Current developments and applications of microfluidic technology toward clinical translation of nanomedicines☆

Abstract Nanoparticulate drug delivery systems hold great potential for the therapy of many diseases, especially cancer. However, the translation of nanoparticulate drug delivery systems from academic research to industrial and clinical practice has been slow. This slow translation can be ascribed to the high batch‐to‐batch variations and insufficient production rate of the conventional preparation methods, and the lack of technologies for rapid screening of nanoparticulate drug delivery systems with high correlation to the in vivo tests. These issues can be addressed by the microfluidic technologies. For example, microfluidics can not only produce nanoparticles in a well‐controlled, reproducible, and high‐throughput manner, but also create 3D environments with continuous flow to mimic the physiological and/or pathological processes. This review provides an overview of the microfluidic devices developed to prepare nanoparticulate drug delivery systems, including drug nanosuspensions, polymer nanoparticles, polyplexes, structured nanoparticles and theranostic nanoparticles. We also highlight the recent advances of microfluidic systems in fabricating the increasingly realistic models of the in vivo milieu for rapid screening of nanoparticles. Overall, the microfluidic technologies offer a promise approach to accelerate the clinical translation of nanoparticulate drug delivery systems. Graphical abstract Figure. No Caption available.

[1]  Mohammad Mahdi Hasani-Sadrabadi,et al.  On‐Chip Fabrication of Paclitaxel‐Loaded Chitosan Nanoparticles for Cancer Therapeutics , 2014 .

[2]  Saif A. Khan,et al.  Transport and reaction in microscale segmented gas-liquid flow. , 2004, Lab on a chip.

[3]  Peter Ertl,et al.  Microfluidic Impedimetric Cell Regeneration Assay to Monitor the Enhanced Cytotoxic Effect of Nanomaterial Perfusion , 2015, Biosensors.

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

[5]  A. deMello Control and detection of chemical reactions in microfluidic systems , 2006, Nature.

[6]  John B. Shoven,et al.  I , Edinburgh Medical and Surgical Journal.

[7]  Alfredo Quinones-Hinojosa,et al.  Continuous microfluidic assembly of biodegradable poly(beta-amino ester)/DNA nanoparticles for enhanced gene delivery. , 2017, Journal of biomedical materials research. Part A.

[8]  Kit S Lam,et al.  The effect of surface charge on in vivo biodistribution of PEG-oligocholic acid based micellar nanoparticles. , 2011, Biomaterials.

[9]  Robert Langer,et al.  Synthesis of polymer-lipid nanoparticles for image-guided delivery of dual modality therapy. , 2013, Bioconjugate chemistry.

[10]  David Sinton,et al.  Formation and shear-induced processing of quantum dot colloidal assemblies in a multiphase microfluidic chip. , 2008, Langmuir : the ACS journal of surfaces and colloids.

[11]  Ikram Ullah Khan,et al.  Microfluidics: a focus on improved cancer targeted drug delivery systems. , 2013, Journal of controlled release : official journal of the Controlled Release Society.

[12]  M. Abdelguerfi,et al.  Introduction 1.2 Parallel Database Systems 1.2.1 Computation Model 2 1.2 Parallel Database Systems Introduction Select * from Employee, Department Where (employee.dept_no @bullet Department.dept_no) and (employee.position = "manager") (a) Sql Request 1.2.2 Engineering Model , 2022 .

[13]  Robert K. Prud'homme,et al.  Flash NanoPrecipitation of Organic Actives and Block Copolymers using a Confined Impinging Jets Mixer , 2003 .

[14]  Xin Cai,et al.  Radioactive 198Au-Doped Nanostructures with Different Shapes for In Vivo Analyses of Their Biodistribution, Tumor Uptake, and Intratumoral Distribution , 2014, ACS nano.

[15]  Reginald B. H. Tan,et al.  Continuous production of redispersible and rapidly-dissolved fenofibrate nanoformulation by combination of microfluidics and spray drying , 2014 .

[16]  Kasper Renggli,et al.  Highly Scalable, Closed‐Loop Synthesis of Drug‐Loaded, Layer‐by‐Layer Nanoparticles , 2016, Advanced functional materials.

[17]  Thierry F. Vandamme,et al.  A new microfluidic setup for precise control of the polymer nanoprecipitation process and lipophilic drug encapsulation , 2012 .

[18]  D. Discher,et al.  Shape effects of filaments versus spherical particles in flow and drug delivery. , 2007, Nature nanotechnology.

[19]  A. Domb,et al.  Chitosan chemistry and pharmaceutical perspectives. , 2004, Chemical reviews.

[20]  G. G. Stokes "J." , 1890, The New Yale Book of Quotations.

