Microfluidic Fabrication Research Articles

Microfluidic Fabrication of Oleosin-Coated Liposomes as Anticancer Drug Carriers with Enhanced Sustained Drug Release

Microfluid-derived liposomes (M-Lipo) exhibit great potential as drug and functional substance carriers in pharmaceutical and food science. However, the low liposome membrane stability, attributed to the liquid core, limits their application range. Oleosin, a natural surfactant protein, can improve the stability of the lipid nanoparticle membrane against various environmental stresses, such as heat, drying, and pH change; in addition, it can enable sustained drug release. Here, we proposed the fabrication of oleosin-coated M-Lipo (OM-Lipo) through self-assembly on a microfluidic chip and the evaluation of its anticancer drug (carmustine) delivery efficiency. Nanoparticle characterization revealed that the oleosin coating slightly lowered the membrane potential of M-Lipo and greatly improved their dispersibility. Additionally, the in vitro drug release profile showed that the oleosin coating improved the sustained release of the hydrophobic drug from the phospholipid bilayer in body temperature. Our results suggest that OM-Lipo has sufficient potential in various fields, based on its easy production, excellent stability, and biocompatibility.

Microfluidic-Generated Injectable Bulking Agents with Biocompatible Surfaces and Their Mid-term Outcomes in a Rat Model with Anal Sphincter Injury.

Bulking agents have gained attention as new, minimally invasive treatments for fecal incontinence. Various materials and surface treatment techniques have been extensively studied to ensure good biocompatibility and long-term stability. Despite significant improvements in biocompatibility, the nonuniform particle size of existing materials has led to other challenges, such as the induction of phagocytosis or reduction of injectability during in vivo tests. This study aimed to conduct a preclinical test of the midterm stability of bulking agents with newly formulated particles with uniform size. To this end, the particles were fabricated using microfluidics, resulting in a narrow size dispersity of less than 5% as the coefficient of variation, which is essentially distinct from conventional bulking agents. The microfluidic fabrication resulted in uniformly sized particles larger than the in vivo migratory limit of 80 μm and in a reduction in maximum injection pressure. Histological staining and microscopic observations confirmed proper positioning of the filler materials in vivo and a negligible immune response for up to 6 months, indicating successful midterm stability.

One-pot microfluidic fabrication of micro ceramic particles

In the quest for miniaturization across technical disciplines, microscale ceramic blocks emerge as pivotal components, with performance critically dependent on precise scales and intricate shapes. Sharp-edged ceramic microparticles, applied from micromachining to microelectronics, require innovative fabrication techniques for high-throughput production while maintaining structural complexity and mechanical integrity. This study introduces a “one-pot microfluidic fabrication” system incorporating two device fabrication strategies, “groove & tongue” and sliding assembling, achieving an unprecedented array of microparticles with diverse, complex shapes and refined precision, outperforming traditional methods in production rate and quality. Optimally designed sintering profiles based on derivative thermogravimetry enhance microparticles’ shape retention and structural strength. Compression and scratch tests validate the superiority of microparticles, suggesting their practicability for diverse applications, such as precise micromachining, sophisticated microrobotics and delicate microsurgical tools. This advancement marks a shift in microscale manufacturing, offering a scalable solution to meet the demanding specifications of miniaturized technology components.

Microfluidic Fabrication of Gelatin-Nano Hydroxyapatite Scaffolds for Enhanced Control of Pore Size Distribution and Osteogenic Differentiation of Dental Pulp Stem Cells.

The combination of gelatin and hydroxyapatite (HA)has emerged as a promising strategy in dental tissue engineering due to its favorable biocompatibility, mechanical properties, and ability to support cellular activities essential for tissue regeneration, rendering them ideal components for hard tissue applications. Besides, precise control over interconnecting porosity is of paramount importance for tissue engineering materials. Conventional methods for creating porous scaffolds frequently encounter difficulties in regulating pore size distribution. This study demonstrates the fabrication of gelatin-nano HA scaffolds with uniform porosity using a T-type junction microfluidic device in a single-step process. Significant improvements in control over the pore size distribution are achieved by regulating the flow parameters, resulting in effective and time-efficient manufacturing comparable in quality to the innovative 3D bioprinting techniques. The overall porosity of the scaffolds exceeded 60%, with a remarkably narrow size distribution. The incorporation of nano-HAinto 3D porous gelatin scaffolds successfully induced osteogenic differentiation in stem cells at both the protein and gene levels, as evidenced by the significant increase in osteocalcin (OCN), an important marker of osteogenic differentiation. The OCN levels are 26 and 43 times higher for gelatin and gelatin-HA scaffolds, respectively, compared to the control group.

