微流控芯片技术在心肌标志物检测中的应用综述

心肌标志物的检测异常,是急性心肌梗死的重要诊断指标之一。对心肌标志物的监测可直接影响心血管疾病患者的临床诊断、危险分层、治疗方案选择和预后判断。微流控芯片集进样、预处理、分离和检测于一体,具有样品需求量小、便携、分析快速等特点,是理想的心肌标志物检测平台。文章根据检测方法的不同,综述了近年来利用微流控芯片平台对心肌标志物的检测。已有检测方法中主要是光学和电学方法。随着传感器技术的发展,更多检测方法被采用。通过及时的综述概括,既可对已有技术和方法起到归纳作用,又可促进微流控芯片在心肌标志物即时诊断领域的发展。     

Prospects of low temperature co-fired ceramic (LTCC) based microfluidic systems for point-of-care biosensing and environmental sensing

Low temperature co-fired ceramic (LTCC) based microfluidic devices are being developed for point-of-care biomedical and environmental sensing to enable personalized health care. This article reviews the prospects of LTCC technology for microfluidic device development and its advantages and limitations in processing capabilities compared to silicon, glass and polymer processing. The current state of the art in LTCC-based processing techniques for fabrication of microfluidic components such as microchannels, chambers, microelectrodes and valves is presented. LTCC-based biosensing applications are discussed under the classification of (a) microreactors, (b) whole cell-based and (c) protein biosensors. Biocompatibility of LTCC pertaining to the development of biosensors and whole cell sensors is also discussed. Other significant applications of LTCC microfluidic systems for detection of environmental contaminants and toxins are also presented. Technological constraints and advantages of LTCC-based microfluidic system are elucidated in the conclusion. The LTCC-based microfluidic devices provide a viable platform for the development of point-of-care diagnostic systems for biosensing and environmental sensing applications.     

EWOD microfluidic systems for biomedical applications

As the technology advances, a growing number of biomedical microelectromechanical systems (bio-MEMS) research involves development of lab-on-a-chip devices and micrototal analysis systems. For example, a portable instrument capable of biomedical analyses (e.g., blood sample analysis) and immediate recording, whether the patients are in the hospital or home, would be a considerable benefit to human health with an excellent commercial viability. Digital microfluidic (DMF) system based on the electrowetting-on-dielectric (EWOD) mechanism is an especially promising candidate for such point-of-care systems. The EWOD-based DMF system processes droplets in a thin space or on an open surface, unlike the usual microfluidic systems that process liquids by pumping them in microchannels. Droplets can be generated and manipulated on EWOD chip only with electric signals without the use of pumps or valves, simplifying the chip fabrication and the system construction. Microfluidic operations by EWOD actuation feature precise droplet actuation, less contamination risk, reduced reagents volume, better reagents mixing efficiency, shorter reaction time, and flexibility for integration with other elements. In addition, the simplicity and portability make the EWOD-based DMF system widely popular in biomedical or chemical fields as a powerful sample preparation platform. Many chemical and biomedical researches, such as DNA assays, proteomics, cell assays, and immunoassays, have been reported using the technology. In this paper, we have reviewed the recent developments and studies of EWOD-based DMF systems for biomedical applications published mostly during the last 5 years.     

Capillary flow-driven blood plasma separation and on-chip analyte detection in microfluidic devices

We report a comprehensive review on the capillary flow-driven blood plasma separation and on-chip analyte detection in microfluidic devices. Blood plasma separation is the primary sample preparation step prior to most biochemical assays. Conventionally, centrifugation is used for the sample preparation process. There are numerous works reporting blood plasma separation in microfluidic devices which aim at miniaturizing the sample preparation procedure. Capillary-based blood plasma separation shows promise in actualizing point-of-care diagnostic devices for applications in resource-limited settings including military camps and rural areas. In this review, the devices have been categorized based on active and passive plasma separation techniques used for the separation of plasma from capillary-driven blood sample. A comparison between different techniques used for blood plasma separation is outlined. On-chip detection of analytes present in the separated plasma obtained using some of these reported devices is also presented and discussed.     

