基于蚁群算法的数字微流控芯片并行测试

可靠性是数字微流控生物芯片的一项重要指标,尤其是在安全性要求较高的应用领域。因此,芯片需要在生产制造后或生化实验前进行充分测试,以排除故障,确保实验结果准确。文中针对芯片的结构故障,提出了一种基于蚁群算法的并行测试方案,实现对较大规模的数字微流控芯片进行多液滴并行测试。该方案首先将芯片模型转化为MTSP模型,并利用蚁群算法分布式计算特性搜索多组优化的测试路径,完成对数字微流控芯片实验路径的测试。实验结果表明,该方案可用于在线测试,并能有效地减少大规模芯片的测试时间,且提高了工作效率。     

数字微流控生物芯片的电极管脚控制信号处理

随着对数字微流控生物芯片的深入研究,直接寻址DMFB需要大量独立控制引脚,显著增加了产品的制造成本。文中根据液滴路由路径,产生液滴路由所经过电极的驱动序列,利用芯片中一个引脚最多所能驱动的电极数量值,对产生的电极驱动序列进行分区,对每个分区中的电极驱动序列进行比对,找出相互兼容的以此来减少控制引脚的数量。实验结果表明,该方案与交叉引用等方法相比,减少了控制引脚的数量,实现了对电极管脚控制信号的处理。     

准分子激光微加工技术结合模塑技术加工微流控芯片

利用准分子激光微加工技术与模塑技术相结合的方法制造微流控芯片。用准分子激光在玻璃基胶层上刻蚀出加工质量较高的微流控生物芯片形貌,通过电铸技术对微流控芯片进行复制,得到反向金属模具。用金属模具通过注塑成型技术用聚碳酸酯注塑出微流控芯片。系统研究了准分子激光的能量密度和工作台移动速度对胶层微通道加工质量的影响;测量并分析了激光刻蚀加工出的微流控芯片原型、电铸的反向金属模板和注塑成型后的微流控芯片的轮廓精度和表面粗糙度,上表面尺度偏差不大于2μm,底面粗糙度小于20 nm。对注塑出的微流控芯片和激光直写刻蚀的几何结构相同的微流控芯片的流动性能进行比较测试。在流速较小时,用激光微加工技术与模塑技术相结合的方法加工的微通道比准分子激光直写法所加工的微通道流动性能更好。     

数字微流控生物芯片并行测试分析和优化

针对数字微流控生物芯片阵列的并行测试过程进行建模,利用测试时间和所需检测测试液滴个数来衡量测试成本,并利用成本函数给出最优的并行测试分块方法.通过matlab分析表明:对任何规模的芯片阵列,其测试成本随着分块数的增大呈先减少后增大的趋势,而成本的最低点就是最优的并行测试分块方法.另外,在并行测试分块数小于测试成本最低点所对应的测试分块数时,测试成本随着测试时间在测试成本中所占的比重的增加而增大,随着测试所需测试的液滴数的增大而减小.而并行测试分块数大于测试成本最低点所对应的测试分块数时,测试成本随着测试时间的比重地增加而减小,随着所需测试的液滴数的增加而增大.这些结论给并行测试的优化提供了重要了依据和指导.     

太赫兹微流控芯片

大多数生物大分子和基团的振动或者转动能级处于太赫兹频段,而其生物活性在水溶液中才能表现出来,由于水对太赫兹波的强烈吸收,从而限制了太赫兹技术的推广和应用。为了研究水溶液中生物样品的反应、变化等动态特性,将太赫兹技术和微流控技术相结合,分别研究了微流控芯片上微流控沟道的尺寸,微流控芯片的材料及其制作流程,最后用去离子水对该芯片进行了初步测试,证明了该太赫兹微流控芯片的可行性。     

微流控生物芯片外部压强与流体流速的探讨

本文针对具有40个微通道的微流控生物芯片,设计了试剂进样装置,研究了几十个芯片的进样压强与芯片各微通道中流体流速之间的关系,目的是为了筛选出流速相对稳定的标准芯片,满足PCR基因扩增的需要。     

对微流控元件的多元化应用分析

微流控元件已经是现在企业及研发人员所离不开的设备,它具有液体流动可控、消耗试样和试剂极少、分析速度成十倍上百倍地提高等特点,且它可以在几分钟甚至更短的时间内进行上百个样品的同时分析,并且可以在线实现样品的预处理及分析全过程。本文即以微流控芯片为基础,讲解了微流控芯片在生命科学领域、化学领域、医学领域的应用。     

基于微流控技术的数字PCR的发展及其应用

作为一种新兴的扩增检测技术,基于微流控的数字聚合酶链式反应(PCR)有着高通量、高灵敏度及高耐受性等优势,因而得到了研究者的广泛关注,其相关技术也在不断的发展中。综述了基于微流控的数字PCR的研究进展,重点讨论了基于微流控的数字PCR的液滴打印技术、多层微流控芯片技术、微珠技术、聚二甲基硅氧烷(PDMS)技术等的不同实现方式。介绍了基于微流控的数字PCR在定量检测、精准分子诊断、肿瘤个性化诊断以及食品安全检测中的应用。最后,对基于微流控的数字PCR技术目前存在的不足和问题进行了阐述,并对其未来的研究方向和发展趋势进行了展望。     