Biomimetic Nanoparticles for Basic Drug Delivery.

Biomimetic nanoparticles (BMNPs) are innovative nanovehicles that replicate the properties of naturally occurring extracellular vesicles, facilitating highly efficient drug delivery across biological barriers to target organs and tissues while ensuring maximal biocompatibility and minimal-to-no toxicity. BMNPs can be utilized for the delivery of therapeutic payloads and for imparting novel properties to other nanotechnologies based on organic and inorganic materials. The application of specifically modified biological membranes for coating organic and inorganic nanoparticles has the potential to enhance their therapeutic efficacy and biocompatibility, presenting a promising pathway for the advancement of drug delivery technologies. This manuscript is grounded in the fundamentals of biomimetic technologies, offering a comprehensive overview and analytical perspective on the preparation and functionalization of BMNPs, which include cell membrane-coated nanoparticles (CMCNPs), artificial cell-derived vesicles (ACDVs), and fully synthetic vesicles (fSVs). This review examines both "top-down" and "bottom-up" approaches for nanoparticle preparation, with a particular focus on techniques such as cell membrane coating, cargo loading, and microfluidic fabrication. Additionally, it addresses the technological challenges and potential solutions associated with the large-scale production and clinical application of BMNPs and related technologies.

All-aqueous microfluidic fabrication of calcium alginate/alkylated chitosan core-shell microparticles with time-sequential functions for promoting whole-stage wound healing

Wound healing comprises a series of complex physiological processes, including hemostasis, inflammation, cell proliferation, and tissue remodeling. Designing new functional biomaterials by biological macromolecules with tailored therapeutic effects to precisely match the unique requirements of each stage is cherished but rarely discussed. Here, we employ all-aqueous microfluidics to fabricate multifunctional core-shell microparticles aimed at promoting whole-stage wound healing. These microparticles feature a core comprising calcium alginate, cellulose nanocrystals and epidermal growth factor, surrounded by a shell made of alkylated chitosan, alginate, and ciprofloxacin (EGF + CNC@Ca-ALG/CIP@ACS core-shell microparticles, D-CSMP). Response surface methodology (RSM) with a combination of central composite rotatable design (CCRD) is used to meticulously optimize the fabrication processes, endowing the resulting D-CSMP with superior capabilities for efficiently encapsulating and controlled releasing CIP and EGF tailored to each stage aligning the healing timeline. The developed D-CSMP demonstrate notable time-sequential functionalities, including promoting blood coagulation, enhancing hemostasis, and exerting antibacterial effects. Furthermore, in a skin injury model, D-CSMP significantly expedite and enhance the chronic wound healing process. In conclusion, our core-shell microparticles with notable time-sequential functions present a versatile and robust approach for wound treatment and related biomedical applications.

Design and batch fabrication of anisotropic microparticles toward small-scale robots using microfluidics: recent advances.

Small-scale robots with shape anisotropy have garnered significant scientific interest due to their enhanced mobility and precise control in recent years. Traditionally, these miniature robots are manufactured using established techniques such as molding, 3D printing, and microfabrication. However, the advent of microfluidics in recent years has emerged as a promising manufacturing technology, capitalizing on the precise and dynamic manipulation of fluids at the microscale to fabricate various complex-shaped anisotropic particles. This offers a versatile and controlled platform, enabling the efficient fabrication of small-scale robots with tailored morphologies and advanced functionalities from the microfluidic-derived anisotropic microparticles at high throughput. This review highlights the recent advances in the microfluidic fabrication of anisotropic microparticles and their potential applications in small-scale robots. In this review, the term 'small-scale robots' broadly encompasses micromotors endowed with capabilities for locomotion and manipulation. Firstly, the fundamental strategies for liquid template formation and the methodologies for generating anisotropic microparticles within the microfluidic system are briefly introduced. Subsequently, the functionality of shape-anisotropic particles in forming components for small-scale robots and actuation mechanisms are emphasized. Attention is then directed towards the diverse applications of these microparticle-derived microrobots in a variety of fields, including pollution remediation, cell microcarriers, drug delivery, and biofilm eradication. Finally, we discuss future directions for the fabrication and development of miniature robots from microfluidics, shedding light on the evolving landscape of this field.

