Microfluidic Process Research Articles

Compensation of input-dependent hydraulic input delay for a model of a microfluidic process under Zweifach–Fung effect

We consider a model of a microfluidic process under Zweifac–Fung effect, which gives rise to a second-order nonlinear, non-affine system with control input that affects the plant both without delay and with an input-dependent delay defined implicitly through an integral of the past input values (that arises from a transport process with transport speed being the control input itself). We construct a predictor-feedback control law that exponentially stabilizes the output to a desired reference point. This is the first time that a predictor-feedback design is constructed that achieves complete input delay compensation for such a type of input delay and despite that control input affects the plant also without delay. This is attributed to the particular structure of the nonlinear system considered, which allows to deriving an implementable formula for the predictor state at the proper prediction horizon. We then identify a class of nonlinear systems with input-dependent input delay of hydraulic type for which complete delay compensation, through construction of an exact predictor state, is achievable.

Control of microfluidic separation processes governed by the Zweifach-Fung effect

This paper addresses several control problems for a prototypical microfluidic process designed for the separation operations of a fluid containing particles. The device is composed of one or several cascaded bifurcations that are traveled by the fluid. The volume fraction of particles in the flow is modified at each bifurcation. Fractionation is caused by the Zweifach–Fung effect, which governs the fluid dynamics in this device. It is a nonlinear effect that solely depends on the ratio of the flow rates in the branches. Propagation through the dead- volumes of the device and its capillary tubings generate input-varying delays of hydraulic type. These hydraulic delays strongly contribute to the complexity of the input–output dynamics to be controlled. The paper presents a model of the device and formulates some concise control problem statements for future research, along with illustrative simulation results. The case of single and dual bifurcation are presented.

PLGA nanoparticles enhanced cardio-protection of scutellarin and paeoniflorin against isoproterenol-induced myocardial ischemia in rats

This study aims to examine the impact of the microfluidic preparation process on the quality of poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) co-delivered with scutellarin (SCU) and paeoniflorin (PAE) in comparison to a conventional emulsification method and to evaluatethe potential cardio-protective effect of SCU-PAE PLGA NPs produced through emulsification method. As compared with microfluidics, the nanoparticles prepared by emulsification method exhibited a smaller size, higher encapsulation efficiency, higher drug loading and lower viscosity for injection. Subsequently, a rat myocardial ischemia (MI) was established using male Sprague-Dawley (SD) rats (250 ± 20 g) subcutaneously injected with 85 mg/kg isoproterenol (ISO) for two consecutive days. The pharmacokinetic findings demonstrated that our SCU-PAE PLGA NPs exhibited prolonged blood circulation time in MI rats, leading to increased levels of SCU and PAE in the heart. This resulted in significant improvements in electrocardiogram and cardiac index, as well as reduced serum levels of CK, LDH, AST. Histopathological analysis using H&E and TUNEL staining provided further evidence of improved cardiac function and decreased apoptosis. Additionally, experiments measuring SOD, MDA, GSH, NO, TNF-α and IL-6 levels indicated that SCU-PAE PLGA NPs may effectively treat MI through oxidative stress and inflammatory pathways, thereby establishing it as a promising therapeutic intervention.

Analytical Validation of a Spiral Microfluidic Chip with Hydrofoil-Shaped Pillars for the Enrichment of Circulating Tumor Cells.

The isolation of circulating tumor cells (CTCs) from peripheral blood with high efficiency remains a challenge hindering the utilization of CTC enrichment methods in clinical practice. Here, we propose a microfluidic channel design for the size-based hydrodynamic enrichment of CTCs from blood in an epitope-independent and high-throughput manner. The microfluidic channel comprises a spiral-shaped part followed by a widening part, incorporating successive streamlined pillars, that improves the enrichment efficiency. The design was tested against two benchmark designs, a spiral microfluidic channel and a spiral microfluidic channel followed by a widening channel without the hydrofoils, by processing 5 mL of healthy blood samples spiked with 100 MCF-7 cells. The results proved that the design with hydrofoil-shaped pillars perform significantly better in terms of recovery (recovery rate of 67.9% compared to 23.6% in spiral and 56.7% in spiral with widening section), at a cost of slightly lower white blood cell (WBC) depletion (depletion rate of 94.2% compared to 98.6% in spiral and 94.2% in spiral with widening section), at 1500 µL/min flow rate. For analytical validation, the design was further tested with A549, SKOV-3, and BT-474 cell lines, yielding recovery rates of 62.3 ± 8.4%, 71.0 ± 6.5%, and 82.9 ± 9.9%, respectively. The results are consistent with the size and deformability variation in the respective cell lines, where the increasing size and decreasing deformability affect the recovery rate in a positive manner. The analysis before and after the microfluidic chip process showed that the process does not affect cell viability.

