Research Strategies for Precise Manipulation of Micro/Nanoparticle Drug Delivery Systems Using Microfluidic Technology: A Review

• Abstract
• Introduction
• Microchannel Structures Employed for Micro/Nanoparticle DDSs
• Microchannel for Enhancing Mixing
• T-Type/Y-Type Mixer
• Hydrodynamic Flow Focusing Mixer
• Split-and-Recombine Mixer
• Obstacle-Based Mixer
• SHM Based on Embedded Obstacle Design
• iLiNP Based on Baffle Obstacle Design
• Capillary-Based Coaxial-Flow Mixer
• High-Speed Vortex/Jet Mixer Based on Flash
• Microchannel for High-Throughput
• Parallel Strategy with Multiple Mixing Units in the Micrometer-Scale Channel (Lower TFR)
• Independent Use Strategy of Millimeter-Scale Channel Mixing Unit (Higher TFR)
• Parallel Strategy with Multiple Mixing Units in Millimeter-Scale Channels (Higher TFR)
• Microchannel Employed for Continuous Manufacturing, Online Monitoring, and Intelligent Feedback
• Strategies for Using Microfluidics to Manipulate Micro/Nanoparticle DDSs Precisely
• Size
• Morphology and Structure
• Stiffness
• Surface Characteristics
• Elasticity
• Application of Microfluidic Technology in DDSs
• Liposome
• Micro/Nanocrystals
• Micelles
• Nanoparticle
• Organic Nanoparticles
• Lipid Nanoparticles
• Polymeric Nanoparticles
• Lipid–Polymer Hybrid Nanoparticles
• Biomimetic Nanoparticles
• Metal–Organic Frameworks
• Inorganic Nanoparticles
• Microsphere
• Giant Unilamellar Vesicles
• Others
• Industrialization: Current Status and Prospects
• Conclusion
• Reference

Abstract

Microfluidic technology facilitates precise control over fluid mixing and interactions between the components, including self-assembly and precipitation. It offers new options for accurately manufacturing particles and holds significant potential in advancing micro/nanoparticle drug delivery systems (DDSs). Various microchannel/microfluidic chips have been explored to construct micro/nanoparticle DDSs. The precise manipulation of particle size, morphology, structure, stiffness, surface characteristics, and elasticity through microfluidic technology relies on specific microchannel geometrical designs and the application of exogenous energy, adhering to the principles of fluid motion. Consequently, this enables reproducible control over critical quality attributes (CQAs), such as particle size and distribution, encapsulation efficiency, drug loading, in vitro and in vivo drug delivery profiles, Zeta potential, and targeting capabilities, for micro/nanoparticle DDSs. In this review, we categorize microfluidic techniques and explore recent research developments in novel microchannel structures spanning the past 5 years (2018–2023) and their applications in micro/nanoparticle DDSs. Additionally, we elucidate the latest manipulation strategies of microfluidic techniques that impact foundational structures related to the CQAs of micro/nanoparticle DDSs. Furthermore, we offer insights into the industrial applications and challenges microfluidic techniques face in the context of novel micro/nanoparticle DDSs.

Introduction

Microfluidic technology involves precise fluid flow control in microchannels characterized by diverse geometries and sizes ranging from micrometers to millimeters. This technology holds significant potential across various domains, including drug screening,[1] drug discovery,[2] drug delivery,[3] [4] [5] [6] [7] [8] [9] biology sciences,[10] drug analysis,[11] [12] and preclinical evaluation.[13] [14] Notably, the application of microfluidics in drug delivery systems (DDSs), such as lipid nanoparticles (LNPs), has witnessed rapid advancement during the coronavirus disease 2019 (COVID-19) pandemic.

The physicochemical properties of micro/nanoparticles primarily depend on their foundational structures, encompassing morphology, size, structure, surface characteristics, stiffness, and elasticity. These attributes play a crucial role in determining the CQAs of micro/nanoparticles, which comprise particle size, polydispersity index (PDI), encapsulation performance, drug loading (DL), zeta potential, release behaviors, targeting capabilities, and stability. An ideal micro/nanoparticle DDS should demonstrate high loading capacity, a controllable preparation process, a narrow particle size distribution, controllable internal structure, surface characteristics, minimal batch-to-batch variation,[15] and, whenever possible, environmentally friendly and sustainable qualities.

Microfluidic technology, with its capacity for achieving uniform and rapid fluid mixing, establishes stable and optimal environments for the self-assembly or nucleation of micro/nanoparticles.[16] [17] [18] Furthermore, the conditions and mixing order of the reaction become conveniently and flexibly adjustable with the application of microfluidic technology.[19] Consequently, microfluidic technology demonstrates outstanding controllability and multifunctionality, enabling the stable and precise control of CQAs by manipulating particle size, internal structure, morphology, stiffness, surface characteristics, and elasticity.[19] [20] [21] [22] [23] [24] Furthermore, the preparation of micro/nanoparticles through microfluidics presents numerous advantages, including a straightforward process, minimal reagent consumption, environmental friendliness, and a requirement for minimal workspace for the equipment.[25]

As scientists explore the intricacies of fluidic behavior within microchannels, their understanding expands, leading to increased utilization of the diverse modes of action of microchannels with distinct architectures for specific micro/nanoparticle DDSs (e.g., liposomes, LNPs, microspheres, nanocrystals, etc.).

Microfluidics can be categorized into two types based on the flow mechanisms of fluids: continuous-flow systems and droplet-based segmented-flow systems.

Diffusive mixing, the foundation of continuous-flow systems, primarily relies on the laminar diffusion of one or more solvents. In this process, molecules transition from areas of higher concentration to lower concentration via Brownian motion, resulting in progressive homogenization ([Fig. 1A]).