[21]  Robert Langer,et al.  Ultra-High Throughput Synthesis of Nanoparticles with Homogeneous Size Distribution Using a Coaxial Turbulent Jet Mixer , 2014, ACS nano.

[22]  H. Maeda,et al.  A Retrospective 30 Years After Discovery of the Enhanced Permeability and Retention Effect of Solid Tumors: Next‐Generation Chemotherapeutics and Photodynamic Therapy—Problems, Solutions, and Prospects , 2016, Microcirculation.

[23]  Ronnie H. Fang,et al.  Large-scale synthesis of lipid-polymer hybrid nanoparticles using a multi-inlet vortex reactor. , 2012, Langmuir : the ACS journal of surfaces and colloids.

[24]  Tsuyoshi Murata,et al.  {m , 1934, ACML.

[25]  Robert Langer,et al.  Synthesis of Size‐Tunable Polymeric Nanoparticles Enabled by 3D Hydrodynamic Flow Focusing in Single‐Layer Microchannels , 2011, Advanced materials.

[26]  Cui Tang,et al.  Effects of particle size and surface charge on cellular uptake and biodistribution of polymeric nanoparticles. , 2010, Biomaterials.

[27]  J. Lewis,et al.  Chaotic mixing in three-dimensional microvascular networks fabricated by direct-write assembly , 2003, Nature materials.

[28]  Mohammad Mahdi Hasani-Sadrabadi,et al.  Microfluidic Directed Synthesis of Alginate Nanogels with Tunable Pore Size for Efficient Protein Delivery. , 2016, Langmuir : the ACS journal of surfaces and colloids.

[29]  Yanhui Zhao,et al.  Microfluidic Hydrodynamic Focusing for Synthesis of Nanomaterials. , 2016, Nano today.

[30]  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.

[31]  Frank Caruso,et al.  Engineering and evaluating drug delivery particles in microfluidic devices. , 2014, Journal of controlled release : official journal of the Controlled Release Society.

[32]  David Sinton,et al.  Flow-directed assembly of block copolymer vesicles in the lab-on-a-chip. , 2012, Langmuir : the ACS journal of surfaces and colloids.

[33]  L. Capretto,et al.  Microfluidic and lab-on-a-chip preparation routes for organic nanoparticles and vesicular systems for nanomedicine applications. , 2013, Advanced drug delivery reviews.

[34]  Lei Wang,et al.  Continuous Microfluidic Self-Assembly of Hybrid Janus-Like Vesicular Motors: Autonomous Propulsion and Controlled Release. , 2015, Small.

[35]  Yi-Ping Ho,et al.  Three-dimensional hydrodynamic focusing method for polyplex synthesis. , 2014, ACS nano.

[36]  R. Donehower,et al.  Drug therapy : paclitaxel (Taxol) , 1995 .

[37]  Jarno Salonen,et al.  Core/Shell Nanocomposites Produced by Superfast Sequential Microfluidic Nanoprecipitation. , 2017, Nano letters.

[38]  N. Annabi,et al.  Microengineered cancer-on-a-chip platforms to study the metastatic microenvironment. , 2016, Lab on a chip.

[39]  A Atilla Hincal,et al.  Sterile, injectable cyclodextrin nanoparticles: effects of gamma irradiation and autoclaving. , 2006, International journal of pharmaceutics.

[40]  M. Ferrari Cancer nanotechnology: opportunities and challenges , 2005, Nature Reviews Cancer.

[41]  Philip M. Kelly,et al.  Transferrin-functionalized nanoparticles lose their targeting capabilities when a biomolecule corona adsorbs on the surface. , 2013, Nature nanotechnology.

[42]  Feng Guo,et al.  A digital microfluidic droplet generator produces self-assembled supramolecular nanoparticles for targeted cell imaging , 2010, Nanotechnology.

[43]  Quai Ernest-Ansermet Influence of the stabilizer coating layer on the purification and freeze-drying of poly(D,L-lactic acid) nanoparticles prepared by an emulsion-diffusion technique , 1998 .

[44]  Rudy Juliano,et al.  Nanomedicine: is the wave cresting? , 2013, Nature Reviews Drug Discovery.

[45]  Yanbin Li,et al.  Interdigitated array microelectrodes based impedance biosensors for detection of bacterial cells. , 2009, Biosensors & bioelectronics.

[46]  Young Jik Kwon,et al.  "Combo" nanomedicine: Co-delivery of multi-modal therapeutics for efficient, targeted, and safe cancer therapy. , 2016, Advanced drug delivery reviews.

[47]  Lu Zhang,et al.  Microfluidic Synthesis of Rigid Nanovesicles for Hydrophilic Reagents Delivery** , 2015, Angewandte Chemie.

[48]  Prabhas V. Moghe,et al.  Kinetically Assembled Nanoparticles of Bioactive Macromolecules Exhibit Enhanced Stability and Cell‐Targeted Biological Efficacy , 2012, Advanced materials.

