Microfluidic Technologies for Advanced Drug Delivery Systems: A Comprehensive Review

Fig.1. Evolution of Drug Delivery from Conventional Systems to Microfluidics

Components Of Microfluidic Devices

Microfluidic devices are integrated platforms consisting of interconnected components that enable the precise transport, mixing, processing and monitoring of very small volumes of fluids. In advanced drug delivery, the performance of each component directly affects critical formulation parameters such as particle size, morphology, drug loading, encapsulation efficiency and reproducibility. The major components include microchannels, micropumps, microvalves, micromixers, reservoirs, sensors and the materials used for device fabrication [25-27]. Recent advances have increasingly focused on integrating fluid handling, actuation and sensing functions within compact microfluidic platforms to improve automation, process control and reproducibility.

Microchannels

Microchannels are the primary pathways through which fluids move within a microfluidic device. They are generally fabricated with dimensions ranging from a few micrometres to several hundred micrometres. Channel dimensions, geometry, surface characteristics and arrangement determine fluid velocity, pressure drop, residence time, mixing efficiency and interfacial interactions [6,25]. Different channel configurations, including straight channels, serpentine channels, T-junctions, flow-focusing channels and branching networks, can be selected according to the intended pharmaceutical application. In drug delivery research, microchannels provide controlled environments for nanoparticle synthesis, liposome formation, emulsification, drug encapsulation and self-assembly processes. Precise control of channel geometry contributes to uniform particle formation and improved batch-to-batch reproducibility [10,11,25].

Micropumps

Micropumps are responsible for transporting fluids through microchannels at controlled flow rates and pressures. Depending on the device design, pumping may be achieved using pressure-driven, pneumatic, mechanical, electroosmotic, centrifugal or other actuation mechanisms. Accurate flow control is essential because the flow rate and flow-rate ratio between formulation streams can strongly influence particle size, mixing, residence time and encapsulation efficiency [26,28]. In advanced drug delivery systems, micropumps provide the actuation mechanism required to deliver controlled volumes of therapeutic agents and formulation components from reservoirs into microfluidic channels. Their integration with valves, chambers and flow-control structures enables precise and automated fluid handling [26,28].

Microvalves

Microvalves regulate the direction, timing and quantity of fluid entering different regions of a microfluidic device. They can be used to start or stop flow, isolate individual channels, control reagent addition and prevent unwanted backflow. Microvalves may employ pneumatic, mechanical, thermal, electrostatic or other actuation mechanisms [28,29]. Microvalves are particularly important in complex microfluidic platforms where multiple formulation components must be introduced sequentially or simultaneously. Their integration with pumps and microchannels enables automated fluid routing and improves the control of multistep microfluidic processes [28,29].

Micromixers

Micromixers facilitate rapid and controlled mixing of two or more fluids within microchannels. Because microfluidic systems commonly operate under laminar-flow conditions, molecular diffusion can limit mixing. Micromixers therefore employ specialized channel geometries or external energy sources to increase interfacial contact and enhance mass transfer [12,30]. Micromixers can broadly be classified as passive or active systems. Passive mixers rely on channel geometry, splitting and recombination, chaotic advection or diffusion, whereas active mixers use external forces such as acoustic, electrical, magnetic, thermal or mechanical energy. Efficient micromixing is particularly important in nanoprecipitation, liposome formation, lipid nanoparticle preparation and nanoemulsion production because mixing conditions influence nucleation, particle growth, size distribution and encapsulation efficiency [11,12,30].

Reservoirs

Reservoirs are storage compartments that hold formulation components, solvents, drug solutions, biological samples or other reagents before they are introduced into the microfluidic system. They may be integrated directly into the device or connected externally to the microfluidic channels. Reservoirs, channels, pumps, valves and mixers collectively form the principal fluid-handling components of integrated microfluidic systems [31]. In pharmaceutical applications, separate reservoirs can be used for active pharmaceutical ingredients, polymers, lipids, surfactants, organic solvents and aqueous phases. Appropriate reservoir design helps maintain a consistent supply of formulation components and facilitates continuous or automated processing [26,31].

Sensors and Detectors

Sensors and detectors provide real-time monitoring of physical and chemical parameters within microfluidic systems. Depending on the application, these components can measure parameters such as temperature, pressure, flow rate, pH, conductivity, concentration, particle formation and other process variables [32,33]. Integration of sensors enables real-time process monitoring and quality control. Monitoring flow rate and pressure can help identify changes in fluid resistance or potential channel blockage, while optical, electrical and electrochemical detection methods can monitor biological or physicochemical events within the microfluidic platform. Sensor integration also supports automation and closed-loop control of microfluidic processes [32,33].

