Recent progress in lab-on-a-chip for pharmaceutical analysis and pharmacological/toxicological test

Abstract As one of emerging applications of lab-on-a-chip, microfluidics contribution to pharmaceutical science has arose increasing attention. The demand of lab-on-a-chip technologies for pharmaceutical science led to the development of Pharm-Lab on a Chip, which represents chip-based platforms for whole chain of pharmacy applications from drug discovery to post marketing product management. Pharm-Lab on a Chip consist of all aspects of chip-based principles, techniques and devices for pharmaceutical analysis, pharmacological/toxicological test and pharmaceutical production. In this review, we focused on the recent advances in utilization of lab-on-a-chip for pharmaceutical analysis and test. The main contents including separation and analysis of drug molecules on a chip, construction of novel pharmacological/toxicological models on a chip, and the application of chip-based models for evaluating drug efficacy and safety. As a summary and prospect, we also try to give insight into the challenges and possible breakthrough of the development of Pharm-Lab on a Chip.

[1]  Seiichi Ishida,et al.  Organs-on-a-chip: Current applications and consideration points for in vitro ADME-Tox studies. , 2018, Drug metabolism and pharmacokinetics.

[2]  Richard M Maceiczyk,et al.  Small but Perfectly Formed? Successes, Challenges, and Opportunities for Microfluidics in the Chemical and Biological Sciences , 2017 .

[3]  Yeoheung Yun,et al.  Three-dimensional (3D) tetra-culture brain on chip platform for organophosphate toxicity screening , 2018, Scientific Reports.

[4]  G. Desmet,et al.  Design and evaluation of microfluidic devices for two-dimensional spatial separations. , 2016, Journal of chromatography. A.

[5]  J Michael Ramsey,et al.  Characterization of Intact Antibody Drug Conjugate Variants Using Microfluidic Capillary Electrophoresis-Mass Spectrometry. , 2016, Analytical chemistry.

[6]  Donald E. Ingber,et al.  Modelling cancer in microfluidic human organs-on-chips , 2019, Nature Reviews Cancer.

[7]  Qionglin Liang,et al.  Necklace‐Like Microfibers with Variable Knots and Perfusable Channels Fabricated by an Oil‐Free Microfluidic Spinning Process , 2018, Advanced materials.

[8]  Jeong-Yeol Yoon,et al.  Organ-on-a-chip for assessing environmental toxicants. , 2017, Current opinion in biotechnology.

[9]  Jeremy D Caplin,et al.  Microfluidic Organ‐on‐a‐Chip Technology for Advancement of Drug Development and Toxicology , 2015, Advanced healthcare materials.

[10]  Damith E W Patabadige,et al.  Micro Total Analysis Systems: Fundamental Advances and Applications. , 2016, Analytical chemistry.

[11]  Masatoshi Maeki Microfluidics for pharmaceutical applications , 2019, Microfluidics for Pharmaceutical Applications.

[12]  Jong Hwan Sung,et al.  A pumpless multi‐organ‐on‐a‐chip (MOC) combined with a pharmacokinetic–pharmacodynamic (PK–PD) model , 2017, Biotechnology and bioengineering.

[13]  D. Marshall,et al.  Microfluidics for single cell analysis. , 2012, Current opinion in biotechnology.

[14]  P. Seeberger,et al.  Integrated on-chip mass spectrometry reaction monitoring in microfluidic devices containing porous polymer monolithic columns. , 2016, The Analyst.

[15]  W. Le,et al.  Recent advances in microfluidic models for cancer metastasis research , 2018 .

[16]  Michael G. Roper,et al.  Microfluidics-to-mass spectrometry: a review of coupling methods and applications. , 2015, Journal of chromatography. A.

[17]  P. E. Verboket,et al.  Multivesicular droplets: a cell model system to study compartmentalised biochemical reactions. , 2017, Lab on a chip.

[18]  Shuo Lin,et al.  Drug cytotoxicity and signaling pathway analysis with three-dimensional tumor spheroids in a microwell-based microfluidic chip for drug screening. , 2015, Analytica chimica acta.

[19]  Paul Vulto,et al.  Kidney-on-a-Chip Technology for Drug-Induced Nephrotoxicity Screening. , 2016, Trends in biotechnology.

[20]  Marco Rasponi,et al.  Beating heart on a chip: a novel microfluidic platform to generate functional 3D cardiac microtissues. , 2016, Lab on a chip.

