Quantitative Determination of Local Density of Iron Oxide Nanoparticles Used for Drug Targeting Employing Inverse Magnetomotive Ultrasound.

Numerous medical applications make use of magnetic nanoparticles, which increase the demand for imaging procedures that are capable of visualizing this kind of particle. Magnetomotive ultrasound (MMUS) is an ultrasound-based imaging modality that can detect tissue, which is permeated by magnetic nanoparticles. However, currently, MMUS can only provide a qualitative mapping of the particle density in the particle-loaded tissue. In this contribution, we present an enhanced MMUS procedure, which enables an estimation of the quantitative level of the local nanoparticle concentration in tissue. The introduced modality involves an adjustment of simulated data to measurement data. To generate these simulated data, the physical processes that arise during the MMUS imaging procedure have to be emulated which can be a computing-intensive proceeding. Since this considerable calculation effort may handicap clinical applications, we further present an efficient approach to calculate the decisive physical quantities and a suitable way to adjust these simulated quantities to the measurement data with only moderate computational effort. For this purpose, we use the result data of a conventional MMUS measurement and the knowledge on the magnetic field quantities and on the mechanical parameters describing the biological tissue, namely, the density, the longitudinal wave velocity, and the shear wave velocity. Experiments on tissue-mimicking phantoms demonstrate that the presented technique can indeed be utilized to determine the local nanoparticle concentration in tissue quantitatively in the correct order of magnitude. By investigating test phantoms of simple geometry, the mean particle concentration of the particle-laden area could be determined with less than 22% deviation to the nominal value.

Inertial cavitation of lyophilized and rehydrated nanoparticles of poly(L-lactic acid) at 835 kHz and 1.8 MPa ultrasound.

Nanoparticles of poly-L-lactic acid dispersed in water and of approximately 120 nm diameter were prepared by a nanoprecipitation method followed by lyophilization together with trehalose. After rehydration, the nanodispersion was exposed to ultrasound at 835 kHz frequency and 1.8 MPa peak negative sound pressure. Substantial levels of broadband noise were surprisingly detected which are attributed to the occurance of inertial cavitation of bubbles present in the dispersion. Inertial cavitation encompasses the formation and growth of gas cavities in the rarefaction pressure cycle which collapse in the compression cycle because of the inwardly-acting inertia of the contracting gas-liquid interface. The intensity of this inertial cavitation over 600 s was similar to that produced by Optison microbubbles used as contrast agents for diagnostic ultrasound. Non-lyophilized nanodispersions produced negligible broadband noise showing that lyophilization and rehydration are requirements for broadband activity of the nanoparticles. Photon correlation spectroscopy indicates that the nanoparticles are not highly aggregated in the nanodispersion and this is supported by scanning (SEM) and transmission (TEM) electron micrographs. TEM visualized non-spherical nanoparticles with a degree of irregular, non-smooth surfaces. Although the presence of small aggregates with inter-particulate gas pockets cannot be ruled out, the inertial cavitation activity can be explained by incomplete wetting of the nanoparticle surface during rehydration of the lyophilizate. Nano-scale gas pockets may be trapped in the surface roughness of the nanoparticles and may be released and coalesce to the size required to nucleate inertial cavitation on insonation at 835 kHz/1.8 MPa.

Modification of in vitro degradation behavior of pure iron with ultrasonication treatment: Comparison of two different pseudo-physiological solutions.

An ultrasonication treatment is developed as an external method to control the degradation behavior of pure iron. Immersion tests (weight loss measurements) and electrochemical measurements were conducted in two different pseudo-physiological solutions, simulated body fluid (SBF) and Dulbecco's modified Eagle medium (DMEM) solution. By the comparison study in these two different solutions, more information and the mechanism of the degradation process can be revealed. Degradation morphologies (with and without ultrasonication treatment) were observed by scanning electron microscope (SEM), and degradation products on the surface were characterized by Fourier transform infrared (FTIR) spectroscopy and X-ray photoelectron spectroscopy (XPS). Moreover, the biocompatibility of iron surfaces after being ultrasonicated was evaluated. Ultrasonication was found to accelerate the degradation rate in DMEM, while it makes no difference in SBF solution; the origin of this different behavior is investigated and discussed. The parameters of the ultrasonication treatment, intensity and frequency, show an influence on the degradation rate. No adverse effects on the proliferation and adhesion of human osteoblast-like cells (MG-63) are observed on surfaces after ultrasonication treatment, as compared to bare iron. Based on these results, ultrasonication treatment is considered to have high potential to control the biodegradation behavior of iron-based materials in an external and flexible manner.

Ultrasonic Defect Characterization in Heavy Rotor Forgings by Means of the Synthetic Aperture Focusing Technique and Optimization Methods.

Ultrasonic nondestructive testing of steel forgings aims at the detection and classification of material inhomogeneities to ensure the components fitness for use. Due to the high price and safety critical nature of large forgings for turbomachinery, there is great interest in the application of imaging algorithms to inspection data. However, small flaw indications that cannot be sufficiently resolved have to be characterized using amplitude-based quantification. One such method is the distance gain size method, which converts the maximum echo amplitudes into the diameters of penny-shaped equivalent size reflectors. The approach presented in this contribution combines the synthetic aperture focusing technique (SAFT) with an iterative inversion scheme to locate and quantify small flaws in a more reliable way. Ultrasonic inspection data obtained in a pulse-echo configuration are reconstructed by means of an Synthetic Focusing Technique (SAFT). From the reconstructed data, the amount and approximate location of small flaws are extracted. These predetermined positions, along with the constrained defect model of a penny-shaped crack, provide the initial parametrization for an elastodynamic simulation based on the Kirchhoff approximation. The identification of the optimal parameter set is achieved through an iteratively regularized Gauss-Newton method. By testing the characterization method on a series of flat-bottom holes under laboratory conditions, we demonstrate that the procedure is applicable over a wide range of defect sizes. To show suitability for large forging inspection, we additionally evaluate the inspection data of a large generator shaft forging of 0.6-m diameter.

