Automated three-dimensional image registration for longitudinal photoacoustic imaging.

Significance: Photoacoustic tomography (PAT) has great potential in monitoring disease progression and treatment response in breast cancer. However, due to variations in breast repositioning, there is a chance of geometric misalignment between images. Further, poor repositioning can affect light fluence distribution and imaging field-of-view, making images different from one another. The net effect is that it becomes challenging to distinguish between image changes due to repositioning effects and those due to true biological variations. Aim: The aim is to develop a three-dimensional image registration framework for geometrically aligning repeated PAT volumetric images, which are potentially affected by repositioning effects such as misalignment, changed radiant exposure conditions, and different fields-of-view. Approach: The proposed framework involves the use of a coordinate-based neural network to represent the displacement field between pairs of PAT volumetric images. A loss function based on normalized cross correlation and Frangi vesselness feature extraction at multiple scales was implemented. We refer to our image registration framework as MUVINN-reg, which stands for multiscale vesselness-based image registration using neural networks. The approach was tested on a longitudinal dataset of healthy volunteer breast PAT images acquired with the hybrid photoacoustic-ultrasound Photoacoustic Mammoscope 3 imaging system. The registration performance was also tested under unfavorable repositioning conditions such as intentional mispositioning, and variation in breast-supporting cup size between measurements. Results: A total of 13 pairs of repeated PAT scans were included in this study. MUVINN-reg showed excellent performance in co-registering each pair of images. The proposed framework was shown to be robust to image intensity shifts and field-of-view changes. Furthermore, MUVINN-reg could align vessels at imaging depths greater than 4 cm. Conclusions: The proposed framework will enable the use of PAT for quantitative and reproducible monitoring of disease progression and treatment response.

An anthropomorphic thyroid phantom for ultrasound-guided radiofrequency ablation of nodules.

BACKGROUND: Needle-based procedures, such as fine needle aspiration and thermal ablation, are often applied for thyroid nodule diagnosis and therapeutic purposes, respectively. With blood vessels and nerves nearby, these procedures can pose risks in damaging surrounding critical structures. PURPOSE: The development and validation of innovative strategies to manage these risks require a test object with well-characterized physical properties. For this work, we focus on the application of ultrasound-guided thermal radiofrequency ablation. METHODS: We have developed a single-use anthropomorphic phantom mimicking the thyroid and surrounding anatomical and physiological structures that are relevant to ultrasound-guided thermal ablation. The phantom was composed of a mixture of polyacrylamide, water, and egg white extract and was cast using molds in multiple steps. The thermal, acoustical, and electrical characteristics were experimentally validated. The ablation zones were analyzed via non-destructive T2 -weighted magnetic resonance imaging scans utilizing the relaxometry changes of coagulated egg albumen, and the temperature distribution was monitored using an array of fiber Bragg grating sensors. RESULTS: The physical properties of the phantom were verified both on ultrasound as well as in terms of the phantom response to thermal ablation. The final temperature achieved (92°C), the median percentage of the nodule ablated (82.1%), the median volume ablated outside the nodule (0.8 mL), and the median number of critical structures affected (0) were quantified. CONCLUSION: An anthropomorphic phantom that can provide a realistic model for development and training in ultrasound-guided needle-based thermal interventions for thyroid nodules has been presented.

A review of a strategic roadmapping exercise to advance clinical translation of photoacoustic imaging: From current barriers to future adoption.

Photoacoustic imaging (PAI), also referred to as optoacoustic imaging, has shown promise in early-stage clinical trials in a range of applications from inflammatory diseases to cancer. While the first PAI systems have recently received regulatory approvals, successful adoption of PAI technology into healthcare systems for clinical decision making must still overcome a range of barriers, from education and training to data acquisition and interpretation. The International Photoacoustic Standardisation Consortium (IPASC) undertook an community exercise in 2022 to identify and understand these barriers, then develop a roadmap of strategic plans to address them. Here, we outline the nature and scope of the barriers that were identified, along with short-, medium- and long-term community efforts required to overcome them, both within and beyond the IPASC group.

Ultrasound imaging in thyroid nodule diagnosis, therapy, and follow-up: Current status and future trends.