[21]  Jianding Qiu,et al.  Separation of chiral compounds using magnetic molecularly imprinted polymer nanoparticles as stationary phase by microchip capillary electrochromatography , 2018, Electrophoresis.

[22]  W. Cui,et al.  Development of a biomimetic liver tumor-on-a-chip model based on decellularized liver matrix for toxicity testing. , 2018, Lab on a chip.

[23]  Jianhua Qin,et al.  A 3D human lung-on-a-chip model for nanotoxicity testing. , 2018, Toxicology research.

[24]  D. Ingber,et al.  Reconstituting Organ-Level Lung Functions on a Chip , 2010, Science.

[25]  Basant Giri,et al.  Advances in paper-analytical methods for pharmaceutical analysis. , 2018, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[26]  F. Sonntag,et al.  A four-organ-chip for interconnected long-term co-culture of human intestine, liver, skin and kidney equivalents. , 2015, Lab on a chip.

[27]  G. Luo,et al.  Screening and evaluation of traditional Chinese medicine by microarray expression analysis. , 2013, Journal of ethnopharmacology.

[28]  D. Ingber,et al.  From 3D cell culture to organs-on-chips. , 2011, Trends in cell biology.

[29]  Antoni Ribas,et al.  Single-cell analysis tools for drug discovery and development , 2015, Nature Reviews Drug Discovery.

[30]  X. Mu,et al.  A modified microfluidic chip for fabrication of paclitaxel-loaded poly(l-lactic acid) microspheres , 2011 .

[31]  G. Luo,et al.  On-demand microfluidic droplet manipulation using hydrophobic ferrofluid as a continuous-phase. , 2011, Lab on a chip.

[32]  Mohsen Akbari,et al.  Microfluidic-Based Multi-Organ Platforms for Drug Discovery , 2016, Micromachines.

[33]  Shahram Seidi,et al.  A new effective on chip electromembrane extraction coupled with high performance liquid chromatography for enhancement of extraction efficiency. , 2015, Analytica chimica acta.

[34]  Thoriq Salafi,et al.  Advancements in microfluidics for nanoparticle separation. , 2016, Lab on a chip.

[35]  G. Whitesides,et al.  Fabrication of microfluidic systems in poly(dimethylsiloxane) , 2000, Electrophoresis.

[36]  P. Yager,et al.  Microfluidic Diffusion-Based Separation and Detection , 1999, Science.

[37]  Jong Hwan Sung,et al.  Organ‐on‐a‐chip technology and microfluidic whole‐body models for pharmacokinetic drug toxicity screening , 2013, Biotechnology journal.

[38]  Julia Hoeng,et al.  A lung/liver-on-a-chip platform for acute and chronic toxicity studies. , 2018, Lab on a chip.

[39]  T. Hope,et al.  A microfluidic culture model of the human reproductive tract and 28-day menstrual cycle , 2017, Nature Communications.

[40]  D. Ingber,et al.  Microfluidic organs-on-chips , 2014, Nature Biotechnology.

[41]  Q. Fang,et al.  Three-Dimensional Cell Culture and Drug Testing in a Microfluidic Sidewall-Attached Droplet Array. , 2017, Analytical chemistry.

[42]  Noel S Ha,et al.  Toward miniaturized analysis of chemical identity and purity of radiopharmaceuticals via microchip electrophoresis , 2018, Analytical and Bioanalytical Chemistry.

[43]  Xinghua Gao,et al.  Nanofiber membrane supported lung-on-a-chip microdevice for anti-cancer drug testing. , 2018, Lab on a chip.

[44]  Bing Yu,et al.  Recent progress in preparation and application of microfluidic chip electrophoresis , 2015 .

[45]  A. Gáspár,et al.  Particle-based liquid chromatographic separations in microfluidic devices - A review. , 2018, Analytica chimica acta.

[46]  Jianding Qiu,et al.  One-step synthesis of mussel-inspired molecularly imprinted magnetic polymer as stationary phase for chip-based open tubular capillary electrochromatography enantioseparation. , 2014, Journal of chromatography. A.

[47]  G. Luo,et al.  Bioinspired Microfibers with Embedded Perfusable Helical Channels , 2017, Advanced materials.

[48]  Qionglin Liang,et al.  Investigation into the hypoxia-dependent cytotoxicity of anticancer drugs under oxygen gradient in a microfluidic device , 2015 .

