bluuebunny/crossref_metadata_2025 huggingface dataset:
Gingival Tissue Inflammation Promotes Increased Matrix Metalloproteinase-12 Production by CD200Rlow Monocyte-Derived Cells in Periodontitis
Authors: Björnfot Holmström Sofia , Clark Reuben , Zwicker Stephanie , Bureik Daniela , Kvedaraite Egle , Bernasconi Eric , Nguyen Hoang Anh Thu , Johannsen Gunnar , Marsland Benjamin J. , Boström Elisabeth A. , Svensson Mattias
Published: November 2017

Irreversible tissue recession in chronic inflammatory diseases is associated with dysregulated immune activation and production of tissue degradative enzymes. In this study, we identified elevated levels of matrix metalloproteinase (MMP)-12 in gingival tissue of patients with the chronic inflammatory disease periodontitis (PD). The source of MMP12 was cells of monocyte origin as determined by the expression of CD14, CD68, and CD64. These MMP12-producing cells showed reduced surface levels of the coinhibitory molecule CD200R. Similarly, establishing a multicellular three-dimensional model of human oral mucosa with induced inflammation promoted MMP12 production and reduced CD200R surface expression by monocyte-derived cells. MMP12 production by monocyte-derived cells was induced by CSF2 rather than the cyclooxygenase-2 pathway, and treatment of monocyte-derived cells with a CD200R ligand reduced CSF2-induced MMP12 production. Further, MMP12-mediated degradation of the extracellular matrix proteins tropoelastin and fibronectin in the tissue model coincided with a loss of Ki-67, a protein strictly associated with cell proliferation. Reduced amounts of tropoelastin were confirmed in gingival tissue from PD patients. Thus, this novel association of the CD200/CD200R pathway with MMP12 production by monocyte-derived cells may play a key role in PD progression and will be important to take into consideration in the development of future strategies to diagnose, treat, and prevent PD.
Mode of Tolerance Induction and Requirement for Aire Are Governed by the Cell Types That Express Self-Antigen and Those That Present Antigen
Authors: Mouri Yasuhiro , Ueda Yoshihiro , Yamano Tomoyoshi , Matsumoto Minoru , Tsuneyama Koichi , Kinashi Tatsuo , Matsumoto Mitsuru
Published: November 2017

Aire controls the fate of autoreactive thymocytes (i.e., clonal deletion or development into regulatory T cells [Tregs]) through transcriptional control of the expression of tissue-restricted self-antigens (TRAs) from medullary thymic epithelial cells (mTECs) and bone marrow (BM)-derived cells. Although TRAs expressed by mTECs and BM-derived cells are suggested to complement each other to generate a full spectrum of TRAs, little is known about the relative contribution of TRAs from each component for establishment of self-tolerance. Furthermore, the precise role of Aire in specific types of Aire-expressing APCs remains elusive. We have approached these issues by generating two different types of transgenic mouse (Tg) model, which express a prefixed model self-antigen driven by the insulin promoter or the Aire promoter. In the insulin-promoter Tg model, mTECs alone were insufficient for clonal deletion, and BM-derived APCs were required for this action by utilizing Ag transferred from mTECs. In contrast, mTECs alone were able to induce Tregs, although at a much lower efficiency in the absence of BM-derived APCs. Importantly, lack of Aire in mTECs, but not in BM-derived APCs, impaired both clonal deletion and production of Tregs. In the Aire-promoter Tg model, both mTECs and BM-derived APCs could independently induce clonal deletion without Aire, and production of Tregs was impaired by the lack of Aire in mTECs, but not in BM-derived APCs. These results suggest that the fate of autoreactive thymocytes together with the requirement for Aire depend on the cell types that express self-antigens and the types of APCs involved in tolerance induction.
Dark Current Leakage in Optoelectronic Hermetic Packages
Authors: Dionet Clara , Perosevic Goran , Javier Jeff , Fernandez Sammie , Hurdle Taylor , Moradi Maziar , Neely Andrew , Ma Kevin , Albarghouti Marwan
Published: November 2017

In this work, the root cause of the increase in dark current occurring over time at high temperature in hermetic packages, such as those used in optoelectronic devices, was investigated. It was observed that hermetic Receiver Optical Subassembly (ROSA) devices show continuously increasing dark current when stressed and monitored at 85°C over an extended period of time, reaching, in some cases, values greater than 500nA. However, this increase in leakage current was recoverable once the package seal is broken, and this behavior was found to be very repeatable. Photodetectors from two different suppliers were tested and found to have dark current which is dependent on the fabrication process, as the photodetector (PD) from supplier 1 (PD1) showed three times higher leakage than the photodetector from supplier 2 (PD2). The main difference between the two photodetectors is that the polyimide layer in PD1 in significantly greater than in PD2. It was also observed that 48 hour pre-seal baking at 120°C keeps the dark current constant at much lower levels, but does not stop it completely from rising over time.
Die Placement Error management for Fan out Applications using Projection Lithography
Authors: Hichri Habib , Abdol Mo , Arendt Markus
Published: November 2017

Photolithography has long been the key patterning technology for structuring organic materials used in advanced packaging applications like flip-chip wafer bumping, electroplated gold, solder bumps, copper pillar technologies and redistribution layers. Photolithography is a key manufacturing process and cost contributor, the careful selection of the right exposure solution is critical to achieve the best possible cost structure in today's industrial lithography applications

