Research Strategies for Precise Manipulation of Micro/Nanoparticle Drug Delivery Systems Using Microfluidic Technology: A Review

 

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Abstract

Microfluidic technology facilitates precise control over fluid mixing and interactions between the components, including self-assembly and precipitation. It offers new options for accurately manufacturing particles and holds significant potential in advancing micro/nanoparticle drug delivery systems (DDSs). Various microchannel/microfluidic chips have been explored to construct micro/nanoparticle DDSs. The precise manipulation of particle size, morphology, structure, stiffness, surface characteristics, and elasticity through microfluidic technology relies on specific microchannel geometrical designs and the application of exogenous energy, adhering to the principles of fluid motion. Consequently, this enables reproducible control over critical quality attributes (CQAs), such as particle size and distribution, encapsulation efficiency, drug loading, in vitro and in vivo drug delivery profiles, Zeta potential, and targeting capabilities, for micro/nanoparticle DDSs. In this review, we categorize microfluidic techniques and explore recent research developments in novel microchannel structures spanning the past 5 years (2018–2023) and their applications in micro/nanoparticle DDSs. Additionally, we elucidate the latest manipulation strategies of microfluidic techniques that impact foundational structures related to the CQAs of micro/nanoparticle DDSs. Furthermore, we offer insights into the industrial applications and challenges microfluidic techniques face in the context of novel micro/nanoparticle DDSs.

Publication History

Received: 10 September 2023

Accepted: 02 April 2024

Article published online:
23 May 2024

© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

• Reference

• 1 Ramezankhani R, Solhi R, Chai YC, Vosough M, Verfaillie C. Organoid and microfluidics-based platforms for drug screening in COVID-19. Drug Discov Today 2022; 27 (04) 1062-1076
  CrossrefPubMedGoogle Scholar
• 2 Maurya R, Gohil N, Bhattacharjee G, Alzahrani KJ, Ramakrishna S, Singh V. Microfluidics device for drug discovery, screening and delivery. Prog Mol Biol Transl Sci 2022; 187 (01) 335-346
  CrossrefPubMedGoogle Scholar
• 3 Fabozzi A, Della Sala F, di Gennaro M. et al. Design of functional nanoparticles by microfluidic platforms as advanced drug delivery systems for cancer therapy. Lab Chip 2023; 23 (05) 1389-1409
  CrossrefPubMedGoogle Scholar
• 4 Kashaninejad N, Moradi E, Moghadas H. Micro/nanofluidic devices for drug delivery. Prog Mol Biol Transl Sci 2022; 187 (01) 9-39
  CrossrefPubMedGoogle Scholar
• 5 Mitchell MJ, Billingsley MM, Haley RM, Wechsler ME, Peppas NA, Langer R. Engineering precision nanoparticles for drug delivery. Nat Rev Drug Discov 2021; 20 (02) 101-124
  CrossrefPubMedGoogle Scholar
• 6 Maged A, Abdelbaset R, Mahmoud AA, Elkasabgy NA. Merits and advances of microfluidics in the pharmaceutical field: design technologies and future prospects. Drug Deliv 2022; 29 (01) 1549-1570
  CrossrefPubMedGoogle Scholar
• 7 Maeki M, Uno S, Niwa A, Okada Y, Tokeshi M. Microfluidic technologies and devices for lipid nanoparticle-based RNA delivery. J Control Release 2022; 344: 80-96
  CrossrefPubMedGoogle Scholar
• 8 Liu Y, Yang G, Hui Y, Ranaweera S, Zhao CX. Microfluidic nanoparticles for drug delivery. Small 2022; 18 (36) e2106580
  CrossrefPubMedGoogle Scholar
• 9 Zimmermann R, Leal BBJ, Braghirolli DI, Pranke P. Production of nanostructured systems: main and innovative techniques. Drug Discov Today 2023; 28 (02) 103454
  CrossrefPubMedGoogle Scholar
• 10 Torkay G, Oeztuerk AB. A stem cell and tissue engineering perspective on microfluidic chips. J Polytechnic 2024; ; published online ahead of print on March, 2024. DOI: 10.2339/politeknik.1094010.
  CrossrefGoogle Scholar
• 11 Kopp MRG, Linsenmeier M, Hettich B. et al. microfluidic shrinking droplet concentrator for analyte detection and phase separation of protein solutions. Anal Chem 2020; 92 (08) 5803-5812
  CrossrefPubMedGoogle Scholar
• 12 Utharala R, Tseng Q, Furlong EEM, Merten CAA. A versatile, low-cost, multiway microfluidic sorter for droplets, cells, and embryos. Anal Chem 2018; 90 (10) 5982-5988
  CrossrefPubMedGoogle Scholar
• 13 Yu F, Choudhury D. Microfluidic bioprinting for organ-on-a-chip models. Drug Discov Today 2019; 24 (06) 1248-1257
  CrossrefPubMedGoogle Scholar
• 14 Wu H, Shi S, Liu Y. et al. Recent progress of organ-on-a-chip towards cardiovascular diseases: advanced design, fabrication, and applications. Biofabrication 2023; 15 (04) 042001
  Google Scholar
• 15 Marre S, Jensen KF. Synthesis of micro and nanostructures in microfluidic systems. Chem Soc Rev 2010; 39 (03) 1183-1202
  CrossrefPubMedGoogle Scholar
• 16 Yaghmur A, Ghazal A, Ghazal R, Dimaki M, Svendsen WE. A hydrodynamic flow focusing microfluidic device for the continuous production of hexosomes based on docosahexaenoic acid monoglyceride. Phys Chem Chem Phys 2019; 21 (24) 13005-13013
  CrossrefPubMedGoogle Scholar
• 17 Zhang L, Chen Q, Ma Y, Sun J. Microfluidic methods for fabrication and engineering of nanoparticle drug delivery systems. ACS Appl Bio Mater 2020; 3 (01) 107-120
  CrossrefPubMedGoogle Scholar
• 18 Shah S, Dhawan V, Holm R, Nagarsenker MS, Perrie Y. Liposomes: advancements and innovation in the manufacturing process. Adv Drug Deliv Rev 2020; 154–155: 102-122
  CrossrefPubMedGoogle Scholar
• 19 Aboelela SS, Ibrahim M, Badruddoza AZM, Tran V, Ferri JK, Roper TD. Encapsulation of a highly hydrophilic drug in polymeric particles: a comparative study of batch and microfluidic processes. Int J Pharm 2021; 606: 120906
  CrossrefPubMedGoogle Scholar
• 20 Chung MT, Kurabayashi K, Cai D. Single-cell RT-LAMP mRNA detection by integrated droplet sorting and merging. Lab Chip 2019; 19 (14) 2425-2434
  CrossrefPubMedGoogle Scholar
• 21 Shrimal P, Jadeja G, Patel S. A review on novel methodologies for drug nanoparticle preparation: microfluidic approach. Chem Eng Res Des 2020; 153: 728-756