Device Materials

The material used to fabricate a microfluidic device influences its mechanical strength, chemical compatibility, optical properties, surface characteristics, manufacturing cost and suitability for pharmaceutical applications. Common materials include PDMS, glass, silicon and thermoplastic polymers [25,27,34].

PDMS: Polydimethylsiloxane is widely used in laboratory-scale microfluidics because of its low cost, optical transparency, elasticity and ease of fabrication. However, its swelling in organic solvents and absorption of hydrophobic compounds can limit its suitability for some pharmaceutical formulations [25,34].

Glass: Glass provides high optical transparency, chemical resistance, thermal stability and compatibility with a broad range of solvents. These properties make it useful for pharmaceutical and analytical microfluidic applications, although fabrication can be relatively expensive and time-consuming [25,27].

Silicon: Silicon provides excellent thermal and chemical stability and allows highly precise microfabrication. However, its opacity, fragility and comparatively high manufacturing cost can limit its use in applications requiring optical observation or large-scale low-cost production [25,27].

Thermoplastic polymers: Thermoplastics such as cyclic olefin copolymer, polymethyl methacrylate and polycarbonate offer low cost, mechanical strength and compatibility with mass-production technologies such as injection moulding and hot embossing. Consequently, they are increasingly attractive for commercial and scalable microfluidic devices [27,34].

Integration of Components for Drug Delivery

The major components of a microfluidic device function as an integrated system rather than as independent units. Reservoirs supply formulation components, micropumps control their movement, microvalves regulate their distribution, microchannels establish the fluidic environment and micromixers control molecular interactions. Sensors provide real-time monitoring and feedback, while the device material determines the overall physical and chemical characteristics of the platform [25,28,32]. The coordinated integration of fluid handling, actuation, mixing, sensing and control components enables increasingly automated microfluidic platforms. Such integration is particularly important for pharmaceutical manufacturing because it can support reproducible formulation, real-time process monitoring and eventual translation toward scalable and commercially viable microfluidic systems [25,27,32,35].

Types Of Microfluidic Technologies

Microfluidic technologies can be broadly classified according to the manner in which fluids are transported, mixed, segmented and manipulated within microscale environments. The major platforms relevant to pharmaceutical and biomedical applications include continuous-flow microfluidics, droplet microfluidics, digital microfluidics, paper-based microfluidics and organ-on-chip microfluidics. Each platform provides distinct advantages in terms of fluid control, automation, throughput, material requirements and suitability for drug formulation or biomedical applications [25,35].

1. Continuous-Flow Microfluidics

Continuous-flow microfluidics involves the continuous introduction and transport of two or more fluid streams through interconnected microchannels. The fluids are controlled using parameters such as flow rate, flow-rate ratio, channel geometry and residence time. Because fluid movement occurs predominantly under laminar-flow conditions, precise control of mixing, diffusion and reaction environments can be achieved. Continuous-flow systems are particularly suitable for reproducible and scalable production of nanoparticles, liposomes, lipid nanoparticles and other drug delivery carriers [10,11,23,24]. One important advantage of continuous-flow microfluidics is the ability to maintain stable formulation conditions over extended processing periods. This makes the approach attractive for pharmaceutical manufacturing because formulation parameters can be continuously monitored and adjusted. For example, controlled mixing of an organic phase containing polymers or lipids with an aqueous phase can promote rapid solvent exchange and controlled nanoparticle self-assembly. Continuous-flow platforms therefore provide a useful bridge between laboratory-scale formulation development and potential continuous pharmaceutical manufacturing [11,25,35].

2. Droplet Microfluidics

Droplet microfluidics generates discrete droplets of one fluid within an immiscible continuous phase. Each droplet can act as an independent microreactor or formulation compartment, allowing chemical reactions, particle formation, drug encapsulation and biological processes to occur in highly controlled volumes. Droplet size and production frequency can be regulated by controlling flow rates, viscosity, interfacial tension, channel geometry and surfactant concentration [19-21]. Common configurations include T-junction, flow-focusing and co-flow devices. The high degree of droplet uniformity makes this technology particularly useful for producing microspheres, microcapsules, nanoemulsions and other encapsulated drug delivery systems. The compartmentalized nature of droplets also facilitates parallel processing and high-throughput screening of formulation conditions [19-22,36].

3. Digital Microfluidics

Digital microfluidics represents a different approach in which individual droplets are manipulated as discrete units rather than being continuously transported through fixed microchannels. Droplets can be transported, merged, split, mixed and dispensed on a programmable surface, most commonly using electrowetting-on-dielectric (EWOD) technology. Electrical control of the surface wettability allows precise manipulation of individual droplets and enables reconfigurable fluidic operations [37,38]. The programmable nature of digital microfluidics makes it particularly attractive for automated and multiplexed biochemical processes. Unlike fixed continuous-flow architectures, digital systems can dynamically change the sequence of operations and manipulate different samples independently. Applications include sample preparation, biochemical analysis, point-of-care testing, drug screening and other biomedical workflows. The reduced reagent requirement and ability to automate multiple operations on a single platform are important advantages for pharmaceutical and biomedical applications [37,38].

