Microfluidic System Research Articles

Investigating reactive transport and precipitation patterns of calcium carbonate in fractured porous media

HypothesisUnderstanding calcium carbonate (CaCO3) precipitation in various polymorphs from nanoparticle size (amorphous calcium carbonate) to microparticle size (vaterite, aragonite, dendrite, calcite) is important for practical applications, including carbon geo-storage (e.g., basalt formations), hydrogen storage, groundwater management, and soil stabilization. Our hypothesis suggests that the interplay of Péclet numbers (Pe), Damköhler numbers (Da), and Supersaturation Index (SI) significantly impacts the evolution of CaCO3 precipitation in fractured porous media in terms of mixing patterns, spatiotemporal evolution, crystal morphology, crystal size, and clogging behavior. ExperimentsThis study takes a novel approach to explore the colloidal formation and precipitation dynamics of CaCO3 within a fractured microfluidic system. Here, calcium chloride (CaCl2) and sodium bicarbonate (NaHCO3) solutions were injected and reacted under varied Pe (0–11), Da (0–1), and SI (2–5). FindingsOur analysis revealed distinct precipitation patterns and mixing types, such as transverse, longitudinal, and incomplete mixing, providing insights into the behavior in fractured porous media. We systematically analyzed the temporal and spatial evolution of precipitation, demonstrating how Pe, Da, and SI dictate precipitation rates and spatial distribution. Additionally, the study uncovered a range of CaCO3 polymorphic forms, illustrating their evolution and coexistence. Morphological changes and crystal sizes were examined to decode nucleation and growth processes. Significantly, our findings highlight the relationship between precipitation and clogging in the fractured medium, offering a deeper understanding of reactive transport in complex porous environments. These insights are crucial for enhancing carbon containment security and storage efficiency in underground formations, improving groundwater remediation techniques, and developing novel construction materials through controlled precipitation processes.

Microfluidic Laser-Induced Nucleation of Iron (II,III) Oxide Nanoparticle-Doped Supersaturated Aqueous KCl Solutions.

A capillary-based microfluidic system designed for nonphotochemical laser-induced nucleation (NPLIN) studies coupled with real-time microscopy was used to study NPLIN of iron (II,III) oxide doped aqueous KCl solutions. Supersaturation was achieved by lowering the solution temperature using thermoelectric cooling, and heating was used for the dissolution of crystals downstream to prevent clogging during the flow. The effect of nanoparticle concentration, supersaturation, laser intensity, and filtration was studied. We report laser-induced nucleation using laser intensities as low as 1 MW/cm2 with nanoparticle number densities of ∼109 particles per mL of solution at KCl supersaturations from 1.06 to 1.08. The number of crystals increased with increasing laser intensity, supersaturation, and nanoparticle concentration. We discuss our results with respect to the colloidal impurity-heating mechanism hypothesis and propose a semiempirical model based on the nanoparticle heating and bubble formation due to the absorption of laser energy.

Study of the Impact of Droplets on Superhydrophobic Surfaces

The potential applications of superhydrophobicity for self-cleaning, microfluidic systems, and so on, inspired by the “lotus leaf effect”, have recently attracted great attention from academia and industry. To date, however, neither experimental nor theoretical studies have reached the scalable application of superhydrophobic surfaces, and no simple methods have been developed to produce durable superhydrophobic surfaces. In this project, conical, cylindrical, and cube microstructures with different shapes and dimensions were prepared by 3D printing. Among these structures, the conical microstructures without further modification exhibited the best hydrophobic performance with a contact angle of 120°. However, the hydrophobic performance of the cube microstructures was significantly improved with the addition of an FAS coating to the surface, reaching 131°. This indicates that, with the help of the coating, the 3D printed materials with special features can be transformed into hydrophobic surfaces. The outcome of this project will be useful in promoting the efficient and low-cost preparation of superhydrophobic functional surfaces and their engineering applications.

