Abstract
Advanced drug delivery systems hold great potential for the diagnosis and treatment of several diseases, and the benefits of nanomedicine-based products in healthcare have recently started to crystallize. Yet, their translation into clinical applications is still considered to be slow, mainly due to high batch-to-batch variation, complexity of preparation, high costs, and compromised scale-up feasibility. Considering the impact that mixing kinetics play on the properties of nanomedicines, microfluidics emerged as a technique to foster the preparation of micro- and nanoparticles with precisely controlled features, such as narrow size distribution, high homogeneity and reproducibility, high drug encapsulation efficiency, and enhanced scale-up feasibility. This chapter provides an overview on recent advances in microfluidic-assisted particle production. The basic principles of flow patterns and regimes are reviewed, as well as the materials and geometries used for the preparation of microfluidic devices. The impact of different parameters of the microfluidic setup on the physicochemical properties of the formulations is also discussed, and some of the most relevant micro- and nanoparticle technologies are reviewed. Possibilities for scale-up and the introduction of microfluidics in industrial settings are also briefly addressed.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Similar content being viewed by others
References
Ag Seleci D, Maurer V, Stahl F, Scheper T, Garnweitner G (2019) Rapid microfluidic preparation of niosomes for targeted drug delivery. Int J Mol Sci 20:4696
Ahadian S, Finbloom JA, Mofidfar M, Diltemiz SE, Nasrollahi F, Davoodi E, Hosseini V, Mylonaki I, Sangabathuni S, Montazerian H, Fetah K, Nasiri R, Dokmeci MR, Stevens MM, Desai TA, Khademhosseini A (2020) Micro and nanoscale technologies in oral drug delivery. Adv Drug Deliv Rev 157:37–62
Akyazi T, Basabe-Desmonts L, Benito-Lopez F (2018) Review on microfluidic paper-based analytical devices towards commercialisation. Anal Chim Acta 1001:1–17
Ali HSM, York P, Ali AMA, Blagden N (2011) Hydrocortisone nanosuspensions for ophthalmic delivery: a comparative study between microfluidic nanoprecipitation and wet milling. J Control Release 149:175–181
Ali MS, Hooshmand N, El-Sayed M, Labouta HI (2021) Microfluidics for development of lipid nanoparticles: paving the way for nucleic acids to the clinic. ACS Appl Bio Mater
Amador C, Gavriilidis A, Angeli P (2004) Flow distribution in different microreactor scale-out geometries and the effect of manufacturing tolerances and channel blockage. Chem Eng J 101:379–390
Amstad E, Kim SH, Weitz DA (2012) Photo- and thermoresponsive polymersomes for triggered release. Angew Chem Int Ed Engl 51:12499–12503
Annabi N, Tamayol A, Uquillas JA, Akbari M, Bertassoni LE, Cha C, Camci-Unal G, Dokmeci MR, Peppas NA, Khademhosseini A (2014) 25th anniversary article: rational design and applications of hydrogels in regenerative medicine. Adv Mater 26:85–124
Anselmo AC, Mitragotri S (2016) Nanoparticles in the clinic. Bioeng Transl Med 1:10–29
Anselmo AC, Mitragotri S (2019) Nanoparticles in the clinic: an update. Bioeng Transl Med 4:e10143
Araújo F, das Neves J, Martins JP, Granja PL, Santos HA, Sarmento B (2017) Functionalized materials for multistage platforms in the oral delivery of biopharmaceuticals. Prog Mater Sci 89:306–344
Arduino I, Liu Z, Iacobazzi RM, Lopedota AA, Lopalco A, Cutrignelli A, Laquintana V, Porcelli L, Azzariti A, Franco M, Santos HA, Denora N (2021a) Microfluidic preparation and in vitro evaluation of iRGD-functionalized solid lipid nanoparticles for targeted delivery of paclitaxel to tumor cells. Int J Pharm 610:121246
Arduino I, Liu Z, Rahikkala A, Figueiredo P, Correia A, Cutrignelli A, Denora N, Santos HA (2021b) Preparation of cetyl palmitate-based PEGylated solid lipid nanoparticles by microfluidic technique. Acta Biomater 121:566–578
Atencia J, Beebe DJ (2005) Controlled microfluidic interfaces. Nature 437:648–655
Batty CJ, Bachelder EM, Ainslie KM (2021) Historical perspective of clinical nano and microparticle formulations for delivery of therapeutics. Trends Mol Med 27:516–519
Beebe DJ, Mensing GA, Walker GM (2002) Physics and applications of microfluidics in biology. Annu Rev Biomed Eng 4:261–286
Bein A, Shin W, Jalili-Firoozinezhad S, Park MH, Sontheimer-Phelps A, Tovaglieri A, Chalkiadaki A, Kim HJ, Ingber DE (2018) Microfluidic organ-on-a-chip models of human intestine. Cell Mol Gastroenterol Hepatol 5:659–668
Belliveau NM, Huft J, Lin PJC, Chen S, Leung AKK, Leaver TJ, Wild AW, Lee JB, Taylor RJ, Tam YK, Hansen CL, Cullis PR (2012) Microfluidic synthesis of highly potent limit-size lipid nanoparticles for in vivo delivery of siRNA. Mol Ther Nucleic Acids 1:e37
Bertoni S, Liu Z, Correia A, Martins JP, Rahikkala A, Fontana F, Kemell M, Liu D, Albertini B, Passerini N, Li W, Santos HA (2018) pH and reactive oxygen species-sequential responsive nano-in-micro composite for targeted therapy of inflammatory bowel disease. Adv Funct Mater 28:1806175