[49]  T. Phillips Recent advances in CE and microchip‐CE in clinical applications: 2014 to mid‐2017 , 2018, Electrophoresis.

[50]  Haifang Li,et al.  Adhesion analysis of single circulating tumor cells on a base layer of endothelial cells using open microfluidics† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c8sc03027h , 2018, Chemical science.

[51]  S. Sugiura,et al.  A multi-throughput multi-organ-on-a-chip system on a plate formatted pneumatic pressure-driven medium circulation platform. , 2017, Lab on a chip.

[52]  S. Ohla,et al.  On-chip integration of organic synthesis and HPLC/MS analysis for monitoring stereoselective transformations at the micro-scale. , 2016, Lab on a chip.

[53]  Shuichi Takayama,et al.  Pharmacokinetic profile that reduces nephrotoxicity of gentamicin in a perfused kidney-on-a-chip , 2016, Biofabrication.

[54]  E. Carrilho,et al.  Recombinant drugs-on-a-chip: The usage of capillary electrophoresis and trends in miniaturized systems - A review. , 2016, Analytica chimica acta.

[55]  Xingyu Jiang,et al.  Microfluidics‐Based Biomaterials and Biodevices , 2018, Advanced materials.

[56]  Mitsutoshi Nakajima,et al.  Recent lab‐on‐chip developments for novel drug discovery , 2017, Wiley interdisciplinary reviews. Systems biology and medicine.

[57]  Q. Fang,et al.  Microfluidics for cell-based high throughput screening platforms - A review. , 2016, Analytica chimica acta.

[58]  G. Luo,et al.  A microfluidic chip of multiple-channel array with various oxygen tensions for drug screening , 2016 .

[59]  Michael L Shuler,et al.  Human-on-a-chip design strategies and principles for physiologically based pharmacokinetics/pharmacodynamics modeling. , 2015, Integrative biology : quantitative biosciences from nano to macro.

[60]  Sicen Wang,et al.  Application of microfluidic chip technology in pharmaceutical analysis: A review , 2018, Journal of pharmaceutical analysis.

[61]  D. Belder,et al.  Joining Microfluidics with Infrared Photodissociation: Online Monitoring of Isomeric Flow-Reaction Intermediates. , 2019, Analytical chemistry.

[62]  M. Fillet,et al.  Microfluidics contribution to pharmaceutical sciences: From drug discovery to post marketing product management , 2018, Journal of pharmaceutical and biomedical analysis.

[63]  Noo Li Jeon,et al.  Microfluidic-based vascularized microphysiological systems. , 2018, Lab on a chip.

[64]  S. Fanali,et al.  Chiral separations in food analysis , 2013 .

[65]  Jin-Ming Lin,et al.  Recent advances in microchip-mass spectrometry for biological analysis , 2014 .

[66]  Y. S. Zhang,et al.  Interplay between materials and microfluidics. , 2017, Nature reviews. Materials.

[67]  Josue A. Goss,et al.  Microfluidic heart on a chip for higher throughput pharmacological studies. , 2013, Lab on a chip.

[68]  D. Beebe,et al.  Controlled microfluidic interfaces , 2005, Nature.

[69]  J. Wikswo,et al.  Fitting tissue chips and microphysiological systems into the grand scheme of medicine, biology, pharmacology, and toxicology , 2017, Experimental biology and medicine.

[70]  Haifang Li,et al.  In Situ Scatheless Cell Detachment Reveals Correlation between Adhesion Strength and Viability at Single-Cell Resolution. , 2018, Angewandte Chemie.

[71]  Jin-Ming Lin,et al.  Single-cell assay on microfluidic devices. , 2019, The Analyst.

[72]  A. Manz,et al.  Lab-on-a-chip: microfluidics in drug discovery , 2006, Nature Reviews Drug Discovery.

[73]  Peter Ertl,et al.  Recent advances in microfluidic technologies for cell-to-cell interaction studies. , 2018, Lab on a chip.

[74]  Woojung Shin,et al.  Microfluidic Organ-on-a-Chip Models of Human Intestine , 2018, Cellular and molecular gastroenterology and hepatology.

[75]  S. Wölfl,et al.  Liver-Kidney-on-Chip To Study Toxicity of Drug Metabolites. , 2018, ACS biomaterials science & engineering.