  CrossrefGoogle Scholar
• 22 Abstiens K, Goepferich AM. Microfluidic manufacturing improves polydispersity of multicomponent polymeric nanoparticles. J Drug Deliv Sci Technol 2019; 49: 433-439
  CrossrefGoogle Scholar
• 23 Amoyav B, Benny O. Controlled and tunable polymer particles' production using a single microfluidic device. Appl Nanosci 2018; 8 (04) 905-914
  CrossrefGoogle Scholar
• 24 Yuan Z, Liu J, Yang Y, He J. Recent advances and application prospects of microfluidic technology for preparation of nanoformulations [in Chinese]. Zhongguo Yiyao Gongye Zazhi 2021; 52 (04) 440-450
  Google Scholar
• 25 Valencia PM, Farokhzad OC, Karnik R, Langer R. Microfluidic technologies for accelerating the clinical translation of nanoparticles. Nat Nanotechnol 2012; 7 (10) 623-629
  CrossrefPubMedGoogle Scholar
• 26 Ding Y, Howes PD, deMello AJ. Recent advances in droplet microfluidics. Anal Chem 2020; 92 (01) 132-149
  CrossrefPubMedGoogle Scholar
• 27 Tian F, Cai L, Liu C, Sun J. Microfluidic technologies for nanoparticle formation. Lab Chip 2022; 22 (03) 512-529
  CrossrefPubMedGoogle Scholar
• 28 Carvalho BG, Ceccato BT, Michelon M, Han SW, de la Torre LG. Advanced microfluidic technologies for lipid nano-microsystems from synthesis to biological application. Pharmaceutics 2022; 14 (01) 141
  CrossrefPubMedGoogle Scholar
• 29 Gonidec M, Puigmartí-Luis J. Continuous- versus segmented-flow microfluidic synthesis in materials science. Crystals (Basel) 2018; 9 (01) 12
  CrossrefGoogle Scholar
• 30 Bayareh M, Ashani MN, Usefian A. Active and passive micromixers: a comprehensive review. Chem Eng Process 2020; 147: 107771
  CrossrefGoogle Scholar
• 31 An Le NH, Deng H, Devendran C. et al. Ultrafast star-shaped acoustic micromixer for high throughput nanoparticle synthesis. Lab Chip 2020; 20 (03) 582-591
  CrossrefPubMedGoogle Scholar
• 32 Liu C, Zhang W, Li Y. et al. Microfluidic sonication to assemble exosome membrane-coated nanoparticles for immune evasion-mediated targeting. Nano Lett 2019; 19 (11) 7836-7844
  CrossrefPubMedGoogle Scholar
• 33 Shrimal P, Jadeja G, Patel S. Ultrasonic enhanced emulsification process in 3D printed microfluidic device to encapsulate active pharmaceutical ingredients. Int J Pharm 2022; 620: 121754
  CrossrefPubMedGoogle Scholar
• 34 Huang PH, Zhao S, Bachman H. et al. Acoustofluidic synthesis of particulate nanomaterials. Adv Sci (Weinh) 2019; 6 (19) 1900913
  CrossrefPubMedGoogle Scholar
• 35 Le NHA, Van Phan H, Yu J, Chan HK, Neild A, Alan T. Acoustically enhanced microfluidic mixer to synthesize highly uniform nanodrugs without the addition of stabilizers. Int J Nanomedicine 2018; 13: 1353-1359
  CrossrefPubMedGoogle Scholar
• 36 Pourabed A, Brenker J, Younas T, He L, Alan T. A Lotus shaped acoustofluidic mixer: high throughput homogenisation of liquids in 2 ms using hydrodynamically coupled resonators. Ultrason Sonochem 2022; 83: 105936
  CrossrefPubMedGoogle Scholar
• 37 Endaylalu SA, Tien WH. A numerical investigation of the mixing performance in a Y-junction microchannel induced by acoustic streaming. Micromachines (Basel) 2022; 13 (02) 338
  CrossrefPubMedGoogle Scholar
• 38 Pourabed A, Younas T, Liu C, Shanbhag BK, He L, Alan T. High throughput acoustic microfluidic mixer controls self-assembly of protein nanoparticles with tuneable sizes. J Colloid Interface Sci 2021; 585: 229-236
  CrossrefPubMedGoogle Scholar
• 39 Bolze H, Riewe J, Bunjes H, Dietzel A, Burg TP. Continuous production of lipid nanoparticles by ultrasound-assisted microfluidic antisolvent precipitation. Chem Eng Technol 2021; 44 (09) 1641-1650
  CrossrefGoogle Scholar
• 40 Rao L, Cai B, Bu LL. et al. Microfluidic electroporation-facilitated synthesis of erythrocyte membrane-coated magnetic nanoparticles for enhanced imaging-guided cancer therapy. ACS Nano 2017; 11 (04) 3496-3505
  CrossrefPubMedGoogle Scholar
• 41 Hou L, Ren Y, Jia Y. et al. Continuously electrotriggered core coalescence of double-emulsion drops for microreactions. ACS Appl Mater Interfaces 2017; 9 (14) 12282-12289
  CrossrefPubMedGoogle Scholar
• 42 Zeng W, Guo P, Jiang P, Liu W, Hong T, Chen C. Combination of microfluidic chip and electrostatic atomization for the preparation of drug-loaded core-shell nanoparticles. Nanotechnology 2020; 31 (14) 145301
  CrossrefPubMedGoogle Scholar
• 43 Al-Hetlani E, Amin MO. Continuous magnetic droplets and microfluidics: generation, manipulation, synthesis and detection. Mikrochim Acta 2019; 186 (02) 55
  CrossrefPubMedGoogle Scholar
• 44 Kahkeshani S, Di Carlo D. Drop formation using ferrofluids driven magnetically in a step emulsification device. Lab Chip 2016; 16 (13) 2474-2480
  CrossrefPubMedGoogle Scholar
• 45 Choi YH, Hwang JS, Han SH, Lee CS, Jeon SJ, Kim SH. Thermo-responsive microcapsules with tunable molecular permeability for controlled encapsulation and release. Adv Funct Mater 2021; 31 (24) 2100782
  CrossrefGoogle Scholar
• 46 Paulsen KS, Deng Y, Chung AJ. DIY 3D microparticle generation from next generation optofluidic fabrication. Adv Sci (Weinh) 2018; 5 (07) 1800252
  CrossrefPubMedGoogle Scholar
• 47 Liu Z, Yang M, Yao W, Wang T, Chen G. Microfluidic ultrasonic cavitation enables versatile and scalable synthesis of monodisperse nanoparticles for biomedical application. Chem Eng Sci 2023; 280: 119052
  CrossrefGoogle Scholar
• 48 Kotnik T, Rems L, Tarek M, Miklavčič D. Membrane electroporation and electropermeabilization: mechanisms and models. Annu Rev Biophys 2019; 48: 63-91
  CrossrefPubMedGoogle Scholar
• 49 Lin L, Wang M, Peng X. et al. Opto-thermoelectric nanotweezers. Nat Photonics 2018; 12 (04) 195-201
  CrossrefPubMedGoogle Scholar
• 50 Tian F, Han Z, Deng J, Liu C, Sun J. Thermomicrofluidics for biosensing applications. VIEW 2021; 2: 20200148
  CrossrefGoogle Scholar
• 51 de Hemptinne A, Gelin P, Ziemecka I, De Malsche W. Microfluidic device for multilayer coating of magnetic microparticles. Powder Technol 2023; 416: 118223
  CrossrefGoogle Scholar