The droplet-based segmented-flow system relies on mixing two immiscible phases, specifically the dispersed and continuous phases. In this system, the immiscible continuous phase separates the dispersed phase into multiple microdroplets, each serving as an individual mixing unit ([Fig. 1B]).[26] Through the application of microfluidic technology, it becomes possible to engineer droplets of diverse sizes and morphologies, including single-emulsion droplets, double-emulsion droplets, multi-emulsion droplets, and multiple cores' droplets. This engineering capability facilitates the creation of particles with varied internal structures and encapsulation patterns ([Fig. 2]). Because the droplet reactor remains unexposed to the microchannel's inner surface, the system prevents material from settling on the inner wall. This characteristic renders the droplet-based segmented-flow system resistant to contamination and compatible with extreme conditions, such as high temperatures or corrosive reagents. Consequently, this system allows for the preparation of micro/nanoparticles from a wide range of materials.[27]

[Fig. 3] shows schematic diagrams illustrating liquid flow patterns in typical microchannels with continuous and segmented systems, respectively.[28] [29]

Microfluidics can be further categorized into passive and active mixing systems, depending on the requirement for introducing external driving forces and the driving mode.[30]

Passive mixing systems rely solely on the energy of liquid flow to drive, guide, and facilitate mixing and separation.[31] In contrast, active mixing systems utilize external forces, such as acoustic,[31] [32] [33] [34] [35] [36] [37] [38] [39] electric,[40] [41] [42] magnetic,[43] [44] thermal,[45] and optical fields,[46] to disrupt the laminar flow. This disruption induces rapid homogenization to enhance mixing performance or prompts specific substances to aggregate or precipitate within a designated time frame. The objective is to achieve faster homogenization, thereby improving mixing performance and generating particles with a smaller size and a narrower distribution.[31] When applied in the construction of micro/nanoparticle DDSs, passive and active mixing systems exhibit distinct characteristics, as detailed in [Table 1] [47] [48] [49] [50] below. The combination and integration of microfluidics with external forces present the possibility of preparing high-quality, versatile micro/nanoparticles with complex structures. An example of the application of an active mixing system is illustrated in [Fig. 4].[51] [52]

Currently, abundant evidence from published research papers attests to the widespread use of microfluidics in constructing micro/nanoparticle DDSs. Leveraging specialized microchannel configurations, microfluidic methodologies are systematically displacing conventional approaches in the fabrication of micro/nanoparticles.

A comprehensive literature search was performed to analyze the potential applications of microfluidics in producing micro/nanoparticle DDSs. PubMed and Web of Science databases were searched, utilizing a combination of keywords to optimize search outcomes. The search criteria encompassed terms such as microfluidic or micromixer or mixing or microchannel or microfluidics or chip (title) and drug OR pharmaceutical OR medical OR drug delivery OR pharmaceutics OR medicine (topic) and particle or particles (topic), not Machine OR micromachine OR engineer OR engineering OR screen OR sensor OR analysis OR separation (topic) and Patent (exclude—document types). The literature search was restricted to articles published between 2018 and 2023.

This review outlines the various types of microchannel structures and their design philosophies utilized in constructing high-quality micro/nanoparticle DDSs from 2018 to 2023. Additionally, we summarize the most recent manipulation strategies employed by microfluidic techniques to influence the foundational constructive features (size, morphology and structure, stiffness, surface characteristics, and elasticity) of micro/nanoparticle DDSs. Finally, we present an outlook on potential industrial applications and the challenges associated with microfluidic techniques in developing innovative micro/nanoparticle DDSs.

Microchannel Structures Employed for Micro/Nanoparticle DDSs

The widespread utilization of microfluidic techniques in micro/nanoparticle DDSs currently encounters three challenges that require attention:

• Traditional microchannel configurations, such as T-shaped/Y-shaped structures, require prolonged mixing times or paths for complete homogenization, impeding efficient micro/nanoparticle fabrication. Therefore, microstructures must be designed to enhance mixing efficacy and reduce mixing durations.

• Some microchannel structures with intricate configurations, like the staggered herringbone mixer (SHM), display superior mixing owing to their internal microstructures. However, these configurations often introduce significant resistance, hindering the high-throughput production of micro/nanoparticles.

• Owing to the relatively enclosed nature of microchannels, integrating microfluidic chips with upstream and downstream equipment in the production process for continuous manufacturing, online monitoring, and intelligent feedback for sustainable product lifecycle management poses a challenge. This integration is also a hurdle in constructing high-quality, intelligent micro/nanoparticle DDSs.

In response to these limitations, pharmaceutical scientists, leveraging various fluidic principles, have constructed various micro/nanoparticle DDSs using microchannels based on different designs. Examples include the T-type/Y-type mixer, hydrodynamic flow focusing mixer (HFF mixer), SHM, invasive LNP production (iLiNP) device, capillary-based coaxial-flow mixer (CFM), confined impingement jet mixer (CIJM), multi-inlet vortex mixer (MIVM), and others. The following sections will introduce commonly used microchannel structures in the drug delivery domain.

Microchannel for Enhancing Mixing

T-Type/Y-Type Mixer

T-type/Y-type mixers, characterized by laminar flow patterns, represent the simplest laminar microchannel configurations. The utilization of T-type/Y-type mixers successfully addresses the heterogeneity inherent in traditional processes. Nevertheless, these designs require extended channels for achieving thorough mixing, leading to larger particle sizes attributable to slow diffusion rates. Consequently, these configurations are progressively being replaced by more sophisticated microchannel structures.

Hydrodynamic Flow Focusing Mixer

Expanding upon the single-layer laminar flow patterns of T-type/Y-type mixers, researchers have advanced the field by developing a multi-layer laminar flow HFF mixer. This innovation involves adjusting the number of channel inlets and introducing three-dimensional (3D) geometric features.

Studies indicate that, compared with traditional T-type/Y-type mixers, the 2D HFF mixer improves the diffusion interface between the two-phase fluids, leading to enhanced mixing efficacy.[53] Siavashy et al prepared cisplatin-loaded magnetic chitosan nanoparticles (NPs) using traditional batch methods and microfluidic techniques based on the HFF mixer. The results demonstrated that NPs fabricated via the HFF mixer exhibited smaller sizes with a narrower distribution than those produced by traditional methods. Furthermore, the microfluidic approach achieved higher encapsulation efficiency and controllable drug release.[53]

Furthermore, the 3D-HFF promotes interfacial contact between different phase fluids within a 3D space, thereby expanding the diffusion area of the fluids. This leads to a further enhancement in mixing efficiency compared with the two-dimensional (2D) HFF. [Fig. 5] [54] provides visual examples of various 2D and 3D HFF microchannels utilized to fabricate NPs.