Enhanced in vivo absorption and biodistribution of curcumin loaded into emulsions with high medium-chain triglyceride content

The health benefits of curcumin have been demonstrated by several clinical studies, but its low bioavailability compromises its functionality. In this regard, emulsions have proven to be effective encapsulation systems for curcumin. Nevertheless, emulsions with a high oil content (50%) may offer some advantages due to the large amount of compound they can incorporate. Therefore, the aim of this work was to study the pharmacokinetics and biodistribution of curcumin when carried in optimized emulsions containing 50% MCT oil and a plant-based emulsifier (soybean lecithin) at 2 h or 4 h post-oral administration to rats. The most stable emulsion was obtained using 50% of oil and a surfactant-oil-ratio 0.1, through a microfluidization process. After the oral administration of the systems (150 mg curcumin/kg body weight), curcumin glucuronide was the main compound present in plasma (AUC0-t = 1556.3 ng·h·ml−1), especially at 2–4 h post-administration. The total curcuminoid bioavailability was increased by 10.6-fold when rats were fed with the curcumin emulsion rather than with a control suspension. Moreover, rats fed with the emulsion showed the highest accumulation of free curcuminoids, which present the highest biological activity, in the liver (129 ng curcumin/g tissue) and brown adipose tissue (193 ng curcumin/g tissue). The obtained results are of great interest since the presence of curcumin in the brown adipose tissue has been shown to play a relevant role in the prevention of obesity and its related metabolic disorders.

Generation of helical multi-functional microfiber motors based on modified microfluidic spinning method

Due to unique asymmetric shapes and easily realized directional movements, helical micromotors are widely used in applications such as drug delivery, cell manipulation, and wastewater purification. However, most of the hydrogel helical microfiber motors were water-based and had a homogeneous polymer network structure, which limited their practical applications like drug release. In this study, an emulsion-based microfluidic spinning method was used to prepare heterogenous helical hydrogel microfiber motors. Fine oil-in-water (O/W) emulsions were used as the inner phase of the microfluidic spinning process. When dichloromethane was used, micromotors with porous structure were formed after solidification and volatilization, improving the catalytic degradation rate of pollutants in water treatment application. When soybean oil was used, fat-soluble drugs were encapsulated successfully and gradually released as the micromotor degraded. Besides, the diameter and pitch size of the prepared fibers could be easily adjusted, and mass manufacturing (>100 m) was achieved.

Development of an automated flow chemistry affinity-based purification process for DNA-encoded chemistry

An automated flow chemistry platform for DNA-encoded library (DEL) technologies requires the integration of a purification process for DNA-tagged substrates. It facilitates the development of further DEL reactions, building block rehearsal, and library synthesis. Therefore, a recently developed, manual affinity-based batch purification process for DNA-tagged substrates based on dispersive solid-phase extraction (DSPE) was transferred to automated flow chemistry using tailored 3D-printed microfluidic devices and open-source lab automation equipment. The immobilization and purification steps use Watson–Crick base pairing for a compound-encoding single-stranded DNA, which allows for the thorough removal of impurities and contaminations by washing steps and operationally simple recovery of the purified DNA-encoded compounds. This work optimized the annealing step for flow incubation and DNA purification was accomplished by flow DSPE washing/elution steps. The manually performed batch affinity-based purification process was compared with the microfluidic process by determining qualitative and quantitative DNA recovery parameters. It aimed at comparing batch and flow purification processes with regard to DNA recovery and purity to benefit from the high potential for automation, precise process control, and higher information density of the microfluidic purification process for DNA-tagged substrates. Manual operations were minimized by applying an automation strategy to demonstrate the potential for integrating the microfluidic affinity-based purification process for DNA-tagged substrates into an automated DNA-encoded flow chemistry platform.Graphical

Droplet-Based Microfluidics as a Platform to Design Food-Grade Delivery Systems Based on the Entrapped Compound Type.

