Literature Review of the Use of Zinc and Zinc Compounds in Paper-Based Microfluidic Devices

Zinc and its compounds, alloys and composites play an important role in the modern day world and find application in almost every aspect that can improve the quality of our lives. This ranges from supplements and pharmaceuticals that are meant to improve our health and wellbeing to additives meant to guard or reduce corrosion in metals. However, over the past several years, a new area of technology has been garnering a great deal of attention and has made use of zinc and its compounds. This is with reference to paper-based microfluidic technology that offers several advantages and that keeps expanding in the amount of applications it covers. In this paper, a review is offered for the applications that have used zinc or zinc compounds in paper-based microfluidic devices.

Rapid fabrication of modular 3D paper-basedmicrofluidic chips using projection-based 3D printing

Paper-based microchips have different advantages,such as better biocompatibility,simple production,and easy handling,making them promising candidates for clinical diagnosis and other fields.This study describes amethod developed to fabricate modular three-dimensional(3D)paper-based microfluidic chips based on projection-based 3D printing(PBP)technology.A series of two-dimensional(2D)paper-based microfluidic modules was designed and fabricated.After evaluating the effect of exposure time on the accuracy of the flow channel,the resolution of this channel was experimentally analyzed.Furthermore,several 3D paper-based microfluidic chips were assembled based on the 2D ones using different methods,with good channel connectivity.Scaffold-based 2D and hydrogel-based 3D cell culture systems based on 3D paper-based microfluidic chips were verified to be feasible.Furthermore,by combining extrusion 3D bioprinting technology and the proposed 3D paper-based microfluidic chips,multiorgan microfluidic chips were established by directly printing 3D hydrogel structures on 3D paperbased microfluidic chips,confirming that the prepared modular 3D paper-based microfluidic chip is potentially applicable in various biomedical applications.

Droplet Pattern Formation and Translation in New Microfluidic Flow- Focusing Devices

We conducted experiments on specially designed microfluidic chips that generate droplets through a microfluidic ow-focusing approach. The fluid flow in the microfluidic channel produced a shear flow field at low Reynolds numbers. The droplets in the microfluidic system exhibited special droplet pattern formations similar to periodic crystal-like lattices because of the competition between shear forces and surface tension. By adjusting the flow rate ratio of the water （droplet phase） to oil （continuous phase） phases and changing the outlet channel widths, the droplets formed monolayer dispersion to double-layer formation to monolayer squeezing when the outlet channel widths were 250 or 300 μm. We also obtained droplets with monolayer dispersion, three-layer arrangements, double-layer squeezing, and monolayer squeezing when the outlet channel width was 350 μm. The outlet channel width was increased to 400 μm, and four-layer arrangements were observed. We also studied the translation of droplet formation, which resulted in a detailed strategy to control drop size and droplet pattern formation for emulsi cation in microfluidic devices. We expect that our strategy can provide theoretical guidance to synthesize dispersion or polydisperse colloid particles.

Fabrication of paper-based devices for in vitro tissue modeling

Paper devices have recently attracted considerable attention as a class of cost-effective cell culture substrates for various biomedical applications.The paper biomaterial can be used to partially mimic the in vivo cell microenvironments mainly due to its natural three-dimensional characteristic.The paper-based devices provide precise control over their structures as well as cell distributions,allowing recapitulation of certain interactions between the cells and the extracellular matrix.These features have shown great potential for the development of normal and diseased human tissue models.In this review,we discuss the fabrication of paper-based devices for in vitro tissue modeling,as well as the applications of these devices toward drug screening and personalized medicine.It is believed that paper as a biomaterial will play an essential role in the field of tissue model engineering due to its unique performances,such as good biocompatibility,eco-friendliness,cost-effectiveness,and amenability to various biodesign and manufacturing needs.