4. Paper-Based Microfluidics

Paper-based microfluidics uses porous materials such as cellulose paper to transport liquids through interconnected pathways primarily by capillary action. These devices can be fabricated at relatively low cost and generally require little or no external pumping equipment. Their simplicity, portability and disposability make them particularly attractive for resource-limited settings and point-of-care applications [39]. Although paper-based microfluidics has been more extensively developed for diagnostics than for pharmaceutical formulation, the technology has potential applications in drug screening, drug delivery and controlled transport of therapeutic compounds. Paper microfluidic devices can integrate sample preparation, fluid transport, reaction and detection within a compact platform. Their low material consumption and simple fabrication also provide opportunities for developing inexpensive disposable pharmaceutical and biomedical devices [39].

5. Organ-on-Chip Microfluidics

Organ-on-chip microfluidics combines microfluidic engineering with cell culture, tissue engineering and biomaterials to reproduce selected structural and physiological characteristics of human organs within microscale devices. These systems generally contain microchannels, living cells or tissues and controlled fluidic environments that can reproduce aspects of tissue architecture, mechanical forces, nutrient transport and cellular interactions [4,40,41]. Organ-on-chip platforms are increasingly important in pharmaceutical research because they provide more physiologically relevant environments for drug screening, toxicity assessment, disease modelling and personalized medicine. Examples include liver-on-chip, kidney-on-chip, lung-on-chip, gut-on-chip and vascular models. These systems can be used to investigate drug absorption, distribution, metabolism and toxicity and may complement conventional cell culture and animal models during drug development [4,40,41].

Comparative significance of different microfluidic technologies

The five platforms differ substantially in their operating principles and pharmaceutical applications. Continuous-flow systems are particularly suitable for reproducible nanoparticle and liposome production, whereas droplet microfluidics provides highly compartmentalized and uniform reaction environments. Digital microfluidics offers programmable and reconfigurable manipulation of individual droplets. Paper-based microfluidics emphasizes low-cost, portable and disposable platforms, while organ-on-chip systems focus primarily on reproducing physiological microenvironments for drug development and personalized medicine [19,25,35-41]. The selection of a particular microfluidic technology therefore depends on the intended application, required throughput, formulation characteristics, degree of automation, material compatibility and scale of operation. Increasingly, hybrid systems that combine continuous-flow, droplet, digital, sensing and organ-on-chip technologies are being investigated to achieve greater flexibility and functional integration in pharmaceutical research [25,35,38,40].

Role Of Microfluidics In Modern Drug Delivery

Microfluidics has emerged as an important enabling technology for the development of advanced drug delivery systems because it provides precise control over fluid flow, mixing, nucleation, self-assembly and particle formation. Compared with conventional bulk formulation techniques, microfluidic systems can provide improved control over particle size, morphology, drug loading, encapsulation efficiency and formulation reproducibility. These characteristics have facilitated the development of a wide range of drug delivery carriers, including polymeric nanoparticles, lipid nanoparticles, liposomes, nanoemulsions, microspheres, hydrogels and micelles [10,11,35,42].

1. Nanoparticles

Microfluidic technology enables the controlled preparation of nanoparticles by regulating mixing conditions, flow rates, solvent exchange and residence time. Rapid and reproducible mixing between an organic phase containing the drug or polymer and an aqueous phase can promote controlled nucleation and particle formation. As a result, microfluidic systems can produce nanoparticles with relatively narrow particle-size distributions and reproducible physicochemical characteristics [11,22-24,42]. Polymeric nanoparticles prepared using microfluidic platforms can incorporate poorly water-soluble drugs, proteins and other therapeutic molecules. Control over formulation conditions can influence particle size, surface characteristics, drug loading and release behaviour. These characteristics make microfluidic nanoparticle production particularly attractive for targeted and controlled drug delivery [22,42].

2. Liposomes

Liposomes are vesicular drug delivery systems composed primarily of phospholipid bilayers and can accommodate both hydrophilic and lipophilic therapeutic agents. Conventional liposome preparation methods may produce heterogeneous vesicle populations and require multiple downstream processing steps. Microfluidic hydrodynamic focusing and related continuous-flow techniques provide improved control over mixing and self-assembly, enabling the production of liposomes with more uniform vesicle sizes [14,15,43]. Microfluidic liposome preparation also permits adjustment of parameters such as flow-rate ratio, lipid concentration and total flow rate. These parameters can influence vesicle size, size distribution, encapsulation efficiency and drug-loading characteristics, making microfluidics a useful approach for reproducible liposomal drug formulation [14,15,43].