• 52 Zheng H, Zhao C, Lu Y. et al. Celastrol-encapsulated microspheres prepared by microfluidic electrospray for alleviating inflammatory pain. Biomater Adv 2023; 149: 213398
  CrossrefPubMedGoogle Scholar
• 53 Siavashy S, Soltani M, Ghorbani-Bidkorbeh F. et al. Microfluidic platform for synthesis and optimization of chitosan-coated magnetic nanoparticles in cisplatin delivery. Carbohydr Polym 2021; 265: 118027
  CrossrefPubMedGoogle Scholar
• 54 Shepherd SJ, Issadore D, Mitchell MJ. Microfluidic formulation of nanoparticles for biomedical applications. Biomaterials 2021; 274: 120826
  CrossrefPubMedGoogle Scholar
• 55 Yang AS, Chuang FC, Chen CK. et al. A high-performance micromixer using three-dimensional Tesla structures for bio-applications. Chem Eng J 2015; 263: 444-451
  CrossrefGoogle Scholar
• 56 Desai D, Guerrero YA, Balachandran V. et al. Towards a microfluidics platform for the continuous manufacture of organic and inorganic nanoparticles. Nanomedicine 2021; 35: 102402
  CrossrefPubMedGoogle Scholar
• 57 Webb C, Forbes N, Roces CB. et al. Using microfluidics for scalable manufacturing of nanomedicines from bench to GMP: a case study using protein-loaded liposomes. Int J Pharm 2020; 582: 119266
  CrossrefPubMedGoogle Scholar
• 58 Ma Z, Tong H, Lin S. et al. Scalable synthesis of lipid nanoparticles for nucleic acid drug delivery using an isometric channel-size enlarging strategy. Nano Res 2023; 17 (04) 2899-2907
  CrossrefGoogle Scholar
• 59 Stroock AD, Dertinger SK, Ajdari A, Mezic I, Stone HA, Whitesides GM. Chaotic mixer for microchannels. Science 2002; 295 (5555): 647-651
  CrossrefPubMedGoogle Scholar
• 60 Cheung CCL, Al-Jamal WT. Sterically stabilized liposomes production using staggered herringbone micromixer: effect of lipid composition and PEG-lipid content. Int J Pharm 2019; 566: 687-696
  CrossrefPubMedGoogle Scholar
• 61 Forbes N, Hussain MT, Briuglia ML. et al. Rapid and scale-independent microfluidic manufacture of liposomes entrapping protein incorporating in-line purification and at-line size monitoring. Int J Pharm 2019; 556: 68-81
  CrossrefPubMedGoogle Scholar
• 62 Roces CB, Lou G, Jain N. et al. Manufacturing considerations for the development of lipid nanoparticles using microfluidics. Pharmaceutics 2020; 12 (11) 1095
  CrossrefPubMedGoogle Scholar
• 63 Sago CD, Lokugamage MP, Paunovska K. et al. High-throughput in vivo screen of functional mRNA delivery identifies nanoparticles for endothelial cell gene editing. Proc Natl Acad Sci U S A 2018; 115 (42) E9944-E9952
  PubMedGoogle Scholar
• 64 Lou G, Anderluzzi G, Schmidt ST. et al. Delivery of self-amplifying mRNA vaccines by cationic lipid nanoparticles: the impact of cationic lipid selection. J Control Release 2020; 325: 370-379
  CrossrefPubMedGoogle Scholar
• 65 Evers MJW, Kulkarni JA, van der Meel R, Cullis PR, Vader P, Schiffelers RM. State-of-the-art design and rapid-mixing production techniques of lipid nanoparticles for nucleic acid delivery. Small Methods 2018; 2: 1700375
  CrossrefGoogle Scholar
• 66 Dimov N, Kastner E, Hussain M, Perrie Y, Szita N. Formation and purification of tailored liposomes for drug delivery using a module-based micro continuous-flow system. Sci Rep 2017; 7 (01) 12045
  CrossrefPubMedGoogle Scholar
• 67 Hamano N, Böttger R, Lee SE. et al. Robust microfluidic technology and new lipid composition for fabrication of curcumin-loaded liposomes: effect on the anticancer activity and safety of cisplatin. Mol Pharm 2019; 16 (09) 3957-3967
  CrossrefPubMedGoogle Scholar
• 68 Shah VM, Nguyen DX, Patel P. et al. Liposomes produced by microfluidics and extrusion: a comparison for scale-up purposes. Nanomedicine 2019; 18: 146-156
  CrossrefPubMedGoogle Scholar
• 69 Hussain MT, Tiboni M, Perrie Y, Casettari L. Microfluidic production of protein loaded chimeric stealth liposomes. Int J Pharm 2020; 590: 119955
  CrossrefPubMedGoogle Scholar
• 70 Molinaro R, Evangelopoulos M, Hoffman JR. et al. Design and development of biomimetic nanovesicles using a microfluidic approach. Adv Mater 2018; 30 (15) e1702749
  CrossrefPubMedGoogle Scholar
• 71 Morikawa Y, Tagami T, Hoshikawa A, Ozeki T. The use of an efficient microfluidic mixing system for generating stabilized polymeric nanoparticles for controlled drug release. Biol Pharm Bull 2018; 41 (06) 899-907
  CrossrefPubMedGoogle Scholar
• 72 Leung AWY, Amador C, Wang LC, Mody UV, Bally MB. What drives innovation: the Canadian touch on liposomal therapeutics. Pharmaceutics 2019; 11 (03) 124
  CrossrefPubMedGoogle Scholar
• 73 Van de Vyver T, Bogaert B, De Backer L. et al. Cationic amphiphilic drugs boost the lysosomal escape of small nucleic acid therapeutics in a nanocarrier-dependent manner. ACS Nano 2020; 14 (04) 4774-4791
  CrossrefPubMedGoogle Scholar
• 74 Vogler J, Böttger R, Al Fayez N. et al. Altering the intra-liver distribution of phospholipid-free small unilamellar vesicles using temperature-dependent size-tunability. J Control Release 2021; 333: 151-161
  CrossrefPubMedGoogle Scholar
• 75 Vu HTH, Streck S, Hook SM, McDowell A. Utilization of microfluidics for the preparation of polymeric nanoparticles for the antioxidant rutin: a comparison with bulk production. Pharm Nanotechnol 2019; 7 (06) 469-483
  CrossrefPubMedGoogle Scholar
• 76 Hama B, Mahajan G, Fodor PS, Kaufman M, Kothapalli CR. Evolution of mixing in a microfluidic reverse-staggered herringbone micromixer. Microfluid Nanofluidics 2018; 22: 54
  CrossrefGoogle Scholar
• 77 Kimura N, Maeki M, Sato Y. et al. Development of the iLiNP device: fine tuning the lipid nanoparticle size within 10 nm for drug delivery. ACS Omega 2018; 3 (05) 5044-5051
  CrossrefPubMedGoogle Scholar
• 78 Kimura N, Maeki M, Sato Y. et al. Development of a microfluidic-based post-treatment process for size-controlled lipid nanoparticles and application to siRNA delivery. ACS Appl Mater Interfaces 2020; 12 (30) 34011-34020
  CrossrefPubMedGoogle Scholar
• 79 Kimura N, Maeki M, Ishida A, Tani H, Tokeshi M. One-step production using a microfluidic device of highly biocompatible size-controlled noncationic exosome-like nanoparticles for RNA delivery. ACS Appl Bio Mater 2021; 4 (02) 1783-1793
