A CMOS-compatible DNA microarray using optical detection together with a highly sensitive nanometallic particle protocol

In this paper, we present a fully CMOS-compatible optical deoxyribonucleic acid (DNA) microarray based on a nanometallic particle detection protocol. Silver-enhanced gold nanoparticle binding in the DNA sample induces opacity, instead of fluorescence, of matching DNA strands on the microarray. The active pixel sensor CMOS chip transduces opacity to electrical form for random-access readout. This system has many unique features, including 1) it is fully compatible with the mainstream standard CMOS technology; 2) its use eliminates the costly external optical scanner; and 3) it is capable of working under ordinary light sources instead of bulky and highly specific UV light sources. Experimental results on the system demonstrate high sensitivity, with concentrations as low as 10 pM detected.     

High-density matrix-addressable AlInGaN-based 368-nm microarray light-emitting diodes

We report on the fabrication of ultraviolet (UV) microarray light-emitting diodes, toward applications including mask-free photolithographic exposure. Devices with 64 /spl times/ 64 elements have been fabricated in matrix-addressed format, generating directed output powers of up to 1 /spl mu/W per 20-/spl mu/m-diameter element at less than 1.0-mA drive current. The resistance of each elemental device was found to depend strongly on the n-GaN stripe length. The center wavelength of the emission was measured to be 368 nm, which is very close to that of an i-line (365 nm) UV light source. To our knowledge, this is the first report detailing the fabrication and performance of such devices operating in the UV.     

DNA analysis by single molecule stretching in nanofluidic biochips

Stretching single DNA molecules by confinement in nanofluidic channels has attracted a great interest during the last few years as a DNA analysis tool. We have designed and fabricated a sealed micro/nanofluidic device for DNA stretching applications, based on the use of the high throughput NanoImprint Lithography (NIL) technology combined with a conventional anodic bonding of the silicon base and Pyrex cover. Using this chip, we have performed single molecule imaging on a bench-top fluorescent microscope system. Lambda phage DNA was used as a model sample to characterize the chip. Single molecules of λ-DNA stained with the fluorescent dye YOYO-1 were stretched in the nanochannel array and the experimental results were analysed to determine the extension factor of the DNA in the chip and the geometrical average of the nanochannel inner diameter. The determination of the extension ratio of the chip provides a method to determining DNA size. The results of this work prove that the developed fabrication process is a good alternative for the fabrication of single molecule DNA biochips and it allows developing a variety of innovative bio/chemical sensors based on single-molecule DNA sequencing devices.     

TMABoost: an integrated system for comprehensive management of tissue microarray data.

In the last decade, high-throughput technologies such as DNA and tissue microarrays (TMAs) have become a means of large-scale investigation of gene expression, providing a plethora of new biomedical data in a relatively short time. Data collection and organization are critical aspects in this process to ensure the quality and reliability of future data interpretation. In this work, we propose a comprehensive approach to handle TMA data with the aim of supporting and promoting biomarker development. We describe a web-based system for the complete management of tissue microarray data in the field of pathology. The system has been in use since June, 2003. Our approach includes automatic localization and identification of tissue microarray samples, and quantitative image analysis that allows high-throughput screening of TMAs by ensuring nonsubjective measures and novel prognosis associations. In this paper, we present the architecture and the components of this system.     

Real-time processing and compression of DNA microarray images.

In this paper, we present a pipeline architecture specifically designed to process and compress DNA microarray images. Many of the pixilated image generation methods produce one row of the image at a time. This property is fully exploited by the proposed pipeline that takes in one row of the produced image at each clock pulse and performs the necessary image processing steps on it. This will remove the present need for sluggish software routines that are considered a major bottleneck in the microarray technology. Moreover, two different structures are proposed for compressing DNA microarray images. The proposed architecture is proved to be highly modular, scalable, and suited for a standard cell VLSI implementation.     