We will introduce a projection exposure technology that uses a 1:1 projection lens; the projection exposure technology provides high resolution patterning performance. With the capability of varying NA from 0.07 to 0.14, a large depth of focus is obtained, that is required to ensure high pattern fidelity when working with thick resists. The projection exposure can also be applied to FOWLP applications, when the die placement data is fed into a software optimization algorithm to correct for it. We will present the projection exposure technology capability in managing the die placement error for FOWLP. In addition, details on the overlay capability of the projection exposure in thin resist are described and a Cost-of-Ownership comparison between different photolithography solutions is discussed.
Antenna Systems for Simultaneous Transmit and Receive (STAR) Applications
Authors: Etellisi Ehab A. , Elmansouri Mohamed A. , Filipovic Dejan S.
Published: November 2017

Several novel wideband co-polarized circulator-less monostatic antenna and array designs for co-channel simultaneous transmit and receive (STAR) applications are presented. The monostatic STAR apertures are demonstrated first by utilizing multi-arm spiral antennas where a set of arms is used for transmitting (TX) and the other set for receiving (RX). Then, square and hexagonal broadside STAR arrays utilizing closely-spaced spiral antennas are introduced. Finally, (quasi) omnidirectional circular STAR arrays based on phase modes orthogonality principles are realized using four wideband monocone antenna elements. The studied configurations are integrated with the proper beamforming networks to excite the desired modes of TX/RX operations leading to theoretically infinite isolation between TX and RX ports. Practically, the achieved isolation is limited by the electrical asymmetries of the used components. Overall, consistent wideband operation, high isolation, and decent far-field performance are achieved for all proposed STAR approaches.
Multi-factor product authentication using integrated Quick Response (QR) code pixelated antenna
Authors: Doroshewitz John , Kaur Amanpreet , Nanzer Jeffrey , Chahal Premjeet
Published: November 2017

A Quick Response (QR) Code style antenna is presented. Such an antenna can provide two-level authentication, both optically through the current QR technology, plus a radio frequency (RF) signature from microstrip patch antenna designed from the QR signature using copper patterning. The antenna is designed through the pixilation of a patch antenna where conductor is present in the dark regions of the optical QR code. The QR based antenna design has a unique frequency and radiation signature and can be used for RF authentication of products. The design process for the pixilation is presented as well as fabrication and measured results of a QR code antenna design. The possibility of using a Genetic Algorithm to create a “library” of acceptable antenna results in accordance with the QR data it represents is also discussed.
Strength assessment for direct-sintered Al2O3-to-Cu joints based on damage modeling
Authors: Lis Adrian , Asama Koji , Matsuda Tomoki , Sano Tomokazu , Hirose Akio
Published: November 2017

Metal-to-ceramics direct sintering was carried out with Al2O3 and Cu / 3 μm Ni / 1 μm Au substrates. The bonding paste consisted of micron-sized Ag2O particles and a reducing solvent that provokes Ag2O-to-Ag reduction during processing accompanied by the formation of Ag nano particles. Five different sets of process parameters resulted in different joint microstructure and strength. The experimental data was used to calibrate an elasto-visco-plastic finite element model of the sintered assembly which yielded a quantitative damage function and criterion to predict the strength of direct-sintered joints. The developed ductile damage formulation introduced a parameter ξ, i.e. the product of equivalent creep strain and stress triaxiality, that controls the tolerable plastic strain at fracture. An extended numerical parameter study subsequently revealed the complex interaction between the joint strength and microstructural joint features. Thinner joints were found to provide a slightly higher strength while the amount of sinter material and costs is significantly reduced. Moreover, it is recommended to aim at a higher level of densification at the edges and corners of sintered joints since these areas apparently contribute more to the overall mechanical strength. The developed concept is capable of tailoring the microstructure of direct-sintered joints according to the requirements or vice versa.
Demonstration of Embedded Cu Trench RDL using Panel Scale Lithography and Photosensitive Dry Film Polymer Dielectrics
Authors: Sundaram Venky , Liu Fuhan , Nair Chandra , Tummala Rao , Kubo Atsushi , Ando Tomoyuki , Best Keith , Shay Corey
Published: November 2017

This paper presents the first demonstration of fine pitch embedded trench RDL on glass substrates using a new family of ultra-high resolution dry film photo-sensitive polymer dielectrics and a new large area panel scale lithography tool. The specific research targets are to demonstrate multilayer RDL scaling to 1um lines and vias at >200 I/Os per mm of die edge for 2.5D interposers and high density fan-out packages.
A Secure Tunable LNA Design for Internet of Things
Authors: Kim Bruce , Cho Sang-Bock
Published: November 2017

This paper describes the design of through-silicon via (TSV)-based inductors for a secure tunable low-noise amplifier (LNA) in Internet of Things (IoT) devices. To improve cybersecurity infrastructure, we designed a tunable LNA with hardware security. Our secure design for tunable LNA uses a ring oscillator-based physically unclonable function (PUF) circuit. For the 3D inductors, we use ferromagnetic materials to achieve high inductance with a good quality factor.
Next Generation Chip Embedding Technology for High Efficient Mid Power Modules
Authors: Essig Kay S. , Chiu CT , Kuo Jarris , Chen Phidia , Yannou Jean-Marc
Published: November 2017

