Single-photon avalanche diode fabricated in standard 55†nm bipolar-CMOS-DMOS technology with sub-20†V breakdown voltage.

This paper presents a single-photon avalanche diode (SPAD) in 55 nm bipolar-CMOS-DMOS (BCD) technology. In order to realize a SPAD having sub-20 V breakdown voltage for mobile applications while preventing high tunneling noise, a high-voltage N-well available in BCD is utilized to implement the avalanche multiplication region. The resulting SPAD has a breakdown voltage of 18.4 V while achieving an excellent dark count rate of 4.4 cps/µm2 at the excess bias voltage of 7 V in spite of the advanced technology node. At the same time, the device achieves a high peak photon detection probability (PDP) of 70.1% at 450 nm thanks to the high and uniform E-field. Its PDP values at 850 and 940 nm, wavelengths of interest for 3D ranging applications reach 7.2 and 3.1%, respectively, with the use of deep N-well. The timing jitter of the SPAD, full width at half maximum (FWHM), is 91 ps at 850 nm. It is expected that the presented SPAD enables cost-effective time-of-flight and LiDAR sensors with the advanced standard technology for many mobile applications.

Region Segmentation of Whole-Slide Images for Analyzing Histological Differentiation of Prostate Adenocarcinoma Using Ensemble EfficientNetB2 U-Net with Transfer Learning Mechanism.

Recent advances in computer-aided detection via deep learning (DL) now allow for prostate cancer to be detected automatically and recognized with extremely high accuracy, much like other medical diagnoses and prognoses. However, researchers are still limited by the Gleason scoring system. The histopathological analysis involved in assigning the appropriate score is a rigorous, time-consuming manual process that is constrained by the quality of the material and the pathologist's level of expertise. In this research, we implemented a DL model using transfer learning on a set of histopathological images to segment cancerous and noncancerous areas in whole-slide images (WSIs). In this approach, the proposed Ensemble U-net model was applied for the segmentation of stroma, cancerous, and benign areas. The WSI dataset of prostate cancer was collected from the Kaggle repository, which is publicly available online. A total of 1000 WSIs were used for region segmentation. From this, 8100 patch images were used for training, and 900 for testing. The proposed model demonstrated an average dice coefficient (DC), intersection over union (IoU), and Hausdorff distance of 0.891, 0.811, and 15.9, respectively, on the test set, with corresponding masks of patch images. The manipulation of the proposed segmentation model improves the ability of the pathologist to predict disease outcomes, thus enhancing treatment efficacy by isolating the cancerous regions in WSIs.

Noise optimization of single-photon avalanche diodes fabricated in 110 nm CMOS image sensor technology.

This paper presents the effect of shallow trench isolation (STI) on the dark count rate (DCR) and after-pulsing probability (APP) of deep-junction-based single-photon avalanche diodes (SPADs). Two different SPADs were fabricated in 110 nm CMOS image sensor technology, one with STI and the other without STI between its anode and cathode. With TCAD simulations and measurements, we have clearly demonstrated that the SPAD without STI enables a dramatic decrease in DCR by more than three orders of magnitude without suffering from the lateral leakage current between the anode and cathode. By excluding the STI from the device, the proposed SPAD also achieves a negligible APP while the SPAD with STI shows a very high APP of 92%. Thanks to the low-noise performance, the proposed SPAD becomes operable with higher excess bias voltage so that it achieves good photon detection probability, 58.3% at 500 nm and 3% at 940 nm, and timing jitter, 71 ps full width at half maximum at 670 nm, when the reverse bias voltage is 17 V.

A CMOS Optoelectronic Receiver IC with an On-Chip Avalanche Photodiode for Home-Monitoring LiDAR Sensors.

This paper presents an optoelectronic receiver (Rx) IC with an on-chip avalanche photodiode (APD) realized in a 0.18-µm CMOS process for the applications of home-monitoring light detection and ranging (LiDAR) sensors, where the on-chip CMOS P+/N-well APD was implemented to avoid the unwanted signal distortion from bondwires and electro-static discharge (ESD) protection diodes. Various circuit techniques are exploited in this work, such as the feedforward transimpedance amplifier for high gain, and a limiting amplifier with negative impedance compensation for wide bandwidth. Measured results demonstrate 93.4-dBΩ transimpedance gain, 790-MHz bandwidth, 12-pA/√Hz noise current spectral density, 6.74-µApp minimum detectable signal that corresponds to the maximum detection range of 10 m, and 56.5-mW power dissipation from a 1.8-V supply. This optoelectronic Rx IC provides a potential for a low-cost low-power solution in the applications of home-monitoring LiDAR sensors.

