Microfluidic Manufacture of Lipid-Based Nanomedicines
Abstract
:1. The Nanomedicine Market and Bottlenecks to Market Entry
2. Lipid-Based Nanomedicines
2.1. Current Methods for Lipid-Based Nanomedicine Manufacture
2.2. Challenges with Lipid-Based Nanomedicine Manufacture and Clinical Translation
3. Microfluidic Manufacture and the Problem of Mixing
3.1. Microfluidic Devices and Principles
3.1.1. Principles of Mass Transfer and Fluid Mixing
3.1.2. Microreactor Design and Mixing
Microreactors with Continuous Flow
Microreactors with Segmented Flow
Micromixer Channel Dimensions and Residence Time Effects
3.1.3. Heat Transfer and Temperature Control
3.2. Materials for Microfluidic Chip Fabrication Applicable for Nanomaterial Production
4. Microfluidic Manufacture of Lipid-Based Nanomedicines: Studies to Date
4.1. Nanomedicines Prepared with T- or Y-Junction (Shaped) Mixers
4.2. Microfluidic Hydrodynamic Flow (MHF) Focusing
4.3. Microfluidic Staggered Herringbone (SHM) (Chaotic) Micromixers
4.4. Bifurcating Mixer
4.5. Baffle Mixers
Delivery System/Lipids | Drug/API | Chip Design | FRR (aq:org) | TFR (mL·min−1) | In Vitro Findings | In Vivo Findings | Optimized Formula | Ref. | ||
---|---|---|---|---|---|---|---|---|---|---|
Mean Diameter (nm) | PDI | LE% | ||||||||
Lipoplex/ DOTAP:EPC:DOPE | pDNA | FF | 10:1 | 140 mm·s−1 | Transfection efficacy ~10 × 107 relative light units (RLU)·mg of protein−1 | NA | ~135 | ~2.3 | NA | [270] |
Patterned walls FF | Transfection efficacy ~6 × 107 RLU·mg of protein−1 | ~115 | ~2.0 | |||||||
Lipid nanoparticles/ mPEG-DSPC:POPC | AmB | NASHM | 3:1 | 12 | IC50: 0.085 μg·mL−1, hemolytic at ≥25 μg·mL−1 | NA | ~39 | ~0.115 | 88 | [271] |
T-junction | 24 | |||||||||
Liposomes/ SPC:Chol (3:1 w/w) | CBD | T-junction and zig zag or split and combine | 1:5 | 10 | NA | NA | ~110 | ~0.13 | ~73 | [236] |
Lipoplex/ DOTAP:DOPE:DOPC:DSPE-PEG2000-FolA or DOTAP:DOPE:DOPC:DSPE-PEG2000 | siRNA | HFF | 9:1 | 0.0167 | In vitro studies on wildtype epithelial carcinoma KB cells show endosomal uptake in the perinuclear region | NA | ~40 | NA | ~60 | [242] |
Targeted Lipoplex/ DODMA:DOTMA or DCChol:EggPC:mPEG-DSPE) modified with Tf | siRNAs (LOR-1284) | HFF | 5:1 | 0.025−2.000 | siRNA complex was stable in serum for 8 h compared to 40% of free siRNA; no significant cytotoxicity in MV4-11 cells; 6.14-fold reduction in IC50 for siRNA complex (105.27 nM) and increased downregulation compared to free siRNA | 20% of IV dose remained in plasma after 24 h (t1/2: 10.2 h, AUC: 5.5 h μg·mL−1) compared to 1% for free siRNA. (t1/2: 2.93 h); 3-fold increase in t1/2 and decreased protein expression by 86%. | ~80 | NA | 91.5 ± 4.5 | [272] |
Transferrin-conjugated Lipoplex (Tf-LNPs-MF)/ DOTMA:DODMA:EPC:Chol:mPEG-Cho | siRNAs | SHM | 3 inlets: 3:1:1 | NA | Increased permeability in HepG-2 cells by Tf receptor mediated uptake | Tf-LNPs-MF-siRNA in blood was >100 ng·mL−1 and t1/2 was 25.6 h 48 h post IV vs. <10 ng·mL−1 and t1/2 of 15.1 h for free siRNA | 132.6 | 0.129 | N/A | [224] |
Lipoplex/ DLinKC2-DMA(cationic lipid):Chol:DSPC:PEG2000-C-DMA | siRNAs | SHM | 3:1 | 0.02−4.00 | NA | 50% silencing in hepatocytes at 10 µg·kg−1 in mice | 28−54 | <0.1 | ~100 | [228] |
Lipoplex/ DSPC:mPEG2000-DMG:Chol:range of cationic lipids | siRNAs | SHM | 1:1:2 (lipids: siRNA: buffer | 1.2 | NA | Gene silencing potency of >90% at 1.0 mg·kg−1 in mice | 90.5 | NA | ∼80 | [258] |