Looping Flexible Fluoropolymer Microcapillary Film Extends Analysis Times for Vertical Microfluidic Blood Testing.

The microfluidic measurement of capillary flow can be used to evaluate the response of biological samples to stimulation, where distance and velocity are altered. Melt-extruded multi-bored microfluidic capillaries allow for high-throughput testing with low device cost, but simple devices may limit control over sample flow when compared to the more complex "lab-on-a-chip" devices produced using advanced microfluidic fabrication methods. Previously, we measured the dynamics of global haemostasis stimulated by thrombin by dipping straight vertical microcapillaries into blood, but only the most rapid response could be monitored, as flow slowed significantly within 30 s. Here, we show an innovative method to extend both the stimulation process and flow measurement time without increasing the cost of the device by adding simple loops to the flexible extruded device. The loops enable longer time-scale measurements by increasing resistance to flow, thereby reducing the dependence on high stimulus concentrations for rapid reactions. The instantaneous velocity and equilibrium heights of straight and looped vertical microcapillary films were assessed with water, plasma and whole blood, showing that the loops create additional frictional resistances, reduce flow velocity and prolong residence times for increased time scales of the stimulation process. A modified pressure balance model was used to capture flow dynamics with the added loop. Looped devices loaded with thrombin and collagen showed an improved detection of blood stimulation responses even with lower stimulus concentrations, compared to straight vertical capillaries. Thrombin-activated blood samples in straight capillaries provided a maximum measurement zone of only 4 mm, while the looped design significantly increased this to 11 mm for much longer time scale measurements. Our results suggest that extending stimulation times can be achieved without complex microfluidic fabrication methods, potentially improving concentration-response blood stimulation assays, and may enhance the accuracy and reliability. We conclude adding a loop to low-cost extruded microfluidic devices may bring microfluidic devices closer to delivering on their promise of widespread, decentralized low-cost evaluation of blood response to stimulation in both research and clinical settings.

Surface Passivation of Norland Optical Adhesive Improves the Guiding Efficiency of Gliding Microtubules in Microfluidic Devices.

The microtubule-kinesin biomolecular motor system, which is vital for cellular function, holds significant promise for nanotechnological applications. In vitro gliding assays have demonstrated the ability to transport microcargo by propelling microtubules across kinesin-coated surfaces. However, the uncontrolled directional motion of microtubules has posed significant challenges, limiting the system's application for precise cargo delivery. Microfluidic devices provide a means to direct microtubule movement through their geometric features. Norland Optical Adhesive (NOA) is valued for its mold-free application in microfluidic device fabrication; however, microtubules often climb up channel walls, limiting controlled movement. In this study, a surface passivation method for NOA is introduced, using polyethylene glycol via a thiol-ene click reaction. This technique significantly improved the directional control and concentration of microtubules within NOA microchannels. This approach presents new possibilities for the precise application of biomolecular motors in nanotechnology, enabling advancements in the design of microfluidic systems for complex biomolecular manipulations.

On the Machinability and Formation of Gas Film Thickness in ECDM of Silica based Pyrex Glass

Electrochemical discharge machining (ECDM) stands out as a preferred method for microfluidic channel fabrication due to its ability to produce required shapes with the least thermal damage along with close tolerances and dimensional accuracy. Recently, there has been significant progress made in the domain of ECDM for parametric analysis, focusing on discharge regime characteristics, but precise control of the hydrodynamic regime remains a challenge. With this view, the present study has been targeted on analyzing the effect of various auxiliary electrodes on the formation of gas film thickness and discharge energy during the fabrication of microchannels using ECDM on silica-based Pyrex glass under varying conditions. Experiments were conducted on an ECDM setup to achieve near damage-free edges of microchannels on the surface silica-based Pyrex glass. Results show the effect of various auxiliary electrodes, applied voltage, and electrolyte concentration on gas film thickness, spark energy, rate of material removal (MRR), and width of overcut (WOC). The optimum parametric level of applied voltage, electrolyte concentration, and auxiliary electrode were 68 V, 35 wt%, and A2 auxiliary electrode, respectively and the best response values were 0.4134 mg min−1, and 40 μm, respectively, for MRR and WOC. In addition, tool wear rate, heat affected zone, and surface morphology of fabricated microchannels was examined using scanning electron microscopy, optical microscope, and energy-dispersive X-ray spectroscopy.