Split-and-Recombine Mixer

The split-and-recombine (SAR) mixer denotes a process where the fluid undergoes continuous splitting and recombination during flow, thereby increasing diffusion opportunities and enhancing mixing efficacy. SAR mixers are typically designed in three dimensions, encompassing symmetrical and asymmetrical configurations. Symmetrical SAR mixers employed in micro/nanoparticle DDSs include the Tesla structure,[55] fluidic trap mixer,[56] and toroidal mixer (TrM; developed by Precision Nano Systems Inc.).[57] Ma et al have developed a 3D-inertial microfluidic mixer, serving as a SAR mixer. This mixer facilitates the scalable synthesis of LNPs, and concurrently, the authors have proposed a theoretical prediction method to ensure equal mixing times across chips of different sizes, further guaranteeing consistency in the particle size and PDI of LNPs ([Fig. 6]).[58] [Fig. 7] provides a schematic illustration of a typical SAR mixer.

The TrM structure developed by Precision Nano Systems Inc. (PNI) is a commercially available SAR mixer. Webb et al discovered that liposomes prepared using both the TrM and SHM mixers exhibited no significant differences in size and shape.[57]

Obstacle-Based Mixer

SHM Based on Embedded Obstacle Design

In 2002, Stroock first introduced the concept of SHM with embedded obstacles on the inner walls of the channel.[59] The repetitive herringbone-staggered structures induce fluid folding, resulting in chaotic laminar flow. This chaotic flow significantly enhances the mixing efficiency compared with traditional free diffusion. Subsequently, scientists have increasingly integrated SHM in constructing various NP DDSs.[22] [60] [61] [62] [63] [64] [65] [66] [67] It has found applications in producing liposomes,[18] [68] [69] [70] polymer NPs,[71] and related nanomedicines.[72] [73] [74]

Researchers employed conventional methods and SHM-based microfluidic techniques to prepare PLGA (poly(lactic-co-glycolic acid)) NPs loaded with rutin. The results demonstrated that NPs fabricated using the microfluidic approach exhibited smaller and more uniform diameters, as well as superior encapsulation and release behaviors.[75]

Furthermore, researchers have developed the reverse-SHM, and fluid dynamics simulations indicate that its mixing performance is essentially consistent with that of the SHM.[76]

iLiNP Based on Baffle Obstacle Design

In 2018, Tokeshi et al introduced the iLiNP mixing device, and subsequent studies have explored its diverse applications. For instance, iLiNP enables precise tuning of LNP sizes within the range of 10 nm,[77] introduces a posttreatment process for size-controlled LNPs for siRNA delivery,[78] facilitates one-step production of biologically compatible noncationic exosome-like NPs for siRNA delivery,[79] and involves a 3D-iLiNP microfluidic device for LNP production.[80] Further applications include the production of LNP-based CRISPR/Cas ribonucleoprotein (RNP) delivery using iLiNP,[81] mass production of LNPs enabled by iLiNP,[82] [83] and the control of liposome lamellarity using iLiNP.[84] [Fig. 8] presents related research on applying iLiNP in micro/nanoparticle DDSs.

In summary, iLiNP has demonstrated substantial potential in LNP fabrication. Beyond size control, lamellarity, and physicochemical properties of liposomes, it also offers the capability to integrate postprocessing steps such as online mixing and dilution for continuous production. Moreover, using eight parallel glass-iLiNP units, the total flow rate (TFR) for LNP preparation can reach up to 160 mL/min.

Capillary-Based Coaxial-Flow Mixer

Capillary-based coaxial-flow mixers (CFMs) are commonly employed for constructing droplet-based segmented-flow systems, facilitating the preparation of microparticulate DDSs like microspheres and microcapsules. Employing CFM, complex-structured microparticles can be manufactured with diverse configurations, facilitating co-encapsulation, sustained release, or controlled release of pharmaceuticals.[85] [Fig. 9] presents related research on CFM in preparing micro/nanoparticle DDSs.

Zhong et al utilized a CFM to create multicomponent microspheres (MCMs) featuring a “Particle in Particle” structure composed of sodium alginate (ALG) shells and gelatin methacrylate cores. These MCMs demonstrate the potential for encapsulating DOX and augmenter of liver regeneration within the shell and the cores, respectively ([Fig. 9]).[86]

High-Speed Vortex/Jet Mixer Based on Flash

High-speed jet/vortex mixers, primarily utilizing flash technology, serve as a pivotal catalyst for the clinical translation of nanomedicines, encompassing two main principles: flash nanocomplexation (FNC) and flash nanoprecipitation (FNP). FNC primarily involves the production of nanomedicines through electrostatic interactions, hydrogen bonding, or metal coordination, leading to polyelectrolyte complexation. Conversely, FNP primarily operates through solvent supersaturation to produce polymer or inorganic NPs.[87] [Fig. 10] illustrates the operational principles of FNC and FNP.

Mixers based on the flash technology include the coaxial jet mixer (CJM),[88] [89] CIJMs,[90] MIVM,[90] CFMs,[91] impingement jet mixer (IJM), swirl mixer,[92] [93] etc. [Fig. 11] illustrates the standalone application of various high-speed vortex/jet mixers.