Ultrasound, the primary imaging modality in thyroid nodule management, suffers from drawbacks including: high inter- and intra-observer variability, limited field-of-view and limited functional imaging. Developments in ultrasound technologies are taking place to overcome these limitations, including three-dimensional-Doppler, -elastography, -nodule characteristics-extraction, and novel machine-learning algorithms. For thyroid ablative treatments and biopsies, perioperative use of three-dimensional ultrasound opens a new field of research. This review provides an overview of the current and future applications of ultrasound, and discusses the potential of new developments and trends that may improve the diagnosis, therapy, and follow-up of thyroid nodules.

Diagnostics in Patients Suspect for Breast Cancer in The Netherlands.

The goal of this study was to describe the variation in hospital-based diagnostic care activities for patients with symptomatology suspect for breast cancer in The Netherlands. Two cohorts were included: the 'benign' cohort (30,334 women suspected of, but without breast cancer) and the 'malignant' cohort (2236 breast cancer patients). Hospital-based financial data was combined with tumor data (malignant cohort) from The Netherlands Cancer Registry. Patterns within diagnostic pathways were analyzed. Factors influencing the number of visits and number of diagnostic care activities until diagnosis were identified in the malignant cohort with multivariable Cox and Poisson regression models. Compared to patients with benign diagnosis, patients with malignant disease received their diagnosis less frequently in one day, after an equal average number of hospital visits and higher average number of diagnostic activities. Factors increasing the number of diagnostic care activities were the following: lower age and higher cM-and cN-stages. Factors increasing the number of days until (malignant) diagnosis were as follows: higher BIRADS-score, screen-detected and higher cN-and cT-stages. Hospital of diagnosis influenced both number of activities and days to diagnosis. The diagnostic care pathway of patients with malignant disease required more time and diagnostic activities than benign disease and depends on hospital, tumor and patient characteristics.

Suite of 3D test objects for performance assessment of hybrid photoacoustic-ultrasound breast imaging systems.

SIGNIFICANCE: During the development and early testing phases of new photoacoustic (PA) breast imaging systems, several choices need to be made in aspects of system design and measurement sequences. Decision-making can be complex for state-of-the-art systems such as 3D hybrid photoacoustic-ultrasound (PA-US) breast imagers intended for multispectral quantitative imaging. These systems have a large set of design choices and system settings that affect imaging performance in different ways and often require trade-offs. Decisions have to be made carefully as they can strongly influence the imaging performance. AIM: A systematic approach to assess the influence of various choices on the imaging performance in carefully controlled laboratory situations is crucial before starting with human studies. Test objects and phantoms are used for first imaging studies, but most reported structures have a 2D geometry and are not suitable to assess all the image quality characteristics (IQCs) of 3D hybrid PA-US systems. APPROACH: Our work introduces a suite of five test objects designed for hybrid PA-US systems with a 3D detection aperture. We present the test object designs and production protocols and explain how they can be used to study various performance measures. To demonstrate the utility of the developed objects, measurements are made with an existing tomographic PA system. RESULTS: Two test objects were developed for measurements of the US detectors' impulse responses and light distribution on the breast surface. Three others were developed to assess image quality and quantitative accuracy of the PA and US modes. Three of the five objects were imaged to demonstrate their use. CONCLUSIONS: The developed test objects allow one to study influences of various choices in design and system settings. With this, IQCs can be assessed as a function of measurement sequence settings for the PA and US modes in a controlled way. Systematic studies and measurements using these objects will help to optimize various system settings and measurement protocols in laboratory situations before embarking on human studies.

Annular Fiber Probe for Interstitial Illumination in Photoacoustic Guidance of Radiofrequency Ablation.

Unresectable liver tumors are commonly treated with percutaneous radiofrequency ablation (RFA). However, this technique is associated with high recurrence rates due to incomplete tumor ablation. Accurate image guidance of the RFA procedure contributes to successful ablation, but currently used imaging modalities have shortcomings in device guidance and treatment monitoring. We explore the potential of using photoacoustic (PA) imaging combined with conventional ultrasound (US) imaging for real-time RFA guidance. To overcome the low penetration depth of light in tissue, we have developed an annular fiber probe (AFP), which can be inserted into tissue enabling interstitial illumination of tissue. The AFP is a cannula with 72 optical fibers that allows an RFA device to slide through its lumen, thereby enabling PA imaging for RFA device guidance and ablation monitoring. We show that the PA signal from interstitial illumination is not affected by absorber-to-surface depth compared to extracorporeal illumination. We also demonstrate successful imaging of the RFA electrodes, a blood vessel mimic, a tumor-mimicking phantom, and ablated liver tissue boundaries in ex vivo chicken and bovine liver samples. PA-assisted needle guidance revealed clear needle tip visualization, a notable improvement to current US needle guidance. Our probe shows potential for RFA device guidance and ablation detection, which potentially aids in real-time monitoring.

