A deep-reinforcement learning approach for optimizing homogeneous droplet routing in digital microfluidic biochips

Over the past two decades,digital microfluidic biochips have been in much demand for safety-critical and biomedical applications and increasingly important in point-of-care analysis,drug discovery,and immunoassays,among other areas.However,for complex bioassays,finding routes for the transportation of droplets in an electrowetting-on-dielectric digital biochip while maintaining their discreteness is a challenging task.In this study,we propose a deep reinforcement learning-based droplet routing technique for digital microfluidic biochips.The technique is implemented on a distributed architecture to optimize the possible paths for predefined source–target pairs of droplets.The actors of the technique calculate the possible routes of the source–target pairs and store the experience in a replay buffer,and the learner fetches the experiences and updates the routing paths.The proposed algorithm was applied to benchmark suitesⅠand Ⅲ as two different test benches,and it achieved significant improvements over state-of-the-art techniques.

Evaluation of specific fecal protein biochips for the diagnosis of colorectal cancer

AIM: To develop and initially test a potential fecal protein biochip for the screening of colorectal cancer(CRC). METHODS: Fecal protein from 20 colorectal cancer patients and 20 healthy controls were extracted from all of the fecal samples and screened for proteomic differences using a Biotin label-based protein array. Candidate proteins were then verified by ELISA. Finally, we will select out the significant protein and a seven-target multiplex fecal protein biochip was generated and tested for 20 fecal samples to determine the effectiveness of the biochip on identifying CRC. And the value of the protein biochip would be discussed. RESULTS: After tested by protein biochip of the fecal protein from 20 colorectal cancer patients and 20 healthy controls and levels of calprotectin, M2-pyruvatekinase, angiopoietin-2, fibroblast growth factor-23(FGF-23), proteins of the matrix metalloproteinase, thrombopoietin(TPO) and interleukin-13(IL-13) were significantly different between CRC and healthy controls. The sensitivity of all the seven proteins combined was 0.7, specificity was 0.4, and area under the receiver operating characteristics was 0.729. The most promising combinations of test proteins were FGF-23, TPO, and IL-13, reaching a sensitivity of 0.7 and a specificity of 0.7. The combination of FGF-23 and TPO scored highest with sensitivity of 0.7 and specificity of 0.8. Its mean that the combination of FGF-23 and TPO has the highest value for the diagnosis of CRC in our study. CONCLUSION: A protein biochip composed of proteins found to be elevated in the feces of colorectal cancer patients has great potential as a noninvasive diagnostic for colorectal cancer. The addition of new protein biomarkers and technologies, as they are discovered, is an excellent avenue of future research.

Biosensors and Biochips Based on BioMEMS and Nanotechnology

In the past two decades,the biological and medical fields have seen great advances in the development of biosensors and bioehips capable of characterizing and quantifying biomolecules.This lecture is meant to discuss the development and applications of advanced electroanalysis,biophotonics,nanotechnology,MEMS- based biosensors and biochips for biomedical diagnostics and physical performances of athlete.

A novel strategy for in situ maskless synthesis of biochips:Self-driving micro-fluid porous type printing (SMPTP)

A novel maskless technique, self-driving micro-fluid porous type printing （SMPTP）, was reported to in situ synthesize oligonucleotide arrays on glass slide, which has the merits of low cost, high quality and simple craft. In SMPTP for fabricating gene- chips, porous fiber tubes with a number of nanometric or micron channels functioned as ＂active letters＂ and were assembled in designed patterns, which are identical to the distribution of monomers in each layer of the array, and four patterns were needed for each layer. By means of capillarity, the synthesis solution was automatically taken into porous tubes assembled in a printing plate and reached the surface. An oligonucleotide array of 160 features with four different 15-mer probes was in situ synthesized using this technique. The four specific oligonucleotide probes, including the matched and the mismatched by the fluorescent target sequence, gave obviously different hybridization fluorescent signals.

A NOVEL TECHNIQUE FOR MULTIPLE FAULTS AND THEIR LOCATIONS DETECTION AND START ELECTRODE SELECTION IN MICROFLUIDIC DIGITAL BIOCHIP

A device,that is used for biomedical operation or safety-critical applications like point-of-care health asssment,massive parallel DNA analysis,automated drug discovery,air-quality monitoring and food-safety testing,must have the attributes like relia bility,dependability and correctness.As the biochips are used for these purposes;therefore,these devices must be fault free all the time.Naturally before usi ng these chips,they must be well tested.We are proposing a novel technique that can detect mutiple fults,locate the fault positions within the biochip,as well as calculate the traversal time if the biochip is fault free.The proposed technique also highlights a new idea how to select the appropriate base node or pseudo source(start electrode).The main idea of the proposed technique is to form multiple loops with the neighboring electrode arrays and then test each loop by traversing test droplet to check whether there is any fault.If a fault is detected then the propoed technique also locates it by backtracking the test droplet.In case,no fault is detected,the biochip is fault free then the proposed technique also calculates the time to traverse the chip.The result suggests that the proposed technique is eficient and shows significant improvement to ca lculate fault-free biochip traversal time over existing method.