Tibbitt and colleagues introduced a CJM to produce polymeric NPs across a broad spectrum of solvents. It was revealed that the properties of the polymer NPs produced by CJM were similar to those obtained through the batch nanoprecipitation method. Yet, the production efficiency of CJM surpassed the batch method by 30-fold. Additionally, enhanced gene silencing effects were observed when using CJM to prepare complexes loaded with siRNA.[88]

The Pfizer COVID-19 vaccine employs an IJM obtained from the KNAUER company (Germany) ([Fig. 12]).[94]

High-speed vortex/jet mixers facilitate the formation of nanocomposites or nanoprecipitates in a cost-effective, large-scale, and controllable manner.[87]

Microchannel for High-Throughput

Although investigators have achieved significant accomplishments in utilizing micro/nanoparticles as vectors for DDSs, unlocking the full potential of these systems requires large-scale production of micro/nanodrugs with precise control over particle properties. It is crucial to enhance production scale without compromising CQAs. To meet industrial demands, researchers currently employ three primary strategies to boost productivity: (1) a parallel strategy with multiple mixing units in micrometer-scale channels (lower TFR); (2) an independent use strategy of millimeter-scale channel mixing units exhibiting microfluidic size characteristics (higher TFR); and (3) a parallel strategy with multiple mixing units in millimeter-scale channels operating at higher TFR.[57] [95] [96]

Parallel Strategy with Multiple Mixing Units in the Micrometer-Scale Channel (Lower TFR)

The lower TFR parallelization strategy was initially proposed in chemical synthesis,[97] and later extended to NP fabrication.[98] This strategy, utilizing a parallel design of “n” microchannel mixing units, enables the TFR to be “n” times the TFR of each mixing unit. Parallel schemes for HFF,[99] [100] [101] SHM,[102] and iLiNP[103] have been employed to enhance the batch production of NPs. [Fig. 13] illustrates various applications of lower TFR in parallel configurations. [Table 2] [104] lists reported instances of enhancing the productivity of microfluidic techniques based on the lower TFR parallelization strategy in the past 5 years.

Shepherd et al reported a highly integrated parallel scheme for SHM, incorporating 128 SHM mixing units, achieving a production rate of 18.4 L/h.[102]

One significant advantage of microchannel parallelization is the ability to scale up to large batches without altering the inherent characteristics of the individual unit. However, a drawback of this strategy is that the performance of the entire mixing system is contingent upon the robustness of the fluidic infrastructure and system operation. A malfunction in a single mixer could compromise the entire platform. Additionally, owing to minor perturbations that typically occur along parallel fluidic networks, the size and distribution of NPs may be affected.

Independent Use Strategy of Millimeter-Scale Channel Mixing Unit (Higher TFR)

The higher TFR millimeter-scale single mixing unit standalone strategy involves the modulation of fluids through millimeter-scale geometries, aiming to enhance throughput while preserving the microscale characteristics of microfluidics (uniform mixing/precipitation environments to support the formation of uniform particles). Examples of such schemes include CFM,[91] CJM,[88] IJM,[90] MIVM,[90] and swirl mixer[92] [105] ([Fig. 11]). [Table 3] lists reported instances of enhancing the productivity of microfluidic techniques based on the independent use strategy of millimeter-scale channel mixing units (higher TFR) in the last 5 years.

Lim et at reported a CJM capable of NP reshaping and controlled synthesis at high production rates.[89] It has also been utilized to produce liposomes[106] and polymer NPs.[88] Xu et al achieved a production yield of curcumin liposomes using the swirl mixer, reaching up to 320 mL/min.[93] According to Lumiere Tech Ltd. (LumTech), the production of IJM can reach up to 60 L/h.[94]

The advantage of the standalone single mixing unit strategy lies in its ability to achieve batch scale up using simple, cost-effective microfluidic devices with minimal instrument operation. However, the design of such channels involves fine-tuning fluid dynamic states, necessitating professionals to bridge the gap for industrial translation. Another drawback is that during the initial phase of developing new formulations, the system operates at a higher TFR, leading to relatively greater reagent consumption.

Parallel Strategy with Multiple Mixing Units in Millimeter-Scale Channels (Higher TFR)

In industrial applications, the abovementioned parallel lower TFR mixing units and higher TFR millimeter-scale single mixing units still encounter limitations regarding production rate enhancement. Therefore, researcher has proposed another constructive strategy derived from combining the abovementioned strategies: (1) parallelized swirl mixer[92] [107]; (2) parallelized IJM[108]; and (3) parallelized fluid trap type mixers.[56] These strategies have emerged as the fastest routes for the industrial production of nanocarriers. [Fig. 14] illustrates a schematic diagram of the combined use of various parallelized millimeter-scale mixing units. [Table 4] lists reported instances of enhancing the productivity of microfluidic techniques based on the parallel strategy with multiple mixing units in millimeter-scale channels in the past 5 years.

In producing the COVID-19 vaccine (COMIRNATY), the parallelization of 100 IJMs is utilized to mix the lipid solution and mRNA solution under a pressure of 400 pounds, facilitating the scalable production of LNPs. This approach ultimately boosts the vaccine output to 100 million doses per month. Currently, in China, Lumiere Tech Ltd. (LumTech) represents KNAUER in offering IJM equipment for LNP preparation. Additionally, their commercially available IJM NanoScaler, by paralleling IJMs (n = 5), employs the same technology at a laboratory scale for preclinical studies (6 L/h).[94]

Microchannel Employed for Continuous Manufacturing, Online Monitoring, and Intelligent Feedback

Because the production of micro/nanoparticles through traditional methods typically involves extensive postprocessing steps (such as dilution, overnight dialysis, etc.), which are numerous and complex, and multiple rounds of processing may induce detrimental effects such as damage or aggregation to the particles, researchers have been actively exploring approaches for the continuous production of micro/nanoparticles based on microfluidic technology in recent years. Kimura et al have achieved the integration of two steps—generation and dilution of LNPs—on one iLiNP device ([Fig. 15]).[78]

Forbes et al have implemented a microfluidic device featuring a SHM structure, integrated with tangential flow filtration and Zetasizer Nano ZS, to accomplish a continuous liposome production process encompassing preparation, purification, and online particle size analysis. The application of this technology ensures a rapid and efficient transition of lipid nanocarriers from the laboratory to production while concurrently mitigating the risks associated with large-scale manufacturing.[61]

Strategies for Using Microfluidics to Manipulate Micro/Nanoparticle DDSs Precisely

Microchannels' high specific surface area allows for the precise construction of micro/nanoparticle DDSs. Furthermore, precisely designed microchannels facilitate uniform and rapid heat and mass transfer, shorten particle preparation time, and rapidly produce uniform particles.[17] [109] [Fig. 16] compares NPs' particle size and morphology produced by conventional nanoprecipitation and microfluidic techniques.[110]