Microfluidic Applications in Prostate Cancer Research.

Prostate cancer is a disease in which cells in the prostate, a gland in the male reproductive system below the bladder, grow out of control and, among men, it is the second-most frequently diagnosed cancer (other than skin cancer). In recent years, prostate cancer death rate has stabilized and, currently, it is the second-most frequent cause of cancer death in men (after lung cancer). Most deaths occur due to metastasis, as cancer cells from the original tumor establish secondary tumors in distant organs. For a long time, classical cell cultures and animal models have been utilized in basic and applied scientific research, including clinical applications for many diseases, such as prostate cancer, since no better alternatives were available. Although helpful in dissecting cellular mechanisms, these models are poor predictors of physiological behavior mainly because of the lack of appropriate microenvironments. Microfluidics has emerged in the last two decades as a technology that could lead to a paradigm shift in life sciences and, in particular, controlling cancer. Microfluidic systems, such as organ-on-chips, have been assembled to mimic the critical functions of human organs. These microphysiological systems enable the long-term maintenance of cellular co-cultures in vitro to reconstitute in vivo tissue-level microenvironments, bridging the gap between traditional cell cultures and animal models. Several reviews on microfluidics for prostate cancer studies have been published focusing on technology advancement and disease progression. As metastatic castration-resistant prostate cancer remains a clinically challenging late-stage cancer, with no curative treatments, we expanded this review to cover recent microfluidic applications related to prostate cancer research. The review includes discussions of the roles of microfluidics in modeling the human prostate, prostate cancer initiation and development, as well as prostate cancer detection and therapy, highlighting potentially major contributions of microfluidics in the continuous march toward eradicating prostate cancer.

Fabrication of Conical Microstructure Array for Stable Droplet Generation Over Wide Flow Rate Range.

Droplet generators with the ability to resist flow fluctuations are of importance for microfluidic chip analysis systems. However, obtaining stably desired-size droplets is still a bugbear since even slight fluctuations can cause polydisperse droplets. In this study, a high-performance droplet generator is achieved with a functional conical array housed in the junction of the channels. The conical microstructures are fabricated through the selective etching of the scratched silicon nitride/silicon (Si3N4/Si) substrate in potassium hydroxide (KOH) etchant, where the combination of lateral and normal material removal contributes to the structure formation. It is found that the key role of the conical microstructures is to regulate the flow rate of the continuous phase, which allows droplet generation to turn to the necking phase and enables droplets to shed more easily. It is also noted that the droplet generator with such a conical array can produce monodisperse droplets in wide-range flow, providing new insights for high-quality device design.

SERS-integrated centrifugal microfluidic platform for the detection and quantification of Chemical Warfare Agents in single-component solution and mixtures

Chemical Warfare Agents (CWAs) are toxic chemicals. Among CWAs, nerve agents are lethal compounds at low concentrations, and, thus, there is the need to detect and quantify the danger. The combination of Surface-Enhanced Raman Spectroscopy (SERS) with centrifugal microfluidic (CM) systems is a possibility for a safer handling and a fast analysis of nerve agents.In this work, the SERS signal from single-component solutions and mixtures of Tabun (GA) and VX were analyzed with Au-capped silicon nanopillar (NP) SERS substrates integrated on a CM platform and recorded with a custom-built Raman System (RS). Univariate and multivariate analysis methods were applied for the quantification. Both GA and VX were detected and quantified individually with Partial Least Squares regression (PLSR) models, with LoD and LoQ values of 7.39 ppm and 22.17 ppm respectively for GA, and 7.13 ppm and 21.39 ppm for VX. Detection and quantification of GA and VX in mixtures was achieved with Supported Vector Machine (SVM), obtaining R2 of the prediction 0.87 and 0.95, respectively.The results obtained show the potential of the SERS-integrated CM platform combined with machine learning analysis as a reliable method for CWAs on-site detection and quantification and for national security applications in real-case scenarios.