[49]  D. Crommelin,et al.  Sterilization of Liposomes by Heat Treatment , 1993, Pharmaceutical Research.

[50]  Wei Liu,et al.  Microfluidic Electroporation-Facilitated Synthesis of Erythrocyte Membrane-Coated Magnetic Nanoparticles for Enhanced Imaging-Guided Cancer Therapy. , 2017, ACS nano.

[51]  D. Weitz,et al.  Tandem emulsification for high-throughput production of double emulsions. , 2017, Lab on a chip.

[52]  Robert Langer,et al.  Engineering of self-assembled nanoparticle platform for precisely controlled combination drug therapy , 2010, Proceedings of the National Academy of Sciences.

[53]  Xiaoyang Xu,et al.  Cancer nanotechnology: the impact of passive and active targeting in the era of modern cancer biology. , 2014, Advanced drug delivery reviews.

[54]  A. Ullrich,et al.  Paul Ehrlich's magic bullet concept: 100 years of progress , 2008, Nature Reviews Cancer.

[55]  Hélder A. Santos,et al.  Microfluidics as a cutting-edge technique for drug delivery applications , 2016 .

[56]  Lei Zhang,et al.  Softer zwitterionic nanogels for longer circulation and lower splenic accumulation. , 2012, ACS nano.

[57]  Jarno Salonen,et al.  Multistaged Nanovaccines Based on Porous Silicon@Acetalated Dextran@Cancer Cell Membrane for Cancer Immunotherapy , 2017, Advanced materials.

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

[59]  Zuleykhan Tomova,et al.  Hydrodynamically driven self-assembly of giant vesicles of metal nanoparticles for remote-controlled release. , 2013, Angewandte Chemie.

[60]  Lei Shao,et al.  Liquid antisolvent preparation of amorphous cefuroxime axetil nanoparticles in a tube-in-tube microchannel reactor. , 2010, International journal of pharmaceutics.

[61]  A. Noyes,et al.  The rate of solution of solid substances in their own solutions , 1897 .

[62]  Lei Gao,et al.  Drug nanocrystals: In vivo performances. , 2012, Journal of controlled release : official journal of the Controlled Release Society.

[63]  Kapil Pant,et al.  Adhesion patterns in the microvasculature are dependent on bifurcation angle. , 2015, Microvascular research.

[64]  S. Walker,et al.  Pharmaceutical innovation by the seven UK-owned pharmaceutical companies (1964-1985). , 1988, British journal of clinical pharmacology.

[65]  H Fessi,et al.  Influence of the stabilizer coating layer on the purification and freeze-drying of poly(D,L-lactic acid) nanoparticles prepared by an emulsion-diffusion technique. , 1998, Journal of microencapsulation.

[66]  Arno Kwade,et al.  Overview of Techniques and Description of Established Processes , 2016 .

[67]  Robert Gurny,et al.  Preparation and characterization of sterile and freeze-dried sub-200 nm nanoparticles. , 2002, International journal of pharmaceutics.

[68]  An-Shik Yang,et al.  A high-performance micromixer using three-dimensional Tesla structures for bio-applications , 2015 .

[69]  I H Sarelius,et al.  A system for culture of endothelial cells in 20-50-microns branching tubes. , 1995, Microcirculation.

[70]  Jiashu Sun,et al.  Microfluidics-mediated assembly of functional nanoparticles for cancer-related pharmaceutical applications. , 2016, Nanoscale.

[71]  Hatem Fessi,et al.  Purification of nanoparticle suspensions by a concentration/diafiltration process , 2004 .

[72]  Jessica C. Hsu,et al.  Tunable, biodegradable gold nanoparticles as contrast agents for computed tomography and photoacoustic imaging. , 2016, Biomaterials.

[73]  Patrick Couvreur,et al.  Design attributes of long-circulating polymeric drug delivery vehicles. , 2015, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[74]  Wei Wang,et al.  Functional polymeric microparticles engineered from controllable microfluidic emulsions. , 2014, Accounts of chemical research.

[75]  Christine Allen,et al.  In Vivo Distribution of Polymeric Nanoparticles at the Whole-Body, Tumor, and Cellular Levels , 2010, Pharmaceutical Research.

[76]  Axel Günther,et al.  Micromixing of miscible liquids in segmented gas-liquid flow. , 2005, Langmuir : the ACS journal of surfaces and colloids.

[77]  Joseph M DeSimone,et al.  Targeted PRINT Hydrogels: The Role of Nanoparticle Size and Ligand Density on Cell Association, Biodistribution, and Tumor Accumulation. , 2015, Nano letters.

