Target detection and quantification using a hybrid hand-held diffuse optical tomography and photoacoustic tomography system

Hybrid imaging methods combining diffuse optical tomography (DOT) and other anatomical or nonoptical functional modalities have been widely investigated to improve imaging performance degraded by the strong optical scattering of biological tissues, through constraining the reconstruction process by prior structures. However, these modalities with different contrast mechanisms may be ineffective in revealing early-staged lesions with high optical contrast but no morphological changes. Photoacoustic tomography (PAT) is particularly useful for visualizing light-absorbing structures embedded in soft tissues with high spatial resolution. Although it is still challenging for PAT to quantitatively disclose the absorption distribution, the modality does provide reliable and specific a priori information differentiating light-absorbing structures of soft tissues and might be more appropriate to guide DOT in lesion diagnosis, as compared with other anatomical or nonoptical functional modalities. In this study, a PAT-guided DOT approach is introduced with both soft- and hard-prior regularizations. The methodology is experimentally validated on small-animal-sized phantoms using a computed-tomography-analogous (CT-analogous) PAT/DOT dual-modality system, focusing on future whole-body applications. The results show that the proposed scheme is capable of effectively improving the quantitative accuracy and spatial resolution of DOT reconstruction.

Photoacoustic imaging combines advantages of both ultrasound imaging and optical imaging to provide high ultrasonic resolution and high optical contrast in noninvasive medical images. A photoacoustic computer tomography （PCT） system with a focused digital phased array transducer is proposed. In particular each element of the transducer array has a thin cylindrical ultrasonic lens to select 2D image plane and suppress the out-of-plane signals to realize photoacoustic computed tomography. A fast full-view photoacoustic imaging system for visualizing tissue structures using a linear transducer array with combined scan, whies; detects photoacoustic signals by combined electronic and mechanical scanning. An improved limited-field filtered back projection algorithm with directivity factors was applied to reconstruct the optical absorption distribution and further improve the lateral resolution. In the experiment, the spatial resolution of this imaging system is determined as 0.2mm, and the slice resolution of Z axis is 1.5mm. Mechanical step scanning was performed, leading to a measurement time of 6.4 seconds per position, and a total scan duration of 150 seconds to obtain the two-dimensional photoacoustic image. High spatial resolution of 2D photoacoustic vascular image and quasi-3D photoacoustic CT for breast cancer imaging are achicned. The experimental results demonstrate that this method and imaging system can realize the high resolution photoacoustic tomography wtich can be applied to noninvasive detection of early breast cancer.

Photoacoustic (PA) imaging is a hybrid imaging technology which combines the best of optical (contrast) and ultrasound (resolution) imaging. PA imaging uses intrinsic contrast agents in the body like blood (hemoglobin), melanin, etc. But the contrast from the intrinsic contrast agents might not be sufficient for different applications. So, external contrast agents are needed for improving the contrast of PA images. Organic dyes, inorganic dyes, and nanomaterials can be used as photoacoustic contrast agents. The major issue with using external contrast agent is that they often need FDA approval to be used for in-vivo studies. Availability of FDA approved contrast agents for PA imaging is very limited. In this work, we present the feasibility of using food and food-based dyes as photoacoustic contrast agents. We use commonly used foods like coffee, tea, chocolate and food colorants as contrast agents. We use alpinion’s E-CUBE dual mode ultrasound and photoacoustic imaging system with mobile Nd:YAG laser pumped by OPO laser to demonstrate the efficiency of the contrast agents. The contrast agents were compared with methylene blue. Out of the many different agents we tested, coffee, chocolate and few other dyes proved as efficient photoacoustic contrast agents. We performed photoacoustic spectroscopy to identify at which wavelength the dye performed best. We also tested the contrast agents for imaging sentinel lymph nodes in rats and the results are very similar to methylene blue. This will enable the transition of photoacoustic imaging to the clinics more easily.