3. Polymeric Nanoparticles

Polymeric nanoparticles are increasingly investigated for controlled and targeted drug delivery because their polymer composition and structure can be engineered to regulate drug release and biological interactions. Microfluidic nanoprecipitation provides rapid and controlled mixing of polymer and drug solutions with an aqueous phase, allowing the formation of nanoparticles under reproducible conditions [22,42,44]. Microfluidic processing can reduce the variability associated with conventional bulk nanoprecipitation and facilitate systematic optimization of formulation variables. Parameters such as polymer concentration, solvent composition, flow-rate ratio and total flow rate can be adjusted to control particle size, morphology and drug encapsulation [22-24,44].

4. Lipid Nanoparticles

Lipid nanoparticles have become particularly important in modern drug delivery because of their ability to encapsulate and protect nucleic acids and other therapeutic molecules. Microfluidic mixing provides rapid and controlled interaction between lipid-containing organic phases and aqueous phases, facilitating the self-assembly of lipid nanoparticles with reproducible size and composition [3,11,45]. The use of microfluidic platforms is especially relevant to the preparation of mRNA and siRNA delivery systems, where particle size, lipid composition, encapsulation efficiency and surface properties can strongly influence biological performance. Precise control of mixing and flow conditions can therefore support the development of lipid nanoparticles for nucleic-acid delivery and vaccine applications [3,45].

5. Nanoemulsions

Nanoemulsions consist of finely dispersed oil and aqueous phases stabilized by suitable surfactants or emulsifiers. Microfluidic emulsification provides controlled manipulation of immiscible fluids and allows droplet formation under defined flow and interfacial conditions. The resulting control over droplet size and size distribution can improve formulation reproducibility [16-18,46]. Microfluidic nanoemulsion systems can be used to formulate poorly water-soluble drugs and other active pharmaceutical ingredients. Flow conditions, channel geometry, interfacial tension and surfactant concentration can be systematically adjusted to obtain nanoemulsions with desired physicochemical characteristics [16,18,46].

6. Microspheres

Microspheres are particulate carriers that can provide controlled or sustained release of therapeutic agents. Droplet-based microfluidic systems can generate highly uniform precursor droplets that subsequently undergo solidification, cross-linking or solvent removal to form microspheres. This approach provides greater control over particle size and uniformity compared with many conventional emulsification techniques [19,21,47]. Microfluidic microsphere preparation can also facilitate the incorporation of drugs, proteins and other active substances into polymeric or biodegradable matrices. Control of droplet size and composition enables systematic adjustment of drug loading and release characteristics [19,22,47].

7. Hydrogels

Hydrogels are three-dimensional polymeric networks capable of absorbing substantial quantities of water and can be engineered for controlled drug release and tissue-engineering applications. Microfluidic technologies can generate hydrogel microspheres, microgels and structured hydrogel systems with controlled dimensions and composition [20,47,48]. Droplet microfluidics is particularly useful for producing monodisperse microgels because individual droplets act as confined reaction compartments. Cross-linking of polymeric materials within these droplets can produce hydrogel particles with controlled size and morphology. Such systems have potential applications in controlled drug delivery, cell encapsulation and regenerative medicine [47,48].

8. Micelles

Micelles are self-assembled colloidal structures formed from amphiphilic molecules and can improve the apparent solubility and delivery of poorly water-soluble drugs. Microfluidic systems provide controlled environments for the self-assembly of amphiphilic polymers or surfactants and can improve the reproducibility of micellar formulations [11,42]. By regulating mixing conditions, solvent exchange and concentration gradients, microfluidic platforms can influence micelle formation and drug incorporation. This approach may be useful for developing nanoscale systems with improved solubility, controlled release and enhanced delivery of hydrophobic therapeutic agents [42,49].

9. Controlled Drug Release

Microfluidics contributes to controlled drug delivery not only by producing drug carriers with reproducible characteristics but also by enabling the engineering of carrier properties that regulate drug release. Particle size, polymer composition, lipid composition, matrix structure, surface properties and drug-loading characteristics can be systematically controlled during microfluidic formulation [11,22,42]. Microfluidic platforms can therefore be used to develop carriers exhibiting sustained, delayed or stimuli-responsive drug release. The ability to precisely control formulation parameters may reduce variability in release profiles and facilitate the development of dosage forms with predictable therapeutic performance [42,49].

