Use of 3D anatomical models in mock circulatory loops for cardiac medical device testing.

INTRODUCTION: Mock circulatory loops (MCLs) are mechanical representations of the cardiovascular system largely used to test the hemodynamic performance of cardiovascular medical devices (MD). Thanks to 3 dimensional (3D) printing technologies, MCLs can nowadays also incorporate anatomical models so to offer enhanced testing capabilities. The aim of this review is to provide an overview on MCLs and to discuss the recent developments of 3D anatomical models for cardiovascular MD testing. METHODS: The review first analyses the different techniques to develop 3D anatomical models, in both rigid and compliant materials. In the second section, the state of the art of MCLs with 3D models is discussed, along with the testing of different MDs: implantable blood pumps, heart valves, and imaging techniques. For each class of MD, the MCL is analyzed in terms of: the cardiovascular model embedded, the 3D model implemented (the anatomy represented, the material used, and the activation method), and the testing applications. DISCUSSIONS AND CONCLUSIONS: MCLs serve the purpose of testing cardiovascular MDs in different (patho-)physiological scenarios. The addition of 3D anatomical models enables more realistic connections of the MD with the implantation site and enhances the testing capabilities of the MCL. Current attempts focus on the development of personalized MCLs to test MDs in patient-specific hemodynamic and anatomical scenarios. The main limitation of MCLs is the impossibility to assess the impact of a MD in the long-term and at a biological level, for which animal experiments are still needed.

Concepts and applications of ultrafast cardiac ultrasound imaging.

The concept of ultrafast echocardiographic imaging has been around for decades. However, only recent progress in ultrasound machine hardware and computer technology allowed to apply this concept to echocardiography. High frame rate echocardiography can visualize phenomena that have never been captured before. It enables a wide variety of potential new applications, including shear wave imaging, speckle tracking, ultrafast Doppler imaging, and myocardial perfusion imaging. The principles of these applications and their potential clinical use will be presented in this manuscript.

Validated Ultrasound Speckle Tracking Method for Measuring Strains of Knee Collateral Ligaments In-Situ during Varus/Valgus Loading.

Current ultrasound techniques face several challenges to measure strains when translated from large tendon to in-situ knee collateral ligament applications, despite the potential to reduce knee arthroplasty failures attributed to ligament imbalance. Therefore, we developed, optimized and validated an ultrasound speckle tracking method to assess the in-situ strains of the medial and lateral collateral ligaments. Nine cadaveric legs with total knee implants were submitted to varus/valgus loading and divided into two groups: "optimization" and "validation". Reference strains were measured using digital image correlation technique, while ultrasound data were processed with a custom-built speckle tracking approach. Using specimens from the "optimization" group, several tracking parameters were tuned towards an optimized tracking performance. The parameters were ranked according to three comparative measures between the ultrasound-based and reference strains: R2, mean absolute error and strains differences at 40 N. Specimens from the "validation" group, processed with the optimal parameters, showed good correlations, along with small mean absolute differences, with correlation values above 0.99 and 0.89 and differences below 0.57% and 0.27% for the lateral and medial collateral ligaments, respectively. This study showed that ultrasound speckle tracking could assess knee collateral ligaments strains in situ and has the potential to be translated to clinics for knee arthroplasty-related procedures.

Phase Change Ultrasound Contrast Agents with a Photopolymerized Diacetylene Shell.