Determination of inhibitory activity of Salvia miltiorrhiza extracts on xanthine oxidase with a paper-based analytical device

A novel paper-based analytical device(PAD)was prepared and applied to determine the xanthine oxidase(XOD)inhibitory activity of Salvia miltiorrhiza extracts(SME).First,polycaprolactone was 3D printed on filter paper and heated to form hydrophobic barriers.Then the modified paper was cut according to the specific design.Necessary reagents including XOD for the colorimetric assay were immobilized on two separate pieces of paper.By simply adding phosphate buffer,the reaction was performed on the double-layer PAD.Quantitative results were obtained by analyzing the color intensity with the specialized device system(consisting of a smartphone,a detection box and sandwich plates).The 3Dprinted detection box was small,with a size of 9.0 cm×7.0 cm×11.5 cm.Color component G performed well in terms of linearity and detection limits and thus was identified as the index.The reaction conditions were optimized using a definitive screening design.Moreover,a 10%glycerol solution was found to be a suitable stabilizer.When the stabilizer was added,the activity of XOD could be maintained for at least 15 days under 4℃ or-20℃ storage conditions.The inhibitory activity of SME was investigated and compared to that of allopurinol.The results obtained with the PAD showed agreement with those obtained with the microplate method.In conclusion,the proposed PAD method is simple,accurate and has a potential for point-of-care testing.It also holds promise for use in rapid quality testing of medicinal herbs,intermediate products,and preparations of traditional Chinese medicines.

Microwave Induced Ethanol Bath Bonding for PMMA Microfluidic Device

High bonding strength,low deformation and convenient procedure are all very important aspects in the microfluidic device fabrication process. In this paper,an improved microwave induced bonding technology is proposed to fabricate microfluidic device based on methyl methacrylate( PMMA). This method employs pure ethanol as the bonding assisted solvent. The ethanol not only acts as the microwave absorbing material,but also works as the organic solvent in bath. The presented research work has shown that the bonding process can be completed in less than 45 s. Furthermore,the convenient bonding only applies microwave oven,beakers and binder clips. Then,we discuss effects of microwave power,bonding time on bonding strength and deformation of microstructures on PMMA microfluidic device. Finally,a 4 layers micro-mixer has been fabricated using the proposed bonding technique which includes 15 trapezoid micro-channels,9 T-type mix units and an X-type mix unit. Experimental results show that the proposed bonding method have some advantages compared with several traditional bonding technologies,such as hot pressing bonding,ultrasonic bonding and solvent assisted bonding methods in respect of bonding strength,deformation and bonding process. The presented work would be helpful for low coat mass production of multilayer polymer microfluidic devices in lab.

Development of PDMS-based Microfluidic Device for Cell-based Assays

In a single step photolithography, muhi-level microfluidic device is fabricated by printing novel architectures on a film photomasks. The whole fabrication process is executed by classical PCB technology without the need to access clean room facilities. Different levels of protruding features on PCB master are produced by exposing a photomask with specifically arranged "windows and rims" architectures, followed by chemical wet etching. Poly(dimethylsiloxane)(PDMS) is then molded against the positive relief master to generate microfluidic device featured with multi-level sandbag structure and peripheral microchannels. This sandbag structure is an analog to traditional dam or weir for particle entrapment. The microstructure does not collapse when subjected to applied pressure, which is suitable for operation on elastic PDMS substrate.Typical immunocytochemcial staining assays were performed in the microdevice to demonstrate the applicability of the sandbag structure for cellular analysis. This simplified microfabrication process employs low-cost materials and minimal specialized equipment and can reproducibly produce mask lines with about 20 μm in width, which is sufficient for most microfluidic applications.

Colorimetric and electrochemical dual-signal detection of uracil-DNA glycosylase using functionalized pure DNA hydrogel on paper-based analytical devices

The development of simple and accurate detection of uracil-DNA glycosylase(UDG)is of great significance for early clinical diagnosis and biomedical research.Here,we on the first effort introduced the uracil bases into the rolling circle amplification(RCA)reaction to produce the functionalized pure DNA hydrogel(PDH)for UDG detection.During RCA process,methylene blue(MB)molecules as the indicators were encapsulated into PDH.The addition of UDG can remove the uracil bases of PDH to generate abasic sites,which are further cleaved with the assistance of apurinic/apyrimidinic endonuclease(APE),thus resulting in the dissociation of PDH to release blue MB.By combining with the paper analytical devices as the signal readout platform,a colorimetric and electrochemical dual-signal biosensor was constructed for convenient and accurate detection of UDG.The proposed MB@PDH-based dual-signal sensing system exhibited good selectivity and high sensitivity with a detection limit of 6.4104 U/mL(electrochemical method).It was also demonstrated that this sensing system showed excellent performance in UDG inhibitor screening,thus providing great potential in UDG-related disease diagnosis and drug discovery.