Sample preconcentration in microfluidic devices

Microfluidic systems have attracted considerable attention and have experienced rapid growth in the past two decades due to advantages associated with miniaturization, integration, and automation. Poor detection sensitivities mainly attributed to the small dimensions of these lab-on-a-chip (LOC) devices; however, sometimes can greatly hinder their practical applications in detecting low-abundance analytes, particularly those in bio-samples. Although off-chip sample pretreatment strategies can be used to address this problem prior to analysis, they may introduce contaminants or lead to an undesirable loss of some original sample volume. Moreover, they are often time-consuming and labor-intensive. Toward the goals of automation, improvement in analytical efficiency, and reductions in sample loss and contamination, many on-chip sample preconcentration techniques based on different working principles for improving the detection sensitivity have been developed and implemented in microchips. The aim of this article is to review recent works in microchip-based sample preconcentration techniques and give detailed discussions about these techniques. We start with a brief introduction regarding the importance of preconcentration techniques in microfluidics and the classification of these techniques based on their concentration mechanisms, followed by in-depth discussions of about these techniques. Finally, personal perspectives on microfluidic-based sample preconcentration will be provided. These advancements in microfluidic sample preconcentration techniques may provide promising strategies for improving the detection sensitivities of LOC devices in many practical applications.     

Microfluidic whole-blood immunoassays

Immunoassay is one of the most widely used biomedical diagnostic methods due to its sensitivity and specificity. Microfluidic lab-on-a-chip technology has the advantages of portability, integration, and automation. The combination of these two technologies leads to a pathway for point-of-care diagnostics using the unprocessed samples such as the whole blood. This article reviews the recent advancement and the major development in the microfluidic-based whole-blood immunoassays. After a survey of the recent studies on microfluidic whole-blood immunoassays, an in-depth review about the detection methods that can be miniaturized and integrated in the immunoassay chips is provided. Point-of-care diagnostics applications require developing a fully integrated, disposable, low-cost, and handheld microfluidic device for the whole-blood immunoassay. In this regard, some comments and suggestions for future research are given.     

3D printing: an emerging tool for novel microfluidics and lab-on-a-chip applications

In the past few years, 3D printing technology has witnessed an explosive growth, penetrating various aspects of our lives. Current best-in-class 3D printers can fabricate micrometer scale objects, which has made fabrication of microfluidic devices possible. The highest achievable resolution is already at nanometer scale, which is continuing to drop. Since geometric complexity is not a concern for 3D printing, novel 3D microfluidics and lab-on-a-chip systems that are otherwise impossible to produce with traditional 2D microfabrication technology have started to emerge in recent years. In this review, we first introduce the basics of 3D printing technology for the microfluidic community and then summarize its emerging applications in creating novel microfluidic devices. We foresee widespread utilization of 3D printing for future developments in microfluidic engineering and lab-on-a-chip technology.     

无透镜微流控成像流动细胞检测与计数系统

在未来面向个人化的生物医疗诊断中,实时的细胞检测与计数具有重要需求.现有的细胞检测和计数系统例如流式细胞仪和血细胞计数器不适用于小型化流动细胞实时检测和计数.通过将CMOS图像传感器芯片和微流控芯片结合,提出了一种用于流动细胞检测和计数的无透镜微流控成像系统,与用于计数静态细胞的其它无透镜微流控成像系统不同,该系统可以通过基于时域差分的运动检测算法检测和计数微流体通道中连续流动的细胞样本.测试结果表明:该系统可以对微流控通道中流动的人体骨髓基质细胞实现自动检测和计数,并具有-6.53％的低统计错误率.该系统提供了面向未来即时应用的细胞检测和计数解决方案.     

Recent advances in optimization and game theoretic control for networked systems

The aim of this paper is to provide an overview, although unnecessarily complete, of recent advances in optimal control, optimization, and game theory for networked systems. First, the recent research results and progress in optimal control and game theory for logical domain networked systems are summarized. Then, the recent developments on networked optimization and game theory for continuous domain systems are presented afterward. Finally, after introducing some recent practical applications of optimal control and game theory on networked systems, we conclude the paper with a short discussion on future research perspectives.     

Electrokinetic mixing in microfluidic systems

The applications of electrokinetics in the development of microfluidic devices have been widely attractive in the past decade. Electrokinetic devices generally require no external mechanical moving parts and can be made portable by replacing the power supply by small battery. Therefore, electrokinetic-based microfluidic systems can serve as a viable tool in creating a lab-on-a-chip (LOC) or micro-total analysis system (μTAS) for use in biological and chemical assays. Mixing of analytes and reagents is a critical step in realizing lab-on-a-chip. This step is difficult due to the low Reynolds numbers flows in microscale devices. Hence, various schemes to enhance micro-mixing have been proposed in the past years. This review reports recent developments in the micro-mixing schemes based on DC and AC electrokinetics, including electrowetting-on-dielectric (EWOD), dielectrophoresis (DEP), and electroosmosis (EO). These electrokinetic-based mixing approaches are generally categorized as either active or passive in nature. Active mixers either use time-dependent (AC or DC field switching) or time-independent (DC field) external electric fields to achieve mixing, while passive mixers achieve mixing in DC fields simply by virtue of their geometric topology and surface properties, or electrokinetic instability flows. Typically, chaotic mixing can be achieved in some ways and is helpful to mixing under large Péclet number regimes. The overview given in this article provides a potential user or researcher of electrokinetic-based technology to select the most favorable mixing scheme for applications in the field of micro-total analysis systems.     