  CrossrefPubMedGoogle Scholar
• 80 Kimura N, Maeki M, Sasaki K. et al. Three-dimensional, symmetrically assembled microfluidic device for lipid nanoparticle production. RSC Advances 2021; 11 (03) 1430-1439
  CrossrefPubMedGoogle Scholar
• 81 Suzuki Y, Onuma H, Sato R. et al. Lipid nanoparticles loaded with ribonucleoprotein-oligonucleotide complexes synthesized using a microfluidic device exhibit robust genome editing and hepatitis B virus inhibition. J Control Release 2021; 330: 61-71
  CrossrefPubMedGoogle Scholar
• 82 Matsuura-Sawada Y, Maeki M, Nishioka T. et al. Microfluidic device-enabled mass production of lipid-based nanoparticles for applications in nanomedicine and cosmetics. ACS Appl Nano Mater 2022; 5 (06) 7867-7876
  CrossrefGoogle Scholar
• 83 Maeki M, Okada Y, Uno S. et al. Mass production system for RNA-loaded lipid nanoparticles using piling up microfluidic devices. Appl Mater Today 2023; 31: 101754
  CrossrefGoogle Scholar
• 84 Matsuura-Sawada Y, Maeki M, Uno S, Wada K, Tokeshi M. Controlling lamellarity and physicochemical properties of liposomes prepared using a microfluidic device. Biomater Sci 2023; 11 (07) 2419-2426
  CrossrefPubMedGoogle Scholar
• 85 Wang J, Wang C, Wang Q. et al. Microfluidic preparation of gelatin methacryloyl microgels as local drug delivery vehicles for hearing loss therapy. ACS Appl Mater Interfaces 2022; 14 (41) 46212-46223
  CrossrefPubMedGoogle Scholar
• 86 Zhong J, Zhang Q, Kuang G, Xia J, Shang L. Multicomponent microspheres with spatiotemporal drug release for post-surgical liver cancer treatment and liver regeneration. Chem Eng J 2023; 455: 140585
  CrossrefGoogle Scholar
• 87 Hu H, Yang C, Li M, Shao D, Mao HQ, Leong KW. Flash technology-based self-assembly in nanoformulation: fabrication to biomedical applications. Mater Today 2021; 42: 99-116
  CrossrefPubMedGoogle Scholar
• 88 Bovone G, Guzzi EA, Tibbitt MW. Flow-based reactor design for the continuous production of polymeric nanoparticles. AIChE J 2019; 65 (12) e16840
  CrossrefGoogle Scholar
• 89 Lim JM, Swami A, Gilson LM. et al. Ultra-high throughput synthesis of nanoparticles with homogeneous size distribution using a coaxial turbulent jet mixer. ACS Nano 2014; 8 (06) 6056-6065
  CrossrefPubMedGoogle Scholar
• 90 Markwalter CE, Prud'homme RK. Design of a small-scale multi-inlet vortex mixer for scalable nanoparticle production and application to the encapsulation of biologics by inverse flash nanoprecipitation. J Pharm Sci 2018; 107 (09) 2465-2471
  CrossrefPubMedGoogle Scholar
• 91 Di D, Qu X, Liu C, Fang L, Quan P. Continuous production of celecoxib nanoparticles using a three-dimensional-coaxial-flow microfluidic platform. Int J Pharm 2019; 572: 118831
  CrossrefPubMedGoogle Scholar
• 92 Tomeh MA, Mansor MH, Hadianamrei R, Sun W, Zhao X. Optimization of large-scale manufacturing of biopolymeric and lipid nanoparticles using microfluidic swirl mixers. Int J Pharm 2022; 620: 121762-121762
  CrossrefPubMedGoogle Scholar
• 93 Xu R, Tomeh MA, Ye S. et al. Novel microfluidic swirl mixers for scalable formulation of curcumin loaded liposomes for cancer therapy. Int J Pharm 2022; 622: 121857
  CrossrefPubMedGoogle Scholar
• 94 (LumTech) LTL. Homepage. Accessed April 5, 2024 at: http://www.lumtech.com.cn
• 95 Han T, Zhang L, Xu H, Xuan J. Factory-on-chip: modularised microfluidic reactors for continuous mass production of functional materials. Chem Eng J 2017; 326: 765-773
  CrossrefGoogle Scholar
• 96 Jeong HH, Issadore D, Lee D. Recent developments in scale-up of microfluidic emulsion generation via parallelization. Korean J Chem Eng 2016; 33 (06) 1757-1766
  CrossrefGoogle Scholar
• 97 DeMello AJ. Control and detection of chemical reactions in microfluidic systems. Nature 2006; 442 (7101): 394-402
  CrossrefPubMedGoogle Scholar
• 98 Karnik R, Gu FX, Basto P. et al. Microfluidic synthesis of organic nanoparticles. U.S. Patent 9381477. July, 2016
  PubMed
• 99 Carugo D, Bottaro E, Owen J, Stride E, Nastruzzi C. Liposome production by microfluidics: potential and limiting factors. Sci Rep 2016; 6: 25876
  CrossrefPubMedGoogle Scholar
• 100 Lim JM, Bertrand N, Valencia PM. et al. Parallel microfluidic synthesis of size-tunable polymeric nanoparticles using 3D flow focusing towards in vivo study. Nanomedicine 2014; 10 (02) 401-409
  CrossrefPubMedGoogle Scholar
• 101 Min KI, Im DJ, Lee HJ, Kim DP. Three-dimensional flash flow microreactor for scale-up production of monodisperse PEG-PLGA nanoparticles. Lab Chip 2014; 14 (20) 3987-3992
  CrossrefPubMedGoogle Scholar
• 102 Shepherd SJ, Warzecha CC, Yadavali S. et al. Scalable mRNA and siRNA lipid nanoparticle production using a parallelized microfluidic device. Nano Lett 2021; 21 (13) 5671-5680
  CrossrefPubMedGoogle Scholar
• 103 Okada Y, Maeki M, Sato Y. et al . Development of an integrated glass-based microfluidic system for mass production of RNA-loaded lipid nanoparticles. Paper presented at: 25th International Conference on Miniaturized Systems for Chemistry and life Sciences; October 10-14, 2021; CA, US
• 104 Belliveau NM, Huft J, Lin PJ. et al. Microfluidic synthesis of highly potent limit-size lipid nanoparticles for in vivo delivery of siRNA. Mol Ther Nucleic Acids 2012; 1 (08) e37
  CrossrefPubMedGoogle Scholar
• 105 Ou Z, Zhang Q, Hu S, Dang Y. Microfluidic system for particle manipulation based on swirl. Appl Phys Lett 2023; 123 (01) 013508
  CrossrefGoogle Scholar
• 106 Costa AP, Xu X, Khan MA, Burgess DJ. Liposome formation using a coaxial turbulent jet in co-flow. Pharm Res 2016; 33 (02) 404-416
  CrossrefPubMedGoogle Scholar
• 107 Toth MJ, Kim T, Kim Y. Robust manufacturing of lipid-polymer nanoparticles through feedback control of parallelized swirling microvortices. Lab Chip 2017; 17 (16) 2805-2813
  CrossrefPubMedGoogle Scholar
• 108 Sealy A. Manufacturing moonshot: how Pfizer makes its millions of Covid-19 vaccine doses. Accessed April 2, 2021 at: https://edition.cnn.com/2021/03/31/health/pfizer-vaccine-manufacturing/index.html
  Google Scholar