[78]  Johan U. Lind,et al.  Instrumented cardiac microphysiological devices via multimaterial three-dimensional printing , 2016 .

[79]  V. Kholodovych,et al.  Sugar-based amphiphilic nanoparticles arrest atherosclerosis in vivo , 2015, Proceedings of the National Academy of Sciences.

[80]  Antonello Barresi,et al.  Nanoprecipitation in confined impinging jets mixers: Production, characterization and scale-up of pegylated nanospheres and nanocapsules for pharmaceutical use , 2012 .

[81]  Mary D. Frame,et al.  A System for Culture of Endothelial Cells in 20–50‐μm Branching Tubes , 1995 .

[82]  J. Wulff,et al.  Microfluidic synthesis of dye-loaded polycaprolactone-block-poly(ethylene oxide) nanoparticles: Insights into flow-directed loading and in vitro release for drug delivery. , 2016, Journal of colloid and interface science.

[83]  Jarno Salonen,et al.  Microfluidic assisted one-step fabrication of porous silicon@acetalated dextran nanocomposites for precisely controlled combination chemotherapy. , 2015, Biomaterials.

[84]  James C. Weaver,et al.  Human Gut-On-A-Chip Supports Polarized Infection of Coxsackie B1 Virus In Vitro , 2017, PloS one.

[85]  Ming Ma,et al.  Microfluidic Encapsulation of Prickly Zinc‐Doped Copper Oxide Nanoparticles with VD1142 Modified Spermine Acetalated Dextran for Efficient Cancer Therapy , 2017, Advanced healthcare materials.

[86]  Y. S. Zhang,et al.  Cancer-on-a-chip systems at the frontier of nanomedicine. , 2017, Drug discovery today.

[87]  Ikram Ullah Khan,et al.  Production of nanoparticle drug delivery systems with microfluidics tools , 2015, Expert opinion on drug delivery.

[88]  Ying Liu,et al.  Self-assembling process of flash nanoprecipitation in a multi-inlet vortex mixer to produce drug-loaded polymeric nanoparticles , 2011 .

[89]  Erfan Dashtimoghadam,et al.  Microfluidic‐Assisted Self‐Assembly of Complex Dendritic Polyethylene Drug Delivery Nanocapsules , 2014, Advanced materials.

[91]  Jörg Huwyler,et al.  Nanomedicine in cancer therapy: challenges, opportunities, and clinical applications. , 2015, Journal of controlled release : official journal of the Controlled Release Society.

[92]  Jukka Rantanen,et al.  High-Throughput Fabrication of Nanocomplexes Using 3D-Printed Micromixers. , 2017, Journal of pharmaceutical sciences.

[93]  Horst-Günter Rubahn,et al.  Influence of geometry on hydrodynamic focusing and long-range fluid behavior in PDMS microfluidic chips , 2012 .

[94]  Lobat Tayebi,et al.  Microfluidic Manipulation of Core/Shell Nanoparticles for Oral Delivery of Chemotherapeutics: A New Treatment Approach for Colorectal Cancer , 2016, Advanced materials.

[95]  Jin-Woo Choi,et al.  A novel in-plane passive microfluidic mixer with modified Tesla structures. , 2004, Lab on a chip.

[96]  Kapil Pant,et al.  Microfluidic devices for modeling cell-cell and particle-cell interactions in the microvasculature. , 2011, Microvascular research.

[97]  Peter York,et al.  Preparation of hydrocortisone nanosuspension through a bottom-up nanoprecipitation technique using microfluidic reactors. , 2009, International journal of pharmaceutics.

[98]  Naoki Sasaki,et al.  Microfluidics for nano-pathophysiology. , 2014, Advanced drug delivery reviews.

[99]  Donald E. Ingber,et al.  Distinct Contributions of Astrocytes and Pericytes to Neuroinflammation Identified in a 3D Human Blood-Brain Barrier on a Chip , 2016, PloS one.

[100]  Robert Langer,et al.  Polymeric nanoparticles for drug delivery. , 2010, Methods in molecular biology.

[101]  Hélder A. Santos,et al.  A Versatile and Robust Microfluidic Platform Toward High Throughput Synthesis of Homogeneous Nanoparticles with Tunable Properties , 2015, Advanced materials.

[102]  Robert Langer,et al.  Single-step assembly of homogenous lipid-polymeric and lipid-quantum dot nanoparticles enabled by microfluidic rapid mixing. , 2010, ACS nano.

[103]  Robert Langer,et al.  Parallel microfluidic synthesis of size-tunable polymeric nanoparticles using 3D flow focusing towards in vivo study. , 2013, Nanomedicine : nanotechnology, biology, and medicine.

[104]  David Sinton,et al.  Flow-directed loading of block copolymer micelles with hydrophobic probes in a gas-liquid microreactor. , 2013, Langmuir : the ACS journal of surfaces and colloids.

