Microfluidics for extracellular vesicle separation and mimetic synthesis: Recent advances and future perspectives

Abstract Extracellular vesicles (EVs) play a critical role in the regulation of various biological processes and pathologies, and have significant utility as potential diagnostic biomarkers and drug delivery systems. That said, conventional methods for EV manipulation and analysis suffer from several drawbacks, including low yield and/or purity, complexity and high cost. For these reasons, there has been growing interest in the development of microfluidic-based tools for fast and efficient EV processing. Herein, we first highlight some of the most interesting recent advances in microfluidic technologies for the separation of EVs, as well as the synthesis of EV mimetics for drug delivery applications. We then discuss the advantages and disadvantages of currently available technologies and provide opinion on some of the most important future challenges and areas of application.

[1]  P. Laktionov,et al.  Isolation of Extracellular Vesicles: General Methodologies and Latest Trends , 2018, BioMed research international.

[2]  Po-Hsun Huang,et al.  Separating extracellular vesicles and lipoproteins via acoustofluidics. , 2019, Lab on a chip.

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

[4]  L. Yobas,et al.  A 'microfluidic pinball' for on-chip generation of Layer-by-Layer polyelectrolyte microcapsules. , 2011, Lab on a chip.

[5]  David W. Greening,et al.  Extracellular vesicles in cancer — implications for future improvements in cancer care , 2018, Nature Reviews Clinical Oncology.

[6]  T. Wurdinger,et al.  Microfluidic isolation and transcriptome analysis of serum microvesicles. , 2010, Lab on a chip.

[7]  J. Lötvall,et al.  Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells , 2007, Nature Cell Biology.

[8]  A. Godwin,et al.  Ultrasensitive detection of circulating exosomes with a 3D-nanopatterned microfluidic chip , 2019, Nature Biomedical Engineering.

[9]  Hakho Lee,et al.  Acoustic purification of extracellular microvesicles. , 2015, ACS nano.

[10]  D. Issadore,et al.  Combining Machine Learning and Nanofluidic Technology To Diagnose Pancreatic Cancer Using Exosomes. , 2017, ACS nano.

[11]  G. Stolovitzky,et al.  Nanoscale lateral displacement arrays for the separation of exosomes and colloids down to 20 nm. , 2016, Nature nanotechnology.

[12]  Bingcheng Lin,et al.  Electrophoretic separations on microfluidic chips , 2007, Journal of Chromatography A.

[13]  Wyatt N Vreeland,et al.  Controlled vesicle self-assembly in microfluidic channels with hydrodynamic focusing. , 2004, Journal of the American Chemical Society.

[14]  S. Gordon,et al.  Circulating microRNAs as Potential Biomarkers of Infectious Disease , 2017, Front. Immunol..

[15]  G. Stolovitzky,et al.  Integrated nanoscale deterministic lateral displacement arrays for separation of extracellular vesicles from clinically-relevant volumes of biological samples. , 2018, Lab on a chip.

[16]  Jacco van Rheenen,et al.  In Vivo Imaging Reveals Extracellular Vesicle-Mediated Phenocopying of Metastatic Behavior , 2015, Cell.

[17]  Jiashu Sun,et al.  λ-DNA- and Aptamer-Mediated Sorting and Analysis of Extracellular Vesicles. , 2019, Journal of the American Chemical Society.

[18]  Molly M Stevens,et al.  Cell-derived vesicles for drug therapy and diagnostics: opportunities and challenges. , 2015, Nano today.

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

[20]  R. Cerione,et al.  Microfluidic isolation of cancer-cell-derived microvesicles from hetergeneous extracellular shed vesicle populations , 2014, Biomedical Microdevices.

[21]  Jaesung Park,et al.  Generation of nanovesicles with sliced cellular membrane fragments for exogenous material delivery. , 2015, Biomaterials.

[22]  S. Gabrielsson,et al.  Altered microRNA profiles in bronchoalveolar lavage fluid exosomes in asthmatic patients. , 2013, The Journal of allergy and clinical immunology.

