Fluidic System Research Articles

WITHDRAWN: Intelligent microscopy to improve cataract surgery

Abstract Phacoemulsification is the most performed surgery in the world. Over the past few years, evidence emerged about the use of artificial intelligence (AI) in cataract surgery video analysis for phase classification and instrument identification. Herein, we propose the use of AI to analyze intraoperative images captured by a surgical microscope to improve the fluidic of the phacoemulsification device. The principle is to develop an AI algorithm for recognizing anterior chamber movements by real-time automated analysis of microscope captured images. When AI recognizes an aspect of the anterior chamber which begins to be emptied, it sends a signal to the fluidic system to adjust the anterior segment depth. We believe that this technique could improve surgery security.

Ion Current Rectification in Extra-Long Nanofunnels

Nanofluidic systems offer new functionalities for the development of high sensitivity biosensors, but many of the interesting electrokinetic phenomena taking place inside or in the proximity of nanostructures are still not fully characterized. Here, to better understand the accumulation phenomena observed in fluidic systems with asymmetric nanostructures, we study the distribution of the ion concentration inside a long (more than 90 µm) micrometric funnel terminating with a nanochannel. We show numerical simulations, based on the finite element method, and analyze how the ion distribution changes depending on the average concentration of the working solutions. We also report on the effect of surface charge on the ion distribution inside a long funnel and analyze how the phenomena of ion current rectification depend on the applied voltage and on the working solution concentration. Our results can be used in the design and implementation of high-performance concentrators, which, if combined with high sensitivity detectors, could drive the development of a new class of miniaturized biosensors characterized by an improved sensitivity.

Integrated microflow cytometry for portable immunophenotypic cell analysis

Flow cytometry is a powerful tool for analyzing cellular phenotypes in a large population of cells, and it is commonly used in many applications from basic research to clinical practice. A major challenge facing miniaturization of flow cytometry is the dichotomous trade-off between performance and portability. To decouple the competing performance parameters, we propose a comprehensive approach for development of integrated microflow (IM) cytometry by (i) replacing a conventional sheath-based fluidic system with a microfluidic device capable of on-chip flow-rate regulation and sheathless cell focusing and (ii) adopting fluorescent nanocrystal labelling that allows multicolor detection with a single excitation source and an emission filter. The IM cytometer consists simply of a laser diode, an optical filter, an objective lens, a CMOS sensor and the microfluidic device, effectively miniaturizing flow cytometry into a portable device with a footprint of 398.4 cm3 and a weight of 613.9 g. We applied the IM cytometer to detect an immunophenotypic difference between two different types of breast cancer cells simply by dropping a sample solution onto the inlet reservoir of the microfluidic device. The IM cytometric operation was performed within 0.8 min of sample dropping, and the cytometric analysis results showed excellent agreement with those of conventional flow cytometry, providing a new direction in miniaturization of flow cytometry while maintaining its functionalities.

Development of a Novel Hanging Drop Platform for Engineering Controllable 3D Microenvironments.

Conventional biomedical research is mostly performed by utilizing a two-dimensional monolayer culture, which fails to recapitulate the three-dimensional (3D) organization and microenvironment of native tissues. To overcome this limitation, several methods are developed to fabricate microtissues with the desired 3D microenvironment. However, they tend to be time-consuming, labor-intensive, or costly, thus hindering the application of 3D microtissues as models in a wide variety of research fields. In the present study, we have developed a pressure-assisted network for droplet accumulation (PANDA) system, an easy-to-use chip that comprises a multichannel fluidic system and a hanging drop cell culture module for uniform 3D microtissue formation. This system can control the desired artificial niches for modulating the fate of the stem cells to form the different sizes of microtissue by adjusting the seeding density. Furthermore, a large number of highly consistent 3D glomerulus-like heterogeneous microtissues that are composed of kidney glomerular podocytes and mesenchymal stem cells have been formed successfully. These data suggest that the developed PANDA system can be employed as a rapid and economical platform to fabricate microtissues with tunable 3D microenvironment and cellular heterogeneity, thus can be employed as tissue-mimicking models in various biomedical research.