Fabrication of microchannels on silica glass by femtosecond laser multi-scan: From surface generation mechanism to morphology control

Femtosecond laser processing has become a critical technique for the microfabrication of hard and brittle materials, particularly in microfluidic device applications. This study focuses on the fabrication of microchannels with controllable cross-sectional profiles in silica glass, a material known for its excellent physical and chemical properties. Through a combination of experimental research and theoretical analysis, the surface generation mechanisms governing microchannel morphology are investigated, alongside the influence of various processing parameters on the surface roughness at the microchannel bottom. A comprehensive optimization method is developed to control sidewall taper and surface roughness by adjusting laser scanning paths and modes. Utilizing a composite scanning approach, the study achieves near-rectangular microchannels with average sidewall taper angles below 5° and surface roughness (Sa) of 2.53 μm. These results provide a new strategy for precise control of microchannel morphology in silica glass, offering significant potential to enhance the efficiency and precision of microfluidic device fabrication, with broad applications in both industrial and research settings.

Portable surface acoustic wave device platform coupled with a paper-based capillary fluidics for real-time biosensing applications

Surface acoustic wave (SAW) sensors have emerged as prominent real-time, label-free biosensors with diverse applications in immunoassays and nucleic acid detection. However, widespread adoption in diagnostics has been impeded by challenges such as miniaturization of instrumentation, microfluidics fabrication and high attenuation in liquid environments. In this study we address these limitations by presenting a portable platform capable of real-time monitoring of a SAW microarray chip comprising up to four sensing channels, combined with a novel paper-based capillary flow channel. For the fabrication of a portable, automated and versatile sensor platform, we integrated a microcontroller, RF components, and a micropump for flow control. Calibration procedures ensured accurate measurements for both amplitude and phase, with a low drift rate (0.72 mdB/h and 1.00 mdeg./h, respectively) and high resolution (2.10 mdB and 6.10 mdeg.), indicating stable operation with minimal interface electronics. The capillary flow channel, implemented by confining the fluid on the sensing surface using a nitrocellulose strip, facilitated laminar and continuous sample flow with minimum damping of the acoustic signal. The sensor system was evaluated with two SAW devices at 100 and 200 MHz using glycerol dilutions within the range of 1 % and 70 %, demonstrating real-time monitoring capabilities and linear correlations between amplitude and phase changes. To prove the biosensing and clinical validity of the SAW newly developed system, DNA adsorption on a poly(L-lysine)-graft-poly(ethylene glycol) (PLL-g-PEG) functionalized SAW-surface was demonstrated with a detection limit of 0.001 μg/mL. Our study demonstrates the feasibility of a portable SAW sensor system coupled with a low-cost and replaceable capillary flow channel for real-time monitoring and biomolecular detection.

Durable superhydrophobic LTA-zeolite coating on PDMS surface with excellent self-cleaning property

Superhydrophobicity is a fundamental characteristic that plays a vital role in various applications, such as self-cleaning coatings, water vapor barriers for flexible electronics, and microfluidic chip fabrication. In this study, we developed a superhydrophobic surface coating on polydimethylsiloxane (PDMS) using Linde Type A (LTA) zeolite crystals, employing a silane coupling strategy. As part of this study, the LTA-zeolite-coated PDMS surface is characterized using various techniques to elucidate its superhydrophobic behavior, and a functionalization mechanism is proposed. The resulting substrate exhibited high surface roughness, with a water contact angle exceeding 155°, a sliding angle below 1°, and a contact angle hysteresis under 10°. This superhydrophobic surface coating effectively repelled water, confirming its excellent self-cleaning properties. Furthermore, the coating withstood three cycles of the Kapton adhesive tape peeling test, 5 h of water-jet hitting, and 72 h of UV light exposure, demonstrating its robustness and strong adhesion to PDMS.

Emulsion-Based Multi-Phase Integrated Microbeads with Inner Multi-Interface Structure Enable Dual-Modal Imaging for Precision Endovascular Embolization.