Preface for advances in biochips

Biochip is essentially a bio-microarray device that can perform hundreds or thousands of simultaneous biochemical reactions.[1, 2] It offers the researchers a new way for large-scale genomic, proteomic and functional genomic analyses. The biochips also enable people to quickly screen large numbers of biological analyses for many different purposes, from disease diagnosis to detection of bioterrorism chemical agents.[3]

A multifunctional integrated simultaneously online screening microfluidic biochip for the examination of “efficacy-toxicity” and compatibility of medicine

A multifunctional integrated microfluidic biochip device was engineered to estimate the activity-toxicity and composition principle of medicine in a cell model in vitro. This biochip could be used for disease cells and healthy cells in two modules of "Yin-Yang" on the same chip for detecting the medicine efficacytoxicity simultaneously, as well as adjust different gradient ratios of concentration through the Christmas tree structure in both "Yin-Yang" modules autonomously for detecting the best compatibility of medicine in maximum efficacy and minimal toxicity. In the applicability experiment, the best concentration of three chemical compounds including dinatin, diosmetin and cisplatin, were detected using the biochip and traditional 96-cell plate. Biochip assays showed perfect positive correlation compared with the results of traditional 96-cell plate, in addition presented advantages as less detection time and much lower price than the traditional 96-cell plate, which indicated the biochip is both convenient and feasible.Thus, the novel microfluidic chip-based multifunctional integrated system congregated the virtues of high throughput, rapid, sensitive, specific, cost-effective, and similar to the physical environment of the human body, which was especially suitable for the medicine efficacy-toxicity and compatibility evaluation.

生物芯片技术在食品检验中的应用研究

随着食品安全问题日益受到关注,生物芯片技术作为一种高效、高通量的检测方法,在食品检验中展现出广阔的应用前景。本文综述了生物芯片技术的原理及其在食品检验中的应用,并探讨了其面临的挑战与未来发展前景。

致病性弧菌检测新技术研究进展

随着人们对水产品需求的增加及致病性弧菌引发的食源性疾病的流行,致病性弧菌对水产养殖业及人类健康造成了巨大威胁,基于此,致病性弧菌检测新技术的开发变得尤为迫切。本文介绍了包括免疫学方法、核酸检测方法、基于生物芯片的检测方法、基于核酸适配体的检测方法、基于肽质量指纹图谱技术的检测方法、基于生物传感器技术的检测方法在内的6项检测技术,分析了其优缺点及其在致病性弧菌中的应用。最后,总结了致病性弧菌检测新技术的研究现状,结合新兴技术指出未来研究方向,为致病性弧菌的快速检测提供参考。

p16INK4a联合人乳头瘤病毒及液基细胞学检查在宫颈上皮内瘤变临床诊断中的应用

目的分析p16INK4a蛋白、人乳头瘤病毒及液基细胞学检查(LCT)在宫颈癌前病变筛查中的检测效率,为宫颈癌的预防和治疗提供依据。方法分析2019年1月—2020年6月广州市妇女儿童医疗中心的139例住院患者的宫颈上皮细胞p16INK4a染色、人乳头瘤病毒检测及宫颈细胞学检测结果。这些病例包括111例宫颈上皮内瘤变(CIN)患者和28例宫颈炎性疾病患者。比较三种方法单独及联合应用筛查CIN病变的效能。结果在对CIN患者的检测中,p16INK4a、生物微流控芯片和宫颈细胞学检测CIN及以上病变的灵敏度分别为91.89%、94.59%和78.20%,特异度分别为57.14%、17.86%和46.43%,AUC分别为0.75、0.56和0.66。而“p16INK4a+LCT”、“p16INK4a+hrHPV”、“LCT+hrHPV”以及三种方法联合检测的灵敏度分别为96.40%、97.30%、94.59%和99.10%,特异度分别为85.71%、92.86%、89.29%和92.86%,AUC分别为0.91、0.95、0.92和0.96。结论p16INK4a和hrHPV联合检测有助于提高诊断的准确性和早期发现率,从而使得能更早进行干预或治疗。通过这种联合应用,可以更准确地鉴别出低级别和高级别的宫颈上皮内瘤变,为个性化的病患管理提供更多信息。

