Recently we discovered a signal amplification mechanism to amplify photocurrent with high efficiency and low noise. Unlike conventional impact ionization used in avalanche photodetectors, the new amplification mechanism can produce high (>1000) gain with very low excess noise factor (<2 for Si) under very low bias voltage (3V). The new amplification mechanism offers a promising solution for light detection for Si-photonics, imaging, and sensing. Physics of this mechanism lies in two subsequent processes i) Auger excitation between mobile and highly localized electrons and ii) electron-phonon coupling. In this paper, experimental results are supported by the proposed physical model using simulations within density functional theory (DFT) framework.
An intrinsic signal amplification mechanism, namely cycling excitation process (CEP), has been demonstrated in a heavily doped and heavily compensated silicon p-n junction diode. The physical process amplifies photo-generated signal at low bias (<5V) and produces ultralow excess noise at least partially attributed to an internal stabilization mechanism via electron-phonon interactions. Auger excitation, which can be calculated with Fermi Golden rule and quasi pseudopotential, and localized carrier ionization by phonon absorption are considered two key processes responsible for the unique device characteristics. A partially compensated p-n junction silicon diode based on the proposed CEP principle has shown high gain of ~6000 at -5V and an excess noise factor as low as 3.5 at this gain level, measured at 635nm wavelength and 1KHz for potential imaging applications.
The optical properties of a receptor-targeted probe designed for dual-modality mapping of the sentinel lymph node (SLN) was optimized. Specific fluorescence brightness was used as the design criterion, which was defined as the fluorescence brightness per mole of the contrast agent. Adjusting the molar ratio of the coupling reactants, IRDye 800CW-NHS-ester and tilmanocept, enabled us to control the number of fluorescent molecules attached to each tilmanocept, which was quantified by H 1 nuclear magnetic resonance spectroscopy. Quantum yields and molar absorptivities were measured for unconjugated IRDye 800CW and IRDye 800CW-tilmanocept (800CW-tilmanocept) preparations at 0.7, 1.5, 2.3, 2.9, and 3.8 dyes per tilmanocept. Specific fluorescence brightness was calculated by multiplication of the quantum yield by the molar absorptivity and the number of dyes per tilmanocept. It predicted that the preparation with 2.3 dyes per tilmanocept would exhibit the brightest signal, which was confirmed by fluorescence intensity measurements using three optical imaging systems. When radiolabeled with Ga 68 and injected into the footpads of mice, the probe identified SLNs by both fluorescence and positron emission tomography (PET) while maintaining high percent extraction by the SLN. These studies demonstrated the feasibility of 800CW-tilmanocept for multimodal SLN mapping via fluorescence and PET–computed tomography imaging.
Semiconductor photodetectors at1550nm wavelengths have been widely used in free space optical communications, sensing, infrared imaging, and quantum information processing. These detectors require high sensitivity with high detection efficiency and a large dynamic range. But for fundamental material and device limits, all these performances cannot be achieved in a single device under the same operating conditions. To overcome this bottleneck, we integrate three coupled gain mechanisms in a single element device, operating below breakdown to obtain a high net gain and at the same time utilize the negative feedback mechanism to minimize the gain fluctuation. This results in an improved signal to noise ratio, which is the key to obtaining a superior sensitivity. Integration of gain mechanisms in an InP-InGaAs device was analytically modeled and experimentally demonstrated.
Ultrasound microbubbles are contrast agents used for diagnostic ultrasound imaging and as carriers for noninvasive payload delivery. Understanding the acoustic properties of individual microbubble formulations is important for optimizing the ultrasound imaging parameters for improved image contrast and efficient payload delivery. We report here a practical and simple optical tool for direct real-time characterization of ultrasound contrast microbubble dynamics based on light scattering. Fourier transforms of raw linear and nonlinear acoustic oscillations, and microbubble cavitations are directly recorded. Further, the power of this tool is demonstrated by comparing clinically relevant microbubble cycle-to-cycle dynamics and their corresponding Fourier transforms.
Early detection is important for many solid cancers but the images provided by ultrasound, magnetic resonance imaging (MRI), and computed tomography applied alone or together, are often not sufficient for decisive early screening/diagnosis. We demonstrate that MRI augmented with fluorescence intensity (FI) substantially improves detection. Early stage murine pancreatic tumors that could not be identified by blinded, skilled observers using MRI alone, were easily identified with MRI along with FI images acquired with photomultiplier tube detection and offset laser scanning. Moreover, we show that fluorescence lifetime (FLT) imaging enables positive identification of the labeling fluorophore and discriminates it from surrounding tissue autofluorescence. Our data suggest combined-modality imaging with MRI, FI, and FLT can be used to screen and diagnose early tumors.
In vivo optical molecular imaging of fluorescent probes predominantly employs continuous wave
techniques to measure fluorescence intensity. Alternatively, time domain techniques permit
measurement of fluorescence lifetime in addition to fluorescence intensity. Fluorescence lifetime
allows discrimination of fluorescent probes with contrasting lifetime or inference of a probe's
environment due to lifetime sensitivity. Here, we present the use of fluorescence lifetime contrast to
evaluate the relative concentrations of a mixture of fluorophores in a scattering medium. This
approach offers the potential to perform dual-probe in vivo optical molecular imaging at a single
wavelength employing lifetime contrast rather than via spectral intensity contrast.