Embedding active dies into the substrate is fulfilling integration requirements for modern communication devices, and furthermore embedding was shown to have beneficial effects on electrical performance and thermal dissipation, especially for mid power modules (from a few hundred watts to 5kW) [1–3]. It comes with strong advantages as the power modules operate at higher frequencies (MHz range) and aim to apply smaller capacitors and inductors. This approach reduces the overall PCB size and weight from system point of view. These beneficial effects were observed especially for embedded power dies that were already mounted in a lead frame cavity when embedding [3]. In this paper we shall report the development of embedded technologies for power modules mounted in a lead frame cavity and compare electrical performance, thermal dissipation and reliability results with conventional PQFN packaging [3]. We shall also report electrical performance in various operation frequency ranges from a few kHz to MHz to address the benefit on high switching frequency power modules for SiC or GaN applications. We will also address if the EMI effect can be eliminated by using chip embedded technology instead of wire bonding connection from driver to gate pad of power MOSFET chip. We will conclude that the challenges of electrical performance and thermal dissipation required for today's power modules can successfully be overcome by next generation power modules based on lead frame chip embedding.
Challenges of Large Format Packaging and Some of Its Assembly Solutions
Authors: Eric Kuah TH , Yuan Hao Ji , Chan Catherine , Kai Wu , Fan Nelson , Ming Li , Lau John , Ng Eric , Li Margie
Published: November 2017

This paper will focus on the technical challenges and solutions that a packaging and/or equipment engineer faces during the encapsulation of a large format substrate - either a wafer or panel substrate. This form of packaging is known as Large Format Packaging (LFP). The technical challenges and solutions discussed here include encapsulant, material dispensing strategies, direction of encapsulation, warpage management and challenges for LFP going forward. LFP as a packaging solution is an option worth exploring when the end user is willing to address its set of engineering challenges appropriately.
Development of Liquid Compression Molding (LCM) Material for Low Warpage
Authors: Kamimura Tsuyoshi , Kawamoto Satomi , Hashimoto Daisuke , Shigeno Yuto , Yoshii Haruyuki , Noma Hirokazu , Ookubo Tomohiro , Takahashi Hisato , Inoue Hidetoshi
Published: November 2017

This paper reports on the study of flexible epoxy resin which lowers modulus to minimize warpage while maintaining high filler content.

Liquid Compression Molding (LCM) material is an encapsulation material applied at the wafer level. LCM requires high reliability and minimized warpage after curing. The flexible epoxy resin was studied to determine if it could be technically feasible to meet the requirements.

Three epoxy resins with different structures, Conventional epoxy, and Flexible epoxy A and B, were examined. Both samples with Flexible epoxy A and B resulted in lower warpage than Conventional resin. Especially, Flexible epoxy B showed the minimal warpage with the lowest modulus. The sample with Epoxy B performs the best at 260 degree Celsius with the minimal warpage.

A reliability test of LCM with Epoxy B was also conducted assuming the application for Fan-out packaging. Epoxy B showed no delamination or cracks under a thermal cycling test up to 1,000 cycles after MSL1 moisture exposure.
Thin Film Capacitor Applications in RF/Microwave Circuits
Authors: Kuhn William B. , Wolf J. Ambrose
Published: November 2017

Thin-film capacitors can be created on various substrates including glass, low-temperature co-fired ceramic (LTCC), and potentially on laminate PC board materials if the surface is sufficiently smooth. This paper looks at the circuit-design issues of how such a technology could be used in high-speed digital and microwave circuits for improving both signal integrity and power integrity (SI/PI). Two primary applications are examined: the formation of a low-inductance power-supply bypass allowing reduced supply ‘noise’, and the formation of AC coupling (DC blocking) circuits with improved signal return-loss.
INDUCTORS USING 2.5D SILICON INTERPOSER WITH THICK RDL AND TSV-LAST TECHNOLOGIES
Authors: Pares G. , Michel J.-P. , Deschaseaux E. , Pernin V. , Giry A. , Ferris P. , Serhan A.
Published: November 2017

Silicon interposers represents an interesting alternatives to organic packages for the fabrication of complex System In Package (SIP) modules especially for RF application. Among the advantages of this technology are the capability to fabricate fine-pitch redistribution layers and also to embed high quality passive components inside the interposer. This allows the passive components to be very close to the active chips resulting in highly integrated and high performance systems. To keep the technology at a reasonable cost these last add-on features need to be fabricated with no or minor additional process steps that the ones needed for the fabrication of the interposer itself.

In this work we present the design and the fabrication of various design of planar and 3D inductor devices fully compatible with the realization of a silicon interposer that is used to host an RF transmitter system operating in the 0.4 to 1 GHz frequency range. The inductors are built using two thick levels of copper RDL, on both sides of a high resistive silicon substrate and connected by through silicon via-last (TSV-last). This later doesn't require additional metallization to be realized.

A dedicated test vehicle was designed to study various inductor types including planar spirals, 3D solenoids and 3D torus. To facilitate the design work, parameterized cells were built for each type of inductors. The structures geometry are designed and optimized, using electromagnetic simulator, to target inductance values in the range of 0.5 to 10 nH while addressing a quality factor greater than 20.

The second part of the paper focuses on the process used to build the test vehicle, especially the realization of thick copper RDL layers on both sides of the interposer silicon wafer and the TSV-last module. Physical and DC electrical characterizations are presented to assess the integrity of the individual technology modules like thick copper RDL and TSV.

