Microfluidics: a transformational tool for nanomedicine development and production

Abstract Microfluidic devices are mircoscale fluidic circuits used to manipulate liquids at the nanoliter scale. The ability to control the mixing of fluids and the continuous nature of the process make it apt for solvent/antisolvent precipitation of drug-delivery nanoparticles. This review describes the use of numerous microfluidic designs for the formulation and production of lipid nanoparticles, liposomes and polymer nanoparticles to encapsulate and deliver small molecule or genetic payloads. The advantages of microfluidics are illustrated through examples from literature comparing conventional processes such as beaker and T-tube mixing to microfluidic approaches. Particular emphasis is placed on examples of microfluidic nanoparticle formulations that have been tested in vitro and in vivo. Fine control of process parameters afforded by microfluidics, allows unprecedented optimization of nanoparticle quality and encapsulation efficiency. Automation improves the reproducibility and optimization of formulations. Furthermore, the continuous nature of the microfluidic process is inherently scalable, allowing optimization at low volumes, which is advantageous with scarce or costly materials, as well as scale-up through process parallelization. Given these advantages, microfluidics is poised to become the new paradigm for nanomedicine formulation and production.

[1]  A. Bangham,et al.  NEGATIVE STAINING OF PHOSPHOLIPIDS AND THEIR STRUCTURAL MODIFICATION BY SURFACE-ACTIVE AGENTS AS OBSERVED IN THE ELECTRON MICROSCOPE. , 1964, Journal of molecular biology.

[2]  A. Bangham,et al.  Diffusion of univalent ions across the lamellae of swollen phospholipids. , 1965, Journal of molecular biology.

[3]  E. Korn,et al.  Single bilayer liposomes prepared without sonication. , 1973, Biochimica et biophysica acta.

[4]  T. Allen,et al.  Subcutaneous administration of liposomes: a comparison with the intravenous and intraperitoneal routes of injection. , 1993, Biochimica et biophysica acta.

[5]  D. Lasič LIPOSOMES in GENE DELIVERY , 1997 .

[6]  D. Quintanar-Guerrero,et al.  Preparation techniques and mechanisms of formation of biodegradable nanoparticles from preformed polymers. , 1998, Drug development and industrial pharmacy.

[7]  R. Müller,et al.  Solid lipid nanoparticles (SLN) for controlled drug delivery - a review of the state of the art. , 2000, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[8]  Luigi Naldini,et al.  Viral vectors for gene therapy: the art of turning infectious agents into vehicles of therapeutics , 2001, Nature Medicine.

[9]  L. Jeffs,et al.  A Scalable, Extrusion-Free Method for Efficient Liposomal Encapsulation of Plasmid DNA , 2005, Pharmaceutical Research.

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

[11]  J. Heyes,et al.  Cationic lipid saturation influences intracellular delivery of encapsulated nucleic acids. , 2005, Journal of controlled release : official journal of the Controlled Release Society.

[12]  E. Allémann,et al.  Development of a nanoprecipitation method intended for the entrapment of hydrophilic drugs into nanoparticles. , 2005, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[13]  V. Torchilin Recent advances with liposomes as pharmaceutical carriers , 2005, Nature Reviews Drug Discovery.

[14]  M. R. Mozafari,et al.  Liposomes: an overview of manufacturing techniques. , 2005, Cellular & molecular biology letters.

[15]  A. Lee,et al.  Design of noninflammatory synthetic siRNA mediating potent gene silencing in vivo. , 2006, Molecular therapy : the journal of the American Society of Gene Therapy.

[16]  A. Parker,et al.  Delivery of RNA Interference , 2006, Cell cycle.

[17]  Matthias John,et al.  RNAi-mediated gene silencing in non-human primates , 2006, Nature.

[18]  Aravind Chakrapani,et al.  Nanoparticles and microparticles as vaccine-delivery systems , 2007, Expert review of vaccines.

