This study illustrates the potential of non-invasive Photoacoustic Microscopy (PAM) to monitor functional changes in a squirrel monkey brain due to peripheral mechanical stimulation. Our unique approach employs a deep Fully Convolutional Neural Network (FCNN) to significantly enhance PAM image quality, improving signal-to-noise ratio and structural similarity index. Notably, functional changes induced by peripheral mechanical stimulation were effectively observed. The study showcases the potential of PAM in neurological applications, advancing our understanding of brain hemodynamics, and the transformative effect of machine learning techniques on PAM image quality, opening new possibilities for future neuroscientific research.
Quantification of fibrosis is critical for the management of inflammatory bowel disease. In this study, photoacoustic (PA) strain imaging were used to estimate intestinal stiffness during the progression of intestinal fibrosis in 23 rabbits in vivo. The tissue was then harvested to measure the young’s modulus ex vivo. Collagen-to-Hb ratio measured using spectroscopic PA imaging was also recorded. Results show that PA-strain is positively correlated to Young’s Modulus with a correlation coefficient of 0.81. PA-strain distinguishes the low histological fibrosis (0-2) and high histological fibrosis (3-5) significantly (p-value<0.001). Collagen-to-Hb ratio and PA-strain are highly correlated with the histological fibrosis (0-5) with correlation of 0.67 and 0.64, respectively.
Quantification of fibrosis is critical for the management of inflammatory bowel disease. In this study, two measurements, collagen-to-Hb ratio quantified by spectroscopic analysis and tissue stiffness quantified by PA-strain, measured by our PA-US balloon catheter were employed to quantify intestinal fibrosis in 23 rabbits in vivo. Results show that both measurements can distinguish the low histological fibrosis (0-2) and high histological fibrosis (3-5) with statistical significance (p-value<0.001). Collagen-to-Hb ratio and PA-strain are highly correlated with the fibrosis stages with correlation of 0.67 and 0.64, respectively. PA-strain is positively correlated to Young’s Modulus measured ex vivo using microelastometer with correlation 0.81.
The feasibility of using photoacoustic imaging (PAI) to measure electrically-evoked hemodynamic responses in a squirrel monkey brain in vivo was examined. A linear-array photoacoustic computed tomography (PACT) system and a high-resolution photoacoustic microscopy (PAM) system were built for imaging subcortical and cortical brain regions, respectively. The hemodynamic responses at multiple cortices, including premotor, primary motor, and primary somatosensory cortices, were monitored. The variations could be observed in all cortices and their underlying cortical and subcortical brain regions. The results from this study validated the potential of PAI technique for multiscale and multi-resolution functional brain mapping for non-human primates.
Stiffness is a biomarker to distinguish intestinal inflammation and fibrosis in Crohn’s disease. This study investigated the performance of an endoscopic photoacoustic (PA)-ultrasound (US) catheter probe in quantifying intestinal stiffness in rabbits in vivo. The probe integrated a miniaturized US array and a side-firing fiber optic inside a medical balloon catheter. During the balloon dilation, the ratios between the intestinal wall deformation and PA signal change were quantified. The strain-PA ratios measured in vivo demonstrated a correlation of 0.8 (n=55, p=0.01) with the Young’s moduli of the assessed intestinal segments determined by microelastometry ex vivo.
The current functional brain mapping techniques such as fMRI and DOI suffer from limited spatial resolution. Photoacoustic (PA) imaging combines the sensitivity of optical imaging to hemodynamic variations, and spatial resolution of ultrasound detection. In this study, we built a label-free PA computed tomography (PACT) system with a ring-shaped ultrasound array to monitor the hemodynamic changes in the primary visual cortex (V1) of mice in response to retinal photostimulation. The responses of wild-type and retinal degenerate (rd1) mice were compared. A linear-array PACT system was also used to measure the visually-evoked subcortical responses. Therefore, PACT is potential tool to study the effect of retinal degeneration of mice on the visual pathway.
Photo-mediated ultrasound therapy (PUT) is a novel, non-invasive, and agent-free therapeutic technique that uses a combination of relatively low-intensity ultrasound bursts and nanosecond laser pulses to selectively and precisely remove highly optically absorptive targets. In this work, we developed an integrated ultrasound photoacoustic theranostic system (UPTS) by combining a ultrasound system (V1, Verasonics) with a pulsed laser system. The results from the ex vivo experiments in rabbit tissues demonstrated that UPTS, by working with appropriate laser wavelengths, can selectively remove tissues such as knee tendon and liver via the cavitation synergistically created by the ultrasound bursts and the laser pulses. Such a theranostic system can deliver effective PUT treatment to biological samples along with real-time monitoring by the integrated ultrasound and photoacoustic imaging.