Bings NH, Wang C, Skinner CD, Colyer CL, Thibault P, Harrison DJ (1999) Microfluidic devices connected to fused-silica capillaries with minimal dead volume. Anal Chem 71:3292–3296
Boleininger J, Kurz A, Reuss V, Sönnichsen C (2006) Microfluidic continuous flow synthesis of rod-shaped gold and silver nanocrystals. Phys Chem Chem Phys 8:3824–3827
Cabral H, Matsumoto Y, Mizuno K, Chen Q, Murakami M, Kimura M, Terada Y, Kano MR, Miyazono K, Uesaka M, Nishiyama N, Kataoka K (2011) Accumulation of sub-100 nm polymeric micelles in poorly permeable tumours depends on size. Nat Nanotechnol 6:815–823
Capretto L, Carugo D, Mazzitelli S, Nastruzzi C, Zhang X (2013) Microfluidic and lab-on-a-chip preparation routes for organic nanoparticles and vesicular systems for nanomedicine applications. Adv Drug Deliv Rev 65:1496–1532
Capretto L, Mazzitelli S, Brognara E, Lampronti I, Carugo D, Hill M, Zhang X, Gambari R, Nastruzzi C (2012) Mithramycin encapsulated in polymeric micelles by microfluidic technology as novel therapeutic protocol for beta-thalassemia. Int J Nanomedicine 7:307–324
Chande C, Riaz N, Harbour V, Noor H, Torralba M, Cheng Y-H, Li Z, Tong A, Voronov R, Basuray S (2020) Universal method for fabricating PDMS microfluidic device using SU8, 3D printing and soft lithography. Technology 08:50–57
Chang CW, Cheng YJ, Tu M, Chen YH, Peng CC, Liao WH, Tung YC (2014) A polydimethylsiloxane-polycarbonate hybrid microfluidic device capable of generating perpendicular chemical and oxygen gradients for cell culture studies. Lab Chip 14:3762–3772
Chen C-H, Shah RK, Abate AR, Weitz DA (2009) Janus particles templated from double emulsion droplets generated using microfluidics. Langmuir 25:4320–4323
Chen D, Love KT, Chen Y, Eltoukhy AA, Kastrup C, Sahay G, Jeon A, Dong Y, Whitehead KA, Anderson DG (2012) Rapid discovery of potent siRNA-containing lipid nanoparticles enabled by controlled microfluidic formulation. J Am Chem Soc 134:6948–6951
Chen W, Li H, Liu Z, Yuan W (2016) Lipopolyplex for therapeutic gene delivery and its application for the treatment of Parkinson’s disease. Front Aging Neurosci 8
Chen Y, Zhang L, Chen G (2008) Fabrication, modification, and application of poly(methyl methacrylate) microfluidic chips. Electrophoresis 29:1801–1814
Cheng S-Y, Heilman S, Wasserman M, Archer S, Shuler ML, Wu M (2007) A hydrogel-based microfluidic device for the studies of directed cell migration. Lab Chip 7:763–769
Cho EC, Xie J, Wurm PA, Xia Y (2009) Understanding the role of surface charges in cellular adsorption versus internalization by selectively removing gold nanoparticles on the cell surface with a I2/KI etchant. Nano Lett 9:1080–1084
Conniot J, Silva JM, Fernandes JG, Silva LC, Gaspar R, Brocchini S, Florindo HF, Barata TS (2014) Cancer immunotherapy: nanodelivery approaches for immune cell targeting and tracking. Front Chem 2
Costa C, Liu Z, Martins JP, Correia A, Figueiredo P, Rahikkala A, Li W, Seitsonen J, Ruokolainen J, Hirvonen S-P, Aguiar-Ricardo A, Corvo ML, Santos HA (2020) All-in-one microfluidic assembly of insulin-loaded pH-responsive nano-in-microparticles for oral insulin delivery. Biomater Sci 8:3270–3277
Damiati S, Kompella UB, Damiati SA, Kodzius R (2018) Microfluidic devices for drug delivery systems and drug screening. Genes 9:103
Damiati SA, Rossi D, Joensson HN, Damiati S (2020) Artificial intelligence application for rapid fabrication of size-tunable PLGA microparticles in microfluidics. Sci Rep 10:19517
Dashtimoghadam E, Mirzadeh H, Taromi FA, Nyström B (2013) Microfluidic self-assembly of polymeric nanoparticles with tunable compactness for controlled drug delivery. Polymer 54:4972–4979
De Rose R, Zelikin AN, Johnston APR, Sexton A, Chong S-F, Cortez C, Mulholland W, Caruso F, Kent SJ (2008) Binding, internalization, and antigen presentation of vaccine-loaded nanoengineered capsules in blood. Adv Mater 20:4698–4703
Dendukuri D, Tsoi K, Hatton TA, Doyle PS (2005) Controlled synthesis of nonspherical microparticles using microfluidics. Langmuir 21:2113–2116
Deng N-N, Meng Z-J, Xie R, Ju X-J, Mou C-L, Wang W, Chu L-Y (2011) Simple and cheap microfluidic devices for the preparation of monodisperse emulsions. Lab Chip 11:3963–3969
Di Santo R, Digiacomo L, Palchetti S, Palmieri V, Perini G, Pozzi D, Papi M, Caracciolo G (2019) Microfluidic manufacturing of surface-functionalized graphene oxide nanoflakes for gene delivery. Nanoscale 11:2733–2741
van Dijke K, Veldhuis G, Schroën K, Boom R (2009) Parallelized EDGE-based droplet generation (EDGE) devices. Lab Chip 9:2824–2830
Ding S, Anton N, Vandamme TF, Serra CA (2016) Microfluidic nanoprecipitation systems for preparing pure drug or polymeric drug loaded nanoparticles: an overview. Expert Opin Drug Deliv 13:1447–1460
Duncanson WJ, Lin T, Abate AR, Seiffert S, Shah RK, Weitz DA (2012) Microfluidic synthesis of advanced microparticles for encapsulation and controlled release. Lab Chip 12:2135–2145