Autoregressive-Model-Based Missing Value Estimation for DNA Microarray Time Series Data

Missing value estimation is important in DNA microarray data analysis. A number of algorithms have been developed to solve this problem, but they have several limitations. Most existing algorithms are not able to deal with the situation where a particular time point (column) of the data is missing entirely. In this paper, we present an autoregressive-model-based missing value estimation method (ARLSimpute) that takes into account the dynamic property of microarray temporal data and the local similarity structures in the data. ARLSimpute is especially effective for the situation where a particular time point contains many missing values or where the entire time point is missing. Experiment results suggest that our proposed algorithm is an accurate missing value estimator in comparison with other imputation methods on simulated as well as real microarray time series datasets.     

A Magnetically Actuated Resonant Mass Sensor With Integrated Optical Readout

Nickel cantilevers with integrated diffraction gratings are used as resonant mass sensors with a resolution of 500 femtograms. Their applicability to biosensing is demonstrated with human opioid receptors. The device is fabricated through a single-mask lithographic process. The microoptical readout provides a simple measurement platform with one external photodiode. Thanks to its ac operation principle, the device is immune to environmental noise and entails a high tolerance to fabrication defects. Obtained signal-to-noise ratio is comparable to that of a high-end Doppler vibrometer. The device with these aspects for systems integration and microarray technology is a candidate for low-cost portable sensors.      

用于微阵列数据分类的子空间融合演化超网络

针对传统模式识别方法在学习具有小样本特性的DNA微阵列数据时存在的过拟合问题,本文提出了一种子空间融合演化超网络模型.该模型通过子空间划分、超边全覆盖和子空间融合三种方法降低模型对初始化的依赖,减少了对数据空间的拟合误差,提高了演化超网络的泛化能力.对四个DNA微阵列数据集的实验结果表明,子空间融合演化超网络的识别率和在小样本训练集下的泛化能力均优于参与对比的其他传统模式识别方法.     

Self-assembly for microscale and nanoscale packaging: steps toward self-packaging

The packaging of microelectromechanical systems (MEMS) and nanoscale devices constitutes an important area of research and development that is vital to the commercialization of such devices. Packaging needs of these devices include interfaces to nonelectronic domains; integration of structures, devices, and subsystems made with incompatible fabrication processes into a single platform; and the ability to handle a very large numbers of parts. Although serial, robotic assembly methods such as pick-and-place have allowed significant manufacturing feats, self-assembly is an attractive option to tackle packaging issues as the size of individual parts decreases below 300 /spl mu/m. In this paper, we review advances made in the usage of self-assembly for packaging and potential directions that growth in this area can assume. In the micrometer scale, we review the use of capillary forces, gravity, shape recognition, and electric fields to guide two- and three-dimensional self-assembly processes. In the nanoscale, we survey the usage of self-assembled molecular monolayers to solve current packaging issues, DNA hybridization for guiding self-assembly processes of nanoscale devices, and methods used to package nanowires or nanotubes into electronic circuits. We conclude with an example of a nanoscale biosensor which directly incorporates the concept of its package into its fabrication process. Even though the idea of a fully self-packaging system has not been demonstrated to date, the body of work reviewed and discussed here presents a solid foundation for the pursuit of this goal.     

Large‐Area Fabrication of Periodic Arrays of Nanoholes in Metal Films and Their Application in Biosensing and Plasmonic‐Enhanced Photovoltaics

Plasmonics is a fast developing research area with a great potential for practical applications. However, the implementation of plasmonic devices requires low cost methodologies for the fabrication of organized metallic nanostructures that covers a relative large area (～1 cm²). Here the patterning of periodic arrays of nanoholes (PANHs) in gold films by using a combination of interference lithography, metal deposition, and lift off is reported. The setup allows the fabrication of periodic nanostructures with hole diameters ranging from 110 to 1000 nm, for 450 and 1800 nm of periodicity, respectively. The large areas plasmonic substrates consist of 2 cm × 2 cm gold films homogeneously covered by nanoholes and gold films patterned with a regular microarray of 200 μm diameter circular patches of PANHs. The microarray format is used for surface plasmon resonance (SPR) imaging and its potential for applications in multiplex biosensing is demonstrated. The gold films homogeneously covered by nanoholes are useful as electrodes in a thin layer organic photovoltaic. This is first example of a large area plasmonic solar cell with organized nanostructures. The fabrication approach reported here is a good candidate for the industrial‐scale production of metallic substrates for plasmonic applications in photovoltaics and biosensing.     

