SignificancePhotoacoustic (PA) technology shows great potential for bone assessment. However, the PA signals in cancellous bone are complex due to its complex composition and porous structure, making such signals challenging to apply directly in bone analysis.AimWe introduce a photoacoustic differential attenuation spectrum (PA-DAS) method to separate the contribution of the acoustic propagation path to the PA signal from that of the source, and theoretically and experimentally investigate the propagation attenuation characteristics of cancellous bone.ApproachWe modified Biot’s theory by accounting for the high frequency and viscosity. In parallel with the rabbit osteoporosis model, we build an experimental PA-DAS system featuring an eccentric excitation differential detection mechanism. Moreover, we extract a PA-DAS quantization parameter—slope—to quantify the attenuation of high- and low-frequency components.ResultsThe results show that the porosity of cancellous bone can be evaluated by fast longitude wave attenuation at different frequencies and the PA-DAS slope of the osteoporotic group is significantly lower compared with the normal group (**p<0.01).ConclusionsFindings demonstrate that PA-DAS effectively differentiates osteoporotic bone from healthy bone, facilitating quantitative assessment of bone mineral density, and osteoporosis diagnosis.
SignificanceCollagen and lipid are important components of tumor microenvironments (TME) and participates in tumor development and invasion. It has been reported that collagen and lipid can be used as a hallmark to diagnosis and differentiate tumors.AimWe aim to introduce photoacoustic spectral analysis (PASA) method that can provide both the content and structure distribution of endogenous chromophores in biological tissues to characterize the tumor-related features for identifying different types of tumors.ApproachEx vivo human tissues with suspected squamous cell carcinoma (SCC), suspected basal cell carcinoma (BCC), and normal tissue were used in this study. The relative lipid and collagen contents in the TME were assessed based on the PASA parameters and compared with histology. Support vector machine (SVM), one of the simplest machine learning tools, was applied for automatic skin cancer type detection.ResultsThe PASA results showed that the lipid and collagen levels of the tumors were significantly lower than those of the normal tissue, and there was a statistical difference between SCC and BCC (p < 0.05), consistent with the histopathological results. The SVM-based categorization achieved diagnostic accuracies of 91.7% (normal), 93.3% (SCC), and 91.7% (BCC).ConclusionsWe verified the potential use of collagen and lipid in the TME as biomarkers of tumor diversity and achieved accurate tumor classification based on the collagen and lipid content using PASA. The proposed method provides a new way to diagnose tumors.
Ocular neovascularization occurs in various eye diseases such as diabetic retinopathy, neovascular macular degeneration, and retinopathy of prematurity. Current treatment methods including conventional laser ablation therapy and anti-vascular endothelial growth factor (VEGF) injection each has drawbacks including collateral tissue damages, frequent administration, high cost, and drug toxicity. We recently developed a novel noninvasive image-guided photo-mediated ultrasound therapy (PUT) which concurrently applies nanosecond laser pulses and millisecond ultrasound bursts to precisely and safely remove pathologic microvessels in the eye. Relying on the mechanism of photoacoustic cavitation, PUT takes advantages of high optical contrast among biological tissues, and can selectively remove microvessels without causing collateral tissue damage.
To achieve personalized treatment with optimal treatment outcome, a multi-modality eye imaging system involving advanced photoacoustic microscopy (PAM) and optical coherence tomography (OCT) has been integrated with the PUT system to provide real-time feedback and online evaluation of the treatment outcome. To assess the performance of this image-guided PUT system, experiments have been conducted on rabbit eye models. During the treatment, cavitation signals were observed and monitored by OCT with good sensitivity, suggesting that OCT can be used to evaluate treatment effect in real time. The PAM was capable of mapping the 3D distributed microvessels with excellent image quality, demonstrating that PAM can help to quantitatively evaluate the treatment outcome. As indicated by the initial results from this study, imaging guidance involving both PAM and OCT could further improve the efficacy and safety of the newly invented PUT, accelerating its translation to ophthalmology clinic.