[76]  Uwe Marx,et al.  Application of Microphysiological Systems to Enhance Safety Assessment in Drug Discovery. , 2018, Annual review of pharmacology and toxicology.

[77]  W. Huck,et al.  Microfluidic Formation of Monodisperse Coacervate Organelles in Liposomes , 2017, Angewandte Chemie.

[78]  Uwe Marx,et al.  A multi-organ chip co-culture of neurospheres and liver equivalents for long-term substance testing. , 2015, Journal of biotechnology.

[79]  Qionglin Liang,et al.  Bismuth iron oxide nanocomposite supported on graphene oxides as the high efficient, stable and reusable catalysts for the reduction of nitroarenes under continuous flow conditions , 2017 .

[80]  Qionglin Liang,et al.  Advances of Microfluidic Technologies Applied in Bio-analytical Chemistry , 2016 .

[81]  Teruo Fujii,et al.  Organ/body-on-a-chip based on microfluidic technology for drug discovery. , 2017, Drug metabolism and pharmacokinetics.

[82]  Milica Radisic,et al.  Advances in organ-on-a-chip engineering , 2018, Nature Reviews Materials.

[83]  Y. Yamini,et al.  Quantitative analysis of clonidine and ephedrine by a microfluidic system: On-chip electromembrane extraction followed by high performance liquid chromatography. , 2017, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[84]  G. Luo,et al.  Comprehensive two-dimensional manipulations of picoliter microfluidic droplets sampled from nanoliter samples. , 2011, Analytical chemistry.

[85]  Qionglin Liang,et al.  Noncovalently functionalized carbon nanotubes immobilized Fe–Bi bimetallic oxides as a heterogeneous nanocatalyst for reduction of nitroaromatics , 2017 .

[86]  D. Beebe,et al.  The present and future role of microfluidics in biomedical research , 2014, Nature.

[87]  K. Jensen,et al.  Cells on chips , 2006, Nature.

[88]  T. Schmidt,et al.  Micro-liquid chromatography mass spectrometry for the analysis of antineoplastic drugs from wipe samples , 2016, Analytical and Bioanalytical Chemistry.

[89]  D. J. Harrison,et al.  Capillary electrophoresis and sample injection systems integrated on a planar glass chip , 1992 .

[90]  Jin-Ming Lin,et al.  Microfluidic technologies in cell isolation and analysis for biomedical applications. , 2017, The Analyst.

[91]  Megan L. McCain,et al.  Ensembles of engineered cardiac tissues for physiological and pharmacological study: heart on a chip. , 2011, Lab on a chip.

[92]  Jin‐Ming Lin,et al.  Online Analysis of Drug Toxicity to Cells with Shear Stress on an Integrated Microfluidic Chip. , 2019, ACS sensors.

[93]  Min Zhang,et al.  Organs-on-chips and Its Applications , 2016 .

[94]  Jong Hwan Sung,et al.  A microfluidic device for a pharmacokinetic-pharmacodynamic (PK-PD) model on a chip. , 2010, Lab on a chip.

[95]  Maaruthy Yelleswarapu,et al.  Microfluidic Assembly of Monodisperse Vesosomes as Artificial Cell Models. , 2017, Journal of the American Chemical Society.

[96]  You‐Ming Zhang,et al.  Chiral Separation of Ofloxacin Enantiomers by Microchip Capillary Electrophoresis with Capacitively Coupled Contactless Conductivity Detection , 2014 .

[97]  Ziyi He,et al.  Recent advances in microfluidic 3D cellular scaffolds for drug assays , 2017 .

[98]  José Luís Dores-Sousa,et al.  Prototyping of thermoplastic microfluidic chips and their application in high-performance liquid chromatography separations of small molecules. , 2017, Journal of chromatography. A.

[99]  Jian Le,et al.  Recent advances in microfluidic devices for bacteria and fungus research , 2019, TrAC Trends in Analytical Chemistry.

[100]  Paul C. H. Li,et al.  Microchip electrophoretic separation and fluorescence detection of chelerythrine and sanguinarine in medicinal plants. , 2015, Talanta.

[101]  Daniel C Leslie,et al.  A Human Disease Model of Drug Toxicity–Induced Pulmonary Edema in a Lung-on-a-Chip Microdevice , 2012, Science Translational Medicine.