A skin-like two-dimensionally pixelized full-color quantum dot photodetector.

Direct full-color photodetectors without sophisticated color filters and interferometric optics have attracted considerable attention for widespread applications. However, difficulties of combining various multispectral semiconductors and improving photon transfer efficiency for high-performance optoelectronic devices have impeded the translation of these platforms into practical realization. Here, we report a low-temperature (<150°C) fabricated two-dimensionally pixelized full-color photodetector by using monolithic integration of various-sized colloidal quantum dots (QDs) and amorphous indium-gallium-zinc-oxide semiconductors. By introducing trap-reduced chelating chalcometallate ligands, highly efficient charge carrier transport and photoresistor-free fine-patterning of QD layers were successfully realized, exhibiting extremely high photodetectivity (>4.2 × 1017 Jones) and photoresponsivity (>8.3 × 103 A W-1) in a broad range of wavelengths (365 to 1310 nm). On the basis of these technologies, a wavelength discriminable phototransistor circuit array (>600 phototransistors) was implemented on a skin-like soft platform, which is expected to be a versatile and scalable approach for wide spectral image sensors and human-oriented biological devices.

A first single-photon avalanche diode fabricated in standard SOI CMOS technology with a full characterization of the device.

This paper reports on the first implementation of a single-photon avalanche diode (SPAD) in standard silicon on insulator (SOI) complementary metal-oxide-semiconductor (CMOS) technology. The SPAD is realized in a circular shape, and it is based on a P(+)/N-well junction along with a P-well guard-ring structure formed by lateral diffusion of two closely spaced N-well regions. The SPAD electric-field profile is analyzed by means of simulation to predict the breakdown voltage and the effectiveness of premature edge breakdown. Measurements confirm these predictions and also provide a complete characterization of the device, including current-voltage characteristics, dark count rate (DCR), photon detection probability (PDP), afterpulsing probability, and photon timing jitter. The SOI CMOS SPAD has a PDP above 25% at 490-nm wavelength and, thanks to built-in optical sensitivity enhancement mechanisms, it is as high as 7.7% at 850-nm wavelength. The DCR is 244 Hz/µm2, and the afterpulsing probability is less than 0.1% for a dead time longer than 200 ns. The SPAD exhibits a timing response without exponential tail and provides a remarkable timing jitter of 65 ps (FWHM). The new device is well suited to operate in backside illumination within complex three-dimensional (3D) integrated circuits, thus contributing to a great improvement of fill factor and jitter uniformity in large arrays.

A fully-integrated 12.5-Gb/s 850-nm CMOS optical receiver based on a spatially-modulated avalanche photodetector.

We present a fully integrated 12.5-Gb/s optical receiver fabricated with standard 0.13-µm complementary metal-oxide-semiconductor (CMOS) technology for 850-nm optical interconnect applications. Our integrated optical receiver includes a newly proposed CMOS-compatible spatially-modulated avalanche photodetector, which provides larger photodetection bandwidth than previously reported CMOS-compatible photodetectors. The receiver also has high-speed CMOS circuits including transimpedance amplifier, DC-balanced buffer, equalizer, and limiting amplifier. With the fabricated optical receiver, detection of 12.5-Gb/s optical data is successfully achieved at 5.8 pJ/bit. Our receiver achieves the highest data rate ever reported for 850-nm integrated CMOS optical receivers.

SNR characteristics of 850-nm OEIC receiver with a silicon avalanche photodetector.

We investigate signal-to-noise ratio (SNR) characteristics of an 850-nm optoelectronic integrated circuit (OEIC) receiver fabricated with standard 0.25-µm SiGe bipolar complementary metal-oxide-semiconductor (BiCMOS) technology. The OEIC receiver is composed of a Si avalanche photodetector (APD) and BiCMOS analog circuits including a transimpedance amplifier with DC-balanced buffer, a tunable equalizer, a limiting amplifier, and an output buffer with 50-Ω loads. We measure APD SNR characteristics dependence on the reverse bias voltage as well as BiCMOS circuit noise characteristics. From these, we determine the SNR characteristics of the entire OEIC receiver, and finally, the results are verified with bit-error rate measurement.

Silicon photonics-wireless interface ICs for micro-/millimeter-wave fiber-wireless networks.

