Flow Phantom Study Research Articles

Magnetic microbubbles for localised imaging and drug delivery: Development, characterisation and preliminary application in vivo

The use of coated microbubbles in therapeutic applications, in particular drug delivery and gene therapy, has become a highly active area of research. There remain, however, some significant challenges to be overcome in order to fully realise the potential of microbubbles in these applications. In particular, the difficulty in controlling the concentration of microbubbles at a given site and in ensuring sufficient proximity between bubbles and target cells, has frequently led to disappointing results from in vivo studies. Recent work has indicated that incorporating magnetic nanoparticles into the microbubble coating may provide an effective strategy for overcoming these challenges. Further investigation to fully understand the mechanisms of enhancement and hence optimise the delivery protocols is however required and this is the aim of the present study. Results will be presented from flow phantom studies demonstrating manipulation of bubble suspensions under physiological flow conditions, from high speed imaging used to investigate the dynamic behaviour of single microbubbles and theoretical modelling conducted to support and interpret the experimental findings. Finally results demonstrating in vivo transfection in a mouse model will be presented confirming successful localisation of the transfection site.

Uniform Vascular Enhancement of Lower-Extremity Artery on CT Angiography Using Test-Injection Monitoring at the Central Level of the Scan Range: A Simulation Flow Phantom Study with Clinical Correlation

To evaluate the efficacy of variable contrast injection durations and scanning delay determined by test injection analysis of computed tomography angiography (CTA) of peripheral arteries. We used a flow phantom that simulates the hemodynamics in a lower extremity artery. We set the flow rate at the pump to 2.0 or 5.0 L/minute. In protocol 1, we adopted a variable contrast injection duration based on the peak enhancement time of the test injection monitoring at the central level of the scan range. In protocol 2, we adopted a fixed contrast injection duration. The scanning delay was determined with a conventional bolus-tracking technique monitoring at the top of the scan range. Mean arterial attenuation and difference between the maximum and minimum attenuation values were calculated. To verify the phantom study results, clinical study, including 16 patients was performed under protocol 1. The mean attenuation values under protocols 1 and 2 were comparable (563.6 Hounsfield units [HU] and 535.0 HU, respectively) at a pump flow rate of 2.0 L/minute; at 5.0 L/minute, they were 289.4 HU and 328.8 HU. The difference between the maximum and minimum attenuation values was smaller under protocol 1 than protocol 2 (76.8 HU vs. 184.9 HU) at a pump flow of 2.0 L/minute and also smaller under protocol 1 than protocol 2 (79.7 HU vs. 203.8 HU) at 5.0 L/minute. In clinical study, the mean attenuation value was 332.6 +/- 51.9 HU, and the difference between the maximum and minimum attenuation values was 55.1 +/- 24.4 HU. The object-specific injection duration based on test injection at the central level of the scan range provides sufficient and constant vascular enhancement at CTA.

Rapid Prototyping Raw Models on the Basis of High Resolution Computed Tomography Lung Data for Respiratory Flow Dynamics

Three-dimensional image reconstruction by volume rendering and rapid prototyping has made it possible to visualize anatomic structures in three dimensions for interventional planning and academic research. Volumetric chest computed tomography was performed on a healthy volunteer. Computed tomographic images of the larger bronchial branches were segmented by an extended three-dimensional region-growing algorithm, converted into a stereolithography file, and used for computer-aided design on a laser sintering machine. The injection of gases for respiratory flow modeling and measurements using magnetic resonance imaging were done on a hollow cast. Manufacturing the rapid prototype took about 40 minutes and included the airway tree from trackea to segmental bronchi (fifth generation). The branching of the airways are clearly visible in the (3)He images, and the radial imaging has the potential to elucidate the airway dimensions. The results for flow patterns in the human bronchial tree using the rapid-prototype model with hyperpolarized helium-3 magnetic resonance imaging show the value of this model for flow phantom studies.

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The purpose of this study was to suppress CSF flow artifacts in the fast FLAIR sequence at 3.0T MRI. We investigated the influence of thickness of the inversion pulse in the sequence on the high-intensity CSF flow artifacts based on the flow phantom and in-vivo studies at 1.5T and 3.0T. Results demonstrated that CSF flow artifacts at 3.0T were clearly stronger than at as 1.5T. Moreover, 3.0T was influenced by the crosstalk between each inversion pulse compared with 1.5T. The optimal setting of inversion pulse for two interleaving acquisitions for fast FLAIR imaging at 3.0T was approximately 1.5 fold on the basis of sum of slice thickness and slice gap. The appropriate setting of thickness of inversion pulse in fast FLAIR imaging reduces the incidence of CSF flow artifacts at 3.0T.