Determination of Cortisol Hormone from Sweat Samples and Interpretation with Microcontroller

Cortisol, known as the body's stress hormone, regulates metabolism, inflammation, and the immune system. It affects various bodily systems such as the nervous, immune, cardiovascular, respiratory, reproductive, and musculoskeletal systems. Normal sweat cortisol levels range from 8 to 142 ng/ml, with elevated levels indicating stress (200 ng/ml in women, 500 ng/ml in men). This study focuses on colorimetric cortisol analysis using a microfluidic layer to collect sweat samples. Samples are mixed with a specific color reagent. Cortisol levels are quantitatively analyzed using Z-Score values and RGB channel density via photographs taken with the ESP 32 module. The aim is to determine cortisol levels, aiding in diagnosing conditions like Cushing's syndrome and Addison's Disease, leveraging wearable technology. The developed system integrates a microcontroller into the wearable microfluidic system for cortisol measurements throughout the day. Data is displayed and recorded on a computer for streamlined cortisol monitoring. The blue tetrazolium method used offers stable colors and rapid reactions (10 minutes). The Limit of Detection (LOD) is 0.3 ug/mL, with a detection limit of 1.1 ug/mL. Combined with the ESP 32 Cam module, the system detects cortisol concentrations from 0.8 – 60 ug/mL.

Convective assembly of silica colloidal particles inside photonic integrated chip-based microfluidic systems for gas sensing applications.

Optofluidics is a new field of modern science that stands at the interface of microfluidics and photonics and has good prospects for application in gas sensors. Microfluidics offers a promising platform for tuning and assembling monolayer structures that are used as sensitive layers for gas detection. Herein, we evaluate the concept of monolayer formation on a silicon nitride substrate enabling a surface coverage up to 59% through a microfluidic convective assembly and couple it with a photonic integrated chip to probe gas sensing performance.

Oocytes Vitrification Using Automated Equipment Based on Microfluidic Chip.

Oocyte vitrification has a wide range of applications in assisted reproduction and fertility preservation. It requires precise cryoprotectant agents (CPAs) loading and removal sequences to alleviate osmotic shock, which requires manual manipulation by an embryologist. In this study, a microfluidic system was developed to facilitate the precise adjustment of the CPA concentration around the oocyte by linear loading and removal of CPA. In addition, the microfluidic-based automated vitrification (MAV) device combines CPA loading/removal process, with vitrification process, thereby achieving automated oocyte vitrification. Oocytes were vitrified by Cryotop/QC manual method and MAV method. The results showed that the survival, cleavage, and blastocyst rates of oocytes were 80.44, 54.17, and 32.95% for the MAV method, which were significantly higher than Cryotop manual method (73.35, 43.73, and 23.67%) (p < 0.05). In MAV, solution injection rate during CPA loading/removal process was designed as a 1-segment, 2-segment, and 4-segment function. Accordingly, three concave loading and convex removal protocols were adopted to vitrify oocytes. Oocytes vitrified using the 4-segment function group exhibited increased survival (86.18%), cleavage (63.29%), and blastocyst (45.58%) rates compared to those vitrified using the 1-segment and 2-segment groups. The oocytes vitrification with the highest concentration of CPA, denoted as VS1-TS1, exhibited the highest survival rate after rewarming (86.18%). In contrast, the VS3-TS3 group, characterized by a CPA concentration half that of VS1-TS1, exhibited lower survival (74.14%) and cleavage (59.31%) rates, but displayed the higher blastocyst rate (50.79%) following oocyte activation. Our study demonstrates potential of the MAV device for oocyte or embryo vitrification.

Improving tumor microenvironment assessment in chip systems through next-generation technology integration.

