Rapid microfabrication of solvent-resistant biocompatible microfluidic devices

This paper presents a rapid, simple, and low-cost fabrication method to prepare solvent resistant and biocompatible microfluidic devices with three-dimensional geometries. The devices were fabricated in thiolene and replicated from PDMS master with high molding fidelity. Good chemical compatibility for organic solvents allows volatile chemicals in synthesis and analysis applications. The surface can be processed to be hydrophobic or hydrophilic for water-in-oil and oil-in-water emulsions. Monodisperse organic solvent droplet generation is demonstrated to be reproducible in thiolene microchannels without swelling. The thiolene surface prevents cell adhesion but normal cell growth and adhesion on glass substrates is not affected by the adjacent thiolene patterns.     

Efficient electrospray ionization from polymer microchannels using integrated hydrophobic membranes

A simple process for realizing stable and reliable electrospray ionization (ESI) tips in polymer microfluidic systems is described. The process is based on the addition of a thin hydrophobic membrane at the microchannel exit to constrain lateral dispersion of the Taylor cone formed during ESI. Using this approach, ESI chips are shown to exhibit well-defined Taylor cones at flow rates as low as 80 nL min(-1) through optical imaging. Furthermore, stable electrospray current has been measured for flow rates as low as 10 nL min(-1) over several hours of continuous operation. Characterization of the electrospray process by optical and electrical monitoring of fabricated ESI chips is reported, together with mass spectrometry validation using myoglobin as a model protein. The novel process offers the potential for low-cost, direct interfacing of disposable polymer microfluidic separation platforms to mass spectrometry.     

A low-cost, manufacturable method for fabricating capillary and optical fiber interconnects for microfluidic devices

Microfluidic chips require connections to larger macroscopic components, such as light sources, light detectors, and reagent reservoirs. In this article, we present novel methods for integrating capillaries, optical fibers, and wires with the channels of microfluidic chips. The method consists of forming planar interconnect channels in microfluidic chips and inserting capillaries, optical fibers, or wires into these channels. UV light is manually directed onto the ends of the interconnects using a microscope. UV-curable glue is then allowed to wick to the end of the capillaries, fibers, or wires, where it is cured to form rigid, liquid-tight connections. In a variant of this technique, used with light-guiding capillaries and optical fibers, the UV light is directed into the capillaries or fibers, and the UV-glue is cured by the cone of light emerging from the end of each capillary or fiber. This technique is fully self-aligned, greatly improves both the quality and the manufacturability of the interconnects, and has the potential to enable the fabrication of interconnects in a fully automated fashion. Using these methods, including a semi-automated implementation of the second technique, over 10,000 interconnects have been formed in almost 2000 microfluidic chips made of a variety of rigid materials. The resulting interconnects withstand pressures up to at least 800psi, have unswept volumes estimated to be less than 10 femtoliters, and have dead volumes defined only by the length of the capillary.     

Frontal photopolymerization for microfluidic applications

Frontal photopolymerization (FPP) offers numerous advantages for the rapid prototyping of microfluidic devices. Quantitative utilization of this method, however, requires a control of the vertical dimensions of the patterned resist material. To address this fundamental problem, we study the ultraviolet (UV) photopolymerization of a series of multifunctional thiolene resists through a combination of experiments and analytical modeling of the polymerization fronts. We describe this nonlinear spatio-temporal growth process in terms of a "minimal" model involving an order parameter phi(x, t) characterizing the extent of monomer-to-polymer conversion, the optical attenuation T(x, t), and the solid front position h(t). The latter exhibits an induction time (or equivalent critical UV dose) characterizing the onset of frontal propagation. We also observe a novel transition between two logarithmic rates of growth, determined by the Beer-Lambert attenuation constants mu(0) and mu(infinity) of the monomer and fully polymerized material, respectively. The measured frontal kinetics and optical transmission of the thiolene resist materials are consistent with our photopolymerization model, exhibiting both "photodarkening" and "photoinvariant" polymerization. This is apparently the first observation of photodarkening reported in FPP. On the basis of these results, multilevel fluidic devices with controlled height are readily fabricated with modulated illumination. A representative two-level microfluidic device, incorporating a chaotic mixer, a T junction, and a series of controlled flow constrictions, illustrates the practical versatility of this fabrication method.     