10. Targeted Drug Delivery

Microfluidics can support targeted drug delivery through the reproducible fabrication of nanoparticles and other carriers with controlled size, surface characteristics and composition. These carriers can subsequently be functionalized with targeting ligands such as antibodies, peptides or other recognition molecules to promote interaction with specific cells or tissues [3,11,42]. The precise control of particle characteristics provided by microfluidic formulation is particularly valuable because particle size, surface charge, morphology and ligand density can influence biodistribution, cellular uptake and therapeutic performance. Consequently, microfluidic technologies provide an important manufacturing platform for developing targeted nanomedicines for cancer and other diseases [3,11,42]. The role of microfluidics in modern drug delivery extends beyond simple particle fabrication. It provides a controlled manufacturing environment in which formulation parameters can be systematically manipulated to produce drug carriers with reproducible and tunable characteristics. The technology therefore connects fundamental fluid mechanics with pharmaceutical formulation, nanotechnology and precision medicine [11,35,42]. The ability to integrate microfluidic formulation with continuous manufacturing, real-time monitoring and automated process control may further improve the scalability and reproducibility of advanced drug delivery systems. Consequently, microfluidics represents an important technological platform for the development of next-generation pharmaceutical formulations [11,25,35,42].

Applications of Microfluidics In Drug Delivery

Microfluidic technology has emerged as an important platform in modern pharmaceutical research, extending beyond conventional particle fabrication to applications in cancer therapy, gene and nucleic-acid delivery, mRNA vaccine development, protein and peptide delivery, ocular and pulmonary drug delivery, brain-targeted delivery, personalized medicine, tissue engineering and organ-on-chip systems. The precise manipulation of fluids at the microscale enables controlled mixing, particle formation, encapsulation and surface engineering, thereby facilitating the development of drug delivery systems with reproducible physicochemical characteristics [50,51,52].

1. Cancer Drug Delivery

Cancer drug delivery is one of the important applications of microfluidic technology. Microfluidic platforms enable the reproducible preparation of polymeric nanoparticles, liposomes, lipid nanoparticles and other nanocarriers containing anticancer agents. Precise control over particle size, morphology, surface characteristics and drug loading can facilitate the development of carriers with improved cellular uptake, controlled drug release and enhanced delivery to tumour tissues [51,52]. Microfluidic synthesis has been investigated for the preparation of functional nanoparticles containing anticancer drugs and targeting components. Control over nanoparticle composition, size and surface modification allows formulation variables to be systematically optimized for cancer therapy. Microfluidic platforms can also be integrated with tumour-on-chip models to investigate nanoparticle transport, cellular uptake and therapeutic responses under physiologically relevant conditions [51,52]. An important advantage of microfluidic cancer nanomedicine is the ability to produce relatively homogeneous carriers while reducing formulation variability. This may facilitate the development of targeted and combination nanotherapies in which multiple therapeutic agents or targeting components are incorporated into a single delivery platform [51,52].

2. Gene Delivery

Microfluidics has become an important technology for the preparation of nanocarriers for gene delivery, particularly for mRNA, siRNA and other nucleic-acid therapeutics. Nucleic acids are susceptible to degradation and generally require protective delivery systems to facilitate cellular uptake and intracellular release. Microfluidic systems provide rapid and controlled mixing of nucleic-acid solutions with lipids or polymers, enabling the formation of nanoparticles with controlled size and high encapsulation efficiency [52,53]. Microfluidic synthesis of lipid nanoparticles is particularly valuable because parameters such as flow rate, flow-rate ratio, lipid composition and mixing conditions can be systematically adjusted. These variables influence nanoparticle size, morphology, encapsulation efficiency and biological performance and can therefore be optimized for gene transfer, RNA delivery and other nucleic-acid-based therapeutic applications [53]. The precise and reproducible nature of microfluidic formulation is especially advantageous for nucleic-acid therapeutics, where changes in carrier characteristics can influence cellular uptake and intracellular delivery. Thus, microfluidics provides an important manufacturing platform for next-generation gene delivery systems [52,53].

3. mRNA Vaccine Delivery

The development of mRNA vaccines has substantially increased interest in microfluidic manufacturing technologies. mRNA can be encapsulated within lipid nanoparticles through controlled microfluidic mixing of an aqueous nucleic-acid phase with an organic lipid phase. Rapid and reproducible mixing promotes lipid self-assembly and facilitates the formation of lipid nanoparticles with controlled particle size and high encapsulation efficiency [50,53]. Microfluidic approaches have been investigated for the preparation of mRNA-LNP vaccine formulations for infectious diseases. Their advantages include rapid mixing, precise control of formulation parameters, reproducibility and reduced material consumption. Microfluidic processing may also facilitate continuous and scalable manufacturing approaches for nucleic-acid vaccines [50,53]. The growing importance of mRNA therapeutics has therefore positioned microfluidic lipid nanoparticle production as a significant area of pharmaceutical research. Further development of integrated and scalable microfluidic manufacturing systems could improve the flexibility and efficiency of mRNA vaccine production [50,53].