Microfluidic applications of functionalized magnetic particles for environmental analysis: focus on waterborne pathogen detection

The continuous surveillance of drinking water is extremely important to provide early warning of contamination and to ensure continuous supplies of healthy drinking water. Isolation and detection of a particular type of pathogen present at low concentration in a large volume of water, concentrating the analyte in a small detection volume, and removing detection inhibiting factors from the concentrated sample, present the three most important challenges for water quality monitoring laboratories. Combining advanced biological detection methods (e.g., nucleic acid-based or immunology-based protocols) with microfluidics and immunomagnetic separation techniques that exploit functionalized magnetic particles has tremendous potential for realization of an integrated system for pathogen detection, in particular, of waterborne pathogens. Taking advantage of the unique properties of magnetic particles, faster, more sensitive, and more economical diagnostic assays can be developed that can assist in the battle against microbial pathogenesis. In this review, we highlight current technologies and methods used for realization of magnetic particle-based microfluidic integrated waterborne pathogen isolation and detection systems, which have the potential to comply in future with regulatory water quality monitoring requirements.     

Applications and perspectives on microfluidic technologies in ships and marine engineering: a review

More than 71% of the earth’s surface area is occupied by ocean, and the shipping has become one of the most common forms of transportation. There are many applications for rapid on-site detection in ships and marine engineering in general. However, owing to the limited space and environmental conditions, large-scale laboratory equipment cannot be utilized on ships and offline examination methods cannot meet the needs for rapid detection and analysis of problems. Microfluidic technologies provide an excellent platform where various biological and chemical reactions can be completed on very small microfluidic chips. The combination of microfluidic technologies and ship and marine engineering will have important theoretical significance and practical value. These applications mainly include ballast water analysis, lubricating oil analysis, monitoring oil spill, ship exhaust gas detection and ship sewage detection. Therefore, in this paper, we have summarized the current applications of microfluidic technologies in ships and marine engineering and suggested prospects for the potential research directions in the future.     

Plastic Microfluidic Systems for High-Throughput Genomic Analysis and Drug Screening

Genomic analysis and drug discovery depend increasingly on rapid, accurate analysis of large sets of sample and extensive compound collections at relatively low cost. By capitalizing on advances in microfabrication, genomics, combinatorial chemistry, and assay technologies, new analytical systems are expected to provide order-of-magnitude increases in analysis throughput along with comparable decreases in per-sample analysis costs. ACLARA's single-use, plastic LabCard™ systems, which transport fluids between reservoirs and through interconnected microchannels using electrokinetic mechanisms, are intended to address these analytical needs. These devices take advantage of recent developments in microfluidic and microfabrication technologies to permit their application to DNA sequencing; genotyping and DNA fragment analysis, as well as pharmaceutical candidate screening, and preparing biological samples for analysis. In a parallel effort, ACLARA has developed a new class of reporter molecules that are particularly well suited to capillary electrophoretic analysis. These electrophoretic mobility tags, called eTag™ reporters, can be used to uniquely label multiplexed sets of oligonucleotide recognition probes or proteins, thereby permitting traditionally homogeneous biochemical reporter assays to be multiplexed for CE analysis. Biochemical multiplexing is key to achieving new thresholds in analytical throughput while maintaining economically viable formats in many application areas. ACLARA's microfluidic, lab-on-a-chip concept promises to revolutionize chemical analysis, similar to the way miniaturization revolutionized computing, making tools continually smaller, more integrated, less expensive, and higher performing.     

