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| Open AccessIntegrating single-cell and spatially resolved transcriptomic strategies to survey the astrocyte response to stroke in male mice
Astrocytes adopt diverse states in response to brain injuries. Here, the authors develop a platform for spatially resolved, single-cell transcriptomics and proteomics, called tDISCO (tissue-digital microfluidic isolation of single cells for -Omics) to uncover the spatial boundaries of molecularly distinct reactive astrocyte populations in stroke.
- Erica Y. Scott
- , Nickie Safarian
- & Maryam Faiz
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Article
| Open AccessA microfluidic platform integrating functional vascularized organoids-on-chip
Vascularization remains a significant challenge in organoid technology. Here, the authors develop a microfluidic platform that enhances organoid growth, function and maturation, by establishing functional perfusable vascular networks.
- Clément Quintard
- , Emily Tubbs
- & Xavier Gidrol
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Article
| Open AccessModeling early pathophysiological phenotypes of diabetic retinopathy in a human inner blood-retinal barrier-on-a-chip
Here the authors develop perfusable inner blood-retinal barrier-specific microvascular networks with human primary retinal microvascular cells. They show that chronic diabetic stimulation leads to the generation of early hallmarks of diabetic retinopathy, including pericyte and capillary dropout, ghost vessels, and inflammation.
- Thomas L. Maurissen
- , Alena J. Spielmann
- & Héloïse Ragelle
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Article
| Open AccessBiporous silica nanostructure-induced nanovortex in microfluidics for nucleic acid enrichment, isolation, and PCR-free detection
Efficient enrichment and isolation of pathogens are crucial for accurate and sensitive disease identification. Here, the authors present a chip equipped with biporous nanofilms that induces a nanovetex in a microfluidic channel for nucleic acid enrichment, isolation, and detection.
- Eunyoung Jeon
- , Bonhan Koo
- & Joonseok Lee
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Article
| Open AccessPick-up single-cell proteomic analysis for quantifying up to 3000 proteins in a Mammalian cell
Single-cell proteomics is of fundamental importance to capture biological heterogeneity, while limited in proteome depth. Here, the authors develop a pick-up single-cell proteomic analysis (PiSPA) workflow to achieve a deep coverage of quantifying up to 3000 protein groups in a mammalian cell.
- Yu Wang
- , Zhi-Ying Guan
- & Qun Fang
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Article
| Open AccessInterindividual- and blood-correlated sweat phenylalanine multimodal analytical biochips for tracking exercise metabolism
The in-depth study on the sweat–blood partitioning mechanisms of amino acids is promising for noninvasive metabolic monitoring. Here, the authors develop a wearable biochip for sweat phenylalanine multimodal analysis aimed at tracking exercise metabolic risk and exploring the sweat–blood correlation.
- Bowen Zhong
- , Xiaokun Qin
- & Lili Wang
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Article
| Open AccessAngiogenesis-on-a-chip coupled with single-cell RNA sequencing reveals spatially differential activations of autophagy along angiogenic sprouts
The functional heterogeneity of autophagy in endothelial cells during angiogenesis remains incompletely understood. Here, the authors apply a 3D angiogenesis-on-a-chip coupled with single-cell RNA sequencing to find distinct autophagy functions in two different endothelial cell populations during angiogenic sprouting.
- Somin Lee
- , Hyunkyung Kim
- & Noo Li Jeon
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Article
| Open AccessHigh throughput intracellular delivery by viscoelastic mechanoporation
Scalability of mechanoporation strategies for intracellular delivery remains challenging. Here, the authors demonstrate a microfluidic approach for delivering mRNA and CRISPR-Cas systems to over 250 million cells per minute.
- Derin Sevenler
- & Mehmet Toner
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Article
| Open AccessDesign automation of microfluidic single and double emulsion droplets with machine learning
Generating microfluidic droplets with application-specific desired characteristics is hard. Here the authors report fluid-agnostic machine learning models capable of accurately predicting device geometries and flow conditions required to generate stable single and double emulsions.
- Ali Lashkaripour
- , David P. McIntyre
- & Polly M. Fordyce
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Article
| Open Access3D bioprinted multilayered cerebrovascular conduits to study cancer extravasation mechanism related with vascular geometry
Geometrical complexities of blood vessels alter biophysical behaviors of circulating tumor cells, influencing cancer metastasis. Here, the authors develop a 3D bioprinted in vitro brain blood vessel-on-a-chip to investigate continuities between vascular geometry and metastatic cancer development.
