Biomaterials2021ReviewDrug Delivery

Microfluidic formulation of nanoparticles for biomedical applications

Shepherd Sj, Issadore D, Mitchell Mj.29 September 2026DOI 10.1016/j.biomaterials.2021.120826

Summary

Nanomedicine translation is limited by non-scalable, batch-variable bulk NP formulation methods that often produce large, polydisperse particles. Microfluidics offers precise control over microscale mixing and nanoprecipitation, enabling more reproducible NPs with controlled size, size distribution, and loading. This review summarizes microfluidic advances for lipid-, polymer-, and inorganic-based NPs. Representative quantitative findings from reviewed literature: - SHM-produced LNPs: 60–90 nm vs ~180 nm by pipette mixing; >90% hepatic gene silencing; up to 7-fold increased mRNA potency. - Parallelized SHM: 72 mL/min;.

Keywords

Nanoparticles Lipid nanoparticle Polymeric PLGA mRNA DNA Microfluidics

Purpose: Nanomedicine translation is limited by non-scalable, batch-variable bulk NP formulation methods that often produce large, polydisperse particles. Microfluidics offers precise control over microscale mixing and nanoprecipitation, enabling more reproducible NPs with controlled size, size distribution, and loading. This review summarizes microfluidic advances for lipid-, polymer-, and inorganic-based NPs.

Hypothesis: No formal experimental hypothesis. Central thesis: microfluidic formulation yields NPs with more controlled physical properties than bulk techniques, improving biomedical performance and clinical translation potential.

Aims: Review microfluidic technologies for NP formulation. - Highlight lipid-based NPs, polymeric NPs, and inorganic NPs. - Summarize device advantages and challenges. - Discuss future directions: scale-independent production via device parallelization and multi-step reactions within droplets.

Delivery system: Lipid-based: liposomes and lipid nanoparticles (LNPs); payloads include siRNA, mRNA, DNA, CRISPR/Cas9 components, and small molecules (e.g., propofol). - Polymeric: PLGA, PLGA-PEG, PCL, PBAE, PCPP, hyaluronic acid, shellac; payloads include drugs, proteins, DNA, and imaging agents. - Inorganic: gold, silver, iron oxide, quantum dots, silica, hafnium oxide; used for imaging, photothermal therapy, and drug delivery. - Microfluidic platforms: hydrodynamic flow focusing (2D/3D HFF), staggered herringbone micromixers (SHMs), bifurcating mixers, baffle mixers, T-junction mixing, droplet-based mixers, jet mixers, Tesla mixers, and spiral channels.

Approach: Narrative review, not primary experimentation. Synthesizes literature comparing bulk and microfluidic NP formulation, with tables of clinically approved NPs and device-NP applications. Covers in vitro, in vivo, and clinical examples.

Key methods: Review-level synthesis of: - Device architecture and mixing mechanism comparisons. - NP characterization: size, PDI, zeta potential, encapsulation efficiency, drug loading. - In vitro assays: transfection, gene silencing, cytotoxicity. - In vivo readouts: biodistribution, pharmacokinetics, gene editing, imaging (MRI, CT, photoacoustic). - Clinical approval/trial status.

Key results: Representative quantitative findings from reviewed literature: - SHM-produced LNPs: 60–90 nm vs ~180 nm by pipette mixing; >90% hepatic gene silencing; up to 7-fold increased mRNA potency. - Parallelized SHM: 72 mL/min; bifurcating NxGen mixers up to 20 L/hr (25-fold increase). - Core/shell PLGA/HF nanocomposites: drug loading >42% vs 6% single microfluidic device and 4% bulk precipitation. - Droplet-based inorganic synthesis: gold NPs ~2.8 nm; dextran-coated iron oxide NPs ~3.6 nm with narrow size distribution. - SHM propofol liposomes: ~300 mg/mL solubility vs 0.15 mg/mL aqueous solubility.

Interpretation: Microfluidics has substantially improved control over NP size, dispersity, and encapsulation efficiency, enabling biomaterial discovery and high-throughput screening. The authors argue that scale-independent parallelization and droplet-based multi-step reactions are key future directions to accelerate clinical translation.

Limitations: Review article: no primary data or systematic meta-analysis. - Focuses on selected NP classes and microfluidic designs, not exhaustive. - Field challenges noted: PDMS solvent incompatibility/swelling, channel clogging/fouling, low single-device throughput (<10 mL/hr), fabrication complexity for solvent-resistant materials, precise droplet pairing/electrode requirements, and limited large-animal/clinical validation for many platforms.

Biochemical Pharmacology*, Volume 173, 2020, Article 113648 DOI/