ObjectiveTo evaluate in vivo a fully integrated photoacoustic tomography imaging system based on Fabry–Pérot ultrasound sensing method applied on porcine abdominal organs. This approach could be used by surgeons during intraoperative clinical procedures.MethodsThe photoacoustic imaging system was fully integrated into a single structure, and the detection technology was based on a Fabry–Pérot interferometer. The detection probe connected to the imaging system was applied directly to the organs of a male “large white” Sus scrofa pig weighing 80 kg, either manually or using a stand, with or without a gel interface. All experiments were performed in compliance with EU Directive 2010/63/EU on animal experimentation (APAFiS #31507).ResultsAll intraperitoneal and retroperitoneal organs were evaluated using photoacoustic imaging. The evaluation of both hollow and solid organs was successfully conducted with consistent three-dimensional image quality. We demonstrate the system’s ability to image blood vessels with diameters ranging from several millimeters down to less than 100 µm. Macroscopic evaluation of the organs using photoacoustic tomography imaging did not reveal any damage or burns caused by the excitation laser.ConclusionTo our knowledge, this is the first reported imaging session of abdominal organs in an in vivo porcine model, performed using a photoacoustic tomography system with Fabry–Pérot interferometer detection. We present a high-resolution photoacoustic tomography system that is closer to routine clinical translation, thanks to a fully integrated system.Relevance statementPhotoacoustic evaluation of organs using a fully integrated system could become a valuable tool for surgical teams for intraprocedural assessment of vascularization.Key PointsPhotoacoustic imaging visualizes blood vessels without contrast agents or ionizing radiation.Photoacoustic imaging systems detect blood vessels ranging from millimeters to 100 µm.Fully integrated photoacoustic imaging systems are autonomously operable by surgical teams.Graphical

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.

The aim of this work is to assess the cerebrovascular reserve capacity (CVRC) by MR PWI and photoacoustic brain imaging with “ACZ” tolerance test in mouse and rat, and to compare their role in evaluating the CVRC. Experimental animals included 2 groups: Wistar-Kyoto rats (WKY) (12-week-old, 235~265g) were assessed by MRI and BALB/c mice (4-week-old, 25~35g body weight) were assessed by our photoacoustic imaging system. On photoacoustic imaging, the diameter of the vascular in the superficial layer of the mouse cortex were measured and compared between the resting and acetazolamide (Acz)-activated mice, which reflected cerebral blood flow (CBF) without blood sampling. MR PWI was performed respectively before and after acetazolamide administrated orally on a clinical 1.5 Tesla GE Signa MR fx/i whole-body MR system. The region of interest (ROI) was chosen in the bilateral frontal lobe to measure the value of rCBV, rCBF and MTT. The results show that there was statistical difference between the resting and acetazolamide (Acz)-activated animals in the values of the diameter of the vascular in the superficial layer of the mouse cortex by photoacoustic imaging and in the values of rCBV and rCBF（P＞0.05）of the rat by MRI. It was concluded that the method of PWI and photoacoustic imaging combined with the “ACZ stress test” can be used to evaluate the CVRC by measuring values of rCBV and rCBF and diameter of the vascular, respectively.

Three-dimensional diffuse optical imaging of hand joints: System description and phantom studies