• 109 van der Woerd M, Ferree D, Pusey M. The promise of macromolecular crystallization in microfluidic chips. J Struct Biol 2003; 142 (01) 180-187
  CrossrefPubMedGoogle Scholar
• 110 Khizar S, Zine N, Errachid A, Jaffrezic-Renault N, Elaissari A. Microfluidic-based nanoparticle synthesis and their potential applications. Electrophoresis 2022; 43 (7–8): 819-838
  CrossrefPubMedGoogle Scholar
• 111 Di J, Gao X, Du Y, Zhang H, Gao J, Zheng A. Size, shape, charge and “stealthy” surface: carrier properties affect the drug circulation time in vivo . Asian J Pharm Sci 2021; 16 (04) 444-458
  CrossrefPubMedGoogle Scholar
• 112 Andar AU, Hood RR, Vreeland WN, Devoe DL, Swaan PW. Microfluidic preparation of liposomes to determine particle size influence on cellular uptake mechanisms. Pharm Res 2014; 31 (02) 401-413
  CrossrefPubMedGoogle Scholar
• 113 Lee JS, Hwang SY, Lee EK. Imaging-based analysis of liposome internalization to macrophage cells: effects of liposome size and surface modification with PEG moiety. Colloids Surf B Biointerfaces 2015; 136: 786-790
  CrossrefPubMedGoogle Scholar
• 114 Feng Q, Zhang L, Liu C. et al. Microfluidic based high throughput synthesis of lipid-polymer hybrid nanoparticles with tunable diameters. Biomicrofluidics 2015; 9 (05) 052604
  CrossrefPubMedGoogle Scholar
• 115 Chen S, Tam YYC, Lin PJC, Sung MMH, Tam YK, Cullis PR. Influence of particle size on the in vivo potency of lipid nanoparticle formulations of siRNA. J Control Release 2016; 235: 236-244
  CrossrefPubMedGoogle Scholar
• 116 Liu D, Zhang H, Fontana F, Hirvonen JT, Santos HA. Microfluidic-assisted fabrication of carriers for controlled drug delivery. Lab Chip 2017; 17 (11) 1856-1883
  CrossrefPubMedGoogle Scholar
• 117 Maeki M, Kimura N, Sato Y, Harashima H, Tokeshi M. Advances in microfluidics for lipid nanoparticles and extracellular vesicles and applications in drug delivery systems. Adv Drug Deliv Rev 2018; 128: 84-100
  CrossrefPubMedGoogle Scholar
• 118 Okuda K, Sato Y, Iwakawa K. et al. On the size-regulation of RNA-loaded lipid nanoparticles synthesized by microfluidic device. J Control Release 2022; 348: 648-659
  CrossrefPubMedGoogle Scholar
• 119 Gimondi S, Guimarães CF, Vieira SF. et al. Microfluidic mixing system for precise PLGA-PEG nanoparticles size control. Nanomedicine 2022; 40: 102482
  CrossrefPubMedGoogle Scholar
• 120 Ahmed H, Stokke BT. Fabrication of monodisperse alginate microgel beads by microfluidic picoinjection: a chelate free approach. Lab Chip 2021; 21 (11) 2232-2243
  CrossrefPubMedGoogle Scholar
• 121 de Carvalho BG, Taketa TB, Garcia BBM, Han SW, de la Torre LG. Hybrid microgels produced via droplet microfluidics for sustainable delivery of hydrophobic and hydrophilic model nanocarriers. Mater Sci Eng C 2021; 118: 111467
  CrossrefPubMedGoogle Scholar
• 122 Balbino TA, Aoki NT, Gasperini AAM. et al. Continuous flow production of cationic liposomes at high lipid concentration in microfluidic devices for gene delivery applications. Chem Eng J 2013; 226: 423-433
  CrossrefGoogle Scholar
• 123 Akhter KF, Mumin MA, Lui EMK, Charpentier PA. Immunoengineering with ginseng polysaccharide nanobiomaterials through oral administration in mice. ACS Biomater Sci Eng 2019; 5 (06) 2916-2925
  CrossrefPubMedGoogle Scholar
• 124 Al-Ahmady ZS, Donno R, Gennari A. et al. Enhanced intraliposomal metallic nanoparticle payload capacity using microfluidic-assisted self-assembly. Langmuir 2019; 35 (41) 13318-13331
  CrossrefPubMedGoogle Scholar
• 125 Sedighi M, Sieber S, Rahimi F. et al. Rapid optimization of liposome characteristics using a combined microfluidics and design-of-experiment approach. Drug Deliv Transl Res 2019; 9 (01) 404-413
  CrossrefPubMedGoogle Scholar
• 126 Sommonte F, Arduino I, Iacobazzi RM. et al. Microfluidic assembly of “Turtle-Like” shaped solid lipid nanoparticles for lysozyme delivery. Int J Pharm 2023; 631: 122479
  CrossrefPubMedGoogle Scholar
• 127 Lengert EV, Trushina DB, Soldatov M, Ermakov AV. Microfluidic synthesis and analysis of bioinspired structures based on CaCO₃ for potential applications as drug delivery carriers. Pharmaceutics 2022; 14 (01) 139
  CrossrefPubMedGoogle Scholar
• 128 Chen Y, Zhao D, Xiao F. et al. Microfluidics-enabled serial assembly of lipid-siRNA-sorafenib nanoparticles for synergetic hepatocellular carcinoma therapy. Adv Mater 2023; 35 (13) e2209672
  CrossrefPubMedGoogle Scholar
• 129 Hao N, Nie Y, Zhang JXJ. Microfluidic flow synthesis of functional mesoporous silica nanofibers with tunable aspect ratios. ACS Sustain Chem& Eng 2018; 6 (02) 1522-1526
  CrossrefGoogle Scholar
• 130 He C, Zeng W, Su Y. et al. Microfluidic-based fabrication and characterization of drug-loaded PLGA magnetic microspheres with tunable shell thickness. Drug Deliv 2021; 28 (01) 692-699
  CrossrefPubMedGoogle Scholar
• 131 Hui Y, Yi X, Hou F. et al. Role of nanoparticle mechanical properties in cancer drug delivery. ACS Nano 2019; 13 (07) 7410-7424
  CrossrefPubMedGoogle Scholar
• 132 Lozano Vigario F, Nagy NA, The MH. et al. The use of a staggered herringbone micromixer for the preparation of rigid liposomal formulations allows efficient encapsulation of antigen and adjuvant. J Pharm Sci 2022; 111 (04) 1050-1057
  CrossrefPubMedGoogle Scholar
• 133 Visaveliya NR, Leishman CW, Ng K. et al. Surface wrinkling and porosity of polymer particles toward biological and biomedical applications. Adv Mater Interfaces 2017; 4 (24) 1700929
  CrossrefGoogle Scholar
• 134 Li M, Liu C, Yin J, Liu G, Chen D. Single-step synthesis of highly tunable multifunctional nanoliposomes for synergistic cancer therapy. ACS Appl Mater Interfaces 2022; 14 (18) 21301-21309
  CrossrefPubMedGoogle Scholar
• 135 Gao Z, Mansor MH, Winder N. et al. Microfluidic-assisted ZIF-silk-polydopamine nanoparticles as promising drug carriers for breast cancer therapy. Pharmaceutics 2023; 15 (07) 1811
  CrossrefPubMedGoogle Scholar
• 136 Lee JB, Zhang K, Tam YY. et al. A Glu-urea-Lys ligand-conjugated lipid nanoparticle/siRNA system inhibits androgen receptor expression in vivo . Mol Ther Nucleic Acids 2016; 5 (08) e348