Microfluidic technology has emerged as a powerful tool for several applications, including chemistry, physics, biology, and engineering. Due to the laminar regime, droplet-based microfluidics enable the development of diverse delivery systems based on food-grade emulsions, such as multiple emulsions, microgels, microcapsules, solid lipid microparticles, and giant liposomes. Additionally, by precisely manipulating fluids on the low-energy-demand micrometer scale, it becomes possible to control the size, shape, and dispersity of generated droplets, which makes microfluidic emulsification an excellent approach for tailoring delivery system properties based on the nature of the entrapped compounds. Thus, this review points out the most current advances in droplet-based microfluidic processes, which successfully use food-grade emulsions to develop simple and complex delivery systems. In this context, we summarized the principles of droplet-based microfluidics, introducing the most common microdevice geometries, the materials used in the manufacture, and the forces involved in the different droplet-generation processes into the microchannels. Subsequently, the encapsulated compound type, classified as lipophilic or hydrophilic functional compounds, was used as a starting point to present current advances in delivery systems using food-grade emulsions and their assembly using microfluidic technologies. Finally, we discuss the limitations and perspectives of scale-up in droplet-based microfluidic approaches, including the challenges that have limited the transition of microfluidic processes from the lab-scale to the industrial-scale.

Investigating the effectiveness of the main channel in microfluidic liquid-liquid extraction process

The liquid-liquid extraction method has been one of the most critical chemical engineering processes for many years. The combination of liquid-liquid extraction and microfluidic systems constitutes a significant advancement in this process in recent years. The inherent advantages of microfluidic systems, due to their micro dimensions and the widespread application of liquid-liquid extraction, have made this process more applicable in various industries. This article focuses on microfluidic systems, discussing the effects of changes and modifications made to the main channel of these systems, as well as the resulting improvements in flow type and channel shape, and their applications. The assessment concludes with a discussion of the prospects of this field.

Effects of Microfluidic Shear on the Plasmid DNA Structure: Implications for Polymeric Gene Delivery Vectors.

Microfluidic manufacturing of advanced gene delivery vectors necessitates consideration of the effects of microfluidic shear forces on the structural integrity of plasmid DNA (pDNA). In this paper, we expose pDNA to variable shear forces in a two-phase, gas-liquid microfluidic reactor and apply gel electrophoresis to analyze the products of on-chip shear-induced degradation. The effects of shear rate, solvent environment, pDNA size, and copolymer complexation on shear-induced degradation are investigated. We find that small naked pDNA (pUC18, 2.7 kb) exhibits shear rate-dependent shear degradation in the microfluidic channels in a mixed organic solvent (dioxane/water/acetic acid; 90/10/<0.1 w/w/w), with the extents of both supercoil isoform relaxation and complete fragmentation increasing as the maximum shear rates increase from 4 × 105 to 2 × 106 s-1. However, over the same range of shear rates, the same pDNA sample shows no evidence of microfluidic shear-induced degradation in a pure aqueous environment. Quiescent control experiments in the same mixed organic solvent prove that a combination of solvent and shear forces is involved in the observed shear-induced degradation. Furthermore, we show that shear degradation effects in mixed organic solvents can be significantly attenuated by complexation of pDNA with the block copolymer polycaprolactone-block-poly(2-vinylpyridine) prior to exposure to microfluidic shear. Finally, we demonstrate that medium (pDSK519, 8.1 kb) and large (pRK290, 20 kb) naked pDNA are more sensitive to shear-induced microfluidic degradation in the mixed organic solvent environment than small pDNA, with both plasmids showing complete fragmentation even at the lowest shear rate, although we found no evidence of shear-induced damage in water for the largest investigated naked pDNA even at the highest flow rate. The resulting understanding of the interplay of the solvent and shear effects during microfluidic processing should inform microfluidic manufacturing routes to new gene therapy formulations.

Microfluidizing Technique Application for Algerian Cymbopogon citratus (DC.) Stapf Effects Enhanced Volatile Content, Antimicrobial, and Anti-Mycotoxigenic Properties.