[105]  Laura Chronopoulou,et al.  A modular microfluidic platform for the synthesis of biopolymeric nanoparticles entrapping organic actives , 2014, Journal of Nanoparticle Research.

[106]  David Sinton,et al.  Morphological control via chemical and shear forces in block copolymer self-assembly in the lab-on-chip. , 2013, ACS nano.

[107]  E. A. Sykes,et al.  Tumour-on-a-chip provides an optical window into nanoparticle tissue transport , 2013, Nature Communications.

[108]  Jarno Salonen,et al.  On‐Chip Self‐Assembly of a Smart Hybrid Nanocomposite for Antitumoral Applications , 2015 .

[109]  James C. Weaver,et al.  Mature induced-pluripotent-stem-cell-derived human podocytes reconstitute kidney glomerular-capillary-wall function on a chip , 2017, Nature Biomedical Engineering.

[110]  Rong Tong,et al.  New Strategies in Cancer Nanomedicine. , 2016, Annual review of pharmacology and toxicology.

[111]  Ying Liu,et al.  Mixing in a multi-inlet vortex mixer (MIVM) for flash nano-precipitation , 2008 .

[112]  Erfan Dashtimoghadam,et al.  Microfluidic self-assembly of polymeric nanoparticles with tunable compactness for controlled drug delivery , 2013 .

[113]  J. Ljubimova,et al.  Nanomedicine therapeutic approaches to overcome cancer drug resistance. , 2013, Advanced drug delivery reviews.

[114]  Do Jin Im,et al.  THREE DIMENSIONAL FLASH FLOW MICROREACTOR FOR SCALE UP PRODUCTION OF MONODISPERSE PEG-PLGA NANOPARTICLES , 2014 .

[115]  Marcel Jaspars,et al.  Hydrocortisone Nanosuspensions for Ophthalmic Delivery : A Comparative Study between Microfluidic Nanoprecipitation and Wet Milling , 2013 .

[116]  Mandy B. Esch,et al.  Body-on-a-chip simulation with gastrointestinal tract and liver tissues suggests that ingested nanoparticles have the potential to cause liver injury. , 2014, Lab on a chip.

[117]  Fan Yang,et al.  Fish-on-a-chip: microfluidics for zebrafish research. , 2016, Lab on a chip.

[118]  Colin L. Raston,et al.  Suppressing regrowth of microfluidic generated drug nanocrystals using polyelectrolyte coatings , 2013 .

[119]  Hideharu Nagasawa,et al.  Design of a New Micromixer for Instant Mixing Based on the Collision of Micro Segments , 2005 .

[120]  Jianfeng Chen,et al.  Controlled Liquid Antisolvent Precipitation of Hydrophobic Pharmaceutical Nanoparticles in a Microchannel Reactor , 2007 .

[121]  Robert Gurny,et al.  Drug loaded poly(lactic acid) nanoparticles produced by a reversible salting-out process : purification of an injectable dosage form , 1993 .

[122]  Martyn Hill,et al.  Mithramycin encapsulated in polymeric micelles by microfluidic technology as novel therapeutic protocol for beta-thalassemia , 2012, International journal of nanomedicine.

[123]  Ruxandra Gref,et al.  Spontaneous Self-Assembly of Polymeric Nanoparticles in Aqueous Media: New Insights From Microfluidics, In Situ Size Measurements, and Individual Particle Tracking. , 2017, Journal of pharmaceutical sciences.

[124]  L. Lee,et al.  Static micromixer-coaxial electrospray synthesis of theranostic lipoplexes. , 2012, ACS nano.

[125]  Wolfgang Albrecht,et al.  Ultrafiltration and microfiltration membranes in latex purification by diafiltration with suction , 2003 .

[126]  Masahiro Nishikawa,et al.  In Vitro and In Vivo Characterization of Drug Nanoparticles Prepared Using PureNano™ Continuous Crystallizer to Improve the Bioavailability of Poorly Water Soluble Drugs , 2016, Pharmaceutical Research.

[127]  Colin L. Raston,et al.  Nanosized drug formulations under microfluidic continuous flow. , 2011, Lab on a chip.

[128]  Feng Guo,et al.  A rapid pathway toward a superb gene delivery system: programming structural and functional diversity into a supramolecular nanoparticle library. , 2010, ACS nano.

[129]  Vinod P. Shah,et al.  Biopharmaceutics Classification System: The Scientific Basis for Biowaiver Extensions , 2002, Pharmaceutical Research.

[130]  Baoquan Ding,et al.  Tunable Rigidity of (Polymeric Core)–(Lipid Shell) Nanoparticles for Regulated Cellular Uptake , 2015, Advanced materials.