Port-wine stain (PWS) is a discoloration of human skin caused by a vascular anomaly (i.e., capillary malformation in the skin). In the past years, several techniques have been developed for characterization and treatment evaluation of PWS. However, each of them has some limitations. Optical methods working in the ballistic regime, such as dermoscopy and VISIA, do not have sufficient penetration to cover the entire scale of PWS. High frequency ultrasound, although with better imaging depth, does not offer sufficient contrast to differentiate PWS and normal skin tissue. Therefore, current endpoint clinical assessment for PWS still relies on physicians’ subjective judgement. In this study, photoacoustic (PA) imaging utilizing light emitting diodes (LED) as the light source was adapted to the evaluation of PWS and response to photodynamic therapy (PDT). PA images as well as US images of the targeted skin area before and at different time points after the treatment were acquired. The imaging results from adults and children were also compared. The imaging findings demonstrate that the PWS levels of adult patients are significantly higher than children (p<0.01), which fits well with the knowledge that the vessel malefaction degree develops with patients’ age. The 2-month follow-up study on four children shows that the average PWS level reduced for 33.60%onstrat (p<0.01) as a result of 3-4 times of PDT treatment. This initial clinical trial on patients suggests PA imaging holds potential for quantitative assessment of PWS in clinical settings.
Transrectal ultrasound (TRUS) guided biopsy is the standard procedure for evaluating the presence of prostate cancer. TRUS, however, has limited sensitivity to prostate tumors, nor can it differentiate aggressive cancer from non-aggressive ones. The emerging photoacoustic (PA) imaging combined with TRUS offers a great promise to solve this overarching issue, especially when powered by tumor-targeting contrast agent. In this work, we studied the feasibility of PA imaging to cover the entire prostate by using light illumination via the urethral track. Experiment was conducted on whole human prostates ex vivo. The light source was an array of light emitting diodes (LED) which has many advantages compared to solid state laser. The LED array was placed in the urethra, delivering light with fluence within the ANSI safety limit. A PA and ultrasound (US) dual modality system acquired the images in the same way as in TRUS. The imaging target was a 1-mm tube filled with ICG solution, mimicking the situation of a prostate tumor labeled with ICG contrast agent. The imaging results demonstrated that PA imaging can detect the ICG-filled tube at any place in the prostate, with an imaging depth over 20 mm. This study validated that PA imaging, when performed in a transrectal manner and combined with transurethral light illumination, is capable of molecular level imaging of the entire prostate noninvasively. The high sensitivity offered by PA imaging in detecting aggressive prostate cancer may contribute to prostate cancer management, e.g., enabling more accurate guidance for needle biopsy.
Hyperosteogeny and Osteoporosis are two common bone diseases that have a high incidence in the middle-aged and elderly groups. Mild symptoms may only affect the daily life of patients, while severe ones are life-threatening. At present, detection methods based on X-ray film and ultrasound are generally applied. However, the former exist errors introduced by manual reading and a certain radiation hazard, the diagnostic results of the latter are not that satisfying as well. Photoacoustic effect combines the advantages of optics for sensitive light absorption contrast and acoustics for lower acoustic scattering in soft tissue. As a non-ionizing and non-invasive technique, its application in biomedicine is also emerging. In this paper, a classification model built on Convolutional Neural Network (CNN) was proposed to achieve automated diagnosis of hyperosteogeny, osteoporosis and normal bone. Time-domain photoacoustic signals generated by different bone types are set as the inputs of the CNN while the output results indicate the corresponding categories of the samples. The analysis results of ex vivo data demonstrated that the established model could accurately accomplish the research of classification. Thus, the proposed method has certain auxiliary value for improving the efficiency, accuracy and objectivity of clinical diagnosis of the three bone types.
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.
In the ultrasonic testing of submarine pipelines by using guided waves, wave energy leakage is a main reason of signal decay. For overcoming the decrease of energy attenuation, the propagation of guided waves of immersion plates is studied in this paper. The dispersion equations of guided waves is numerically solved. Then the appropriated modes of which phase velocity are small or large are selected for optical Schlieren visualization and propagation of leaky waves is discussed. It is shown that selecting some modes of which imaginary part are small can retard guided wave decay and extend length of testing.