Optical signatures of radiofrequency ablation in biological tissues.

Accurate monitoring of treatment is crucial in minimally-invasive radiofrequency ablation in oncology and cardiovascular disease. We investigated alterations in optical properties of ex-vivo bovine tissues of the liver, heart, muscle, and brain, undergoing the treatment. Time-domain diffuse optical spectroscopy was used, which enabled us to disentangle and quantify absorption and reduced scattering spectra. In addition to the well-known global (1) decrease in absorption, and (2) increase in reduced scattering, we uncovered new features based on sensitive detection of spectral changes. These absorption spectrum features are: (3) emergence of a peak around 840 nm, (4) redshift of the 760 nm deoxyhemoglobin peak, and (5) blueshift of the 970 nm water peak. Treatment temperatures above 100 °C led to (6) increased absorption at shorter wavelengths, and (7) further decrease in reduced scattering. This optical behavior provides new insights into tissue response to thermal treatment and sets the stage for optical monitoring of radiofrequency ablation.

Novel imaging techniques for intraoperative margin assessment in surgical oncology: A systematic review.

Inadequate margins continue to occur frequently in patients who undergo surgical resection of a tumor, suggesting that current intraoperative methods are not sufficiently reliable in determining the margin status. This clinical demand has inspired the development of many novel imaging techniques that could help surgeons with intraoperative margin assessment. This systematic review provides an overview of novel imaging techniques for intraoperative margin assessment in surgical oncology, and reports on their technical properties, feasibility in clinical practice and diagnostic accuracy. PubMed, Embase, Web of Science and the Cochrane library were systematically searched (2013-2018) for studies reporting on imaging techniques for intraoperative margin assessment. Patient and study characteristics, technical properties, feasibility characteristics and diagnostic accuracy were extracted. This systematic review identified 134 studies that investigated and developed 16 groups of techniques for intraoperative margin assessment: fluorescence, advanced microscopy, ultrasound, specimen radiography, optical coherence tomography, magnetic resonance imaging, elastic scattering spectroscopy, bio-impedance, X-ray computed tomography, mass spectrometry, Raman spectroscopy, nuclear medicine imaging, terahertz imaging, photoacoustic imaging, hyperspectral imaging and pH measurement. Most studies were in early developmental stages (IDEAL 1 or 2a, n = 98); high-quality stage 2b and 3 studies were rare. None of the techniques was found to be clearly superior in demonstrating high feasibility as well as high diagnostic accuracy. In conclusion, the field of imaging techniques for intraoperative margin assessment is highly evolving. This review provides a unique overview of the opportunities and limitations of the currently available imaging techniques.

Tunable blood oxygenation in the vascular anatomy of a semi-anthropomorphic photoacoustic breast phantom.

SIGNIFICANCE: Recovering accurate oxygenation estimations in the breast with quantitative photoacoustic tomography (QPAT) is not straightforward. Accurate light fluence models are required, but the unknown ground truth of the breast makes it difficult to validate them. Phantoms are often used for the validation, but most reported phantoms have a simple architecture. Fluence models developed in these simplistic objects are not accurate for application on the complex tissues of the breast. AIM: We present a sophisticated breast phantom platform for photoacoustic (PA) and ultrasound (US) imaging in general, and specifically for QPAT. The breast phantom is semi-anthropomorphic in distribution of optical and acoustic properties and contains wall-less channels with blood. APPROACH: 3D printing approaches are used to develop the solid 3D breast phantom from custom polyvinyl chloride plastisol formulations and additives for replicating the tissue optical and acoustic properties. A flow circuit was developed to flush the channels with bovine blood with a controlled oxygen saturation level. To showcase the phantom's functionality, PA measurements were performed on the phantom with two oxygenation levels. Image reconstructions with and without fluence compensation from Monte Carlo simulations were analyzed for the accuracy of oxygen saturation estimations. RESULTS: We present design aspects of the phantom, demonstrate how it is developed, and present its breast-like appearance in PA and US imaging. The oxygen saturations were estimated in two regions of interest with and without using the fluence models. The fluence compensation positively influenced the SO2 estimations in all cases and confirmed that highly accurate fluence models are required to minimize estimation errors. CONCLUSIONS: This phantom allows studies to be performed in PA in carefully controlled laboratory settings to validate approaches to recover both qualitative and quantitative features sought after in in-vivo studies. We believe that testing with phantoms of this complexity can streamline the transition of new PA technologies from the laboratory to studies in the clinic.