Microsphere-based embolic agents have gained prominence in transarterial embolization (TAE) treatment, a critical minimally invasive therapy widely applied for a variety of diseases such as hypervascular tumors and acute bleeding. However, the development of microspheres with long-term, real-time, and repeated X-ray imaging as well as ultrasound imaging remains challenging. In this study, emulsion-based dual-modal imaging microbeads with a unique internal multi-interface structure is developed for TAE treatment. The embolic microbeads are fabricated from a solidified oil-in-water (O/W) emulsion composed of crosslinked CaAlg-based aqueous matrix and dispersed radiopaque iodinated oil (IO) droplets through a droplet-based microfluidic fabrication method. The CaAlg-IO microbeads exhibit superior X-ray imaging visibility due to the incorporation of exceptionally high iodine level up to 221 mgImL-1, excellent ultrasound imaging capability attributed to the multi-interface structure of the O/W emulsion, great microcatheter deliverability thanks to their appropriate biomechanical properties and optimal microbead density, and extended drug release behavior owing to the biodegradation nature of the embolics. Such an embolic agent presents a promising emulsion-based platform to utilize multi-phased structures for improving endovascular embolization performance and assessment capabilities.

An Alternative Micro-Milling Fabrication Process for Rapid and Low-Cost Microfluidics.

Microfluidics is an important technology for the biomedical industry and is often utilised in our daily lives. Recent advances in micro-milling technology have allowed for rapid fabrication of smaller and more complex structures, at lower costs, making it a viable alternative to other fabrication methods. The microfluidic chip fabrication developed in this research is a step-by-step process with a self-contained wet milling chamber. Additionally, ethanol solvent bonding is used to allow microfluidic chips to be fully fabricated within approximately an hour. The effect of using this process is tested with quantitative contact profileometery data to determine the expected surface roughness in the microchannels. The effect of surface roughness on the controllability of microparticles is tested in functional microfluidic chips using image processing to calculate particle velocity. This process can produce high-quality channels when compared with similar studies in the literature and surface roughness affects the control of microparticles. Lastly, we discuss how the outcomes of this research can produce rapid and higher-quality microfluidic devices, leading to improvement in the research and development process within the fields of science that utilise microfluidic technology. Such as medicine, biology, chemistry, ecology, and aerospace.

Evolution of materials, geometries, and fabrication of sweat patches and their use in high-throughput point-of-care/onsite sensing

Sweat is a non-invasive fluid used to monitor various medically relevant analytes for disease diagnosis and healthcare monitoring. Sweat patches are used to collect contaminant-free sweat from individuals in any setting. In the past 50 years, sweat patches have evolved on various fronts, like fabrication methods, materials, and microfluidic channel designs. The primary goal of this study is to explore the evolution of sweat patches over the last 50 years in terms of materials such as polydimethylsiloxane (PDMS), adhesives, and other polymers, as well as microfluidic channel geometries and fabrication approaches. In addition, modern sweat patches are integrated with electrodes and electronic systems that enable sweat collection and in-situ analysis. The sweat patches are classified into two classes: early and modern sweat patches. Further, applications of these sweat patches in monitoring hydration, performance, metabolites, and disease diagnosis have been elaborately discussed. In the end, the conclusion and future outlook are discussed to give insight into further research.

Elucidating the mechanism of overcuring in microchannels fabricated via vat photopolymerization (VPP) for precise microfluidic chip printing

Vat Photopolymerization (VPP) technology is highly regarded for precision micromachining applications like microfluidic chip fabrication, owing to its fine resolution, adaptability, and rapid prototyping capabilities. However, the challenge of resin over-curing resulting from UV energy penetration poses a significant obstacle in microchannel printing. This study addresses this challenge by investigating the intricate relationship between resin properties and over-curing. Diverse microfluidic chips were printed utilizing VPP technology, and the overall cross-sectional over-curing characteristics of the channels were systematically examined. A novel combination of the classical UV light curing model and computational Fluid-Structure Interaction (FSI) model with the VPP printing process was proposed to examine the complex hydrodynamics and exfoliation dynamics within VPP-printed microchannels. The simulation results suggest that resins with higher viscosities and surface roughness are better suited for microchannel printing. Subsequent experiments using five different resins verified these findings and showed that the microchannels obtained with resins of lower viscosity and surface roughness resins have an irregular trapezoidal cross-section, which is uncontrollable and unpredictable and seriously affects the microchannel printing accuracy. Conversely, resins with higher viscosity and surface roughness have an ideal rectangular cross-section, which can be compensated by the model further refined printing to print microchannel. Finally, microfluidic chips were printed using "high precision 8 K resin" and "8 K-clay resin" with higher viscosity and surface roughness. The results proved that the microchannels printed by these resins had the desired rectangular cross-section, which was consistent with the "DLP light-curing" model. This study elucidates, for the first time, the intricate interplay between resin properties, printing structure, and microchannel over-curing, and this provides a solid groundwork for advancing high-precision microfluidic chip fabrication via DLP printing.

