, in partially degassed water, the growth is much slower since, even for the highest temperature we achieve, the water remains undersaturated.
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http://dx.doi.org/10.1021/acs.jpcc.9b05374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6768170PMC
September 2019

Continuous focusing, fractionation and extraction of anionic analytes in a microfluidic chip.

Lab Chip 2019 09;19(19):3238-3248

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

Electrokinetic focusing and separation methods, specifically ion concentration polarization focusing (ICPF), provide a very powerful and easy to use analytical tool for several scientific fields. Nevertheless, the concentrated and separated analytes are effectively trapped inside the chip in picoliter volumes. In this article we propose an ICPF device that allows continuous and selective extraction of the focused analytes. A theoretical background is presented to understand the dynamics of the system and a 1D model was developed that describes the general behavior of the system. We demonstrate the selective extraction of three fluorescent model anionic analytes and we report selective extraction of the analytes at a 300-fold increased concentration.
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http://dx.doi.org/10.1039/c9lc00434cDOI Listing
September 2019

Ion Concentration Polarization for Microparticle Mesoporosity Differentiation.

Langmuir 2019 Jul 16;35(30):9704-9712. Epub 2019 Jul 16.

BIOS-Lab on a chip group, MESA+ Institute for Nanotechnology , Max Planck-University of Twente Center for Complex Fluid Dynamics University of Twente , Drienerlolaan 5 , Enschede , The Netherlands.

Microparticle porosity is normally determined in bulk manner providing an ensemble average that hinders establishing the individual role of each microparticle. On the other hand, single particle characterization implies expensive technology. We propose to use ion concentration polarization to measure differences in mesoporosity at the single particle level. Ion concentration polarization occurs at the interface between an electrolyte and a porous particle when an electric field is applied. The extent of ion concentration polarization depends, among others, on the mesopore size and density. By using a fluorescence marker, we could measure differences in concentration polarization between particles with 3 and 13 nm average mesopore diameters. A qualitative model was developed in order to understand and interpret the phenomena. We believe that this inexpensive method could be used to measure differences in mesoporous particle materials such as catalysts.
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http://dx.doi.org/10.1021/acs.langmuir.9b00802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6671885PMC
July 2019

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

Postdeposition UV-Ozone Treatment: An Enabling Technique to Enhance the Direct Adhesion of Gold Thin Films to Oxidized Silicon.

ACS Nano 2019 Jun 13;13(6):6782-6789. 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 found that continuous films of gold (Au) on oxidized silicon (SiO) substrates, upon treatment with ultraviolet (UV)-ozone, exhibit strong adhesion to the SiO support. Importantly, the enhancement is independent of micro- or nanostructuring of such nanometer-thick films. Deposition of a second Au layer on top of the pretreated Au layer makes the adhesion stable for at least 5 months in environmental air. Using this treatment method enables us to large-scale fabricate various SiO-supported Au structures at various thicknesses with dimensions spanning from a few hundreds of nanometers to a few micrometers, without the use of additional adhesion layers. We explain the observed adhesion improvement as polarization-induced increased strength of AuSi bonds at the Au-SiO interface due to the formation of a gold oxide monolayer on the Au surface by the UV-ozone treatment. Our simple and enabling method thus provides opportunities for patterning Au micro/nanostructures on SiO substrates without an intermediate metallic adhesion layer, which is critical for biosensing and nanophotonic applications.
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http://dx.doi.org/10.1021/acsnano.9b01403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6595434PMC
June 2019

Separation of spermatozoa from erythrocytes using their tumbling mechanism in a pinch flow fractionation device.

Microsyst Nanoeng 2019 20;5:24. Epub 2019 May 20.

1BIOS Lab on a Chip Group, MESA+Institute for Nanotechnology, Technical Medical Centre, University of Twente, Enschede, The Netherlands.