We present two types of Si photonics-wireless interface (PWI) integrated circuits (ICs) realized in standard Si technology. Our PWI ICs convert optical signals into radio-frequency (RF) signals for downlink remote antenna units in fiber-wireless networks. Characterization and modeling of Si avalanche photodetectors (APDs) fabricated in two different Si technologies are carried out and used for PWI IC design. A 5-GHz RF-over-fiber PWI IC composed of APD, preamplifier, and power amplifier (PA) is fabricated in 0.18-µm CMOS technology and its performance is verified by 54-Mb/s wireless local area network data transmission. A 60-GHz baseband-over-fiber PWI IC containing APD, baseband photoreceiver, 60-GHz binary phase-shift keying (BPSK) modulator, and 60-GHz PA is realized in 0.25-µm SiGe BiCMOS technology. Error-free transmission of 1.6-Gb/s BPSK data in 60 GHz with this PWI IC is successfully achieved.

An integrated 12.5-Gb/s optoelectronic receiver with a silicon avalanche photodetector in standard SiGe BiCMOS technology.

An optoelectronic integrated circuit (OEIC) receiver is realized with standard 0.25-µm SiGe BiCMOS technology for 850-nm optical interconnect applications. The OEIC receiver consists of a Si avalanche photodetector, a transimpedance amplifier with a DC-balanced buffer, a tunable equalizer, and a limiting amplifier. The fabricated OEIC receiver successfully detects 12.5-Gb/s 2(31)-1 pseudorandom bit sequence optical data with the bit-error rate less than 10(-12) at incident optical power of -7 dBm. The OEIC core has 1000 µm x 280 µm chip area, and consumes 59 mW from 2.5-V supply. To the best of our knowledge, this OEIC receiver achieves the highest data rate with the smallest sensitivity as well as the best power efficiency among integrated OEIC receivers fabricated with standard Si technology.

Formulation variation and in vitro-in vivo correlation for a rapidly swellable three-layered tablet of tamsulosin HCl.

In order to develop a preferable once-a-day oral tablet formulation, various formulations of three-layered tablets containing tamsulosin HCl as a hydrophilic model drug were evaluated and compared with a commercial reference, tamsulosin OCAS®. When the test tablet was exposed to a release medium, the medium quickly permeated to the mid-layer and the two barrier layers swelled surrounding the mid-layer rapidly. Volume expansion showed faster and enough swelling of the three-layered tablet up to 2 h. Larger amount of barrier layers caused reduced release kinetics and a high molecular weight polymer showed more resistance against agitation force. A formulation with water-soluble mid-layer showed fast erosion decreasing its volume significantly. On the pharmacokinetic study, the mean ratio of area under the curve (AUC) and C(max) for the test formulation to the reference was 0.69 and 0.84, respectively, showing that the absorption of the drug was less complete than the reference. Plasma concentration at 24 h of the test formulation was higher than the reference. The Wagner-Nelson method showed that decreased initial dissolution rate might be the cause of the less complete absorption. On considering in vitro-in vivo correlation (IVIVC), level A, the reference (R²=0.981) showed more linear relationship than the test (R²=0.918) due to the decreased dissolution and absorption rate of the formulation. This result suggests that the in vitro dissolution profiles and release kinetics might be useful in correlating absorption kinetics as well as overall plasma drug concentration-time profiles for formulation studies.

A silicon avalanche photodetector fabricated with standard CMOS technology with over 1 THz gain-bandwidth product.

We present a silicon avalanche photodetector (APD) fabricated with standard complementary metal-oxide-semiconductor (CMOS) technology without any process modification or special substrates. The CMOS-APD is based on N+/P-well junction, and its current-voltage characteristics, responsivity, avalanche gain, and photodetection frequency response are measured. Gain-bandwidth product over 1 THz is achieved with the CMOS-APD having avalanche gain of 569 and 3-dB photodetection bandwidth of 3.2 GHz.

Application of a rapid and selective method for the simultaneous determination of carebastine and pseudoephedrine in human plasma by liquid chromatography-electrospray mass spectrometry for bioequivalence study in Korean subjects.

We describe a simple, rapid and sensitive high-performance liquid chromatography-electrospray ionization tandem mass spectrometric method that was developed for the simultaneous determination of carebastine and pseudoephedrine in human plasma using cisapride as an internal standard. Acquisition was performed in multiple-reaction monitoring mode by monitoring the transitions: m/z 500.43 > 167.09 for carebastine and m/z 166.04 > 147.88 for pseudoephedrine. The devised method involves a simple single-step liquid-liquid extraction with ethyl acetate. Chromatographic separation was performed on a C(18) reversed-phase chromatographic column at 0.2 mL/min by isocratic elution with 10 mM ammonium formate buffer-acetonitrile (30:70, v/v; adjusted to pH 3.3 with formic acid). The devised method was validated over 0.5-100 ng/mL of carebastine and 5-1000 ng/mL of pseudoephedrine with acceptable accuracy and precision, and was successfully applied to a bioequivalence study involving a single oral dose (10 mg of ebastine plus 120 mg of pseudoephedrine complex) to healthy Korean volunteers.