High-throughput cell and spheroid mechanics in virtual fluidic channels

Microfluidics by soft lithography has proven to be of key importance for biophysics and life science research. While being based on replicating structures of a master mold using benchtop devices, design modifications are time consuming and require sophisticated cleanroom equipment. Here, we introduce virtual fluidic channels as a flexible and robust alternative to microfluidic devices made by soft lithography. Virtual channels are liquid-bound fluidic systems that can be created in glass cuvettes and tailored in three dimensions within seconds for rheological studies on a wide size range of biological samples. We demonstrate that the liquid-liquid interface imposes a hydrodynamic stress on confined samples, and the resulting strain can be used to calculate rheological parameters from simple linear models. In proof-of-principle experiments, we perform high-throughput rheology inside a flow cytometer cuvette and show the Young’s modulus of isolated cells exceeds the one of the corresponding tissue by one order of magnitude.

A 3D-Printed Microfluidic Device with Integrated Electrochemical Sensors for Autonomous Habitability Assessment and Life Detection.

A 3D-printed microfluidic device coupled with a fluidic processing system was developed to enable autonomous end-to-end sample handling and electrochemical characterization of an ocean world analogue solution – synthetic seawater (SW). This dual-channel microfluidic cell was populated with 14 electrodes and performed electrochemical measurements similar to those used in the MECA Wet Chemistry Laboratory on board NASA’s Phoenix Lander that landed on Mars in 2008. Biological and metallic redox events were evaluated using cyclic voltammetry with Au, Pt, and glassy carbon electrodes, with the latter displaying superior sensitivity and selectivity. Conductivity and pH were measured using Pt and iridium oxide electrodes respectively, and SW anions such as chloride were quantified using chronopotentiometry with a Ag electrode. The fluidic handling system demonstrated sample transportation to the microfluidic device for electrochemical measurements, and could be readily adapted to accommodate different pre-processing steps. Overall, this study demonstrates the use of electrochemical sensors as part of an autonomous microfluidic handling system that would be functionally analogous to an electrochemical instrument designed for Ocean World exploration.

Liquid dispensing in the adhesive hairy pads of dock beetles.

Many insects can climb on smooth inverted substrates using adhesive hairy pads on their legs. The hair-surface contact is often mediated by minute volumes of liquid, which form capillary bridges in the contact zones and aid in adhesion. The liquid transport to the contact zones is poorly understood. We investigated the dynamics of liquid secretion in the dock beetle Gastrophysa viridula by quantifying the volume of the deposited liquid footprints during simulated walking experiments. The footprint volume increased with pad-surface contact time and was independent of the non-contact time. Furthermore, the footprint volume decreased to zero after reaching a threshold cumulative volume (approx. 30 fl) in successive steps. This suggests a limited reservoir with low liquid influx. We modelled our results as a fluidic resistive system and estimated the hydraulic resistance of a single attachment hair of the order of MPa · s/fl. The liquid secretion in beetle hairy pads is dominated by passive suction of the liquid during the contact phase. The high calculated resistance of the secretion pathway may originate from the nanosized channels in the hair cuticle. Such nanochannels presumably mediate the transport of cuticular lipids, which are chemically similar to the adhesive liquid.

