Testing and Diagnosis of Realistic Defects in Digital Microfluidic Biochips

Microfluidics-based biochips are soon expected to revolutionize biosensing, clinical diagnostics and drug discovery. Robust off-line and on-line test techniques are required to ensure system dependability as these biochips are deployed for safety-critical applications. Due to the underlying mixed-technology and mixed-energy domains, biochips exhibit unique failure mechanisms and defects. We first relate some realistic defects to fault models and observable errors. We next set up an experiment to evaluate the manifestations of electrode-short faults. Motivated by the experimental results, we present a testing and diagnosis methodology to detect catastrophic faults and locate faulty regions. The proposed method is evaluated using a biochip performing real-life multiplexed bioassays.     

数字微流控生物芯片微液滴优化调度

数字微流控生物芯片出现,使得单片并行多样品、多试剂、多生物检测量的大规模生物检测系统成为现实,需要在有限的芯片资源中优化调度各样品和试剂以减少检测时间.由于优化调度是一个NP完全问题,本文提出了以多样品检测完成时间为适应度函数,以样品和试剂混合操作类型集合为染色体,并将该染色体分别赋以一整数值代表混合操作优先级高低,同时,将染色体基因分为可同时进行混合操作而资源不冲突基因和有限任意项基因两部份,并对有限任意项基因进行移位、交叉等遗传操作,达到优化调度接近最优解.所提出算法编码基因数从(4Sm*Rn)!降低到Sm*Rn,极大改善了算法效率和并行检测所需时间.     

引脚约束的数字微流控生物芯片在线并行测试

随着数字微流控生物芯片在生化领域中的广泛应用,对芯片可靠性和制造成本的要求也越来越高,在线测试对于确保微流控生物芯片正常工作异常重要。该文针对引脚约束的数字微流控生物芯片,提出一种基于改进最大最小蚁群算法的在线并行测试方案,在满足各种约束条件的情况下,采用伪随机比例原则,建立禁忌判断策略,自适应地改变信息素的残留系数,实现引脚约束数字微流控生物芯片的在线并行测试。实验结果表明,该方法可以同时用于离线和在线测试,相对于单液滴离线和在线测试,可有效减少芯片的测试时间,提高了测试工作效率。     

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.      

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。     

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.     

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.

     

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.     

Fault Diagnosis in Lab-on-Chip Using Digital Microfluidic Logic Gates

Fault diagnosis is needed for a lab-on-chip to facilitate defect tolerance using reconfiguration. Previously proposed techniques for reading test outcomes and for pulse-sequence analysis are cumbersome and error-prone. We present a fault-diagnosis method to locate a single defective cell and multiple rows/columns with defective cells in a digital microfluidic array. The proposed method can also locate an unknown number of rows/columns-under-test with defective cells. It utilizes digital microfluidic exclusive-or gates to implement an output compactor. The microfluidic compactor can compress 2 ^r distinct test outcomes to a r-droplet signature. This approach obviates the need for capacitive sensing test-outcome circuits for analysis. We analyze the probability of misdiagnosis and use the compression ratio as a measure to evaluate the proposed fault-diagnosis method.     

Programmable Functionalization of Surfactant‐Stabilized Microfluidic Droplets via DNA‐Tags

Droplet‐based microfluidics has emerged as a powerful tool in synthetic biology. For many applications, chemical functionalization of the droplets is a key process. Therefore, a straightforward and broadly applicable approach is developed to functionalize the inner periphery of microfluidic droplets with diverse reactive groups and components. Instead of covalent modification of the droplet‐stabilizing surfactants, this method relies on cholesterol‐tagged DNA that self‐assembles at the droplet periphery. The cholesterol‐tagged DNA serves as an attachment handle for the recruitment of complementary DNA. The complementary DNA can carry diverse functional groups. We exemplify our method by demonstrating the attachment of amine groups, DNA nanostructures, microspheres, a minimal actin cortex, and leukemia cells to the droplet periphery. It is further shown that the DNA‐mediated attachment to the droplet periphery is temperature‐responsive and reversible. It is envisioned that droplet functionalization via DNA handles will help to tailor droplet interfaces for diverse applications—featuring programmable assembly, unique addressability, and stimuli‐responsiveness.     

基于介质上电润湿的数字微流控器件的模拟

根据介质上电润湿的基本理论,利用计算流体动力学软件CFD—ACE＋,成功模拟出了典型的“三明治”结构数字微流控器件中水滴输运、产生、分离和合并的全过程。模拟结果显示,上下极板间距和液滴输运速度之间呈线性关系;并且,当极板间距大于200μm时,液滴分离容易失败。模拟结果与已有的实验结果符合的非常好。     

Rapid and Controllable Digital Microfluidic Heating by Surface Acoustic Waves

Fast and controllable surface acoustic wave (SAW) driven digital microfluidic temperature changes are demonstrated. Within typical operating conditions, the direct acoustic heating effect is shown to lead to a maximum temperature increase of about 10 °C in microliter water droplets. The importance of decoupling droplets from other on‐chip heating sources is demonstrated. Acoustic‐heating‐driven temperature changes reach a highly stable steady‐state value in ≈3 s, which is an order of magnitude faster than previously published. This rise time can even be reduced to ≈150 ms by suitably tailoring the applied SAW‐power excitation profile. Moreover, this fast heating mechanism can lead to significantly higher temperature changes (over 40 °C) with higher viscosity fluids and can be of much interest for on‐chip control of biological and/or chemical reactions.     

几种诊断测试系统的简单方法

测试系统的状态是否正常关系到测试器件的准确性和测试精度。有经验的硬件工程师和软件工程师经常会发现有时测试系统虽然自诊断通过，但测试器件时却参数测试不准确、功能测试失效等。这往往叫人无从下手。本文介绍几种通过软件编程、利用简单仪表来有效的诊断测试系统的方法。     

数字传声器的测试标准及方法

分析了现行国家标准和行业标准对数字传声器的适用性及其应予修改和补充的内容,介绍了相关的数字传声器性能测试的原理及方法。     

数字视频的全面认识和分层测试

该论文由《广播与电视技术》2007年第6期、第7期、第8期刊出。主要内容包括：对数字视频的层次构架进行的全面分析，通过借用信息系统的层次模型，对高清、标清，压缩、无压缩的数字视频进行了层次模型解析，并通过对应于各层次的技术指标．针对实际工作中常见的问题和业内广泛存在的一些困惑，提出了对数字视频系统性能进行分层测试和全面考察的观点和技术思路。     

数字电缆测试标准的辨析

阐述了YD/T 1019-2001I、SO/IEC 11801-2002、TIA/EIA 568系列标准在测试数字电缆时的主要差异。通过对标准中各项核心指标的比较和分析,希望引起业界重视,提高对数字电缆测试方法以及测试标准的正确认识,走出以往的测试误区,以达到使测试人员能正确选择测试标准、避免误判的目的。