The last part of the work is dedicated to the electrical characterization of the inductor devices in the targeted RF frequency range. Experimental results are presented and discussed in order to give some insight on the impact of the different design parameters on the performances of the inductors.
In-line advanced process control solution for the fabrication of micro-bumps
Authors: Alliata Dario , Godny Stephane , Serrecchia Cleonisse , Combier Tristan , Sippel Astrid , Gastaldo Philippe
Published: November 2017

In this paper, Confocal Chromatic Microscopy was investigated to characterize the micro-bump fabrication process. We designed and fabricated in house a new detector that integrates through the same optical chromatic lens two light beams that are reflected into a 2D line scan camera and a spectrometer to obtain on the fly 2D and 3D information while scanning the wafer surface.

We inspected 300 mm round wafers hosting arrays of copper micro-bumps down to 10 μm in width and 5 μm in height at post Cu growing and etching step.

The 2D inspection revealed the presence of partial μbumps, shifted and missing μbumps. The 3D inspection could recognize shorter and taller bumps and determine the coplanarity of each bump population at die level. This information could be used to classify GOOD and BAD dies over the wafer, so that after dicing only known good dies would be used in the following advanced packaging step. In this way, the risk of shorts and / or missing contact is minimized when stacking dies either on a wafer or on a die.
Highly Reliable Cu Wiring Layer of 1/1 μm Line/Space Using Newly Designed Insulation Barrier Film
Authors: Mitsukura Kazuyuki , Abe Shinichiro , Toba Masaya , Minegishi Tomonori , Kurafuchi Kazuhiko
Published: November 2017

The interposer or fan-out packaging technology with ultra-fine line/space has been required in order to achieve high density interconnection between chips with low cost. In this paper, we propose the iBF (insulation barrier film) to satisfy the insulation reliability of 1/1 μm ultra-fine trench wiring. The features of iBF are very low moisture absorptivity less than 0.3%, chloride ion impurities less than 1.0 ppm and high resistance to hydrolysis. In addition, iBF has good adhesive strength to Ti and Cu. The trench wiring was fabricated for mechanical and insulation reliability evaluation using photosensitive dielectric, then covered with iBF. The obtained trench wiring with 2/2, 1.5/1.5 and 1/1 μm line/space has passed the reliability tests such as moisture sensitivity level 2, thermal cycling test and biased HAST (highly accelerated stress test). We have also verified high resolution of photosensitive dielectric and fabrication of ultra-fine trench wiring on iBF to realize fine multi-layer wiring.
Co-Simulation Based Multi-Chip Module Design Flow and Wi-Fi Module Example with Integrated BAW and LNA
Authors: Dekosky Jeff , Nair Deepukumar , Carastro Larry , Knapp Scott
Published: November 2017

This paper discusses an improved design flow for hybrid Multi-Chip Modules comprising of MMICs and other components. A full 3D electromagnetic co-simulation flow is proposed. Application of such a flow is demonstrated with an MCM receiver module which has a bulk acoustic wave pre-filter, a Low Noise Amplifier with a digital bypass function, and a classical 6th order filter implemented with discrete components. Detailed simulation data is provided on each component of the system and the final MCM module, that demonstrates the use of the design flow. Finally, simulation results are compared to measured data from fabricated modules to prove the validity of our design approach
Encapsulation of Microelectronic Assemblies for use in Harsh Environments
Authors: Varner H. , Mahaffey J. , Marinis T. , DiBiasio C.
Published: November 2017

Microelectronic systems that are intended for use in high shock and vibration environments are encapsulated to achieve stable and reliable operation. The physical design of the electronic assembly, the material properties of the encapsulant, and the magnitude and frequency of the inertial loading must all be factored into the system design. Overall robustness to shock and vibration are improved by minimizing the physical size and mass of the system, which increases its stiffness and reduces the magnitude of the inertial forces that must be supported. This work describes the development of an encapsulation process and facilities that are optimized for building high-reliability microelectronic systems that range between one and five cubic centimeters in volume. Finite Element Analysis (FEA) is used to ensure that sensitive components are not overstressed by the encapsulant as a result of residual curing stresses and inertial loading effects. Computational Fluid Dynamics (CFD) software is used to model the filling process, with the objective of identifying locations prone to void formation. The CFD models are validated via cross sectioning mechanical replicas of the system and by encapsulating enclosures fitted with viewing windows to allow sequential photographs of the progression of the fill frontier.

During fabrication, the encapsulant is dispensed under vacuum while being observed with a stereoscopic microscope. An essential component of the process is characterization of the encapsulant materials. Coefficient of thermal expansion and cure shrinkage of the encapsulant are determined by casting a sample onto a thin metal strip and extracting stress parameters with equations of a bimetallic strip. The surface energies of the encapsulant on materials in the system are measured by a modified sessile drop technique in which the material is dispensed on a coupon, cured and then measured with a profilometer. These tests are performed on each lot of material when received and periodically afterwards to monitor the condition of inventory. This paper provides a detailed description of the design process and facilities using examples from representative products.
Ablative Laser Patterning of Polymeric Dielectric Materials
Authors: Matos-Pérez Cristina R. , Blumenshine Deborah , Kirchner Lisa M. , Flaim Tony , Puligadda Rama , Hichri Habib , Arendt Markus , Lee Seongkuk
Published: November 2017