Medicinal plant extracts are a promising source of bioactive minor contents. The present study aimed to evaluate the distinguished volatile content of Algerian Cymbopogon citratus (DC.) Stapf before and after the microfluidization process and their related antimicrobial and anti-mycotoxigenic impacts and changes. The GC-MS apparatus was utilized for a comparative examination of Algerian lemongrass essential oil (LGEO) with its microfluidization nanoemulsion (MF-LGEO) volatile content. The MF-LGEO was characterized using Zetasizer and an electron microscope. Cytotoxicity, antibacterial, and antifungal activities were determined for the LGEO and MF-LGEO. The result reflected changes in the content of volatiles for the MF-LGEO. The microfluidizing process enhanced the presence of compounds known for their exceptional antifungal and antibacterial properties in MF-LGEO, namely, neral, geranial, and carvacrol. However, certain terpenes, such as camphor and citronellal, were absent, while decanal, not found in the raw LGEO, was detected. The droplet diameter was 20.76 ± 0.36 nm, and the polydispersity index (PDI) was 0.179 ± 0.03. In cytotoxicity studies, LGEO showed higher activity against the HepG2 cell line than MF-LGEO. Antibacterial LGEO activity against Gram-positive bacteria recorded an inhibitory zone from 41.82 ± 2.84 mm to 58.74 ± 2.64 mm, while the zone ranged from 12.71 ± 1.38 mm to 16.54 ± 1.42 mm for Gram-negative bacteria. Antibacterial activity was enhanced to be up to 71.43 ± 2.54 nm and 31.54 ± 1.01 nm for MF-LGEO impact against Gram-positive and Gram-negative pathogens. The antifungal effect was considerable, particularly against Fusarium fungi. It reached 17.56 ± 1.01 mm and 13.04 ± 1.37 mm for LGEO and MF-LGEO application of a well-diffusion assay, respectively. The MF-LGEO was more promising in reducing mycotoxin production in simulated fungal growth media due to the changes linked to essential compounds content. The reduction ratio was 54.3% and 74.57% for total aflatoxins (AFs) and ochratoxin A (OCA) contents, respectively. These results reflect the microfluidizing improvement impact regarding the LGEO antibacterial, antifungal and anti-mycotoxigenic properties.

Research on Integrated 3D Printing of Microfluidic Chips.

Microfluidic chips have the advantages of miniaturization, integration, and portability, and are widely used in the early diagnosis of major diseases, personalized medical treatment, environmental detection, health quarantine, and other fields. The existing microfluidic chip manufacturing process is difficult to operate because of complex three-dimensional channels, complicated manufacturing steps, limited printing materials, the difficulty of operating the bonding process, and the need to purchase expensive new equipment. In this paper, an integrated molding method for microfluidic chips that integrates 3D printing and polymer dissolution technology is proposed. First, the channel mold of poly(vinyl alcohol) (PVA) or high impact polystyrene (HIPS) is dissolved to complete the manufacturing of the microfluidic chip channel. The integrated 3D-forming method of microfluidic chips proposed in this paper can manufacture microchannels inside the microfluidic chip, avoid the bonding process, and eliminate the need for rapid alignment of microchannels, material modification, and other operations, thus improving the stability of the process. Finally, by comparing the microchannels made by PVA and HIPS, it is concluded that the quality of the microchannels made by HIPS is obviously better than that made by PVA. This paper provides a new idea for the fabrication of microfluidic chips and the application of HIPS.

Immune-Modulating Lipid Nanomaterials for the Delivery of Biopharmaceuticals.

In recent years, with the approval of preventative vaccines for pandemics, lipid nanoparticles have become a prominent RNA delivery vehicle. The lack of long-lasting effects of non-viral vectors is an advantage for infectious disease vaccines. With the introduction of microfluidic processes that facilitate the encapsulation of nucleic acid cargo, lipid nanoparticles are being studied as delivery vehicles for various RNA-based biopharmaceuticals. In particular, using microfluidic chip-based fabrication processes, nucleic acids such as RNA and proteins can be effectively incorporated into lipid nanoparticles and utilized as delivery vehicles for various biopharmaceuticals. Due to the successful development of mRNA therapies, lipid nanoparticles have emerged as a promising approach for the delivery of biopharmaceuticals. Biopharmaceuticals of various types (DNA, mRNA, short RNA, proteins) possess expression mechanisms that are suitable for manufacturing personalized cancer vaccines, while also requiring formulation with lipid nanoparticles. In this review, we describe the basic design of lipid nanoparticles, the types of biopharmaceuticals used as carriers, and the microfluidic processes involved. We then present research cases focusing on lipid-nanoparticle-based immune modulation and discuss the current status of commercially available lipid nanoparticles, as well as future prospects for the development of lipid nanoparticles for immune regulation purposes.

Vertically Aligned Boron Nitride Nanosheets Films for Superior Electronic Cooling.