(Invited) Nanosurface Fluidic Devices for Electrochemical Sensing and Biosensing

Diagnostics of pathogenic and genetic disease (such as cancer) at the point of need, in particular at early-stage, requires dynamic manipulation and concentration of a small number of target molecules at individual single-molecule level, which currently limit microfluidic technologies. In my lab, we focus on engineering of new approaches in lab-on-chip technology via synergistically combining nanostructured materials with fluidic sample delivery systems to enhance the sensitivity and selectivity of the detection. Nanostructured materials boost the sensor resolution and show higher biochemical sensitivity and selectivity by significant amplification of the detection sites. We investigate 1) fabrication of novel nanostructured platforms based on 3D materials such as gold and 2D materials such as graphene and molybdenum disulfide, 2) integration of nanostructures with fluid sample delivery and biological assays (based on DNA/antibody) and 3) implementation of the device for detection of small molecules, pathogenic disease, and cancer genomics. In this regard, we address fundamental questions including: optimal interface of nanostructures with fluidic devices; target isolation, preparation and concentration in fluidic devices. We have successfully implemented the nanosurface fluidic devices for rapid and quantitative detection of bacteria such as Escherichia coli (E.coli) and Methicillin-resistant Staphylococcus aureus (MRSA), electrochemical detection of small molecules such as Dopamine and optical detection of extracellular vesicles (EVs).

3D printed fluidic platform with in-situ covalently immobilized polymer monolithic column for automatic solid-phase extraction

In this work, 3D stereolithographic printing is proposed for the first time for the fabrication of fluidic devices aimed at in-situ covalent immobilization of polymer monolithic columns. Integration in advanced flow injection systems capitalized upon programmable flow was realized for fully automatic solid-phase extraction (SPE) and clean-up procedures as a ‘front-end’ to on-line liquid chromatography. The as-fabricated 3D-printed extraction column devices were designed to tolerate the pressure drop of forward-flow fluidic systems when handling large sample volumes as demonstrated by the determination of anti-microbial agents, plastic additives and monomers as models of emerging contaminants (4-hydroxybenzoic acid, methylparaben, phenylparaben, bisphenol A and triclosan). Decoration of the monolithic phase with gold nanoparticles (AuNPs) was proven most appropriate for the enrichment of phenolic-type target compounds. In particular, the absolute recoveries for the tested analytes ranged from 73 to 92% both in water and saliva samples. The 3D printed composite monolith showed remarkable analytical features in terms of loading capacity (2 mg g−1), breakthrough volume (10 mL), satisfactory batch-to-batch reproducibility (<9% RSD), and easy on-line coupling of the SPE device to HPLC systems. The fully automatic 3D-printed SPE-HPLC hyphenated system was also exploited for the on-line extraction, matrix clean-up and determination of triclosan in 200 μL of real saliva samples.

A miniaturized, self-sustaining, and integrable bio-solar power system

Abstract We demonstrate a practical and sustainable bacterial power source for low-power electronic applications. Self-sustainable electricity is produced from revolutionarily structured microliter-scale bio-solar cells using a co-culture of heterotrophic and autotrophic bacteria. Two bio-solar cells are integrated on a single chip and connected in series, continuously generating light-responsive electricity from heterotrophic bacterial respiration with the organic substrates produced by photosynthetic autotrophs. Agar-based anolyte, catholyte, and salt-bridge provided solid-state ionic environments for more efficient syntrophic interactions between co-cultures without bacterial competition, further enhancing the device performance and lifespan. The solid-phase platform allows versatile device configuration in a small footprint without a cumbersome fluidic feeding system and permits easy integration and operation with solid-state applications. The device is sealed with a gas-permeable polydimethylsiloxane (PDMS) membrane to facilitate gas exchange to the bacteria and cathodic reactions, even ideally allowing for replenishing bacterial gasses from environments for self-sustainable energy harvesting. A DC-DC booster circuit is integrated with the stacked bio-solar cells to increase the operational voltage (~500 mV) to a maximum output of >3 V for self-powering an on-chip, light-emitting diode (LED). This is the first demonstration of the microliter-scale bio-solar cell as a practical power source.