Phase change contrast agents for ultrasound (US) imaging consist of nanodroplets (NDs) with a perfluorocarbon (PFC) liquid core stabilized with a lipid or a polymer shell. Liquid ↔ gas transition, occurring in the core, can be triggered by US to produce acoustically active microbubbles (MBs) in a process named acoustic droplet vaporization (ADV). MB shells containing polymerized diacetylene moiety were considered as a good trade off between the lipid MBs, showing optimal attenuation, and the polymeric ones, displaying enhanced stability. This work reports on novel perfluoropentane and perfluorobutane NDs stabilized with a monolayer of an amphiphilic fatty acid, i.e. 10,12-pentacosadiynoic acid (PCDA), cured with ultraviolet (UV) irradiation. The photopolymerization of the diacetylene groups, evidenced by the appearance of a blue color due to the conjugation of ene-yne sequences, exhibits a chromatic transition from the nonfluorescent blue color to a fluorescent red color when the NDs are heated or the pH of the suspension is basic. An estimate of the molecular weights reached by the polymerized PCDA in the shell, poly(PCDA), has been obtained using gel permeation chromatography and MALDI-TOF mass spectrometry. The poly(PCDA)/PFC NDs show good biocompatibility with fibroblast cells. ADV efficiency and acoustic properties before and after the transition were tested using a 1 MHz probe, revealing a resonance frequency between 1 and 2 MHz similar to other lipidic MBs. The surface of PCDA shelled NDs can be easily modified without influencing the stability and the acoustic performances of droplets. As a proof of concept we report on the conjugation of cyclic RGD and PEG chains of the particles to support targeting ability toward endothelial cells.

Area of the pressure-strain loop during ejection as non-invasive index of left ventricular performance: a population study.

BACKGROUND: Previous studies highlighted the usefulness of integrating left ventricular (LV) deformation (strain) and hemodynamic parameters to quantify LV performance. In a population sample, we investigated the anthropometric and clinical determinants of a novel non-invasive index of LV systolic performance derived from simultaneous registration of LV strain and brachial pressure waveforms. METHODS: Three hundred fifty-six randomly recruited subjects (44.7% women; mean age, 53.9 years; 47.5% hypertensive) underwent echocardiographic and arterial data acquisition. We constructed pressure-strain loops from simultaneously recorded two-dimensional LV strain curves and brachial pressure waveforms obtained by finger applanation tonometry. We defined the area of this pressure-strain loop during ejection as LV ejection work density (EWD). We reported effect sizes as EWD changes associated with a 1-SD increase in covariables. RESULTS: In multivariable-adjusted analyses, higher EWD was associated with age, female sex and presence of hypertension (P ≤ 0.0084). In both men and women, EWD increased independently with augmentation pressure (effect size: + 59.1 Pa), central pulse pressure (+ 65.7 Pa) and pulse wave velocity (+ 44.8 Pa; P ≤ 0.0006). In men, EWD decreased with relative wall thickness (- 29.9 Pa) and increased with LV ejection fraction (+ 23.9 Pa; P ≤ 0.040). In women, EWD increased with left atrial (+ 76.2 Pa) and LV end-diastolic (+ 43.8 Pa) volume indexes and with E/e' ratio (+ 51.1 Pa; P ≤ 0.026). CONCLUSION: Older age, female sex and hypertension were associated with higher EWD. Integration of the LV pressure-strain loop during ejection might be a useful tool to non-invasively evaluate sex-specific and interdependent effects of preload and afterload on LV myocardial performance.

Cardiac Troponin T Concentrations, Reversible Myocardial Ischemia, and Indices of Left Ventricular Remodeling in Patients with Suspected Stable Angina Pectoris: a DOPPLER-CIP Substudy.