Cubosomes/ DOTAP:Glycerol monooleate (GMO):GMO-PEG2000 | siRNAs | SHM | 6:1 | 4 | Gene-knockdown efficiency of 73.6% for a ρ = nDOTAP/nNA of 3 vs. Lipofectamine (45.8%) efficiency; Up to ρ = 10, no significant damage to cell membranes. | NA | 77 | 0.06 | >90% | [273] |
Lipid nanoparticles/ YSK05 (cationic pH-sensitive lipid):Chol:mPEG2000-DMG | siRNA | SHM | 3:1 | 1.5 | Particles with 1%, 1.25%, and 1.5% w/w and <2% mPEG (67.1, 57.3, and 53.8 nm) show high and similar gene silencing efficiencies | FVII gene silencing activity of 50% Chol-rich 1% mPEG-LNPs was higher than 3% mPEG-LNPs | 32−67 | NA | ∼100 | [274] |
Lipid nanoparticles/ YSK05 (cationic pH-sensitive lipid):Chol:mPEG2000-DMG | siRNA | Baffle mixers | 3:1 | 0.5 | NA | YSK-LNPs showed high FVII gene-silencing activity with no dose dependency | 80 | 0.1 | >90% | [269] |
Liposomes/ EPC:DMPC:DPPC:DSPC | Metformin (M) and glipizide (G) | NASHM | 5:1 | 5–15 | Sustained release was achieved | NA | 80–90 | 0.11–0.22 | ~20 (M) ~40 (G) | [250] |
Lipid nanoparticles/ DSPC:D-Lin-MC3-DMA:Chol:PEG-DMG | siRNA | NASHM | 3:1 | 12 | 79% mRNA knockdown produced by 1 μg siRNA | 15 mg·kg−1 (3 doses IV over 24 h) results in a 100% uptake in peripheral blood cells that remain positive until day 10; no liver toxicity or other biochemical alternation; after 10 IV doses over 35 days, luciferase signal decreased 0.75-fold, while it increased in control mice 1.6-fold; 60% knockdown efficiency of BCR-ABL by LNP-anti-BCR-ABL siRNA in sorted leukemia cells from the myelosarcoma mouse tissue | 55.03 | 0.046 | >90 | [275] |
Liposomes/ DSPC:mPEG2000-DSPE | Dox, ICU | SHM | 10:1 and/or 16:1 | 5 | After 48 h, ~90% of drug was released (first order); less cytotoxic to MCF-7, MDA-MB 231 and BT-474 breast cancer cells vs. free doxorubicin | NA | ~100 | 0.2 | >80 | [276] |
Liposomes/ DMPC:DPPC:DSPC | Curcumin | NASHM | 5:1 | 17 | Increased 700-fold the aqueous curcumin solubility | When co-administered with cisplatin, it enhances cisplatin’s efficacy in multiple mouse tumor models with decreased nephrotoxicity | ~125 | <0.2 | 87.7 | [277] |
Nanoemulsions/ Cold-pressed hempseed oil:lecithin:Poloxamer 188 | Hempseed oil | NASHM | 4:1 | 12 | >98% Caco-2 cell viability; increased uptake by 38.2% | NA | 62 | 0.032 | > 99 | [278] |
Liposomes/ HSPC:DOPC:mPEG2000-DSPE | Dox | NASHM | 9:1 | 10 | Burst release (20–30%) followed by <10% release over 7 days at 37 °C or during 3 weeks storage at 4 °C | Higher tumor accumulation (5–6% dose/g) at days 1 and 4. | ~50 | <0.2 | > 80 | [279] |
Liposomes/ EPC or DMPC or DPPC or DSPC or PS:Chol | OVA | NASHM | 3:1 | 15 | Longer chain lipids have slower release rates; burst release observed within 12 h followed by a slower release rate | NA | 60–100 | <0.2 | 20–35 | [280] |
Liposomes/ EPC:Chol | Propofol | NASHM | 3:1 | 2 | Burst release (40%,1 h) reaching 90% within 8 h | NA | ~40 | 0.4 | 85 | [264] |
Liposomes/DMPC:Chol:DEPE-PEG2000:DSPE-PEG2000—FA or DSPE-PEG2000-Cys-TAT(CYGRKKRRQRRR) 55:40:3:1 molar ratio | Folic acid (FA) | HFF | 16:1 | 28.8 µL/min | FA and TAT liposomes have 37% and 98% increased targeting in SKOV3 cell spheroids compared to TAT liposomes and FA liposomes, respectively | Improved tumor targeting and longer tumor retention (up to 72 h); 140%, 136%, and 62% higher tumor accumulation than pegylated liposomes and FA or TAT targeted liposomes, respectively | ~60 | <0.3 | NA | [223] |
