RSC Advances2019ReviewDrug Delivery

Microfluidic Assisted Synthesis of PLGA Drug Delivery Systems

Sima Rezvantalab And Mostafa Keshavarz Moraveji29 September 2026DOI 10.1039/c8ra08972h

Summary

PLGA is a biocompatible, biodegradable copolymer widely used in drug delivery systems (DDS), but conventional bulk synthesis methods suffer from poor control over particle size, broad size distribution, low drug loading/encapsulation efficiency, and burst release. Microfluidic systems offer a tightly controlled, reproducible alternative with low material consumption, but the field lacks a consolidated overview to guide researchers in selecting. ### 8.1 Microfluidic Type Determines Particle Size Scale - Droplet-based microfluidics → PLGA microparticles (typically 1–1000 μm) - Continuous microfluidics → PLGA nanoparticles (typically 10–1000 nm) - Exception: Lee.

Keywords

PLGA Drug delivery Polymeric Microfluidics Nanoparticles Cellular uptake siRNA

Purpose: PLGA is a biocompatible, biodegradable copolymer widely used in drug delivery systems (DDS), but conventional bulk synthesis methods suffer from poor control over particle size, broad size distribution, low drug loading/encapsulation efficiency, and burst release. Microfluidic systems offer a tightly controlled, reproducible alternative with low material consumption, but the field lacks a consolidated overview to guide researchers in selecting appropriate microfluidic platforms for PLGA-based DDS production.

Hypothesis: As this is a review article, there is no single testable hypothesis. The authors' central thesis is:

> If microfluidic systems are used for PLGA DDS synthesis, then particles with tunable size, narrow size distribution, higher drug loading/encapsulation efficiency, and reduced burst release can be achieved compared to conventional bulk methods — with the choice of microfluidic type (droplet-based vs. continuous) determining whether microparticles (MPs) or nanoparticles (NPs) are produced.

Aims: Primary aim: To comprehensively review PLGA-based DDS produced via microfluidic systems, addressing the impact of solvent and microfluidic system design on particle size and properties. - Secondary aims: - To classify and describe microfluidic designs (droplet-based vs. continuous phase flow) and their respective flow regimes (dripping, jetting, squeezing) and geometries (cross-flow, co-flow, flow-focusing). - To establish the relationship between microfluidic type and final particle size (droplet-based → MPs; continuous → NPs). - To review specific PLGA DDS subtypes: PEG-PLGA NPs, Lipid-PLGA NPs, core-shell MPs, and Janus MPs. - To identify challenges (clogging, fouling, low throughput, PDMS incompatibility) and strategies to overcome them (parallelization, 3D designs, high-throughput mixers).

Delivery system:

Feature: Polymer; Description: PLGA (poly(lactic-co-glycolic acid)), various LA:GA ratios (50:50, 75:25, 85:15) and molecular weights (10–100 kDa)

Feature: Particle Types; Description: Nanoparticles (NPs), microparticles (MPs), core-shell MPs, Janus MPs, polymersomes, microcapsules

Feature: Payloads; Description: Hydrophobic drugs (PTX, DOX, camptothecin, dexamethasone, celecoxib, sorafenib), hydrophilic drugs (cisplatin, DOX hydrochloride), proteins (insulin, GFP), imaging agents (CdSe/ZnS QDs, gold NPs, SPIONs), siRNA

Feature: Surface Modifications; Description: PEGylation (PEG-PLGA), lipid coatings (lipid-PLGA), targeting ligands (PSMA ligand, transferrin)

Feature: Microfluidic Materials; Description: PDMS, glass capillaries, aluminum, silicon, polyimide, fluoroelastomer, brass

Feature: Microfluidic Designs; Description: Droplet-based: T-junction, co-flow, flow-focusing, cross-flow; Continuous: 2D/3D hydrodynamic focusing (HF), coaxial tube devices

Approach: This is a narrative review synthesizing literature from the past two decades on PLGA DDS produced in microfluidic systems. The authors:

Surveyed microfluidic designs and categorized them by flow configuration (droplet-based vs. continuous).
Analyzed the relationship between microfluidic type and particle size using a compilation of reported size ranges (Fig. 5).
Examined specific PLGA DDS subtypes (PEG-PLGA, Lipid-PLGA, core-shell MPs, Janus MPs) with representative studies.
Discussed opportunities, challenges, and translational considerations.