[19]  Wyatt N Vreeland,et al.  Microfluidic directed formation of liposomes of controlled size. , 2007, Langmuir : the ACS journal of surfaces and colloids.

[20]  A. Tsourkas,et al.  Size, charge and concentration dependent uptake of iron oxide particles by non-phagocytic cells. , 2008, Biomaterials.

[21]  Dion R. Brocks,et al.  Impact of lipoproteins on the biological activity and disposition of hydrophobic drugs: implications for drug discovery , 2008, Nature Reviews Drug Discovery.

[22]  Peng George Wang,et al.  A facile microfluidic method for production of liposomes. , 2008, Anticancer research.

[23]  Joseph E. Reiner,et al.  Preparation of nanoparticles by continuous-flow microfluidics , 2008 .

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

[25]  Bo Yu,et al.  Microfluidic methods for production of liposomes. , 2009, Methods in enzymology.

[26]  Daniel G. Anderson,et al.  Knocking down barriers: advances in siRNA delivery , 2009, Nature Reviews Drug Discovery.

[27]  K. G. Rajeev,et al.  Rational design of cationic lipids for siRNA delivery , 2010, Nature Biotechnology.

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

[29]  R. Dahm,et al.  Transfection Techniques for Neuronal Cells , 2010, The Journal of Neuroscience.

[30]  L. J. Lee,et al.  Ultrasound-enhanced microfluidic synthesis of liposomes. , 2010, Anticancer research.

[31]  Randy Crawford,et al.  Analysis of lipid nanoparticles by Cryo-EM for characterizing siRNA delivery vehicles. , 2011, International journal of pharmaceutics.

[32]  L. J. Lee,et al.  Microfluidic assembly of lipid-based oligonucleotide nanoparticles. , 2011, Anticancer research.

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

[34]  Hari Singh Nalwa,et al.  Medical applications of nanoparticles in biological imaging, cell labeling, antimicrobial agents, and anticancer nanodrugs. , 2011, Journal of biomedical nanotechnology.

[35]  Daniel A. Balazs,et al.  Liposomes for Use in Gene Delivery , 2010, Journal of drug delivery.

[36]  C. Hansen,et al.  Correction to “Lipid Nanoparticles Containing siRNA Synthesized by Microfluidic Mixing Exhibit an Electron-Dense Nanostructured Core” , 2012, The Journal of Physical Chemistry. C, Nanomaterials and Interfaces.

[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]  Nathan M Belliveau,et al.  Microfluidic Synthesis of Highly Potent Limit-size Lipid Nanoparticles for In Vivo Delivery of siRNA , 2012, Molecular therapy. Nucleic acids.

[39]  Moritz Beck-Broichsitter,et al.  Optimising the self-assembly of siRNA loaded PEG-PCL-lPEI nano-carriers employing different preparation techniques. , 2012, Journal of Controlled Release.

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

[41]  Pedro M. Valencia,et al.  Targeted Polymeric Therapeutic Nanoparticles: Design, Development and Clinical Translation , 2012 .

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

[43]  Dirk van Swaay,et al.  Microfluidic methods for forming liposomes. , 2013, Lab on a chip.

[44]  Jie Chen,et al.  Nanoparticles for gene delivery. , 2013, Small.

[45]  G. Vladisavljević,et al.  Preparation of liposomes: a novel application of microengineered membranes--from laboratory scale to large scale. , 2013, Colloids and surfaces. B, Biointerfaces.

[46]  Don L. DeVoe,et al.  Microfluidic Synthesis of PEG- and Folate-Conjugated Liposomes for One-Step Formation of Targeted Stealth Nanocarriers , 2013, Pharmaceutical Research.

[47]  P. Cullis,et al.  Lipid nanoparticle delivery systems for siRNA-based therapeutics , 2013, Drug Delivery and Translational Research.

[48]  P. Cullis,et al.  Advances in Lipid Nanoparticles for siRNA Delivery , 2013, Pharmaceutics.

[49]  Soodabeh Davaran,et al.  Liposome: classification, preparation, and applications , 2013, Nanoscale Research Letters.