Lipoplex/DSPC:cholesterol: DOTAB or DDAB or D-Lin-MC3-DMA:DMG-PEG2000, | mRNA or ssDNA, Poly A | NxGen | 5:1–1:1 | 12−200 | NA | NA | <100 | <0.25 | >90 | [266] |
Liposomes/HSPC:Chol:DSPE-PEG2000 56:38:5 molar ratio and EPC:Chol 45:55 molar ratio | Dox | M110P Microfluidizer® | Pressures of 5–20 Kpsi | 1–3 cycles | NA | NA | 100–110 | <0.2 | 97–98 | [281] |
Techniques | Mechanism | Separation Marker | Sizes Separated (nm) | Efficiency (%) | Throughput (mL·min−1) | Pros | Cons |
---|---|---|---|---|---|---|---|
Field flow fractionation | Asymmetrical flow FFF | Size | 5–250 | 87–88 | 0.4–1.1 | Very high throughput with high separation efficiency | Specific sample/solvent systems and compatible membrane |
Centrifugal | Centrifugal force | Size, density | 50–200 | - | 0.0075 | High throughput, density gradient, and dilution not required | Discontinuous |
Optical | Optical force | Size, refractive index, polarizability | 70–1000 | - | 0.010–0.375 | High separation efficiency | Heating and photodamage, low throughput |
Affinity capture | Surface interactions | Antigenic site, hydrophobicity, charge | 100 | - | 0.010 | High capture efficiency and purity | Expensive, multiple preparation steps |
Electrophore-sis | Uniform electric field | Size, charge | <50 | 97 | 0.0004 | Very high separation efficiency and resolution | Flow rate change with chemistry (buffers, wall effects) |
Dielectropho-resis | Nonuniform electric field | Polarizability and size | 30–60 | 85–100 | 0.000009 | High throughput and separation efficiency | Requires high voltage, depends on medium conductivity, very low throughput |
Magnetopho-resis | Magnetic field | Size, magnetic properties | 5–200 | 90 | 0.300 | Very high throughput, low cost | Long time for magnetic bead antibody labeling |
Acoustopho-resis | Ultrasonic sound wave | Size, density, compressibility | <200 | >90 | 0.00043–0.00081 | High separation efficiency, controlled cut off separation | Complex fabrication, limited device material to transmit acoustic power efficiently |
Ion concentration polarization | Electric field | Size, electrophoretic mobility | 100–500 | - | 0.0005 | Low voltage, no need for internal electrode | Low resolution on small size particles, low throughput |
Electrohydro-dynamic vortices | Traveling waves, ohmic heating | Size, charge | 200 | ~100 | 0.000033 | High separation efficiency | Complex fabrication of microelectrode, low throughput |
Deterministic lateral displacement | Laminar flow stream | Size, deformability | 190–2000 | ~100 | 0.00001 | Controllable cutoff size, simple and efficient, high separation efficiency (20 nm resolution) | Very low throughput, precise fabrication required, pillar clogging is possible |
Hydrodyna-mic filtration | Hydrodynamic sieving | Size | 100–1000 | - | 0.001 | Simple, high separation efficiency, medium throughput | Prone to clogging |
Spiral microfluidics | Dean vortices | Size, shape | 590–7320 | 95 | 0.010 | Very high separation efficiency, simple | Prone to particle-particle interactions and diffusion disruption |