- Wonbin Park
- , Jae-Seong Lee
- & Dong-Woo Cho
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Article
| Open AccessMass production of lumenogenic human embryoid bodies and functional cardiospheres using in-air-generated microcapsules
Current methods to generate spheroids are associated with low production throughputs, limiting clinical and industrial translation. Here the authors present a clean ultra-high-throughput in-air microfluidic platform for mass production of lumenogenic embryoid bodies and functional cardiospheres.
- Bas van Loo
- , Simone A. ten Den
- & Jeroen Leijten
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Article
| Open AccessA magneto-activated nanoscale cytometry platform for molecular profiling of small extracellular vesicles
Exosomal PD-L1 (exoPD-L1) is a biomarker predicting immunotherapeutic responses. Here the authors report NanoEPIC, a nanoscale cytometry platform that enables phenotypic sorting and exoPD-L1 profiling from blood plasma by using magnetic-activated ranking to differentiate exosomal subpopulations.
- Kangfu Chen
- , Bill T. V. Duong
- & Shana O. Kelley
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Article
| Open AccessDroplet-based high-throughput single microbe RNA sequencing by smRandom-seq
Population level transcriptomics measurements miss bacterial heterogeneity. Here the authors report smRandom-seq, a droplet-based high-throughput single-microbe RNA-seq assay, using random primers for in situ cDNA generation, droplets for single-microbe barcoding, and CRISPR-based rRNA depletion.
- Ziye Xu
- , Yuting Wang
- & Yongcheng Wang
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Article
| Open AccessIn situ synthesis and dynamic simulation of molecularly imprinted polymeric nanoparticles on a micro-reactor system
Molecularly imprinted polymers are useful elements in sensing and biomedical research but their fabrication is challenging. Here, the authors report a micro-reactor for in situ and continuous production of molecularly imprinted polymers.
- Özgecan Erdem
- , Ismail Eş
- & Fatih Inci
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Article
| Open AccessDroplet-based bisulfite sequencing for high-throughput profiling of single-cell DNA methylomes
Single-cell DNA methylomic studies offer high resolution to differentiate cell subsets based on their epigenomic features. Here, the authors demonstrate Drop-BS, a droplet-based single-cell bisulfite sequencing library preparation method, for DNA methylome profiling.
- Qiang Zhang
- , Sai Ma
- & Chang Lu
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Article
| Open AccessRapid prototyping of high-resolution large format microfluidic device through maskless image guided in-situ photopolymerization
The utility of microfluidic devices has been limited by several drawbacks including low resolution, inferior feature fidelity, poor repeatability. Here the authors address these challenges by developing a strategic approach of image guided in-situ maskless lithography to fabricate a variety of microfluidic devices and resolve critical proximity effect and size limitations in rapid prototyping.
- Ratul Paul
- , Yuwen Zhao
- & Yaling Liu
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Article
| Open AccessHighly efficient platelet generation in lung vasculature reproduced by microfluidics
Highly efficient generation of platelets in the vasculature. Here, Zhao et al. show that the mouse platelet precursor cell, megakaryocytes, generate physiological numbers of functional platelets when passaged repeatedly through pulmonary vasculature.
- Xiaojuan Zhao
- , Dominic Alibhai
- & Alastair W. Poole
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Article
| Open AccessMultinuclear 1D and 2D NMR with 19F-Photo-CIDNP hyperpolarization in a microfluidic chip with untuned microcoil
The main limitations in NMR techniques are low sensitivity and the requirement for complex instrumentation. Here the authors show that a microfluidic chip with a single untuned planar spiral microcoil, combined with laser-light induced hyperpolarization, allows for multidimensional and heteronuclear Nuclear Magnetic Resonance spectroscopy on picomole quantities of material.
- M. Victoria Gomez
- , Sander Baas
- & Aldrik H. Velders
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Article
| Open AccessHigh-throughput single nucleus total RNA sequencing of formalin-fixed paraffin-embedded tissues by snRandom-seq
Formalin-fixed paraffin-embedded (FFPE) tissues constitute a vast and valuable patient material bank, but single nucleus RNAseq using such tissues is challenging. Here the authors develop a droplet-based method called snRandom-seq for high-throughput and sensitive single nucleus RNA-seq of FFPE samples.
