Synthesis of hollow, magnetic Fe/Ga-based oxide nanospheres using a bubble templating method in a microfluidic system

This paper describes a new approach to synthesize hollow nanospheres in a microfluidic system using air bubbles as templates. A new microfluidic system which integrates a micro-mixer, a micro-condenser channel, microvalves, a micro-heater, and a micro-temperature sensor, to form an automatic micro-reactor, is used to generate air bubbles that assist in the synthesis of hollow Fe/Ga-based oxide nanospheres. Experimental data show that Fe/Ga-based oxide nanoparticles with a diameter of 157 ± 26 nm can be successfully synthesized. The formation mechanism is that the seed nanoparticles are attaching themselves onto the bubbles to form a solid shell. The magnetic properties of the hollow Fe/Ga-based oxide nanospheres are also measured. This may be a promising platform to synthesize hollow nanoparticles for drug delivery applications.     

Surface-Micromachined Parylene Dual Valves for On-Chip Unpowered Microflow Regulation

This paper presents the world's first surface-micromachined parylene dual-valved microfluidic system for on-chip unpowered microflow regulation. Incorporating a normally closed and a normally open passive check valve in a back-to-back configuration inside a microchannel, the dual-valved system has successfully regulated the pressure/flow rate of air and liquid without power consumption or electronic/magnetic/thermal transduction. By exclusively using parylene C (poly-para-xylylene C) as the structural material, the fabricated valves have higher flexibility to shunt flows in comparison to other conventional thin-film valves. A state-of-the-art multilayer polymer surface-micromachining technology is applied here to fabricate parylene microvalves of various designs. The parylene-based devices are completely biocompatible/implantable and provide an economical paradigm for fluidic control in integrated lab-on-a-chip systems. Design, fabrication, and characterization of the parylene dual valves are discussed in this paper. Testing results have successfully demonstrated that the microflow regulation of the on-chip dual-valved system can achieve a bandpass profile in which the pressure control range is 0-50 mmHg with corresponding flow rates up to 2 mL/min for air flow and 1 muL/min flow rate for water flow. This regulation range is suitable for controlling biological conditions in human health care, with potential applications including drug delivery and regulation of elevated intraocular pressure (IOP) in glaucoma patients     

Self-optimizing, thermally adaptive microfluidic flow structures

Although microfluidic devices offer many benefits, high fluid shear stresses in such devices are an undesirable consequence of miniaturization. In the present study, we present an adaptive “smart” design that mitigates the effects of high shear stresses in microfluidic-based devices by autonomously optimizing its internal flow structure. This concept was demonstrated by testing a prototype microscale thermal-fluid device that responded to changes in the local thermal environment. The autonomous, self-optimizing functionality was achieved using poly(N-isopropylacrylamide) hydrogel actuated microvalves, which independently controlled the flow to four distinct regions within the device. The experimental results showed that the device optimized its internal topological flow arrangement such that fluid was delivered only to regions where cooling was required. As a result, a series of spatially distributed thermal loads were dissipated with minimal pumping power consumption.     

Ferrofluid actuation with varying magnetic fields for micropumping applications

Magnetic nanoparticle suspensions and their manipulation are becoming an alternative research line. They have vital applications in the field of microfluidics such as microscale flow control in microfluidic circuits, actuation of fluids in microscale, and drug delivery mechanisms. In microscale, it is possible and beneficial to use magnetic fields as actuators of such ferrofluids, where these fluids could move along a dynamic gradient of magnetic field so that a micropump could be generated with this technique. Thus, magnetically actuated ferrofluids could have the potential to be used as an alternative micro pumping system. Magnetic actuation of nanofluids is becoming an emergent field that will open up new possibilities in various fields of engineering. Different families of devices actuating ferrofluids were designed and developed in this study to reveal this potential. A family of these devices actuates discrete plugs, whereas a second family of devices generates continuous flows in tubes of inner diameters ranging from 254?μm to 1.56?mm. The devices were first tested with minitubes to prove the effectiveness of the proposed actuation method. The setups were then adjusted to conduct experiments on microtubes. Promising results were obtained from the experiments. Flow rates up to 120 and 0.135?μl/s were achieved in minitubes and microtubes with modest maximum magnetic field magnitudes of 300?mT for discontinuous and continuous actuation, respectively. The proposed magnetic actuation method was proven to work as intended and is expected to be a strong alternative to the existing micropumping methods such as electromechanical, electrokinetic, and piezoelectric actuation. The results suggest that ferrofluids with magnetic nanoparticles merit more research efforts in micro pumping.     