Men suffering from azoospermia can father a child, by extracting spermatozoa from a testicular biopsy sample. The main complication in this procedure is the presence of an abundance of erythrocytes. Currently, the isolation of the few spermatozoa from the sample is manually performed due to ineffectiveness of filtering methods, making it time consuming and labor intensive. The spermatozoa are smaller in both width and height than any other cell type found in the sample, with a very small difference compared with the erythrocyte for the smallest, making this not the feature to base the extraction on. However, the length of the spermatozoon is 5× larger than the diameter of an erythrocyte and can be utilized. Here we propose a microfluidic chip, in which the tumbling behavior of spermatozoa in pinched flow fractionation is utilized to separate them from the erythrocytes. We show that we can extract 95% of the spermatozoa from a sample containing 2.5% spermatozoa, while removing around 90% of the erythrocytes. By adjusting the flow rates, we are able to increase the collection efficiency while slightly sacrificing the purity, tuning the solution for the available sample in the clinic.
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http://dx.doi.org/10.1038/s41378-019-0068-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6527678PMC
May 2019

Large-scale fabrication of highly ordered sub-20 nm noble metal nanoparticles on silica substrates without metallic adhesion layers.

Microsyst Nanoeng 2018 23;4. Epub 2018 Apr 23.

1BIOS Lab-on-a-Chip Group, MESA+ Institute for Nanotechnology, MIRA Institute for Biomedical Technology and Technical Medicine, Max Planck Center for Complex Fluid Dynamics, University of Twente, Enschede, 7522 NB The Netherlands.

Periodic noble metal nanoparticles offer a wide spectrum of applications including chemical and biological sensors, optical devices, and model catalysts due to their extraordinary properties. For sensing purposes and catalytic studies, substrates made of glass or fused-silica are normally required as supports, without the use of metallic adhesion layers. However, precise patterning of such uniform arrays of silica-supported noble metal nanoparticles, especially at sub-100 nm in diameter, is challenging without adhesion layers. In this paper, we report a robust method to large-scale fabricate highly ordered sub-20 nm noble metal nanoparticles, i.e., gold and platinum, supported on silica substrates without adhesion layers, combining displacement Talbot lithography (DTL) with dry-etching techniques. Periodic photoresist nanocolumns at diameters of ~110 nm are patterned on metal-coated oxidized silicon wafers using DTL, and subsequently transferred at a 1:1 ratio into anti-reflection layer coating (BARC) nanocolumns with the formation of nano-sharp tips, using nitrogen plasma etching. These BARC nanocolumns are then used as a mask for etching the deposited metal layer using inclined argon ion-beam etching. We find that increasing the etching time results in cone-shaped silica features with metal nanoparticles on the tips at diameters ranging from 100 nm to sub-30 nm, over large areas of 3×3 cm. Moreover, subsequent annealing these sub-30 nm metal nanoparticle arrays at high-temperature results in sub-20 nm metal nanoparticle arrays with ~10 uniform particles.
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http://dx.doi.org/10.1038/s41378-017-0001-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6161447PMC
April 2018

In-Channel Responsive Surface Wettability for Reversible and Multiform Emulsion Droplet Preparation and Applications.

ACS Appl Mater Interfaces 2019 May 24;11(18):16934-16943. Epub 2019 Apr 24.

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

We report on a simple approach for in-channel functionalization of a polydimethylsiloxane (PDMS) surface to obtain a switchable and reversible wettability change between hydrophilic and hydrophobic states. The thermally responsive polymer, poly( N-Isopropylacrylamide) (PNIPAAm), was grafted on the surface of PDMS channels by UV-induced surface grafting. PNIPAAm-grafted PDMS (PNIPAAm-g-PDMS) surface wettability can be thermally tuned to obtain water contact angles varying in the range of 24.3 to 106.1° by varying temperature at 25-38 °C. By selectively modifying the functionalized area in the microfluidic channels, multiform emulsion droplets of oil-in-water (O/W), water-in-oil (W/O), oil-in-water-in-oil (O/W/O), and water-in-oil-in-water (W/O/W) could be created on-demand. Combining solid surface wettability and liquid-liquid interfacial properties, tunable generation of O/W and W/O droplet and stratified flows were enabled in the same microfluidic device with either different or the same two-phase fluidic systems, by properly heating/cooling thermal-responsive microfluidic channels and choosing suitable surfactants. Controllable creation of O/W/O and W/O/W droplets was also achieved in the same microfluidic device, by locally heating or cooling the droplet generation areas with integrated electric heaters to achieve opposite surface wettability. Hollow microcapsules were prepared using double emulsion droplets as templates in the microfluidic device with sequential hydrophobic and hydrophilic channel segments, demonstrating the strength of the proposed approach in practical applications.
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http://dx.doi.org/10.1021/acsami.9b03160DOI Listing
May 2019

Fluorescence-Based Observation of Transient Electrochemical and Electrokinetic Effects at Nanoconfined Bipolar Electrodes.