- Ziye Xu
- , Tianyu Zhang
- & Yongcheng Wang
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Article
| Open AccessModeling of three-dimensional innervated epidermal like-layer in a microfluidic chip-based coculture system
Skin-nerve crosstalk is a major element of skin physiological pathology. Here the authors report a 3D innervated epidermal keratinocyte layer as a sensory neuron-epidermal keratinocyte coculture model on a microfluidic chip using the slope-based air-liquid interfacing culture and spatial compartmentalization.
- Jinchul Ahn
- , Kyungeun Ohk
- & Sang-Hoon Lee
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Review Article
| Open AccessSmartphone-based platforms implementing microfluidic detection with image-based artificial intelligence
Smartphone-based mobile health platforms have drawn increasing attention from researchers developing point-of-care testing devices. Here the authors summarize recent progress and future directions of approaches combining microfluidics and artificial intelligence.
- Bangfeng Wang
- , Yiwei Li
- & Bi-Feng Liu
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Article
| Open AccessWell-TEMP-seq as a microwell-based strategy for massively parallel profiling of single-cell temporal RNA dynamics
Gene expression of cells is a heterogeneous and dynamic program involved in various biological processes. Here, authors develop Well-TEMPseq, a high-throughput, cost-effective, and accurate method for massively parallel profiling of the temporal dynamics of single-cell gene expression.
- Shichao Lin
- , Kun Yin
- & Chaoyong Yang
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Article
| Open AccessDirect digital sensing of protein biomarkers in solution
There are limitations with current protein sensing methods. Here the authors report DigitISA, a digital immunosensor assay based on microchip electrophoretic separation and single-molecule detection that enables quantitation of protein biomarkers in a single, solution-phase step.
- Georg Krainer
- , Kadi L. Saar
- & Tuomas P. J. Knowles
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Article
| Open AccessBioprinting microporous functional living materials from protein-based core-shell microgels
Extrusion bioprinting can be used to produce living materials but controlling cell microenvironments is challenging. Here, the authors use a type of core-shell microgel ink that decouples cell culture from material processing to produce functional materials with a range of potential applications.
- Yangteng Ou
- , Shixiang Cao
- & Tuomas P. J. Knowles
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Article
| Open AccessMicrofluidic vortex focusing for high throughput synthesis of size-tunable liposomes
Liposomes are widely used in pharmaceuticals yet trade-offs between uniform size and mass production, limit production and application. Here, the authors report on the design of a microfluidic vortex focusing microfluidic technique which can mass produce liposomes with controlled size and low variability.
- Jung Yeon Han
- , Joseph N. La Fiandra
- & Don L. DeVoe
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Article
| Open AccessLow cost and massively parallel force spectroscopy with fluid loading on a chip
Single molecule force spectroscopy methods are often low throughput and have high instrument cost. Here the authors report FLO-Chip, a low-cost, high throughput technique using microfluidics for multiplexed mechanical manipulation of many individual molecules via molecular fluid loading on-a-chip.
- Ehsan Akbari
- , Melika Shahhosseini
- & Carlos E. Castro
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Article
| Open AccessModeling human HSV infection via a vascularized immune-competent skin-on-chip platform
Understanding host responses to Herpes simplex virus (HSV) in humans is challenging. Here the authors report a vascularised 3D ‘skin-on-chip’ that mimics human skin architecture and is competent to immune-cell and drug perfusion; they use this to model HSV infection.
- Sijie Sun
- , Lei Jin
- & Jia Zhu
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Perspective
| Open AccessA sound approach to advancing healthcare systems: the future of biomedical acoustics
Acoustic techniques are moving towards the clinic. Here the authors highlight recent developments in the areas of acoustic mechanobiology, point-of-care diagnostics, in vivo manipulation and tissues engineering, and provide their thoughts on the current challenges and directions for future work.
- Joseph Rufo
- , Peiran Zhang
- & Tony Jun Huang
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Article
| Open AccessHigh throughput, label-free isolation of circulating tumor cell clusters in meshed microwells
Metastatic CTC clusters remain relatively unexplored due to the lack of optimized and practical technologies for their detection. Here the authors report Cluster-Wells to isolate CTC clusters in whole blood; they show this allows viable cluster retrieval for further molecular and functional analysis.
- Mert Boya
- , Tevhide Ozkaya-Ahmadov
- & A. Fatih Sarioglu
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Perspective
| Open AccessMicrofluidics for understanding model organisms
Building small-scale tools for biology research eliminates the need for time-consuming methods and enables novel experimental paradigms. Here, the authors discuss microfluidics' potential for manipulating or stimulating model organisms and identify barriers to making these tools accessible.