Fluid structure interaction of cantilever micro and nanotubes conveying magnetic fluid with small size effects under a transverse magnetic field

Micro and nanotubes have found major application in fluidic systems as channels for conveying fluid. In some micro and nanofluidic applications such as drug delivery, a transverse magnetic field can be used to guide the fluid flow by generating an axial force in the flow direction. An important issue in the design of micro and nanofluidic systems is the structural vibration caused by the fluid flow. In the current study, we investigate the effect of transverse magnetic field on the vibration of cantilever micro and nanotubes conveying fluid by considering the small size effects. We couple the nonlocal Euler–Bernoulli beam model with Navier–Stokes theory to determine a fluid structure interaction (FSI) model for the vibration analysis of the system. We modify the FSI governing equation by driving a velocity correction factor to consider the effect of transverse magnetic field on the fluid flow’s pattern through the tube. Then, we use the Galerkin’s method to obtain the frequency diagrams for the instability analysis of the system. We show that the transverse magnetic field can have a substantial effect on the dynamics of tube conveying fluid by increasing the system’s natural frequencies and critical flow velocity which contributes to the flutter instability. We also discover that although the transverse magnetic field plays a crucial role on dynamics of microstructures, its effect on the dynamics of nanotubes is not significant and can be ignored.

Enhancement of solute clearance using pulsatile push-pull dialysate flow for the Quanta SC+: A novel clinic-to-home haemodialysis system.

The SC+ haemodialysis system developed by Quanta Dialysis Technologies is a small, easy-to-use dialysis system designed to improve patient access to self-care and home haemodialysis. A prototype variant of the standard SC+ device with a modified fluidic management system generating a pulsatile push-pull dialysate flow through the dialyser during use has been developed for evaluation. It was hypothesized that, as a consequence of the pulsatile push-pull flow through the dialyser, the boundary layers at the membrane surface would be disrupted, thereby enhancing solute transport across the membrane, modifying protein fouling and maintaining the surface area available for mass and fluid transport throughout the whole treatment, leading to solute transport (clearance) enhancement compared to normal haemodialysis (HD) operation. The pumping action of the SC+ system was modified by altering the sequence and timings of the valves and pumps associated with the flow balancing chambers that push and pull dialysis fluid to and from the dialyser. Using this unique prototype device, solute clearance performance was assessed across a range of molecular weights in two related series of laboratory bench studies. The first measured dialysis fluid moving across the dialyser membrane using ultrasonic flowmeters to establish the validity of the approach; solute clearance was subsequently measured using fluorescently tagged dextran molecules as surrogates for uraemic toxins. The second study used human blood doped with uraemic toxins collected from the spent dialysate of dialysis patients to quantify solute transport. In both, the performance of the SC+ prototype was assessed alongside reference devices operating in HD and pre-dilution haemodiafiltration (HDF) modes. Initial testing with fluorescein-tagged dextran molecules (0.3 kDa, 4 kDa, 10 kDa and 20 kDa) established the validity of the experimental pulsatile push-pull operation in the SC+ system to enhance clearance and demonstrated a 10 to 15% improvement above the current HD mode used in clinic today. The magnitude of the observed enhancement compared favourably with that achieved using pre-dilution HDF with a substitution fluid flow rate of 60 mL/min (equivalent to a substitution volume of 14.4 L in a 4-hour session) with the same dialyser and marker molecules. Additional testing using human blood indicated a comparable performance to pre-dilution HDF; however, in contrast with HDF, which demonstrated a gradual decrease in solute removal, the clearance values using the pulsatile push-pull method on the SC+ system were maintained over the entire duration of treatment. Overall albumin losses were not different. Results obtained using an experimental pulsatile push-pull dialysis flow configuration with an aqueous blood analogue and human blood ex vivo demonstrate an enhancement of solute transport across the dialyser membrane. The level of enhancement makes this approach comparable with that achieved using pre-dilution HDF with a substitution fluid flow rate of 60 mL/min (equivalent to a substitution volume of 14.4 L in a 4-hour session). The observed enhancement of solute transport is attributed to the disruption of the boundary layers at the fluid-membrane interface which, when used with blood, minimizes protein fouling and maintains the surface area.

Evaluation of prospective directions of production of fluidics systems

the modern possibilities of manufacturing technologies of pneumatic automation systems based on fluidic switching elements are considered. The perceptivity of using the fluidic systems as the alternative to using the relay automation systems is noted.