BACKGROUND: Cardiac troponin T concentrations measured with high-sensitivity assays (hs-cTnT) provide important prognostic information for patients with stable coronary artery disease (CAD). However, whether hs-cTnT concentrations mainly reflect left ventricular (LV) remodeling or recurrent myocardial ischemia in this population is not known. METHODS: We measured hs-cTnT concentrations in 619 subjects with suspected stable CAD in a prospectively designed multicenter study. We identified associations with indices of LV remodeling, as assessed by cardiac MRI and echocardiography, and evidence of myocardial ischemia diagnosed by single positron emission computed tomography. RESULTS: Median hs-cTnT concentration was 7.8 ng/L (interquartile range, 4.8-11.6 ng/L), and 111 patients (18%) had hs-cTnT concentrations above the upper reference limit (>14 ng/L). Patients with hs-cTnT >14 ng/L had increased LV mass (144 ± 40 g vs 116 ± 34 g; P < 0.001) and volume (179 ± 80 mL vs 158 ± 44 mL; P = 0.006), lower LV ejection fraction (LVEF) (59 ± 14 vs 62 ± 11; P = 0.006) and global longitudinal strain (14.1 ± 3.4% vs 16.9 ± 3.2%; P < 0.001), and more reversible perfusion defects (P = 0.001) and reversible wall motion abnormalities (P = 0.008). Age (P = 0.009), estimated glomerular filtration rate (P = 0.01), LV mass (P = 0.003), LVEF (P = 0.03), and evidence of reversible myocardial ischemia (P = 0.004 for perfusion defects and P = 0.02 for LV wall motion) were all associated with increasing hs-cTnT concentrations in multivariate analysis. We found analogous results when using the revised US upper reference limit of 19 ng/L. CONCLUSIONS: hs-cTnT concentrations reflect both LV mass and reversible myocardial ischemia in patients with suspected stable CAD.

3D Tendon Strain Estimation Using High-frequency Volumetric Ultrasound Images: A Feasibility Study.

Estimation of strain in tendons for tendinopathy assessment is a hot topic within the sports medicine community. It is believed that, if accurately estimated, existing treatment and rehabilitation protocols can be improved and presymptomatic abnormalities can be detected earlier. State-of-the-art studies present inaccurate and highly variable strain estimates, leaving this problem without solution. Out-of-plane motion, present when acquiring two-dimensional (2D) ultrasound (US) images, is a known problem and may be responsible for such errors. This work investigates the benefit of high-frequency, three-dimensional (3D) US imaging to reduce errors in tendon strain estimation. Volumetric US images were acquired in silico, in vitro, and ex vivo using an innovative acquisition approach that combines the acquisition of 2D high-frequency US images with a mechanical guided system. An affine image registration method was used to estimate global strain. 3D strain estimates were then compared with ground-truth values and with 2D strain estimates. The obtained results for in silico data showed a mean absolute error (MAE) of 0.07%, 0.05%, and 0.27% for 3D estimates along axial, lateral direction, and elevation direction and a respective MAE of 0.21% and 0.29% for 2D strain estimates. Although 3D could outperform 2D, this does not occur in in vitro and ex vivo settings, likely due to 3D acquisition artifacts. Comparison against the state-of-the-art methods showed competitive results. The proposed work shows that 3D strain estimates are more accurate than 2D estimates but acquisition of appropriate 3D US images remains a challenge.

Cardiovascular magnetic resonance myocardial feature tracking using a non-rigid, elastic image registration algorithm: assessment of variability in a real-life clinical setting.

BACKGROUND: Cardiovascular magnetic resonance myocardial feature tracking (CMR-FT) is a promising technique for quantification of myocardial strain from steady-state free precession (SSFP) cine images. We sought to determine the variability of CMR-FT using a non-rigid elastic registration algorithm recently available in a commercial software package (Segment, Medviso) in a real-life clinical setting. METHODS: Firstly, we studied the variability in a healthy volunteer who underwent 10 CMR studies over five consecutive days. Secondly, 10 patients were selected from our CMR database yielding normal findings (normal group). Finally, we prospectively studied 10 patients with known or suspected myocardial pathology referred for further investigation to CMR (patient group). In the patient group a second study was performed respecting an interval of 30 min between studies. All studies were manually segmented at the end-diastolic phase by three observers. In all subjects left ventricular (LV) circumferential and radial strain were calculated in the short-axis direction (EccSAX and ErrSAX, respectively) and longitudinal strain in the long-axis direction (EllLAX). The level of CMR experience of the observers was 2 weeks, 6 months and >20 years. RESULTS: Mean contouring time was 7 ± 1 min, mean FT calculation time 13 ± 2 min. Intra- and inter-observer variability was good to excellent with an coefficient of reproducibility (CR) ranging 1.6% to 11.5%, and 1.7% to 16.0%, respectively and an intraclass correlation coefficient (ICC) ranging 0.89 to 1.00 and 0.74 to 0.99, respectively. Variability considerably increased in the test-retest setting with a CR ranging 4.2% to 29.1% and an ICC ranging 0.66 to 0.95 in the patient group. Variability was not influenced by level of expertise of the observers. Neither did the presence of myocardial pathology at CMR negatively impact variability. However, compared to global myocardial strain, segmental myocardial strain variability increased with a factor 2-3, in particular for the basal and apical short-axis slices. CONCLUSIONS: CMR-FT using non-rigid, elastic registration is a reproducible approach for strain analysis in patients routinely scheduled for CMR, and is not influenced by the level of training. However, further improvement is needed to reliably depict small variations in segmental myocardial strain.