Acoustic characterization of a new trisacryl contrast agent. Part II: Flow phantom study and in vivo quantification

The biocompatible trisacryl particles (TMP) are made of a cross-linked acrylic copolymer. Their inherent acoustic properties, studied for a contrast agent application, have been previously demonstrated in a in vitro Couette device. To measure their acoustic behaviour under circulating blood conditions, the TMP backscatter enhancement was further evaluated on a home-made flow phantom at different TMP doses (0.12–15.6 mg/ml) suspended in aqueous and blood media, and in nude mice (aorta and B16 grafted melanoma). Integrated backscatter (IB) was measured by spectral analysis of the Doppler signals recorded from an ultrasound system (Aplio ®) combined with a 12-MHz probe. Doppler phantom experiments revealed a maximal IB of 17 ± 0.88 dB and 7.5 ± 0.7 dB in aqueous and blood media, respectively. IB measured on mice aorta, in pulsed Doppler mode, confirmed a constant maximal value of 7.29 ± 1.72 dB over the first minutes after injection of a 7.8 mg/ml TMP suspension. Following the injection, a 60% enhancement of intratumoral vascularization detection was observed in power Doppler mode. A preliminary histological study revealed inert presence of some TMP in lungs 8 and 16 days after injection. Doppler phantom experiments on whole blood allowed to anticipate the in vivo acoustic behaviour. Both protocols demonstrated TMP effectiveness in significantly increasing Doppler signal intensity and intratumoral vascularization detection. However, it was also shown that blood conditions seemed to shadow the TMP contrast effect, as compared to in vitro observations. These results encourage further investigations on the specific TMP targeting and on their bio-distribution in the different tissues.

Simplified laser-speckle-imaging analysis method and its application to retinal blood flow imaging.

Laser speckle imaging (LSI) is widely used to study blood flow at high spatiotemporal resolution. Several papers recently pointed out that the commonly used LSI equation involves an approximation that could result in incorrect data analysis. We investigated the impact of such an approximation and introduced a simplified analysis method to improve computation time. Flow phantom studies were performed for validation. Moreover, we demonstrated a novel LSI application by imaging blood flow of rat retinas under normal and physiologic-challenge conditions. Because blood-flow abnormality is implicated in many retinal diseases, LSI could provide valuable physiologic, and potentially diagnostic, information.

Evaluation of blood flow velocity vector measurement accuracy: Numerical simulation and flow phantom studies of Rankine’s vortex

A new method to measure the velocity vector of blood flow on the observation plane was recently developed [Ohtsuki and Tanaka, J. Visuali. 9, 69–82 (2006)]. The method is based on the calculation of stream functions. To evaluate the accuracy of this method, we have studied the velocity distribution of Rankine’s vortex in numerical simulation and experiments. The vortex of the simulation model was 50 mm in radius, the forced vortex was 20 mm in radius, and the maximum velocity of the vortex was 50 cm/s. The differences between the velocity profiles of the vortex obtained by this method and by simulation were less than 10%, although the accuracy depended on the angle of the observation plane. Furthermore, we conducted phantom experiments in which the vortex was created in degassed water by using a magnetic stirrer. Color Doppler data of the vortex flow were acquired using a ultrasonic diagnostic system (SSD-6500, Aloka, Japan) and the velocity vector distribution was calculated. The experimental results were in good agreement with the simulation model. We conclude that the reliability of this method is very high. The results suggest great potential of the new velocity vector method for quantitative diagnosis of cardiac functions.

OP09.01: Evaluation of the vascularization index; a flow phantom study

Three-dimensional power Doppler (3D-PD) ultrasound provides flow indices to quantify blood flow characteristics within a chosen volume of interest (e.g. ovary, tumor, placenta). The aim of the study was to assess and evaluate Vascularization Index (VI) data, using a specially built flow phantom with a known vascular diameter and a known volume of fluid pumped through it. A Voluson 730 Expert 3D-PD ultrasound machine was used, with a vaginal probe (RIC5–9) clipped onto a holding apparatus. ‘Fractional moving blood volume’ (FMBV) was simulated by pumping blood-mimicking fluid flow (10–100 ml/hr) through a plastic tube (diameter 0.65 mm) within a virtual spherical volume (content 137.12 cm3) of the ultrasound machine. VI was determined at different pulse repetition frequency (PRF) settings, with minimal and maximal wall motion filter (WMF) settings. The flow phantom showed that detection of FMBV at different flow velocities, depends on PRF—and WMF settings. At a PRF of 0.3 KHz, flow velocities of about 2 cm/s are fully registered. Using VI, at fully detected flow, actual FMBV within the tube is about 37 times overestimated. We find there is a significant overestimation of FMBV in 3D PD mode when a single small vessel is investigated, which is inherent to the method, because of limited spatial resolution. If reference vessels or objects with known vascularity can be established, the overestimation effect may be reduced.