With the new demands and challenges of personalized therapies, including gene and cell therapies, it becomes vital to design nanodrugs precisely.[5] The capacity of microfluidics to manipulate and control the formation of micro/nanoparticles is mainly a function of the control of their fundamental construction, including size, morphology and structure, stiffness, surface characteristics, and elasticity. By shaping the abovementioned fundamental construction, precisely controlled CQAs of micro/nanoparticle DDSs with predictable particle size and distribution, zeta potential, stability, release characteristics, targeting capacity, and cellular uptake of the final production can be achieved.[111] [112] [113] [114] [115] [116]

Size

Microfluidics enables the continuous preparation of various monodisperse particles with controllable sizes.[117] [118] [119] Microfluidic technology has been employed in the production of particles of different sizes, including ALG microgels with diameters of 8 to 28 μm,[120] hybrid microgels with diameters of 70 to 90 μm,[121] liposomes with diameters of 100 to 300 nm,[122] ginseng polysaccharide NPs with diameters of approximately 20 nm,[123] LNPs with diameters of approximately 20 nm,[104] and gold NPs with diameters of 2 to 4 nm.[124] [Fig. 17] shows examples of using microfluidics to control micro/nanoparticle size.

Sedighi et al prepared liposomes with well-defined sizes and robust qualities, with the size controllable by adjusting the TFR and other parameters.[125] Kimura et al utilized an iLiNP device to achieve controlled preparation of LNPs with sizes at 10 nm intervals in the 20 to 100 nm range. NPs loaded with siRNA and prepared using this device exhibited effective gene silencing efficacy in vivo.[77]

Morphology and Structure

Microfluidics presents the capability for controlled preparation of functional micro/nanoparticles with specific shapes tailored for diverse applications. For instance, it can control the densities and void sizes of polymeric materials, influencing the characteristics of DDSs, such as stability and degradation rates.[126] [127] [Fig. 18] provides examples of how microfluidics can control the morphology and structure of micro/nanoparticles.

Chen et al employed a microfluidics-enabled serial assembly to achieve the co-encapsulation of siRNA and Sorafenib. This microfluidics platform facilitated the regulation of fast and slow processes on a single chip, enabling the sequential self-assembly of sorafenib, siRNA, and lipids. The resulting lipid-siRNA-sorafenib NPs demonstrated outstanding anticancer effects in vivo.[128]

Using microfluidics, Hao et al synthesized mesoporous silica nanofibers with varying aspect ratios and diameters.[129] Additionally, microfluidics can modulate microspheres' shell size and thickness, thereby adjusting their release profiles.[130]

Stiffness

The stiffness of drug-loaded micro/nanoparticles plays a crucial role in determining their deformability, influencing circulation profiles, cellular uptake, and aggregation and penetration behavior.[131] Microfluidics is a valuable tool for preparing NPs with varying stiffness, enabling the exploration of how particle stiffness impacts drug release. [Fig. 19] shows examples of microfluidics employed to control micro/nanoparticle stiffness.

Lozano Vigario et al utilized an SHM to produce highly rigid anionic liposomes, offering a rapid, size-tunable, and scalable method for generating rigid tolerogenic liposomes.[132]

Liu et al employed the multifunctional microfluidic ultrasonic cavitation method to synthesize NPs in a controlled, nonclogging, and scalable manner. Leveraging its cavitation mode, this approach enabled the synthesis of soft and fragile mRNA-LNPs. Additionally, compared with conventional microfluidic techniques, the method yielded smaller particles with a more uniform distribution and demonstrated robust, scalable production capacity, achieving a throughput of up to 1.6 g/h.[47]

Surface Characteristics

Surface modification is a highly effective strategy for enhancing targeting efficiency and extending the circulation time of micro/nanoparticle DDSs. Microfluidics enables precise manipulation of particle surface characteristics, as illustrated in [Fig. 20].[133]

Using a one-step methodology, Li et al employed microfluidics to prepare complex multifunctional nanoliposomes with highly controllable surface characteristics, particle sizes, and photodynamic and chemodynamical effects. This study fully exploited the capabilities of microfluidics for precise manipulation, laying the foundation for constructing customized functional NPs.[134]

Gao et al demonstrated the fabrication of structurally complex CUR@ZIF-SF-PDA NPs using the swirl mixer. This channel sequentially achieved the formation of ZIF-8 metal–organic framework (MOF), encapsulation of curcumin, and coating with silk fibroin (SF) and polydopamine (PDA). Microfluidic rapid mixing exhibited a unique advantage over conventional methods in constructing NPs with appropriate charge density and controllable particle size.[135]

Microfluidics has also been instrumental in surface modification or ligand conjugation of LNPs to achieve targeted delivery to specific cells/organs. In addition to Glu-urea-Lys ligand-conjugated siRNA-LNPs,[136] transferrin-conjugated siRNA-TfLNP,[137] peptides, and antibody-conjugated LNPs have been successfully prepared using the microfluidic technology.[138]

Elasticity

When considering embolic drug delivery, the intrinsic elasticity and deformability of micro/nanoparticles play a pivotal role in their function as embolic DDSs. Microfluidics presents an avenue for constructing micro/nanoparticles with tunable elasticity, controllable swelling, and adjustable release properties, as shown in [Fig. 21].

Yang et al introduced an innovative strategy for the facile fabrication of monodisperse poly(vinyl alcohol) (PVA) microspheres with controllable elastic properties for embolization using a glass microcapillary. PVA microspheres' elasticity and swelling ratios become adjustable through precise control of microfluidic parameters. These microspheres exhibit high DL owing to their significant swelling and negatively charged properties. This study provides valuable insights for the easy fabrication of monodisperse PVA microspheres with controllable elasticity, swelling ratio, and DL, facilitating efficient embolization therapy and drug delivery applications.[139]

Application of Microfluidic Technology in DDSs

Microfluidic technology has played a significant role in the preparation of a wide range of micro/nanoparticle DDSs, encompassing liposomes, micro/nanocrystals, NPs, and microspheres/microcapsules, as well as biomimetic particles.[54]

[Tables 5] and [6] present instances of the preparation of NPs and microparticles, respectively, using microfluidic technology in recent years.