Extension of the angular spectrum method to model the pressure field of a cylindrically curved array transducer.

An extension to the angular spectrum approach for modelling pressure fields of a cylindrically curved array transducer is described in this paper. The proposed technique is based on representing the curved transducer surface as a set of planar elements whose contributions are combined at a selected intermediate plane from which the field is further propagated using the conventional angular spectrum approach. The accuracy of the proposed technique is validated through comparison with Field II simulations.

High variability in strain estimation errors when using a commercial ultrasound speckle tracking algorithm on tendon tissue.

BACKGROUND: Ultrasound speckle tracking offers a non-invasive way of studying strain in the free Achilles tendon where no anatomical landmarks are available for tracking. This provides new possibilities for studying injury mechanisms during sport activity and the effects of shoes, orthotic devices, and rehabilitation protocols on tendon biomechanics. PURPOSE: To investigate the feasibility of using a commercial ultrasound speckle tracking algorithm for assessing strain in tendon tissue. MATERIAL AND METHODS: A polyvinyl alcohol (PVA) phantom, three porcine tendons, and a human Achilles tendon were mounted in a materials testing machine and loaded to 4% peak strain. Ultrasound long-axis cine-loops of the samples were recorded. Speckle tracking analysis of axial strain was performed using a commercial speckle tracking software. Estimated strain was then compared to reference strain known from the materials testing machine. Two frame rates and two region of interest (ROI) sizes were evaluated. RESULTS: Best agreement between estimated strain and reference strain was found in the PVA phantom (absolute error in peak strain: 0.21 ± 0.08%). The absolute error in peak strain varied between 0.72 ± 0.65% and 10.64 ± 3.40% in the different tendon samples. Strain determined with a frame rate of 39.4 Hz had lower errors than 78.6 Hz as was the case with a 22 mm compared to an 11 mm ROI. CONCLUSION: Errors in peak strain estimation showed high variability between tendon samples and were large in relation to strain levels previously described in the Achilles tendon.

Three-dimensional analysis of implanted magnetic-resonance-visible meshes.

OBJECTIVE: Our primary objective was to develop relevant algorithms for quantification of mesh position and 3D shape in magnetic resonance (MR) images. METHODS: In this proof-of-principle study, one patient with severe anterior vaginal wall prolapse was implanted with an MR-visible mesh. High-resolution MR images of the pelvis were acquired 6 weeks and 8 months postsurgery. 3D models were created using semiautomatic segmentation techniques. Conformational changes were recorded quantitatively using part-comparison analysis. An ellipticity measure is proposed to record longitudinal conformational changes in the mesh arms. The surface that is the effective reinforcement provided by the mesh is calculated using a novel methodology. The area of this surface is the effective support area (ESA). RESULTS: MR-visible mesh was clearly outlined in the images, which allowed us to longitudinally quantify mesh configuration between 6 weeks and 8 months after implantation. No significant changes were found in mesh position, effective support area, conformation of the mesh's main body, and arm length during the period of observation. Ellipticity profiles show longitudinal conformational changes in posterior arms. CONCLUSIONS: This paper proposes novel methodologies for a systematic 3D assessment of the position and morphology of MR-visible meshes. A novel semiautomatic tool was developed to calculate the effective area of support provided by the mesh, a potentially clinically important parameter.