- Nolan Frey
- , Utku M. Sönmez
- & Philip LeDuc
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Perspective
| Open AccessA role for microfluidic systems in precision medicine
Precision oncology is important for patient treatment. Here the authors review the current applications of microfluidic systems to cancer precision medicine, and discuss the issues that must be addressed prior to getting these technologies into the clinic.
- Jose M. Ayuso
- , María Virumbrales-Muñoz
- & David J. Beebe
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Article
| Open AccessTracking Brownian motion in three dimensions and characterization of individual nanoparticles using a fiber-based high-finesse microcavity
Tracking of nanoparticle dynamics in solution often require labelling. Here, the authors use a high-finesse microcavity and simultaneously measure dispersive frequency shifts of three transverse modes, demonstrating 3D tracking of unlabelled single nanospheres, and quantitatively determine their physical properties.
- Larissa Kohler
- , Matthias Mader
- & David Hunger
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Article
| Open AccessMicrofluidic device with brain extracellular matrix promotes structural and functional maturation of human brain organoids
Brain organoids derived from human pluripotent stem cells can model human brain development and disease, though current culture systems fail to ensure reliable production of high-quality organoids. Here the authors combine human brain extracellular matrix and culture in a microfluidic device to promote structural and functional maturation of human brain organoids.
- Ann-Na Cho
- , Yoonhee Jin
- & Seung-Woo Cho
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Article
| Open AccessAcoustoelectronic nanotweezers enable dynamic and large-scale control of nanomaterials
Precise and dynamic manipulation of nano-objects on a large scale has been challenging. Here, the authors introduce acoustoelectronic nanotweezers, combining precision of electronic tweezers with large-field dynamic control of acoustic tweezers, demonstrating complex patterning of sub-100 nm objects.
- Peiran Zhang
- , Joseph Rufo
- & Tony Jun Huang
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Article
| Open AccessCurvature in the reproductive tract alters sperm–surface interactions
The effect of fallopian tube’s curvature on sperm motion has not been studied in detail. Here, the authors use droplet microfluidics to create soft curved interfaces, revealing a dynamic switch in sperm motility from a progressive surface-aligned mode at low curvatures, to an aggressive surface-attacking mode at high curvatures.
- Mohammad Reza Raveshi
- , Melati S. Abdul Halim
- & Reza Nosrati
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Article
| Open AccessLabel-free characterization of organic nanocarriers reveals persistent single molecule cores for hydrocarbon sequestration
In-situ methods are important for investigating the local structure and function in molecular nanostructures but such investigations often involve laborious labeling methods that can disrupt behavior or are not fast enough to capture stimuli-responsive phenomena. Here, the authors use X-rays resonant with molecular bonds to demonstrate an in-situ nanoprobe that eliminates the need for labels and enables data collection times within seconds.
- Terry McAfee
- , Thomas Ferron
- & Brian A. Collins
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Article
| Open AccessMicrofluidic platform accelerates tissue processing into single cells for molecular analysis and primary culture models
Existing methods for tissue dissociation are inefficient and lead to variable outcomes and biases. Here, the authors present a microfluidic platform that combines digestion, disaggregation and filtration of tissue to allow single cell analysis and RNA sequencing.
- Jeremy A. Lombardo
- , Marzieh Aliaghaei
- & Jered B. Haun
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Article
| Open AccessA partially self-regenerating synthetic cell
A fundamental function of living systems is regenerating essential components. Here the authors design an artificial cell using a minimal transcription-translation system in microfluidic reactors for sustained regeneration of multiple essential proteins.
- Barbora Lavickova
- , Nadanai Laohakunakorn
- & Sebastian J. Maerkl
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Article
| Open AccessDigital microfluidic isolation of single cells for -Omics
Multi-Omic approaches are a powerful way for obtaining in-depth understanding of a cell’s state. Here the authors present DISCO, combining digital microfluidics, laser cell lysis, and artificial intelligence-driven image processing to analyze single-cell genomes, transcriptomes and proteomes in a mixed population.
- Julian Lamanna
- , Erica Y. Scott
- & Aaron R. Wheeler
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Article
| Open AccessA fast impedance-based antimicrobial susceptibility test
There is an urgent need to develop simple and fast antimicrobial susceptibility tests. Here, Spencer et al. describe a label-free test that can deliver results within an hour, consisting of a 30-min antibiotic treatment followed by single-cell analysis of phenotypic responses with microfluidic impedance cytometry.