We have developed a safe, noninvasive imaging-guided localized antivascular method, namely photo-mediated ultrasound therapy (PUT), by applying synchronized laser and ultrasound pulses. Through our experimental and theoretical studies, we demonstrate that cavitation plays a key role in PUT. PUT promotes cavitation activity in blood vessels by concurrently applying ultrasound bursts and nanosecond laser pulses. The collapse of cavitation can induce damage to blood vessel endothelial cells, resulting in occlusion of microvessels. This study presents the effect of laser pulse energy, laser pulse length, ultrasound intensity, and synchronization time between laser and ultrasound. We found that, in order to produce controllable blood vessel occlusion, linear oscillation of cavitation (or non-inertial cavitation) might be the key, while strong collapse of cavitation (inertial cavitation) might induce bleeding. Under the guidance an optical coherence tomography (OCT) system, we utilized PUT to remove microvessels in the rabbit choroid. We were able to monitor cavitation activity in real-time in vivo during PUT treatment, and predict treatment outcome. Histology findings confirmed that fibrin clots were developed in the microvessels in the treated region, while no damage was found in the surrounding tissue.
Transrectal ultrasound (TRUS) guided biopsy is the standard procedure for evaluating the presence and aggressiveness of prostate cancer (PCa). The microarchitecture of each biopsied tissue is assigned a Gleason score, a highly prognostic architecture-based grading system for PCa. Due to the limited sensitivity of TRUS imaging to PCa, less than 10% of the sample cores are clinically significant, yet the false negative rate could be 20% at the initial biopsies. A diagnostic modality that can assess the microarchitectures within the prostates in vivo without tissue extraction could significantly reduce the unnecessary biopsy cores and the post-procedure complications. Our previous study has shown that photoacoustic physio-chemical analysis (PAPCA) can quantify the architectural heterogeneities in the prostate. Our recently developed needle PA probe has facilitated the minimally invasive acquisition of PA signals with sufficient temporal length and narrow dynamic range in deep tissue for statistics-based PAPCA.
This study investigates the PCa diagnosis by PAPCA of the signals acquired by the needle PA probe. A total of 45 interstitial measurements were acquired (21 in normal and 24 in cancerous regions) in 10 ex vivo human prostates. A significant difference was found in the architectural heterogeneities between the normal and cancerous regions (p<0.005). Areas-under-the-curve of 0.8 has been observed for identifying PCa using the quantitative features. Quantification of the architectural changes in vivo in a transgenic mouse model of PCa is under investigation. The preliminary test has shown a significant difference between the normal and cancerous mouse prostates ex vivo (p<0.005).
Wet age-related macular degeneration (AMD) is a leading cause of vision loss in the United States. Choroidal neovascularization (CNV), the creation of new blood vessels in the choroid layer of the eye, plays a central role in the pathophysiology of wAMD. Despite advanced anti-VEGF therapy, 20% of patients become legally blind and other 30% suffer significant vision loss after 5 years. Given the significant burden imposed by wAMD on a growing aging population, there is an urgent need for developing new therapeutic techniques to remove microvessels induced by CNV. We developed a safe, noninvasive imaging-guided photo-mediated ultrasound therapy (PUT) technique as a localized antivascular method, and applied it to remove microvessels in the rabbit choroid. This technique promotes cavitation activity in blood vessels by concurrently applying ultrasound bursts and nanosecond laser pulses. The collapse of cavitation can induce damage to blood vessel endothelial cells, resulting in occlusion of microvessels. PUT takes advantages of the high native optical contrast among biological tissues, and has the unique capability to self-target microvessels without causing surrounding damages. Under the guidance of a fundus camera and an optical coherence tomography (OCT) system, our PUT system now has the capability to precisely target the treating area before the treatment procedure (through the fundus camera), and real-time intra-treatment cavitation monitor to evaluate the therapeutic effect (through the OCT system). Additionally, the safety of PUT technique is confirmed by histopathological studies.