As the semiconductor technology and the field evolves, the need for new applications can facilitate the development of new materials and processes. Device size is continuously shrinking, and materials that have low stress can promote new developments. In this paper, the focus is on three polymeric platforms that can be used as dielectric materials with the added advantage of being patternable via laser ablation. The dielectric materials were carefully designed to exhibit low stress (low modulus and high elongation), good temperature stability, and high absorbance for laser patterning. Additionally, these materials possess a distinctly advantageous, heretofore unseen property: production of little to no debris post-ablation. Several advantages of using laser ablation as the patterning tool is that it allows room temperature processing, higher throughput, and improved resolution. In this paper, it will be demonstrated that successful patterning via laser ablation of new dielectric materials can be achieved which is beneficial to new applications and technologies.
14nm Chip Package Interaction (CPI) Technology Development
Authors: Fu Lei , Low YS , Bhagavat Milind , Barber Ivor
Published: November 2017

This paper presents the 14 nm chip and package interaction (CPI) challenges and development by using 140 um minimum pitch with SnAg bump in flip chip BGA package. We evaluated 14 nm back-end-of-line (BEOL) film strength/structure / adhesion with large die size of 21×21 mm2 and optimized bumping technology by passing all the CPI reliability tests (QTC, Precon, UBHAST, TCJ, MSV, and HTS) with following the JEDEC standard. We also evaluated assembly with different bump foot print at 140um bump pitch with SnAg bump, and no assembly issues were encountered. Crack stop plays very critical role in defending the crack propagation into the die active area. In our development, we observed reliability failure with severe test condition TCG (−45°C to 125°C), but passed TCJ (0°C to 100°C) with single wall crack stop on the large die size. With increasing crack stop width which enhanced the mechanical strength of crack stop, both TCG and TCJ passed. So it is strongly recommended to use wider crack stop for large dies to eliminate any failures.
Morphological and Electrical Stability Studies of Pt/Yttria-Stabilized Zirconia Nanocomposite Thin Film Cathodes for Microfabricated Solid Oxide Fuel Cells
Authors: Rottmayer Michael , Singh Raj , Huang Hong
Published: November 2017

Microfabricated solid oxide fuel cells (mSOFCs) have recently gained attention as a promising technology for portable power applications. At present, porous Pt is the most common cathode being investigated for mSOFCs, which has poor bulk ionic conductivity and suffers from instability due to Ostwald ripening. Nanocomposite materials based on Pt/Yttria-Stabilized Zirconia (YSZ) are a promising alternative approach for high performance mSOFCs because of their potential for providing mixed ionic-electronic conduction, improving adhesion to the YSZ electrolyte, and improving oxygen diffusion characteristics over a pure Pt material. The objective of this research was to systematically explore the processing of the nanocomposite thin films to achieve stable morphological and electrical properties for use as a mSOFC cathode. A percolation theory model was utilized to guide the processing of the Pt/YSZ composition, ensuring a networked connection of ionic- and electronic-conduction through the electrode. The Pt/YSZ nanocomposite cathodes were deposited by co-sputtering. It was observed that the Ar deposition pressure played a key role in stabilizing the morphology of the film to higher temperatures, up of 600°C. Analyses of the Pt/YSZ composite microstructure and composition by TEM confirmed an interconnected network of Pt and YSZ thereby suggesting that it is a viable candidate as a high performance and stable cathode material for mSOFCs.
Wire Bonding Looping Solutions for High Density System-in-Package (SiP)
Authors: Milton Basil , Kwon Odal , Huynh Cuong , Qin Ivy , Chylak Bob
Published: November 2017

System-in-Package (SiP) have seen a lot of growth in recent years especially in mobile devices due to its higher level of system integration, more design flexibility and smaller form factor. Two or more semiconductor die and passive components are usually present in a SiP device. Die to die bonding and increased I/O density are two common challenges associated with wire bonding in SiPs. High density SiP packages often have high I/O counts and tight wire clearance. As a result, the requirements for wire bond looping are high. To avoid wire shorts, the wire bond loops need to be well designed in order to have optimal wire clearance between various tiers of wire loops as well as neighboring loops. The formed loops need to have low wire sway after wire bonding and low wire sweep after molding. Due to the existence of multiple dies and other passive components within the same package, special wire bond loops with long flat lengths and sharp bending angles are sometimes necessary to clear the die edges and the other components. In this paper, we will review a few new wire bonding looping solutions including 3D looping design software, 3D loop clearance checking and multi-tier loop formation improvements. A robust package design is essential to improve production yield. A 3D looping design software has been developed to evaluate the robustness of various package designs from a wire looping perspective. The software is able to detect potential issues early on in the design cycle and evaluate alternatives quickly, therefore reduces the time to market and improves design robustness. A spatial 3D clearance checking tool has been developed to detect any interference between the densely populated wire loops. The tool can also detect interference between the wires and the edges of different dies. Furthermore, the wire clearance against various components in the package can also be assessed. Process engineers can leverage the clearance check tool and the 3D visualization of wires, multiple dies and components to aid wire bonding looping optimization. Multi-tier looping requires a large range of loop height and wire length capability. In order to achieve optimal looping for high density multi-tier applications, a separate wire bonding looping software has been developed to generate optimal wire bonding motion trajectories that can achieve the loop shapes designed by the 3D looping design software. An example of 6 loop tier application is developed and results are analyzed to show the wire bonding capabilities including looping height from 75um to 500um and wire length up to 5mm.
A novel production process for 10 μm microvias.
Authors: Renbi Abdelghani , Delsing Jerker
Published: November 2017

This work investigates the capability of drilling and metallization of microvias of diameter less than 10 μm with aspect ratios of 1–10, using a fully additive process.