Functional microfluidics:theory,microfabrication,and applications

Microfluidic devices are composed of microchannels with a diameter ranging from ten to a few hundred micrometers.Thus,quite a small(10-9–10-18l)amount of liquid can be manipulated by such a precise system.In the past three decades,significant progress in materials science,microfabrication,and various applications has boosted the development of promising functional microfluidic devices.In this review,the recent progress on novel microfluidic devices with various functions and applications is presented.First,the theory and numerical methods for studying the performance of microfluidic devices are briefly introduced.Then,materials and fabrication methods of functional microfluidic devices are summarized.Next,the recent significant advances in applications of microfluidic devices are highlighted,including heat sinks,clean water production,chemical reactions,sensors,biomedicine,capillaric circuits,wearable electronic devices,and microrobotics.Finally,perspectives on the challenges and future developments of functional microfluidic devices are presented.This review aims to inspire researchers from various fields engineering,materials,chemistry,mathematics,physics,and more—to collaborate and drive forward the development and applications of functional microfluidic devices,specifically for achieving carbon neutrality.

Microfluidic thermotaxic selection of highlymotile sperm and in vitro fertilization

The selection of the most motile and functionally competent sperm is an essential basis for in vitro fertilization(IVF)and normal embryonic development.Widely adopted clinical approaches for sperm sample processing intensely rely on centrifugation and wash steps that may induce mechanical damage and oxidative stress to sperm.Although a few microfluidic sperm sorting devices may avoid these adverse effects by exploiting intrinsic guidance mechanisms of sperm swimming,none of these approaches have been fully validated by clinical-grade assessment criteria.In this study,a microfluidic sperm sorting device that enables the selection of highly motile and functional sperm via their intrinsic thermotaxis is presented.Bioinspired by the temperature microenvironment in the fallopian tube during natural sperm selection,a microfluidic device with controllable temperature gradients along the sperm separation channel was designed and fabricated.This study investigated the optimal temperature conditions for human sperm selection and fully characterized thermotaxis-selected sperm with 45 human sperm samples.Results indicated that a temperature range of 35–36.5℃along the separation channel significantly improves human sperm motility rate((85.25±6.28)%vs.(60.72±1.37)%;P=0.0484),increases normal sperm morphology rate((16.42±1.43)%vs.(12.55±0.88)%;P<0.0001),and reduces DNA fragmentation((7.44±0.79)%vs.(10.36±0.72)%;P=0.0485)compared to the nonthermotaxis group.Sperm thermotaxis is species-specific,and selected mouse sperm displayed the highest motility in response to a temperature range of 36–37.5℃ along the separation channel.Furthermore,IVF experiments indicated that the selected sperm permitted an increased fertilization rate and improved embryonic development from zygote to blastocyst.This microfluidic thermotaxic selection approach will be translated into clinical practice to improve the IVF success rate for patients with oligozoospermia and asthenozoospermia.

Filter paper as electrolyte flow transport using vaporized methanol as fuel in a microfluidic fuel cell:Experimental and numerical simulation

In this work,we present a design of a paper-based microfluidic fuel cell(μFC),which employs the spontaneous capillary flow of reactant solutions in a filter paper to accomplish passive conveyance of the fuel and oxidant.This self-pumping device uses methanol vapor as a fuel.The gas phase in the microfluidic fuel cell increases the fuel supply to the anode due to a higher diffusion coefficient of 1.5×10^(-5)m^(2)s^(-1)compared with 5×10^(-9)m^(2)s^(-1)for liquid phase.An air-breathing cathode is incorporated to paper-basedμFC through which atmospheric oxygen is continuously supplied.The paper-basedμFC performance is studied by polarization curves and chronoamperometry to determinate the power output and stability.Peak power of 1.49mW and a stable current of 1.35mA at 0.35V for 28h can be achieved with this prototype under room temperature.To interpret the device performance a numerical model is developed and validated with the experimental polarization curve.The fuel and oxidant concentration profiles in the electrodes from the model demonstrates a constant species availability at the cathode and anode and explains the stable current obtained in the experimental measurements.Subsequently,a stack of four MμFCFP was developed and evaluated in both series and parallel connections.In the parallel configuration,a maximum open circuit potential(OCP)of 0.69V with a maximum current and power output of 34.53 mA and 4.14 mW are delivered,respectively.Conversely,in the series connection,a total current of 7.35mA,an OCP of 2.39V and a maximum power of 3.57 mW are reached.As a proof of concept,the stack successfully operates a 3 green LEDs array,each requiring a 2.1-2.5V and 4.2-5 mW power to function,for a continuous duration of 3 h.