Rapidly in situ forming biodegradable hydrogels by combining alginate and hydroxyapatite nanocrystal

The in situ forming biodegradable polymer scaffolds are important biomaterials for tissue engineering and drug delivery.Hydrogels derived from natural proteins and polysaccharides are ideal tissue engineering scaffolds since they resemble the extracellular matrices of the tissue comprising various amino acids and sugar based macromolecules.This work presented an injectable system from partially oxidized alginate and hydroxyapatite(HAP) nanocrystal for tissue engineering and drug delivery applications.In sit...     

Generation of disk-like hydrogel beads for cell encapsulation and manipulation using a droplet-based microfluidic device

We report a droplet-based microfluidic synthetic technique to generate disk-like hydrogel beads for cell encapsulation and manipulation. Utilizing this microfluidic synthetic technique, the size of the disk-like calcium alginate (CA) hydrogel beads and the number of cells encapsulated in the disk-like CA hydrogel beads could be well controlled by individually adjusting the flow rates of reagents. As a proof-of-concept, we demonstrated that single cell (yeast cell or mammalian cell) could be successfully encapsulated into disk-like CA hydrogel beads with high cell viability. Taking advantage of the flat top/bottom surfaces of disk-like CA hydrogel beads, cell division processes in culture media were clearly observed and recorded at a desired position without rolling and moving. This facile microfluidic chip provides a feasible method for size-controlled disk-like hydrogel beads generation and cell encapsulation. It could be a promising candidate for cell division observation and quantitative biological study in lab-on-a-chip applications.     

Equilibrium swelling and kinetics of pH-responsive hydrogels: models, experiments, and simulations

The widespread application of ionic hydrogels in a number of applications like control of microfluidic flow, development of muscle-like actuators, filtration/separation and drug delivery makes it important to properly understand these materials. Understanding hydrogel properties is also important from the standpoint of their similarity to many biological tissues. Typically, gel size is sensitive to outer solution pH and salt concentration. In this paper, we develop models to predict the swelling/deswelling of hydrogels in buffered pH solutions. An equilibrium model has been developed to predict the degree of swelling of the hydrogel at a given pH and salt concentration in the solution. A kinetic model has been developed to predict the rate of swelling of the hydrogel when the solution pH is changed. Experiments are performed to characterize the mechanical properties of the hydrogel in different pH solutions. The degree of swelling as well as the rate of swelling of the hydrogel are also studied through experiments. The simulations are compared with experimental results and the models are found to predict the swelling/deswelling processes accurately.     

Development of microfluidic devices incorporating non-spherical hydrogel microparticles for protein-based bioassay

This paper describes the fabrication of a microfluidic device for use in protein-based bioassays that effectively incorporates poly(ethylene glycol) (PEG) hydrogel microparticles within a defined region. The microfluidic device is composed of a polymerization chamber and reaction chamber that are serially connected through the microchannel. Various shapes and sizes of hydrogel microparticles were fabricated in the polymerization chamber by photopatterning and moved to the reaction chamber by pressure-driven flow. All of the hydrogel microparticles were retained within the reaction chamber due to an in-chamber integrated microfilter with smaller mesh size than hydrogel microparticles. Hydrogel microparticles were able to encapsulate enzymes without losing their activity, and different concentrations of glucose were detected by sequential bienzymatic reaction of hydrogel-entrapped glucose oxidase (GOX) and peroxidase (POD) inside the microfluidic device using fluorescence method. Importantly, there was a linear correspondence between fluorescence intensity and the glucose concentration over the physiologically important range of 1.00–10.00 mM. D. Choi and E. Jang contributed equally to this work.     