[131]  Bin Li,et al.  Dual-functional lipid-like nanoparticles for delivery of mRNA and MRI contrast agents. , 2017, Nanoscale.

[132]  S. Mitragotri,et al.  Elasticity of nanoparticles influences their blood circulation, phagocytosis, endocytosis, and targeting. , 2015, ACS nano.

[133]  Robert Langer,et al.  Microfluidic platform for controlled synthesis of polymeric nanoparticles. , 2008, Nano letters.

[134]  Robert Langer,et al.  Preclinical Development and Clinical Translation of a PSMA-Targeted Docetaxel Nanoparticle with a Differentiated Pharmacological Profile , 2012, Science Translational Medicine.

[135]  Rod Smallwood,et al.  A comparison of imaging methodologies for 3D tissue engineering , 2010, Microscopy research and technique.

[136]  Jason Riordon,et al.  Microfluidic Synthesis of Photoresponsive Spool-Like Block Copolymer Nanoparticles: Flow-Directed Formation and Light-Triggered Dissociation , 2015 .

[137]  Enza Torino,et al.  A Microfluidic Platform to design crosslinked Hyaluronic Acid Nanoparticles (cHANPs) for enhanced MRI , 2016, Scientific Reports.

[138]  Justin J Cooper-White,et al.  Biopolymer microparticle and nanoparticle formation within a microfluidic device. , 2008, Langmuir : the ACS journal of surfaces and colloids.

[139]  L Biganzoli,et al.  EORTC 10968: a phase I clinical and pharmacokinetic study of polyethylene glycol liposomal doxorubicin (Caelyx, Doxil) at a 6-week interval in patients with metastatic breast cancer. European Organization for Research and Treatment of Cancer. , 2002, Annals of oncology : official journal of the European Society for Medical Oncology.

[140]  Yujun Song,et al.  Microfluidic Synthesis of Nanohybrids. , 2017, Small.

[141]  Warren C W Chan,et al.  Mediating tumor targeting efficiency of nanoparticles through design. , 2009, Nano letters.

[142]  Eric T. Wang,et al.  Barcoded nanoparticles for high throughput in vivo discovery of targeted therapeutics , 2017, Proceedings of the National Academy of Sciences.

[143]  Andreas Zumbusch,et al.  Fluorescent conjugated block copolymer nanoparticles by controlled mixing. , 2012, Chemical communications.

[144]  Hongyuan Jiang,et al.  Large-Scale Single Particle and Cell Trapping based on Rotating Electric Field Induced-Charge Electroosmosis. , 2016, Analytical chemistry.

[145]  M. Uesaka,et al.  Accumulation of sub-100 nm polymeric micelles in poorly permeable tumours depends on size. , 2011, Nature nanotechnology.

[146]  David Sinton,et al.  Flow-directed block copolymer micelle morphologies via microfluidic self-assembly. , 2011, Journal of the American Chemical Society.

[147]  Sebastian Seiffert,et al.  Microfluidic Synthesis of Advanced Microparticles for Encapsulation and Controlled Release{ a Introduction Lab on a Chip , 2022 .

[148]  Rainer H Müller,et al.  Nanocrystal technology, drug delivery and clinical applications , 2008, International journal of nanomedicine.

[149]  R. Adrian,et al.  Transition from laminar to turbulent flow in liquid filled microtubes , 2004 .

[150]  Sang-Hoon Lee,et al.  A 3D alcoholic liver disease model on a chip. , 2016, Integrative biology : quantitative biosciences from nano to macro.

[151]  Sang-Hoon Lee,et al.  Central Nervous System and its Disease Models on a Chip. , 2015, Trends in biotechnology.

[152]  A. Mikos,et al.  Size matters: molecular weight affects the efficiency of poly(ethylenimine) as a gene delivery vehicle. , 1999, Journal of biomedical materials research.

[153]  I. Mezić,et al.  Chaotic Mixer for Microchannels , 2002, Science.

[154]  Dagmar Steinhauser,et al.  Preparation of monodisperse block copolymer vesicles via flow focusing in microfluidics. , 2010, Langmuir : the ACS journal of surfaces and colloids.

[155]  Peter Wick,et al.  Engineered nanomaterial uptake and tissue distribution: from cell to organism , 2013, International journal of nanomedicine.

[156]  Wim E Hennink,et al.  Circulation kinetics and biodistribution of dual-labeled polymersomes with modulated surface charge in tumor-bearing mice: comparison with stealth liposomes. , 2011, Journal of controlled release : official journal of the Controlled Release Society.

[157]  Tza-Huei Wang,et al.  The convergence of quantum-dot-mediated fluorescence resonance energy transfer and microfluidics for monitoring DNA polyplex self-assembly in real time , 2009, Nanotechnology.

