Full‐field 3D photoacoustic imaging based on plane transducer array and spatial phase‐controlled algorithm

Compared to piezoelectric based photoacoustic (PA) scanners, the planar Fabry-Perot (FP) scanner has several advantages. It can provide small element size with high sensitivity, a smooth broadband frequency response, and is transparent to excitation light. This enables the FP scanner to provide excellent high-resolution in vivo PA images of soft tissue to depths up to approximately 10 mm. However, unlike piezoelectric scanners, the FP scanner in its current form cannot provide a pulse-echo ultrasound (US) as well as a PA image, which is useful because of the additional tissue contrast it provides. To address this, a dual mode FP scanner-based system that, for the first time, can acquire co-registered 3D PA and US images has been developed. In order to provide an optical US generation capability, the FP ultrasound sensor was coated with a novel Gold-Nanoparticle-PDMS composite which was excited with nanosecond laser pulses to generate plane wave US pulses. By modifying the FP sensor in this way, it now acts as an US transmitter as well as a receiver. The coating is highly absorbing at the US generation wavelength (>95%) but transparent at the PA excitation wavelength, the latter to allow the system to also operate in PA imaging mode as before. The generated US pulses exhibited peak pressures in the MPa range, which is comparable to the output of conventional piezoelectric based medical US scanners. The pulses had a broad bandwidth (>40 MHz) and the emitted wavefront was planar to within λ/10 at 10 MHz. PA and pulse-echo US signals were mapped in turn by the FP scanner over centimetre scale areas with a step size of 100 μm and an element size of 64 μm. The -3dB bandwidth of the FP sensor was 30 MHz. Reconstruction methods using a k-space formulation recovered co-registered 3D PA and US images. The system’s lateral spatial resolution was evaluated by imaging a line target at depths up to 10 mm and ranged between 50 and 120 μm for both modes. Arbitrarily shaped 3D objects were imaged to demonstrate the volumetric US imaging capability of the scanner. Tissue mimicking phantoms, with impedance mismatches representative of soft tissues, and ex vivo tissue samples were imaged with the system as well as a conventional clinical US scanner for comparison. Finally, the system obtained promising high-resolution 3D dual mode PA-US images for a variety of phantoms with contrast based on both optical absorption and acoustic impedance. This novel all-optical system has the potential to add complementary morphological contrast to photoacoustic vascular images which could aid the clinical assessment of superficial tumours, lymph node disease and other conditions.

This study investigated the feasibility of photoacoustic (PA) imaging of bone and characterization of bone features. By conducting the experiments on bovine femoral heads ex vivo, the light and ultrasonic penetration in bones was studied, together with the depth of PA imaging and measurement in bones. Then, the possibility of three-dimensional (3D) PA imaging of bones by raster scanning of the focusing transducer was studied. The micro-computerized tomography images of the bovine ribs with and without ethylenediaminetetraacetic acid (EDTA) treatment indicated that the 3D PA images could present the changes of bone microstructure resulting from the EDTA treatment. By using PA spectral analysis, the bone samples with and without the treatment of EDTA solution can be distinguished, and the microstructures can be characterized. This study was based on the bovine bone whose size is comparable to human bones, suggesting that PA technology can be used as a novel bone diagnostic technique.

Photoacoustic (PA) imaging technology is expected to be applied to clinical assessment for peripheral vascularity. We started a clinical evaluation with the prototype PA imaging system we recently developed. Prototype PA imaging system was composed with in-house Q-switched Alexandrite laser system which emits short-pulsed laser with 750 nm wavelength, handheld ultrasound transducer where illumination optics were integrated and signal processing for PA image reconstruction implemented in the clinical ultrasound (US) system. For the purpose of quantitative assessment of PA images, an image analyzing function has been developed and applied to clinical PA images. In this analyzing function, vascularity derived from PA signal intensity ranged for prescribed threshold was defined as a numerical index of vessel fulfillment and calculated for the prescribed region of interest (ROI). Skin surface was automatically detected by utilizing B-mode image acquired simultaneously with PA image. Skinsurface position is utilized to place the ROI objectively while avoiding unwanted signals such as artifacts which were imposed due to melanin pigment in the epidermal layer which absorbs laser emission and generates strong PA signals. Multiple images were available to support the scanned image set for 3D viewing. PA images for several fingers of patients with systemic sclerosis (SSc) were quantitatively assessed. Since the artifact region is trimmed off in PA images, the visibility of vessels with rather low PA signal intensity on the 3D projection image was enhanced and the reliability of the quantitative analysis was improved.