Reactive oxygen species (ROS) are believed to be involved in many diseases and injuries to the
brain, but the molecular processes are not well understood due to a lack of in vivo imaging
techniques to evaluate ROS. The fluorescent oxidation products of dihydroethidium (DHE) can
monitor ROS production in vivo. Here we demonstrate the novel optical imaging of brain in live
mice to measure ROS production via generation of fluorescent DHE oxidation products (ox-DHE)
by ROS. We show that in Sod2+/- mice, which have partial loss of a key antioxidant enzyme,
superoxide dismutase-2, that ox-DHE fluorescence intensity was significantly higher than in hSOD1
mice, which have four-fold overexpression of superoxide dismutase-1 activity, which had almost no
ox-DHE fluorescence, confirming specificity of ox-DHE to ROS production. The DHE oxidation
products were also confirmed by detecting a characteristic fluorescence lifetime of the oxidation
product, which was validated with ex vivo measurements.
In vivo acousto-optic imaging promises to provide optical contrast at superior ultrasound spatial resolution. The main
challenge is to detect ultrasound-modulated photons in the overwhelming presence of un-modulated photons. We have
demonstrated in vitro detection of ultrasound-modulated photons with a variety of detection methods. Furthermore, we
have detected ultrasound-modulated fluorescence offering potential for acousto-optic molecular imaging. Moreover, we
have demonstrated the use of ultrasound microbubbles to significantly enhance the acousto-optic signal at the ultrasound
frequency with the additional generation of higher order harmonic frequencies. Here the results from our various
detection methods, ultrasound-modulated fluorescence, and enhancement with microbubbles are presented.
A time-domain optical method to evaluate the concentration (n), lifetime (), and depth (d) of a fluorescent inclusion is described by the complete analysis of the fluorescence temporal point-spread function (TPSF). The behavior of parameters in the fluorescence TPSF is explored, and we demonstrate the method with experimental data from a localized fluorescent inclusion in scattering media to recover images of n, , and d. The method has potential application for in vivo fluorescence imaging.
In the last few years there has been a growing interest in the use of small animal optical molecular imaging systems to
conduct preclinical studies. Most of these imaging systems are based on continuous wave (CW) technology to measure
the bioluminescence or fluorescence light intensity from optical probes in small animals. The eXplore OptiTM is
currently the only commercially available imaging system based on time domain (TD) technology. In addition to
measuring the light intensity, the TD approach provides extra information to help determine the depth and concentration
of optical probes in small animals. Furthermore, the TD approach uniquely allows the fluorescence lifetime of a
fluorophore-based optical probe to be measured. Recently, our single wavelength eXplore-OptiTM system has been
upgraded to a multi-wavelength (eXplore OptixTM-MX) system with the addition of 3 laser wavelengths and
corresponding filters. This has enabled us to image a variety of fluorophores for different preclinical applications.
Preliminary results evaluating the performance of the eXplore-OptiTM-MX are presented employing fluorophores with
different spectral and lifetime characteristics.
The advent of optical molecular probes has taken optical imaging beyond approaches limited to intrinsic optical contrast mechanisms. Fluorophores are typically used as the source of contrast for optical molecular probes and the field of optical molecular imaging is concerned with measuring and quantifying their in vivo biodistribution and pharmacokinetics. Most optical molecular imaging systems are based on Continuous Wave (CW) approaches which enable rapid, full-body imaging of small animals and readily yield images of probe location, however quantification of probe concentration is challenging. Time Domain (TD) approaches, although more expensive and complicated than CW, provide more information to assist in determining the probe location and concentration. Moreover, the TD approach permits access to measuring the fluorophore lifetime which can be indicative of the probe's environment. The eXplore OptixTM system, developed by ART (Canada) and distributed by GE Healthcare, has enabled TD optical molecular imaging of small animals in vivo and preliminary studies conducted with the system will be presented. In addition, the initial research and development of a full-field TD optical molecular imaging system incorporating a high-power laser for area illumination and a gated-intensified CCD camera for area detection will be presented.
The advent of optical molecular probes has taken optical imaging beyond approaches limited to intrinsic optical contrast mechanisms. Fluorophores are typically used as the source of contrast for optical molecular probes and the field of optical molecular imaging is concerned with measuring and quantifying their in vivo biodistribution and pharmacokinetics. Most optical molecular imaging systems are based on Continuous Wave (CW) approaches which enable rapid, full-body imaging of small animals and readily yield images of probe location, however quantification of probe concentration is challenging. Time Domain (TD) approaches, although more expensive and complicated than CW, provide more information to assist in determining the probe location and concentration. Moreover, the TD approach permits access to measuring the fluorophore lifetime which can be indicative of the probe’s environment. Existing TD approaches involve a point source and detector which are sequentially scanned over the sample and can take several minutes to acquire the data compared to the rapid imaging offered by CW. The system presented here employs a high power, near infrared, pulsed laser to provide area illumination and a temporally gated intensified CCD camera to permit area detection in order to enable rapid, full-body, TD optical molecular imaging of small animals in vivo. The system is described and preliminary in vitro and in vivo measurements are presented.
A time-resolved imaging technique has been used to obtain 2D near-IR images of a solid phantom with optical properties very similar to those of breast tissue. The phantom consisted of a highly scattering plastic slab, 54 mm thick, containing four small cylindrical blocks of contrasting optical properties. Imaging involved translating a beam of pulses in two dimensions across the surface of the phantom while recording the temporal distribution of the transmitted light at the opposite surface with a streak camera. The entire imaging process was performed automatically under computer control. Images generated using the earliest arriving light improved the visibility of the embedded cylinders compared to continuous light transillumination, but those images corresponding to flight times less than around 700ps were severly degraded due to a lack of detected photons. This degradation was partially overcome while still achieving a significant gain in contrast and resolution by comparison of the data to a photon transport model of the temporal distributions and using the model predictions as high signal-to-noise versions of the original data. All the embedded cylinders were revealed with sub-centimeter resolution.
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