The tumor microenvironment (TME) comprises a diverse array of cells, both cancerous and non-cancerous, including stromal cells and immune cells. Complex interactions among these cells play a central role in driving cancer progression, impacting critical aspects such as tumor initiation, growth, invasion, response to therapy, and the development of drug resistance. While targeting the TME has emerged as a promising therapeutic strategy, there is a critical need for innovative approaches that accurately replicate its complex cellular and non-cellular interactions; the goal being to develop targeted, personalized therapies that can effectively elicit anti-cancer responses in patients. Microfluidic systems present notable advantages over conventional in vitro 2D co-culture models and in vivo animal models, as they more accurately mimic crucial features of the TME and enable precise, controlled examination of the dynamic interactions among multiple human cell types at any time point. Combining these models with next-generation technologies, such as bioprinting, single cell sequencing and real-time biosensing, is a crucial next step in the advancement of microfluidic models. This review aims to emphasize the importance of this integrated approach to further our understanding of the TME by showcasing current microfluidic model systems that integrate next-generation technologies to dissect cellular intra-tumoral interactions across different tumor types. Carefully unraveling the complexity of the TME by leveraging next generation technologies will be pivotal for developing targeted therapies that can effectively enhance robust anti-tumoral responses in patients and address the limitations of current treatment modalities.

Modeling Hemodynamics in Three-Dimensional, Biomimetic, Branched, Microfluidic, Vascular Networks.

Neovascularization has been extensively studied because of its significant role in both physiological processes and diseases. The significance of vascular microfluidic platforms lies in its essential role in recreating an in vitro environment capable of supporting cellular and tissue systems through the process of neovascularization. Biomechanical properties in a tissue engineered system use fluid flow and transport properties to recapitulate physiological systems. This enables mimicry of organ systems which can further personalized and regenerative medicine. Thus, fluid hemodynamics can be used to study these flow patterns and create a system that mimics real physiological pathways and processes. The establishment of stable flow pathways encourages endothelial cells (ECs) ECs to undergo neovascularization. Specifically, the shear stress applied in capillary beds generates the increased proliferation and differentiation of ECs to build larger microcirculatory beds. Here, we describe a mathematical model that uses branching patterns and vessel morphology to predict hemodynamic parameters in capillary beds. A retinal capillary bed is used as one-use case of our model to show how the mathematical framework can be used to determine hemodynamic parameters for any microfluidic system. In doing so, this tool can be altered to be used to supplement emerging research areas in neovascularization.

Lab-In-Fiber Optofluidic Device for Droplet Digital Polymerase Chain Reaction (DdPCR) with Real-Time Monitoring.

Droplet microfluidic systems have emerged as indispensable and advanced tools in contemporary biological science. A prominent example is the droplet digital polymerase chain reaction (ddPCR), which plays a pivotal role in next-generation sequencing and the detection of rare nucleic acids or mutations. However, existing optical detection configurations are bulky, intricate, and costly, and require meticulous optical alignment to optimize fluorescence sensing. Herein, we propose a lab-in-fiber optofluidic system (LiFO), which provides a stable and compact footprint, self-alignment, and enhanced optical coupling for high-accuracy ddPCR. Moreover, LiFO could expand its capabilities for multiangle-scattering light collection in which we collect focused forward-scattering light (fFSL) to enable real-time droplet counting and size monitoring. To accomplish these attributes, LiFO incorporates optical fibers, along with fabricated PDMS grooves, for a self-aligned optical setup to implement simultaneous fluorescence and scattering detection. Furthermore, LiFO harnesses the concept of flowing droplets functioning as microlenses, which allows us to collect and translate fFSL signals into droplet size information. We have demonstrated the effectiveness of LiFO in ddPCR applications, illustrating its capacity to enhance the accuracy and precision of DNA quantification. Notably, LiFO exhibits improved linearity in the measurement of serial DNA dilutions, reflected by an increase in R2 from 0.956 to 0.997. These results demonstrate the potential of LiFO to serve as a valuable tool across a wide spectrum of droplet microfluidic platforms, offering opportunities for advancement in practical applications.