Distinguishing between acute and chronic intestinal obstruction is essential for the treatment of Crohn's disease (CD). We have demonstrated the capability of spectroscopy photoacoustic (PA) imaging in quantifying hemoglobin and collagen changes. We also developed strain-PA imaging as a novel method for quantifying the intestinal stiffness, which is a mechanical marker of CD. In this study, we combined the spectroscopy and stiffness measurements using a catheter probe and examined the proposed approach in a rabbit model of CD in vivo. The quantitative accuracy of the imaging was validated by histology and micro-elastometry.
To eliminate the limited angle effect of photoacoustic imaging based on ultrasound linear array, spatially distributed ultrasound sensor array is applied. The accurate sensor array position determines the quality of the imaging results. We proposed two methods based on photoacoustic and ultrasound signals to enhance the imaging quality using a full-ring array. Photoacoustic signals are used to regress the position of each element sensor. In phantom study and mouse brain study, imaging results can yield details clearly with average error rate of less than 50 μm. The proposed methods can contribute to precise biomedical imaging in future application scenarios.
Photoacoustic (PA) imaging has shown its capability of characterizing intestinal inflammation and fibrosis endoscopically. With the purpose of clinical translation, we developed an endoscopic probe integrating an intracardiac ultrasound array and an 800 µm side-firing fiber optic inside a medical balloon catheter. The catheter probe, when collapsed, fits to the instrument channel of a colonoscope and can inflate for acoustic coupling when positioned at the disease location inside intestine. The performance of the probe in assessing the disease conditions including inflammation, fibrosis and muscle hypertrophy is under investigation in rabbits in vivo. The imaging results are validated by histopathology.
KEYWORDS: Photoacoustic spectroscopy, Imaging spectroscopy, Spectroscopy, Photoacoustic imaging, Human subjects, Inflammation, Brain-machine interfaces, Animal model studies, In vivo imaging, Collagen
Identifying fibrosis against inflammation in the intestinal strictures is critical to the management of CD.
Our pioneering study has shown that spectroscopic photoacoustic (PA) imaging is capable of
differentiating inflammatory and fibrotic intestinal strictures in animals in vivo. We also validated the
feasibility of acquiring PA signals from intestinal strictures transcutaneously. In this study, we further
investigated the capability of transcutaneous PA imaging in characterizing intestinal inflammation and
fibrosis in human subjects. The findings in PA imaging were validated by US Doppler images and
histopathology.
Our previous research has demonstrated that photoacoustic (PA) imaging is capable of evaluating the pathological condition in human peripheral joints affected by inflammatory arthritis. In this work, we tested the performance of a PA imaging system based on the LED light source and its performance for arthritis imaging. The LED-based PA imaging system not only has less cost but also has smaller footprint and, hence, is more portable and convenient for use in rheumatology clinic. 2D B-scan PA and US images of each metacarpophalangeal (MCP) joint were acquired along the sagittal sections. Along the same sections, US Doppler images were also acquired. Images from 12 joints with clinically active arthritis (i.e., positive on Doppler US), 5 joints with subclinically active arthritis (i.e., negative on Doppler US), and 12 joints of normal volunteers were compared. The blood volume in each joint reflecting hyperemia was quantified by counting the density of the color pixels in each pseudo-color PA image. T-tests were conducted to evaluate whether PA imaging can differentiate the three groups. The results from this study suggest that LED-based PA imaging is capable of detecting hyperemia as an important biomarker of joint inflammation. In addition, PA imaging could differentiate the subclinically active arthritis group and the normal group while Doppler US could not, suggesting that PA imaging has higher sensitivity to mildly hyperemia when compared to Doppler US. The imaging technique presented may contribute to rheumatology clinic by providing a new tool for early diagnosis and treatment evaluation of joint inflammation.
KEYWORDS: Reconstruction algorithms, Transducers, Signal to noise ratio, Photoacoustic imaging, Computer simulations, Signal detection, Photoacoustic spectroscopy, Interference (communication), Real time imaging, Image restoration
Delay and Sum (DAS) is one of the most common beamforming algorithms for photoacoustic imaging reconstruction that can function well in real-time imaging for its simplicity and quickness. However, high sidelobes and intense artifacts usually appear in the reconstructed image using DAS algorithm. To solve this problem, a novel beamforming algorithm called Multiple Delay and Sum with Enveloping (multi-DASE) is introduced in this paper, which can suppress sidelobes and artifacts efficiently. Compared to DAS, multi-DASE beamforming algorithm calculates not only the initial beamformed signal but also the N-shaped photoacoustic signal for each pixel. Firstly, Delay and Sum is performed multiply based on time series to recover the N-shaped photoacoustic signal for each pixel in the reconstructed image. And then, the recovered signal is enveloped to transform the N-shaped wave into a pulse wave to remove the negative part of the signal. Finally, signal suppression is performed on the enveloped signal which can lead to the suppression of sidelobes and artifacts in the reconstructed image. The multi-DASE beamforming algorithm was tested on the simulated data acquired with MATLAB k-Wave Toolbox. Experiment was also conducted to evaluate the efficiency of the multiDASE algorithm for clinical application. Both in computer simulation and experiment, our multi-DASE beamforming algorithm showed great performance in removing artifacts and improving image quality. In our multi-DASE beamforming algorithm, only fundamental operations and Discrete Fourier Transform (DFT) are performed, which means it can be a promising method for real-time clinical application.