Eggersdorfer ML, Zheng W, Nawar S, Mercandetti C, Ofner A, Leibacher I, Koehler S, Weitz DA (2017) Tandem emulsification for high-throughput production of double emulsions. Lab Chip 17:936–942
Eusner T, Hale M, Hardt DE (2010) Process robustness of hot embossing microfluidic devices. J Manuf Sci Eng 132
Farokhzad OC, Langer R (2009) Impact of nanotechnology on drug delivery. ACS Nano 3:16–20
Ferreira Soares DC, Domingues SC, Viana DB, Tebaldi ML (2020) Polymer-hybrid nanoparticles: current advances in biomedical applications. Biomed Pharmacother 131:110695
Feynman RP (1960) There's plenty of room at the bottom. An invitation to enter a new field of physics. Eng Sci 23:22–36
Fontana F, Ferreira MPA, Correia A, Hirvonen J, Santos HA (2016) Microfluidics as a cutting-edge technique for drug delivery applications. J Drug Deliv Sci Technol 34:76–87
Fontana F, Martins JP, Torrieri G, Santos HA (2019) Nuts and bolts: microfluidics for the production of biomaterials. Adv Mater Technol 4:1800611
Fontana F, Shahbazi M-A, Liu D, Zhang H, Mäkilä E, Salonen J, Hirvonen JT, Santos HA (2017) Multistaged nanovaccines based on porous silicon@acetalated dextran@cancer cell membrane for cancer immunotherapy. Adv Mater 29:1603239
Friedman AD, Claypool SE, Liu R (2013) The smart targeting of nanoparticles. Curr Pharm Des 19:6315–6329
Friend J, Yeo L (2010) Fabrication of microfluidic devices using polydimethylsiloxane. Biomicrofluidics 4:026502
Ftouni J, Penhoat M, Addad A, Payen E, Rolando C, Girardon J-S (2012) Highly controlled synthesis of nanometric gold particles by citrate reduction using the short mixing, heating and quenching times achievable in a microfluidic device. Nanoscale 4:4450–4454
Fujiwara M, Yamamoto F, Okamoto K, Shiokawa K, Nomura R (2005) Adsorption of duplex DNA on mesoporous silicas: possibility of inclusion of DNA into their mesopores. Anal Chem 77:8138–8145
Gao Y, Chen Y, Ji X, He X, Yin Q, Zhang Z, Shi J, Li Y (2011) Controlled intracellular release of doxorubicin in multidrug-resistant cancer cells by tuning the shell-pore sizes of mesoporous silica nanoparticles. ACS Nano 5:9788–9798
Garbuzenko OB, Winkler J, Tomassone MS, Minko T (2014) Biodegradable Janus nanoparticles for local pulmonary delivery of hydrophilic and hydrophobic molecules to the lungs. Langmuir 30:12941–12949
Garstecki P, Fuerstman MJ, Stone HA, Whitesides GM (2006) Formation of droplets and bubbles in a microfluidic T-junction—scaling and mechanism of break-up. Lab Chip 6:437–446
Ghazal A, Gontsarik M, Kutter JP, Lafleur JP, Ahmadvand D, Labrador A, Salentinig S, Yaghmur A (2017) Microfluidic platform for the continuous production and characterization of multilamellar vesicles: a synchrotron small-angle X-ray scattering (SAXS) study. J Phys Chem Lett 8:73–79
Gong MM, Sinton D (2017) Turning the page: advancing paper-based microfluidics for broad diagnostic application. Chem Rev 117:8447–8480
Grigsby CL, Ho Y-P, Lin C, Engbersen JFJ, Leong KW (2013) Microfluidic preparation of polymer-nucleic acid nanocomplexes improves nonviral gene transfer. Sci Rep 3:3155
Grosse A, Grewe M, Fouckhardt H (2001) Deep wet etching of fused silica glass for hollow capillary optical leaky waveguides in microfluidic devices. J Micromech Microeng 11:257–262
Grover WH, Ivester RH, Jensen EC, Mathies RA (2006) Development and multiplexed control of latching pneumatic valves using microfluidic logical structures. Lab Chip 6:623–631
Grover WH, Skelley AM, Liu CN, Lagally ET, Mathies RA (2003) Monolithic membrane valves and diaphragm pumps for practical large-scale integration into glass microfluidic devices. Sens Actuators B Chem 89:315–323
Hao N, Nie Y, Zhang JXJ (2018) Microfluidic flow synthesis of functional mesoporous silica nanofibers with tunable aspect ratios. ACS Sustain Chem Eng 6:1522–1526
Hatch AV, Herr AE, Throckmorton DJ, Brennan JS, Singh AK (2006) Integrated preconcentration SDS-PAGE of proteins in microchips using photopatterned cross-linked polyacrylamide gels. Anal Chem 78:4976–4984
He F, Cheng Y, Xu Z, Liao Y, Xu J, Sun H, Wang C, Zhou Z, Sugioka K, Midorikawa K, Xu Y, Chen X (2010) Direct fabrication of homogeneous microfluidic channels embedded in fused silica using a femtosecond laser. Opt Lett 35:282–284
Herranz-Blanco B, Ginestar E, Zhang H, Hirvonen J, Santos HA (2017) Microfluidics platform for glass capillaries and its application in droplet and nanoparticle fabrication. Int J Pharm 516:100–105
Hong M, Zhu S, Jiang Y, Tang G, Pei Y (2009) Efficient tumor targeting of hydroxycamptothecin loaded PEGylated niosomes modified with transferrin. J Control Release 133:96–102
Hui Y, Yi X, Hou F, Wibowo D, Zhang F, Zhao D, Gao H, Zhao C-X (2019) Role of nanoparticle mechanical properties in cancer drug delivery. ACS Nano 13:7410–7424
Hyuk Im S, Jeong U, Xia Y (2005) Polymer hollow particles with controllable holes in their surfaces. Nat Mater 4:671–675
Jahn A, Stavis SM, Hong JS, Vreeland WN, DeVoe DL, Gaitan M (2010) Microfluidic mixing and the formation of nanoscale lipid vesicles. ACS Nano 4:2077–2087