Real‐time blood flow imaging using autocalibrated spiral sensitivity encoding

A novel spiral phase contrast (PC) technique was developed for high temporal resolution imaging of blood flow without cardiac gating. An autocalibrated spiral sensitivity encoding (SENSE) method is introduced and used to reconstruct PC images. Numerical simulations and a flow phantom study were performed to validate the technique. To study the accuracy of the flow measurement in vivo, a high-resolution cardiac experiment was performed and a subset of undersampled SENSE reconstructed data were reconstructed. Good agreement between the velocity measurement from the fully-sampled and undersampled data was achieved. Real-time experiments were performed to measure blood velocity in the ascending aorta and aortic valve, and during a Valsalva maneuver. The results demonstrate the potential of this technique for real-time flow imaging.

Lower Extremity: Low-Dose Contrast Agent Intraarterial MR Angiography in Patients—Initial Results

Institutional review board approval and patient consent were obtained. A low-dose injection protocol for intraarterial three-dimensional (3D) gadolinium-enhanced magnetic resonance (MR) angiography was derived from femoral flow phantom studies and prospectively evaluated in patients with peripheral arterial occlusive disease (PAOD). All MR angiograms were obtained at 1.5 T with a T1-weighted gradient-echo sequence. MR angiograms of a gadolinium dilution series (0.8-200.0 mmol/L) were acquired in a femoral phantom at different flow rates. Signal-to-noise ratios (SNRs) above the 75% threshold of the measured maximum were considered optimal. The lowest optimal concentration was injected intraarterially in nine patients to obtain 3D MR angiograms of the thigh and calf station. Contrast-to-noise ratios (CNRs) were calculated for four arterial segments. The low optimal concentration of 50 mmol/L (20-mL bolus volume), about 5% of the total permissible dose, showed SNRs larger than the 75% threshold in the phantom study. In patients, this concentration led to high-spatial-resolution angiograms with mean CNRs of 70.0 +/- 14.5 (+/- standard deviation) for the superficial femoral artery and 47.5 +/- 13.4 at the infrapopliteal level. Low-dose contrast agent intraarterial 3D MR angiography showed high arterial enhancement, enabling assessment of lower extremity arteries in patients with PAOD and multiple injections--a crucial precondition for MR-guided endovascular interventions.

Effective blood signal suppression using double inversion‐recovery and slice reordering for multislice fast spin‐echo MRI and its application in simultaneous proton density and T2 weighted imaging

To design a multislice double inversion-recovery fast spin-echo (FSE) sequence, with k-space reordered by inversion time at slice position (KRISP) technique, to produce black-blood vessel wall magnetic resonance imaging (MRI). In this sequence, central k-space sampling for each slice is required at inversion time (TI) of the blood signal. To fill the entire k-space, the peripheral lines are obtained less or greater the TI and using a rotating slice order. Blood flow signal suppression was first evaluated using a phantom. Simulation studies were used to investigate FSE image quality. The final sequence was then applied to the rabbit abdominal aorta MRI at 4.7 T. In the flow phantom study, artifacts from slow-flowing water were substantially reduced by the KRISP technique; residual water spins were dephased by the strong phase-encoding gradient required for peripheral k-space. These dephased spins flowed into the slice plane where the center of k-space was being acquired at the TI of the flowing water signal. Multislice black-blood MR images were successfully obtained in the rabbit abdomen using the sequence with the k-trajectory optimized by the simulation study. The KRISP technique was effective both in multislice double inversion-recovery FSE and in blood signal suppression.

High-pass-low-pass (HP-LP) reconstruction of CINE phase-contrast MRI.

A new interpretation of CINE phase-contrast (PC) MRI is presented in which flowing blood is shown to induce separate high- and low-temporal-frequency components in the resulting image sequence. The flow velocities can then be extracted from the ratio of these two components, independently of any unknown phase offset. This interpretation leads to new insights into improving temporal resolution, eliminating noise, and reducing acquisition time in PC imaging. A specific example explored in this article uses a technique related to unaliasing by Fourier-encoding the overlaps using the temporal dimension (UNFOLD) to acquire PC velocity measurements at 54-68 time points in the cardiac cycle, all within a single breath-hold of <20 s. In experimental studies, these techniques were shown to yield improved signal-to-noise ratios (SNRs) in a flow phantom and cerebrospinal fluid (CSF) flow studies, and to resolve the formation of a flow vortex during left ventricular (LV) filling in humans.