ACS Appl Mater Interfaces 2019 Apr 27;11(14):13777-13786. Epub 2019 Mar 27.

Department of Mechanical Engineering , University of California Santa Barbara , Santa Barbara , California 93106 , United States.

Bipolar electrodes (BPEs) are conductors that, when exposed to an electric field, polarize and promote the accumulation of counterionic charge near their poles. The rich physics of electrokinetic behavior near BPEs has not yet been rigorously studied, with our current understanding of such bipolar effects being restricted to steady-state conditions (under constant applied fields). Here, we reveal the dynamic electrokinetic and electrochemical phenomena that occur near nanoconfined BPEs throughout all stages of a reaction. Specifically, we demonstrate, both experimentally and through numerical modeling, that the removal of an electric field produces solution-phase charge imbalances in the vicinity of the BPE poles. These imbalances induce intense and short-lived nonequilibrium electric fields that drive the rapid transport of ions toward specific BPE locations. To determine the origin of these electrokinetic effects, we monitored the movement and fluorescent behavior (enhancement or quenching) of charged fluorophores within well-defined nanofluidic architectures via real-time optical detection. By systematically varying the nature of the fluorophore, the concentration of the electrolyte, the strength of the applied field, and oxide growth on the BPE surface, we dissect the ion transport events that occur in the aftermath of field-induced polarization. The results contained in this work provide new insights into transient bipolar electrokinetics that improve our understanding of current analytical platforms and can drive the development of new micro- and nanoelectrochemical systems.
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http://dx.doi.org/10.1021/acsami.9b01339DOI Listing
April 2019

Microfluidics Assisted Fabrication of Three-Tier Hierarchical Microparticles for Constructing Bioinspired Surfaces.

ACS Nano 2019 03 15;13(3):3638-3648. Epub 2019 Mar 15.

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

Construction of textured bioinspired surfaces with refined structures that exhibit superior wetting properties is of great importance for many applications ranging from self-cleaning, antibiofouling, anti-icing, oil/water separation, smart membrane, and microfluidic devices. Previously, the preparation of artificial surfaces generally relies on the combination of different approaches together, which is a lack of flexibility to control over the individual architecture unit, the surface topology, as well as the complex procedure needed. In this work, we report a method for rapid fabrication of three-tier hierarchical microunits (structures consisting of multiple levels) using a facile droplet microfluidics approach. These units include the first-tier microspheres consisting of the second-tier close-packed polystyrene (PS) nanoparticles decorated with the third-tier elegant polymer nanowrinkles. These nanowrinkles on the PS nanoparticles are formed according to the interfacial instability induced by gradient photopolymerization of N-isopropylacrylamide (NIPAM) monomers. The formation process and topologies of nanowrinkles can be regulated by the photopolymerization process and the fraction of carboxylic groups on the PS nanoparticle surface. Such a hierarchical microsphere mimics individual units of bioinspired surfaces. Therefore, the surfaces from self-assembly of these fabricated two-tier and three-tier hierarchical microunits collectively exhibit "gecko" and "rose petal" wetting states, with the micro- and nanoscale structures amplifying the initial hydrophobicity but still being highly adhesive to water. This approach offers promising advantages of high-yield fabrication, precise control over the size and component of the microspheres, and integration of microfluidic droplet generation, colloidal nanoparticle self-assembly, and interfacial polymerization-induced nanowrinkles in a straightforward manner.
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http://dx.doi.org/10.1021/acsnano.9b00245DOI 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

Integrated internal standards: A sample prep-free method for better precision in microchip CE.

Electrophoresis 2019 03 20;40(5):756-765. Epub 2018 Dec 20.