Pendant breast immobilization and positioning in photoacoustic tomographic imaging.

This work describes the design, development and added value of breast-supporting cups to immobilize and position the pendant breast in photoacoustic tomographic imaging. We explain the considerations behind the choice of the material, the shape and sizes of a cup-shaped construct for supporting the breast in water in an imaging tank during full-breast imaging. We provide details of the fabrication, and other processing and testing procedures used. Various experiments were conducted to demonstrate the added value of using these cups. We show that breast movement during a measurement time of four minutes is reduced from maximum 2 mm to 0.1 mm by the use of cups. Further, the presence of the cup, centered in the aperture leading to the imaging tank, ensures that the breast can be reproducibly positioned at the center of the field-of-view of the detection aperture in the tank. Finally, since an accurate delineation of the water-tissue boundary can now be made, the use of the cup enables accurate application of a two-speed of sound model for reconstruction. All in all, we demonstrate that the use of cups to support the breast provides clear enhancement in contrast and resolution of breast images in photoacoustic imaging.

Tomographic imaging with an ultrasound and LED-based photoacoustic system.

Pulsed lasers in photoacoustic tomography systems are expensive, which limit their use to a few clinics and small animal labs. We present a method to realize tomographic ultrasound and photoacoustic imaging using a commercial LED-based photoacoustic and ultrasound system. We present two illumination configurations using LED array units and an optimal number of angular views for tomographic reconstruction. The proposed method can be a cost-effective solution for applications demanding tomographic imaging and can be easily integrated into conventional linear array-based ultrasound systems. We present a potential application for finger joint imaging in vivo, which can be used for point-of-care rheumatoid arthritis diagnosis and monitoring.

Spatially compounded plane wave imaging using a laser-induced ultrasound source.

This work presents spatially compounded plane wave imaging using a laser-induced ultrasound source. The plane wave source consisted of a 30 µm thick film of carbon black-doped PDMS cured on a 100 µm thick polyester substrate and presented a rectangular aperture of 40 × 3 mm. It was placed in front of a linear ultrasound array, passing through the imaging plane allowing overlap of the detection plane and the insonification plane. Illumination was provided by an array of optical fibre bundles placed above the imaging plane, at an angle. We will first present the general imaging set up and instrumentation used, after which details are given on the fabrication of the transmitter itself and on the objects that were imaged. Comparing laser-induced and conventional ultrasound images of wire phantoms shows the point-spread-function to be, in general, slightly better laterally in the conventional case but more homogeneous throughout the imaging plane with the laser-induced source. Imaging of a tissue-mimicking phantom shows a 55% improvement in contrast between a tumour and the background when using laser-induced ultrasound, as compared to the conventional case.

A Partially-Learned Algorithm for Joint Photo-acoustic Reconstruction and Segmentation.

In an inhomogeneously illuminated photoacoustic image, important information like vascular geometry is not readily available, when only the initial pressure is reconstructed. To obtain the desired information, algorithms for image segmentation are often applied as a post-processing step. In this article, we propose to jointly acquire the photoacoustic reconstruction and segmentation, by modifying a recently developed partially learned algorithm based on a convolutional neural network. We investigate the stability of the algorithm against changes in initial pressures and photoacoustic system settings. These insights are used to develop an algorithm that is robust to input and system settings. Our approach can easily be applied to other imaging modalities and can be modified to perform other high-level tasks different from segmentation. The method is validated on challenging synthetic and experimental photoacoustic tomography data in limited angle and limited view scenarios. It is computationally less expensive than classical iterative methods and enables higher quality reconstructions and segmentations than the state-of-the-art learned and non-learned methods.

Current and future trends in photoacoustic breast imaging.