[50]  Chunyang Xiong,et al.  Mass production of highly monodisperse polymeric nanoparticles by parallel flow focusing system , 2013 .

[51]  K. G. Rajeev,et al.  Biodegradable lipids enabling rapidly eliminated lipid nanoparticles for systemic delivery of RNAi therapeutics. , 2013, Molecular therapy : the journal of the American Society of Gene Therapy.

[52]  Mohammad Mahdi Hasani-Sadrabadi,et al.  Microfluidic assisted self-assembly of chitosan based nanoparticles as drug delivery agents. , 2013, Lab on a chip.

[53]  P. Sunthar,et al.  Influence of micro-mixing on the size of liposomes self-assembled from miscible liquid phases. , 2013, Chemistry and physics of lipids.

[54]  P. Cullis,et al.  Liposomal drug delivery systems: from concept to clinical applications. , 2013, Advanced drug delivery reviews.

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

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

[57]  B. MacVicar,et al.  Lipid Nanoparticle Delivery of siRNA to Silence Neuronal Gene Expression in the Brain , 2013, Molecular therapy. Nucleic acids.

[58]  Yvonne Perrie,et al.  High-throughput manufacturing of size-tuned liposomes by a new microfluidics method using enhanced statistical tools for characterization. , 2014, International journal of pharmaceutics.

[59]  D. DeVoe,et al.  Microfluidic-Enabled Liposomes Elucidate Size-Dependent Transdermal Transport , 2014, PloS one.

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

[61]  P. Cullis,et al.  Development of lipid nanoparticle formulations of siRNA for hepatocyte gene silencing following subcutaneous administration. , 2014, Journal of controlled release : official journal of the Controlled Release Society.

[62]  Bryan Hoang,et al.  Docetaxel-carboxymethylcellulose nanoparticles display enhanced anti-tumor activity in murine models of castration-resistant prostate cancer. , 2014, International journal of pharmaceutics.

[63]  P. Cullis,et al.  Lipid Nanoparticles for Short Interfering RNA Delivery , 2014, Advances in Genetics.

[64]  P. Cullis,et al.  Development and clinical applications of siRNA-encapsulated lipid nanoparticles in cancer , 2014 .

[65]  Shyh-Dar Li,et al.  A highly tumor-targeted nanoparticle of podophyllotoxin penetrated tumor core and regressed multidrug resistant tumors. , 2015, Biomaterials.

[66]  P. Cullis,et al.  Microfluidic Mixing: A General Method for Encapsulating Macromolecules in Lipid Nanoparticle Systems. , 2015, The journal of physical chemistry. B.

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

[68]  Dan Peer,et al.  Systemic Gene Silencing in Primary T Lymphocytes Using Targeted Lipid Nanoparticles. , 2015, ACS nano.

[69]  M. Gleave,et al.  siRNA Lipid Nanoparticle Potently Silences Clusterin and Delays Progression When Combined with Androgen Receptor Cotargeting in Enzalutamide-Resistant Prostate Cancer , 2015, Clinical Cancer Research.

[70]  Yvonne Perrie,et al.  Microfluidic-controlled manufacture of liposomes for the solubilisation of a poorly water soluble drug. , 2015, International journal of pharmaceutics.

[71]  N. Kaji,et al.  A strategy for synthesis of lipid nanoparticles using microfluidic devices with a mixer structure , 2015 .

[72]  Xingyu Jiang,et al.  Microfluidic Synthesis of Hybrid Nanoparticles with Controlled Lipid Layers: Understanding Flexibility-Regulated Cell-Nanoparticle Interaction. , 2015, ACS nano.

[73]  P. Cullis,et al.  Production of limit size nanoliposomal systems with potential utility as ultra-small drug delivery agents , 2015, Journal of liposome research.

[74]  Yvonne Perrie,et al.  Designing liposomal adjuvants for the next generation of vaccines. , 2016, Advanced drug delivery reviews.