The microvia has been produced using a sequential build up layer of urethane through which the via has been produced. The urethane layer is applied using spin-coating. Current process setting produces a 15 μm layer thickness. For thicker urethane, multiple layers are applied. Drilling of the via-hole through is made using 266 nm UV laser.

The metallisation of the via-hole was made using a process called Covalent Bonded Metallisation (CBM). This process modifies the urethane surface by a grafting process where polymers are covalently bonded to the surface where metallisation is desired. A roughly 5 μm thin film of the used grafting solution is applied to the substrate surface. The grafting process is initiated by laser which draws the patterns where copper is desired.

After laser drawing, the substrate is cleaned with deionized water. Next, the substrate is through a commercial chemical-copper process which builds copper only at the laser initiated patterns. Copper thicknesses of 1 μm is easily achievable. To increase the copper thickness, the substrate may be run into thick building chemical-copper process to achieve thicknesses up to 8 μm.
Identification and Quantitation of Asparagine and Citrulline Using High-Performance Liquid Chromatography (HPLC)
Authors: Bai Cheng , Reilly Charles C. , Wood Bruce W.
Published: November 2017

High-performance liquid chromatography (HPLC) analysis was used for identification of two problematic ureides, asparagine and citrulline. We report here a technique that takes advantage of the predictable delay in retention time of the co-asparagine/citrulline peak to enable both qualitative and quantitative analysis of asparagine and citrulline using the Platinum EPS reverse-phase C18 column (Alltech Associates). Asparagine alone is eluted earlier than citrulline alone, but when both of them are present in biological samples they may co-elute. HPLC retention times for asparagine and citrulline were influenced by other ureides in the mixture. We found that at various asparagines and citrulline ratios [= 3:1, 1:1, and 1:3; corresponding to 75:25, 50:50, and 25:75 (μMol m−1/μMol ml−1)], the resulting peak exhibited different retention times. Adjustment of ureide ratios as internal standards enables peak identification and quantification. Both chemicals were quantified in xylem sap samples of pecan [ Carya illinoinensis (Wangenh.) K. Koch] trees. Analysis revealed that tree nickel nutrition status affects relative concentrations of Urea Cycle intermediates, asparagine and citrulline, present in sap. Consequently, we concluded that the HPLC methods are presented to enable qualitative and quantitative analysis of these metabolically important ureides.
Unexpected Different Binding of Mistletoe Lectins from Plant Extracts to Immobilized Lactose and N-acetylgalactosamine
Authors: Hajtò Tibor , Krisztina Fodor , Ildikò Aponyi , Zsolt Pallai , Pèter Balogh , Pèter Németh , Pàl Perjési
Published: November 2017

Mistletoe Extracts (ME) are of growing interest to pharmacological research because of their apoptosis-inducing/cytostatic and immunomodulatory effects. The standardization of the three different groups of Mistletoe Isolectins (ML-I, II and III) is often rendered more difficult since the primary structures are nearly identical. Their classification is based on their Galactose- and N-acetyl-D-galactosamine (GalNAc)-specificity which was measured by various inhibitory assays. The aim of the present study was to improve the characterization of the direct binding activity of the isolectins from ME to immobilized lactose, GalNAc and to the oligosaccharide asialofetuin. After careful ultrafiltration of fresh ME, affinity chromatography was carried out using lactose-agarose, GalNAc—agarose and asialofetuin—affigel 15 columns. MLs were further purified by Sephadex G-100 or by cation exchange chromatography which was adapted to a Fast Protein Liquid Chromatography (FPLC) system. Proteins from both fresh plants and commercial ME were able to bind immobilized lactose to a considerable extent. The majority of this lectin has a B-chain with a Molecular Weight (MW) of 34kD and an A-chain with a MW of 29 kD (ML-I). Only a minor part of the lactose-binding proteins has a lower MW, namely 32kD and 27kD (MLII). However, neither MLs which were eluted from lactose columns, nor the proteins from fresh plant or ME showed a direct binding to the immobilized GalNAc. In spite of this deficiency, GalNAc was able to induce a considerable (25% and 32%) inhibitory effect on their binding to immobilized asialofetuin indicating a discrepancy between the lectin binding and inhibiting effects of GalNAC. Consequently, for an improved standardization of ME more specific sugar molecules are necessary.
Microalbuminuria Measured by three Different Methods, Blood Pressure and Cardiovascular Risk Factors in Elderly Swedish Males
Authors: Florvall Gösta , Basu Samar , Helmersson Johanna , Larsson Anders
Published: November 2017