A Hybrid Carrier System Based on Origami Nanostrucutures and Layer‐by‐Layer Microparticles

Recent progress in DNA nanotechnology allows the fabrication of 3D structures that can be loaded with a large variety of molecular cargos and even be responsive to external stimuli. This makes the use of DNA nanostructures a promising approach for applications in nanomedicine and drug delivery. However, their low stability in the extra‐ and intracellular environment as well as low cellular uptake rates and release rates from endosomes into the cytoplasm hamper the efficient and targeted use of DNA nanostructures in medical applications. Here, such major obstacles are overcome by integrating DNA origami nanostructures into superordinated layer‐by‐layer based microparticles made from biopolymers. The modular assembly of the polymer layer allows a high‐density incorporation of the DNA structures at different depth. This enables controllable protection of the DNA nanostructures over extended durations in a broad range of extra‐ and intracellular conditions without compromising the cell viability. Furthermore, by producing protein‐complexed DNA nanostructures it is demonstrated that molecular cargo can be conveniently integrated into the developed hybrid system. This work provides the basis for a new multistage carrier system allowing for an efficient and protected transport of active agents inside responsive DNA nanostructures.     

FIB/SEM双束系统在微纳米材料电学性能测试中的应用

电学性能测试是微纳米材料物性研究的重要组成部分,测试电极的制备是其中一个难点。光学光刻、电子束曝光或聚焦离子束加工是三种不同的电极制备技术。每种技术都有自己的特点,采用何种技术取决于微纳米材料的尺寸、形态及测试目的等诸多因素。此外,选择适当的制样方法对后续的电学性能测试也很关键。本文以一台配备了电子束曝光功能附件的聚焦离子束( FIB)/扫描电子显微镜( SEM)双束系统为工具,结合光学光刻等其它加工技术,详细介绍了其针对不同类型微纳米材料进行电极制备的过程和方法。     

Information Visualization for DNA Microarray Data Analysis: A Critical Review

Graphical representation may provide effective means of making sense of the complexity and sheer volume of data produced by DNA microarray experiments that monitor the expression patterns of thousands of genes simultaneously. The ability to use ldquoabstractrdquo graphical representation to draw attention to areas of interest, and more in-depth visualizations to answer focused questions, would enable biologists to move from a large amount of data to particular records they are interested in, and therefore, gain deeper insights in understanding the microarray experiment results. This paper starts by providing some background knowledge of microarray experiments, and then, explains how graphical representation can be applied in general to this problem domain, followed by exploring the role of visualization in gene expression data analysis. Having set the problem scene, the paper then examines various multivariate data visualization techniques that have been applied to microarray data analysis. These techniques are critically reviewed so that the strengths and weaknesses of each technique can be tabulated. Finally, several key problem areas as well as possible solutions to them are discussed as being a source for future work.     

Duplex DNA/Graphene Oxide Biointerface: From Fundamental Understanding to Specific Enzymatic Effects

The exploration and fabrication of nano‐biointerfaces have fundamental significance and practical importance in many fields including chemistry, biology, and materials science. Recently, the integration of DNA with graphene has been substantially advanced. It is well known that single‐stranded (ss) DNA can interact with graphene (or graphene oxide) via π–π stacking. However, for the case of DNA duplex/graphene, the studies are still not conclusive. Most work does not address the question of whether or how dsDNA is attracted to graphene oxide (GO). Here the interaction of DNA/GO is systematically investigated and its nanobiological effects, molecular recognition, and biosensing are explored. It is demonstrated that GO can adsorb DNA duplexes, which is possibly facilitated by partial deformation of the double helix on GO. Additionally dsDNA on GO shows specific effects on enzymatic degradation, which could be effectively cleaved by DNA enzyme I and restriction endonucleases as EcoR I, whereas it is highly resistant to degradation by Exo III. An improved understanding of the behavior of these GO/DNA entities will facilitate the development of applications in biomedicine, biosensing, and bionanotechnology.     