Cost-Effective Fabrication of Polydimethylsiloxane (PDMS) Microfluidics for Point-of-Care Application

Microfluidics fabrication pertains to the construction of small-scale devices and systems that manipulate and control small volumes of fluids. This process involves precise engineering and manufacturing procedures aimed at designing and producing these devices, which find applications in healthcare, environmental monitoring, and chemical analysis. The present study showcases an inexpensive approach to fabricate microfluidics channels using PDMS biopolymer and soft lithography technique to achieve laminar fluid flow. Initially, a robust and adhesive mold was created by fabricating a master template using several layers of SU-8 5 and SU-8 2015 negative photoresists. Subsequently, PDMS microfluidics channels were replicated and sealed onto a glass substrate through plasma bonding treatment. High-power microscopy images and profilometer analyses demonstrated successful fabrication with minimal deviation from the initial designs and the fabricated devices (less than 0.07 mm, less than 0.6°). Both the SU-8 master template and PDMS replicate displayed average microchannel height values and surface roughness of 100 μm and 0.26 μm or lower, respectively. Additionally, the fluid test confirmed laminar flow without any leakage post plasma oxidation, indicating the completion of an efficient and cost-effective fabrication process.

Validation of Fluid Flow Speed Behavior in Capillary Microchannels Using Additive Manufacturing (SLA Technology)

This research explores fluid flow speed behavior in capillary channels using additive manufacturing, focusing on stereolithography (SLA). It aims to validate microchannels fabricated through SLA for desired fluid flow characteristics, particularly capillary-driven flow. The methodology involves designing, fabricating, and characterizing microchannels via SLA, with improvements such as an air-cleaning step facilitating the production of microchannels ranging from 300 to 1000 µm. Experimental validation assesses fluid flow speed behavior across channels of varying dimensions, evaluating the impact of channel geometry, surface roughness, and manufacturing parameters. The findings affirm the feasibility and efficacy of SLA in producing microchannels with consistent and predictable fluid flow behavior between 300 to 800 µm. This study contributes insights into microfluidic device fabrication techniques and enhances the understanding of fluid dynamics in capillary-driven systems. Overall, it underscores the potential of additive manufacturing, specifically SLA, in offering cost-effective and scalable solutions for microfluidic applications. The validated fluid flow speed behavior in capillary channels suggests new avenues for developing innovative microfluidic devices with improved performance and functionality, marking a significant advancement in the field.

Double-Sided Tape in Microfluidics: A Cost-Effective Method in Device Fabrication.

The demand for easy-to-use, affordable, accessible, and reliable technology is increasing in biological, chemical, and medical research. Microfluidic devices have the potential to meet these standards by offering cost-effective, highly sensitive, and highly specific diagnostic tests with rapid performance and minimal sample volumes. Traditional microfluidic device fabrication methods, such as photolithography and soft lithography, are time-consuming and require specialized equipment and expertise, making them costly and less accessible to researchers and clinicians and limiting the applicability and potential of microfluidic devices. To address this, researchers have turned to using new low-cost materials, such as double-sided tape for microfluidic device fabrication, which offers simple and low-cost processes. The innovation of low-cost and easy-to-make microfluidic devices improves the potential for more devices to be transitioned from laboratories to commercialized products found in stores, offices, and homes. This review serves as a comprehensive summary of the growing interest in and use of double-sided tape-based microfluidic devices in the last 20 years. It discusses the advantages of using double-sided tape, the fabrication techniques used to create and bond microfluidic devices, and the limitations of this approach in certain applications.