Thermally conductive and electrically insulating thermal interface materials (TIMs) are highly desired for electronic cooling. To improve heat transfer efficiency, thermally conductive fillers with a high loading content have been incorporated into the polymer-based TIMs. However, this is usually at the expense of the interfacial thermal resistance reduction and reliability. In this study, vertically aligned boron nitride nanosheet films (VBNFs) have been prepared by a scalable microfluidic spinning process and template-assisted chemical vapor deposition conversion method. A further high-temperature annealing was applied to achieve high crystallinity. VBNFs have been applied as fillers to fabricate TIMs and achieve a superior through-plane thermal conductivity of 6.4 W m-1 K-1 and low modulus of 2.2 MPa at low BN loading of 9.85 vol %, benefitting from the well-aligned vertical sheet structure and high crystallinity. In addition, the fabricated TIMs present high-volume resistivity and breakdown strength, satisfying the electrical insulation demands. The high thermal conductivity and low modulus contribute an outstanding cooling performance to the TIMs in the heat dissipation application for high-power LEDs. This template-assisted conversion technology for the fabrication of orientated BN nanosheets structure and the prepared high-performance TIMs pave the way for efficient thermal management of high-power electronics.

Enhanced stability, formulations, and rheological properties of nanoemulsions produced with microfludization for eco-friendly process

HypothesisEco-friendly processes that are emerging around the world require mass production of low-energy, low-cost nanoemulsions. The process involving the high-concentrated nanoemulsions and diluting them with a large amount of solvent can certainly save the cost; however, not much detailed research has been conducted on the stability mechanism and rheological characteristics of high-concentrated nanoemulsions. ExperimentsIn this study, we produced nanoemulsions via the microfluidization (MF) process, comparing their dispersion stability and rheological characteristics with macroemulsions across various oil and surfactant concentrations. Droplet mobility and dispersion stability depended on these concentrations, with Asakura-Osawa-type attractive depletion considering interparticle interaction's role in stability changes. We investigated nanoemulsions' long-term stability based on turbidity and droplet size changes over four weeks, proposing a stability diagram showing four different states depending on emulsification conditions. FindingsWe explored the microstructure of emulsions under varying mixing conditions, observing their effects on droplet mobility and rheological properties. We monitored changes in rheology, turbidity, and droplet size over 4 weeks, establishing stability diagrams for macro- and nanoemulsions. The stability diagrams revealed that the stability of emulsions are sensitively dependent on the droplet size, concentrations, surfactant cocentrations and the strcture of coexistent phases in case of macroscopic segregation are significantly different depending on the droplet sizes. We identified their respective stability mechanisms and discovered the relationship between stability and rheological properties for highly concentrated nanoemulsion.

Food Emulsion Gels from Plant-Based Ingredients: Formulation, Processing, and Potential Applications.

Recent advances in the understanding of formulations and processing techniques have allowed for greater freedom in plant-based emulsion gel design to better recreate conventional animal-based foods. The roles of plant-based proteins, polysaccharides, and lipids in the formulation of emulsion gels and relevant processing techniques such as high-pressure homogenization (HPH), ultrasound (UH), and microfluidization (MF), were discussed in correlation with the effects of varying HPH, UH, and MF processing parameters on emulsion gel properties. The characterization methods for plant-based emulsion gels to quantify their rheological, thermal, and textural properties, as well as gel microstructure, were presented with a focus on how they can be applied for food purposes. Finally, the potential applications of plant-based emulsion gels, such as dairy and meat alternatives, condiments, baked goods, and functional foods, were discussed with a focus on sensory properties and consumer acceptance. This study found that the implementation of plant-based emulsion gel in food is promising to date despite persisting challenges. This review will provide valuable insights for researchers and industry professionals looking to understand and utilize plant-based food emulsion gels.

Graphene prepared by microfluidization process using induced parallel orientation strategy to enhance anti-corrosion of photocurable epoxy coatings

Graphene has excellent application prospects in anti-corrosion coatings because of its perfect impermeability. Unfortunately, graphene sheets rich in surface defects lead to a significant reduction in impermeability, and also tend to spontaneously aggregate and randomly arrange in the resin matrix to form conductive network, which exacerbates electrochemical corrosion reactions. Herein, a green, one-step method for preparing low-defect and few-layer modified graphene was proposed. Graphene was prepared and modified in one step from graphite by using calcein (CA) under microfluidization process to obtain CA noncovalent modified graphene (CAG) with 2–5 layers of sheets. CAG/epoxy (EP) coatings with high orientation were prepared by spinning and curing simultaneously. The coatings show excellent long-term anti-corrosion performance. After immersion for 55 days in 3.5 wt% NaCl solution, the impedance modulus of CAG0.5%/EP coating was about three orders of magnitude higher than that of EP coating. It is worth noting that when the CAG content increased to 1 %, the impedance value remained above 1.8 × 1011 Ω cm2. The excellent anti-corrosive properties of the composite coating can be attributed to the extremely high orientation of graphene, which prevents the formation of conductive pathways and maximizes the barrier effect of graphene. In parallel, the modified graphene reduces the agglomeration between the graphene sheet and imparts excellent interfacial bonding with the epoxy, thus avoiding the formation of micro-cracks in the coating.