Jahn A, Vreeland WN, DeVoe DL, Locascio LE, Gaitan M (2007) Microfluidic directed formation of liposomes of controlled size. Langmuir 23:6289–6293
Jahn A, Vreeland WN, Gaitan M, Locascio LE (2004) Controlled vesicle self-assembly in microfluidic channels with hydrodynamic focusing. J Am Chem Soc 126:2674–2675
Jamal F, Jean-Sébastien G, Maël P, Edmond P, Christian R (2012) Gold nanoparticle synthesis in microfluidic systems and immobilisation in microreactors designed for the catalysis of fine organic reactions. Microsyst Technol 18:151–158
Jena RK, Yue CY, Lam YC (2012) Micro fabrication of cyclic olefin copolymer (COC) based microfluidic devices. Microsyst Technol 18:159–166
Jenjob R, Phakkeeree T, Seidi F, Theerasilp M, Crespy D (2019) Emulsion techniques for the production of pharmacological nanoparticles. Macromol Biosci 19:e1900063
Jensen KF (2017) Flow chemistry—microreaction technology comes of age. AICHE J 63:858–869
Karnik R, Gu F, Basto P, Cannizzaro C, Dean L, Kyei-Manu W, Langer R, Farokhzad OC (2008) Microfluidic platform for controlled synthesis of polymeric nanoparticles. Nano Lett 8:2906–2912
Kawakatsu T, Kikuchi Y, Nakajima M (1997) Regular-sized cell creation in microchannel emulsification by visual microprocessing method. J Amer Oil Chem Soc 74:317–321
Khan IU, Serra CA, Anton N, Vandamme TF (2015) Production of nanoparticle drug delivery systems with microfluidics tools. Expert Opin Drug Deliv 12:547–562
Khan SA, Günther A, Schmidt MA, Jensen KF (2004) Microfluidic synthesis of colloidal silica. Langmuir 20:8604–8611
KianvashRad N, Barkhordari E, Mostafavi SH, Aghajani M (2019) Optimizing microfluidic preparation parameters of nanosuspension to evaluate stability in nanoprecipitation of stable-iodine (127I). SN Appl Sci 1:1054
Kim K, Lee J-B (2007) High aspect ratio tapered hollow metallic microneedle arrays with microfluidic interconnector. Microsyst Technol 13:231–235
Kim S-H, Kim JW, Cho J-C, Weitz DA (2011) Double-emulsion drops with ultra-thin shells for capsule templates. Lab Chip 11:3162–3166
Kim T, Kwon S (2006) Design, fabrication and testing of a catalytic microreactor for hydrogen production. J Micromech Microeng 16:1752–1760
Kimura N, Maeki M, Sato Y, Note Y, Ishida A, Tani H, Harashima H, Tokeshi M (2018) Development of the iLiNP device: fine tuning the lipid nanoparticle size within 10 nm for drug delivery. ACS Omega 3:5044–5051
Kobayashi I, Nakajima M, Chun K, Kikuchi Y, Fujita H (2002) Silicon array of elongated through-holes for monodisperse emulsion droplets. AICHE J 48:1639–1644
Koh CG, Zhang X, Liu S, Golan S, Yu B, Yang X, Guan J, Jin Y, Talmon Y, Muthusamy N, Chan KK, Byrd JC, Lee RJ, Marcucci G, Lee LJ (2010) Delivery of antisense oligodeoxyribonucleotide lipopolyplex nanoparticles assembled by microfluidic hydrodynamic focusing. J Control Release 141:62–69
Köhler JM, Romanus H, Hübner U, Wagner J (2007) Formation of star-like and core-shell AuAg nanoparticles during two- and three-step preparation in batch and in microfluidic systems. J Nanomater 2007:098134
Krishnamoorthy K, Mahalingam M (2015) Selection of a suitable method for the preparation of polymeric nanoparticles: multi-criteria decision making approach. Adv Pharm Bull 5:57–67
Kuiper S, van Rijn CJM, Nijdam W, Elwenspoek MC (1998) Development and applications of very high flux microfiltration membranes. J Membr Sci 150:1–8
Le TC, Zhai J, Chiu W-H, Tran PA, Tran N (2019) Janus particles: recent advances in the biomedical applications. Int J Nanomedicine 14:6749–6777
Leung MHM, Shen AQ (2018) Microfluidic assisted nanoprecipitation of PLGA nanoparticles for curcumin delivery to leukemia Jurkat cells. Langmuir 34:3961–3970
Li H, Fan Y, Kodzius R, Foulds IG (2012a) Fabrication of polystyrene microfluidic devices using a pulsed CO2 laser system. Microsyst Technol 18:373–379
Li H, Steckl AJ (2019) Paper microfluidics for point-of-care blood-based analysis and diagnostics. Anal Chem 91:352–371
Li XJ, Valadez AV, Zuo P, Nie Z (2012b) Microfluidic 3D cell culture: potential application for tissue-based bioassays. Bioanalysis 4:1509–1525
Lim J-M, Swami A, Gilson LM, Chopra S, Choi S, Wu J, Langer R, Karnik R, Farokhzad OC (2014) Ultra-high throughput synthesis of nanoparticles with homogeneous size distribution using a coaxial turbulent jet mixer. ACS Nano 8:6056–6065
Lin C-H, Lee G-B, Lin Y-H, Chang G-L (2001) A fast prototyping process for fabrication of microfluidic systems on soda-lime glass. J Micromech Microeng 11:726–732
Lin Q, Chen J, Zhang Z, Zheng G (2013) Lipid-based nanoparticles in the systemic delivery of siRNA. Nanomedicine 9:105–120
Liu D, Cito S, Zhang Y, Wang C-F, Sikanen TM, Santos HA (2015a) A versatile and robust microfluidic platform toward high throughput synthesis of homogeneous nanoparticles with tunable properties. Adv Mater 27:2298–2304
Liu D, Zhang H, Cito S, Fan J, Mäkilä E, Salonen J, Hirvonen J, Sikanen TM, Weitz DA, Santos HA (2017b) Core/Shell nanocomposites produced by superfast sequential microfluidic nanoprecipitation. Nano Lett 17:606–614
