Fabrication Of Microfluidic Chips Research Articles

Design and Fabrication of a High Performance Microfluidic Chip for Blood Plasma Separation: Modelling and Prediction of System Behaviour via CFD Method.

This paper presents a single-step microfluidic system designed for passive separation of human fresh blood plasma using direct capillary forces. Our microfluidic system is composed of a cylindrical well between upper and lower channel pairs produced by soft photolithography. The microchip was fabricated based on hydrophobicity differences upon suitable cylindrical surfaces using gravitational and capillary forces and lateral migration of plasma and red blood cells. The plasma radiation was applied to attach the polymeric segment (polydimethylsiloxane (PDMS)) to the glass. Meanwhile, Tween 80 was used as a surfactant to increase the hydrophobicity of the lateral channel surfaces. This led to the higher movement of whole blood, including plasma. Fick's law of diffusion was validated for this diffusion transfer, the Navier-Stokes equation was used for the momentum balance, and the Laplace equation was utilized for the dynamics of the mesh. A model with high accuracy using the COMSOL Multiphysics software was created to predict the capillary forces and chip model validation. RBCs (red blood cells) were measured by the H3 cell counter instrument, by which 99% plasma purity was achieved. Practically, 58.3% of the plasma was separated from the blood within 12 min. Correlation between plasma separation results obtained from software and experimental data showed a coefficient of determination equal to 0.9732. This simple, rapid, stable, and reliable microchip can be considered as a promising candidate for providing plasma in point-of-care diagnostics.

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.

Reversible bonding of microfluidics: Review and applications.

With the development of microfluidic technology, new materials and fabrication methods have been constantly invented in the field of microfluidics. Bonding is one of the key steps for the fabrication of enclosed-channel microfluidic chips, which have been extensively explored by researchers globally. The main purpose of bonding is to seal/enclose fabricated microchannels for subsequent fluid manipulations. Conventional bonding methods are usually irreversible, and the forced detachment of the substrate and cover plate may lead to structural damage to the chip. Some of the current microfluidic applications require reversible bonding to reuse the chip or retrieve the contents inside the chip. Therefore, it is essential to develop reversible bonding methods to meet the requirements of various applications. This review introduces the most recent developments in reversible bonding methods in microfluidics and their corresponding applications. Finally, the perspective and outlook of reversible bonding technology were discussed in this review.

Salinity-Based Molecular Communication in Microfluidic Channels

In this work, we present a novel portable, flexible and easy-to-use experimental setup for investigating salinity-based information transmission in microfluidic channels. At the receiver, the different salinity-levels are detected by a customized electronic circuit, which measures electrical conductivity via electrodes in the microfluidic channel. We provide a detailed description of the setup, including the microfluidic chip fabrication. Moreover, we develop a rigorous mathematical model of each testbed component and an end-to-end model of the system, which we have verified through experiments. Finally, we analyzed the error performance of the setup using optimum and sub-optimum detection algorithms, such as the Viterbi algorithm and threshold detection.

Recent Advances in Organ-on-Chips Integrated with Bioprinting Technologies for Drug Screening.

Currently, the demand for more reliable drug screening devices has made scientists and researchers develop novel potential approaches to offer an alternative to animal studies. Organ-on-chips are newly emerged platforms for drug screening and disease metabolism investigation. These microfluidic devices attempt to recapitulate the physiological and biological properties of different organs and tissues using human-derived cells. Recently, the synergistic combination of additive manufacturing and microfluidics has shown a promising impact on improving a wide array of biological models. In this review, different methods are classified using bioprinting to achieve the relevant biomimetic models in organ-on-chips, boosting the efficiency of these devices to produce more reliable data for drug investigations. In addition to the tissue models, the influence of additive manufacturing on microfluidic chip fabrication is discussed, and their biomedical applications are reviewed.

Fabrication of spectroscopic microfluidic chips for mastitis detection in raw milk

Mastitis is a disease that directly affects the quantity and quality of milk produced by dairy cows, which can have a negative impact on the income generated from selling the milk. Severe inflammation caused by this mammary disease can result in up to 1 × 106 white blood cells per milliliter of cow milk. Currently, the California mastitis test is a popular chemical inspection test, but its error rate of over 40% is a significant factor in the ongoing spread of mastitis. In this study, a new microfluidic device was designed and fabricated to identify normal, sub-clinical, and clinical mastitis. This portable device allows for precise and analysis of results within a second. The device was designed to screen somatic cells and a staining process was added to identify somatic cells using single-cell process analysis. The fluorescence principle was used to identify the infection status of the milk, which was analyzed using a mini-spectrometer. The accuracy of the device was tested, and it was found to determine the infection status with 95% accuracy, compared to the accuracy obtained using the Fossomatic machine. By introducing this new microfluidic device, it is believed that the spread of mastitis in dairy cows can be significantly reduced, leading to higher quality and more profitable milk production.