微流控芯片中电渗流的数值模拟与仿真研究

从电渗流形成的基本理论入手,推导了电场和流场双物理场耦合的控制方程.运用多物理场数值计算分析软件建立了长为1000μm,宽为100μm的二维流道,在微流道中间250~750μm的区域施加了直流电压,并在数值模拟中还原了微流道内壁和微流体的物理属性,计算得出了各段流体的速度场,进而得出了各段流体的流型.通过二维流道压力分布分析了微流道中各段产生不同流型的原因.对微流控芯片中的电动流动的功能原理分析及优化设计具有借鉴意义.     

The microscopy cell (MicCell), a versatile modular flowthrough system for cell biology, biomaterial research, and nanotechnology

We describe a novel microfluidic perfusion system for high-resolution microscopes. Its modular design allows pre-coating of the coverslip surface with reagents, biomolecules, or cells. A poly(dimethylsiloxane) (PDMS) layer is cast in a special molding station, using masters made by photolithography and dry etching of silicon or by photoresist patterning on glass or silicon. This channel system can be reused while the coverslip is exchanged between experiments. As normal fluidic connectors are used, the link to external, computer-programmable syringe pumps is standardized and various fluidic channel networks can be used in the same setup. The system can house hydrogel microvalves and microelectrodes close to the imaging area to control the influx of reaction partners. We present a range of applications, including single-molecule analysis by fluorescence correlation spectroscopy (FCS), manipulation of single molecules for nanostructuring by hydrodynamic flow fields or the action of motor proteins, generation of concentration gradients, trapping and stretching of live cells using optical fibers precisely mounted in the PDMS layer, and the integration of microelectrodes for actuation and sensing.     

Electronically controllable microvalves based on smart hydrogels: magnitudes and potential applications

Electronically controllable microvalves based on temperature sensitive hydrogels as actuators are described. A thermal-electronic interface was used for electronic control of the liquid flow. The hydrogel actuators were directly placed in a flow channel. They used the process medium as the swelling agent. Because of the direct placement into the channel the elastic properties of the hydrogel actuator were utilized to improve the pressure insensitivity, to achieve high particle tolerance and to avoid a leakage flow. The microvalves show an extremely simple structure. They can be fabricated using conventional micro technology within a few technical steps. The microvalves can also be miniaturized to a currently unrivalled extent of about 4 /spl mu/m/spl times/4 /spl mu/m/spl times/1/spl mu/m. Valves for "laboratory on chip" applications can already be obtained. The switching times of the electronically controllable microvalves based on hydrogels are 0.3 s to 10 s.     

Fabrication and characterization of hydrogel-based microvalves

Several microvalves utilizing stimuli-responsive hydrogel materials have been developed. The hydrogel components are fabricated inside microchannels using a liquid phase polymerization process. In-channel processing greatly simplifies device construction, assembly, and operation since the functional components are fabricated in situ and can perform both sensing and actuation functions. Two in situ photopolymerization techniques, "laminar stream mode" and "mask mode," have been explored. Three two-dimensional (2-D) valves were fabricated and tested (response time, pressure drop, maximum differential pressure). In addition, a hydrogel/PDMS three-dimensional (3-D) hybrid valve that physically separates the sensing and regulated streams was demonstrated. Analytical modeling was performed on the 3-D valve. Hydrogel-based microvalves have a number of advantages over conventional microvalves, including relatively simple fabrication, no external power requirement, no integrated electronics, large displacement (185 μm), and large force generation (22 mN)     

Disk-like hydrogel bead-based immunofluorescence staining toward identification and observation of circulating tumor cells