Light-emitting diode (LED) light sources have recently been introduced to photoacoustic imaging (PAI). The LEDs enable a smaller footprint for PAI systems when compared to laser sources, thereby improving system portability and allowing for improved access. An LED-based PAI system has been employed to identify inflammatory arthritis in human hand joints. B-mode ultrasound (US), Doppler, and PAIs were obtained from 12 joints with clinically active arthritis, five joints with subclinically active arthritis, and 12 normal joints. The quantitative assessment of hyperemia in joints by PAI demonstrated statistically significant differences among the three conditions. The imaging results from the subclinically active arthritis joints also suggested that the LED-based PAI has a higher sensitivity to angiogenic microvascularity compared to US Doppler imaging. This initial clinical study on arthritis patients validates that PAI can be a potential imaging modality for the diagnosis of inflammatory arthritis.
The change of tissue elasticity has been recognized as a biomarker of many disease conditions. Elastography has been investigated by observing the strain and stress correlation or shear wave propagation in tissue. The strain measurement can be achieved via speckle tracking in ultrasound (US) and optical modalities whereas the stress in deep tissue cannot be directly measured. Assuming that the collapsing of the vasculature could reflect the stress exerted on a tissue volume, the photoacoustic (PA) signals of the hemoglobin content within the vasculature could be an alternative measurement of the stress. This study investigates the strain-PA correlation with phantoms and a rat model in vivo. Parallel PA-US imaging was achieved by combining a compact linear US array and fiber optics delivering 720nm illumination. The phantom study simulated the vasculature with a piece of sponge soaked in ink, and the surrounding tissue with porcine gel with varied elasticity. The strain was generated by pushing the PA-US probe against the phantom surface. A correlation of 0.9 was found between the strain within the sponge and the PA signal changes. The rat model possesses inflammatory and fibrotic intestinal strictures comparable to those in the Crohn’s disease patients. The strain within the strictures was achieved by pushing the PA-US probe against the rats’ abdominal walls. Approximately twice more significant PA signal changes were observed in the fibrotic strictures than those in inflammatory ones under the same strain (p<0.001). All the results support that strain-PA imaging is capable of estimating the tissue elasticity.
Crohn’s disease (CD) is a chronic autoimmune disease of the intestinal tract affecting 700,000 people in the United States. The pathology of CD is characterized by obstructing intestinal strictures due to inflammation (with high levels of hemoglobin), fibrosis (with high levels of collagen), or a combination of both. The accurate characterization of the intestinal strictures is critical, as the fibrotic intestinal strictures have to be removed surgically. Currently, there is no imaging modality that can differentiate the fibrotic and inflammatory strictures. Standard diagnosis by endoscopic biopsy suffers from the post-procedure complications, and limited sampling locations and depth.
Combining the optical spectroscopy and ultrasound (US) imaging, photoacoustic (PA) imaging is an ideal tool for resolving the molecular components of the intestinal strictures. This study investigates the feasibility of differentiating the fibrotic and inflammatory intestinal strictures using PA-US parallel imaging in a rat model in vivo. A linear US array was used to acquire US and PA imaging transcutaneously. PA imaging with endoscopic and transcutaneous illumination was attempted in 12 and 10 animals, respectively. The PA images were acquired at 750, 850 and 1310 nm. The PA pixel intensities within the intestinal stricture regions were quantified. Blood oxygenation, as well as the relative ratio between the total hemoglobin and collagen contents, were derived. Significant differences were observed between the fibrotic and inflammatory strictures (p<0.05). The penetration of the noninvasive transcutaneous PA imaging was also tested in human subjects using a low-frequency probe. Penetration as deep as 6 cm was achieved.