Speckle tracking echocardiography in fetuses diagnosed with congenital diaphragmatic hernia.

OBJECTIVE: The aim of this study is to evaluate cardiac function in fetuses with congenital diaphragmatic hernia (CDH) using speckle tracking. METHOD: Case-control study assessed cardiac contractility in consecutive fetuses with CDH. Controls were anatomically normal fetuses, adjusted for gestational age. Speckle tracking software calculated ventricular peak longitudinal velocity, displacement and strain. Pulmonary hypoplasia was assessed using observed/expected lung-to-head ratio (O/E LHR). RESULTS: Thirty-eight fetuses with CDH (29 left and nine right) were evaluated at a mean gestational age of 26.9 ± 2.5 weeks. In six fetuses, the acquired images were of insufficient quality (feasibility 83%). Velocity and displacement showed regional differences, as well as significant differences between the ventricular walls, similar to control fetuses. Strain measurements also demonstrated regional differences yet less uniformly arranged. In left CDH, we observed increased strain values in the left ventricle compared with controls (-18.7 ± 7.2 vs -15.1 ± 4.9). There was no correlation between strain values in the left ventricle and O/E LHR. In fetuses with right CDH, deformation analysis was not different from controls. CONCLUSIONS: In fetuses with CDH, no cardiac dysfunction could be detected despite the often concurrent hypoplasia of ipsilateral cardiac structures. In fetuses with left CDH, the decrease in ventricular size coincides with increased strain values in the free left ventricular wall.

BEAS-Net: a Shape-Prior-Based Deep Convolutional Neural Network for Robust Left Ventricular Segmentation in 2D Echocardiography.

Left ventricle (LV) segmentation of 2D echocardiography images is an essential step in the analysis of cardiac morphology and function and - more generally - diagnosis of cardiovascular diseases. Several deep learning (DL) algorithms have recently been proposed for the automatic segmentation of the LV, showing significant performance improvement over the traditional segmentation algorithms. However, unlike the traditional methods, prior information about the segmentation problem, e.g. anatomical shape information, is not usually incorporated for training the DL algorithms. This can degrade the generalization performance of the DL models on unseen images if their characteristics are somewhat different from those of the training images, e.g. low-quality testing images. In this study, a new shape-constrained deep convolutional neural network (CNN) - called BEAS-Net - is introduced for automatic LV segmentation. The BEAS-Net learns how to associate the image features, encoded by its convolutional layers, with anatomical shape-prior information derived by the B-spline explicit active surface (BEAS) algorithm to generate physiologically meaningful segmentation contours when dealing with artifactual or low-quality images. The performance of the proposed network was evaluated using three different in-vivo datasets and was compared a deep segmentation algorithm based on the U-Net model. Both networks yielded comparable results when tested on images of acceptable quality, but the BEAS-Net outperformed the benchmark DL model on artifactual and low-quality images.

Strain rate during isovolumic relaxation as a prognostic biomarker for long-term cardiovascular morbidity and mortality: an exploratory study on a general population.