微流控拉曼检测芯片的制备与应用

微流控芯片系统具有高效率、低损耗、高安全系数、高灵敏度等优势,表面增强拉曼散射(SERS)光谱具有灵敏度高以及指纹效应强等优点。从两方面对微流控拉曼检测芯片进行综述:微流控芯片通道和SERS基底的制备以及微流控拉曼检测芯片的集成与应用。最后讨论了SERS微流控芯片在便携化应用方面的挑战和机遇,并对整个领域的未来发展方向与前景进行了展望。     

飞秒激光直写技术制备功能化微流控芯片研究进展

飞秒激光具有独特的超短脉宽和极高的峰值强度,飞秒激光直写技术已广泛用于功能化微流控芯片的制备。从3个方面针对基于飞秒激光直写技术的微流控芯片进行综述:不同材料微流控芯片中的飞秒激光功能器件集成技术、飞秒激光集成微流控芯片的多功能应用以及微流控芯片的高效率飞秒激光加工技术。通过对飞秒激光直写技术在微流控领域的研究结果进行总结与归纳,为飞秒激光直写技术制备微流控芯片的研究、应用及发展方向提供参考。     

On-Line Test of Pin-Constrained Digital Microfluidic Biochips with Connect-5 Structure

Digital microfluidic biochips (DMFBs) are widely used in the field of biochemistry. Effective off-line and on-line test for the biochips are required to ensure the system reliability. For direct addressing digital microfluidic biochips (DDMFBs), each control pin corresponds to only one electrode, and that can facilitate the testing of such biochips. However, in pin-constrained digital microfluidic biochips (PDMFBs), multiple electrodes may share one control pin, and thus the testing will be more difficult. In this paper, the pin constraint formula for PDMFBs with connect-5 structure is derived. A novel pin assignment scheme is also proposed, which can conduct on-line test that rarely considered by the previous methods. Furthermore, a hybrid method combining the priority strategy and genetic algorithm is introduced for the on-line test of pin-constrained digital microfluidic biochip with connect-5 structure. The simulation results show that the shortest test path acquired by the proposed method is equal to the optimal value of Euler path, which indicates that the method can effectively implement the on-line test of PDMFBs with connect-5 structure.

     

Test Planning in Digital Microfluidic Biochips Using Efficient Eulerization Techniques

Digital microfluidic technology is now being extensively used for implementing a lab-on-a-chip. Microfluidic biochips are often used for safety-critical applications, clinical diagnosis, and for genome analysis. Thus, devising effective and faster testing methodologies to warrant correct operations of these devices after manufacture and during bioassay operations, is very much needed. In this paper, we propose an Euler tour based technique to obtain the route plan of a test droplet for the purpose of structural testing of biochips. The method is applicable to various digital microfluidic biochip architectures, e.g., fully reconfigurable arrays, application specific biochips, pin-constrained irregular geometry biochips, and to defect-tolerant biochips. We show that in general, the optimal Eulerization and subsequent determination of an Euler tour in the graph model of a biochip can be abstracted in terms of the classical Chinese postman problem. The Euler tour can be identified by running the classical Hierholzer’s algorithm, which relies on a simple cycle decomposition and splicing method. This improved Eulerization technique leads to an efficient test plan for the chip. This can also be used in phase-based test planning that yields savings in testing time. The method provides a unified approach towards structural testing and can be easily adopted to design a droplet routing procedure for functional testing of digital microfluidic biochips.     

Testing and Diagnosis of Digital Microfluidic Biochips using Multiple Droplets

Digital microfluidic biochip is a promising alternative to the traditional cumbersome laboratory equipment. Such automated biochips are used in many critical applications. Hence dependability is an essential attribute before the chip is in use. Due to mixed integration technologies, these chips have some unique failures. Hence robust offline and online tests are proposed to check the health of the biochips. When a chip undergoes a test in offline mode, then the entire biochip should be available for testing, whereas for the online mode test droplet might be stalled due to unavailability of the next cell in the routing path. However, in both the scenarios one or more droplets route across the chip and the arrival time is also recorded at the destination. So here we have proposed two test schemes to know the correctness of any biochip. Diagnosability is an important feature to find the exact position of the faulty electrode. Our proposed scheme reduces the overall testing and diagnosis time significantly. It also provides an alternative routing path in biochip for fault tolerance.

     

Testing of Low-cost Digital Microfluidic Biochips with Non-Regular Array Layouts

Digital microfluidic biochips with non-regular arrays are of interest for clinical diagnostic applications in a cost-sensitive market segment. Previous techniques for biochip testing are limited to regular microfluidic arrays. We present an automatic test pattern generation (ATPG) method for non-regular digital microfluidic chips. The ATPG method can generate test patterns to detect catastrophic defects in non-regular arrays where the full reconfigurability of the digital microfluidic platform is not utilized. It automates test-stimulus design and test-resource selection, in order to minimize the test application time. We also present an integer linear programming model for the compaction of test patterns, while maintaining the desired fault coverage. We utilize two fabricated biochips with non-regular microfluidic arrays to evaluate the proposed ATPG method.     