A novel fabrication technique to minimize poly(dimethylsiloxane)‐microchannels deformation under high‐pressure operation

PDMS is one of the most common materials used for the flow delivery in the microfluidics chips, since it is clear, inert, nontoxic, and nonflammable. Its inexpensiveness, straightforward fabrication, and biological compatibility have made it a favorite material in the exploratory stages of the bio‐microfluidic devices. If small footprint assays want to be performed while keeping the throughput, high pressure‐rated channels should be used, but PDMS flexibility causes an important issue since it can generate a large variation of microchannel geometry. In this work, a novel fabrication technique based on the prevention of PDMS deformation is developed. A photo‐sensible thiolene resin (Norland Optical Adhesive 63, NOA 63) is used to create a rigid coating layer over the stiff PDMS micropillar array, which significantly reduces the pressure‐induced shape changes. This method uses the exact same soft lithography manufacturing equipment. The verification of the presented technique was investigated experimentally and numerically and the manufactured samples showed a deformation 70% lower than PDMS conventional samples.     

微流控高通量试样引入技术的研究进展

如何实现外部宏观系统与芯片微观系统之间的衔接一直是微流控芯片分析领域中一个重要的研究课题。本文结合作者所在研究组的工作及成果,介绍了当前微流控高通量试样引入技术的研究进展。其中分别介绍了基于固定储液池、流通池和取样探针3种模式的微流控芯片系统试样引入系统,以及基于毛细管的微流控高通量试样引入系统。此外,还对该领域研究发展的前景进行了展望。     

Disposable roll-to-roll hot embossed electrophoresis chip for detection of antibiotic resistance gene mecA in bacteria

We present a high-throughput roll-to-roll (R2R) manufacturing process for foil-based polymethyl methacrylate (PMMA) chips of excellent optical quality. These disposable, R2R hot embossed microfluidic chips are used for the identification of the antibiotic resistance gene mecA in Staphylococcus epidermidis. R2R hot embossing is an emerging manufacturing technology for polymer microfluidic devices. It is based on continuous feeding of a thermoplastic foil through a pressurized area between a heated embossing cylinder and a blank counter cylinder. Although mass fabrication of foil-based microfluidic chips and their use for biological applications were foreseen already some years ago, no such studies have been published previously.     

Biofunctionalization of electrowetting-on-dielectric digital microfluidic chips for miniaturized cell-based applications

In this paper we report on the controlled biofunctionalization of the hydrophobic layer of electrowetting-on-dielectric (EWOD) based microfluidic chips with the aim to execute (adherent) cell-based assays. The biofunctionalization technique involves a dry lift-off method with an easy to remove Parylene-C mask and allows the creation of spatially controlled micropatches of biomolecules in the Teflon-AF(?) layer of the chip. Compared to conventional methods, this method (i) is fully biocompatible; and (ii) leaves the hydrophobicity of the chip surface unaffected by the fabrication process, which is a crucial feature for digital microfluidic chips. In addition, full control of the geometry and the dimensions of the micropatches is achieved, allowing cells to be arrayed as cell clusters or as single cells on the digital microfluidic chip surface. The dry Parylene-C lift-off technique proves to have great potential for precise biofunctionalization of digital microfluidic chips, and can enhance their use for heterogeneous bio-assays that are of interest in various biomedical applications.     

Microfluidic chips for biological and medical research

Advantages of devices on a microchip platform are discussed in comparison with traditional systems. Stages and processes of creation of microfluidic chips are considered. The basic technologies of formation micro- and nanostructures on a substrate from various materials and techniques for microchip sealing are introduced. Special attention is given to microfluidic chips for separation and analysis of nucleic acids and proteins, as well as to microchips for PCR. Examples of integrated systems on the basis of microfluidic technique are considered. Data on the commercialization of devices based on microfluidic chips are presented.     

微流控芯片免疫分析方法研究进展

综述了微流控芯片免疫分析方法研究新进展。对有关芯片进行了初步分类，并评述了各类芯片的性能与优缺点。尤为关注免疫分析微流控芯片在临床诊断、环境分析等领域的应用研究。引用文献33篇。     

玻璃微流控芯片廉价快速制作方法的研究

研究了一种玻璃微流控芯片的快速、低成本制作工艺和方法. 该方法采用商品化的显微载玻片(soda-lime玻璃)作为芯片基质材料, 利用AZ 4620光刻胶代替传统工艺中的溅射金属层或多晶硅/氮化硅层作为玻璃刻蚀的掩膜层, 同时利用一种紫外光学胶键合方法代替传统熔融键合方法实现芯片的键合, 整个工艺对玻璃基质材料要求低, 普通微流控芯片(深度小于50 μm)制作流程仅需约3.5 h, 可降低制作成本, 缩短制作周期. 还系统地研究了光刻胶厚度、光刻胶硬烘时间和玻璃腐蚀液配比对玻璃微流控芯片制作的影响, 获得了优化的工艺参数.     