Presenting highly sensitive functional information in subsurface tissue with spatial resolution comparable to ultrasound imaging, the emerging photoacoustic (PA) imaging may shed new lights to early diagnosis and treatment monitoring of human inflammatory arthritis. This paper will introduce our recent development of LED-based PA imaging and its application to human inflammatory arthritis. Facilitated by the high pulse repetition rate of the LED arrays, extensive averaging of PA signal can be performed, which boosts the signal-to-noise ratio of the LED-based PA imaging system to levels comparable to laser-based PA imaging systems. In the experiments on arthritis patients and normal volunteers, each target finger joint is scanned using the LED-based PA imaging system which is integrated with a B-scan ultrasound (US) facilitating dual imaging modalities simultaneously. 2D PA and US of a sagittal section in the joint can be acquired in a real-time fashion with a frame rate up to 30 Hz; while a series of 2D images acquired along the cross sections of the joint can be reconstructed into a 3D image for analyzing the volumetric biomarkers of joint inflammation. In this initial study on human subjects, we have confirmed the feasibility of LED-based PA imaging in detecting and characterizing arthritic joints by evaluating the hemodynamic changes associated with soft-tissue inflammation. PA imaging findings are compared to the results from Doppler US acquired using a commercial US unit. This study demonstrates that the LED-based PA imaging can be developed into a point-of-care diagnostic tool for rheumatology and radiology clinics.
In B-mode images from dual-sided ultrasound, it has been shown that by delineating structures suspected of being
relatively homogeneous, one can enhance limited angle tomography to produce speed of sound images in the same view
as X-ray Digital Breast Tomography (DBT). This could allow better breast cancer detection and discrimination, as well
as improved registration of the ultrasound and X-ray images, because of the similarity of SOS and X-ray contrast in the
breast. However, this speed of sound reconstruction method relies strongly on B-mode or other reflection mode
segmentation. If that information is limited or incorrect, artifacts will appear in the reconstructed images. Therefore, the
iterative speed of sound reconstruction algorithm has been modified in a manner of simultaneously utilizing the image
segmentations and removing most artifacts. The first step of incorporating a priori information is solved by any nonlinearnonconvex
optimization method while artifact removal is accomplished by employing the fast split Bregman method to
perform total-variation (TV) regularization for image denoising. The proposed method was demonstrated in simplified
simulations of our dual-sided ultrasound scanner. To speed these computations two opposed 40-element ultrasound linear
arrays with 0.5 MHz center frequency were simulated for imaging objects in a uniform background. The proposed speed
of sound reconstruction method worked well with both bent-ray and full-wave inversion methods. This is also the first
demonstration of successful full-wave medical ultrasound tomography in the limited angle geometry. Presented results
lend credibility to a possible translation of this method to clinical breast imaging.
Photoacoustic spectrum analysis (PASA) offers potential advantages in identifying optically absorbing microstructures in biological tissues. Working at high ultrasound frequency, PASA is capable of identifying the morphological features of cells based on their intrinsic optical absorption. Adipocyte size is correlated with metabolic disease risk in the form of diabetes mellitus, thus it can be adopted as a pathology predictor to evaluate the condition of obese patient, and can be helpful for assessing the patient response to bariatric surgery. In order to acquire adipocyte size, usually adipose tissue biopsy is performed and histopathology analysis is conducted. The whole procedure is not well tolerated by patients, and is also labor and cost intensive. An unmet need is to quantify and predict adipocyte size in a mild and more efficient way. This work aims at studying the feasibility to analyze the adipocyte size of human fat tissue using the method of PASA. PA measurements were performed at the optical wavelength of 1210 nm where lipid has strong optical absorption, enabling the study of adipocyte without need of staining. Both simulation and ex vivo experiments have been completed. Good correlation between the quantified photoacoustic spectral parameter slope and the average adipocyte size obtained by the gold-standard histology has been established. This initial study suggests the potential opportunity of applying PASA to future clinical management of obesity.
Osteoporosis is a progressive bone disease which is characterized by a decrease in the bone mass and deterioration in bone micro-architecture. In theory, photoacoustic (PA) imaging analysis has potential to obtain the characteristics of the bone effectively. Previous study demonstrated that photoacoustic spectral analysis (PASA) method with the qualified parameter slope could provide an objective assessment of bone microstructure and deterioration. In this study, we tried to compare PASA method with the traditional quantitative ultrasound (QUS) method in osteoporosis assessment. Numerical simulations of both PA and ultrasound (US) signal are performed on computerized tomographic (CT) images of trabecular bone with different bone mineral densities (BMDs). Ex vivo experiments were conducted on porcine femur bone model of different BMDs. We compared the quantified parameter slope and the broadband ultrasound attenuation (BUA) coefficient from the PASA and QUS among different bone models, respectively. Both the simulation and ex vivo experiment results show that bone with low BMD has a higher slope value and lower BUA value. Our result demonstrated that the PASA method has the same efficacy with QUS in bone assessment, considering PA is a non-ionizing, non-invasive technique, PASA method holds potential for clinical diagnosis in osteoporosis and other bone diseases.
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