Optofluidics:the interaction between light and flowing liquids in integrated devices

Optofluidics is a rising technology that combines microfluidics and optics.Its goal is to manipulate light and flowing liquids on the micro/nanoscale and exploiting their interaction in optofluidic chips.The fluid flow in the on-chip devices is reconfigurable,non-uniform and usually transports substances being analyzed,offering a new idea in the accurate manipulation of lights and biochemical samples.In this paper,we summarized the light modulation in heterogeneous media by unique fluid dynamic properties such as molecular diffusion,heat conduction,centrifugation effect,light-matter interaction and others.By understanding the novel phenomena due to the interaction of light and flowing liquids,quantities of tunable and reconfigurable optofluidic devices such as waveguides,lenses,and lasers are introduced.Those novel applications bring us firm conviction that optofluidics would provide better solutions to high-efficient and high-quality lab-on-chip systems in terms of biochemical analysis and environment monitoring.

Designer substrates and devices for mechanobiology study

Both biological and engineering approaches have contributed significantly to the recent advance in the field of mechanobiology.Collaborating with biologists,bio-engineers and materials scientists have employed the techniques stemming from the conventional semiconductor industry to rebuild cellular milieus that mimic critical aspects of in vivo conditions and elicit cell/tissue responses in vitro.Such reductionist approaches have help to unveil important mechanosensing mechanism in both cellular and tissue level,including stem cell differentiation and proliferation,tissue expansion,wound healing,and cancer metastasis.In this mini-review,we discuss various microfabrication methods that have been applied to generate specific properties and functions of designer substrates/devices,which disclose cell-microenvironment interactions and the underlying biological mechanisms.In brief,we emphasize on the studies of cell/tissue mechanical responses to substrate adhesiveness,stiffness,topography,and shear flow.Moreover,we comment on the new concepts of measurement and paradigms for investigations of biological mechanotransductions that are yet to emerge due to on-going interdisciplinary efforts in the fields of mechanobiology and microengineering.

Microfluidics-based assay on the effects of microenvironmental geometry and aqueous flow on bacterial adhesion behaviors

Abstract A new microfluidic system with four different microchambers （a circle and three equilateral concave polygons） was designed and fabricated using poly（dimethylsiloxane） （PDMS） and the soft lithography method. Using this microfluidic device at six flow rates （5, 10, 20, 30, 40, and 50 μL/h）, the effects of microenvironmental geometry and aqueous flow on bacterial adhesion behaviors were investigated. Escherichia coli HB101 pGLO, which could produce a green fluorescent protein induced by L-arabinose, was utilized as the model bacteria. The results demonstrated that bacterial adhesion was significantly related to culture time, microenvironment geometry, and aqueous flow rates. Adhered bacterial density increased with the culture time. Initially, the adhesion occurred at the microchamber sides, and then the entire chamber was gradually covered with increased culture time. Adhesion densities in the side zones were larger than those in the center zones because of the lower shearing force in the side zone. Also, the adhesion densities in the complex chambers were larger than those in the simple chambers. At low flow rates, the orientation of adhered bacteria was random and disorderly. At high flow rates, bacterial orientation became close to the streamline and oriented toward the flow direction; All these results implied that bacterial adhesion tended to occur in complicated aqueous flow areas.The present study provided an on-chip flow system for physiological behavior of biological cells, as well as provided a strategic cue for the prevention of bacterial infection and biofilm formation.

Scalable Methods for Device Patterning as an Outstanding Challenge in Translating Paper-Based Microfluidics from the Academic Benchtop to the Point-of-Care

Paper-based microfluidic devices offer unparalleled adaptability for the development of low-cost,point-of-care analytical tests.The potential for these devices to drastically improve access to healthcare around the globe is obvious,but very few tests have found success in clinical environments.Here,we identify manufacturing-specifically,methods to pattern paper devices at large scales-as a major barrier to translating prototype paper-based devices from the academic benchtop to the field.We introduce current methods used to pattern papers and discuss their utility as means to prototype and manufacture paper-based devices.

The Development of the Heparin Monitoring System Based on Microfluidics Technology

Heparin monitoring is widely used to measure the anticoagulant effect of unfractionated heparin and adjust the dose to keep within the target treatment range. This technology has applications in many fields and also prospects in the future. Its application has the advantages of rapidity, high throughput and minimum sample consumption. Many point of care devices for heparin monitoring are available. The CoaguChek device only requires a small sample size, which is obtained through a fingerstick. Over the last few years, the point-of-care (POC) testing was used widely for its convenience, efficiency, and faster turnaround times.