Improvement of mixing efficiency in twisted micromixers: The impact of cross-sectional shape and eccentricity ratio

Microfluidic mixers with twisted geometries show promise for high mixing efficiency, especially at elevated flow rates. However, there is a lack of understanding regarding the optimal geometrical parameters to enhance mixing across various Reynolds numbers. This study aimed to explore the influence of pitch number, cross-section geometry, and eccentricity ratio on the performance of the twisted micromixer. The flow field in these micromixers was solved numerically and the mixing index and pressure drop were calculated for Reynolds numbers of 1 to 400. Twisted micromixers with rectangular cross-sections and aspect ratios of 0.5 and 2 outperformed those with square cross-sections by up to 34% in mixing efficiency, exceeding 90% efficiency for Reynolds numbers from 1 to 400. Moreover, the eccentricity ratio (ER) was studied for the first time in twisted micromixers in this study and demonstrated a critical role in improving the mixing performance. For low to intermediate Reynolds numbers, the highest ER of 0.75 showed the best performance, while for high Reynolds numbers, an ER of 0.5 was optimal. These insights offer valuable direction for designing high-performance micromixers for advanced microfluidic systems.

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.

Microfluidics Relevant Approaches in Drug Delivery System Treatment of Cancer – A Review

Microfluidics technology is a promising method for creating advanced drug delivery systems, particularly in cancer detection and treatment. These systems provide accurate, efficient, and user-friendly methods for cancer detection and treatment by examining small samples. Microfluidic devices can produce nanoparticles for medication administration and identify cancer-diagnostic variables from biological fluids. Due to their high sensitivity, high throughput, and low cost, microfluidics may be useful in cancer study. While not currently used in clinical settings, microfluidic systems are expected to replace current technologies as the primary means of cancer diagnosis and treatment. Microfluidic lab-on-a-chip platforms have shown potential in designing novel procedures for cancer detection, therapy, and disease follow-up, as well as developing new drug delivery systems for cancer treatment. They are also being considered a rising method in natural disease studies due to their small volume and ability to be used in clinical settings.[1,2.3] Keywords: Microfluidics, detection, treatment

The dynamics of capillary flow in an open-channel system featuring trigger valves.

Trigger valves are fundamental features in capillary-driven microfluidic systems that stop fluid at an abrupt geometric expansion and release fluid when there is flow in an orthogonal channel connected to the valve. The concept was originally demonstrated in closed-channel capillary circuits. We show here that trigger valves can be successfully implemented in open channels. We also show that a series of open-channel trigger valves can be placed alongside or opposite a main channel resulting in a layered capillary flow. We developed a closed form model for the dynamics of the flow at trigger valves based on the concept of average friction length and successfully validated the model against experiments. For the main channel, we discuss layered flow behavior in the light of the Taylor-Aris dispersion theory and in the channel turns by considering Dean theory of mixing. This work has potential applications in autonomous microfluidics systems for biosensing, at-home or point-of-care sample preparation devices, hydrogel patterning for 3D cell culture and organ-on-a-chip models.

A Preliminary Analysis of Circulating Tumor Microemboli from Breast Cancer Patients during Follow-Up Visits.

Most breast cancer-related deaths are caused by distant metastases and drug resistance. It is important to find appropriate biomarkers to monitor the disease and to predict patient responses after treatment early and accurately. Many studies have found that clustered circulating tumor cells, with more correlations with metastatic cancer and poor survival of patients than individual ones, are promising biomarkers. Eighty samples from eleven patients with breast cancer during follow-up visits were examined. By using a microfluidic chip and imaging system, the number of circulating tumor cells and microemboli (CTC/CTM) were counted to assess the distribution in stratified patients and the potential in predicting the disease condition of patients after treatments during follow-up visits. Specific components and subtypes of CTM were also preliminarily investigated. Compared to CTC, CTM displayed a distinguishable distribution in stratified patients, having a better AUC value, in predicting the disease progression of breast cancer patients during follow-up visits in this study. Four subtypes were categorized from the identified CTM by considering different components. In combination with CEA and CA153, enumerated CTC and CTM from individual patients were applied to monitor the disease condition and patient response to the therapy during follow-up visits. The CTM and its subtypes are promising biomarkers and valuable tools for studying cancer metastasis and longitudinally monitoring cancer patients during follow-up visits.