  CrossrefPubMedGoogle Scholar
• 137 Li Y, Lee RJ, Huang X. et al. Single-step microfluidic synthesis of transferrin-conjugated lipid nanoparticles for siRNA delivery. Nanomedicine 2017; 13 (02) 371-381
  CrossrefPubMedGoogle Scholar
• 138 Jia Z, Gong Y, Pi Y. et al. pPB peptide-mediated siRNA-loaded stable nucleic acid lipid nanoparticles on targeting therapy of hepatic fibrosis. Mol Pharm 2018; 15 (01) 53-62
  CrossrefPubMedGoogle Scholar
• 139 Yang SH, Ju XJ, Deng CF. et al. Controllable fabrication of monodisperse poly(vinyl alcohol) microspheres with droplet microfluidics for embolization. Ind Eng Chem Res 2022; 61 (34) 12619-12631
  CrossrefGoogle Scholar
• 140 Zhu Y, Xiao W, Zhong W. et al. Study of the skin-penetration promoting effect and mechanism of combined system of curcumin liposomes prepared by microfluidic chip and skin penetrating peptides TD-1 for topical treatment of primary melanoma. Int J Pharm 2023; 643: 123256
  CrossrefPubMedGoogle Scholar
• 141 Yu H, Dyett BP, Zhai J, Strachan JB, Drummond CJ, Conn CE. Formation of particulate lipid lyotropic liquid crystalline nanocarriers using a microfluidic platform. J Colloid Interface Sci 2023; 634: 279-289
  CrossrefPubMedGoogle Scholar
• 142 Younis MA, Sato Y, Elewa YHA, Kon Y, Harashima H. Self-homing nanocarriers for mRNA delivery to the activated hepatic stellate cells in liver fibrosis. J Control Release 2023; 353: 685-698
  CrossrefPubMedGoogle Scholar
• 143 Yang K, Ni M, Xu C. et al. Microfluidic one-step synthesis of a metal-organic framework for osteoarthritis therapeutic microRNAs delivery. Front Bioeng Biotechnol 2023; 11: 1239364
  CrossrefPubMedGoogle Scholar
• 144 Wang Q, Xu W, Li Q. et al. Coaxial electrostatic spray-based preparation of localization missile liposomes on a microfluidic chip for targeted treatment of triple-negative breast cancer. Int J Pharm 2023; 643: 123220
  CrossrefPubMedGoogle Scholar
• 145 Ahmad M, Khan S, Shah SMH. et al. Formulation and optimization of repaglinide nanoparticles using microfluidics for enhanced bioavailability and management of diabetes. Biomedicines 2023; 11 (04) 1064
  CrossrefPubMedGoogle Scholar
• 146 Zhou JE, Sun L, Liu L. et al. Hepatic macrophage targeted siRNA lipid nanoparticles treat non-alcoholic steatohepatitis. J Control Release 2022; 343: 175-186
  CrossrefPubMedGoogle Scholar
• 147 Santhanes D, Wilkins A, Zhang H, John Aitken R, Liang M. Microfluidic formulation of lipid/polymer hybrid nanoparticles for plasmid DNA (pDNA) delivery. Int J Pharm 2022; 627: 122223
  CrossrefPubMedGoogle Scholar
• 148 Maeki M, Okada Y, Uno S. et al. Production of siRNA-loaded lipid nanoparticles using a microfluidic device. J Vis Exp 2022; (181) e62999
  Google Scholar
• 149 Xia Y, Xu R, Ye S. et al. Microfluidic formulation of curcumin-loaded multiresponsive gelatin nanoparticles for anticancer therapy. ACS Biomater Sci Eng 2023; 9 (06) 3402-3413
  CrossrefPubMedGoogle Scholar
• 150 Shen Y, Yuk SA, Kwon S, Tamam H, Yeo Y, Han B. A timescale-guided microfluidic synthesis of tannic acid-Fe^III network nanocapsules of hydrophobic drugs. J Control Release 2023; 357: 484-497
  CrossrefPubMedGoogle Scholar
• 151 Lei Y, Kilker S, Lee Y. A nozzle simulation chip toward high-throughput formation of curcumin-loaded zein nanoparticles with tunable properties. J Food Sci 2023; 88 (08) 3524-3537
  CrossrefPubMedGoogle Scholar
• 152 O'Brien Laramy MN, Costa AP, Cebrero YM. et al. Process robustness in lipid nanoparticle production: a comparison of microfluidic and turbulent jet mixing. Mol Pharm 2023; 20 (08) 4285-4296
  CrossrefPubMedGoogle Scholar
• 153 Greco A, Gabold B, Chen S. et al. Microfluidic mixing as platform technology for production of chitosan nanoparticles loaded with different macromolecules. Eur J Pharm Biopharm 2023; 188: 170-181
  CrossrefPubMedGoogle Scholar
• 154 Cao X, Liu Q, Shi W. et al. Microfluidic fabricated bisdemethoxycurcumin thermosensitive liposome with enhanced antitumor effect. Int J Pharm 2023; 641: 123039
  CrossrefPubMedGoogle Scholar
• 155 Bendre A, Hegde V, Ajeya KV. et al. Microfluidic-assisted synthesis of metal-organic framework -alginate micro-particles for sustained drug delivery. Biosensors (Basel) 2023; 13 (07) 737
  CrossrefPubMedGoogle Scholar
• 156 Alam SB, Wang F, Qian H, Kulka M. Apolipoprotein C3 facilitates internalization of cationic lipid nanoparticles into bone marrow-derived mouse mast cells. Sci Rep 2023; 13 (01) 431
  CrossrefPubMedGoogle Scholar
• 157 Schemberg J, Abbassi AE, Lindenbauer A. et al. Synthesis of biocompatible superparamagnetic iron oxide nanoparticles (SPION) under different microfluidic regimes. ACS Appl Mater Interfaces 2022; 14 (42) 48011-48028
  CrossrefPubMedGoogle Scholar
• 158 Karimi-Soflou R, Karkhaneh A, Shabani I. Size-adjustable self-assembled nanoparticles through microfluidic platform promotes neuronal differentiation of mouse embryonic stem cells. Biomater Adv 2022; 140: 213056
  CrossrefPubMedGoogle Scholar
• 159 Jaradat E, Weaver E, Meziane A, Lamprou DA. Microfluidic paclitaxel-loaded lipid nanoparticle formulations for chemotherapy. Int J Pharm 2022; 628: 122320
  CrossrefPubMedGoogle Scholar
• 160 Younis MA, Khalil IA, Elewa YHA, Kon Y, Harashima H. Ultra-small lipid nanoparticles encapsulating sorafenib and midkine-siRNA selectively-eradicate sorafenib-resistant hepatocellular carcinoma in vivo . J Control Release 2021; 331: 335-349
  CrossrefPubMedGoogle Scholar
• 161 Yang YN, Ge C, He J, Lu WG. Novel worm-like micelles for hydrochloride doxorubicin delivery: preparation, characterization, and in vitro evaluation. Pharmaceutical Fronts 2022; 4 (04) e284-e294
  Article in Thieme ConnectGoogle Scholar
• 162 Zheng Y, Chen H, Lin X, Li M, Zhao Y, Shang L. Scalable production of biomedical microparticles via high-throughput microfluidic step emulsification. Small 2023; 19 (17) e2206007
  CrossrefPubMedGoogle Scholar
• 163 Su Y, Liu J, Tan S, Liu W, Wang R, Chen C. PLGA sustained-release microspheres loaded with an insoluble small-molecule drug: microfluidic-based preparation, optimization, characterization, and evaluation in vitro and in vivo . Drug Deliv 2022; 29 (01) 1437-1446