4. Protein and Peptide Delivery

Proteins and peptides present significant formulation challenges because of their susceptibility to degradation, aggregation, denaturation and enzymatic breakdown. Microfluidic systems provide controlled environments for incorporating these macromolecules into polymeric, lipid-based and hydrogel carriers while minimizing variations associated with conventional processing methods [55]. Microfluidic technologies are also useful for protein manipulation, formulation screening and controlled processing. Precise regulation of fluidic conditions allows formulation parameters to be systematically optimized while reducing unnecessary consumption of valuable biological materials. This is particularly important for expensive proteins, peptides and other biologically active macromolecules [55]. The integration of microfluidic systems with particle fabrication and analytical techniques may therefore support the development of protein- and peptide-loaded carriers with improved encapsulation, stability and controlled-release characteristics [55].

5. Ocular Drug Delivery

Microfluidic technologies have potential applications in ocular drug delivery through the fabrication of nanoscale and microscale carriers and microengineered delivery systems. Ocular drug delivery is challenging because of physiological barriers such as tear drainage, corneal barriers and restricted penetration into posterior ocular tissues. Microfluidic fabrication can provide controlled particle size, composition and drug loading, which may contribute to improved ocular residence and localized drug delivery [50,52]. Microfluidic platforms can potentially be used to prepare nanoparticles, microspheres and other particulate systems for sustained ocular drug delivery. Control over carrier characteristics may facilitate optimization of drug release and tissue interaction. However, direct clinical translation of microfluidic-manufactured ocular drug delivery systems remains relatively limited and this area should therefore be considered an emerging application.

6. Pulmonary Drug Delivery

Microfluidic technology is increasingly being investigated for pulmonary drug delivery because it enables controlled fabrication of inhalable nanoparticles, microspheres and lipid-based carriers. Such systems can be designed to achieve appropriate aerodynamic characteristics, improve pulmonary deposition and provide localized drug delivery while potentially reducing systemic exposure [57,58]. A recent 2026 study demonstrated the microfluidic fabrication of dexamethasone-loaded silk fibroin microspheres for targeted pulmonary drug delivery. The microfluidic approach produced microspheres with controlled characteristics and demonstrated high encapsulation efficiency and sustained drug release, supporting the potential of microfluidic fabrication for localized pulmonary therapy [57]. Another recent study investigated pulmonary surfactant nanoparticles for lung-targeted drug delivery, demonstrating the potential of microfluidic nanoparticle fabrication for producing inhalable nanosystems with controlled formulation characteristics. Such approaches may be particularly useful for improving drug deposition and retention in the lungs and for delivering therapeutic agents to specific pulmonary tissues [58]. These developments demonstrate the potential of microfluidics to integrate particle engineering with pulmonary drug delivery requirements. Nevertheless, aerodynamic performance, device compatibility, long-term stability and large-scale manufacturing remain important considerations for clinical translation.

7. Brain-Targeted Drug Delivery

The blood-brain barrier represents a major obstacle to effective delivery of therapeutic agents to the central nervous system. Microfluidic technologies can contribute to brain-targeted drug delivery through two complementary approaches: the reproducible fabrication of nanocarriers and the development of microfluidic blood-brain-barrier or brain-on-chip models for evaluating drug transport and cellular interactions [59]. Microfluidic BBB models can reproduce selected structural and physiological characteristics of the neurovascular interface and provide controlled platforms for studying barrier permeability and drug transport. Such models can be used to investigate the interaction of nanoparticles with brain endothelial cells and to evaluate strategies designed to improve therapeutic transport across the BBB [59]. Microfluidic systems therefore have potential both as drug-carrier manufacturing platforms and as experimental models for evaluating CNS delivery strategies. Further integration of brain-on-chip systems with advanced nanocarriers may contribute to the development of more effective treatments for neurological disorders [59].

8. Personalized Medicine

Microfluidics provides an attractive technological platform for personalized medicine because very small quantities of patient-derived samples can be processed under precisely controlled conditions. Microfluidic systems can integrate sample preparation, drug exposure, cellular analysis and formulation screening within compact platforms, enabling investigation of patient-specific responses to therapeutic agents [52,60]. Organ-on-chip systems are particularly relevant because they can incorporate patient-derived cells or tissues and reproduce selected physiological characteristics of individual patients. Such systems can be used for personalized drug screening, disease modelling and investigation of patient-specific therapeutic responses [60]. The combination of microfluidics with patient-derived biological materials therefore provides an opportunity to move from generalized treatment strategies towards more individualized therapeutic approaches [52,60].