Sir: We read with great interest the article entitled “Correlations between Tracer Injection Sites and Lymphatic Pathways in the Leg: A Near-Infrared Fluorescence Lymphography Study” by Shinaoka et al.1 Their publication clearly demonstrates the four distinct lymphatic groups of the lymphatic system in the lower extremity: anteromedial, anterolateral, posterolateral, and posteromedial. This information will definitely improve our practice in near-infrared fluorescence lymphography using indocyanine green. However, as the authors described in the Results section, connections between the posteromedial and anteromedial groups were not identified using near-infrared fluorescence lymphography because they overlapped each other in different layers. These days, a new imaging technology called photoacoustic imaging is becoming more popular in many clinical fields including plastic surgery,2 and a Japanese research group has succeeded in developing a real-time, three-dimensional, photoacoustic visualization system with a wide field of view for investigational use.3 Recently, we applied this system for indocyanine green lymphography, and introduced it as “photoacoustic lymphangiography.”4,5 In photoacoustic lymphangiography, images are acquired as the distribution of light-absorbing tissue components such as hemoglobin or melanin, and optical absorption contrast imaging agents such as indocyanine green in the lymphatic channels, with high spatial resolution. Using lasers with two alternating wavelengths, blood vessels and lymphatic vessels can be discriminated. After injection of indocyanine green into the dorsum of the forefoot and below the medial malleolus, one of the healthy subjects enrolled in our clinical study5 showed a crossing with an overpass of the anteromedial group and an underpass of the posteromedial group in the medial side of the lower leg (Fig. 1). The connections between the groups were not found in the three-dimensional observation; the passes were in different layers. Compared with the venous system, the underpass (posteromedial group) was in parallel with the great saphenous vein, whereas the lymphatics in the overpass (anteromedial group) were in parallel with subdermal venules (Fig. 2). [See Video (online), which demonstrates photoacoustic lymphangiographic images of the same person. The posteromedial group and the anteromedial group are discriminated.] {"href":"Single Video Player","role":"media-player-id","content-type":"play-in-place","position":"float","orientation":"portrait","label":"Video.","caption":"This video demonstrates photoacoustic lymphangiographic images of the same person. The posteromedial group and the anteromedial group are discriminated.","object-id":[{"pub-id-type":"doi","id":""},{"pub-id-type":"other","content-type":"media-stream-id","id":"1_fc2ldesh"},{"pub-id-type":"other","content-type":"media-source","id":"Kaltura"}]} Fig. 1.: Photoacoustic lymphangiographic image showing the lymphatic vessels on the medial side of the left lower leg of a healthy 56-year-old woman. The injection site (asterisk) below the medial malleolus visualized the posteromedial (PM) group (purple), whereas the anteromedial (AM) group (blue) was continuous from the dorsum of the foot. The posteromedial group was deeper than the anteromedial group.Fig. 2.: Photoacoustic lymphangiographic image of the same patient as in Figure 1 showing blood vessels also. The posteromedial group (purple) was in parallel with the great saphenous vein (arrowheads), whereas the lymphatics in the anteromedial group (blue) were in parallel with subdermal venules (arrows).As the authors stressed in the Discussion section, the site below the medial malleolus seemed to be one of the important injection sites for comprehensive mapping of the lymphatics in the lower extremity, including a deep pathway in parallel with the saphenous vein on the medial side. Although photoacoustic lymphangiography could successfully show anteromedial and posteromedial groups three-dimensionally at the same time, near-infrared fluorescence lymphography hardly distinguishes them because the anteromedial group obscures the underpass. To visualize the underpass with near-infrared fluorescence lymphography, it is recommended that indocyanine green should be administered below the medial malleolus first, and the injection to the dorsum of the forefoot should be suspended until the observation of the underpass is finished. ACKNOWLEDGMENTS This work was funded by the ImPACT Program of the Council for Science, Technology, and Innovation (Cabinet Office, Government of Japan). This research is in accordance with the ethical standards of the ethics committee at Keio University Hospital and Certified Review Board of Keio, and with the Declaration of Helsinki of 1975, as revised in 1983. This trial is registered under the name “A Clinical Study to Visualize Lymph Vessels Using Photoacoustic Imaging,” Japan Registry of Clinical Trials identification number jRCTs032180204 (https://rctportal.niph.go.jp/en/detail?trial_id=jRCTs032180204). DISCLOSURE Dr. Aiso is a CEO of Luxonus, Inc., the developing company of the photoacoustic imaging system discussed in this article. The other authors have no financial interests to disclose.

Photoacoustic (PA) imaging is an emerging modality, which combines the high optical absorption contrast of biological chromophores with centimeter imaging depths and sub-millimeter resolution of ultrasonic (US) waves. However, PA imaging through cortical bone remains an unmet challenge. Cortical bone is an anisotropic medium, which is not accurately modeled using existing PA image reconstruction methods. In this Letter, we address the PA source localization problem for imaging through a cortical bone-mimicking layer. Our approach accounts for both refraction and elastic anisotropy to accurately reconstruct US and PA images in the presence of a cortical bone replica. We demonstrate our technique using a PA and US experiment, where we image a 700 μm diameter target beneath a cortical bone-mimicking plate. Pulse-echo US experiment is used to estimate the wavespeed in each layer and create an anatomical image of the bone replica, and the PA source is reconstructed using the wavespeed model defined with US. We compute the thickness of the plate with less than 1% error, whereas isotropic assumptions overestimate the thickness by 20% or more. Incorporating both refraction and anisotropy accurately localizes the target with PA and US at the true depth, whereas isotropic assumptions blur the lateral dimension and mislocate the target depth by 1.5–4 mm.

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.