Controllable droplet generation at a microfluidic T-junction using AC electric field

We investigated the influence of an alternate current (AC) electric field on droplet generation in a T-junction device. We used sodium chloride solution with various conductivities to adjust the response time of the fluidic system. At constant flow rates of both continuous and dispersed phases, the critical parameters for the droplet formation process are the magnitude, the frequency of the applied voltage and the conductivity of the dispersed phase. The response of the droplet formation process to AC excitation is characterised by the relative area of the formed droplet. The relative response time of the fluidic system to the applied AC voltage is characterised by the relative response time that is proportional to the ratio of the AC frequency to the conductivity of the dispersed phase. An accurate prediction of the breakdown voltage for the walls also proved robustness of our model. Furthermore, experiments were repeated with 0.5 g/L and 1 g/L xanthan gum solutions as non-Newtonian fluids. The results reveal the negligible influence of viscoelasticity on the droplet formation process. On-demand size controllable generation of non-Newtonian droplets is subsequently demonstrated following the same trend of the Newtonian counterparts.

Development of a Droplet Microfluidics Device Based on Integrated Soft Magnets and Fluidic Capacitor for Passive Extraction and Redispersion of Functionalized Magnetic Particles

AbstractBased on a recent droplet microfluidic device for target molecules' extraction, purification, and redispersion, here an original fluidic control system is proposed to improve the device versatility and usability. This approach relies on the coupling of functionalized magnetic particles handling by integrated soft magnets and a passive droplet splitting control at a channel junction. To reach the high standards required for bioassays' implementation, this device integrates a pressure‐driven variable volume component, acting as a fluidic capacitor, which allows a passive and controlled self‐triggered droplet fingering in a dead‐end channel. The working principle is described, and the modeling of the induced fingering phenomenon by an electric analogy is presented. Then, the achieved finger length is characterized as a function of geometrical and material properties of the fluidic capacitor. The complete device configuration guarantees extraction and purification efficiencies higher than 97% and 95%, respectively, showing high‐throughput particles handling between droplets with a passive droplet splitting control. Finally, this technology is successfully applied to gene expression study for cancer diagnosis by performing magnetic particle–based messenger RNA (mRNA) extraction followed by reverse transcription (RT) and quantitative polymerase chain reaction (RT‐qPCR) analysis.

Modeling cationic adduction of oligonucleotides using electrospray desorption ionization.

Cationic adduction causes poor sensitivity and increases spectral complexity during mass spectral analysis of oligonucleotides and alkylamines are used to reduce this adduction. It is unclear the effect of the physiochemical properties of the alkylamines on the reduction of the cationic adduction. All samples were directly infused into a Synapt G2 HDMS quadrupole time-of-flight (TOF) hybrid mass spectrometer in negative ion electrospray ionization mode through the native built-in fluidics system. The infusion flow rate was set to 50 μL/min. The TOFMS tuning parameters were as follows: capillary voltage -2.0 kV, cone voltage 25 V, extraction cone voltage 2 V, source temperature 125°C, desolvation temperature 450°C, cone gas flow rate 0 L/h, and desolvation gas (nitrogen) flow rate 1000 L/h. A quantitative model was created to predict the optimized alkylamine for MS analysis, while a qualitative model was generated to explain the most important physiochemical properties: proton affinity (13.83%), gas-phase basicity (11.79%), pKa (11.47%), boiling point (10.73%), MW (10.3%), Henry's Law Constant (9.56%), and partition coefficient (logP) (9.44%). The quantitative model was applied to RNA (microRNA) and a phosphorothioate and predicts the trend of cationic adduction. Two models are described to understand the physiochemical properties that contribute to the adduction and to provide users a quick mathematical tool to predict the best choice of alkylamine to lower cationic adduction and decrease spectral complexity while enhancing sensitivity.