9. Tissue Engineering

Microfluidic technology has important applications in tissue engineering because it enables precise spatial and temporal control of cells, biomaterials, nutrients and biochemical factors. Microfluidic platforms can be used to generate cell-laden droplets, hydrogel microspheres, vascular-like structures and other tissue-engineered constructs with controlled dimensions and architecture [60]. Microfluidic systems can also generate controlled gradients of growth factors and other signalling molecules. These gradients can be used to investigate cell migration, proliferation and differentiation and to develop tissue constructs with more controlled biological organization. Microfluidic hydrogel systems may also function as platforms for localized and sustained drug delivery within engineered tissues [60]. Thus, the integration of microfluidics, biomaterials and tissue engineering provides opportunities for developing multifunctional systems capable of combining tissue regeneration with controlled therapeutic delivery [60].

10. Organ-on-Chip Platforms

Organ-on-chip technology represents one of the most advanced biomedical applications of microfluidics. These systems combine microfluidic channels with living cells, tissues or organoids to reproduce selected structural and physiological characteristics of human organs. Examples include lung-on-chip, liver-on-chip, kidney-on-chip, gut-on-chip, heart-on-chip and vascular models [60]. Organ-on-chip platforms can be used for drug screening, toxicity assessment, disease modelling, pharmacological evaluation and personalized medicine. Controlled fluid flow within these systems can reproduce selected aspects of physiological microenvironments that are difficult to reproduce using conventional static two-dimensional cell cultures [60]. The integration of organ-on-chip technology with artificial intelligence and automated image or data analysis may further improve drug evaluation. Artificial intelligence can assist in analysing complex biological responses, identifying patterns and predicting therapeutic or toxicological outcomes [61]. Such integration may contribute to more efficient preclinical drug development and reduce dependence on conventional experimental approaches. The applications of microfluidics in drug delivery extend from drug-carrier fabrication to therapeutic evaluation, disease modelling and personalized treatment development. Microfluidic platforms can produce nanoparticles, liposomes, lipid nanoparticles, microspheres and other carriers with controlled physicochemical characteristics. They also provide important platforms for nucleic-acid delivery, vaccine development, pulmonary delivery and emerging brain-targeted and ocular delivery approaches [50-53,57-60]. The convergence of microfluidics with nanotechnology, biomaterials, organ-on-chip technology, real-time sensing, automation and artificial intelligence is expected to further expand its role in pharmaceutical research and development. However, the maturity of these applications differs considerably. Nanoparticle and lipid nanoparticle manufacturing is relatively advanced, whereas applications such as personalized therapeutic manufacturing, ocular delivery and integrated organ-on-chip drug delivery remain areas of active research [52,53,60,61]. Overall, microfluidics provides a versatile technological bridge between formulation development, controlled drug delivery, biological evaluation and personalized medicine. Continued improvements in device design, manufacturing scalability, regulatory standardization and integration with automated technologies will be important for translating these applications from laboratory-scale research into clinically and commercially viable drug delivery systems.

Advantages of Microfluidic Drug Delivery

Microfluidic technology offers several advantages over conventional formulation techniques because it enables precise control of fluid flow, mixing, particle formation and drug encapsulation. These characteristics make microfluidics particularly suitable for the development of advanced drug delivery systems [10,25,42,62].

1. Precise Particle Size Control

Controlled flow rates, mixing conditions and residence times enable the production of nanoparticles and microparticles with narrow size distributions and predictable characteristics [11,42,63].

2. High Encapsulation Efficiency

Rapid and controlled mixing facilitates efficient drug incorporation into nanoparticles, liposomes and lipid-based carriers, reducing drug wastage and improving payload delivery [3,42,63].

3. Uniform Formulations

The controlled microenvironment minimizes variations in mixing and particle formation, resulting in more uniform particle size, morphology and drug loading [10,25,63].

4. Reduced Reagent Consumption

Microfluidic devices operate with very small fluid volumes, reducing the consumption of drugs, polymers, lipids, solvents and other formulation materials. This is particularly beneficial during formulation screening of expensive biological molecules [62,64].

5. Rapid Synthesis

Short diffusion distances and efficient mass transfer enable rapid mixing, nanoprecipitation and self-assembly, reducing formulation processing time [10,42,63].

6. Automation

Microfluidic devices can integrate pumps, valves, mixers and sensors, enabling automated formulation, monitoring and process control with reduced human intervention [5,32,64].

7. High Reproducibility

Precise regulation of flow rate, concentration, temperature and mixing conditions improves batch-to-batch consistency and reproducibility of critical quality attributes [25,42,63].

8. Scalability Potential

Continuous-flow operation and parallelization or numbering-up of microfluidic channels provide potential pathways for increasing production capacity while maintaining controlled formulation conditions [25,50,65].

9. Controlled Drug Release

Microfluidic control over particle size, polymer composition, lipid composition and drug loading can be used to develop carriers with sustained or controlled drug-release profiles [49,62].