Rapid Prototyping of Multi-Functional and Biocompatible Parafilm®-Based Microfluidic Devices by Laser Ablation and Thermal Bonding.

In this paper, we report a simple, rapid, low-cost, biocompatible, and detachable microfluidic chip fabrication method for customized designs based on Parafilm®. Here, Parafilm® works as both a bonding agent and a functional membrane. Its high ultimate tensile stress (3.94 MPa) allows the demonstration of high-performance actuators such as microvalves and micropumps. By laser ablation and the one-step bonding of multiple layers, 3D structured microfluidic chips were successfully fabricated within 2 h. The consumption time of this method (~2 h) was 12 times less than conventional photolithography (~24 h). Moreover, the shear stress of the PMMA-Parafilm®-PMMA specimens (0.24 MPa) was 2.13 times higher than that of the PDMS-PDMS specimens (0.08 MPa), and 0.56 times higher than that of the PDMS-Glass specimens (0.16 MPa), showing better stability and reliability. In this method, multiple easily accessible materials such as polymethylmethacrylate (PMMA), PVC, and glass slides were demonstrated and well-incorporated as our substrates. Practical actuation devices that required high bonding strength including microvalves and micropumps were fabricated by this method with high performance. Moreover, the biocompatibility of the Parafilm®-based microfluidic devices was validated through a seven-day E. coli cultivation. This reported fabrication scheme will provide a versatile platform for biochemical applications and point-of-care diagnostics.

Microinjection in C. elegans by direct penetration of elastomeric membranes.

The nematode worm C. elegans is widely used in basic and translational research. The creation of transgenic strains by injecting DNA constructs into the worm's gonad is an essential step in many C. elegans research projects. This paper describes the fabrication and use of a minimalist microfluidic chip for performing microinjections. The worm is immobilized in a tight-fitting microchannel, one sidewall of which is a thin elastomeric membrane through which the injection pipet penetrates to reach the worm. The pipet is neither broken nor clogged by passing through the membrane, and the membrane reseals when the pipet is withdrawn. Rates of survival and transgenesis are similar to those in the conventional method. Novice users found injections using the device easier to learn than the conventional method. The principle of direct penetration of elastomeric membranes is adaptable to microinjections in a wide range of organisms including cells, embryos, and other small animal models. It could, therefore, lead to a new generation of microinjection systems for basic, translational, and industrial applications.

Fabrication of PEG-Plasticized Epoxy Resin-Based Microfluidic Chips by Casting over PMMA Mold for PCR Applications: Influence CO2 Laser-Ablation Parameters of Mold

Despite dimethyl siloxane (PDMS) being one of the most used microfluidics chips, its micromachining techniques are infeasible for the mass production of commercial devices. This study proposed Epoxy Resin (ER) as a promising, cost-effective alternative to PDMS in lab-on-chip applications, including Polymerase Chain Reactions (PCR). Moreover, a novel, rapid and non-photolithographic approach has been developed for micromachining epoxy microfluidic chips. A new method for fabricating epoxy resin and polyethylene glycol (PEG) hybrid (ER-PEG) microchannels was developed by casting replication over PMMA molds. A PMMA piece was engraved with a CO2 laser in the raster mode to produce the mold for the ER-PEG casting first. A positive mold was fabricated from a polymethyl methacrylic acid (PMMA) sheet (6mm) by CO2 laser ablation. The microfluidic chips with the negative pattern were replicated by casting thermoset epoxy resin onto the micro-machined PMMA mold. The entire process, from device design conception to working device, can be completed in minutes. Herein, to enhance the surface roughness (Ra) of the ablated mold surface, different Distances to Focus (DF) were tried. The low Ra in the mold results in a low Ra in the replica. Also, the performance of ER-PEG in PCR was evaluated to verify the compatibility of the chip material to the PCR test.

Using 3D printing to fabricate microfluidic chips for biosensing applications

This paper gives details on the use of 3D smart printing technology to fabricate microfluidic chips for integration into biosensors for the detection and diagnosis of diseases. Additive manufacturing, also known as 3D printing, is a process used to create complex, three-dimensional objects by adding layer upon layer of material until the desired shape is formed. Microfluidic chips are used to manipulate fluids through separation and mixing. Conventional microfluidic chip fabrication methods are expensive, require much experience to operate, and are time consuming, while 3D printing offers a solution to these challenges. The 3D printing technique prints models designed using a computer-aided design software such as Autodesk Fusion 360. In this work the authors show example microfluidic chips which were printed using a 3D printer, these include an X-channel chip, Y-channel chip and a lateral flow chip which can all be integrated with biosensing setups.