Highly efficient CRISPR-mediated genome editing through microfluidic droplet cell mechanoporation

Clustered regularly interspaced short palindromic repeats (CRISPR)-based editing tools have transformed the landscape of genome editing. However, the absence of a robust and safe CRISPR delivery method continues to limit its potential for therapeutic applications. Despite the emergence of various methodologies aimed at addressing this challenge, issues regarding efficiency and editing operations persist. We introduce a microfluidic gene delivery system, called droplet cell pincher (DCP), designed for highly efficient and safe genome editing. This approach combines droplet microfluidics with cell mechanoporation, enabling encapsulation and controlled passage of cells and CRISPR systems through a microscale constriction. Discontinuities created in cell and nuclear membranes upon passage facilitate the rapid CRISPR-system internalization into the nucleus. We demonstrate the successful delivery of various macromolecules, including mRNAs (~98%) and plasmid DNAs (~91%), using this platform, underscoring the versatility of the DCP and leveraging it to achieve successful genome engineering through CRISPR–Cas9 delivery. Our platform outperforms electroporation, the current state-of-the-art method, in three key areas: single knockouts (~6.5-fold), double knockouts (~3.8-fold), and knock-ins (~3.8-fold). These results highlight the potential of our platform as a next-generation tool for CRISPR engineering, with implications for clinical and biological cell-based research.

A miniaturized microfluidic nanoplasmonic sensor with cavity reflection enhancement for ultrasensitive molecular interaction analysis

Molecular binding kinetics quantification is pivotal in the design of antibodies, small-molecule drugs, and early diagnosis of complex disease. This study presents a portable microfluidic system, featuring a nanoplasmonic sensor with cavity reflection enhancement (NSCRE), designed for the ultrasensitive detection and analysis of molecular interactions. This device comprises liquid flow paths, generic fiber spectrometers, a versatile NSCRE sensor chip, and a novel data analysis system. Furthermore, a neural network data processing system is developed based on a deep learning model to decrease significant data fluctuations caused by air segments. This “all-in-one” platform, integrating multifunctional, easy-to-use, and renewable NSCRE biosensors, boasts detection capabilities for both slow and rapid kinetics. It can automatically monitor interactions between molecules across a broad range of molecular weights (0.259–150 kDa), allowing for real-time, ultra-sensitive, and highly selective analysis. In addition, the platform with CRE effect facilitates a 7.2-fold increase in reflection intensity signals compared to that of a sensor without CRE. The immunoglobulin G detection with a limit of detection of 73 pM based on this device, showing a 50-fold increase in sensitivity compared to previously reported values. The miniaturized automatic detection system paves a new path for the use of molecular interaction analysis in life science research, drug discovery, early diagnosis, and other fields.

Synergistic potential of stem cells and microfluidics in regenerative medicine.

Regenerative medicine has immense potential to revolutionize healthcare by using regenerative capabilities of stem cells. Microfluidics, a cutting-edge technology, offers precise control over cellular microenvironments. The integration of these two fields provides a deep understanding of stem cell behavior and enables the development of advanced therapeutic strategies. This critical review explores the use of microfluidic systems to culture and differentiate stem cells with precision. We examined the use of microfluidic platforms for controlled nutrient supply, mechanical stimuli, and real-time monitoring, providing an unprecedented level of detail in studying cellular responses. The convergence of stem cells and microfluidics holds immense promise for tissue repair, regeneration, and personalized medicine. It offers a unique opportunity to revolutionize the approach to regenerative medicine, facilitating the development of advanced therapeutic strategies and enhancing healthcare outcomes.