[158]  Yue Yu,et al.  A disease model of diabetic nephropathy in a glomerulus-on-a-chip microdevice. , 2017, Lab on a chip.

[159]  Jennifer I. Hare,et al.  Challenges and strategies in anti-cancer nanomedicine development: An industry perspective. , 2017, Advanced drug delivery reviews.

[160]  J. Wulff,et al.  Controlling Structure and Function of Polymeric Drug Delivery Nanoparticles Using Microfluidics. , 2017, Molecular pharmaceutics.

[161]  Moritz Beck-Broichsitter,et al.  Optimized preparation of pDNA/poly(ethylene imine) polyplexes using a microfluidic system. , 2012, Lab on a chip.

[162]  Kevin Braeckmans,et al.  Assessing nanoparticle toxicity in cell-based assays: influence of cell culture parameters and optimized models for bridging the in vitro-in vivo gap. , 2013, Chemical Society reviews.

[163]  Axel Günther,et al.  A microfabricated gas-liquid segmented flow reactor for high-temperature synthesis: the case of CdSe quantum dots. , 2005, Angewandte Chemie.

[164]  Pierre-Alexandre Vidi,et al.  Breast on-a-chip: mimicry of the channeling system of the breast for development of theranostics. , 2011, Integrative biology : quantitative biosciences from nano to macro.

[165]  K. Iyer,et al.  Microfluidic fabrication of cationic curcumin nanoparticles as an anti-cancer agent. , 2012, Nanoscale.

[166]  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.

[167]  Xiaoyang Xu,et al.  Cancer Nanomedicine: From Targeted Delivery to Combination Therapy , 2015, Trends in molecular medicine.

[168]  Thomai Panagiotou,et al.  Production of Norfloxacin Nanosuspensions Using Microfluidics Reaction Technology through Solvent/Antisolvent Crystallization , 2009 .

[169]  Nicolas Anton,et al.  Microfluidic nanoprecipitation systems for preparing pure drug or polymeric drug loaded nanoparticles: an overview , 2016, Expert opinion on drug delivery.

[170]  Hongbo Zhang,et al.  Microfluidic-assisted fabrication of carriers for controlled drug delivery. , 2017, Lab on a chip.

[171]  Mauro Ferrari,et al.  Principles of nanoparticle design for overcoming biological barriers to drug delivery , 2015, Nature Biotechnology.

[172]  Carmen Popescu,et al.  Conversion of Nanosuspensions into Dry Powders by Spray Drying: A Case Study , 2008, Pharmaceutical Research.

[173]  Yi Wang,et al.  Medical devices on chips , 2017, Nature Biomedical Engineering.

[174]  Samir Mitragotri,et al.  Flow and adhesion of drug carriers in blood vessels depend on their shape: a study using model synthetic microvascular networks. , 2010, Journal of controlled release : official journal of the Controlled Release Society.

[175]  Michael P. Brenner,et al.  Production of amorphous nanoparticles by supersonic spray-drying with a microfluidic nebulator , 2015, Science.

[176]  Robert Langer,et al.  Single step reconstitution of multifunctional high-density lipoprotein-derived nanomaterials using microfluidics. , 2013, ACS nano.

[177]  Robert Langer,et al.  Microfluidic system for studying the interaction of nanoparticles and microparticles with cells. , 2005, Analytical chemistry.

[178]  M. Eblan,et al.  Clinical Translation of Nanomedicine. , 2015, Chemical reviews.

[179]  Michael Wirth,et al.  Bionanoprobes to study particle-cell interactions. , 2009, Journal of nanoscience and nanotechnology.

[180]  C. Macosko,et al.  A simple confined impingement jets mixer for flash nanoprecipitation. , 2012, Journal of pharmaceutical sciences.

[181]  Se-Kwon Kim,et al.  Log-scale dose response of inhibitors on a chip. , 2011, Analytical chemistry.

[182]  Christian Holtze,et al.  High throughput production of single core double emulsions in a parallelized microfluidic device. , 2012, Lab on a chip.

[183]  Michael G. Olsen,et al.  Flow Characteristics in a Scaled-up Multi-inlet Vortex Nanoprecipitation Reactor , 2015 .

[184]  Antonello Barresi,et al.  Smart mixers and reactors for the production of pharmaceutical nanoparticles: Proof of concept , 2009 .

[185]  Vincent M. Rotello,et al.  Tuning Payload Delivery in Tumour Cylindroids using Gold Nanoparticles , 2010, Nature nanotechnology.

[186]  Guodong Sui,et al.  Analysis of PM2.5-induced cytotoxicity in human HaCaT cells based on a microfluidic system. , 2017, Toxicology in vitro : an international journal published in association with BIBRA.

[187]  Tae Hyun Yoon,et al.  A new perspective on in vitro assessment method for evaluating quantum dot toxicity by using microfluidics technology. , 2010, Biomicrofluidics.