Laser-induced fluorescence spectroscopy and imaging ofsemiconductor wafers

Fluorescence spectra of selected films used in microelectronic fabrication have been recorded. We have used a 0.125-m focal length spectrophotometer and a 400-line/mm grating resulting in 4.2-nm spectral resolution. The optical setup employs a laser at 364 nm for excitation and a dark-field collection configuration-a geometry that we routinely use for laser scanning for inspection purposes. A simple, though thorough, analysis and methodology for the removal of the system spectral response is presented. Results show that films used in microelectronic fabrication, in general, yield a broadband fluorescence spectrum under 364-nm excitation. Further, a scanning system that bases the image contrast on laser-induced fluorescence from the wafer surface is described and demonstrated. It is shown that this is a particularly useful inspection/review modality when the wafer is at poly/metal process level and the contaminant is a fall-on or residue of an organic material     

Gridline: automatic grid alignment DNA microarray scans

We present a new automatic grid alignment algorithm for detecting two-dimensional (2-D) arrays of spots in DNA microarray images. Our motivation for this work is the lack of automation in high-throughput microarray data analysis that leads to a) spatial inaccuracy of located spots and hence inaccuracy of extracted information from a spot and b) inconsistency of extracted features due to manual selection of grid alignment parameters. The proposed grid alignment algorithm is novel in the sense that 1) it can detect irregularly row- and column-spaced spots in a 2-D array, 2) it is independent of spot color and size, 3) it is general to localize a grid of other primitive shapes than the spot shapes, 4) it can perform grid alignment on any number of input channels, 5) it reduces the number of free parameters to minimum by data driven optimization of most algorithmic parameters, and 6) it has a built-in speed versus accuracy tradeoff mechanism to accommodate user's requirements on performance time and accuracy of the results. The developed algorithm also automatically identifies multiple blocks of 2-D arrays, as it is the case in microarray images, and compensates for grid rotations in addition to grid translations.     

On sputtered thin-films of chrome,nitrided chrome and nickel-chromium

Sputter deposited thin-film chromium, chromium-nitride and nickel-chromium have been evaluated for use in resistor fabrication. Some of the data obtained is qualitatively similar to that obtained in thin-film investigation, however, from a practical point of view the data contained herein is of a quantitative nature and might prove useful to those involved in thin-film resistor manufacture (results were obtained on a commercially available system). Relatively little data has been reported on reactively sputtered chromium in argon/nitrogen mixtures. The data presented here indicate that although not suitable for resistor fabrication, reactively sputtered chrome may be useful as thin-film thermistors.     

Microfabricated magnetic bead polydimethylsiloxane microarrays

Bead-based technologies are an attractive alternative to classical microarrays due to the high surface area of the beads which enables the immobilization of large numbers of probe molecules leading to increased kinetics and improved signal/noise ratios. A simple, versatile and inexpensive method for the fabrication of magnetic bead arrays is presented. The beads are first assembled into silicon pyramidal wells that have been fabricated by established microfabrication techniques and then mounted onto the apex of PDMS pyramids that replicate the silicon substrates by replica moulding. The bead arrays were used to detect oligonucleotide target sequences for the pathogenic avian H5N1 flu virus and results indicated that superior signal/noise ratios could be achieved compared to those from a classical microarray format.     

A Passive Authentication System Based on Optical Variable Nano/Micro-Structures

A new optical authentication and security system using optical variable nano/micro-structures (OVNs) is presented. The proposed design features a passive authentication method using a simple optical system found in common fabrication facilities. The passive authentication is obtained by insertion of an OVN image directly on a processing layer or divided between multiple layers of the fabrication process. Authentic fabrication process is validated when the proper alignment (reconstructed image, for example) at the end of the fabrication is achieved. Simple proof-of-concept devices with the OVN-based authentication system are presented along with the optical images of the resulting authentication patterns.