[23]  Hakho Lee,et al.  Label-free detection and molecular profiling of exosomes with a nano-plasmonic sensor , 2014, Nature Biotechnology.

[24]  Fredrik Westerlund,et al.  A nano flow cytometer for single lipid vesicle analysis. , 2017, Lab on a chip.

[25]  D. J. Harrison,et al.  Planar chips technology for miniaturization and integration of separation techniques into monitoring systems. Capillary electrophoresis on a chip , 1992 .

[26]  Utkan Demirci,et al.  An integrated double-filtration microfluidic device for isolation, enrichment and quantification of urinary extracellular vesicles for detection of bladder cancer , 2017, Scientific Reports.

[27]  James P K Armstrong,et al.  Re-Engineering Extracellular Vesicles as Smart Nanoscale Therapeutics. , 2017, ACS nano.

[28]  Biana Godin,et al.  Ciliated micropillars for the microfluidic-based isolation of nanoscale lipid vesicles. , 2013, Lab on a chip.

[29]  B. Ye,et al.  Magnetic-Based Microfluidic Device for On-Chip Isolation and Detection of Tumor-Derived Exosomes. , 2018, Analytical chemistry.

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

[31]  D. Lyden,et al.  Asymmetric-flow field-flow fractionation technology for exomere and small extracellular vesicle separation and characterization , 2019, Nature Protocols.

[32]  M. Matsumoto,et al.  Decreased miR-26a Expression Correlates with the Progression of Podocyte Injury in Autoimmune Glomerulonephritis , 2014, PloS one.

[33]  G. Angelini,et al.  Human Pericardial Fluid Contains Exosomes Enriched with Cardiovascular-Expressed MicroRNAs and Promotes Therapeutic Angiogenesis , 2017, Molecular therapy : the journal of the American Society of Gene Therapy.

[34]  J. Lötvall,et al.  Detailed analysis of the plasma extracellular vesicle proteome after separation from lipoproteins , 2018, Cellular and Molecular Life Sciences.

[35]  J. Sturm,et al.  Continuous Particle Separation Through Deterministic Lateral Displacement , 2004, Science.

[36]  T. Huang,et al.  Acoustofluidic Synthesis of Particulate Nanomaterials , 2019, Advanced science.

[37]  Ismail Hafez,et al.  Bottom-up design and synthesis of limit size lipid nanoparticle systems with aqueous and triglyceride cores using millisecond microfluidic mixing. , 2012, Langmuir : the ACS journal of surfaces and colloids.

[38]  Yoichiroh Hosokawa,et al.  Focusing of sub-micrometer particles in microfluidic devices. , 2019, Lab on a chip.

[39]  Hung-Jen Wu,et al.  Microfluidics for exosome isolation and analysis: enabling liquid biopsy for personalized medicine. , 2017, Lab on a chip.

[40]  Manabu Tokeshi,et al.  Development of the iLiNP Device: Fine Tuning the Lipid Nanoparticle Size within 10 nm for Drug Delivery , 2018, ACS omega.

[41]  M. Toner,et al.  Nanoporous micro-element arrays for particle interception in microfluidic cell separation. , 2012, Lab on a chip.

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

[43]  Jaesung Park,et al.  Isolation of extracellular vesicle from blood plasma using electrophoretic migration through porous membrane , 2016 .

[44]  A. deMello,et al.  Oscillatory Viscoelastic Microfluidics for Efficient Focusing and Separation of Nanoscale Species. , 2019, ACS nano.

[45]  D. DeVoe,et al.  High Throughput Nanoliposome Formation Using 3D Printed Microfluidic Flow Focusing Chips , 2019, Advanced Materials Technologies.

[46]  Graça Raposo,et al.  Shedding light on the cell biology of extracellular vesicles , 2018, Nature Reviews Molecular Cell Biology.