Liposome

As microfluidic technology continues to advance, it is anticipated that it will revolutionize traditional industrial processes for liposomes. [Fig. 22] shows the conventional large-scale liposome production process alongside the transformative impact of microfluidic technology on existing production processes.

Numerous examples of preparing liposomes based on microchannels such as T-type, Y-type,[140] iLiNP,[84] SHM,[57] [60] TrM,[57] etc. are shown in [Tables 5] and [6].[141] [142] [143] [144] [145] [146] [147] [148] [149] [150] [151] [152] [153] [154] [155] [156] [157] [158] [159] [160] [161] [162] [163] [164] [165] [166] [167] [168]

Micro/Nanocrystals

In conventional methods for micro/nanocrystals, issues such as broad particle distribution and inconsistent reproducibility are prevalent. This can be particularly problematic for sustained-release micro/nanocrystals, where a wider particle distribution may impact release characteristics, leading to issues like burst release effects and potential adverse reactions, thereby presenting challenges in clinical safety.

Until now, researchers have increasingly attempted to prepare micro/nanocrystals by using the microfluidic technology based on Y-type and S-type[164] and other approaches.[164] [169] For instance, Liu et al employed microfluidic technology, integrating a Y-type mixer and an S-type channel, to produce microcrystals of dolutegravir sodium. This approach minimized the risks of channel blockage during continuous crystallization by segregating crystal nucleation from subsequent crystal growth. The resulting microcrystals exhibited small particle sizes, a narrow distribution, and a distinctive prismatic shape.[164]

Ahmad utilized a Y-type mixer to fabricate Repaglinide nanocrystals, achieving a particle size of 71.31 ± 11 nm and a PDI of 0.072, thereby enhancing efficacy and safety profiles.[145]

In another innovative approach, Coliaie et al harnessed microfluidic technology to modulate the crystallization kinetics of O-aminobenzoic acid, identifying distinct crystal forms through various microfluidic channels. These novel designs play a pivotal role in supporting the Food and Drug Administration's (FDA's) initiative to promote innovation in continuous manufacturing, significantly contributing to advancements in drug development.[169]

Micelles

In contrast to traditional methods of micelle fabrication, microfluidics demonstrates a significant advantage in the production of micelles. In this process, polymeric precursors dissolved in a water-miscible organic solvent are introduced into a microchannel (HFF mixer[158] or Tesla mixer[161]) and mixed with water. This interaction induces the aggregation of the hydrophobic segments of the amphiphilic copolymers, leading to the self-assembly of micelles.[158]

Karimi-Soflou et al utilized the HFF mixer to create micelles designed for intracellular retinoic acid release on demand. These micelles offer adjustable sizes and precisely controlled physio-biological properties, thereby facilitating efficient neuronal differentiation.[158]

Nanoparticle

The advantage of NPs as DDSs lies in their high structural malleability, enabling precise design and laying the foundation for targeted drug delivery.[5] NPs are categorized into two main types: organic and inorganic.

Organic Nanoparticles

Lipid Nanoparticles

The microfluidic mixing method has been recognized as the most successful manufacturing technology for preparing LNPs at a good manufacturing practices (GMP) scale. Onpattro, Comirnaty, and Spikevax are produced using microfluidic technology.[57] As an excellent carrier for nucleic acid delivery, LNP has been efficiently prepared using SHM,[62] [63] [64] [65] [170] [171] [172] IJM,[108] TrM,[147] and iLiNP.[77] [78] [80] [81] [82] [148] The LNPs loaded with nucleic acids, prepared using the abovementioned microchannels, exhibit a small size, uniform distribution, high EE, and high gene delivery efficiency.

RNPs as active components can mitigate the off-target effects present in conventional nucleotide molecules. However, the denaturation of RNPs in the presence of ethanol and the challenges associated with their encapsulation complicate the incorporation of RNPs within LNPs. Suzuki et al prepared LNPs loaded with RNPs using a tri-inlet iLiNP microfluidic device. By rapidly diluting the ethanol phase, the denaturation of RNPs was avoided. The results demonstrated that the RNP-loaded LNPs achieved gene editing with commendable gene knockout efficiency (97%) and base substitution rate (23%).[81]

Polymeric Nanoparticles

There is a growing focus on preparing polymeric NPs using microfluidic technology. Employing microfluidic techniques for synthesizing polymeric NPs can significantly enhance DL and EE. Furthermore, this approach provides finer control over drug release compared with traditional methods. Researchers have employed various microfluidic devices, including HFF,[23] [173] [174] SHF,[71] [175] and two-phase droplet microfluidics,[176] to fabricate synthetic polymeric NPs.

Martins et al developed PLGA NPs loaded with Efavirenz using conventional and microfluidic techniques. The results demonstrated that NPs prepared using microfluidic technology exhibited a smaller size (73 versus 133 nm), higher EE (80.7% versus 32.7%), and increased DL (10.8% versus 3.2%) compared with the conventional method.[177]

Sequential nanoprecipitation is a method to enhance the DL of NPs. Leveraging the unique design of microfluidic devices and the theory of sequential precipitation, achieving high DL and responsive release is feasible under specific conditions.[178]

Lipid–Polymer Hybrid Nanoparticles

Lipid–polymer hybrid NPs combine the advantages of biodegradable polymer NPs with the biomimetic benefits of lipid materials, addressing certain limitations associated with lipid and biodegradable polymer NPs.[179] [180]

Researchers have recently utilized microfluidic technology to fabricate various hybrid NPs. The synthesis of hybrid NPs typically involves multistage one-step methods or multi-level microchannel platforms to achieve NP precipitation and lipid self-assembly encapsulation sequentially. Several microfluidic devices have been employed for the preparation of hybrid NPs (PLGA–lipid hybrid NPs[42] and polyethyleneimine hybrid NPs[181]), such as HFF device,[42] multistage microfluidic chip devices,[128] microfluidic devices based on glass capillaries,[182] TrM,[147] and three-inlet microfluidic chip devices.[183]