Photoacoustic imaging, a noninvasive imaging based on optical excitation and ultrasonic detection, enables one to visualize the distribution of hemoglobin and acquire a map of microvessels without using contrast agents. We examined whether it helps visualize periprostatic microvessels and improves visualization of the neurovascular bundle. We developed a photoacoustic imaging (PAI) system with a hand-held probe combining optical illumination and a conventional linear array ultrasound probe. In experiments with a phantom model, it was able to visualize vessels with diameters as small as 300 μm within a depth of 10 mm. We also developed a TRUS type probe for our photoacoustic imaging system and used it to intraoperatively monitor periprostatic tissues in seven patients with clinically organ-confined prostate cancer who were undergoing non-nerve-sparing retropubic radical prostatectomy. Images of periprostatic tissues from resected prostatectomy specimens were also obtained using the linear photoacoustic probe, and the consistency of the microvessel distribution and co-existence of nerve fibers was examined by double immunostaining of paraffin-embedded sections with anti-CD31 and anti-S-100 antibodies. Intraoperative monitoring of periprostatic tissues with the TRUS photoacoustic probe showed substantial signals on the posterolateral surface of the prostate and clearly demonstrated the location and extent of the neurovascular bundle better than does TRUS alone. Photoacoustic images of the periprostatic tissues in resected specimens also showed substantial signals that were especially strong on the posterolateral surface of the prostate. Nerve fibers were closely co-localized with periprostatic microvessels and the pattern of their distribution was consistent with that of PAI signals. The intraoperative photoacoustic imaging located the microvascular complex in the neurovascular bundle. Moreover, the neurovascular bundle was easier to identify by PAI than by TRUS alone, suggesting that PAI could be helpful in nerve-sparing radical prostatectomy.

Optoacoustic tomography (OAT) is a promising imaging modality for human breast cancer imaging, with higher resolution and deeper penetration compared to other optical imaging modalities such as diffuse optical tomography or optical coherence tomography. It yields a resolution of 1 mm at depth up to 2 cm. But there is an inherent conflict between the limitations imposed on laser power and the need to adequately penetrate a substantial portion of the breast. To achieve sufficient penetration at every view angle, instead of illuminating the whole breast all at once, sometimes illumination is focused onto a small region of the breast and rotated along with the transducer array to cover the entire object. This paper evaluates the effect of this rotating partial illumination design on OAT image reconstruction. The optical process is simulated by conducting Monte Carlo simulations on a numerical phantom mimicking a real breast, with various specially designed illumination schemes. The acoustic process is simulated by incorporating the transducer's spatial impulse response. Iterative reconstruction is applied to estimate the OAT image. We conclude that rotating partial illumination introduces inconsistency into the system equation, and the degree of inconsistency determines the reconstruction quality.

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.

While photoacoustic imaging is capable of producing high-resolution biomedical images with optical absorption contrast, optical property quantification has thus far remained challenging. One reason for this is that laser-induced photoacoustic signal amplitudes are proportional to not only the local optical absorption coefficient, but also the local laser fluence in the tissue. Unfortunately, local laser fluence is often unknown, but could possibly be estimated if local bulk tissue optical properties were known. One method to estimate tissue optical properties is a technique known as oblique incidence diffuse reflectance (OIR). We report on an integrated OIR and photoacoustic imaging system and demonstrate, using phantom experiments, improved ability to quantitatively estimate optical properties of a turbid medium.

Ultrasound imaging is widely used to guide minimally invasive procedures, but the visualization of the invasive medical device and the procedure’s target is often challenging. Photoacoustic imaging has shown great promise for guiding minimally invasive procedures, but clinical translation of this technology has often been limited by bulky and expensive excitation sources. In this work, we demonstrate the feasibility of guiding minimally invasive procedures using a dual-mode photoacoustic and ultrasound imaging system with excitation from compact arrays of light-emitting diodes (LEDs) at 850 nm. Three validation experiments were performed. First, clinical metal needles inserted into biological tissue were imaged. Second, the imaging depth of the system was characterized using a blood-vessel-mimicking phantom. Third, the superficial vasculature in human volunteers was imaged. It was found that photoacoustic imaging enabled needle visualization with signal-to-noise ratios that were 1.2 to 2.2 times higher than those obtained with ultrasound imaging, over insertion angles of 26 to 51 degrees. With the blood vessel mimicking phantom, the maximum imaging depth was 38 mm. The superficial vasculature of a human middle finger and a human wrist were clearly visualized in real-time. We conclude that the LED-based system is promising for guiding minimally invasive procedures with peripheral tissue targets.