Systemic Sclerosis (SSc) is an autoimmune disease characterized by a triad of inflammation, vasculopathy, and fibrosis of the skin and internal organs such as gastrointestinal tract, heart, lungs, and kidneys. SSc can lead to premature death especially when there is cardiopulmonary involvement. At early stages, SSc is characterized by an alteration of blood vessel network and hypoxia in the fingertip. Imaging these parameters could lead to early diagnosis of SSc patients. In this study, we investigated the feasibility to detect and diagnose SSc by imaging the oxygen saturation in the nail-bed using photoacoustics (PA) and estimating skin thickening using high-frequency ultrasound (HFUS). Thirty-one subjects (adult man and women) participated in this study: 12 patients with systemic sclerosis, 5 patients with early systemic sclerosis, 5 subjects with primary Raynaud’s phenomenon, and 9 healthy volunteers. The measurements showed that both the nail bed oxygen saturation (77.9% ±10.5 vs. 94.8% ±2.8, p < 0.0001) and the skin thickness (0.51 ±0.17 mm vs. 0.31 ±0.06 mm, p<0.005) of patients with SSc was significantly different compared to healthy volunteers. Most importantly the measurements showed a significant difference between early SSc and primary Raynaud’s phenomenon for both oxygen saturation (80.8 ± 8.1% vs. 93.9 ± 1.1%) and skin thickness (0.48 ± 0.06 mm vs. 0.27 ± 0.01 mm). The PA and HFUS data was supported by conventional capillaroscopy imaging performed on all participants. This pilot study demonstrates the possibility to use photoacoustics and high-frequency ultrasound as a diagnostic tool for early detection of systemic sclerosis.
Light fluence inside turbid media can be experimentally mapped by measuring ultrasonically modulated light (Acousto-optics). To demonstrate the feasibility of fluence corrected Photoacoustic (PA) imaging, we have realized a tri-modality (i.e. photoacoustic, acousto-optic and ultrasound) tomographic small animal imaging system. Wherein PA imaging provides high resolution map of absorbed optical energy density, Acousto-optics yields the fluence distribution map in the corresponding PA imaging plane and Ultrasound provides morphological information. Further, normalization of the PA image with the acousto-optically measured fluence map results in an image that directly represents the optical absorption.
Human epidermal growth factor receptor 2 (HER2) is commonly found overexpressed in human cancers, among which breast cancers, resulting in a more aggressive tumor phenotype. Identification of HER2-expression is clinically relevant, because cancers overexpressing this marker are amenable to HER2-directed therapies, among which antibodies trastuzumab and pertuzumab. Here, we investigate the feasibility and advantage of acousto-optically assisted fluence compensated PA imaging over PA imaging alone in visualizing and quantifying HER2 expression. For this experiment, nude mice were xenografted with human breast cancer cell lines SKBR3 and BT474 (both HER2 overexpressing), as well as HER2-negative MDA-MB-231. To visualize HER2 expression in these mice, HER2 monoclonal antibody pertuzumab (Perjeta®, Roche), was conjugated to near-infrared dye IRDye 800CW (800CW, LICOR Biosciences) at a ratio of 1∶2 antibody to 800CW. When xenograft tumors measured ≥ 100 mm3, mice received 100 µg 800CW-pertuzumab intravenously. Three days post injection, mice were scanned for fluorescence signal with an IVIS scanner. After fluorescence scans, mice were euthanized and imaged in our PA tomographic imaging system.
Ultrasound flow imaging is widely used for quantification of blood flow in vivo, but estimating low flow velocities remains challenging. Pulsed photoacoustic flowmetry could be an alternative – but has not been shown capable of deep in vivo imaging so far. A new photoacoustic system is proposed, that has more potential for deep in-vivo applications. In this work the system is tested in vitro. In contrast to earlier research, 1064 nm NIR laser irradiation is used, that would allow deeper in-vivo light penetration. For detection, a 15 MHz transducer with lower in-vivo tissue ultrasound attenuation is used. Both changes are not trivial, as they reduce the overall visibility of the photoacoustic signals from red blood cells. This work shows the flow estimation performance of this system in vitro, and aims to serve as a point of reference when moving to an in-vivo application. Using this 15 MHz transducer, 1D flow profiles of flowing blood were extracted. The jitter (standard error) in the velocity estimation over the profiles was 10% when estimating flow of particles and 20% with whole blood; the bias in flow estimation was roughly 30%.