Inertial microfluidics | Shear and wall lift | Size, shape | 590–1980 | - | - | Very high throughput, separation efficiency, simple | Prone to particle–particle interactions and diffusion disruption |
Electrostatic sieving | Electric double-layer force | Size, charge | 19–50 | 97 | 0.0006 | Very high separation efficiency, controllable cut-off size | Separation only possible in low ionic strength conditions, low throughput |
Bacterial chemotaxis | Chemotaxis, diffusion, and bacterial motility | Selective adhesion on bacteria | 320–390 | 81 | 0.000013 | Simple, low cost | Requires antibody conjugation for selective adhesion to bacteria, very low throughput, and relatively medium separation efficiency |
5. Further Application and Processes of Microfluidic Approaches
5.1. Purification Strategies
5.2. Analysis on a Chip and Production with a High Throughput
5.3. Scale-Up Manufacture
6. Future Perspectives and Challenges
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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System | Components | Diameter (nm)/Shape | Manufacturing | Pros | Cons | Refs. |
---|---|---|---|---|---|---|
Transferosomes | Edge activators, phospholipids | Less than 300/spherical bilayer | Vortexing, sonication, rotary film, or reverse-phase evaporations | Good stability, higher penetration | Susceptible to oxidative degradation | [36,90] |
Liposomes | Cholesterol, phospholipids, essential oils | 10–1000/spherical bilayers | Solvent dispersion, mechanical dispersion, detergent removal | Controlled release, drug protection, solubility improvement for hydrophobic drugs, high biodistribution and bioavailability | Rigid structure, limited penetration across the stratum corneum | [28,29,32,33,62,90] |
Nanostructured lipid carriers (NLCs) | Liquid and solid lipids, surfactants | 50–1000/spherical single layer | Sonication, micro emulsification, high-pressure homogenization | High cell uptake, appropriate protection of therapeutics in acidic pH, biodegradable and biocompatible, simplicity of drug entrapment, long shelf-life, more sustainable drug dissolution, high payload, reduced loss of drug during storage | Solid/liquid lipid ratio optimization difficulties | [52,53,91,92,93] |
Solid lipid nanoparticles (SLNs) | Surfactants, solid lipids | 50–1000/spherical single layer | Sonication, micro emulsification, high-pressure homogenization | High cell uptake, appropriate protection of therapeutics in acidic pH, biodegradable and biocompatible ingredients, simplicity of drug entrapment, long shelf-life | Gelling tendency | [50,51,52,91,92,93,94,95,96,97,98] |
Ethosomes | Phospholipids, edge activator, high concentration of a low-molecular-weight alcohol (ethanol ≤45% w/w), water | <200 or 300/spherical with diverse lamellarities | Solvent dispersion, ethanol injection–sonication, thin-film hydration, reverse-phase evaporation, transmembrane pH gradient, extrusion, and sonication | Increased efficacy and therapeutic index, reduce toxicity of API, improved permeation, entrapment of lipophilic, hydrophilic, and amphiphilic agents, simplicity of manufacturing, noninvasive, better solubility and stability, selective passive targeting | Low production yield, only for potent drugs, skin dermatitis or irritation may occur, drug leakage during transfer from organic to water media | [99,100] |