Bead-based polymerase chain reaction on a microchip

We present a bead-based approach to microfluidic polymerase chain reaction (PCR), enabling fluorescent detection and sample conditioning in a single microchamber. Bead-based PCR, while not extensively investigated in microchip format, has been used in a variety of bioanalytical applications in recent years. We leverage the ability of bead-based PCR to accumulate fluorescent labels following DNA amplification to explore a novel DNA detection scheme on a microchip. The microchip uses an integrated microheater and temperature sensor for rapid control of thermal cycling temperatures, while the sample is held in a microchamber fabricated from (poly)dimethylsiloxane and coated with Parylene. The effects of key bead-based PCR parameters, including annealing temperature and concentration of microbeads in the reaction mixture, are studied to achieve optimized device sensitivity and detection time. The device is capable of detecting a synthetically prepared section of the Bordetella pertussis genome in as few as 10 temperature cycles with times as short as 15?min. We then demonstrate the use of the procedure in an integrated device; capturing, amplifying, detecting, and purifying template DNA in a single microfluidic chamber. These results show that this method is an effective method of DNA detection which is easily integrated in a microfluidic device to perform additional steps such as sample pre-conditioning.     

Optofluidic integration for microanalysis

This review describes recent research in the application of optical techniques to microfluidic systems for chemical and biochemical analysis. The “lab-on-a-chip” presents great benefits in terms of reagent and sample consumption, speed, precision, and automation of analysis, and thus cost and ease of use, resulting in rapidly escalating adoption of microfluidic approaches. The use of light for detection of particles and chemical species within these systems is widespread because of the sensitivity and specificity which can be achieved, and optical trapping, manipulation and sorting of particles show significant benefits in terms of discrimination and reconfigurability. Nonetheless, the full integration of optical functions within microfluidic chips is in its infancy, and this review aims to highlight approaches, which may contribute to further miniaturisation and integration.     

Engineering microfluidic concentration gradient generators for biological applications

This paper reviews the latest developments in the design and fabrication of concentration gradient generators for microfluidics-based biological applications. New gradient generator designs and their underlying mass transport principles are discussed. The review provides a blueprint for design considerations of concentration gradients in different applications, specifically biological studies. The paper discusses the basic phenomena associated with microfluidic gradient generation and the different gradient generation modes used in static and dynamic biological assays. Finally, the paper summarizes all factors to consider when using concentration gradient generators and puts forward perspectives on the future development of these devices.     

Utilization of nanoparticles in microfluidic systems for optical detection

An increasing interest has been shown in microfluidic systems due to their properties including low consumption of reagents, short analysis time and easy integration. However, despite of these advantages over conventional methods, some limitations in sensitivity and selectivity still exist in microfluidic systems. Recently advancements in nanotechnology offer some new approaches for the detection of target analytes with high sensitivity and selectivity. As a result, it is an appropriate method to enhance the detection sensitivity through a combination between microfluidic system and nanotechnology. Optical detection is a dominant technique in microfluidics because of its noninvasive nature and easy coupling. Numerous studies that integrate optical microfluidic system with nanotechnology have been reported in recent years. Therefore, optical microfluidic systems in combination with nanomaterials (NMs) are reviewed in our work. We illustrate the functions of different NMs in optical microfluidic systems and the efforts of different researchers to improve the performance of devices. After the introduction of different nanoparticle-based optical detection methods, challenges and future directions in the development of nanoparticle-based optical detection schemes in microfluidics have also been discussed.     

Microfluidic-based biosensors toward point-of-care detection of nucleic acids and proteins

This article reviews state-of-the-art microfluidic biosensors of nucleic acids and proteins for point-of-care (POC) diagnostics. Microfluidics is capable of analyzing small sample volumes (10⁻⁹–10⁻¹⁸ l) and minimizing costly reagent consumption as well as automating sample preparation and reducing processing time. The merger of microfluidics and advanced biosensor technologies offers new promises for POC diagnostics, including high-throughput analysis, portability and disposability. However, this merger also imposes technological challenges on biosensors, such as high sensitivity and selectivity requirements with sample volumes orders of magnitude smaller than those of conventional practices, false response errors due to non-specific adsorption, and integrability with other necessary modules. There have been many prior review articles on microfluidic-based biosensors, and this review focuses on the recent progress in last 5 years. Herein, we review general technologies of DNA and protein biosensors. Then, recent advances on the coupling of the biosensors to microfluidics are highlighted. Finally, we discuss the key challenges and potential solutions for transforming microfluidic biosensors into POC diagnostic applications.     

Magnetic bead handling on-chip: new opportunities for analytical applications

This review describes recent advances in the handling and manipulation of magnetic particles in microfluidic systems. Starting from the properties of magnetic nanoparticles and microparticles, their use in magnetic separation, immuno-assays, magnetic resonance imaging, drug delivery, and hyperthermia is discussed. We then focus on new developments in magnetic manipulation, separation, transport, and detection of magnetic microparticles and nanoparticles in microfluidic systems, pointing out the advantages and prospects of these concepts for future analysis applications.