Flow imaging is an important technique in a range of disease areas, but estimating low flow speeds, especially near the walls of blood vessels, remains challenging. Pulsed photoacoustic flow imaging can be an alternative since there is little signal contamination from background tissue with photoacoustic imaging. We propose flow imaging using a clinical photoacoustic system that is both handheld and portable. The system integrates a linear array with 7.5 MHz central frequency in combination with a high-repetition-rate diode laser to allow high-speed photoacoustic imaging—ideal for this application. This work shows the flow imaging performance of the system in vitro using microparticles. Both two-dimensional (2-D) flow images and quantitative flow velocities from 12 to 75 mm/s were obtained. In a transparent bulk medium, flow estimation showed standard errors of ∼7% the estimated speed; in the presence of tissue-realistic optical scattering, the error increased to 40% due to limited signal-to-noise ratio. In the future, photoacoustic flow imaging can potentially be performed in vivo using fluorophore-filled vesicles or with an improved setup on whole blood.
Real-time ultrasound/photoacoustic in-vivo imaging will be demonstrated using a portable, dual-modality photoacoustic and ultrasound imager that features a pulsed diode laser integrated into an hand-held ultrasound probe. The 800-nm-wavelength diode provides 0.6 mJ pulses after the probe aperture in a 20 mm × 4 mm rectangular beam and can be fired at 210 Hz, limited by the Maximum Permissible Exposure.
In-vivo imaging that will be demonstrated will include finger-joint imaging for future early detection of inflammation in rheumatoid diseases. New photoacoustic techniques that might increase the sensitivity of the detection of inflammation, such as PA Doppler, will also be discussed.
This article [J. Biomed. Opt.. 19, (6 ), 066002 (2014)] was originally published online on 2 June 2014 with a typo in the author list. The authors are correct as listed above. This article was corrected online on 6 June 2014. It appears correctly in print.
Knowledge of the local optical fluence in biological tissue is of fundamental importance for biomedical optical techniques to achieve quantification. We report a method to noninvasively measure the local optical fluence in optically inhomogeneous scattering media. The concept is based on two aspects: the local tagging of light using ultrasonic modulation and the photon path reversibility principle. Our method has advantages over known computational-based fluence mapping techniques, for its purely experimental nature and without the requirement of prior knowledge of the optical properties of the medium. We provide a theoretical formalism and validation of the method with experiments in tissue-like phantoms. Further, we combine our method with photoacoustic imaging and compensate the photoacoustic signals for fluence variations in optically inhomogeneous media.
Recently, we presented an add-on to a photoacoustic (PA) computed tomography imager that permits the simultaneous imaging of ultrasound (US) transmission parameters such as the speed of sound (SOS), without additional measurements or instruments. This method uses strong absorbers positioned outside the object in the path of light for producing laser-induced US to interrogate the object in a conventional PA imager. Here, we investigate the feasibility of using this approach, first with PA to pin-point the location of photothermal therapeutic agents and then with serial SOS tomograms to image and monitor the resulting local temperature changes when the agents are excited with continuous wave (CW) light. As the object we used an agar-based tissue-mimicking cylinder carrying beads embedded with different concentrations of gold nanospheres. PA and SOS tomograms were simultaneously acquired as the gold nanospheres were photothermally heated using a 532-nm CW laser. In a first approximation, using the relation between SOS of water and temperature, the SOS tomograms were converted into temperature maps. The experimental results were verified using simulations: Monte Carlo modeling of light propagation through a turbid medium and using the obtained absorbed energy densities in heat diffusion modeling for spatial temperature distribution.