[47]  Bob S. Carter,et al.  Rapid Isolation and Detection of Exosomes and Associated Biomarkers from Plasma. , 2017, ACS nano.

[48]  Yuanjin Zhao,et al.  Biodegradable core-shell carriers for simultaneous encapsulation of synergistic actives. , 2013, Journal of the American Chemical Society.

[49]  C. Kahn,et al.  Extracellular miRNAs: From Biomarkers to Mediators of Physiology and Disease. , 2019, Cell metabolism.

[50]  Guoqing Hu,et al.  Field-Free Isolation of Exosomes from Extracellular Vesicles by Microfluidic Viscoelastic Flows. , 2017, ACS nano.

[51]  Raghu Kalluri,et al.  The biology, function, and biomedical applications of exosomes , 2020, Science.

[52]  Gaurav Sahay,et al.  Rapid discovery of potent siRNA-containing lipid nanoparticles enabled by controlled microfluidic formulation. , 2012, Journal of the American Chemical Society.

[53]  M. Baudoin,et al.  Acoustic Tweezers for Particle and Fluid Micromanipulation , 2020, Annual Review of Fluid Mechanics.

[54]  Guoqing Hu,et al.  Particle manipulations in non-Newtonian microfluidics: A review. , 2017, Journal of colloid and interface science.

[55]  Jesse V Jokerst,et al.  The Exosome Total Isolation Chip. , 2017, ACS nano.

[56]  Jaesung Park,et al.  Microfluidic fabrication of cell-derived nanovesicles as endogenous RNA carriers. , 2014, Lab on a chip.

[57]  Michael J Heller,et al.  Integrated Analysis of Exosomal Protein Biomarkers on Alternating Current Electrokinetic Chips Enables Rapid Detection of Pancreatic Cancer in Patient Blood. , 2018, ACS nano.

[58]  Diane M Simeone,et al.  Microfluidic device (ExoChip) for on-chip isolation, quantification and characterization of circulating exosomes. , 2014, Lab on a chip.

[59]  Peng Zhang,et al.  Ultrasensitive microfluidic analysis of circulating exosomes using a nanostructured graphene oxide/polydopamine coating. , 2016, Lab on a chip.

[60]  Bob S. Carter,et al.  Chip-based analysis of exosomal mRNA mediating drug resistance in glioblastoma , 2015, Nature Communications.

[61]  Dongqing Li,et al.  Separation of nanoparticles by a nano-orifice based DC-dielectrophoresis method in a pressure-driven flow. , 2016, Nanoscale.

[62]  Tae-Hyeong Kim,et al.  Exodisc for Rapid, Size-Selective, and Efficient Isolation and Analysis of Nanoscale Extracellular Vesicles from Biological Samples. , 2017, ACS nano.

[63]  Jaesung Park,et al.  Microfluidic filtration system to isolate extracellular vesicles from blood. , 2012, Lab on a chip.

[64]  Qingming Shen,et al.  Highly Sensitive Electrochemical Detection of Tumor Exosomes Based on Aptamer Recognition-Induced Multi-DNA Release and Cyclic Enzymatic Amplification. , 2018, Analytical chemistry.

[65]  J. Khandurina,et al.  Bioanalysis in microfluidic devices. , 2002, Journal of chromatography. A.

[66]  P. Neužil,et al.  DEP-on-a-Chip: Dielectrophoresis Applied to Microfluidic Platforms , 2019, Micromachines.

[67]  Subra Suresh,et al.  Isolation of exosomes from whole blood by integrating acoustics and microfluidics , 2017, Proceedings of the National Academy of Sciences.

[68]  Young-Ho Cho,et al.  High-purity capture and release of circulating exosomes using an exosome-specific dual-patterned immunofiltration (ExoDIF) device. , 2017, Nanoscale.

[69]  Shang-Chun Guo,et al.  Microfluidics-based on-a-chip systems for isolating and analysing extracellular vesicles , 2018, Journal of extracellular vesicles.