Zeng et al combined HFF with electrospray to fabricate PLGA/DPPG (1,2-dipalmitoyl-sn-glycero-3-phosphoglycerol) hybrid NPs. In their study, a mixed solution of DPPG and PLGA was transferred into the microchannel, and subsequently, DPPG spontaneously covered the PLGA surface through electrostatic repulsion, forming an outer shell to enhance the stability of the hybrid NPs.[42]

Lipid–polymer hybrid NPs based on microfluidic technology also exhibit prominent advantages in delivering nucleic acid-based drugs.[181] [184] [185] Wei et al developed a special lipid/polymer hybrid NP-encapsulated siRNA. Unlike traditional methods, the microfluidic technology offers enhanced protection for siRNA enveloped within the core, exhibiting superior circulation time. Additionally, hybrid NPs based on this microfluidic approach demonstrated a significant downregulation of corresponding gene and protein expression and a notable inhibitory effect on tumor growth.[181]

Biomimetic Nanoparticles

Drug-loaded NPs, “camouflaged” with the natural biomembrane of cells or exosomes, exhibit reduced immune clearance and enhanced targeting, showcasing significant potential in drug delivery.[186] [187] Currently, biomimetic NPs primarily rely on active mixing systems. In recent years, ultrasonic microfluidics[32] and microfluidic electroporation[40] [188] have been developed to fabricate biomimetic NPs.

Liu et al utilized an ultrasonic microfluidic method to prepare exosome membrane-coated PLGA NPs. The first stage involved an HFF in an ultrasonic bath to form monodispersed PLGA NPs. In the second stage, a double helical channel was employed, extending the residence time to 30 milliseconds, facilitating effective rupture of the exosome membrane under strong ultrasonic stress (≈100 KPa). Simultaneously, the exosome membrane reassembled on the outside of the PLGA NPs. Utilizing this microfluidic approach, the exosome membrane achieved an EE exceeding 90%, with its surface proteins remaining intact and correctly oriented. Ultimately, the circulation half-life increased sevenfold compared with conventional lipid PLGA NPs.[32]

An alternative approach to creating a membrane mimicking the natural one involves integrating lipid nanostructures with molecules found in mammalian membranes or extracellular vesicles. Molinaro et al employed a microfluidic method to incorporate leukocyte membrane proteins composed of DPPC (1,2-dipalmitoyl-sn-glycero-3-phosphocholine), DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine), and cholesterol into nanovesicles. This nanostructure exhibited biological functions similar to those of the donor cells.[70]

Metal–Organic Frameworks

MOFs are novel crystalline nanoporous materials developed in recent years.[189] High DL and controlled release can be achieved by adjusting the size, functionality, and geometric structure of the porous framework in metal–organic NPs. Microfluidic technology enables the continuous fabrication of MOFs with controllable morphologies.[190] [191]

Balachandran et al employed an integrated multistage microchannel microfluidic platform to synthesize lymph node and tumor-targeting aptamer-modified biozeolitic imidazolate framework (BioZIF-8) in a one-step approach. ZIF-8 loaded with different molecules (doxorubicin, siRNA, and bovine serum albumin) and aptamer modification on the BioZIF-8 surface were accomplished by two stages on one chip. This strategy shortens the overall time from 15 hours (traditional approach) to approximately 10 minutes and enables the loading of various biomolecules.[192]

Hu et al utilized microfluidic strategies to incorporate natural enzymes into MOFs. The dynamic alteration in the concentration of MOF precursors within the microfluidic resulted in structural cavities within the MOFs. These cavities were instrumental in the proficient encapsulation and safeguarding of the enzymes. Compared with traditional methodologies, the enzyme–MOF hybrids synthesized via this method exhibited enhanced enzymatic activity.[191] Consequently, it is plausible to anticipate that this innovative modality offers substantial potential in the encapsulation and conveyance of protein-centric therapeutics.

Inorganic Nanoparticles

Inorganic NPs generally feature a larger specific surface area than organic NPs.[193] [194] Many inorganic NPs exhibit unique optical, photothermal, and magnetic characteristics, rendering them well-suited for therapeutic applications, hyperthermia, and magnetically induced tumor targeting. These distinct characteristics position inorganic NPs as promising candidates for drug delivery.

Segmented droplet microfluidic techniques are predominantly employed in producing inorganic NPs, resulting in finer particle sizes.

Hao et al employed two spiral laminar flow microreactors to synthesize triangular silver core-silica shell nanocomposites with tunable shell thicknesses. This approach can sequentially combine individual reaction processes (such as nucleation, growth, and coating) within a single system. The internalization efficiency of triangular particles by PANC-1 (human pancreatic cancer cells) and MCF-7 (human breast cancer cells) was higher than that of spherical particles. This discovery unveils a new direction in rationally designing functional nanostructures to enhance their biological functionalities.[195]

Microfluidic technology is acknowledged as an emerging field for synthesizing metal NPs. To date, researchers have used multistage microfluidic techniques to prepare Cu NPs,[196] Pd NPs based on the T-type method,[197] and Gd NPs.[198]

Bemetz et al employed a 3D HFF device to produce magnetic iron oxide NPs, eliminating channel fouling and demonstrating precise control over diameter.[199] Furthermore, microfluidic technology has been applied to generate various metal oxide NPs,[157] such as TiO₂ NPs[200] and CeO₂ NPs.[201]

Schemberg et al have synthesized superparamagnetic iron oxide NPs using three distinct systems: batch system, continuous-flow regime (T-type), and segmented-flow regime (T-type). The findings indicate that the continuous-flow system can produce NPs with a smaller size and better stability than the segmented-flow system. Both flow systems enhance the characteristics of the NPs relative to the batch system.[157]

Microsphere

Microfluidic technology offers notable advantages in rapidly and efficiently preparing single-phase and multiple emulsions.[202] As a result, it is recognized as an innovative technique for creating highly controllable and monodisperse microspheres.[130] [165] [203] [204]