Cochleates | Phospholipid–cation precipitates (formed by a continuous, solid, lipid bilayer sheet rolled up in a spiral) | 100–1000/cylindrical shape | Trapping method (a bridging agent is mixed with an aqueous lipid suspension), hydrogel method, dialysis, emulsification–lyophilization, microfluidic method, solvent injection | Nonimmunogenic, noninflammatory, and nontoxic, a stable structure due to their tightly packed nature, less susceptible to oxidation of both the encapsulated drug and the phospholipids, sustained release is achievable, enhanced shelf-life, improvements in oral bioavailability of drugs | Aggregation on storage, high production cost | [56,101] |
Method | Mechanism | Suitability for Continuous Manufacturing |
---|---|---|
Bangham | Rehydration of thin lipid film | Not practical—needs continuous dehydration/rehydration steps |
Sonication | Sonication of aqueous lipid suspensions | Requires small-scale batch operation to ensure sonication efficiency |
Reverse-phase evaporation | Aqueous phase added to organic phase and evaporated to form liposomes | Very complex to regulate continuous solvent evaporation, sterile boundary hard to establish |
Detergent depletion | Liposomes forms through detergent–lipid interaction | Slow process with difficult-to-establish sterile boundary, detergent use generally disadvantageous |
Microfluidic channel | Intersection of lipid and API solutions in micromixers | Continuous but small/medium scale that can be upscaled in parallel |
High-pressure homogenization | Liposome formation through high-pressure mixing | Very high pressures required, difficulty in sterilizing equipment |
Heating | Heating of lipid aqueous/glycerol solution to form liposomes | Hydration step and high temperatures make continuous production impractical |
Supercritical fluid methods | Use of supercritical fluids as solvent for lipids instead | High pressures required for feed vessels make resupply/continuous operation impractical |
Dense gas | Use of dense gas as solvent for lipids | High pressures required for feed vessels make resupply/continuous operation impractical |
Dual asymmetric centrifugation | Mechanical turbulence and cavitation | Only for batch sizes ~1 g or less |
Ethanol/ether injection | Precipitation of liposome from organic phase into aqueous | Simple process with inherently continuous liposome formation step |
Crossflow | In-line precipitation of liposome from organic phase into aqueous | Simple process with inherently continuous liposome formation step |
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Osouli-Bostanabad, K.; Puliga, S.; Serrano, D.R.; Bucchi, A.; Halbert, G.; Lalatsa, A. Microfluidic Manufacture of Lipid-Based Nanomedicines. Pharmaceutics 2022, 14, 1940. https://doi.org/10.3390/pharmaceutics14091940
Osouli-Bostanabad K, Puliga S, Serrano DR, Bucchi A, Halbert G, Lalatsa A. Microfluidic Manufacture of Lipid-Based Nanomedicines. Pharmaceutics. 2022; 14(9):1940. https://doi.org/10.3390/pharmaceutics14091940
Chicago/Turabian StyleOsouli-Bostanabad, Karim, Sara Puliga, Dolores R. Serrano, Andrea Bucchi, Gavin Halbert, and Aikaterini Lalatsa. 2022. "Microfluidic Manufacture of Lipid-Based Nanomedicines" Pharmaceutics 14, no. 9: 1940. https://doi.org/10.3390/pharmaceutics14091940