AIMS: Left ventricular (LV) strain rate (SR) during early relaxation correlates with LV filling pressures and has been assessed as a prognostic biomarker in several cardiac diseases. Conversely, even though LV SR during isovolumic relaxation (SRIVR) is more strongly related to invasive measurements of LV diastolic function, to date, studies on the role of SRIVR in the long-term prognosis assessment are lacking. Thus, the goal of this study was to assess the potential additive prognostic value of SRIVR on top of conventional cardiovascular risk factors in a general population. METHODS: 657 subjects (mean age 51.6y; 47.6% males) were included in this study and, besides clinical and standard echocardiographic assessment, tissue Doppler imaging (TDI)-based SR was measured during IVR (SRIVR), early diastole (SRe), and atrial contraction (SRa) in the mid-segment of the inferior, inferolateral, lateral, and septal wall of the LV. RESULTS: During the follow-up period (median 12.1 years), the total number of major adverse cardiac events was 85 (13.4%). Overall, after adjustment for known cardiovascular risk factors and important echocardiographic indices in a multivariable-adjusted Cox regression model, SRIVR of the inferolateral wall (SRIVRinflat) remained an independent predictor of fatal and nonfatal cardiac events (HR: 1.49, p = 0.016), along with GLS (HR: 1.35, p = 0.027), age (HR: 1.09, p < 0.001), and male sex (HR: 2.06, p = 0.037). None of SRIVR measured in the other myocardial walls were associated with cardiac outcome. CONCLUSION: SRIVRinflat predicted adverse outcome in the general population, on top of conventional cardiovascular factors. However, its incremental value as a prognosticator remained limited.

A patient-specific echogenic soft robotic left ventricle embedded into a closed-loop cardiovascular simulator for advanced device testing.

Cardiovascular medical devices undergo a large number of pre- and post-market tests before their approval for clinical practice use. Sophisticated cardiovascular simulators can significantly expedite the evaluation process by providing a safe and controlled environment and representing clinically relevant case scenarios. The complex nature of the cardiovascular system affected by severe pathologies and the inherently intricate patient-device interaction creates a need for high-fidelity test benches able to reproduce intra- and inter-patient variability of disease states. Therefore, we propose an innovative cardiovascular simulator that combines in silico and in vitro modeling techniques with a soft robotic left ventricle. The simulator leverages patient-specific and echogenic soft robotic phantoms used to recreate the intracardiac pressure and volume waveforms, combined with an in silico lumped parameter model of the remaining cardiovascular system. Three different patient-specific profiles were recreated, to assess the capability of the simulator to represent a variety of working conditions and mechanical properties of the left ventricle. The simulator is shown to provide a realistic physiological and anatomical representation thanks to the use of soft robotics combined with in silico modeling. This tool proves valuable for optimizing and validating medical devices and delineating specific indications and boundary conditions.

Ultrasound Shear Wave Elastography in Cardiology.

The advent of high-frame rate imaging in ultrasound allowed the development of shear wave elastography as a noninvasive alternative for myocardial stiffness assessment. It measures mechanical waves propagating along the cardiac wall with speeds that are related to stiffness. The use of cardiac shear wave elastography in clinical studies is increasing, but a proper understanding of the different factors that affect wave propagation is required to correctly interpret results because of the heart's thin-walled geometry and intricate material properties. The aims of this review are to give an overview of the general concepts in cardiac shear wave elastography and to discuss in depth the effects of age, hemodynamic loading, cardiac morphology, fiber architecture, contractility, viscoelasticity, and system-dependent factors on the measurements, with a focus on clinical application. It also describes how these factors should be considered during acquisition, analysis, and reporting to ensure an accurate, robust, and reproducible measurement of the shear wave.

Evolution of Natural Myocardial Shear Wave Behavior in Young Hearts: Determinant Factors and Reproducibility Analysis.

BACKGROUND: Myocardial diastolic function assessment in children by conventional echocardiography is challenging. High-frame rate echocardiography facilitates the assessment of myocardial stiffness, a key factor in diastolic function, by measuring the propagation velocities of myocardial shear waves (SWs). However, normal values of natural SWs in children are currently lacking. The aim of this study was to explore the behavior of natural SWs among children and adolescents, their reproducibility, and the factors affecting SW velocities from childhood into adulthood. METHODS: One hundred six healthy children (2-18 years of age) and 62 adults (19-80 years of age) were recruited. High-frame rate images were acquired using a modified commercial scanner. An anatomic M-mode line was drawn along the ventricular septum, and propagation velocities of natural SWs after mitral valve closure were measured in the tissue acceleration-coded M-mode display. RESULTS: Throughout life, SW velocities after mitral valve closure exhibited pronounced age dependency (r = 0.73; P < .001). Among the pediatric population, SW velocities correlated significantly with measures of cardiac geometry (septal thickness and left ventricular end-diastolic dimension), local hemodynamics (systolic blood pressure), and echocardiographic parameters of systolic and diastolic function (global longitudinal strain, mitral E/e' ratio, isovolumic relaxation time, and mitral deceleration time) (P < .001). In a multivariate analysis including all these factors, the predictors of SW velocities were age, mitral E/e', and global longitudinal strain (r = 0.81). CONCLUSIONS: Natural myocardial SW velocities in children can be detected and measured. SW velocities showed significant dependence on age and diastolic function. Natural SWs could be a promising additive tool for the assessment of diastolic function among children.