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

Point-of-care systems based on microchip capillary electrophoresis require single-use, disposable microchips prefilled with all necessary solutions so an untrained operator only needs to apply the sample and perform the analysis. While microchip fabrication can be (and has been) standardized, some manufacturing differences between microchips are unavoidable. To improve analyte precision without increasing device costs or introducing additional error sources, we recently proposed the use of integrated internal standards (ISTDs): ions added to the BGE in small concentrations which form system peaks in the electropherogram that can be used as a measurement reference. Here, we further expand this initial proof-of-principle test to study a clinically-relevant application of K ion concentrations in human blood; however, using a mock blood solution instead of real samples to avoid interference from other obstacles (e.g. cell lysis). Cs as an integrated ISTD improves repeatability of K ion migration times from 6.97% to 0.89% and the linear calibration correlation coefficient (R ) for K quantification from 0.851 to 0.967. Peak area repeatability improves from 11.6-13.3% to 4.75-5.04% at each K concentration above the LOQ. These results further validate the feasibility of using integrated ISTDs to improve imprecision in disposable microchip CE devices by demonstrating their application for physiological samples.
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http://dx.doi.org/10.1002/elps.201800393DOI Listing
March 2019

Flow focusing through gels as a tool to generate 3D concentration profiles in hydrogel-filled microfluidic chips.

Lab Chip 2019 01;19(2):206-213

BIOS Lab-on-a-Chip Group, University of Twente, Enschede, The Netherlands.

Laminar flow patterning is an iconic microfluidic technology used to deliver chemicals to specific regions on a two-dimensional surface with high spatial fidelity. Here we present a novel extension of this technology using Darcy flow within a three-dimensional (3D) hydrogel. Our test device is a simple 3-inlet microfluidic channel, totally filled with collagen, a cured biological hydrogel, where the concentration profiles of solutes are manipulated via the inlet pressures. This method allows solutes to be delivered with 50 micron accuracy within the gel, as we evidence by controlling concentration profiles of 40 kDa and 1 kDa fluorescent polysaccharide dyes. Furthermore, we design and test a 3D-printed version of our device with an extra two inlets for control of the vertical position of the concentration profile, demonstrating that this method is easily extensible to control of the concentration profile in 3D.
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http://dx.doi.org/10.1039/c8lc01140kDOI 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

Giant and explosive plasmonic bubbles by delayed nucleation.

Proc Natl Acad Sci U S A 2018 07 11;115(30):7676-7681. Epub 2018 Jul 11.

Physics of Fluids Group, Max Planck Center Twente for Complex Fluid Dynamics and J. M. Burgers Centre for Fluid Mechanics, MESA+ Institute for Nanotechnology, University of Twente, 7500 AE Enschede, The Netherlands;

When illuminated by a laser, plasmonic nanoparticles immersed in water can very quickly and strongly heat up, leading to the nucleation of so-called plasmonic vapor bubbles. While the long-time behavior of such bubbles has been well-studied, here, using ultrahigh-speed imaging, we reveal the nucleation and early life phase of these bubbles. After some delay time from the beginning of the illumination, a giant bubble explosively grows, and collapses again within 200 μs (bubble life phase 1). The maximal bubble volume [Formula: see text] remarkably increases with decreasing laser power, leading to less total dumped energy E. This dumped energy shows a universal linear scaling relation with [Formula: see text], irrespective of the gas concentration of the surrounding water. This finding supports that the initial giant bubble is a pure vapor bubble. In contrast, the delay time does depend on the gas concentration of the water, as gas pockets in the water facilitate an earlier vapor bubble nucleation, which leads to smaller delay times and lower bubble nucleation temperatures. After the collapse of the initial giant bubbles, first, much smaller oscillating bubbles form out of the remaining gas nuclei (bubble life phase 2). Subsequently, the known vaporization dominated growth phase takes over, and the bubble stabilizes (life phase 3). In the final life phase 4, the bubble slowly grows by gas expelling due to heating of the surrounding. Our findings on the explosive growth and collapse during the early life phase of a plasmonic vapor bubble have strong bearings on possible applications of such bubbles.
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http://dx.doi.org/10.1073/pnas.1805912115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6065032PMC
July 2018

Enhanced ion transport using geometrically structured charge selective interfaces.