[102]  Milica Radisic,et al.  High-Content Assessment of Cardiac Function Using Heart-on-a-Chip Devices as Drug Screening Model , 2017, Stem Cell Reviews and Reports.

[103]  Z. Duan,et al.  Innovation for hepatotoxicity in vitro research models: A review , 2018, Journal of applied toxicology : JAT.

[104]  Julio Saez-Rodriguez,et al.  A microfluidics platform for combinatorial drug screening on cancer biopsies , 2018, Nature Communications.

[105]  Ali Khademhosseini,et al.  Organ‐on‐a‐Chip for Cancer and Immune Organs Modeling , 2019, Advanced healthcare materials.

[106]  Murat Cirit,et al.  Interconnected Microphysiological Systems for Quantitative Biology and Pharmacology Studies , 2018, Scientific Reports.

[107]  Xingyu Jiang,et al.  Synthesizing Living Tissues with Microfluidics. , 2018, Accounts of chemical research.

[108]  Wenming Liu,et al.  Construction of single-cell arrays and assay of cell drug resistance in an integrated microfluidic platform. , 2016, Lab on a chip.

[109]  D. Weitz,et al.  Microfluidic fabrication of microparticles for biomedical applications. , 2018, Chemical Society reviews.

[110]  C. Zamani,et al.  Toward a comprehensive microextraction/determination unit: A chip silicon rubber polyaniline-based system and its direct coupling with gas chromatography and mass spectrometry. , 2016, Journal of separation science.

[111]  Zhi Zhu,et al.  Hydrogel Droplet Microfluidics for High-Throughput Single Molecule/Cell Analysis. , 2017, Accounts of chemical research.

[112]  Aoife Morrin,et al.  Microfluidic paper analytical device for the chromatographic separation of ascorbic acid and dopamine , 2015 .

[113]  J. Collins,et al.  Bone marrow–on–a–chip replicates hematopoietic niche physiology in vitro , 2014, Nature Methods.

[114]  A. Herr,et al.  Microfluidics: reframing biological enquiry , 2015, Nature Reviews Molecular Cell Biology.

[115]  Donald E Ingber,et al.  Microfabrication of human organs-on-chips , 2013, Nature Protocols.

[116]  Ning Gan,et al.  A microchip electrophoresis-based assay for ratiometric detection of kanamycin by R-shape probe and exonuclease-assisted signal amplification. , 2018, Talanta.

[117]  Wu Liu,et al.  Chemical operations on a living single cell by open microfluidics for wound repair studies and organelle transport analysis† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c8sc05104f , 2018, Chemical science.

[118]  Lidong Qin,et al.  Recent Progress of Microfluidics in Translational Applications , 2016, Advanced healthcare materials.

[119]  Kangning Ren,et al.  Miniaturized high throughput detection system for capillary array electrophoresis on chip with integrated light emitting diode array as addressed ring-shaped light source. , 2009, Lab on a chip.

[120]  A. Manz,et al.  Revisiting lab-on-a-chip technology for drug discovery , 2012, Nature Reviews Drug Discovery.

[121]  S. Fanali,et al.  Advanced analytical techniques for fat-soluble vitamin analysis , 2017 .

[122]  Steven C George,et al.  A vascularized and perfused organ-on-a-chip platform for large-scale drug screening applications. , 2017, Lab on a chip.

[123]  M. Shuler Advances in organ-, body-, and disease-on-a-chip systems. , 2018, Lab on a chip.

[124]  Qiushui Chen,et al.  Biochemical analysis on microfluidic chips , 2016 .

[125]  Boyang Zhang,et al.  Organ‐On‐A‐Chip Platforms: A Convergence of Advanced Materials, Cells, and Microscale Technologies , 2018, Advanced healthcare materials.

[126]  Jong Hwan Sung,et al.  Recent Advances in Body-on-a-Chip Systems. , 2018, Analytical chemistry.

[127]  Murat Cirit,et al.  Maximizing the impact of microphysiological systems with in vitro-in vivo translation. , 2018, Lab on a chip.

[128]  Jinyi Wang,et al.  On-Chip Construction of Liver Lobule-like Microtissue and Its Application for Adverse Drug Reaction Assay. , 2016, Analytical chemistry.

[129]  Ian J Pardoe,et al.  Optimization of Surface-Enhanced Raman Spectroscopy Conditions for Implementation into a Microfluidic Device for Drug Detection. , 2016, Analytical chemistry.