Rapid and simple method for determination of cephradine in human plasma using liquid chromatography-tandem mass spectrometry (LC-MS/MS): application to the bioequivalence study.

A rapid and simple procedure was developed for the determination of cephradine in human plasma using liquid chromatography coupled with electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS). After trichloroacetic acid (TCA) precipitation of proteins from plasma samples, cephradine and cefaclor (the internal standard; IS) were eluted on a CN column. The isocratic mobile phase used consisted of acetonitrile-water-formic acid (25:75:0.1, v/v/v). Cephradine and the IS were both detected in multiple reaction monitoring (MRM) mode at the transitions: m/z 350.0 --> 90.8 for cephradine and m/z 368.1 --> 106.0 for the IS, respectively. The calibration curve was linear over the concentration range from 0.05 to 50 microg/ml, and correlation coefficients were greater than 0.996. The coefficient of variation of assay precision was less than 9.36%, and its accuracy ranged from 87.92% to 111.16%. The chromatographic run time for each plasma sample was less than 3 min. The developed method was successfully applied to a bioequivalence study of cephradine in healthy male volunteers.

Development and validation of a high performance liquid chromatography-tandem mass spectrometry for the determination of etodolac in human plasma.

A simple and specific method using a one-step liquid-liquid extraction (LLE) with butyl acetate followed by high performance liquid chromatography (HPLC) coupled with positive ion electrospray ionization tandem mass spectrometry (ESI-MS/MS) detection was developed for the determination of etodolac in human plasma, using indomethacin as an internal standard (IS). Chromatographic separation was performed isocratically using a Capcellpak MGII C(18) column with 65% acetonitrile and 35% water containing 10mM ammonium formate (adjusted to pH 3.5 with formic acid). Acquisition was performed in multiple reaction monitoring (MRM) mode by monitoring the transitions: m/z 287.99>172.23 for etodolac and m/z 357.92>139.01 for IS. The method was validated to determine its selectivity, linearity, sensitivity, precision, accuracy, recovery and stability. The limit of quantitation (LLOQ) was 0.1microg/mL with a relative standard deviation of less than 15%. The devised method provides an accurate, precise and sensitive tool for determining etodolac levels in plasma.

Peroxynitrite and myocardial contractility: in vivo versus in vitro effects.

Generation of peroxynitrite (ONOO-) as a result of altered redox balance has been shown to affect cardiac function; however, inconsistencies in the data exist, particularly for myocardial contractility. The hypothesis that the cardiac impact of ONOO- formation depends on its site of generation, intravascular or intramyocardial, was examined. Cardiac contractility was assessed by pressure-volume analysis to delineate vascular versus cardiac changes on direct infusion of ONOO- into the right atria of conscious dogs both with normal cardiac function and in heart failure. Additionally, ONOO- was administered to isolated murine cardiomyocytes to mimic in situ cardiac generation. When infused in vivo, ONOO- had little impact on inotropy but led to systemic arterial dilation, likely as a result of rapid decomposition to NO2- and NO3-. In contrast, infused ONOO- was long lived enough to abolish beta-adrenergic (dobutamine)-stimulated contractility/relaxation, most likely through catecholamine oxidation to aminochrome. When administered to isolated murine cardiomyocytes, ONOO- induced a rapid reduction in sarcomere shortening and whole cell calcium transients, although neither decomposed ONOO- or NaNO2 had any effect. Thus, systemic generation of ONOO- is unlikely to have primary cardiac effects, but may modulate cardiac contractile reserve, via blunted beta-adrenergic stimulation, and vascular tone, as a result of generation of NO2- and NO3-. However, myocyte generation of ONOO- may impair contractile function by directly altering Ca2+ handling. These data demonstrate that the site of generation within the cardiovascular system largely dictates the ability of ONOO- to directly or indirectly modulate cardiac pump function.

Direct left ventricle to great cardiac vein retroperfusion: a novel alternative to myocardial revascularization.