Investigation on gas/water two-phase flow in quartz nanopores from molecular perspectives

Understanding the gas/water two-phase occurrence, flow patterns, and underlying mechanisms in quartz nanopores is crucial for gas transport and production in shale reservoirs. In this study, we investigated the flow characteristics of methane and water in hydroxylated quartz nanopores employing the grand canonical Monte Carlo (GCMC) and molecular dynamics (MD) simulations and focused on elucidating the effects of water saturation, pressure gradient and ion concentration in various aperture nanopores. Results show that water molecules preferentially adsorb on the hydrophilic quartz surface to form water film, increasing methane flow friction and reducing its slippage velocity significantly. Water bridges are formed to wrap gas bubbles and hinder the gas flow with increased water saturation. The water phase occupies a larger pore space with increasing water saturation resulting in an increase in methane effective viscosity and a decrease in apparent permeability. The water bridge is broken under the joint action of external force and gas driving when the pressure gradient is much larger, leading to a dramatic growth of gas flow, and the high-speed gas will produce a shear driving effect on the thick water layers. Ions will weaken the formation of hydrogen bonds between water molecules, but the flux of the water phase decreases with the increasing ion concentration due to the combined impact of ion spatial structure and electroviscous effects and counteracts the gas phase, thus impeding its flow. This study shed light on the flow phenomena of gas/water phases in hydrophilic nanopores. The results are expected to provide some insight into energy and environmental issues, such as fracturing fluid optimization, enhanced gas recovery (EGR) by water flooding, and the fabrication of microfluidic chips.

다공성 막을 포함하는 미세유체칩을 이용한 항암 지질나노입자 연속 생산 공정

다공성 막을 중간층으로 갖는 폴리디메틸실록산 미세유체칩을 이용하여 항암 약물인 독소루비신을 함유한 지질나노입자를 연속적인 공정으로 제조하였다. 불연속상으로는 지질, 독소루비신, 및 라우릭 산을 함유한 에탄올상을, 연속상으로는 증류수를 각각 시린지펌프를 이용하여 미세유체칩에 투입하였다. 작은 기공을 갖는 다공성막을 사용하고, 연속상의 유속이 높을 수록 작은 지질나노입자가 제조되었다. 라우릭 산은 지질나노입자의 콜로이드 안정성을 증가시켜 주었고, 독소루비신과 라우릭 산의 첨가는 HeLa 암세포주에서 높은 세포 독성을 나타내었다. 이러한 미세유체칩은 다른 약물은 물론, mRNA와 siRNA를 함유한 지질나노입자제조에 응용될 수 있다.

Role of Polymers in Microfluidic Devices.

Polymers are sustainable and renewable materials that are in high demand due to their excellent properties. Natural and synthetic polymers with high flexibility, good biocompatibility, good degradation rate, and stiffness are widely used for various applications, such as tissue engineering, drug delivery, and microfluidic chip fabrication. Indeed, recent advances in microfluidic technology allow the fabrication of polymeric matrix to construct microfluidic scaffolds for tissue engineering and to set up a well-controlled microenvironment for manipulating fluids and particles. In this review, polymers as materials for the fabrication of microfluidic chips have been highlighted. Successful models exploiting polymers in microfluidic devices to generate uniform particles as drug vehicles or artificial cells have been also discussed. Additionally, using polymers as bioink for 3D printing or as a matrix to functionalize the sensing surface in microfluidic devices has also been mentioned. The rapid progress made in the combination of polymers and microfluidics presents a low-cost, reproducible, and scalable approach for a promising future in the manufacturing of biomimetic scaffolds for tissue engineering.