Solid supports for micro analytical systems

The development of micro analytical systems requires that fluids are able to interact with the surface of the microfluidic chip in order to perform analysis such as chromatography, solid phase extraction, and enzymatic digestion. These types of analyses are more efficient if there are solid supports within the microfluidic channels. In addition, solid supports within microfluidic chips are useful in producing devices with multiple functionalities. In recent years there have been many approaches introduced for incorporating solid supports within chips. This review will explore several state of the art methods and applications of introducing solid supports into chips. These include packing chips with beads, incorporating membranes into chips, creating supports using microfabrication, and fabricating gels and polymer monoliths within microfluidic channels.     

Next-generation integrated microfluidic circuits

This mini-review provides a brief overview of recent devices that use networks of elastomeric valves to minimize or eliminate the need for interconnections between microfluidic chips and external instruction lines that send flow control signals. Conventional microfluidic control mechanisms convey instruction signals in a parallel manner such that the number of instruction lines must increase as the number of independently operated valves increases. The devices described here circumvent this "tyranny of microfluidic interconnects" by the serial encoding of information to enable instruction of an arbitrary number of independent valves with a set number of control lines, or by the microfluidic circuit-embedded encoding of instructions to eliminate control lines altogether. Because the parallel instruction chips are the most historical and straightforward to design, they are still the most commonly used approach today. As requirements for instruction complexity, chip-to-chip communication, and real-time on-chip feedback flow control arise, the next generation of integrated microfluidic circuits will need to incorporate these latest interconnect flow control approaches.     

Analytical and numerical study of Joule heating effects on electrokinetically pumped continuous flow PCR chips

Joule heating is an inevitable phenomenon for microfluidic chips involving electrokinetic pumping, and it becomes a more important issue when chips are made of polymeric materials because of their low thermal conductivities. Therefore, it is very important to develop methods for evaluating Joule heating effects in microfluidic chips in a relatively easy manner. To this end, two analytical models have been established and solved using the Green's function for evaluating Joule heating effects on the temperature distribution in a microfluidic-based PCR chip. The first simplified model focuses on the understanding of Joule heating effects by ignoring the influences of the boundary conditions. The second model aims to consider practical experimental conditions. The analytical solutions to the two models are particularly useful in providing guidance for microfluidic chip design and operation prior to expensive chip fabrication and characterization. To validate the analytical solutions, a 3-D numerical model has also been developed and the simultaneous solution to this model allows the temperature distribution in a microfluidic PCR chip to be obtained, which is used to compare with the analytical results. The developed numerical model has been applied for parametric studies of Joule heating effects on the temperature control of microfluidic chips.     

Performing microchannel temperature cycling reactions using reciprocating reagent shuttling along a radial temperature gradient

This study develops a novel temperature cycling strategy for executing temperature cycling reactions in laser-etched poly(methylmethacrylate) (PMMA) microfluidic chips. The developed microfluidic chip is circular in shape and is clamped in contact with a circular ITO heater chip of an equivalent diameter. Both chips are fabricated using an economic and versatile laser scribing process. Using this arrangement, a self-sustained radial temperature gradient is generated within the microfluidic chip without the need to thermally isolate the different temperature zones. This study demonstrates the temperature cycling capabilities of the reported microfluidic device by a polymerase chain reaction (PCR) process using ribulose 1,5-bisphosphate carboxylase large subunit (rbcL) gene as a template. The temperature ramping rate of the sample inside the microchannel is determined from the spectral change of a thermochromic liquid crystal (TLC) solution pumped into the channel. The present results confirm that a rapid thermal cycling effect is achieved despite the low thermal conductivity of the PMMA substrate. Using IR thermometry, it is found that the radial temperature gradient of the chip is approximately 2 degrees C mm(-1). The simple system presented in this study has considerable potential for miniaturizing complex integrated reactions requiring different cycling parameters.     

Injection molded microfluidic chips featuring integrated interconnects

An injection molding process for the fabrication of disposable plastic microfluidic chips with a cycle time of 2 min has been designed, developed, and implemented. Of the sixteen commercially available grades of cyclo-olefin copolymer (COC) that were screened for autofluorescence and transparency to ultraviolet (UV) light, Topas 8007 x 10 was identified as the most suitable for production. A robust solid metal mold insert defining the microfluidic channels was rapidly microfabricated using a process that significantly reduces the time required for electroplating. No wear of the insert was observed even after over 1000 cycles. The chips were bonded by thermal fusion using different bonding conditions. Each condition was tested and its suitability evaluated by burst pressure measurements. The COC microfluidic chips feature novel, integrated, reversible, standardized, ready-to-use interconnects that enable operation at pressures up to 15.6 MPa, the highest value reported to date. The suitability of these UV transparent, high pressure-resistant, disposable devices was demonstrated by in situ preparation of a high surface area porous polymer monolith within the channels.     