Liu D, Zhang H, Fontana F, Hirvonen JT, Santos HA (2017a) Microfluidic-assisted fabrication of carriers for controlled drug delivery. Lab Chip 17:1856–1883
Liu D, Zhang H, Fontana F, Hirvonen JT, Santos HA (2018a) Current developments and applications of microfluidic technology toward clinical translation of nanomedicines. Adv Drug Deliv Rev 128:54–83
Liu D, Zhang H, Herranz-Blanco B, Mäkilä E, Lehto V-P, Salonen J, Hirvonen J, Santos HA (2014) Microfluidic assembly of monodisperse multistage pH-responsive polymer/porous silicon composites for precisely controlled multi-drug delivery. Small 10:2029–2038
Liu D, Zhang H, Mäkilä E, Fan J, Herranz-Blanco B, Wang C-F, Rosa R, Ribeiro AJ, Salonen J, Hirvonen J, Santos HA (2015b) Microfluidic assisted one-step fabrication of porous silicon@acetalated dextran nanocomposites for precisely controlled combination chemotherapy. Biomaterials 39:249–259
Liu H, Nakajima M, Nishi T, Kimura T (2005) Effect of channel structure on preparation of a water-in-oil emulsion by polymer microchannels. Eur J Lipid Sci Technol 107:481–487
Liu Z, Fontana F, Python A, Hirvonen JT, Santos HA (2020) Microfluidics for production of particles: mechanism, methodology, and applications. Small 16:1904673
Liu Z, Li Y, Li W, Xiao C, Liu D, Dong C, Zhang M, Mäkilä E, Kemell M, Salonen J, Hirvonen JT, Zhang H, Zhou D, Deng X, Santos HA (2018b) Multifunctional nanohybrid based on porous silicon nanoparticles, gold nanoparticles, and acetalated dextran for liver regeneration and acute liver failure theranostics. Adv Mater 30:1703393
Lizotte T (2008) Vacuum isostatic micro molding of microfluidic structures into polytetrafluoroethylene (PTFE) materials paper presented at the SPIE Photonics Europe, Strasbourg, France
Manshadi MKD, Khojasteh D, Abdelrehim O, Gholami M, Sanati-Nezhad A (2021) In: Rahimpour MR, Kamali R, Amin Makarem M, Manshadi MKD (eds) Advances in bioenergy and microfluidic applications. Elsevier, pp 387–406
Martins JP, das Neves J, de la Fuente M, Celia C, Florindo H, Günday-Türeli N, Popat A, Santos JL, Sousa F, Schmid R, Wolfram J, Sarmento B, Santos HA (2020) The solid progress of nanomedicine. Drug Deliv. Transl Res 10:726–729
Martins JP, Liu D, Fontana F, Ferreira MPA, Correia A, Valentino S, Kemell M, Moslova K, Mäkilä E, Salonen J, Hirvonen J, Sarmento B, Santos HA (2018b) Microfluidic nanoassembly of bioengineered chitosan-modified FcRn-targeted porous silicon nanoparticles @ hypromellose acetate succinate for oral delivery of antidiabetic peptides. ACS Appl Mater Interfaces 10:44354–44367
Martins JP, Torrieri G, Santos HA (2018a) The importance of microfluidics for the preparation of nanoparticles as advanced drug delivery systems. Expert Opin Drug Deliv 15:469–479
Mathaes R, Winter G, Besheer A, Engert J (2015) Non-spherical micro- and nanoparticles: fabrication, characterization and drug delivery applications. Expert Opin Drug Deliv 12:481–492
Matsumura Y, Maeda H (1986) A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res 46:6387–6392
McCreedy T (2001) Rapid prototyping of glass and PDMS microstructures for micro total analytical systems and micro chemical reactors by microfabrication in the general laboratory. Anal Chim Acta 427:39–43
Mitchell MJ, Billingsley MM, Haley RM, Wechsler ME, Peppas NA, Langer R (2021) Engineering precision nanoparticles for drug delivery. Nat Rev Drug Discov 20:101–124
Morimoto Y, Tan W-H, Tsuda Y, Takeuchi S (2009) Monodisperse semi-permeable microcapsules for continuous observation of cells. Lab Chip 9:2217–2223
Muck A, Wang J, Jacobs M, Chen G, Chatrathi MP, Jurka V, Výborný Z, Spillman SD, Sridharan G, Schöning MJ (2004) Fabrication of poly(methyl methacrylate) microfluidic chips by atmospheric molding. Anal Chem 76:2290–2297
Mulligan MK, Rothstein JP (2012) Scale-up and control of droplet production in coupled microfluidic flow-focusing geometries. Microfluid Nanofluid 13:65–73
Nge PN, Rogers CI, Woolley AT (2013) Advances in microfluidic materials, functions, integration, and applications. Chem Rev 113:2550–2583
Nguyen N-T (2012) In: Nguyen N-T (ed) Micromixers (second edition). William Andrew Publishing, Oxford, pp 1–8
Niculescu A-G, Chircov C, Bîrcă AC, Grumezescu AM (2021) Nanomaterials synthesis through microfluidic methods: an updated overview. Nano 11
Nie Z, Xu S, Seo M, Lewis PC, Kumacheva E (2005) Polymer particles with various shapes and morphologies produced in continuous microfluidic reactors. J Am Chem Soc 127:8058–8063
Nielsen JB, Hanson RL, Almughamsi HM, Pang C, Fish TR, Woolley AT (2020) Microfluidics: innovations in materials and their fabrication and functionalization. Anal Chem 92:150–168
Nightingale AM, Bannock JH, Krishnadasan SH, O'Mahony FTF, Haque SA, Sloan J, Drury C, McIntyre R, deMello JC (2013) Large-scale synthesis of nanocrystals in a multichannel droplet reactor. J Mater Chem A 1:4067–4076
Nightingale AM, de Mello JC (2010) Microscale synthesis of quantum dots. J Mater Chem 20:8454–8463