Non-invasive detection of breast cancer has been regarded as the holy grail of applications for photoacoustic (optoacoustic) imaging right from the early days of re-discovery of the method. Two-and-a-half decades later we report on the state-of-the-art in photoacoustic breast imaging technology and clinical studies. Even within the single application of breast imaging, we find imagers with various measurement geometries, ultrasound detection characteristics, illumination schemes, and image reconstruction strategies. We first analyze the implications on performance of a few of these design choices in a generic imaging system, before going into detailed descriptions of the imagers. Per imaging system we present highlights of patient studies, which barring a couple are mostly in the nature of technology demonstrations and proof-of-principle studies. We close this work with a discussion on several aspects that may turn out to be crucial for the future clinical translation of the method.

Semi-anthropomorphic photoacoustic breast phantom.

Imaging parameters of photoacoustic breast imaging systems such as the spatial resolution and imaging depth are often characterized with phantoms. These objects usually contain simple structures in homogeneous media such as absorbing wires or spherical objects in scattering gels. While these kinds of basic phantoms are uncluttered and useful, they do not challenge the system as much as a breast does, and can thereby overestimate the system's performance. The female breast is a complex collection of tissue types, and the acoustic and optical attenuation of these tissues limit the imaging depth, the resolution and the ability to extract quantitative information. For testing and challenging photoacoustic breast imaging systems to the full extent before moving to in vivo studies, a complex breast phantom which simulates the breast's most prevalent tissues is required. In this work we present the first three dimensional multi-layered semi-anthropomorphic photoacoustic breast phantom. The phantom aims to simulate skin, fat, fibroglandular tissue and blood vessels. The latter three are made from custom polyvinyl chloride plastisol (PVCP) formulations and are appropriately doped with additives to obtain tissue realistic acoustic and optical properties. Two tumors are embedded, which are modeled as clusters of small blood vessels. The PVCP materials are surrounded by a silicon layer mimicking the skin. The tissue mimicking materials were cast into the shapes and sizes expected in the breast using 3D-printed moulds developed from a magnetic resonance imaging segmented numerical breast model. The various structures and layers were assembled to obtain a realistic breast morphology. We demonstrate the phantom's appearance in both ultrasound imaging as photoacoustic tomography and make a comparison with a photoacoustic image of a real breast. A good correspondence is observed, which confirms the phantom's usefulness.

Twente Photoacoustic Mammoscope 2: system overview and three-dimensional vascular network images in healthy breasts.

We present the Twente Photoacoustic Mammoscope 2, a photoacoustic breast imaging system employing a tomographic configuration. It images one breast pendant inside an imaging tank filled with water while a woman lies prone on a bed. A dual-head laser (755 and 1064 nm) illuminates the breast with one beam directed at the nipple and nine beams directed at the sides. Ultrasound signals are detected using 12 arc-shaped arrays, each curving along the pendant breast. Each array comprises 32 piezocomposite elements each with a center frequency of 1 MHz. The imaging tank and the ultrasound arrays rotate around the breast in steps to obtain additional multiple projections. Three-dimensional images are reconstructed using a filtered backprojection algorithm. The system is described in detail, and measurements on a test object are presented. As part of a preliminary study to assess the system's in vivo performance, the breasts of two healthy volunteers were imaged. These images show the breast contour, the nipple, and the vascular anatomy within the breast. In the nipple of one case, multiple high-intensity "hot spots" are observed, which we suspect are associated with the lactiferous ducts terminating in the nipple.

Photoacoustic imaging in percutaneous radiofrequency ablation: device guidance and ablation visualization.

Percutaneous radiofrequency ablation (RFA) is gaining importance as a locoregional treatment for tumors in several organs including the liver, lung, kidney and bone. In RFA, the tumor is eradicated with the direct application of heat using alternating current through a needle electrode positioned under imaging guidance. Various imaging methods are used in the RFA ablation procedure but these have drawbacks. In this work, we introduce photoacoustic (PA) imaging as a new method with potential to visualize the targeting of RFA needle into a region of interest and to report on the extent of ablation achieved. We demonstrate the proof-of-concept in using PA imaging together with ultrasound imaging on ex vivo biological samples in the laboratory simulating relevant clinical scenarios in RFA. These include guidance of the RFA needle to target tissue, mapping of simulated blood vessels during needle insertion and differentiation between ablated and surrounding tissue. The results of this first investigation into the use of PA imaging to assist RFA procedures are encouraging. We discuss the challenges encountered, the scope for future work and envisaged clinical application.