Cell Segmentation and Tracking in Microfluidic Platform

In this research, we have concentrated on trajectory extraction based on image segmentation and data association in order to provide an economic and complete solution for rapid microfluidic cell migration experiments. We applied region scalable active contour model to segment the individual cells and then employed the ellipse fitting technique to process touching cells. Subsequently, we have also introduced a topology based technique to associate the cells between consecutive frames. This scheme achieves satisfactory segmentation and tracking results on the datasets acquired by our microfluidic platform.

基于纸基微芯片的样本前处理方法研究进展

纸基微芯片(μPADs)是一种以纸质材料为基底的简易、便携式检测平台,在临床诊断、食品质量控制和环境监测等领域显示出极大的应用前景。作为快速检测平台,纸基微芯片除了需要对目标物进行快速定量,还要完成样本的前处理过程。科学家近年来开发了多种基于纸基微芯片的样本前处理方法,用于不同样本中目标物的分析。由于纸基具有强兼容性能,增强纸基芯片的样本前处理功能并将其与各种快速检测方法联用,能极大地扩展纸基微芯片的应用领域。该文对纸基微芯片的自驱动以及纸基微芯片自驱动与外驱动相结合的样本前处理方法进行了总结,概述了纸基微芯片在目标分析物提取、富集等前处理方面的研究进展,探讨了各种纸基微芯片前处理方法的优点和局限性。另外还展望了纸基微芯片的发展方向—除了不断提高样品前处理能力来扩展其在样本制备中的应用,还需要开发商业化的纸基微芯片来满足各类行业的检测需求。

Ultra-sensitive detection of uranyl ions with a specially designed high-efficiency SERS-based microfluidic device

The uranyl ion(UO22+) poses high risks to human health and the environment, hence its detection and monitoring is of utmost significance. However, the development of an ultra-sensitive, high-efficiency and convenient approach for on-site detection of UO22+ remains a challenge. Herein, a reliable and reusable surface-enhanced Raman spectroscopy(SERS)-based microfluidic biosensor was developed for rapid detection of UO22+ in real samples. The detection protocol involved the reaction of 5′-Rhodamine B(RhB)-labeled double-stranded DNA for UO22+-specific DNAzyme-cleavage reaction in a U-shaped microchannel. Then, the reaction products were delivered into three parallel samples for high-throughput tests by SERS biochips,where 3 D ZnO-Ag mesoporous nanosheet arrays(MNSs) were modified with a single-stranded DNA(ssDNA). The ssDNAwas sequence-complementary with the 5′-RhB-labeled cleaved-stranded DNA(csDNA) from the reaction products. By the hybridization of ssDNA and csDNA, the signal probe RhB was fixed close to the surface of the ZnO-Ag MNSs to enhance the Raman signal. The limit of detection for UO22+ with the microfluidic-SERS biosensor was 3.71×10-15 M. An over 20,000-fold selectivity towards UO22+ response was also achieved in the presence of 15 other metal ions. The high-throughput microfluidicSERS biosensor operated well for practical UO22+ detection, with excellent recoveries in contaminated river and tap water from95.2% to 106.3%(relative standard deviation(RSD)<6.0%, n=6). Although the SERS-based microfluidic biosensor developed in this study was deployed for the detection of UO22+, the reusable and high-efficiency system may be expanded to the detection of other analytes on-site.

A titanium dioxide nanorod array as a high-affinity nano-bio interface of a microfluidic device for efficient capture of circulating tumor cells

Nanomaterials show promising opportunities to address clinical problems （such as insufficient capture of circulating tumor cells; CTCs） via the high surface area-to-volume ratio and high affinity for biological cells. However, how to apply these nanomaterials as a nano-bio interface in a microfluidic device for efficient CTC capture with high specificity remains a challenge. In the present work, we first found that a titanium dioxide （TiO2） nanorod array that can be conveniently prepared on multiple kinds of substrates has high affinity for tumor cells. Then, the TiO2 nanorod array was vertically grown on the surface of a microchannel with hexagonally patterned Si micropillars via a hydrothermal reaction, forming a new kind of a micro-nano 3D hierarchically structured microfluidic device. The vertically grown TiO2 nanorod array was used as a sensitive nano-bio interface of this 3D hierarchically structured microfluidic device, which showed high efficiency of CTC capture （76.7% ± 7.1%） in an artificial whole-blood sample.