UNFOLD using a temporal subtraction and spectral energy comparison technique.

In dynamic MRI, several methods have been demonstrated to increase acquisition speed by decreasing the number of sequential phase encodings. The UNFOLD technique interleaves the measurements of k-space, reconstructs aliased images from each k-space interleaf, and applies a temporal low-pass filter to obtain the nonaliased images. However, low-pass filter resolution of the nonaliased images fails if there is overlap between the spatially aliased temporal spectra. In this study a subtraction method was used to remove the static portion of the image. The aliased and nonaliased dynamic portions are then resolved by comparing the temporal energy of bands in the power spectrum. This method was combined with the 3D 2 x 2 UNFOLD (a factor of 2 interleaves in two directions) technique. The combination resulted in a factor of 4 improvement in acquisition speed. Application of this method to a time-resolved, contrast-enhanced flow phantom study is presented.

Real-time color flow MRI

A real-time interactive color flow MRI system capable of rapidly visualizing cardiac and vascular flow is described. Interleaved spiral phase contrast datasets are acquired continuously, while real-time gridding and phase differencing is used to compute density and velocity maps. These maps are then displayed using a color overlay similar to what is used by ultrasound. For cardiac applications, 6 independent images/sec are acquired with in-plane resolution of 2.4 mm over a 20 cm field of view (FOV). Sliding window reconstruction achieves display rates up to 18 images/sec. Appropriate tradeoffs are made for other applications. Flow phantom studies indicate this technique accurately measures velocities up to 2 m/sec, and accurately captures real-time velocity waveforms (comparable to continuous wave ultrasound). In vivo studies indicate this technique is useful for imaging cardiac and vascular flow, particularly valvular regurgitation. Arbitrary scan planes can be quickly localized, and flow measured in any direction.

Good resolution of contrast-enhanced MRA using USPIO on coronal plane acquisition: experimental evaluation of time-of-flight effect using flow phantom and animal study.

The major disadvantage of 3D TOF MRA is the saturation effect (1-4), even in 3D acquisition. The orientation of the blood vessel to the slice plane is crucial for magnetic resonance angiography. When flowing spins travel parallel to imaging plane, they receive many RF pulses, which decreases the signal (5-7). This is the saturation effect. Maximum enhancement occurs when blood flow is perpendicular to the imaging plane and near the imaging plane that receives the minimum number of RF pulses. When imaging the abdominal aorta and lower extremities, this method requires scanning the long imaging segment of vessels using axial plane and results in a prolonged study time (3,8-12). Recently, scans were obtained parallel to flow after the dynamic gadolinium injection (9,13), which resulted in good images in many areas. But it is not known how flow enhi~ncement effects contributed to the contrast-enhanced MR angiography. We have developed a new contrast agent, AMI-227, which has long blood half-life, so the change of the concentration can be ignored. Using this contrast agent, we directly compare the 3D TOF MRA scanning results obtained in both axial and coronal sections.

Flow velocity of the cortical vein and its effect on functional brain MRI at 1.5T: preliminary results by cine-MR venography.

The purpose of this study is to demonstrate the effect of altering flow velocity of cerebral cortical veins as the source of the signal change observed in functional magnetic resonance imaging (fMRI) of the brain. 10 healthy volunteers were examined after instructions in self-paced hand grasping. Experiments were performed using a 1.5-Tesla whole body MR scanner with a conventional two-dimensional gradient echo sequence (TR/TE/flip angle 400/60/40, first order flow rephased, reduced band width 8 Hz/pixel). Flow velocity measurements were performed for the cortical veins which corresponded to the activated areas depicted on fMRI. Velocity was estimated from the cine-MR venography (cine-MRV) with a tagging technique. Flow phantom studies were performed to delineate the effect of flow velocity differences upon the subtraction images of fMRI. The cine-MRV revealed increased flow velocity of the cortical veins during activation in seven volunteers, with a mean velocity difference of 15 mm/sec. Flow phantom studies suggested that the increased flow velocity may result in changes of the flow signal profile due to oblique flow displacement. Subtraction of the two images with different flow profiles produces flow signal enhancement. Increased flow velocity of the cortical veins during the activation is an important factor which contributes to the signal of fMRI.