BACKGROUND: As the number of patients with diffuse coronary artery disease continues to grow, there is renewed interest in alternative methods of perfusing the ischemic myocardium. We tested the feasibility of myocardial retroperfusion via a direct left ventricle-to-great cardiac vein (LV-GCV) conduit to support regional contractility in this setting. METHODS: LV-GCV flow was established using an extracorporeal circuit in 5 dogs. Left ventricle (LV) pressure, aortic pressure, regional myocardial segment length, and circuit blood flow were measured prior to left anterior descending coronary artery (LAD) ligation, following LAD ligation, and after LV-GCV circuit placement. To eliminate backward flow during diastole, an in-line flow regulator was placed. Regional myocardial function was quantified by pressure-segment length loop area divided by end-diastolic segment length (PSLA/EDSL). RESULTS: LAD ligation reduced PSLA/EDSL from 10.0 +/- 1.2 mm Hg mm to 1.6 +/- 0.3 mm Hg mm (P < .05). With LV-GCV retroperfusion, mean peak systolic flow was +152 +/- 14 mL/min, mean peak diastolic flow was -39 +/- 11 mL/min, and net mean flow was +36 +/- 13 mL/min. Regional function recovered to approximately 39% of baseline (3.9 +/- 0.4 mm Hg mm, P < .05). Upon elimination of backflow, mean flow increased to +41 +/- 12 mL/min and regional function recovered even further to approximately 47% of baseline (4.6 +/- 0.7 mm Hg mm, P < .05). CONCLUSIONS: A LV-GCV circuit can significantly restore regional function to the acutely ischemic myocardium. An inline valve that eliminates backward diastolic flow improves regional function even further. This approach may provide an effective therapy for diffuse coronary disease not amenable to traditional revascularization strategies.

Intramyocardial left ventricle-to-coronary artery stent: a novel approach for the treatment of coronary artery disease.

BACKGROUND: The direct intramyocardial left ventricle-to-coronary artery stent may provide an optional minimally invasive technique for coronary artery bypass graft surgery. We seek to test whether blood flow and regional myocardial function improve with this stent in totally ischemic myocardium. METHODS: The stent device was implanted in 8 anesthetized dogs using an open chest approach, arteriotomy of the proximal left anterior descending coronary artery, and connection of the vessel to the left ventricular chamber. Regional coronary blood flow and myocardial function were monitored under three conditions: normal coronary flow (baseline), coronary ligation, and stent flow. RESULTS: Left anterior descending coronary ligation markedly reduced coronary artery blood flow and regional myocardial function. With flow solely from the stent, the blood flow pattern changed to one with high peak forward flow during systole compared with baseline (94.8 +/- 48.9 versus 56.8 +/- 21.1 mL/min; p < 0.05) and one with significant negative backflow during diastole compared with baseline (-37.4 +/- 23.1 versus 11.3 +/- 17.2 mL/min; p < 0.05). However, the resultant mean forward flow increased to approximately 50% of baseline compared with less than 5% of baseline after coronary ligation. Regional myocardial function diminished entirely after coronary ligation, but recovered to approximately 60% of baseline with the stent. Normal systemic hemodynamics and global ventricular contractile function were maintained with the stent. CONCLUSIONS: The left ventricle-to-coronary artery stent is a simple and readily deployable device that allows the perfusion of epicardial vessels directly from the left ventricle and can provide significant blood flow to improve the performance of ischemic myocardium. It may provide an effective, alternative means of treating coronary artery disease when standard coronary artery bypass graft surgery is not suitable.

Involvement of CCAAT/enhancer-binding protein alpha in haptoglobin gene expression by all-trans-retinoic acid.

Several acute-phase plasma proteins, including haptoglobin (Hp), are induced in the liver in response to inflammation. Recently, we found that Hp gene expression is up-regulated by all-trans-retinoic acid (ATRA) in the extrahepatic monocytic cell line, THP-1. To investigate the molecular mechanism underlying ATRA-induced Hp gene expression, we analyzed the induction of transcription factor CCAAT/enhancer-binding protein (C/EBP) isoforms in ATRA-stimulated THP-1 cells and their binding to the Hp promoter. Western blot analysis showed that treatment with ATRA increased C/EBPalpha and beta expression, but decreased that of C/EBPdelta. Electrophoretic mobility shift and supershift assays demonstrated that only C/EBPalpha of the C/EBP isoforms bound to the C/EBP DNA-binding sites in the Hp promoter. Furthermore, when ATRA-dependent Hp induction was inhibited by sodium butyrate or auranofin, induction of C/EBPalpha, but not C/EBPbeta, was also diminished. These results suggest that C/EBPalpha is involved in the activation of Hp gene expression by ATRA in human monocytic cells.