Optimum Combined Lenses for Confocal Biochip Scanning System

Laboratory on a chip technology has attracted wide interest in recent years, where the sample preparation, bio chemical reaction, separation, detection and analysis are performed in a small biochip of the size of a fingernail. To obtain a high detection sensitivity of 1 fluors/μm 2 (one fluorescence molecule per square micrometer) in biochip scanning systems, the scanning objective lens is required to have a high numerical aperture (>0.5), very small focal spot (<5 μm), and long back focal length (>3 mm). This study presents the design of optimum combined lenses including scanning objective and fluorescence focal lenses. The scanning objective had a high numerical aperture (NA) of 0.72, a very small focal spot of 1.67 μm, a long back focal length of 3.2 mm, and a high resolving power of 760 lines/mm. The fluorescence focal lenses had an NA of 0.3, a fluorescence focal spot of 16 μm, a long back focal length of 16.7 mm and a resolving power of 590 lines/mm. The phase aberrations of the combined lenses, including the aspherical aberration and the chromatic aberration corresponding to wavelengths of 532, 570, 635, and 670 nm, were well corrected. The encircled energy diagram of the lenses was within the diffraction limit. The study also included the focal spot diagram, the optical path difference diagram, the transverse ray fan plot, and the modulation transfer function. A confocal biochip scanning system with designed combined lenses was developed and some experiments were conducted on a multi channel biochip.

MODELING,SIMULATION,AND OPTIMIZATION OF SURFACE ACOUSTIC WAVE DRIVEN MICROFLUIDIC BIOCHIPS

We will be concerned with the mathematical modeling, numerical simulation, and shape optimization of micro fluidic biochips that are used for various biomedical applications. A particular feature is that the fluid flow in the fluidic network on top of the biochips is in- duced by surface acoustic waves generated by interdigital transducers. We are thus faced with a multiphysics problem that will be modeled by coupling the equations of piezoelectricity with the compressible Navier-Stokes equations. Moreover, the fluid flow exhibits a multiscale character that will be taken care of by a homogenization approach. We will discuss and analyze the mathematical models and deal with their numerical solution by space-time discretizations featuring appropriate finite element approximations with respect to hierarchies of simplicial triangulations of the underlying computational domains. Simulation results will be given for the propagation of the surface acoustic waves on top of the piezoelectric substrate and for the induced fluid flow in the microchannels of the fluidic network. The performance of the operational behavior of the biochips can be significantly improved by shape optimization. In particular, for such purposes we present a multilevel interior point method relying on a predictor-corrector strategy with an adaptive choice of the continuation steplength along the barrier path. As a specific example, we will consider the shape optimization of pressure driven capillary barriers between microchannels and reservoirs.

基于生物芯片技术的生乳中兽药检测方法验证及其应用

为验证生物芯片技术在生乳兽药检测方面的效果并进行推广应用,针对80种常见兽药,采用生物芯片快速检测法对生乳样品进行检测,并同时采用高效液相色谱-串联质谱(high performance liquid chromatographytandem mass spectrometry,HPLC-MS/MS)法确认。结果表明:生物芯片法检出限符合国家标准检出限要求,且部分优于国家标准;该方法线性范围较宽,相关系数均>0.99,线性范围内呈良好的相关性;通过阴性样品加标回收实验,对加入2倍与4倍检出限的标准样品进行测定,加标回收率为70%~130%,变异系数为5%~10%;该方法前处理简单、检测周期短、灵敏度高、通量大,适合大批量样品的快速筛查。利用以上方法对2022—2023年采自上海辖区内的100批次生乳进行检测发现,含有兽药残留的生乳共10批,其中链霉素检出4批(检出值5.86~10.26μg/kg),磺胺吡啶检出3批(检出值1.09~1.42μg/kg),磺胺间二甲氧嘧啶检出2批(检出值1.38~1.46μg/kg),阿维菌素检出1批(检出值1.75μg/kg),经过国标方法确证,以上检出值均远低于国际组织、农业农村部公告或国家标准限量规定。生物芯片法相较于传统的HPLC-MS/MS法具有灵敏度高、线性范围宽和检测速度快等优势,可作为生乳兽药残留快速检测的补充手段,具有较高的应用价值。

The Experiment and Design of Confocal Laser Scanner for Biochip

In this article ,we chiefly discuss optical part and photoelectrical part, and analyze the result data to make out the relationship between pinhole and special resolution and the influence of PMT on the result data.