Blood vessels are the only system to provide nutrients and oxygen to every part of the body. Many diseases can have significant effects on blood vessel formation, so that the vascular network can be a cue to assess malicious tumor and ischemic tissues. Various imaging techniques can visualize blood vessel structure, but their applications are often constrained by either expensive costs, contrast agents, ionizing radiations, or a combination of the above. Photoacoustic imaging combines the high-contrast and spectroscopic-based specificity of optical imaging with the high spatial resolution of ultrasound imaging, and image contrast depends on optical absorption. This enables the detection of light absorbing chromophores such as hemoglobin with a greater penetration depth compared to purely optical techniques. We present here a skeletonization algorithm for vessel architectural analysis using non-invasive photoacoustic 3D images acquired without the administration of any exogenous contrast agents. 3D photoacoustic images were acquired on rats (n = 4) in two different time points: before and after a burn surgery. A skeletonization technique based on the application of a vesselness filter and medial axis extraction is proposed to extract the vessel structure from the image data and six vascular parameters (number of vascular trees (NT), vascular density (VD), number of branches (NB), 2D distance metric (DM), inflection count metric (ICM), and sum of angles metric (SOAM)) were calculated from the skeleton. The parameters were compared (1) in locations with and without the burn wound on the same day and (2) in the same anatomic location before (control) and after the burn surgery. Four out of the six descriptors were statistically different (VD, NB, DM, ICM, p < 0.05) when comparing two anatomic locations on the same day and when considering the same anatomic location at two separate times (i.e. before and after burn surgery). The study demonstrates an approach to obtain quantitative characterization of the vascular network from 3D photoacoustic images without any exogenous contrast agent which can assess microenvironmental changes related to disease progression.

.Significance: Photoacoustic (PA) imaging can provide structural, functional, and molecular information for preclinical and clinical studies. For PA imaging (PAI), non-ideal signal detection deteriorates image quality, and quantitative PAI (QPAI) remains challenging due to the unknown light fluence spectra in deep tissue. In recent years, deep learning (DL) has shown outstanding performance when implemented in PAI, with applications in image reconstruction, quantification, and understanding.Aim: We provide (i) a comprehensive overview of the DL techniques that have been applied in PAI, (ii) references for designing DL models for various PAI tasks, and (iii) a summary of the future challenges and opportunities.Approach: Papers published before November 2020 in the area of applying DL in PAI were reviewed. We categorized them into three types: image understanding, reconstruction of the initial pressure distribution, and QPAI.Results: When applied in PAI, DL can effectively process images, improve reconstruction quality, fuse information, and assist quantitative analysis.Conclusion: DL has become a powerful tool in PAI. With the development of DL theory and technology, it will continue to boost the performance and facilitate the clinical translation of PAI.

Photoacoustic imaging (PAI) provides optical contrast at depth beyond the optical transport mean free path. From the generation of ultrasound by light absorption, images can be reconstructed at the acoustic resolution ( 100 μm) with a penetration of a few cm. The design of imaging systems often leads to limited view artifacts, where a part of the information needed for a complete reconstruction of the objects is missing. We theoretically show that a dynamic approach based on the analysis of fluctuations induced by blood flow can suppress visibility artefacts. We demonstrate the performance of 3D Photoacoustic Fluctuation imaging (PAFI) using a spherical array with limited number of channels (256 elements, 8 MHz) in the chicken embryo model. Due to the low number of channels, standard PAI reconstructions additionally suffer from a poor contrast, which is enhanced by 2 to 3-fold using PAFI. We present an implementation of simultaneous PAFI and Ultrasound Power Doppler and present some results with coupled flow direction evaluations and optical contrast. Photoacoustic fluctuation imaging overcomes many limitations of conventional imaging and will be further evaluated for in-vivo imaging.

To assess the value of three-dimensional (3D) image reconstructions of two-dimensional (2D) data from contiguous non-overlapping slices in the diagnosis of spinal trauma, 21 patients with a total of 36 injured vertebrae and 4 normal controls were examined. Forty plain films in two planes, 40 axial CT scans with multiplanar reformatted (MPR) 2D reconstructions and 40 sets of 3D images (surface rendering technique) were independently evaluated by four readers. The final diagnosis was defined after a panel review of clinical, surgical and imaging findings on all modalities. The 3D image reconstructions were not as accurate as axial CT with MPR 2D reconstructions in the diagnosis of vertebral body (n = 20) and posterior element fractures (n = 35). Dislocation (n = 3) was equally well detected by all imaging modalities. Narrowing of the spinal canal (n = 17) was best assessed by either MPR 2D CT or 3D images. A rotational component was diagnosed more accurately by 3D images, followed by 2D CT and plain films. Thus, 3D images combined with MPR 2D CT reconstructions are an important adjunct for an accurate diagnosis of spinal trauma, especially when a rotational component is suspected.