Fabrication and Optical Modeling of Micro‐Porous Membranes Index‐Matched with Water for On‐Line Sensing Applications

AbstractMembranes made of perfluorinated materials having a refractive index close to that of water enable straightforward detection of water solutes at the interface, hence providing a novel sensing tool for fluidic systems. Here it is reported the production by non‐solvent induced phase separation and characterization of microporous membranes made of Hyflon AD, an amorphous copolymer of tetrafluoroethylene. Their optical turbidity when soaked in liquids having different refractive indices is studied and the data are interpreted with an optical model linking scattered light and structural features of the membrane. The average polymer and pore chord lengths obtained in this way scale with the filtering pore size measured by capillary flow porometry. Then, the optical response of the membranes when soaked in aqueous surfactant solutions is investigated and the effects of the molecular adsorption on the internal membrane surface is successfully interpreted by an extension of the model. Overall, the results show that index‐matched membranes can be designed and produced to provide a simple optical detection of the composition of the soaking liquid or to monitor the initial stage of membrane fouling.

The EcAMSat fluidic system to study antibiotic resistance in low earth orbit: Development and lessons learned from space flight

The E. coli AntiMicrobial Satellite (EcAMSat) was a successful spaceflight mission that performed an autonomous experiment to investigate the effects of microgravity on the antibiotic resistance of uropathogenic E. coli; the latest in a series of biology-focused CubeSats developed at NASA Ames Research Center. While maintaining the bacteria at 37 °C, the payload delivered growth medium, different doses of the antibiotic gentamicin, and finally the metabolic indicator alamarBlue to each of 48 microwells in the fluidic card. An LED and detector system was used to monitor the changes in absorbance in each experiment well at three wavelengths (470, 525, and 615 nm), from which the growth of cells and their metabolic activity could be measured. The success of the mission was in part due to leveraging lessons learned and proven technologies from previous bio-CubeSat missions, including modified spare hardware from the PharmaSat payload. This paper details the design and assembly of the biofluidic system payload; the modifications to the PharmaSat hardware required to run the EcAMSat experiment and the challenges those changes created; and finally, the testing approach employed to ensure the success of the payload during the flight campaign.

Dissipative particle dynamics with energy conservation: Isoenergetic integration and transport properties.

Simulations of nano- to micro-meter scale fluidic systems under thermal gradients require consistent mesoscopic methods accounting for both hydrodynamic interactions and proper transport of energy. One such method is dissipative particle dynamics with energy conservation (DPDE), which has been used for various fluid systems with non-uniform temperature distributions. We propose an easily parallelizable modification of the velocity-Verlet algorithm based on local energy redistribution for each DPDE particle such that the total energy in a simulated system is conserved up to machine precision. Furthermore, transport properties of a DPDE fluid are analyzed in detail. In particular, an analytical approximation for the thermal conductivity coefficient is derived, which allows its a priori estimation for a given parameter set. Finally, we provide approximate expressions for the dimensionless Prandtl and Schmidt numbers, which characterize fluid transport properties and can be adjusted independently by a proper selection of model parameters. In conclusion, our results strengthen the DPDE method as a very robust approach for the investigation of mesoscopic systems with temperature inhomogeneities.

Biocatalytic Feedback-Controlled Non-Newtonian Fluids.

Non-Newtonian fluids are ubiquitous in daily life and industrial applications. Herein, we report an intelligent fluidic system integrating two distinct non-Newtonian rheological properties mediated by an autocatalytic enzyme reaction. Associative polyelectrolytes bearing a small amount of ionic and alkyl groups are engineered: by carefully balancing the charge density and the hydrophobic effect, the polymer solutions demonstrate a unique shear thickening property at low pH while shear thinning at high pH. The urea-urease clock reaction is utilized to program a feedback-induced pH change, leading to a strong upturn of the nonlinear viscoelastic properties. As long as the chemical fuel is supplied, two distinct non-Newtonian states can be achieved with a tunable lifetime span. As a proof of concept, we demonstrate how the physical energy-driven nonequilibrium properties can be manipulated by a chemical-fueled process.