Nisisako T, Ando T, Hatsuzawa T (2012) High-volume production of single and compound emulsions in a microfluidic parallelization arrangement coupled with coaxial annular world-to-chip interfaces. Lab Chip 12:3426–3435
Nisisako T, Torii T (2008) Microfluidic large-scale integration on a chip for mass production of monodisperse droplets and particles. Lab Chip 8:287–293
Nunes JK, Tsai SSH, Wan J, Stone HA (2013) Dripping and jetting in microfluidic multiphase flows applied to particle and fiber synthesis. J Phys D Appl Phys 46:114002
Nunes PS, Ohlsson PD, Ordeig O, Kutter JP (2010) Cyclic olefin polymers: emerging materials for lab-on-a-chip applications. Microfluid Nanofluid 9:145–161
Obeid MA, Khadra I, Albaloushi A, Mullin M, Alyamani H, Ferro VA (2019) Microfluidic manufacturing of different niosomes nanoparticles for curcumin encapsulation: physical characteristics, encapsulation efficacy, and drug release. Beilstein J Nanotechnol 10:1826–1832
Odera T, Hirama H, Kuroda J, Moriguchi H, Torii T (2014) Droplet formation behavior in a microfluidic device fabricated by hydrogel molding. Microfluid Nanofluid 17:469–476
Ogończyk D, Węgrzyn J, Jankowski P, Dąbrowski B, Garstecki P (2010) Bonding of microfluidic devices fabricated in polycarbonate. Lab Chip 10:1324–1327
Okushima S, Nisisako T, Torii T, Higuchi T (2004) Controlled production of monodisperse double emulsions by two-step droplet breakup in microfluidic devices. Langmuir 20:9905–9908
Olanrewaju A, Beaugrand M, Yafia M, Juncker D (2018) Capillary microfluidics in microchannels: from microfluidic networks to capillaric circuits. Lab Chip 18:2323–2347
Panagiotou T, Mesite SV, Fisher RJ (2009) Production of norfloxacin nanosuspensions using microfluidics reaction technology through solvent/antisolvent crystallization. Ind Eng Chem Res 48:1761–1771
Papi M, Pozzi D, Palmieri V, Caracciolo G (2022) Principles for optimization and validation of mRNA lipid nanoparticle vaccines against COVID-19 using 3D bioprinting. Nano Today 43:101403
Park C, Han YD, Kim HV, Lee J, Yoon HC, Park S (2018) Double-sided 3D printing on paper towards mass production of three-dimensional paper-based microfluidic analytical devices (3D-μPADs). Lab Chip 18:1533–1538
Park K (2007) Nanotechnology: what it can do for drug delivery. J Control Release 120:1–3
Pentecost AM, Martin RS (2015) Fabrication and characterization of all-polystyrene microfluidic devices with integrated electrodes and tubing. Anal Methods 7:2968–2976
Piruska A, Nikcevic I, Lee SH, Ahn C, Heineman WR, Limbach PA, Seliskar CJ (2005) The autofluorescence of plastic materials and chips measured under laser irradiation. Lab Chip 5:1348–1354
Qin D, Xia Y, Whitesides GM (2010) Soft lithography for micro- and nanoscale patterning. Nat Protoc 5:491–502
Quintanar-Guerrero D, Allémann E, Fessi H, Doelker E (1998) Preparation techniques and mechanisms of formation of biodegradable nanoparticles from preformed polymers. Drug Dev Ind Pharm 24:1113–1128
Rahil Hasan M, Anzar N, Tyagi M, Yadav N, Narang J (2021) In: Hussain CM, Shukla SK, Joshi GM (eds) Functionalized nanomaterials based devices for environmental applications. Elsevier, pp 175–198
Regehr KJ, Domenech M, Koepsel JT, Carver KC, Ellison-Zelski SJ, Murphy WL, Schuler LA, Alarid ET, Beebe DJ (2009) Biological implications of polydimethylsiloxane-based microfluidic cell culture. Lab Chip 9:2132–2139
Ren K, Zhou J, Wu H (2013) Materials for microfluidic chip fabrication. Acc Chem Res 46:2396–2406
Riahi R, Tamayol A, Shaegh SAM, Ghaemmaghami AM, Dokmeci MR, Khademhosseini A (2015) Microfluidics for advanced drug delivery systems. Curr Opin Chem Eng 7:101–112
Romanowsky MB, Abate AR, Rotem A, Holtze C, Weitz DA (2012) High throughput production of single core double emulsions in a parallelized microfluidic device. Lab Chip 12:802–807
Rondeau E, Cooper-White JJ (2008) Biopolymer microparticle and nanoparticle formation within a microfluidic device. Langmuir 24:6937–6945
Russo M, Grimaldi AM, Bevilacqua P, Tammaro O, Netti PA, Torino E (2017) PEGylated crosslinked hyaluronic acid nanoparticles designed through a microfluidic platform for nanomedicine. Nanomedicine 12:2211–2222
Sackmann EK, Fulton AL, Beebe DJ (2014) The present and future role of microfluidics in biomedical research. Nature 507:181–189
Samaridou E, Heyes J, Lutwyche P (2020) Lipid nanoparticles for nucleic acid delivery: current perspectives. Adv Drug Deliv Rev 154-155:37–63
Sanjay ST, Zhou W, Dou M, Tavakoli H, Ma L, Xu F, Li X (2018) Recent advances of controlled drug delivery using microfluidic platforms. Adv Drug Deliv Rev 128:3–28
Serra CA, Chang Z (2008) Microfluidic-assisted synthesis of polymer particles. Chem Eng Technol 31:1099–1115
Shah RK, Shum HC, Rowat AC, Lee D, Agresti JJ, Utada AS, Chu L-Y, Kim J-W, Fernandez-Nieves A, Martinez CJ, Weitz DA (2008) Designer emulsions using microfluidics. Mater Today 11:18–27
Shang L, Nienhaus K, Nienhaus GU (2014) Engineered nanoparticles interacting with cells: size matters. J Nanobiotechnol 12:5