[130]  Marco Rasponi,et al.  Bioprinting 3D microfibrous scaffolds for engineering endothelialized myocardium and heart-on-a-chip. , 2016, Biomaterials.

[131]  Wonjung Kim,et al.  Paper-Based Flow Fractionation System Applicable to Preconcentration and Field-Flow Separation. , 2016, Analytical chemistry.

[132]  Yiping Cui,et al.  Pharmacokinetics-on-a-Chip Using Label-Free SERS Technique for Programmable Dual-Drug Analysis. , 2017, ACS sensors.

[133]  Wenxin Wang,et al.  Application of a microfluidic chip-based 3D co-culture to test drug sensitivity for individualized treatment of lung cancer. , 2013, Biomaterials.

[134]  Ning Hu,et al.  Multisensor-integrated organs-on-chips platform for automated and continual in situ monitoring of organoid behaviors , 2017, Proceedings of the National Academy of Sciences.

[135]  Uwe Marx,et al.  Functional coupling of human pancreatic islets and liver spheroids on-a-chip: Towards a novel human ex vivo type 2 diabetes model , 2017, Scientific Reports.

[136]  Nafisur Rahman,et al.  Analytical techniques in pharmaceutical analysis: A review , 2017 .

[137]  Kai Zhang,et al.  A gravity-actuated technique for flexible and portable microfluidic droplet manipulation , 2010 .

[138]  Shulin Zhao,et al.  A microchip electrophoresis-based fluorescence signal amplification strategy for highly sensitive detection of biomolecules. , 2016, Chemical communications.

[139]  G. Luo,et al.  Controlling gas/liquid exchange using microfluidics for real-time monitoring of flagellar length in living Chlamydomonas at the single-cell level. , 2012, Lab on a chip.

[140]  Jongyoon Han,et al.  Microfluidic modelling of the tumor microenvironment for anti-cancer drug development. , 2019, Lab on a chip.

[141]  Thomas C. Ferrante,et al.  Small airway-on-a-chip enables analysis of human lung inflammation and drug responses in vitro , 2015, Nature Methods.

[142]  Ali Khademhosseini,et al.  Multi-tissue interactions in an integrated three-tissue organ-on-a-chip platform , 2017, Scientific Reports.

[143]  Qionglin Liang,et al.  Simultaneous Assay of Oxygen-Dependent Cytotoxicity and Genotoxicity of Anticancer Drugs on an Integrated Microchip. , 2018, Analytical chemistry.

[144]  W. Chan,et al.  Clarifying intact 3D tissues on a microfluidic chip for high-throughput structural analysis , 2016, Proceedings of the National Academy of Sciences.

[145]  Zhongze Gu,et al.  Organ-on-a-Chip Systems: Microengineering to Biomimic Living Systems. , 2016, Small.

[146]  Rosanne M. Guijt,et al.  Miniaturised total chemical-analysis systems (μTAS) that periodically convert chemical into electronic information , 2018, Sensors and Actuators B: Chemical.

[147]  D. Huh,et al.  Organs-on-chips at the frontiers of drug discovery , 2015, Nature Reviews Drug Discovery.

[148]  Jin‐Ming Lin,et al.  Microfluidic Devices in the Fast-Growing Domain of Single-Cell Analysis. , 2018, Chemistry.

[149]  Anthony Atala,et al.  Organoid-on-a-chip and body-on-a-chip systems for drug screening and disease modeling. , 2016, Drug discovery today.

[150]  Wentao Su,et al.  Assessment of cadmium-induced nephrotoxicity using a kidney-on-a-chip device. , 2017, Toxicology research.

[151]  H. Gomes,et al.  Development of paper-based color test-strip for drug detection in aquatic environment: Application to oxytetracycline. , 2015, Biosensors & bioelectronics.

[152]  D. Weitz,et al.  Single-cell analysis and sorting using droplet-based microfluidics , 2013, Nature Protocols.

[153]  Y. S. Zhang,et al.  Mimicking Human Pathophysiology in Organ‐on‐Chip Devices , 2018, Advanced Biosystems.

[154]  Wei Zhang,et al.  Organs on microfluidic chips: A mini review , 2014, Science China Chemistry.

[155]  Qionglin Liang,et al.  Egg-like magnetically immobilized nanospheres: A long-lived catalyst model for the hydrogen transfer reaction in a continuous-flow reactor , 2017, Nano Research.