微流控纸芯片在环境分析检测中的应用

近年来,微流控纸芯片由于低成本、便携化、检测快等优点,在需要快速检测的环境分析领域中展现出了巨大的应用前景。该综述从微流控纸芯片在环境分析中的应用角度,总结归纳了微流控纸芯片在环境分析中的最新研究进展,并展望了其在未来的发展趋势与挑战。论文内容引用150余篇源于科学引文索引(SCI)与中文核心期刊中的相关论文。该综述包括微流控纸芯片在环境检测中的优势与制造方法介绍;电化学法、荧光法、比色法、表面增强拉曼法、集成传感法等基于纸芯片的先进分析方法介绍;根据环境分析目标物种类,如重金属离子、营养盐、农药、微生物、抗生素以及其他污染物等,对纸芯片的最新应用现状进行了举例评述;基于微流控纸芯片的环境分析研究的未来发展趋势和前景展望。通过综述近期相关研究,表明微流控纸芯片从提出至今虽然只有十几年的发展历程,但其在环境分析研究中的发展却十分迅速。微流控纸芯片可以根据不同的环境条件和检测要求灵活选择制作与分析方法,实现最佳的检测效果。但是微流控纸芯片也面临一些挑战,如纸张机械强度不足、流体控制程度不佳等问题。这些问题指出了微流控纸芯片在环境检测领域的发展趋势,相信随着不断深入的研究,纸芯片将会在未来的环境分析中发挥更大作用。     

Packaging of microfluidic chips via interstitial bonding technique.

In this paper, we describe an interstitial bonding technique for packaging of microfluidic chips. The cover plate is first placed on top of the microfluidic chip, followed by dispensing the UV-curable resin into the resin-loading reservoirs. With the interstitial space between the cover plate and the microfluidic chip connecting to the loading reservoirs, the UV-curable resin wicks through capillary force action and hydrostatic pressure generated by the liquid level in the resin-loading reservoirs. When reaching the microchannels, the UV-curable resin stops flowing into the microchannels due to the force balance between the surface tension and hydrostatic pressure. The assembly is then placed under the UV light, followed by further curing in the thermal oven. It is found that there is no leakage from the bonded microfluidic chips and a good DNA separation result was obtained by using the microfluidic chips as fabricated. This bonding technique is relatively simple and fast, which can be applied to the packaging of microfluidic chips made from hybrid materials with complicated designs as long as the interstitial space connects to the loading reservoirs.     

Advances in the preparation of porous polymer monoliths in capillaries and microfluidic chips with focus on morphological aspects

Porous polymer monoliths have emerged as unique materials for many applications, including liquid-chromatographic analyses at an unrivaled speed, solid-phase extraction, and enzyme immobilization in capillary and microfluidic chip format. This article reviews the state of the art in the preparation of monoliths in narrow-bore capillaries and microfluidic chips and their miniaturization under conditions of spatial confinement. New developments in their preparation mainly using free radical polymerization techniques with a focus on morphological aspects in view of homogeneous porous materials are described. The suitability of monoliths for analysis of both large and small molecules is also discussed.     

New family of fluorinated polymer chips for droplet and organic solvent microfluidics

We present a new family of microfluidic chips hot embossed from a commercial fluorinated thermoplastic polymer (Dyneon THV). This material shares most of the properties of fluoro polymers (very low surface energy and resistance to chemicals), but is easier to process due to its relatively low melting point. Finally, as an elastic material it also allows easy world to chip connections. Fluoropolymer films can be imprinted by hot embossing from PDMS molds prepared by soft lithography. Chips are then sealed by an original technique (termed Monolithic-Adhesive-Bonding), using two different grades of fluoropolymer to obtain uniform mechanical, chemical and surface properties. This fabrication process is well adapted to rapid prototyping, but it also has potential for low cost industrial production, since it does not require any curing or etching step. We prepared microfluidic devices with micrometre resolution features, that are optically transparent, and that provide good resistance to pressure (up to 50 kPa). We demonstrated the transport of water droplets in fluorinated oil, and fluorescence detection of DNA within the droplets. No measurable interaction of the droplets with the channels wall was observed, alleviating the need for surface treatment previously necessary for droplet applications in microfluidic chips. These chips can also handle harsh organic solvents. For instance, we demonstrated the formation of chloroform droplets in fluorinated oil, expanding the potential for on chip microchemistry.