Microalbuminuria is associated with hypertension and is a strong risk factor for subsequent chronic disease, both renal and coronary heart disease (CHD), Presently there are several methods available for measurement of microalbuminuria. The aim of this study was to evaluate if the three different methods gave similar information or if one of the assays were superior to the others. Blood pressure, inflammatory markers and cardiovascular mortality and morbidity were correlated with urine albumin analysed with a point-of-care testing (POCT) instrument, nephelometric determination of albumin and albumin/creatinine ratio in elderly males. The study population consisted of 103 diabetic and 603 nondiabetic males (age 77 years) in a cross-sectional study. We analyzed urine albumin with a HemoCue® Urine Albumin POCT instrument and a ProSpec® nephelometer and albumin/creatinine ratio. There were strong correlations between both systolic and diastolic blood pressure and all three urine albumin methods (p < 0.0001). There were also significant correlations between the different urine albumin measurements and serum amyloid A component, high-sensitivity C-reactive protein and interleukin-6. The three different urine albumin methods studied provided similar information in relation to cardiovascular disease. There was a strong correlation between systolic and diastolic blood pressure and microalbuminuria in both the whole study population and in nondiabetic males emphasizing the role of hypertension in glomerular damage. The good correlation between the studied urine albumin measurements show that all three methods can be used for monitoring urine albumin excretion.
Comparison of Gas Chromatography-Mass Spectrometry and Gas Chromatography-Tandem Mass Spectrometry with Electron Ionization and Negative-Ion Chemical Ionization for Analyses of Pesticides at Trace Levels in Atmospheric Samples
Authors: Raina Renata , Hall Patricia
Published: November 2017

A comparison of detection limits of gas chromatography-mass spectrometry (GC-MS) in selected ion monitoring (SIM) with gas chromatography-tandem mass spectrometry (GC-MS/MS) in selected reaction monitoring (SRM) mode with both electron ionization (EI) and negative-ion chemical ionization (NCI) are presented for over 50 pesticides ranging from organochlorines (OCs), organophosphorus pesticides (OPs) and pre-emergent herbicides used in the Canadian prairies (triallate, trifluralin, ethalfluralin). The developed GC-EI/SIM, GC-NCI/SIM, and GC-NCI/SRM are suitable for the determination of pesticides in air sample extracts at concentrations <100 pg µL-1(< 100 pg m-3in air). No one method could be used to analyze the range of pre-emergent herbicides, OPs, and OCs investigated. In general GC-NCI/SIM provided the lowest method detection limits (MDLs commonly 2.5-10 pg µL-1) along with best confirmation (<25% RSD of ion ratio), while GC-NCI/SRM is recommended for use where added selectivity or confirmation is required (such as parathion-ethyl, tokuthion, carbofenothion). GC-EI/SRM at concentration < 100 pg µL-1was not suitable for most pesticides. GC-EI/SIM was more prone to interference issues than NCI methods, but gave good sensitivity (MDLs 1-10 pg µL-1) for pesticides with poor NCI response (OPs: sulfotep, phorate, aspon, ethion, and OCs: alachlor, aldrin, perthane, and DDE, DDD, DDT).
Determination of Trace Amounts of Lead Using the Flotation-spectrophotometric method
Authors: Shiri Sabah , Delpisheh Ali , Haeri Ali , Poornajaf Abdolhossein , Golzadeh Babak , Shiri Sina
Published: November 2017

The present study describes a simple and highly selective method for separation, preconcentration and spectrophotometric determination of extremely low concentrations of lead. It is based on flotation of a complex of Pb2+ ions and Alizarin yellow between aqueous and n-hexane interface at pH = 6. The proposed procedure is also applied for determination of lead in both tap water and prepared sea water samples. Beer's Law was obeyed over the concentration range of 3.86 × 10-8 To 8.20 × 10-7 molL-1 (8-170 ngmL-1) with an apparent molar absorptivity of 1.33 × 106 molL-1 cm-1 for a 100 mL aliquot of the water sample. The detection limit (n = 10) was 8.7 × 10-9 molL-1 (1.0 ngmL-1) and the Relative standard deviation (R.S.D), (n = 10) for 7.2 × 10-7 molL-1 (150 ngmL-1) of Pb (II) was 4.36%. A notable advantage of the method is that the determination of Pb (II) is free from the interference of almost all cations and ions found in the environment and waste water samples. The determination of Pb (II) in tap and synthetic seawater samples was also carried out by the present method. The results were satisfactorily comparable so that the applicability of the proposed method was confirmed to the real samples.
High-Performance Liquid Chromatographic Method for Determination of Phenytoin in Rabbits Receiving Sildenafil
Authors: Khedr Alaa , Moustafa Mohamed , Abdel-Naim Ashraf B. , Alahdal Abdulrahman , Mosli Hisham
Published: November 2017

A validated high-performance liquid chromatographic (HPLC) method for determination of phenytoin (PHN), para-hydroxy metabolite of phenytoin (POH) and sildenafil (SIL) in rabbit plasma is described. The method is based on extraction on Sep-Pak C18 solid support using ethyl acetate and ether as eluents and monitoring at 220 nm. The extracted samples were analyzed by HPLC using Agilent Zorbax Extended C18 column (150 mm x 4.6 mm internal diameter) and isocratic elution with a mobile phase consist of 29% acetonitrile and 71% sodium acetate solution (0.02 M, pH 4.6). The method was fully validated for linearity and range, selectivity, precision, stability, recovery, and robustness. The linearity of the method was in the range of 0.15 to 39 µg /ml for PHN and 0.15 to 33 µg/ml for both POH and SIL. Limits of detection (LOD) of PHN, POH, and SIL were 0.15 ± 0.01, 0.15 ± 0.01, and 0.15 ± 0.01 µg/ml, respectively. The % recovery of PHN, POH, and SIL from rabbit plasma were, 101.88 ± 0.12, 99.16 ± 0.25, and 99.49 ± 0.33, respectively. The method was applied on plasma collected from rabbits at different time intervals after receiving 30 mg/kg PHN-Na with (and without) 8 mg/kg SIL citrate.
Pharmacotherapy Update: Hyoscine Butylbromide in the Treatment of Abdominal Spasms
Authors: Samuels Leslie A.
Published: November 2017