KEYWORDS: Deconvolution, Signal processing, Signal detection, Image quality, Transducers, Photoacoustic imaging, Tissue optics, Ultrasonography, Reconstruction algorithms, Signal to noise ratio
Photoacoustic (PA) signal of an ideal optical absorb particle is a single N-shape wave. PA signals of a complicated biological tissue can be considered as the combination of individual N-shape waves. However, the N-shape wave basis not only complicates the subsequent work, but also results in aliasing between adjacent micro-structures, which deteriorates the quality of the final PA images. In this paper, we propose a method to improve PA image quality through signal processing method directly working on raw signals, which including deconvolution and empirical mode decomposition (EMD). During the deconvolution procedure, the raw PA signals are de-convolved with a system dependent point spread function (PSF) which is measured in advance. Then, EMD is adopted to adaptively re-shape the PA signals with two constraints, positive polarity and spectrum consistence. With our proposed method, the built PA images can yield more detail structural information. Micro-structures are clearly separated and revealed. To validate the effectiveness of this method, we present numerical simulations and phantom studies consist of a densely distributed point sources model and a blood vessel model. In the future, our study might hold the potential for clinical PA imaging as it can help to distinguish micro-structures from the optimized images and even measure the size of objects from deconvolved signals.
Photoacoustic physio-chemical analysis (PAPCA) is a recently developed technology capable of simultaneously quantifying the content of molecular components and the corresponding microarchitectures in biological tissue. We have successfully quantified the diagnostic information in livers with PAPCA. In this study, we implemented PAPCA to the diagnosis of prostate cancers. 4 human prostates were scanned ex vivo. The PA signals from normal and cancerous regions in the prostates were acquired by an interstitial needle PA probe. A total of 14 interstitial measurements, including 6 within the normal regions and 8 in the cancerous regions, were acquired. The observed changes in molecular components, including lipid, collagen and hemoglobin were consistent with the findings by other research groups. The changes were quantified by PA spectral analysis (PASA) at wavelengths where strong optical absorption of the relevant molecular components was found. Statistically significant differences among the PASA parameters were observed (p=0.025 at significance of 0.05). A support vector machine model for differentiating the normal and cancerous tissue was established. With the limited number of samples, an 85% diagnostic accuracy was found. The diagnostic information in the PCPCA can be further enriched by targeted optical contrast agents visualizing the microarchitecture in PCa tissues. F3 PAA-PEG nanoparticles was employed to stain the PCa cells in a transgenic mouse model, in which the microarchitectures of normal and cancerous prostate tissues are comparable to that in human. Statistically significant differences were observed between the contrast-enhanced normal and cancerous regions (p=0.038 at a significance of 0.05).
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.
Gold nanoparticles (AuNPs) have been extensively explored as a model nanostructure in nanomedicine and have been widely used to provide advanced biomedical research tools in diagnostic imaging and therapy. Due to the necessity of targeting AuNPs to individual cells, evaluation and visualization of AuNPs in the cellular level is critical to fully understand their interaction with cellular environment. Currently imaging technologies, such as fluorescence microscopy and transmission electron microscopy all have advantages and disadvantages. In this paper, we synthesized AuNPs by femtosecond pulsed laser ablation, modified their surface chemistry through sequential bioconjugation, and targeted the functionalized AuNPs with individual cancer cells. Based on their high optical absorption contrast, we developed a novel, label-free imaging method to evaluate and visualize intracellular AuNPs using photoacoustic microscopy (PAM). Preliminary study shows that the PAM imaging technique is capable of imaging cellular uptake of AuNPs in vivo at single-cell resolution, which provide an important tool for the study of AuNPs in nanomedicine.