Rifled microtubes with helical and conductive ribs for endurable sensing device

Helical fibers represent of one of the most extraordinary objects in living organisms and have recently produced through a coaxial microfluidic spinning process. But the requirement of collection capillaries may limit scalable production because of blockage liability, structural rigidity and cumbersome fabrication of capillary. Structural vulnerability of helical fibers could also limit their practical applications, e.g., in fabric and as wearable devices. Herein for the first time we showed that helical fibers could be produced solely with a core steel needle with double concentric sleeves through a coaxial wet spinning process, without the requirement of microfluidic spinning capillary. They were encapsulated into protection microtubes in an unprecedented form of rifled microtubes with helical ribs. The presence of protection microtubes promote not only their mechanical properties, but also structural endurance to various practical circumstances. These rifled microtubes could serve as endurable and sensitive wearable strain/stress sensors (up to ∼300% strain and ∼100 kPa stress) to monitor various human motions, without showing conspicuous performance decay even after >104 cycles of measurements. This study offers not only a facile and scalable pathway of producing helical fibers, but also an unprecedented platform of rifled microtubes as endurable and sensible sensors of strain and pressure.

Microfluidics for Polymer Microparticles: Opinion on Sustainability and Scalability

The microfluidic production of simple (microspheres) and core–shell (microcapsules) polymer microparticles, often called microencapsulation, has been the scope of several research works since the 1980s. It is a fast, thrifty, and efficient process because of its controlled properties, tuneability, and yield, which can reach 100%. However, the question of its greenness, sustainability, and scalability remains unclear, and more awareness/education is required in this field. The sustainability of production processes using microfluidic techniques can be realized/discussed based on three pillars: (i) waste generation, (ii) the solvents employed, and (iii) raw materials. On the other hand, although the scaling-up of these processes was reported on in several papers as procedures in which hundreds or thousands of microfluidic chips are set in parallel, the sustainability of this scale-up has not been addressed to our knowledge. This opinion paper highlights the advantages of microfluidic encapsulation processes, their greenness according to the above-mentioned pillars, (i–iii) and the necessary considerations to scale them up while preserving their sustainability.

Complex Structures Made Simple - Continuous Flow Production of Core Cross-Linked Polymeric Micelles for Paclitaxel Pro-Drug-Delivery.

Translating innovative nanomaterials to medical products requires efficient manufacturing techniques that enable large-scale high-throughput synthesis with high reproducibility. Drug carriers in medicine embrace a complex subset of tasks calling for multifunctionality. Here, the synthesisof pro-drug-loaded core cross-linked polymeric micelles (CCPMs) in a continuous flow processis reported, which combines the commonly separated steps of micelle formation, core cross-linking, functionalization, and purification into a single process. Redox-responsive CCPMs are formed from thiol-reactive polypept(o)ides of polysarcosine-block-poly(S-ethylsulfonyl-l-cysteine) and functional cross-linkers based on dihydrolipoic acid hydrazide for pH-dependent release of paclitaxel. The precisely controlled microfluidic process allows the production of spherical micelles (Dh = 35nm) with low polydispersity values (PDI < 0.1) while avoiding toxic organic solvents and additives with unfavorable safety profiles. Self-assembly and cross-linking via slit interdigital micromixers produces 350-700mg of CCPMs/h per single system, while purification by online tangential flow filtration successfully removes impurities (unimer ≤ 0.5%). The formed paclitaxel-loaded CCPMs possess the desired pH-responsive release profile, display stable drug encapsulation, an improved toxicity profile compared to Abraxane (a trademark of Bristol-Myers Squibb), and therapeutic efficiency in the B16F1-xenotransplanted zebrafish model. The combination of reactive polymers, functional cross-linkers, and microfluidics enables the continuous-flow synthesis of therapeutically active CCPMs in a single process.