Assays toward analysis of rare heterogeneous cells among identical specimen raise a significant challenge in many cell biological studies and clinical diagnosis applications. In this work, we report a disk-like hydrogel bead-based stratagem for rare cell researches at single cell level after a facile microfluidic-based particle synthesis approach. Cells of interested can be encapsulated into alginate droplets which are subsequently solidified into disk-like calcium alginate hydrogel beads and the bead size and cell number inside can be precisely controlled. Due to stability, permeability and disk-like shape of calcium alginate beads, cells immobilized in the disk-like beads can be treated with different chemicals with limited mechanical or fluidic operation influences and observed without distortion comparing with conventional methods or droplet microfluidic methods. Identification of circulating tumor cells, related to early-stage cancer diagnosis, is targeted to demonstrate the potential of our technique in rare cell analysis. This hydrogel bead-based stratagem is performed in immunofluorescence staining treatment and observation of cancer cells from normal hematological cells in blood sample. This method would have a great potential in single cell immobilization, manipulations and observation for biochemical cellular assays of rare cells.     

Continuous generation of hydrogel beads and encapsulation of biological materials using a microfluidic droplet-merging channel

In this paper, we describe a method for encapsulation of biomaterials in hydrogel beads using a microfluidic droplet-merging channel. We devised a double T-junction in a microfluidic channel for alternate injection of aqueous fluids inside a droplet unit carried within immiscible oil. With this device, hydrogel beads with diameter <100 μm are produced, and various solutions containing cells, proteins and reagents for gelation could merge with the gel droplets with high efficiency in the broad range of flow rates. Mixing of reagents and reactions inside the hydrogel beads are continuously observed in a microchannel through a microscope. By enabling serial injection of each liquid with the dispersed gel droplets after they are produced from the oil-focusing channel, the device simplifies the sample preparation process, and gel-bead fabrication can be coupled with further assay continuously in a single channel. Instantaneous reactions of enzyme inside hydrogel and in-situ formation of cell-containing beads with high viability are demonstrated in this report.     

Development of microfluidic alginate microbead generator tunable by pulsed airflow injection for the microencapsulation of cells

Recently, microbead generation and microencapsulation of cells using microfluidic technology have been actively pursued for various applications. However, most of the proposed systems are not only technically demanding, but might also be harmful to the encapsulated cells. To tackle these issues, this study reports a microfluidic alginate microbead generator consisting of a polydimethylsiloxane (PDMS) microfluidic chip and an integrated quartz microcapillary tube. The working principle is based on the use of a pulsed airflow to segment a continuous alginate suspension flow to form suspension fragments in a microchannel and then alginate microbeads when they were delivered out the microfluidic system to a sterile calcium chloride solution through a microcapillary tube. In this study, the alginate suspension fragments with varied sizes in the microchannel can be generated either by modulating the alginate suspension flow rate or the pulsation frequency of airflow injection. By fine tuning the size of them, the alginate microbeads can be generated in a size-controllable manner. Results showed that alginate microbeads with the size ranging from 150 to 370 μm in diameter can be generated at the suspension flow rate and airflow injection frequency ranges of 2–4 μl/min and 0.6–35 Hz, respectively. Besides, the alginate microbeads generated by the system were tested with excellent size uniformity (CV: 3.1–5.1%). Moreover, its application for the microencapsulation of chondrocytes in alginate microbeads was also demonstrated with high cell viability (96 ± 2%). As a whole, the proposed device has paved an alternative route to perform alginate microbead generation or microencapsulation of cells in a simple, continuous, controllable, uniform, cell friendly, and less contaminated manner.     

Magnetofluidic spreading in microchannels

We investigate the spreading phenomena caused by the interaction between a uniform magnetic field and a magnetic fluid in microchannels. The flow system consists of two liquids: a ferrofluid and a mineral oil. The ferrofluid consists of superparamagnetic nanoparticles suspended in an oil-based carrier. Under a uniform magnetic field, the superparamagnetic particles are polarized and represent magnetic dipoles. The magnetization of the magnetic nanoparticles leads to a force resulting in the change of diffusion behavior inside the microchannel. Mixing due to secondary flow close to the interface also contributes to the spreading of the ferrofluid. The magnetic force acting on the liquid/liquid interface is caused by the mismatch of magnetization between the nanoparticles and surrounding liquid in a multiphase flow system. This paper examines the roles of magnetic force in the observed spreading phenomena. The effect of particles on the flow field is also considered. These phenomena would allow simple wireless control of a microfluidic system without changing the flow rates. These phenomena can potentially be used for focusing and sorting in cytometry.     