[156]  X. Mu,et al.  Oil–water biphasic parallel flow for the precise patterning of metals and cells , 2014, Biomedical microdevices.

[157]  D. Ingber,et al.  Human gut-on-a-chip inhabited by microbial flora that experiences intestinal peristalsis-like motions and flow. , 2012, Lab on a chip.

[158]  Sung-Jin Park,et al.  Instrumented cardiac microphysiological devices via multi-material 3D printing , 2016, Nature materials.

[159]  M. Radisic,et al.  Biodegradable scaffold with built-in vasculature for organ-on-a-chip engineering and direct surgical anastomosis , 2016, Nature materials.

[160]  Xiancheng Li,et al.  Design and Construction of a Multi-Organ Microfluidic Chip Mimicking the in vivo Microenvironment of Lung Cancer Metastasis. , 2016, ACS applied materials & interfaces.

[161]  Xingyu Jiang,et al.  Why microfluidics? Merits and trends in chemical synthesis. , 2017, Lab on a chip.

[162]  R. Oleschuk,et al.  Advances in Microchip Liquid Chromatography. , 2018, Analytical chemistry.

[163]  D. Ingber,et al.  Human kidney proximal tubule-on-a-chip for drug transport and nephrotoxicity assessment. , 2013, Integrative biology : quantitative biosciences from nano to macro.

[164]  Hui-Ling Lee,et al.  Rapid analysis of traditional Chinese medicine Pinellia ternata by microchip electrophoresis with electrochemical detection. , 2018, Journal of separation science.

[165]  W. Coltro,et al.  Separation of carbohydrates on electrophoresis microchips with controlled electrolysis , 2019, Electrophoresis.

[166]  A. van den Berg,et al.  Mass spectrometric detection of short-lived drug metabolites generated in an electrochemical microfluidic chip. , 2015, Analytical chemistry.

[167]  A. S. Nezhad,et al.  Towards fully integrated liquid chromatography on a chip: Evolution and evaluation , 2018 .

[168]  Alan Wells,et al.  Liver ‘organ on a chip’ , 2017, Experimental cell research.

[169]  Feng Jin,et al.  Recent advances in single cell manipulation and biochemical analysis on microfluidics. , 2019, The Analyst.

[170]  D. Belder,et al.  HPLC-MS with Glass Chips Featuring Monolithically Integrated Electrospray Emitters of Different Geometries. , 2016, Analytical chemistry.

[171]  G. Luo,et al.  A droplet-based microfluidic device for long-term culture and longitudinal observation of Caenorhabditis elegans , 2012, BioChip Journal.

[172]  H. H. See,et al.  Rapid quantification of quinine by multi‐stacking in a portable microchip electrophoresis system , 2018, Electrophoresis.

[173]  G. Luo,et al.  A Microfluidic Hydrogel Chip with Orthogonal Dual Gradients of Matrix Stiffness and Oxygen for Cytotoxicity Test , 2018, BioChip Journal.

[174]  D. Belder,et al.  Enantioselective reaction monitoring utilizing two-dimensional heart-cut liquid chromatography on an integrated microfluidic chip. , 2016, Lab on a chip.

[175]  S. Maspoch,et al.  An effective microfluidic based liquid-phase microextraction device (μLPME) for extraction of non-steroidal anti-inflammatory drugs from biological and environmental samples. , 2016, Analytica chimica acta.

[176]  A. A. Castrejón-Pita,et al.  Microfluidic chambers using fluid walls for cell biology , 2018, Proceedings of the National Academy of Sciences.

[177]  Ali Khademhosseini,et al.  Microfluidics for drug discovery and development: from target selection to product lifecycle management. , 2008, Drug discovery today.

[178]  D. Willems,et al.  Analysis of Raw Biofluids by Mass Spectrometry Using Microfluidic Diffusion-Based Separation. , 2017, Analytical methods : advancing methods and applications.

[179]  Gong Cheng,et al.  A Spontaneous 3D Bone-On-a-Chip for Bone Metastasis Study of Breast Cancer Cells. , 2018, Small.

[180]  Jin-Ming Lin,et al.  Multi-channel microfluidic chip-mass spectrometry platform for cell analysis , 2017 .

[181]  Robert T Kennedy,et al.  Advances in and prospects of microchip liquid chromatography. , 2016, Trends in analytical chemistry : TRAC.