  CrossrefPubMedGoogle Scholar
• 164 Liu F, Luo W, Qiu J, Guo Y, Zhao S, Bao B. Continuous antisolvent crystallization of dolutegravir sodium using microfluidics. Ind Eng Chem Res 2022; 61 (19) 6693-6702
  CrossrefGoogle Scholar
• 165 Zhou J, Zhai Y, Xu J, Zhou T, Cen L. Microfluidic preparation of PLGA composite microspheres with mesoporous silica nanoparticles for finely manipulated drug release. Int J Pharm 2021; 593: 120173
  CrossrefPubMedGoogle Scholar
• 166 Yang D, Gao K, Bai Y. et al. Microfluidic synthesis of chitosan-coated magnetic alginate microparticles for controlled and sustained drug delivery. Int J Biol Macromol 2021; 182: 639-647
  CrossrefPubMedGoogle Scholar
• 167 Yeh SI, Fu CY, Sung CY, Kao SC. Microfluidic fabrication of porous PLGA microspheres without pre-emulsification step. Microfluid Nanofluidics 2023; 27: 47
  CrossrefGoogle Scholar
• 168 Chen M, Guo X, Shen L. et al. Monodisperse CaCO₃-loaded gelatin microspheres for reversing lactic acid-induced chemotherapy resistance during TACE treatment. Int J Biol Macromol 2023; 231: 123160
  CrossrefPubMedGoogle Scholar
• 169 Coliaie P, Kelkar MS, Nere NK, Singh MR. Continuous-flow, well-mixed, microfluidic crystallization device for screening of polymorphs, morphology, and crystallization kinetics at controlled supersaturation. Lab Chip 2019; 19 (14) 2373-2382
  CrossrefPubMedGoogle Scholar
• 170 Quagliarini E, Renzi S, Digiacomo L. et al. Microfluidic formulation of DNA-loaded multicomponent lipid nanoparticles for gene delivery. Pharmaceutics 2021; 13 (08) 1292
  CrossrefPubMedGoogle Scholar
• 171 Sato Y, Okabe N, Note Y. et al. Hydrophobic scaffolds of pH-sensitive cationic lipids contribute to miscibility with phospholipids and improve the efficiency of delivering short interfering RNA by small-sized lipid nanoparticles. Acta Biomater 2020; 102: 341-350
  CrossrefPubMedGoogle Scholar
• 172 Mucker EM, Karmali PP, Vega J. et al. Lipid nanoparticle formulation increases efficiency of DNA-vectored vaccines/immunoprophylaxis in animals including transchromosomic bovines. Sci Rep 2020; 10 (01) 8764
  CrossrefPubMedGoogle Scholar
• 173 Lari AS, Zahedi P, Ghourchian H, Khatibi A. Microfluidic-based synthesized carboxymethyl chitosan nanoparticles containing metformin for diabetes therapy: in vitro and in vivo assessments. Carbohydr Polym 2021; 261: 117889
  CrossrefPubMedGoogle Scholar
• 174 Huang KS, Yang CH, Wang YC, Wang WT, Lu YY. Microfluidic synthesis of vinblastine-loaded multifunctional particles for magnetically responsive controlled drug release. Pharmaceutics 2019; 11 (05) 212
  CrossrefPubMedGoogle Scholar
• 175 Chiesa E, Greco A, Riva F. et al. Staggered herringbone microfluid device for the manufacturing of chitosan/TPP nanoparticles: systematic optimization and preliminary biological evaluation. Int J Mol Sci 2019; 20 (24) 6212
  CrossrefPubMedGoogle Scholar
• 176 Huang Y, Jazani AM, Howell EP, Reynolds LA, Oh JK, Moffitt MG. Microfluidic shear processing control of biological reduction stimuli-responsive polymer nanoparticles for drug delivery. ACS Biomater Sci Eng 2020; 6 (09) 5069-5083
  CrossrefPubMedGoogle Scholar
• 177 Martins C, Araújo F, Gomes MJ. et al. Using microfluidic platforms to develop CNS-targeted polymeric nanoparticles for HIV therapy. Eur J Pharm Biopharm 2019; 138: 111-124
  CrossrefPubMedGoogle Scholar
• 178 Liu D, Zhang H, Cito S. et al. Core/shell nanocomposites produced by superfast sequential microfluidic nanoprecipitation. Nano Lett 2017; 17 (02) 606-614
  CrossrefPubMedGoogle Scholar
• 179 Mandal B, Bhattacharjee H, Mittal N. et al. Core-shell-type lipid-polymer hybrid nanoparticles as a drug delivery platform. Nanomedicine 2013; 9 (04) 474-491
  CrossrefPubMedGoogle Scholar
• 180 Scopel R, Falcao MA, Cappellari AR. et al. Lipid-polymer hybrid nanoparticles as a targeted drug delivery system for melanoma treatment. Int J Polym Mater 2022; 71 (02) 127-138
  CrossrefGoogle Scholar
• 181 Wei W, Sun J, Guo XY. et al. Microfluidic-based holonomic constraints of siRNA in the kernel of lipid/polymer hybrid nanoassemblies for improving stable and safe in vivo delivery. ACS Appl Mater Interfaces 2020; 12 (13) 14839-14854
  CrossrefPubMedGoogle Scholar
• 182 Tahir N, Madni A, Li W. et al. Microfluidic fabrication and characterization of Sorafenib-loaded lipid-polymer hybrid nanoparticles for controlled drug delivery. Int J Pharm 2020; 581: 119275
  CrossrefPubMedGoogle Scholar
• 183 Wan F, Bohr SS, Kłodzińska SN. et al. Ultrasmall TPGS-PLGA hybrid nanoparticles for site-specific delivery of antibiotics into Pseudomonas aeruginosa biofilms in lungs. ACS Appl Mater Interfaces 2020; 12 (01) 380-389
  CrossrefPubMedGoogle Scholar
• 184 Yang R, Deng Y, Huang B. et al. A core-shell structured COVID-19 mRNA vaccine with favorable biodistribution pattern and promising immunity. Signal Transduct Target Ther 2021; 6 (01) 213
  CrossrefPubMedGoogle Scholar
• 185 Nie T, He Z, Zhou Y. et al. Surface coating approach to overcome mucosal entrapment of DNA nanoparticles for oral gene delivery of glucagon-like peptide 1. ACS Appl Mater Interfaces 2019; 11 (33) 29593-29603
  CrossrefPubMedGoogle Scholar
• 186 Bose RJC, Paulmurugan R, Moon J, Lee SH, Park H. Cell membrane-coated nanocarriers: the emerging targeted delivery system for cancer theranostics. Drug Discov Today 2018; 23 (04) 891-899
  CrossrefPubMedGoogle Scholar
• 187 Herrmann IK, Wood MJA, Fuhrmann G. Extracellular vesicles as a next-generation drug delivery platform. Nat Nanotechnol 2021; 16 (07) 748-759
  CrossrefPubMedGoogle Scholar
• 188 Yang L, Sun L, Zhang H, Bian F, Zhao Y. Ice-inspired lubricated drug delivery particles from microfluidic electrospray for osteoarthritis treatment. ACS Nano 2021; 15 (12) 20600-20606
  CrossrefPubMedGoogle Scholar
• 189 Zou D, Yu L, Sun Q. et al. A general approach for biomimetic mineralization of MOF particles using biomolecules. Colloids Surf B Biointerfaces 2020; 193: 111108
  CrossrefPubMedGoogle Scholar