Echo machine-imposed limit on transmitral spectral Doppler velocity-profile analysis

We have previously developed a kinematic model of ventricular filling. Its application to in vivo transmitral Doppler velocity profiles provides a quantitative characterization of filling. However, the model parameters computed by solving the “inverse problem” may depend on ultrasound machine type and setting ( e.g., gain, baseline filter, dynamic range). To determine machine-based effects on the computed model parameters, we performed a flow phantom study using Acuson and HP echocardiography machines at various settings. We compared maximum velocity envelopes (MVEs), as well as the model fit to these MVEs, for 3 simulated waveforms imaged by both machines. For all 3 waveforms, the machines generated comparable MVEs, fit by the model within a mean-square difference of 5E-5 (m/s) 2. The associated variations in model parameters for the 3 waveforms were not uniform. Two waveforms showed slight variation between machines, with model parameters varying by less than 6%. The shortest duration waveform showed model parameter variations of 10–15%. Analysis of the parameter space for this waveform showed a constant mean-square error contour that was larger than that for the other two, causing similar small variations in measured MVEs to result in larger differences in the parameter estimates for this waveform. Because this method completely eliminates inter- and intraobserver variability, we conclude that, within the limits established, the slight contour variations due to machine type and setting should not affect this method's applicability in clinical Doppler-flow analysis.

Error in MR volumetric flow measurements due to ordered phase encoding in the presence of flow varying with respiration.

Respiratory ordered phase encoding is often employed in MRI studies to reduce image artifacts due to breathing motion. The purpose of this work was to evaluate error caused by the use of respiratory ordering of phase encoding in MR cine phase-contrast (CPC) volumetric flow measurements when the flow rate is sensitive to respiration. It was hypothesized that this effect is due to the systematic biasing of a respiratory-induced phase modulation function in k-space. A theoretical model for the effects of respiration was developed and then tested in flow phantom studies and in normal volunteer studies. In phantom experiments, the use of respiratory ordering induced an error of as much as 13% in CPC volumetric flow measurements. In preliminary volunteer studies, error was as high as 26% in superior vena cava flow measurements versus less than 1% error in the ascending aorta. It is concluded that a potential for error exists in CPC volumetric flow measurements obtained with the use of respiratory ordering schemes. Volunteer studies with larger numbers are warranted. Clinical applications in which this effect may be important include flow measurements in vessels subject to variations in flow due to respiration, such as the venae cavae, pulmonary vasculature, and portal vein.

Portal blood flow in the presence or absence of diffuse liver disease: measurement by phase contrast MR imaging.

In patients with diffuse liver disease, the portal flow dynamics change markedly in accordance with disease progression and would provide a useful index of progression of stage. Portal blood flow (PBF) was measured by phase contrast magnetic resonance imaging (MRI) in 21 patients with diffuse liver disease and 20 healthy volunteers. The MRI method was validated by a flow phantom study. The mean PBF could be measured in 6.8 min without breath-holding. Doppler ultrasound measurements of PBF volume were obtained reproducibly in all the healthy volunteers and were shown to correlate with the MRI values (Doppler: 12.5 +/- 3.2 cm3/s, MRI: 12.0 +/- 3.3 cm3/s; mean +/- SD). The PBF volume of patients with chronic hepatitis showed no significant difference from that of the healthy volunteers. In patients with liver cirrhosis, the PBF volume ranged from 5.01 to 32.3 cm3/s. A significant increase in PBF volume was caused in one patient by massive intrahepatic shunting and a significant decrease was caused in two patients by massive extrahepatic shunting. The measurement of PBF by phase contrast MRI is clinically useful in predicting intrahepatic or extrahepatic shunting in patients with liver cirrhosis, and may be of value in detecting the progression of stage in diffuse liver diseases.

Turbulent Fluctuation Velocity: The Most Significant Determinant of Signal Loss in Stenotic Vessels

Studies of flow in a 90%-stenosis phantom were conducted to elucidate the parameters and mechanisms responsible for signal loss in MR angiographic images. The studies independently evaluated the effect of velocity, Reynolds number, turbulent fluctuation velocity, and turbulence intensity on the amount of post-stenotic signal loss. Results suggested that the magnitude of the turbulent fluctuation velocity, not merely the presence of turbulence or the intensity of turbulence, was the parameter that determined the extent of the signal loss. The study suggests that future flow phantom studies should be conducted with fluids having physiologic velocities and viscosities to obtain accurate levels of turbulent fluctuation velocities and hence reproduce results of in-vivo signal-loss patterns. The mechanism for signal loss is that the temporal and spatial variations of the turbulent fluctuation velocity cause a range of phases to be present within a voxel. Examination of the theoretical aspects of fluid turbulence suggest that shortening gradient durations and imaging during diastole may help reduce signal loss.