[182]  P. Dittrich,et al.  Microfluidics to Mimic Blood Flow in Health and Disease , 2018 .

[183]  M. Monsur Ali,et al.  Droplet microfluidics for single-molecule and single-cell analysis in cancer research, diagnosis and therapy , 2014 .

[184]  D. Belder,et al.  Chip-based high-performance liquid chromatography for high-speed enantioseparations. , 2015, Analytical chemistry.

[185]  Jin‐Ming Lin,et al.  Cell analysis on chip-mass spectrometry , 2018, TrAC Trends in Analytical Chemistry.

[186]  G. Luo,et al.  Single-Cell-Arrayed Agarose Chip for in Situ Analysis of Cytotoxicity and Genotoxicity of DNA Cross-Linking Agents. , 2016, Analytical chemistry.

[187]  Wu Liu,et al.  Online Monitoring of Lactate Efflux by Multi-Channel Microfluidic Chip-Mass Spectrometry for Rapid Drug Evaluation , 2016 .

[188]  Jin-Ming Lin,et al.  Dean flow assisted cell ordering system for lipid profiling in single-cells using mass spectrometry. , 2018, Chemical communications.

[189]  Albert van den Berg,et al.  A chip system for size separation of macromolecules and particles by hydrodynamic chromatography. , 2002, Analytical chemistry.

[190]  Yi-Ming Liu,et al.  Rapid quantification of aloin A and B in aloe plants and aloe-containing beverages, and pharmaceutical preparations by microchip capillary electrophoresis with laser induced fluorescence detection. , 2018, Journal of separation science.

[191]  O. Pertz,et al.  Microfluidic platform for single cell analysis under dynamic spatial and temporal stimulation. , 2018, Biosensors & bioelectronics.

[192]  Niraj K Inamdar,et al.  Microfluidic cell culture models for tissue engineering. , 2011, Current opinion in biotechnology.

[193]  Anne Riu,et al.  Investigation of the effect of hepatic metabolism on off-target cardiotoxicity in a multi-organ human-on-a-chip system. , 2018, Biomaterials.

[194]  Yongjian Ai,et al.  Dehydration-triggered shape morphing based on asymmetric bubble hydrogel microfibers. , 2018, Soft matter.

[195]  Jong Hwan Sung,et al.  Organ‐on‐a‐Chip Technology for Reproducing Multiorgan Physiology , 2018, Advanced healthcare materials.

[196]  M. Masár,et al.  Precise determination of N-acetylcysteine in pharmaceuticals by microchip electrophoresis. , 2016, Journal of separation science.

[197]  Patrick T. McGrath,et al.  A high-throughput device for size based separation of C. elegans developmental stages. , 2014, Lab on a chip.

[198]  Min Huang,et al.  Nanoliter-Scale Oil-Air-Droplet Chip-Based Single Cell Proteomic Analysis. , 2018, Analytical chemistry.

[199]  X. Mu,et al.  Design and fabrication of a liver-on-a-chip platform for convenient, highly efficient, and safe in situ perfusion culture of 3D hepatic spheroids. , 2018, Lab on a chip.

[200]  G. Whitesides The origins and the future of microfluidics , 2006, Nature.

[201]  M. Ding,et al.  Hydrogel microfibers with perfusable folded channels for tissue constructs with folded morphology , 2018, RSC advances.

[202]  Leslie Y Yeo,et al.  Microfluidic devices for bioapplications. , 2011, Small.

[203]  Sean P Sheehy,et al.  A linked organ-on-chip model of the human neurovascular unit reveals the metabolic coupling of endothelial and neuronal cells , 2018, Nature Biotechnology.

[204]  A. Vasan,et al.  A microfluidic platform for drug screening in a 3D cancer microenvironment. , 2017, Biosensors & bioelectronics.

[205]  D. Belder,et al.  Seamless Combination of High-Pressure Chip-HPLC and Droplet Microfluidics on an Integrated Microfluidic Glass Chip. , 2017, Analytical chemistry.

[206]  Hojae Bae,et al.  Organ-On-A-Chip: Development and Clinical Prospects Toward Toxicity Assessment with an Emphasis on Bone Marrow , 2015, Drug Safety.

[207]  M. Mujika,et al.  Improved microfluidic platform for simultaneous multiple drug screening towards personalized treatment. , 2019, Biosensors & bioelectronics.