循环水养殖系统中3种生物填料的挂膜、微生物群落组成及对大口黑鲈生长的影响

为探索大口黑鲈循环水养殖系统中适宜的水处理生物填料,以方形海绵、Mutag Biochip 30和流化球生物填料为研究对象,以初始体质量为(20.46±0.46)g的大口黑鲈为养殖对象,分析生物填料的挂膜时间及微生物群落组成,并评估大口黑鲈的生长情况。结果表明,自然挂膜条件下,3种生物填料的挂膜时间为17~21 d。16S rDNA高通量测序结果表明,在门水平,填料生物膜和对应养殖水体中的细菌微生物群落优势菌相同,均为变形菌门(Proteobacteria)、放线菌门(Actinobacteriota);在属水平,生物填料和对应养殖水体中细菌微生物群落组成有所差异,养殖水体的优势菌为雷夫松氏菌(Leifsonia)、Incertae_sedis,而生物填料的生物膜中,热单胞菌属(Thermomonas)是方形海绵组的优势菌,Mutag Biochip 30和流化球组的优势菌相同,为硝化螺旋菌属(Nitrospira)。养殖试验结果表明,经过44 d养殖,方形海绵组大口黑鲈的末体质量、增重率显著高于其他试验组,饲料系数显著低于Mutag Biochip 30组,不同生物填料组大口黑鲈的存活率无显著差异。综上,在短期内,方形海绵是一种较为实用的循环水养殖水处理生物填料。

Nanoscale 3D Printing Technique Uses Micro-Pyramids to Build Better Biochips

This nanoprinting process allows researchers to 3D print more material on a biochip than ever before,making it easier to study biomedical issues.Making biochips,a key technology in studying disease,just got a little easier.This new nanoprinting process?uses gold-plated pyramids,an LED light,and photochemical reactions to print more organic material on the surface of one single biochip than ever before.The technique uses an array of polymer pyramids that are covered in gold and mounted onto an atomic force mi-

Research and applications of biochip technologies

Biochip as a new research field has enjoyed its rapid development in the past 10 years. Using microfabrication technology, thousands or hundred thousands of biological molecules can be assembled on a centimeter square microchip. Those chip-based devices can be used to analyze mutations, antigens, cells, etc. Compared with the traditional analytical instruments, chip-based micro total analytical systems have many advantages, such as reduced size, lower consumption of both reagents and energy contamination-free, etc. Biochip technology is believed to revolutionize the future research in life sciences, disease diagnosis, drug discovery forensic sciences and outer space exploitation in the coming

High hydrosilylation efficiency of porous silicon SiHx species produced by Pt-assisted chemical etching for biochip fabrication

Porous silicon (PSi) prepared from Pt metal-assisted chemical etching (MaCE) was demonstrated to possess higher hydrosilylation efficiency (～57%) than anodized PSi (～11%) by surface reaction with ω-undecenyl alcohol (UO).Deconvolution of the SiHx (x=1-3) stretching bands revealed the abundance of SiH 2 species on MaCE PSi was 53%,～10% higher than on anodized samples,while both of SiH 1 and SiH 3 were ～5% lower correspondently on MaCE PSi than on anodized samples.The surface SiHx abundances were suggested to account for the higher hydrosilylation efficiency on MaCE PSi.Optimization of Pt-assisted chemical etching parameters suggested a 7-15 nm thick Pt-coating and an etching time of 3-10 min for biochip applications.Scanning electron microscopy images revealed that an isotropic top meso-porous layer was beneficial for hydrosilylation and long-term durability under ambient conditions.To end,an example of histidine-tagged protein immobilization and microarray was illustrated.Combining the materials' property,surface chemistry,and micro-fabrication technology together,we envision that silicon based biochip applications have a prosperous future.

连续微流控生物芯片下一种多阶段启发式的流层物理协同设计算法

为了提高连续微流控生物芯片(CFMBs)中的流层物理协同设计质量和效率,该文分3阶段实现布局布线协同设计。(1)布局预处理阶段:通过提出的逻辑布局和组件方向布局调整方法,得到组件优异的逻辑位置和逻辑方向。(2)组件映射和包围盒间隙布局调整阶段:基于包围盒策略,把布局预处理结果映射到实际物理设计空间中,并通过包围盒间隙布局调整,获得最佳包围盒间隙。(3)收缩布局调整阶段:基于组件间的连通图关系,提出了沿流通道收缩和多图收缩两种新的布局调整方法。实验结果表明,与现有最佳的启发式算法对比,该文算法在芯片流层整体面积、流通道交叉点数和流通道总长度上分别优化20.22%,54.66%和71.62%,加速比为177.12,显著提升了设计质量和效率。