Researchers typically employ multiphase HFF[163] and CFM[166] for microsphere fabrication. Su et al employed multiphase HFF to prepare sustained-release PLGA microspheres, showcasing a sustained-release profile without an initial burst release.[163]

In another study, He et al used a droplet-based microfluidic device to manufacture monodisperse PLGA magnetic arterial chemoembolization microspheres loaded with paclitaxel. These microspheres, characterized by tunable size and shell thickness, displayed delayed and smooth release kinetics without burst release behavior. Moreover, they exhibited superior magnetic responsiveness.[130]

Giant Unilamellar Vesicles

Giant unilamellar vesicles (GUVs), characterized by diameters exceeding 1 µm and typically ranging between 10 and 30 µm, have analogous size to biological cells, making them effective individual microliter reactors. Using microfluidic technology for GUV production represents a groundbreaking paradigm in advancing artificial cells. Employing this method to create GUVs provides several advantages, including monodispersity, high-throughput production, elevated encapsulation efficiency, and the ability to form asymmetric lipid bilayers mirroring those commonly observed in biological cell membranes.[205]

Droplet-based microfluidic technology has the advantage of precisely controlling chamber dimensions and structures.[206] Various microfluidic channels have been used for the preparation of GUVs, including T-type,[207] [208] HFF,[209] and CFM.[210] [211]

Weiss et al successfully constructed monodisperse cell-like GUV chambers loaded with lipid membranes and cytoskeletal proteins by integrating microfluidic technology with pico-injection techniques. The resulting GUVs closely resemble the physiological environment.[207]

Yandrapalli et al introduced a high-throughput microfluidic technique based on a water-in-oil-in-water (W/O/W) approach, enabling controlled preparation of GUVs ranging from 10 to 130 µm. These designed cell-like vesicles effectively encapsulated various substances, including pDNA (96%), small unilamellar vesicles with a size of 50 nm (94%), and fibroblasts (75%).[212]

Michelon et al utilized a capillary-based CFM to fabricate monodisperse and stable W/O/W emulsion droplets, subsequently generating GUVs for delivering active drugs.[211] In summary, the high-throughput fabrication of biomimetic artificial cells through microfluidic technology is a feasible and promising avenue.

Others

Incorporating the aforementioned vehicles into microgels enhances the development of gel-based DDSs with superior designs. Notably, integrating liposomes into gels has emerged as an attractive strategy for minimizing adverse effects in drug delivery. Moreover, incorporating liposomes into the polymer matrix within gels shows significant potential in mitigating burst release effects attributed to lipid instability.[213] [214] Microfluidic technology has been introduced to encapsulate proteins,[215] NPs,[121] viral carriers,[216] and nonviral carriers[217] within microgels.

Additionally, microfluidic technology can also be employed for the preparation of cubosomes.[218] Kim et al employed self-assembly on an SHM to fabricate a cubosome with a complex array of interlocking membranes. This cubosome was utilized for encapsulating a substantial quantity of siRNA. Additionally, the inherent fusion properties of cubosomes facilitated rapid escape from endosomes, ensuring efficient siRNA delivery into HeLa cells.[218]

Industrialization: Current Status and Prospects

As a novel paradigm for constructing micro/nanoparticle DDSs, microfluidic technology has undergone significant exploration in the literature. However, its full potential in the pharmaceutical industry remains to be fully realized, and several factors contribute to this delay. (1) Limitations in translation: the interdisciplinary nature of the field requires collaboration among biologists, microfluidics engineers, mechanical engineers, and other experts, making successful translation challenging yet essential. (2) Clogging and contamination: the small dimensions of microchannels can lead to clogging and the generation of impurities, affecting mixing efficiency and scalability. Managing and cleaning these contaminants are critical considerations. (3) Infrastructure improvement: effective microfluidic systems for micro/nanoparticle production often require enhancements in facility hardware. Meeting compliance with GMP and regulatory standards poses a significant bottleneck in integrating new technologies into producing and applying precision pharmaceutical formulations.

Fortunately, in 2020, FDA and European Medicines Agency approvals for COVID-19 vaccines based on LNPs acted as catalysts for expanding the microfluidic technique in the pharmaceutical industry. The market demand has accelerated the adoption of microfluidic technology in pharmaceutical processes by several manufacturing companies. Noteworthy international manufacturers including Coring, Ehrfeld, Dolomite, Knauer, PNI, and Chinese pharmaceutical companies focusing on DDSs are actively intensifying collaborations with mainstream microfluidic equipment suppliers such as Micro & Nano Technologies (Shanghai) Inc., Suzhou Aitesen Pharmaceutical Equipment Co. Ltd., and Lumiere Tech Ltd. (LumTech).

Conclusion

In conclusion, microfluidic technology exhibits the capability to precisely control various attributes such as size, morphology, structure, stiffness, surface properties, and elasticity of micro/nanoparticle DDSs, including liposomes, micro/nanocrystals, NPs, microspheres, GUVs, and others. As microfluidic technology advances more functionalized micro/nanoparticles as DDSs with novel structures and specific properties will emerge. This progression opens up new possibilities for personalized and precise disease diagnosis and treatment strategies.

Furthermore, a new trend is emerging in the field of drug delivery based on microfluidic technology as the transformation of laboratory research into industrial applications gains momentum. It is anticipated that pharmacists, leveraging disease characteristics, will significantly enhance their capacity to rapidly design and fabricate specific, innovative, and functionalized micro/nano formulation products. In summary, whether viewed through the lens of new trends in continuous manufacturing, personalized precision therapy, or considering the concepts of process control technology and process analytical technology advocated in current regulatory policies, the utilization of microfluidic technology is poised to create unprecedented opportunities for precise drug delivery.

Conflict of Interest

None declared.

Acknowledgments

We sincerely acknowledge Yulin Ye and other members from Suzhou Aitesen Pharmaceutical Equipment Co., Ltd. for their suggestions in the prospects section of this work.

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Address for correspondence

Publication History

Received: 10 September 2023

Accepted: 02 April 2024

Article published online:
23 May 2024

© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

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