[188]  Lobat Tayebi,et al.  On-chip synthesis of fine-tuned bone-seeking hybrid nanoparticles. , 2015, Nanomedicine.

[189]  Robert K. Prud'homme,et al.  Chemical Processing and Micromixing in Confined Impinging Jets , 2003 .

[190]  K. Beningo,et al.  Fc-receptor-mediated phagocytosis is regulated by mechanical properties of the target. , 2002, Journal of cell science.

[191]  Martyn Hill,et al.  Mechanism of co-nanoprecipitation of organic actives and block copolymers in a microfluidic environment , 2012, Nanotechnology.

[192]  Teck Chuan Lim,et al.  A microfluidic 3D hepatocyte chip for drug toxicity testing. , 2009, Lab on a chip.

[193]  Robert Langer,et al.  Microfluidic technologies for accelerating the clinical translation of nanoparticles. , 2012, Nature nanotechnology.

[194]  Lei Shao,et al.  Microfluidic Fabrication of Monodispersed Pharmaceutical Colloidal Spheres of Atorvastatin Calcium with Tunable Sizes , 2010 .

[195]  David M. Shaw,et al.  Defining Nano, Nanotechnology and Nanomedicine: Why Should It Matter? , 2016, Sci. Eng. Ethics.

[196]  Monya Baker,et al.  Screening: the age of fishes , 2010, Nature Methods.

[197]  Pei Zhong,et al.  A Microfluidic System with Surface Patterning for Investigating Cavitation Bubble(s)-Cell Interaction and the Resultant Bioeffects at the Single-cell Level. , 2017, Journal of visualized experiments : JoVE.

[198]  Maria Helena Andrade Santana,et al.  Production of hyaluronic acid (HA) nanoparticles by a continuous process inside microchannels: Effects of non-solvents, organic phase flow rate, and HA concentration , 2012 .

[199]  B R Goldspiel,et al.  Paclitaxel (Taxol) , 1994, Pharmacotherapy.

[200]  Yaping Li,et al.  Physicochemical characteristics of nanoparticles affect circulation, biodistribution, cellular internalization, and trafficking. , 2013, Small.

[201]  P. Couvreur Nanoparticles in drug delivery: past, present and future. , 2013, Advanced drug delivery reviews.

[202]  Robert K Prud'homme,et al.  Mechanism for rapid self-assembly of block copolymer nanoparticles. , 2003, Physical review letters.

[203]  Robert Langer,et al.  Microfluidic platform for combinatorial synthesis and optimization of targeted nanoparticles for cancer therapy. , 2013, ACS nano.

[204]  R. Piva,et al.  roduction of polymeric micelles by microfluidic technology for combined drug elivery : Application to osteogenic differentiation of human periodontal igament mesenchymal stem cells ( hPDLSCs ) , 2012 .

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

[206]  Victor Sebastian,et al.  Continuous synthesis of drug-loaded nanoparticles using microchannel emulsification and numerical modeling: effect of passive mixing , 2016, International journal of nanomedicine.

[207]  Leaf Huang,et al.  Nanoparticles evading the reticuloendothelial system: role of the supported bilayer. , 2009, Biochimica et biophysica acta.

[208]  Robert Langer,et al.  Mass production and size control of lipid-polymer hybrid nanoparticles through controlled microvortices. , 2012, Nano letters.

[209]  S. Stainmesse,et al.  Freeze-drying of nanoparticles: formulation, process and storage considerations. , 2006, Advanced drug delivery reviews.

[210]  J. Hong,et al.  New tools and new biology: Recent miniaturized systems for molecular and cellular biology , 2013, Molecules and cells.

[211]  Wei Li,et al.  A Nano‐in‐Nano Vector: Merging the Best of Polymeric Nanoparticles and Drug Nanocrystals , 2017 .

[212]  Jose Luis Santos,et al.  Scalable fabrication of size-controlled chitosan nanoparticles for oral delivery of insulin. , 2017, Biomaterials.

[213]  Rustem F. Ismagilov,et al.  Dynamics of Drosophila embryonic patterning network perturbed in space and time using microfluidics , 2005, Nature.

[214]  Esther Amstad,et al.  Stabilization of the Amorphous Structure of Spray-Dried Drug Nanoparticles. , 2016, The journal of physical chemistry. B.

[215]  Matthew G Moffitt,et al.  Multiscale Control of Hierarchical Structure in Crystalline Block Copolymer Nanoparticles Using Microfluidics. , 2015, Macromolecular rapid communications.

[216]  Lei Shao,et al.  Microfluidic synthesis of amorphous cefuroxime axetil nanoparticles with size-dependent and enhanced dissolution rate , 2010 .