The lateral imaging characteristic of an acoustic lens is similar to the well-known object-image relationship of an optical lens. In this paper, axial signal analysis is carried on and reconstruction methods for a sample's axial photoacoustic (PA) image are researched based on the acoustic-lens PA imaging system. The integral and envelope methods are both proposed to reconstruct a sample's axial PA image, which has only been achieved approximately by the PA signals' peak values obtained by a peak-holding circuit in previous reports. And the envelope method is proposed for the first time. Hilbert transform was used to obtain the envelope of the sample's PA signals and axial PA images. Simulation results show that the integral method is appropriate for low frequency samples, and that the envelope reconstruction method can provide low frequency information of the PA images of samples. So for a sample, it would be best to combine the two methods together.

A requirement to reconstruct photoacoustic (PA) image is to have a synchronized channel data acquisition with laser firing. Unfortunately, most clinical ultrasound (US) systems don’t offer an interface to obtain synchronized channel data. To broaden the impact of clinical PA imaging, we propose a PA image reconstruction algorithm utilizing US B-mode image, which is readily available from clinical scanners. US B-mode image involves a series of signal processing including beamforming, followed by envelope detection, and end with log compression. Yet, it will be defocused when PA signals are input due to incorrect delay function. Our approach is to reverse the order of image processing steps and recover the original US post-beamformed radio-frequency (RF) data, in which a synthetic aperture based PA rebeamforming algorithm can be further applied. Taking B-mode image as the input, we firstly recovered US postbeamformed RF data by applying log decompression and convoluting an acoustic impulse response to combine carrier frequency information. Then, the US post-beamformed RF data is utilized as pre-beamformed RF data for the adaptive PA beamforming algorithm, and the new delay function is applied by taking into account that the focus depth in US beamforming is at the half depth of the PA case. The feasibility of the proposed method was validated through simulation, and was experimentally demonstrated using an acoustic point source. The point source was successfully beamformed from a US B-mode image, and the full with at the half maximum of the point improved 3.97 times. Comparing this result to the ground-truth reconstruction using channel data, the FWHM was slightly degraded with 1.28 times caused by information loss during envelope detection and convolution of the RF information.

We developed a photoacoustic (PA) tomography system based on a full-ring transducer array and a parallel data acquisition system. In addition to rapid imaging, the position of the imaging plane can also be recognized.

As a molecular imaging modality, photoacoustic (PA) imaging has been in the spotlight because it can provide an optical contrast image of physiological information and a relatively deep imaging depth. However, its sensitivity is limited despite the use of exogenous contrast agents due to the background PA signals generated from nontargeted absorbers, such as blood and boundaries between different biological tissues. In addition, clutter artifacts generated in both in-plane and out-of-plane imaging region degrade the sensitivity of PA imaging. We propose a method to eliminate the nontargeted PA signals. For this study, we used a dual-modal ultrasound (US)-PA contrast agent that is capable of generating both the backscattered US and PA signals in response to the transmitted US and irradiated light, respectively. The US images of the contrast agents are used to construct a masking image that contains the location information about the target site and is applied to the PA image acquired after contrast agent injection. In vitro and in vivo experimental results demonstrated that the masking image constructed using the US images makes it possible to completely remove nontargeted PA signals. The proposed method can be used to enhance the clear visualization of the target area in PA images.

Photoacoustic tomography (PAT) offers structural and functional imaging of living biological tissue with highly sensitive optical absorption contrast and excellent spatial resolution comparable to medical ultrasound (US) imaging. We report the development of a fully integrated PAT and US dual-modality imaging system, which performs signal scanning, image reconstruction and display for both photoacoustic (PA) and US imaging all in a truly real-time manner. The backprojection (BP) algorithm for PA image reconstruction is optimized to reduce the computational cost and facilitate parallel computation on a state of the art graphics processing unit (GPU) card. For the first time, PAT and US imaging of the same object can be conducted simultaneously and continuously, at a real time frame rate, presently limited by the laser repetition rate of 10 Hz. Noninvasive PAT and US imaging of human peripheral joints in vivo were achieved, demonstrating the satisfactory image quality realized with this system. Another experiment, simultaneous PAT and US imaging of contrast agent flowing through an artificial vessel was conducted to verify the performance of this system for imaging fast biological events. The GPU based image reconstruction software code for this dual-modality system is open source and available for download from http://sourceforge.net/projects/pat realtime .