No primary experimental data is presented; all data are compiled from cited references.

Key methods: The review compiles and analyzes data from referenced studies using:

Particle size characterization: DLS, SEM, TEM (as reported in cited works)
Drug loading and encapsulation efficiency: Reported as percentages from cited studies
In vitro release kinetics: Cumulative release profiles
Cellular uptake: Confocal microscopy, flow cytometry (from cited studies)
In vivo efficacy: Tumor volume measurements, biodistribution (from cited studies)
Microfluidic mixing characterization: Mixing time simulations, flow regime analysis (Reynolds number effects)
Throughput analysis: Production rates (g/day or kg/day) from cited studies

Key results: ### 8.1 Microfluidic Type Determines Particle Size Scale - Droplet-based microfluidics → PLGA microparticles (typically 1–1000 μm) - Continuous microfluidics → PLGA nanoparticles (typically 10–1000 nm) - Exception: Lee et al. produced PLGA NPs (70–500 nm) via droplet-based microfluidics using DMSO/solvent extraction; fast evaporation of DMC produced MPs (3–30 μm).

8.2 Drug Loading and Encapsulation Efficiency: - Microfluidic PLGA NPs showed higher drug loading and encapsulation efficiency compared to bulk methods (Fig. 6III). - Sequential capillary configuration increased PTX loading from 6.7% to 42.6% and SFN from 6.2% to 45.2% compared to single-step process. - Core-shell MPs with GelMa crosslinking achieved encapsulation efficiency of ~46–61% for CPT and 85–93% for DOX hydrochloride, depending on shell thickness (22–60 μm). - Dual drug-loaded MPs showed synergistic antitumor effect: <20% HCT116 cells and <10% HepG2 cells survived vs. ~50% and ~60% killing with individual drugs.

8.3 Size Control Parameters: - Flow rate ratio: Higher flow ratios → larger NPs (Fig. 6II); higher Reynolds numbers → smaller NPs (Fig. 6V). - Microchannel diameter: Decreasing from 600 to 130 μm reduced NP size from ~133 nm to ~28 nm. - Polymer molecular weight: Increasing PLGA MW from 10 to 90 kDa increased NP size from ~26 to 150 nm. - Polymer concentration: Increasing from 10 to 50 mg/mL increased NP size from 13 to 26 nm. - Mixing time: 3D designs reduced mixing time (2D flat HF: 29 ms; 3D arc: 16 ms; 3D double spiral: 14.5 ms at 2.5 mL/h).

8.4 Throughput Achievements: - Parallel 3D HF devices (8 parallel): reduced batch time for 25 mg from 5 h to <20 min. - 3-layer PDMS with 100 channels: 0.5–2.0 mL/h polymer flow rate. - 3D HF with parallel polyimide films: up to 331 g/day of PEG-PLGA NPs. - Turbulent jet micromixer: >3 kg/day — highest reported throughput.

8.5 In Vivo Performance: - DOX-loaded PLGA-PEG NPs with pH-sensitive shell (PEG-b-PDPA) significantly suppressed drug-resistant tumor growth (MCF-7/ADR) compared to free DOX (Fig. 6VII, VIII). - Lipid-PLGA NPs (~100% cellular uptake) vs. free DOX (~30%) in MCF-7/ADR cells; NPs completely eliminated from body after 24 h (Fig. 6XI). - Targeted NPs (14% mole targeted polymer) increased LNCaP cell uptake and tumor accumulation up to 3.5-fold vs. bare PLGA-PEG NPs.