3D-printed membrane microvalves and microdecoder

A microfluidic system for multichannel switching and multiphase flow control has potential uses in pneumatic soft robotics and biological sampling systems. At present, the membrane microvalves used in microfluidic systems are mostly constructed using a multilayer bonding process so that the device cannot withstand high pressures. In this paper, we demonstrate a design method and the properties of a bondless membrane microvalve fabricated using a commercial 3D printer. We used a multijet (MJP) 3D printer to print a 100-μm-thick and 6-mm-diameter membrane from a relatively hard material (1700 MPa). The membrane’s high toughness ensures that it does not need negative pressure to reopen. The measured operation frequency was less than 2.5 Hz under a pneumatic pressure of 14.5 kPa. We also 3D-printed an integrated Quake-style microfluidic decoder network by combining 8 valves in series to demonstrate the integrability of the microvalve. The decoder chip was demonstrated to control the ON/OFF state of the four coded fluidic channels, with the droplets being generated from selected channels according to the valve action. Therefore, such 3D-printed microvalves are highly integrable, have a high manufacturing efficiency, and can be applied in pneumatic controllers, sample switchers and integrated print heads.

     

Design and simulation of a normally closed glucose sensitive hydrogel based microvalve

In drug delivery systems microvalves are the key components that have been developed for active control of drugs. In this research a normally closed microvalve with a glucose sensitive hydrogel actuating system is designed and simulated. Swelling of the hydrogel forces a silicone rubber membrane to deflect and causes the valve to be opened. The component of the valve that can be opened because of the hydrogel pressure is a silicon nitride cantilever beam which is sealed with a parylene layer. Simulations have been done by FEM analysis and the results show that membrane deflection is large enough to enable the valve to be opened and the fluid to flow through the microchannel. For both rectangular and trapezoidal microchannels with various hydraulic diameters, output flow rates less than 50 μl/min to several hundreds of μl/min can be achieved. Final design has been optimized for the opening point of microvalve at glucose concentration of 15 mM. Overall investigation has been done for a microvalve with specific dimensions and with 4 kPa input pressure the output flow rate of 100 μl/min has been generated which is in the desired range.     

Microfluidic devices harboring unsealed reactors for real-time isothermal helicase-dependent amplification

High-throughput microchip devices used for nucleic-acid amplification require sealed reactors. This is to prevent evaporative loss of the amplification mixture and cross-contamination, which may occur among fluidically connected reactors. In most high-throughput nucleic-acid amplification devices, reactor sealing is achieved by microvalves. Additionally, these devices require micropumps to distribute amplification mixture into an array of reactors, thereby increasing the device cost, and adding complexity to the chip fabrication and operation processes. To overcome these limitations, we report microfluidic devices harboring open (unsealed) reactors in conjunction with a single-step capillary based flow scheme for sequential distribution of amplification mixture into an array of reactors. Concern about evaporative loss in unsealed reactors have been addressed by optimized reactor design, smooth internal reactor surfaces, and incorporation of a localized heating scheme for the reactors, in which isothermal, real-time helicase-dependent amplification (HDA) was performed.     

Tapered microvalves fabricated by off-axis X-ray exposures

 A method for creating angled structures for use in microvalve devices applicable to control of liquid flow is presented. This technique utilizes a modified LIGA process with successive angled and rotated exposures into free standing acrylic sheets to form a tapered valve seat structure. These valve seats are integrated with bulk micromachined silicon diaphragms and tapered PMMA valve bosses to complete the microvalve. The long term goal of this research effort is to develop a normally-closed, low power, microfabricated valve for use in an implantable drug delivery system. This paper reports on the design and fabrication of microvalves using off-axis LIGA exposures. Flow testing and fluid handling characterization results are also presented. Received: 25 August 1997 Accepted: 22 October 1997