Sound velocity measurement is of great importance to the application of biomedical especially in the research of acoustic detection and acoustic tomography. Using correct sound velocities in each medium other than one unified sound propagation speed, we can effectively enhance sound based imaging resolution. Photoacoustic tomography (PAT), is defined as cross-sectional or three-dimensional (3D) imaging of a material based on the photoacoustic effect and it is a developing, non-invasive imaging method in biomedical research. This contribution proposes a method to concurrently calculate multiple acoustic speeds in different mediums. Firstly, we get the size of infra-structure of the target by B-mode ultrasonic imaging method. Then we build the photoacoustic (PA) image of the same target with different acoustic speed in different medium. By repeatedly evaluate the quality of reconstruct PA image, we dynamically calibrate the acoustic speeds in different medium to build a finest PA image. Thus, we take these speeds of sound as the correct acoustic propagation velocities in according mediums. Experiments show that our non-invasive method can yield correct speed of sound with less than 0.3% error which might benefit future research in biomedical science.
Photoacoustic (PA) technique involving both ultrasound and light has been explored for potential application in the assessment of bone health. The optical and ultrasound penetration in bone have been studied. The feasibility of conducting 3D PA imaging of bone, and performing quantitative evaluation of bone microstructures by using photoacoustic spectrum analysis (PASA) has also been investigated. The findings from the experiments demonstrate that PA measurement could offer information of bone mineral density and bone microstructure, both relevant to bone health.
Laser-induced thermotherapy (LITT), i.e. tissue destruction induced by a local increase of temperature by means of laser light energy transmission, has been frequently used for minimally invasive treatments of various diseases such as benign thyroid nodules and liver cancer. The emerging photoacoustic (PA) imaging, when integrated with ultrasound (US), could contribute to LITT procedure. PA can enable a good visualization of percutaneous apparatus deep inside tissue and, therefore, can offer accurate guidance of the optical fibers to the target tissue. Our initial experiment demonstrated that, by picking the strong photoacoustic signals generated at the tips of optical fibers as a needle, the trajectory and position of the fibers could be visualized clearly using a commercial available US unit. When working the conventional US Bscan mode, the fibers disappeared when the angle between the fibers and the probe surface was larger than 60 degree; while working on the new PA mode, the fibers could be visualized without any problem even when the angle between the fibers and the probe surface was larger than 75 degree. Moreover, with PA imaging function integrated, the optical fibers positioned into the target tissue, besides delivering optical energy for thermotherapy, can also be used to generate PA signals for on-line evaluation of LITT. Powered by our recently developed PA physio-chemical analysis, PA measurements from the tissue can provide a direct and accurate feedback of the tissue responses to laser ablation, including the changes in not only chemical compositions but also histological microstructures. The initial experiment on the rat liver model has demonstrated the excellent sensitivity of PA imaging to the changes in tissue temperature rise and tissue status (from native to coagulated) when the tissue is treated in vivo with LITT.
Stiffness of arteries, especially small arteries, is an important marker for many diseases and a good parameter to evaluate the risks of cardiovascular problems. In this research, we proposed a new method for measurement of local arterial distensibility by using photoacoustic microscopy (PAM) technology. Taking advantages from its excellent sensitivity and high spatial resolution, PAM can evaluate the morphology and volume change of a small artery accurately without involving any contrast agent. When working in the linear elastic range of a vessel, measuring the initial and the distended diameters of the vessel before and after pressure change facilitates quantitative assessment of vessel distensibility. The preliminary experiment on well-controlled gel phantoms demonstrates the feasibility of this technology.
Photoacoustic (PA) measurements encode the information associated with both physical microstructures and chemical contents in biological tissues. A two-dimensional physio-chemical spectrogram (PCS) can be formulated by combining the power spectra of PA signals acquired at a series of optical wavelengths. The analysis of PCS, or namely PA physio-chemical analysis (PAPCA), enables the quantification of the relative concentrations and the spatial distributions of a variety of chemical components in the tissue. This study validated the feasibility of PAPCA in characterizing liver conditions during the progression of non-alcoholic fatty liver disease. A catheter based setup facilitating measurement in deep tissues was also tested.
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