Sharp KV, Adrian RJ (2004) Transition from laminar to turbulent flow in liquid filled microtubes. Exp Fluids 36:741–747
Sia SK, Whitesides GM (2003) Microfluidic devices fabricated in poly(dimethylsiloxane) for biological studies. Electrophoresis 24:3563–3576
Silvestrini S, Carofiglio T, Maggini M (2013) Shape-selective growth of silver nanoparticles under continuous flow photochemical conditions. Chem Commun 49:84–86
Sohrabi S, Kassir N, Keshavarz Moraveji M (2020) Droplet microfluidics: fundamentals and its advanced applications. RSC Adv 10:27560–27574
Song Y, Modrow H, Henry LL, Saw CK, Doomes EE, Palshin V, Hormes J, Kumar CSSR (2006) Microfluidic synthesis of cobalt nanoparticles. Chem Mater 18:2817–2827
Stepanyan R, Lebouille JG, Slot JJ, Tuinier R, Stuart MA (2012) Controlled nanoparticle formation by diffusion limited coalescence. Phys Rev Lett 109:138301
Stroock AD, Dertinger SK, Ajdari A, Mezic I, Stone HA, Whitesides GM (2002) Chaotic mixer for microchannels. Science 295:647–651
Studart AR, Shum HC, Weitz DA (2009) Arrested coalescence of particle-coated droplets into nonspherical supracolloidal structures. J Phys Chem B 113:3914–3919
Stylios GK (2013) There is plenty of room at the bottom, R.P. Feynman. Int J Cloth Sci Technol 25
Sun J, Zhang L, Wang J, Feng Q, Liu D, Yin Q, Xu D, Wei Y, Ding B, Shi X, Jiang X (2015) Tunable rigidity of (polymeric core)–(lipid shell) nanoparticles for regulated cellular uptake. Adv Mater 27:1402–1407
Suriya Prabha A, Dorothy R, Jancirani S, Rajendran S, Singh G, Senthil Kumaran S (2020) In: Rajendran S, Mukherjee A, Nguyen TA, Godugu C, Shukla RK (eds) Nanotoxicity. Elsevier, pp 143–165
Thorsen T, Roberts RW, Arnold FH, Quake SR (2001) Dynamic pattern formation in a vesicle-generating microfluidic device. Phys Rev Lett 86:4163–4166
Thu VT, Mai AN, Le The T, Van Trung H, Thu PT, Tien BQ, Thuat NT, Lam TD (2016) Fabrication of PDMS-based microfluidic devices: application for synthesis of magnetic nanoparticles. J Electron Mater 45:2576–2581
Tomeh MA, Zhao X (2020) Recent advances in microfluidics for the preparation of drug and gene delivery systems. Mol Pharm 17:4421–4434
Tong J, Nakajima M, Nabetani H, Kikuchi Y, Maruta Y (2001) Production of oil-in-water microspheres using a stainless steel microchannel. J Colloid Interface Sci 237:239–248
Toy R, Peiris PM, Ghaghada KB, Karathanasis E (2013) Shaping cancer nanomedicine: the effect of particle shape on the in vivo journey of nanoparticles. Nanomedicine 9:121–134
Utada AS, Chu LY, Fernandez-Nieves A, Link DR, Holtze C, Weitz DA (2007b) Dripping, jetting, drops, and wetting: The magic of microfluidics. MRS Bull 32:702–708
Utada AS, Fernandez-Nieves A, Stone HA, Weitz DA (2007a) Dripping to jetting transitions in coflowing liquid streams. Phys Rev Lett 99:094502
Valencia PM, Basto PA, Zhang L, Rhee M, Langer R, Farokhzad OC, Karnik R (2010) Single-step assembly of homogenous lipid-polymeric and lipid-quantum dot nanoparticles enabled by microfluidic rapid mixing. ACS Nano 4:1671–1679
Veiseh O, Tang BC, Whitehead KA, Anderson DG, Langer R (2015) Managing diabetes with nanomedicine: challenges and opportunities. Nat Rev Drug Discov 14:45–57
Verma A, Stellacci F (2010) Effect of surface properties on nanoparticle-cell interactions. Small 6:12–21
Vladisavljević GT, Khalid N, Neves MA, Kuroiwa T, Nakajima M, Uemura K, Ichikawa S, Kobayashi I (2013) Industrial lab-on-a-chip: design, applications and scale-up for drug discovery and delivery. Adv Drug Deliv Rev 65:1626–1663
Wabuyele MB, Ford SM, Stryjewski W, Barrow J, Soper SA (2001) Single molecule detection of double-stranded DNA in poly(methylmethacrylate) and polycarbonate microfluidic devices. Electrophoresis 22:3939–3948
Wagner J, Köhler JM (2005) Continuous synthesis of gold nanoparticles in a microreactor. Nano Lett 5:685–691
Wagner J, Tshikhudo TR, Köhler JM (2008) Microfluidic generation of metal nanoparticles by borohydride reduction. Chem Eng J 135:S104–S109
Wagner V, Dullaart A, Bock A-K, Zweck A (2006) The emerging nanomedicine landscape. Nat Biotechnol 24:1211–1217
Wallace GG, Higgins MJ, Moulton SE, Wang C (2012) Nanobionics: the impact of nanotechnology on implantable medical bionic devices. Nanoscale 4:4327–4347
Wang B, Shum HC, Weitz DA (2009a) Fabrication of monodisperse toroidal particles by polymer solidification in microfluidics. ChemPhysChem 10:641–645
Wang J, Li W, Zhang L, Ban L, Chen P, Du W, Feng X, Liu B-F (2017) Chemically edited exosomes with dual ligand purified by microfluidic device for active targeted drug delivery to tumor cells. ACS Appl Mater Interfaces 9:27441–27452
Wang JT, Wang J, Han JJ (2011) Fabrication of advanced particles and particle-based materials assisted by droplet-based microfluidics. Small 7:1728–1754
Wang Q-A, Wang J-X, Li M, Shao L, Chen J-F, Gu L, An Y-T (2009b) Large-scale preparation of barium sulphate nanoparticles in a high-throughput tube-in-tube microchannel reactor. Chem Eng J 149:473–478