Offline Error Detection in MEDA-Based Digital Microfluidic Biochips Using Oscillation-Based Testing Methodology

Digital microfluidics is an emerging class of lab-on-a-chip system. Reliability is a critical performance parameter as these biochips are employed in various safety-critical biomedical applications. With the introduction of highly scalable, reconfigurable and field programmable Micro-Electrode-Dot-Array (MEDA) architecture, the limitation of conventional DMFBs in varying the droplet size/volume in fine grain manner has been resolved. However, the MEDA-based biochips must be adequately tested upon fabrication to guarantee the correctness of bioassays. In this work, an offline testing approach based on Oscillation-Based Testing (OBT) methodology is presented for MEDA-based digital microfluidic biochips. Various simulations were performed for droplet-electrode short fault model involving single and multiple micro-electrodes. Furthermore, the loss of droplet volume due to the presence of defect was analyzed using COMSOL Multiphysics. The simulation results based on PSpice and COMSOL show that the proposed approach is effective for detecting defects in MEDA-based biochips.     

Design Automation and Test Solutions for Digital Microfluidic Biochips

Microfluidics-based biochips are revolutionizing high-throughput sequencing, parallel immunoassays, blood chemistry for clinical diagnostics, and drug discovery. These devices enable the precise control of nanoliter volumes of biochemical samples and reagents. They combine electronics with biology, and they integrate various bioassay operations, such as sample preparation, analysis, separation, and detection. Compared to conventional laboratory procedures, which are cumbersome and expensive, miniaturized biochips offer the advantages of higher sensitivity, lower cost due to smaller sample and reagent volumes, system integration, and less likelihood of human error. This tutorial paper provides an overview of droplet-based “digital” microfluidic biochips. It describes emerging computer-aided design (CAD) tools for the automated synthesis and optimization of biochips from bioassay protocols. Recent advances in fluidic-operation scheduling, module placement, droplet routing, pin-constrained chip design, and testing are presented. These CAD techniques allow biochip users to concentrate on the development of nanoscale bioassays, leaving chip optimization and implementation details to design-automation tools.      

Scheduling algorithms for reservoir- and mixer-aware sample preparation with microfluidic biochips

In recent years, microfluidic biochips are being dominantly used for implementing a wide range of biochemical laboratory protocols (bioprotocols) on hand-held devices. Accurate preparation of fluid-samples is a fundamental preprocessing step that is needed in many bioprotocols. Oftentimes, for point-of-service microfluidic devices, the number of reservoirs built on-chip may be far less than that of the reactant fluids to be used in an assay. Hence, during the execution of an assay, several fluids are to be unloaded from the reservoirs to make room for loading new fluids stored off-line. Such unload-wash-load steps (switching) may be required several times, and these steps, being manual, significantly impact assay-completion time. In this paper, we address the problem of biochemical mixture preparation and propose Reservoir- and Mixer-constrained Scheduling (RMS) algorithm that executes a given mixing tree aiming to minimize the number of reactant-switching from input reservoirs. We also consider certain constraints on the availability of concurrent mixing modules. The proposed scheduling scheme can not only be applied to a number of mixture preparation algorithms but also to a general class of microfluidic devices such as digital, paper-based, and flow-based biochips. Simulation results over a large number of target ratios show that given the mixing trees obtained by standard mixing algorithms such as MinMix/RMA/CoDOS, RMS reduces switching steps (on average by 40.3%/41.9%/33%) at the cost of increasing mixing time (by only 3.5%/6.2%/4.8%), compared to an existing scheduling scheme invoked with reservoir constraints.     

Tabu search-based synthesis of digital microfluidic biochips with dynamically reconfigurable non-rectangular devices

Microfluidic biochips are replacing the conventional biochemical analyzers, and are able to integrate on-chip all the necessary functions for biochemical analysis. The “digital” microfluidic biochips are manipulating liquids not as a continuous flow, but as discrete droplets, and hence they are highly reconfigurable and scalable. A digital biochip is composed of a two-dimensional array of cells, together with reservoirs for storing the samples and reagents. Several adjacent cells are dynamically grouped to form a virtual device, on which operations are performed. So far, researchers have assumed that throughout its execution, an operation is performed on a rectangular virtual device, whose position remains fixed. However, during the execution of an operation, the virtual device can be reconfigured to occupy a different group of cells on the array, forming any shape, not necessarily rectangular. In this paper, we present a Tabu Search metaheuristic for the synthesis of digital microfluidic biochips, which, starting from a biochemical application and a given biochip architecture, determines the allocation, resource binding, scheduling and placement of the operations in the application. In our approach, we consider changing the device to which an operation is bound during its execution, to improve the completion time of the biochemical application. Moreover, we devise an analytical method for determining the completion time of an operation on a device of any given shape. The proposed heuristic has been evaluated using a real-life case study and ten synthetic benchmarks.