Lab Chip 2018 05;18(11):1652-1660

Soft Matter, Fluidics and Interfaces, MESA+ Institute for Nanotechnology, University of Twente, The Netherlands.

A microfluidic platform containing charged hydrogels is used to investigate the effect of geometry on charge transport in electrodialysis applications. The influence of heterogeneity on ion transport is determined by electrical characterization and fluorescence microscopy of three different hydrogel geometries. We found that electroosmotic transport of ions towards the hydrogel is enhanced in heterogeneous geometries, as a result of the inhomogeneous electric field in these systems. This yields higher ionic currents for equal applied potentials when compared to homogeneous geometries. The contribution of electroosmotic transport is present in all current regimes, including the Ohmic regime. We also found that the onset of the overlimiting current occurs at lower potentials due to the increased heterogeneity in hydrogel shape, owing to the non-uniform electric field distribution in these systems. Pinning of ion depletion and enrichment zones is observed in the heterogeneous hydrogel systems, due to electroosmotic flows and electrokinetic instabilities. Our platform is highly versatile for the rapid investigation of the effects of membrane topology on general electrodialysis characteristics, including the formation of ion depletion zones on the micro-scale and the onset of the overlimiting current.
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http://dx.doi.org/10.1039/c7lc01220aDOI Listing
May 2018

Capillary Pinning Assisted Patterning of Cell-Laden Hydrogel Microarrays in Microchips.

Methods Mol Biol 2018 ;1771:225-238

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

We present a capillary pinning technique that gives complete control on the local patterning of hydrogel structures in closed microchips. The technique relies on selective trapping of liquids at predefined locations in a microchip using capillary barriers. In selective patterning, the abrupt expansion in the cross-sectional geometry of a microchannel at capillary barriers results in a confined advancement of the liquid-air meniscus. This protocol describes a detailed procedure to design and fabricate microarrays of different hydrogel types, fabricated with photopolymerization or thermogelation. The process can be subdivided into two parts. First, a PDMS microchip containing microfeatures with customized patterns is fabricated. Second, the microchip is filled with a hydrogel precursor to be cross-linked by either photopolymerization or thermogelation. The production of the microchip takes approximately 2 days, depending on the substrate selection. Preparation of the hydrogel solutions takes 1-2 h, whereas the patterning and reaction to cross-link the hydrogels is completed in a few minutes.
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http://dx.doi.org/10.1007/978-1-4939-7792-5_18DOI Listing
February 2019

Electrofusion of single cells in picoliter droplets.

Sci Rep 2018 02 27;8(1):3714. Epub 2018 Feb 27.

University of Twente, MESA+ Institute for Nanotechnology and MIRA Institute for Biomedical Technology, Faculty of Electrical Engineering, Mathematics and Computer Science, BIOS Lab on a Chip group, 7500AE, Enschede, The Netherlands.

We present a microfluidic chip that enables electrofusion of cells in microdroplets, with exchange of nuclear components. It is shown, to our knowledge for the first time, electrofusion of two HL60 cells, inside a microdroplet. This is the crucial intermediate step for controlled hybridoma formation where a B cell is electrofused with a myeloma cell. We use a microfluidic device consisting of a microchannel structure in PDMS bonded to a glass substrate through which droplets with two differently stained HL60 cells are transported. An array of six recessed platinum electrode pairs is used for electrofusion. When applying six voltage pulses of 2-3 V, the membrane electrical field is about 1 MV/cm for 1 ms. This results in electrofusion of these cells with a fusion yield of around 5%. The operation with individual cell pairs, the appreciable efficiency and the potential to operate in high-throughput (up to 500 cells sec) makes the microdroplet fusion technology a promising platform for cell electrofusion, which has the potential to compete with the conventional methods. Besides, this platform is not restricted to cell fusion but is also applicable to various other cell-based assays such as single cell analysis and differentiation assays.
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http://dx.doi.org/10.1038/s41598-018-21993-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5829161PMC
February 2018
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