Design and fabrication of aspiration microfluidic channel for oocyte characterization

The development potential for oocytes can be predicted by their mechanical properties. One important parameter that is measured to calculate oocyte hardness is Cortical Tension (CT). In this work, for the first time, we present the design, simulation, and fabrication of a new aspiration microfluidic chip to measure the CT of oocytes and then predict their maturation capability in the Germinal Vesicle (GV) stage. This high-performance technique facilitates oocyte characterization and is a promising alternative to traditional methods such as MicroPipette Aspiration (MPA). The proposed technique involves considerably simpler operation, less specialized equipment, and less technical skill than MPA. The proposed microfluidic channel also promises faster measurements. It is shown that in order to completely continue the growth process of oocytes in GV stage, the CT should be in a certain range: very low or very high CTs lead to unsuccessful growth. The obtained results show that 79% of oocytes with the CT between 1.5 and 3 nN/μm reach the Metaphase II (MII) stage, whereas the growth for 78% of oocytes with the CT less than 1.5 nN/μm or higher than 3 nN/μm stops at the GV or Germinal Vesicle Break Down (GVBD) stages. Another property, kvis, that points to the viscous behavior of oocytes is also measured. It is seen that 80% of GV oocytes with the kvis values between 15 and 30 k Pa s/m reach the MII stage.

Microfluidic Acoustophoresis for Flowthrough Separation of Gram-Negative Bacteria using Aptamer Affinity Beads.

This article describes the fabrication and operation of microfluidic acoustophoretic chips using a microfluidic acoustophoresis technique and aptamer-modified microbeads that can be used for the fast, efficient isolation of Gram-negative bacteria from a medium. This method enhances the separation efficiency using a mix of long, square microchannels. In this system, the sample and buffer are injected into the inlet port through a flow controller. For bead centering and sample separation, AC power is applied to the piezoelectric transducer via a function generator with a power amplifier to generate acoustic radiation force in the microchannel. There is a bifurcated channel at both the inlet and outlet, enabling simultaneous separation, purification, and concentration. The device has a recovery rate of >98% and purity of 97.8% up to a 10x dose concentration. This study has demonstrated a recovery rate and purity higher than the existing methods for separating bacteria, suggesting that the device can separate bacteria efficiently.

Rapid fabrication of microfluidic mixer chip by non-isothermal molding method based on resistance heating principle and its application in pesticide residue detection

This paper proposed a rapid fabrication process for polymethylmethacrylate (PMMA) microfluidic mixer chip by non-isothermal method based on resistance heating principle, and the prepared microfluidic mixer chip was successfully applied to the portable pesticide residue detection device. Firstly, the creep test of PMMA was carried out and the six units Maxwell constitutive model was fitted by Prony series. Secondly, the resistance heating device was designed, the influence of current on heating temperature and heating time was investigated, the effect of current on energy consumption was analyzed. Thirdly, the non-isothermal molding simulation and experiment of PMMA were carried out, the quality of PMMA microfluidic mixer chip fabricated by non-isothermal molding was investigated. Finally, the microfluidic mixer chip was adopted to the designed pesticide residue detection device, and the detection sensitivity of the device is 0.0375 mol−1. The research results provide a reference for the efficient preparation of microchannels and the development of portable detection equipment.

PDMS Organ-On-Chip Design and Fabrication: Strategies for Improving Fluidic Integration and Chip Robustness of Rapidly Prototyped Microfluidic In Vitro Models.

The PDMS-based microfluidic organ-on-chip platform represents an exciting paradigm that has enjoyed a rapid rise in popularity and adoption. A particularly promising element of this platform is its amenability to rapid manufacturing strategies, which can enable quick adaptations through iterative prototyping. These strategies, however, come with challenges; fluid flow, for example, a core principle of organs-on-chip and the physiology they aim to model, necessitates robust, leak-free channels for potentially long (multi-week) culture durations. In this report, we describe microfluidic chip fabrication methods and strategies that are aimed at overcoming these difficulties; we employ a subset of these strategies to a blood–brain-barrier-on-chip, with others applied to a small-airway-on-chip. Design approaches are detailed with considerations presented for readers. Results pertaining to fabrication parameters we aimed to improve (e.g., the thickness uniformity of molded PDMS), as well as illustrative results pertaining to the establishment of cell cultures using these methods will also be presented.