- Daniel C. Spencer
- , Teagan F. Paton
- & Hywel Morgan
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Article
| Open AccessSegmented flow generator for serial crystallography at the European X-ray free electron laser
Due to the pulsed nature of X-ray free electron laser (XFEL) instruments the majority of protein crystals, which are injected using continuous jet injection techniques are wasted. Here, the authors present a microfluidic device to deliver aqueous protein crystal laden droplets segmented with an immiscible oil and demonstrate that with this device an approx. 60% reduction in sample waste was achieved for data collection of 3-deoxy-D-manno-octulosonate 8-phosphate synthase crystals at the EuXFEL.
- Austin Echelmeier
- , Jorvani Cruz Villarreal
- & Alexandra Ros
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Article
| Open AccessPurification of HCC-specific extracellular vesicles on nanosubstrates for early HCC detection by digital scoring
Extracellular vesicles (EVs) are present in circulation at relatively early stages of disease, providing potential opportunities for early cancer diagnosis. Here, the authors report a covalent chemistry-based hepatocellular carcinoma (HCC)-specific EV purification system for early detection of HCC by performing digital scoring on the purified EVs.
- Na Sun
- , Yi-Te Lee
- & Yazhen Zhu
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Article
| Open AccessMulti-omic single-cell snapshots reveal multiple independent trajectories to drug tolerance in a melanoma cell line
Detailed understanding of how cancer cells transition from a drug sensitive to a tolerant state is lacking. Here, using single cell proteomic and metabolic data the authors uncover that isogenic BRAF mutant melanoma cells can take two distinct paths to become tolerant to BRAF inhibition.
- Yapeng Su
- , Melissa E. Ko
- & James R. Heath
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Article
| Open AccessAutomated mass spectrometry imaging of over 2000 proteins from tissue sections at 100-μm spatial resolution
Imaging mass spectrometry is a powerful emerging tool for mapping the spatial distribution of biomolecules across tissue surfaces. Here the authors showcase an automated technology for deep proteome imaging that utilizes ultrasensitive microfluidics and a mass spectrometry workflow to analyze tissue voxels, generating quantitative cell-type-specific images.
- Paul D. Piehowski
- , Ying Zhu
- & Kristin E. Burnum-Johnson
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Article
| Open AccessContinuous artificial synthesis of glucose precursor using enzyme-immobilized microfluidic reactors
Ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO) is a difficult enzyme to work with. Here, the authors covalently immobilized it in a microfluidic reactor to enhance its storage/thermal stabilities and reusability, which enabled the continuous artificial synthesis of glucose precursor.
- Yujiao Zhu
- , Ziyu Huang
- & Xuming Zhang
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Article
| Open AccessSpatiotemporal control of coacervate formation within liposomes
The understanding of liquid-liquid phase separation is crucial to cell biology and benefits from cell-mimicking in vitro assays. Here, the authors develop a microfluidic platform to study coacervate formation inside liposomes and show the potential of these hybrid systems to create synthetic cells.
- Siddharth Deshpande
- , Frank Brandenburg
- & Cees Dekker
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Article
| Open AccessMicrofluidic multipoles theory and applications
Microfluidic multipoles use arrays of sources and sinks to confine fluids and reagents without the use of physical channels. Here the authors use conformal mappings to predict both convective and diffusive transport in these flows and 3D print multipoles to automate surface-based immunoassays.
- Pierre-Alexandre Goyette
- , Étienne Boulais
- & Thomas Gervais
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Article
| Open AccessMiniaturised interaction proteomics on a microfluidic platform with ultra-low input requirements
Affinity purification-mass spectrometry (AP-MS) can identify endogenous protein interactions but the need for high amounts of input material still limits its applicability. Here, the authors present a microfluidic-based AP-MS workflow that can capture protein interactions from 50─100-fold less input material than conventional approaches.
- Cristina Furlan
- , René A. M. Dirks
- & Michiel Vermeulen
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Article
| Open AccessContractile forces in platelet aggregates under microfluidic shear gradients reflect platelet inhibition and bleeding risk
Platelet aggregates generate contractile forces that contribute to their cohesion and adhesion. Here, Ting et al. develop a microfluidic device to measure contractile forces generated by platelet aggregates, and find it can detect the response of platelets to pharmacological agents and predict bleeding risk in trauma patients.
- Lucas H. Ting
- , Shirin Feghhi
- & Nathan J. Sniadecki