8.6 Morphology Control: - Core-shell MPs: Achieved by W/O/W double emulsion templates; shell thickness affects encapsulation efficiency and release. - Janus MPs: Produced by phase separation in droplets; solvent choice (DMC vs. DCM) and polymer ratio (PLGA:PCL) control morphology (Janus, patchy, core-shell). - Surface texture: Controllable by PEG content in PLGA blends; higher PEG → bumpy surface → faster drug release. - Hollow/porous MPs: Achieved via gas encapsulation or double emulsion templates.

Interpretation: The authors claim that microfluidic systems represent a powerful platform for producing PLGA-based DDS with sophisticated features (targeting ligands, stimuli-responsiveness, co-loading of incompatible drugs) that are difficult to achieve via bulk methods. They emphasize that the choice of microfluidic type is critical: droplet-based systems yield MPs with complex morphologies (core-shell, Janus, multiple cores), while continuous systems yield NPs with narrow size distribution. The authors assert that despite limitations (clogging, fouling, low throughput, PDMS incompatibility), the technology holds great potential for advancing drug delivery systems, and knowledge gained from the reviewed examples can guide researchers in selecting proper reactants, microfluidic type, and process parameters.

Limitations: Stated by authors: - PDMS incompatibility: PDMS is susceptible to organic solvents, not resistant to high temperature/pressure, and difficult to modify for varying hydrophobicity. - Clogging and fouling: PLGA NP precipitation causes microchannel clogging; many failed chips in lab. - Low throughput: Limited production scale cannot meet industrial demand; only few reports of high production rates suitable for preclinical/clinical demands. - Online characterization/purification: Difficult to achieve in microscale. - High cost: Glass, PTFE, and aluminum microchannels are expensive; aluminum has limited scale. - 3D microfluidics complexity: Difficult to achieve stable flow and reproducible manner. - Nano-scale droplet manipulation: Requires large amounts of power; almost impossible to online characterize and control.

Implicit limitations: - Review does not include meta-analysis or quantitative comparison across studies. - No discussion of regulatory pathways for microfluidic-produced DDS. - Limited coverage of scale-up validation for clinical manufacturing. - No cost-effectiveness analysis. - Most cited studies are proof-of-concept with limited long-term stability data.

Summary Table: PLGA DDS in Microfluidics:

DDS Type: PLGA NPs; Microfluidic Type: Continuous (2D HF); Size Range: 70–500 nm; Key Advantage: Narrow size distribution; Representative Ref.: Karnik et al., 2008

DDS Type: PEG-PLGA NPs; Microfluidic Type: Continuous (3D HF); Size Range: 26–150 nm; Key Advantage: Long circulation, immune evasion; Representative Ref.: Rhee et al., 2011

DDS Type: Lipid-PLGA NPs; Microfluidic Type: Continuous (2D HF); Size Range: ~62–87 nm; Key Advantage: Hydrophobic drug loading, prolonged circulation; Representative Ref.: Feng et al., 2015

DDS Type: Core-shell MPs; Microfluidic Type: Droplet-based; Size Range: 15–50 μm; Key Advantage: Dual drug delivery, sequential release; Representative Ref.: Li et al., 2017

DDS Type: Janus MPs; Microfluidic Type: Droplet-based; Size Range: ~24 μm; Key Advantage: Incompatible drug co-loading; Representative Ref.: Min et al., 2016

DDS Type: PLGA MPs; Microfluidic Type: Droplet-based; Size Range: 1–100 μm; Key Advantage: Controlled size, narrow distribution; Representative Ref.: Xu et al., 2009

DDS Type: PLGA microspheres; Microfluidic Type: Droplet-based; Size Range: 10–50 μm; Key Advantage: Reduced burst release; Representative Ref.: Xu et al., 2009

DDS Type: Hollow MPs; Microfluidic Type: Droplet-based; Size Range: <7 μm; Key Advantage: Multidrug delivery; Representative Ref.: Vasiliauskas et al., 2015

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