Nanofiber self-consistent additive manufacturing process for 3D microfluidics

3D microfluidic devices have emerged as powerful platforms for analytical chemistry, biomedical sensors, and microscale fluid manipulation. 3D printing technology, owing to its structural fabrication flexibility, has drawn extensive attention in the field of 3D microfluidics fabrication. However, the collapse of suspended structures and residues of sacrificial materials greatly restrict the application of this technology, especially for extremely narrow channel fabrication. In this paper, a 3D printing strategy named nanofiber self-consistent additive manufacturing (NSCAM) is proposed for integrated 3D microfluidic chip fabrication with porous nanofibers as supporting structures, which avoids the sacrificial layer release process. In the NSCAM process, electrospinning and electrohydrodynamic jet (E-jet) writing are alternately employed. The porous polyimide nanofiber mats formed by electrospinning are ingeniously applied as both supporting structures for the suspended layer and percolating media for liquid flow, while the polydimethylsiloxane E-jet writing ink printed on the nanofiber mats (named construction fluid in this paper) controllably permeates through the porous mats. After curing, the resultant construction fluid–nanofiber composites are formed as 3D channel walls. As a proof of concept, a microfluidic pressure-gain valve, which contains typical features of narrow channels and movable membranes, was fabricated, and the printed valve was totally closed under a control pressure of 45 kPa with a fast dynamic response of 52.6 ms, indicating the feasibility of NSCAM. Therefore, we believe NSCAM is a promising technique for manufacturing microdevices that include movable membrane cavities, pillar cavities, and porous scaffolds, showing broad applications in 3D microfluidics, soft robot drivers or sensors, and organ-on-a-chip systems.

A Protocol for Fabrication and on-Chip Cell Culture to Recreate PAH-Afflicted Pulmonary Artery on a Microfluidic Device.

Pulmonary arterial hypertension (PAH) is a rare pulmonary vascular disease that affects people of all ethnic origins and age groups including newborns. In PAH, pulmonary arteries and arterioles undergo a series of pathological changes including remodeling of the entire pulmonary vasculatures and extracellular matrices, mis-localized growth of pulmonary arterial cells, and development of glomeruloid-like lesions called plexiform lesions. Traditionally, various animal and cellular models have been used to understand PAH pathophysiology, investigate sex-disparity in PAH and monitor therapeutic efficacy of PAH medications. However, traditional models can only partially capture various pathological features of PAH, and they are not adaptable to combinatorial study design for deciphering intricately intertwined complex cellular processes implicated in PAH pathogenesis. While many microfluidic chip-based models are currently available for major diseases, no such disease-on-a-device model is available for PAH, an under investigated disease. In the absence of any chip-based models of PAH, we recently proposed a five-channel polydimethylsiloxane (PDMS)-based microfluidic device that can emulate major pathological features of PAH. However, our proposed model can make a bigger impact on the PAH field only when the larger scientific community engaged in PAH research can fabricate the device and develop the model in their laboratory settings. With this goal in mind, in this study, we have described the detailed methodologies for fabrication and development of the PAH chip model including a thorough explanation of scientific principles for various steps for chip fabrication, a detailed list of reagents, tools and equipment along with their source and catalogue numbers, description of laboratory setup, and cautionary notes. Finally, we explained the methodologies for on-chip cell seeding and application of this model for studying PAH pathophysiology. We believe investigators with little or no training in microfluidic chip fabrication can fabricate this eminently novel PAH-on-a-chip model. As such, this study will have a far-reaching impact on understanding PAH pathophysiology, unravelling the biological mystery associated with sexual dimorphism in PAH, and developing PAH therapy based on patient sex and age.

Multi-Resin Masked Stereolithography (MSLA) 3D Printing for Rapid and Inexpensive Prototyping of Microfluidic Chips with Integrated Functional Components.

Stereolithography based 3D printing of microfluidics for prototyping has gained a lot of attention due to several advantages such as fast production, cost-effectiveness, and versatility over traditional photolithography-based microfabrication techniques. However, existing consumer focused SLA 3D printers struggle to fabricate functional microfluidic devices due to several challenges associated with micron-scale 3D printing. Here, we explore the origins and mechanism of the associated failure modes followed by presenting guidelines to overcome these challenges. The prescribed method works completely with existing consumer class inexpensive SLA printers without any modifications to reliably print PDMS cast microfluidic channels with channel sizes as low as ~75 μm and embedded channels with channel sizes as low ~200 μm. We developed a custom multi-resin formulation by incorporating Polyethylene glycol diacrylate (PEGDA) and Ethylene glycol polyether acrylate (EGPEA) as the monomer units to achieve micron sized printed features with tunable mechanical and optical properties. By incorporating multiple resins with different mechanical properties, we were able to achieve spatial control over the stiffness of the cured resin enabling us to incorporate both flexible and rigid components within a single 3D printed microfluidic chip. We demonstrate the utility of this technique by 3D printing an integrated pressure-actuated pneumatic valve (with flexible cured resin) in an otherwise rigid and clear microfluidic device that can be fabricated in a one-step process from a single CAD file. We also demonstrate the utility of this technique by integrating a fully functional finger-actuated microfluidic pump. The versatility and accessibility of the demonstrated fabrication method have the potential to reduce our reliance on expensive and time-consuming photolithographic techniques for microfluidic chip fabrication and thus drastically lowering our barrier to entry in microfluidics research.