• 190 Cui J, Gao N, Yin X. et al. Microfluidic synthesis of uniform single-crystalline MOF microcubes with a hierarchical porous structure. Nanoscale 2018; 10 (19) 9192-9198
  CrossrefPubMedGoogle Scholar
• 191 Hu C, Bai Y, Hou M. et al. Defect-induced activity enhancement of enzyme-encapsulated metal-organic frameworks revealed in microfluidic gradient mixing synthesis. Sci Adv 2020; 6 (05) eaax5785
  CrossrefPubMedGoogle Scholar
• 192 Balachandran YL, Li X, Jiang X. Integrated microfluidic synthesis of aptamer functionalized biozeolitic imidazolate framework (BioZIF-8) targeting lymph node and tumor. Nano Lett 2021; 21 (03) 1335-1344
  CrossrefPubMedGoogle Scholar
• 193 Yang G, Liu Y, Jin S, Zhao CX. Development of core-shell nanoparticle drug delivery systems based on biomimetic mineralization. ChemBioChem 2020; 21 (20) 2871-2879
  CrossrefPubMedGoogle Scholar
• 194 Tengjisi HY, Hui Y, Yang G, Fu C, Liu Y, Zhao CX. Biomimetic core-shell silica nanoparticles using a dual-functional peptide. J Colloid Interface Sci 2021; 581 (Pt A): 185-194
  CrossrefPubMedGoogle Scholar
• 195 Hao N, Nie Y, Xu Z, Zhang JXJ. Ultrafast microfluidic synthesis of hierarchical triangular silver core-silica shell nanoplatelet toward enhanced cellular internalization. J Colloid Interface Sci 2019; 542: 370-378
  CrossrefPubMedGoogle Scholar
• 196 Xu L, Peng J, Srinivasakannan C. et al. Synthesis of copper nanoparticles by a T-shaped microfluidic device. RSC Advances 2014; 4 (48) 25155-25159
  CrossrefGoogle Scholar
• 197 Pekkari A, Say Z, Susarrey-Arce A. et al. Continuous microfluidic synthesis of Pd nanocubes and PdPt core-shell nanoparticles and their catalysis of NO₂ reduction. ACS Appl Mater Interfaces 2019; 11 (39) 36196-36204
  CrossrefPubMedGoogle Scholar
• 198 Li X, Feng Q, Jiang X. Microfluidic synthesis of Gd-based nanoparticles for fast and ultralong MRI signals in the solid tumor. Adv Healthc Mater 2019; 8 (20) e1900672
  CrossrefPubMedGoogle Scholar
• 199 Bemetz J, Wegemann A, Saatchi K. et al. Microfluidic-based synthesis of magnetic nanoparticles coupled with miniaturized NMR for online relaxation studies. Anal Chem 2018; 90 (16) 9975-9982
  CrossrefPubMedGoogle Scholar
• 200 Deng N, Wang Y, Luo G. A novel method for fast and continuous preparation of superfine titanium dioxide nanoparticles in microfluidic system. Particuology 2022; 60: 61-67
  CrossrefGoogle Scholar
• 201 Yao H, Wang Y, Jing Y, Luo G. Ultrafast, continuous and shape-controlled preparation of CeO2 nanostructures: nanorods and nanocubes in a microfluidic system. Ind Eng Chem Res 2018; 57 (22) 7525-7532
  CrossrefGoogle Scholar
• 202 Mahdavi Z, Rezvani H, Keshavarz Moraveji M. Core-shell nanoparticles used in drug delivery-microfluidics: a review. RSC Advances 2020; 10 (31) 18280-18295
  CrossrefPubMedGoogle Scholar
• 203 Su Y, Zhang B, Sun R. et al. PLGA-based biodegradable microspheres in drug delivery: recent advances in research and application. Drug Deliv 2021; 28 (01) 1397-1418
  CrossrefPubMedGoogle Scholar
• 204 Zhu C, Yang H, Shen L. et al. Microfluidic preparation of PLGA microspheres as cell carriers with sustainable Rapa release. J Biomater Sci Polym Ed 2019; 30 (09) 737-755
  CrossrefPubMedGoogle Scholar
• 205 Kamiya K, Takeuchi S. Giant liposome formation toward the synthesis of well-defined artificial cells. J Mater Chem B Mater Biol Med 2017; 5 (30) 5911-5923
  CrossrefPubMedGoogle Scholar
• 206 Seo H, Lee H. Recent developments in microfluidic synthesis of artificial cell-like polymersomes and liposomes for functional bioreactors. Biomicrofluidics 2021; 15 (02) 021301
  CrossrefPubMedGoogle Scholar
• 207 Weiss M, Frohnmayer JP, Benk LT. et al. Sequential bottom-up assembly of mechanically stabilized synthetic cells by microfluidics. Nat Mater 2018; 17 (01) 89-96
  CrossrefPubMedGoogle Scholar
• 208 Schaich M, Cama J, Al Nahas K. et al. An integrated microfluidic platform for quantifying drug permeation across biomimetic vesicle membranes. Mol Pharm 2019; 16 (06) 2494-2501
  CrossrefPubMedGoogle Scholar
• 209 Deshpande S, Dekker C. On-chip microfluidic production of cell-sized liposomes. Nat Protoc 2018; 13 (05) 856-874
  CrossrefPubMedGoogle Scholar
• 210 Arriaga LR, Huang Y, Kim SH. et al. Single-step assembly of asymmetric vesicles. Lab Chip 2019; 19 (05) 749-756
  CrossrefPubMedGoogle Scholar
• 211 Michelon M, Huang YT, de la Torre LG, Weitz DA, Cunha RL. Single-step microfluidic production of W/O/W double emulsions as templates for beta-carotene-loaded giant liposomes formation. Chem Eng J 2019; 366: 27-32
  CrossrefGoogle Scholar
• 212 Yandrapalli N, Petit J, Bäumchen O, Robinson T. Surfactant-free production of biomimetic giant unilamellar vesicles using PDMS-based microfluidics. Commun Chem 2021; 4 (01) 100
  CrossrefPubMedGoogle Scholar
• 213 Costa C, Liu Z, Martins JP. et al. All-in-one microfluidic assembly of insulin-loaded pH-responsive nano-in-microparticles for oral insulin delivery. Biomater Sci 2020; 8 (12) 3270-3277
  CrossrefPubMedGoogle Scholar
• 214 Yang JL, Zhu Y, Wang F, Deng LF, Xu XY, Cui WG. Microfluidic liposomes-anchored microgels as extended delivery platform for treatment of osteoarthritis. Chem Eng J 2020; 400: 126004
  CrossrefGoogle Scholar
• 215 Gikanga B, Maa YF. A review on mixing-induced protein particle formation: the puzzle of bottom-mounted mixers. J Pharm Sci 2020; 109 (08) 2363-2374
  CrossrefPubMedGoogle Scholar
• 216 Madrigal JL, Sharma SN, Campbell KT, Stilhano RS, Gijsbers R, Silva EA. Microgels produced using microfluidic on-chip polymer blending for controlled released of VEGF encoding lentivectors. Acta Biomater 2018; 69: 265-276
  CrossrefPubMedGoogle Scholar
• 217 Deveza L, Ashoken J, Castaneda G. et al. Microfluidic synthesis of biodegradable polyethylene-glycol microspheres for controlled delivery of proteins and DNA nanoparticles. ACS Biomater Sci Eng 2015; 1 (03) 157-165
  CrossrefPubMedGoogle Scholar
• 218 Kim H, Sung J, Chang Y, Alfeche A, Leal C. Microfluidics synthesis of gene silencing cubosomes. ACS Nano 2018; 12 (09) 9196-9205
  CrossrefPubMedGoogle Scholar