Wang S, Wannasarit S, Figueiredo P, Li J, Correia A, Xia B, Wiwattanapatapee R, Hirvonen J, Liu D, Li W, Santos HA (2020) Superfast and controllable microfluidic inking of anti-inflammatory melanin-like nanoparticles inspired by cephalopods. Mater Horiz 7:1573–1580
Wang W, Zhang M-J, Xie R, Ju X-J, Yang C, Mou C-L, Weitz DA, Chu L-Y (2013) Hole–shell microparticles from controllably evolved double emulsions. Angew Chem Int Ed 52:8084–8087
Webb C, Forbes N, Roces CB, Anderluzzi G, Lou G, Abraham S, Ingalls L, Marshall K, Leaver TJ, Watts JA, Aylott JW, Perrie Y (2020) Using microfluidics for scalable manufacturing of nanomedicines from bench to GMP: a case study using protein-loaded liposomes. Int J Pharm 582:119266
Weng C-H, Huang C-C, Yeh C-S, Lei H-Y, Lee G-B (2008) Synthesis of hexagonal gold nanoparticles using a microfluidic reaction system. J Micromech Microeng 18:035019
Whitesides GM (2006) The origins and the future of microfluidics. Nature 442:368–373
Wu M-H, Huang S-B, Lee G-B (2010) Microfluidic cell culture systems for drug research. Lab Chip 10:939–956
Wujcik EK, Monty CN (2013) Nanotechnology for implantable sensors: carbon nanotubes and graphene in medicine. Wiley Interdiscip Rev Nanomed Nanobiotechnol 5:233–249
Xia Y, Whitesides GM (1998) Soft lithography. Angew Chem Int Ed Engl 37:550–575
Xu S, Nie Z, Seo M, Lewis P, Kumacheva E, Stone HA, Garstecki P, Weibel DB, Gitlin I, Whitesides GM (2005) Generation of monodisperse particles by using microfluidics: control over size, shape, and composition. Angew Chem Int Ed Engl 44:724–728
Yang S, Guo F, Kiraly B, Mao X, Lu M, Leong KW, Huang TJ (2012) Microfluidic synthesis of multifunctional Janus particles for biomedical applications. Lab Chip 12:2097–2102
Yao X, Chen Z, Chen G (2009) Fabrication of PMMA microfluidic chips using disposable agar hydrogel templates. Electrophoresis 30:4225–4229
Yeh C-H, Lin P-W, Lin Y-C (2009) Chitosan microfiber fabrication using a microfluidic chip and its application to cell cultures. Microfluid Nanofluid 8:115
Ying Y, Chen G, Zhao Y, Li S, Yuan Q (2008) A high throughput methodology for continuous preparation of monodispersed nanocrystals in microfluidic reactors. Chem Eng J 135:209–215
Yu B, Lee RJ, Lee LJ (2009) Microfluidic methods for production of liposomes. Methods Enzymol 465:129–141
Zhang H, Chiao M (2015) Anti-fouling coatings of poly(dimethylsiloxane) devices for biological and biomedical applications. J Med Biol Eng 35:143–155
Zhang H, Liu D, Shahbazi M-A, Mäkilä E, Herranz-Blanco B, Salonen J, Hirvonen J, Santos HA (2014) Fabrication of a multifunctional nano-in-micro drug delivery platform by microfluidic templated encapsulation of porous silicon in polymer matrix. Adv Mater 26:4497–4503
Zhang L, Wang W, Ju X-J, Xie R, Liu Z, Chu L-Y (2015) Fabrication of glass-based microfluidic devices with dry film photoresists as pattern transfer masks for wet etching. RSC Adv 5:5638–5646
Zhang P, Du C, Huang T, Hu S, Bai Y, Li C, Feng G, Gao Y, Li Z, Wang B, Hirvonen JT, Fan J, Santos HA, Liu D (2022) Surface adsorption-mediated ultrahigh efficient peptide encapsulation with a precise ratiometric control for type 1 and 2 diabetic therapy. Small:2200449
Zhao C-X, Middelberg APJ (2016) In: Aliofkhazraei M (ed) Handbook of nanoparticles. Springer International Publishing, Cham, pp 455–473
Zhao Y, Shum HC, Chen H, Adams LL, Gu Z, Weitz DA (2011) Microfluidic generation of multifunctional quantum dot barcode particles. J Am Chem Soc 133:8790–8793
Zhou J, Ellis AV, Voelcker NH (2010) Recent developments in PDMS surface modification for microfluidic devices. Electrophoresis 31:2–16
Zhu P, Wang L (2017) Passive and active droplet generation with microfluidics: a review. Lab Chip 17:34–75
Zielińska A, Carreiró F, Oliveira AM, Neves A, Pires B, Venkatesh DN, Durazzo A, Lucarini M, Eder P, Silva AM, Santini A, Souto EB (2020) Polymeric nanoparticles: production, characterization, toxicology and ecotoxicology. Molecules 25:3731
Zook JM, Vreeland WN (2010) Effects of temperature, acyl chain length, and flow-rate ratio on liposome formation and size in a microfluidic hydrodynamic focusing device. Soft Matter 6:1352–1360
Acknowledgements
Financial support from the Sigrid Jusélius Foundation and the Academy of Finland (Grant No. 331151) is acknowledged.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Ethics declarations
The authors declare no conflict of interest.
Rights and permissions
Copyright information
© 2023 The Author(s), under exclusive license to Springer Nature Switzerland AG
About this chapter
Cite this chapter
Martins, J.P., Santos, H.A. (2023). Microfluidics as a Tool for the Synthesis of Advanced Drug Delivery Systems. In: Lamprou, D. (eds) Nano- and Microfabrication Techniques in Drug Delivery . Advanced Clinical Pharmacy - Research, Development and Practical Applications, vol 2. Springer, Cham. https://doi.org/10.1007/978-3-031-26908-0_13
Download citation
DOI: https://doi.org/10.1007/978-3-031-26908-0_13
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-031-26907-3
Online ISBN: 978-3-031-26908-0
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)