Abdominal pain is one of the most common reasons why people seek medical care, and is often due to spasm of intra-abdominal visceral organs. Hyoscine butylbromide (HBB) is a quaternary ammonium compound which blocks the action of acetylcholine at parasympathetic sites (both muscarinic and nicotinic receptors) in smooth muscle, and in secretory glands. It causes decreased motility of the gastrointestinal tract and the urogenital tracts, and is useful in the treatment of spasms in these regions. Side effects are common, but tend to be minor and self limiting. Evidence exists to support its use in the management of non-specific colicky abdominal pain (in adults and children); irritable bowel syndrome; labor and delivery; dysmenorrhea; as an adjunct in the therapy of late stage cancer patients with inoperable bowel malignancies; and to facilitate improved resolution in certain imaging techniques. It may also be useful in certain procedures, such as colonoscopy and sigmoidoscopy, and may be useful in the management of renal colic (although NSAIDs seem clinically superior). The role of HBB in the management of esophageal food obstruction is unclear at this time; further studies need to be done.
Pharmacotherapy Update: Quetiapine use in Bipolar Disorder—What does the evidence tell us?
Authors: Taylor Mark , Mackay Kirsty , Shajahan Polash
Published: November 2017

Bipolar disorder is a common and serious illness usually requiring long term medication. We critically review the available evidence surrounding the increasing use of quetiapine, a second generation antipsychotic, in both the acute and maintenance phases of bipolar disorder. Large scale, randomized controlled data supports the use of quetiapine in both acute mania and acute bipolar depression, as a safe and effective treatment and probably best used in combination with a traditional ‘mood stabiliser’ such as lithium or divalproex. Also, quetiapine monotherapy has been shown to be effective in bipolar depression. Two recently published studies also confirm that quetiapine in combination with either lithium or divalproex ‘adds value’ to the maintenance treatment of bipolar disorder in terms of delaying relapse compared to either lithium or divalproex alone. Quetiapine is generally well tolerated, although further work on long term weight gain and emergent diabetes would be helpful.
Nonalcoholic Fatty Liver Disease: Epidemiology, Pathogenesis, Natural History, Diagnosis, and Current Treatment Options
Authors: Banini Bubu A. , Sanyal Arun J.
Published: November 2017

Nonalcoholic fatty liver disease (NAFLD) is on the rise and has become a major etiology for chronic liver disease. It is frequently associated with obesity, insulin resistance, hypertension, and dyslipidemia and is considered the hepatic manifestation of metabolic syndrome. In this review, we present a summary of the epidemiology and pathogenesis of NAFLD, and discuss the clinical evaluation and stratification of NAFLD patients into low, intermediate, and high risk with respect to liver-related outcomes. While diet and exercise are the cornerstone of treatment in all patients, the low rate of adherence and inadequacy of these recommendations necessitate pharmacologic intervention, especially in intermediate- and high-risk patients. We discuss vitamin E and pioglitazone which are often used as first-line therapy by many practitioners, with pentoxifylline and liraglutide as backup agents. Several drugs are in advanced-phase clinical trials and will likely change the landscape for management of NAFLD in the very near future.
Eculizumab in the Treatment of Paroxysmal Nocturnal Hemoglobinuria
Authors: Hill Anita
Published: November 2017

Paroxysmal nocturnal hemoglobinuria (PNH) is a potentially life-threatening acquired clonal stem cell disorder resulting in hemolysis and thrombosis. A somatic mutation in the phosphatidylinositol glycan A gene in hematopoietic stem cells results in a deficiency of the complement regulatory proteins, CD55 and CD59. There is a consequent increased sensitivity to complement mediated lysis. Eculizumab is a recombinant, humanized monoclonal antibody directed against C5 of the complement system. It blocks terminal complement activation and the formation of the membrane attack complex. It has been demonstrated in 3 clinical studies that this blockade of the terminal complement system effectively and significantly prevents intravascular hemolysis thereby abolishing or reducing the need for transfusions, reduces thromboses, improves quality of life and appears to prevent renal damage and improve pulmonary pressures. The drug is very well tolerated with few safety concerns. Case reports of the use of eculizumab in pregnancy, cold agglutinin disease and atypical hemolytic syndrome are also described.
Insomnia: A Review of the Use of Eszopiclone
Authors: Dautovich Natalie D. , Williams Jacob M. , McCrae Christina S.
Published: November 2017

The present paper presents a review of the literature examining the efficacy of eszopiclone for treating insomnia. The purpose of the paper was to evaluate both the statistical and clinical efficacy of eszopiclone for treating insomnia. Both subjective and objective assessments of insomnia were evaluated across various sleep variables. Additionally, the efficacy of eszopiclone for treating insomnia comorbid with other conditions (sleep disordered breathing, psychiatric diagnoses, peri/post-menopause, rheumatoid arthritis), transient insomnia, and across diverse samples (adults, older adults, and samples pooled by race) was reviewed. Finally, the impact of eszopiclone use on daytime functioning was examined.