10. Improved Targeting Potential

Microfluidically prepared nanoparticles can be engineered with controlled surface characteristics and functionalized with targeting ligands, supporting targeted delivery to specific tissues or cells [51,52]. The major advantages of microfluidic drug delivery include precise particle-size control, high encapsulation efficiency, formulation uniformity, reduced reagent consumption, rapid synthesis, automation, high reproducibility and scalability potential. These advantages enable microfluidics to function not only as a formulation technique but also as an integrated platform for controlled and reproducible development of advanced drug delivery systems [25,42,62-65].

CHALLENGES AND LIMITATIONS OF MICROFLUIDIC DRUG DELIVERY

Despite its advantages in the precise formulation of advanced drug delivery systems, microfluidic technology still faces several technical, economic and regulatory barriers that limit its widespread pharmaceutical and industrial adoption. Addressing these challenges is essential for translating laboratory-scale microfluidic formulations into robust, standardized and commercially viable manufacturing processes [24,65].

Fabrication Cost

The fabrication of microfluidic devices may require specialized equipment, cleanroom facilities, microfabrication techniques and high-quality materials. Although materials such as PDMS can be relatively inexpensive for laboratory prototypes, sophisticated devices incorporating integrated pumps, valves, sensors and automated control systems can substantially increase production costs. The cost becomes particularly important when disposable devices are required for sterile pharmaceutical manufacturing [66].

Device Complexity

Advanced microfluidic platforms may incorporate multiple channels, pumps, valves, mixers, sensors and control systems within a small device. Designing, fabricating and operating such integrated systems requires expertise in microengineering, fluid mechanics, materials science and pharmaceutical formulation. Small variations in channel dimensions, surface properties or operating conditions can influence fluid behaviour and formulation performance. This technical complexity may make device development and routine operation challenging [67].

Channel Clogging and Fouling

Channel blockage is a significant operational problem, particularly during the production of concentrated nanoparticles, microparticles, precipitating formulations or viscous drug delivery systems. Particle aggregation, precipitation, air bubbles and adsorption of formulation components onto channel surfaces can reduce flow efficiency or completely obstruct the device. Channel fouling may also alter surface properties and affect particle formation. Appropriate channel geometry, surface modification, filtration, optimized concentrations and controlled operating conditions are therefore required to minimize clogging [68,69].

Scale-Up Challenges

Scaling microfluidic formulations from laboratory quantities to industrial production remains one of the major challenges. Simply increasing the dimensions or flow rate of a microchannel may alter the fluid dynamics and compromise the optimized formulation conditions. Numbering-up, involving the parallel operation of multiple identical channels or devices, provides an alternative approach but introduces additional challenges related to uniform flow distribution, synchronization, device-to-device variability and process monitoring. Developing robust continuous manufacturing strategies is therefore essential for large-scale production [70,71].

Regulatory Issues

Microfluidic drug delivery systems may involve novel combinations of formulation processes, materials, devices and active pharmaceutical ingredients, creating regulatory challenges. Regulatory assessment must address the safety, quality, performance and reproducibility of both the drug formulation and the manufacturing process. Critical quality attributes such as particle size, polydispersity, drug loading, encapsulation efficiency, sterility and stability must be appropriately controlled. Clear regulatory frameworks specifically addressing complex microfluidic manufacturing platforms are still developing [72].

Industrial Translation

Many microfluidic technologies remain at the proof-of-concept or laboratory-development stage. Transitioning from research prototypes to commercially viable pharmaceutical manufacturing requires robust device fabrication, reliable operation, process validation, equipment compatibility and economic feasibility. Pharmaceutical manufacturers must also consider integration with upstream material preparation, downstream purification, sterilization, filling and packaging operations. The absence of established industrial workflows can slow the adoption of microfluidic technologies [12,74].

Standardization

Standardization is essential for ensuring consistent performance between microfluidic devices, laboratories and manufacturing facilities. Differences in channel dimensions, device materials, surface characteristics, flow conditions and operating protocols can lead to variations in formulation outcomes. Standardized methods for device fabrication, process characterization, critical quality attributes and performance testing are therefore required. Establishing common terminology, validated analytical methods and internationally accepted manufacturing standards would facilitate comparison between studies and accelerate regulatory acceptance [75]. The major challenges associated with microfluidic drug delivery are interconnected. High fabrication costs and device complexity can affect scalability, while channel clogging and device-to-device variability can compromise reproducibility. Regulatory uncertainty and insufficient standardization can further delay industrial translation. Future development should therefore focus not only on improving microfluidic formulation performance but also on developing cost-effective devices, scalable numbering-up strategies, robust continuous manufacturing processes, standardized operating procedures and regulatory frameworks. Overcoming these barriers will be critical for converting microfluidic drug delivery from an advanced laboratory technology into a reliable and commercially viable pharmaceutical manufacturing platform.

Table. 1. Representative recent studies demonstrating the application of microfluidic technologies in the development, optimization and evaluation of advanced drug delivery systems (2018–2026).