Introduction: There is an urgent clinical need to develop noninvasive biomarkers that early detect tumor responses to anti-angiogenic therapy. Treatment response in ovarian cancer patients is assessed with transvaginal ultrasound imaging of tumor size and CA125 screening. We hypothesized that combining photoacoustic (PA) imaging to non-invasively visualize tumor vascular architecture, with serum diagnostics using endothelial biomarkers, would yield a sensitive and readily translatable approach for monitoring response to anti-angiogenic therapy. Methods: Ovarian tumors were established in nude mice by orthotopic injection of OV2008 cells at day 0. At day 10 mice were randomized into groups of at least n = 10. Baseline PA imaging and submandibular blood draw were performed, then repeated 24h after dosing with a peptibody that prevents the interaction of secreted angiopoietin 1 (Ang1; agonist) and 2 (Ang2; antagonist) with the receptor tyrosine kinase Tie2, or vehicle, on days 13, 16 and 19. Mice were then sacrificed and tumors excised for histology. Results: PA imaging uses endogenous hemoglobin light absorption to generate contrast. At 797nm, we found a 1.5-fold increase in hemoglobin-weighted signal in vehicle mice by day 19, while treated mice remained close to the baseline (n=9; p=0.008). The oxyhemoglobin-weighted PA signal (837nm/797nm) was elevated by 20% in treated mice but decreased 15% in vehicle mice (n=9; p&amp;lt;0.01). This indicated treated mice had significantly lower tumor vessel density but improved function of residual vessels. To gain insight into the mechanism of drug action, we measured host serum angiopoietins over the treatment time course. Ang1 in vehicle mice increased by 1.5-fold (n=10; p&amp;lt;0.0001) and was significantly higher than treated mice by day 19 (n=10; p=0.03). Ang2 was identical between treatment groups and healthy control mice (n=10; p=0.65). Elevated Ang1 in the circulation of vehicle mice is consistent with excess Ang1 promoting vascular remodeling and plasticity in tumors, while normalization in treated mice allows vessel stabilization. Immunofluorescence (IF) confirmed this by indicating that CD31 positive vessel density was 30% lower in treated mice but their tumor vessel coverage of desmin-positive pericytes was 2.5-fold higher. Conclusions: We have shown for the first time that PA imaging and serum angiopoietin levels measure complementary parameters that indicate response to angiopoietin blockade in ovarian cancer. PA imaging noninvasively detected drug-induced vessel regression and normalization, giving a functional readout of response. This modality can be readily combined with transvaginal ultrasound. The drug action was mediated by normalization of mAng1 levels, indicated by serum measures and IF. Importantly, this work supports the combined use of in vitro and in vivo diagnostics to monitor response to anti-angiogenic therapy in clinical trials. Citation Format: Sarah E. Bohndiek, Laura Sasportas, Steven Machtaler, Jesse V. Jokerst, Sharon Hori, Sanjiv S. Gambhir. Molecular photoacoustic imaging and serum diagnostics rapidly detect response to angiopoietin 1 and 2 blockade in ovarian cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2047. doi:10.1158/1538-7445.AM2014-2047

Photoacoustic (PA) imaging holds great promise for preclinical research and clinical practice. However, most studies rely on the laser wavelength in the first near-infrared (NIR) window (NIR-I, 650-950 nm), while few studies have been exploited in the second NIR window (NIR-II, 1000-1700 nm), mainly due to the lack of NIR-II absorbing contrast agents. We herein report the synthesis of a broadband absorbing PA contrast agent based on semiconducting polymer nanoparticles (SPN-II) and apply it for PA imaging in NIR-II window. SPN-II can absorb in both NIR-I and NIR-II regions, providing the feasibility to directly compare PA imaging at 750 nm with that at 1064 nm. Because of the weaker background PA signals from biological tissues in NIR-II window, the signal-to-noise ratio (SNR) of SPN-II resulted PA images at 1064 nm can be 1.4-times higher than that at 750 nm when comparing at the imaging depth of 3 cm. The proof-of-concept application of NIR-II PA imaging is demonstrated in in vivo imaging of brain vasculature in living rats, which showed 1.5-times higher SNR as compared with NIR-I PA imaging. Our study not only introduces the first broadband absorbing organic contrast agent that is applicable for PA imaging in both NIR-I and NIR-II windows but also reveals the advantages of NIR-II over NIR-I in PA imaging.

Three-dimensional (3D) image reconstruction methods allied to spiral CT (SCT) or MR angiography (MRA) are used in clarifying the anatomy of complex aortic anatomy. Two patients with superior mediastinal masses suggestive of aneurysms of the anomalous right subclavian artery were examined. Both patients were examined using breath-hold SCT and one by breath-hold MRA. Three-dimensional images were reconstructed using a surface rendering technique for the SCT examinations and by a maximum intensity projection technique for MRA. Two cases of aneurysmal anomalous right subclavian artery were diagnosed by SCT with 3D image reconstruction. One case was also examined by MRA with 3D image reconstruction which confirmed the findings of SCT. The use of the 3D techniques clarified the complicated anatomy and avoided the need for angiography. Two cases are illustrated of 3D imaging of complicated aortic branch anatomy due to aneurysms of anomalous right subclavian artery. Image quality was good and no further imaging by more invasive techniques was required.