Phase-change ultrasound contrast agents for proton range verification: towards anin vivoapplication.

Objective.In proton therapy, range uncertainties prevent optimal benefit from the superior depth-dose characteristics of proton beams over conventional photon-based radiotherapy. To reduce these uncertainties we recently proposed the use of phase-change ultrasound contrast agents as an affordable and effective range verification tool. In particular, superheated nanodroplets can convert into echogenic microbubbles upon proton irradiation, whereby the resulting ultrasound contrast relates to the proton range with high reproducibility. Here, we provide a firstin vivoproof-of-concept of this technology.Approach.First, thein vitrobiocompatibility of radiation-sensitive poly(vinyl alcohol) perfluorobutane nanodroplets was investigated using several colorimetric assays. Then,in vivoultrasound contrast was characterized using acoustic droplet vaporization (ADV) and later using proton beam irradiations at varying energies (49.7 MeV and 62 MeV) in healthy Sprague Dawley rats. A preliminary evaluation of thein vivobiocompatibility was performed using ADV and a combination of physiology monitoring and histology.Main results.Nanodroplets were non-toxic over a wide concentration range (<1 mM). In healthy rats, intravenously injected nanodroplets primarily accumulated in the organs of the reticuloendothelial system, where the lifetime of the generated ultrasound contrast (<30 min) was compatible with a typical radiotherapy fraction (<5 min). Spontaneous droplet vaporization did not result in significant background signals. Online ultrasound imaging of the liver of droplet-injected rats demonstrated an energy-dependent proton response, which can be tuned by varying the nanodroplet concentration. However, caution is warranted when deciding on the exact nanodroplet dose regimen as a mild physiological response (drop in cardiac rate, granuloma formation) was observed after ADV.Significance.These findings underline the potential of phase-change ultrasound contrast agents forin vivoproton range verification and provide the next step towards eventual clinical applications.

A Preliminary Investigation of Radiation-Sensitive Ultrasound Contrast Agents for Photon Dosimetry.

Radiotherapy treatment plans have become highly conformal, posing additional constraints on the accuracy of treatment delivery. Here, we explore the use of radiation-sensitive ultrasound contrast agents (superheated phase-change nanodroplets) as dosimetric radiation sensors. In a series of experiments, we irradiated perfluorobutane nanodroplets dispersed in gel phantoms at various temperatures and assessed the radiation-induced nanodroplet vaporization events using offline or online ultrasound imaging. At 25 °C and 37 °C, the nanodroplet response was only present at higher photon energies (≥10 MV) and limited to <2 vaporization events per cm2 per Gy. A strong response (~2000 vaporizations per cm2 per Gy) was observed at 65 °C, suggesting radiation-induced nucleation of the droplet core at a sufficiently high degree of superheat. These results emphasize the need for alternative nanodroplet formulations, with a more volatile perfluorocarbon core, to enable in vivo photon dosimetry. The current nanodroplet formulation carries potential as an innovative gel dosimeter if an appropriate gel matrix can be found to ensure reproducibility. Eventually, the proposed technology might unlock unprecedented temporal and spatial resolution in image-based dosimetry, thanks to the combination of high-frame-rate ultrasound imaging and the detection of individual vaporization events, thereby addressing some of the burning challenges of new radiotherapy innovations.