Photoacoustics is a hybrid imaging modality that is based on the detection of acoustic waves generated by absorption of pulsed light by tissue chromophors. In current research, this technique uses large and costly photoacoustic systems with a low frame rate imaging. To open the door for widespread clinical use, a compact, cost effective and fast system is required. In this paper we report on the development of a small compact handset pulsed laser probe which will be connected to a portable ultrasound system for real-time photoacoustic imaging and ultrasound imaging. The probe integrates diode lasers driven by an electrical driver developed for very short high power pulses. It uses specifically developed highly efficient diode stacks with high frequency repetition rate up to 10 kHz, emitting at 800nm wavelength. The emitted beam is collimated and shaped with compact micro optics beam shaping system delivering a homogenized rectangular laser beam intensity distribution. The laser block is integrated with an ultrasound transducer in an ergonomically designed handset probe. This handset is a building block enabling for a low cost high frame rate photoacoustic and ultrasound imaging system. The probe was used with a modified ultrasound scanner and was tested by imaging a tissue mimicking phantom.
Optical excitation based imaging modalities, with aim to image structures deep inside the scattering medium, suffer from
quantification problem. We propose a methodology to solve the problem of non-invasively mapping the fluence in
optically heterogeneous medium without the need of prior knowledge of its optical properties. We present a theoretical
model of our concept and provide proof of principle with Monte Carlo simulations. Simulation results show that it is
possible to measure the local light fluence in highly scattering medium in absolute terms. Furthermore, we performed an
experiment to validate the concept as a strategy to measure local fluence in relative manners. We used reflection mode
acousto optics (AO) in our experiment, and showed that with this method we can measure local light fluence (in relative
term) in highly scattering medium.
Quantitative measurements of the chromophores concentration in vivo present a challenge in photoacoustic imaging. The
obtained signal depends on the absorbed optical density which is the product of absorption coefficient and local fluence.
As a result of wavelength-dependent optical attenuation and scattering, the local fluence in biological media varies with
depth and the optical wavelength. This fluence heterogeneity needs to be compensating in the order to recover the
absolute absorption coefficient. In this paper we describe a new approach to recover the absolute optical absorption
coefficient from measured PA signals based in combination between photoacoustic and acousto-optic signals. The
present method is based on two principles, a given photon trajectory through a scattering medium can be travelled in two
directions with equal probability and photons which traverse a certain volume can be labeled in that volume with the use
of focused ultrasound. We give proof of the principle using Monte Carlo simulation and we demonstrate the
experimental feasibility of the technique in tissue-mimicking phantom by correcting a fluence heterogeneity caused by
the optical diffusion.
Both mechanical and optical imaging of biological tissue can provide relevant contrasts in terms of biomedical tissue
characterization. While ultrasound imaging can easily be performed at depth thanks to the weak scattering of ultrasound
in soft tissue, the optical spatial resolution is limited for thick tissue by the strong scattering of light. In this paper, we
present a technique involving the optical detection of a transient displacement caused by the acoustic radiation force
created at cm depth by a focused intense short ultrasound burst (typically ~millisecond). This localized displacement
disturbs the optical paths and allows localizing the information with a resolution dictated by the ultrasound spatial
distribution. Using a high-speed camera, our objective was to detect and time-resolve displacements in the focal region
and the associated propagation shear waves. Experiments were carried out in attenuating tissue-like media illuminated by
a continuous laser source. In this work, we refined the optical detection scheme in order to work with low photons flux,
based on two-phase heterodyne interferometry setup. We used tissue-mimicking phantoms with different optical and
shear mechanical contrast. We demonstrate that it is possible to detect both types of contrast, and moreover to
discriminate between these two types of contrast.
We present a camera-based optical detection scheme designed to detect the transient motion created by the acoustic radiation force in elastic media. An optically diffusive tissue mimicking phantom was illuminated with coherent laser light, and a high speed camera (2 kHz frame rate) was used to acquire and cross-correlate consecutive speckle patterns. Time-resolved transient decorrelations of the optical speckle were measured as the results of localised motion induced in the medium by the radiation force and subsequent propagating shear waves. As opposed to classical acousto-optic techniques which are sensitive to vibrations induced by compressional waves at ultrasonic frequencies, the proposed technique is sensitive only to the low frequency transient motion induced in the medium by the radiation force. It therefore provides a way to assess both optical and shear mechanical properties.
We study the statistical behavior of TCP traffic traces through their wavelet decomposition, and show that the marginal distribution of the wavelet coefficients is a 1.5- stable law. Taking advantage of the correlation between the Haar coefficients, we then give a representation to the signal in terms of Weakly Self-Affine functions, which are a generalization of `fractal' functions, and allow a parsimonious representation of the data.
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