An ultrasound tomography system with polyvinyl alcohol (PVA) moldings for coupling: in vivo results for 3-D pulse-echo imaging of the female breast.

Full-angle spatial compounding (FASC) is a concept for pulse-echo imaging using an ultrasound tomography (UST) system. With FASC, resolution is increased and speckles are suppressed by averaging pulse-echo data from 360°. In vivo investigations have already shown a great potential for 2-D FASC in the female breast as well as for finger-joint imaging. However, providing a small number of images of parallel cross-sectional planes with enhanced image quality is not sufficient for diagnosis. Therefore, volume data (3-D) is needed. For this purpose, we further developed our UST add-on system to automatically rotate a motorized array (3-D probe) around the object of investigation. Full integration of external motor and ultrasound electronics control in a custom-made program allows acquisition of 3-D pulse-echo RF datasets within 10 min. In case of breast cancer imaging, this concept also enables imaging of near-thorax tissue regions which cannot be achieved by 2-D FASC. Furthermore, moldings made of polyvinyl alcohol hydrogel (PVA-H) have been developed as a new acoustic coupling concept. It has a great potential to replace the water bath technique in UST, which is a critical concept with respect to clinical investigations. In this contribution, we present in vivo results for 3-D FASC applied to imaging a female breast which has been placed in a PVA-H molding during data acquisition. An algorithm is described to compensate time-of-flight and consider refraction at the water-PVA-H molding and molding-tissue interfaces. Therefore, the mean speed of sound (SOS) for the breast tissue is estimated with an image-based method. Our results show that the PVA-H molding concept is applicable and feasible and delivers good results. 3-D FASC is superior to 2-D FASC and provides 3-D volume data at increased image quality.

A high-frequency ultrasound imaging system combining limited-angle spatial compounding and model-based synthetic aperture focusing.

High-frequency ultrasound (HFUS) imaging systems are routinely used for medical diagnostics (skin, eyes) and for medical research (small animal imaging). Although systems with array transducers are already commercially available, imaging systems with single-element transducers are still of interest and available as well, because this type of transducer is less complex, less expensive, and technically mature. Nevertheless, drawbacks exist, for example, the need for mechanical scanning units and the limited depth of field. In this paper, we present a high-frequency (20 MHz) ultrasound imaging system equipped with a spherically focused transducer. Limited-angle spatial compounding is utilized to improve the image contrast, to suppress speckle and noise, and to reduce imaging artifacts. To overcome the limitation in depth of field, the system uses a novel synthetic aperture focusing technique based on the correlation of the recorded echo signals with the simulated point spread function of the imaging system. This method results in lower side lobe levels and greater noise reduction compared with delay-and-sum focusing, which is demonstrated by wire phantom measurements. When used in combination with limited-angle spatial compounding, as presented in this paper, the resulting image quality is superior to conventional single-element HFUS imaging systems and to array systems. Examples of measurements on tissue phantoms and small animals (ex vivo) are presented and discussed in detail.

Computer aided diagnosis of parotid gland lesions using ultrasonic multi-feature tissue characterization.

In this article, an ultrasound based system for computer aided characterization of biologic tissue and its application to differential diagnosis of parotid gland lesions is proposed. Aiming at an automated differentiation between malignant and benign cases, the system is based on a supervised classification using tissue-describing features derived from ultrasound radio-frequency (RF) echo signals and image data. Standard diagnostic ultrasound equipment was employed to acquire ultrasound RF echo data from parotid glands of 138 patients. Lesions were manually demarcated as regions-of-interest (ROIs) in the B-mode images. Spectral ultrasound backscatter and attenuation parameters are estimated from diffraction corrected RF data, yielding spatially resolved parameter images. Histogram based statistical measures derived from the parameters distributions inside the ROI are used as tissue describing features. In addition, texture features and shape descriptors are extracted from demodulated ultrasound image data. The features are processed by a maximum likelihood classifier. An optimal set of 10 features was chosen by a sequential forward selection algorithm. The classifier's performance is evaluated using total cross validation and receiver operating characteristic (ROC) analysis. As a reference method, postoperative pathohistologic analysis was conducted and proved malignancy or prospective malignancy in 51 patients. The classification using the proposed system yielded an area under the ROC curve of 0.91, proving significant potential for differentiating between malignant and benign parotid gland lesions.

A method to expedite data acquisition for multiple spatial-temporal analyses of tissue perfusion by contrast-enhanced ultrasound.

For semiquantitative analyses of tissue perfusion using contrast-enhanced ultrasound the acquisition and processing of time intensity curves (TIC) is required. These TICs can be computed for each pixel of an image plane, yielding parametric images of classification numbers like "blood volume" and "flow rate." The expenditure of time for data acquisition and analysis typically limits semiquantitative perfusion imaging to a single image plane in 2-D. 3-D techniques, however, provide a higher diagnostic value since more information (e.g., of an entire lesion) is obtained. Moreover, spatial compounding, being a 2-D-technique where an object is imaged from different viewing angles, is known to improve image quality by reducing artifacts and speckle noise. Both techniques, 3-D and compounding, call for optimized acquisition and processing of TICs in several image planes (3-D) or in several (overlapping) sections of the same image plane (compounding) to decrease the time needed for data acquisition. Here, an approach of interleaved imaging is presented which is applicable, among others, to contrast perfusion imaging using the replenishment method. The total acquisition time is decreased by sequentially scanning image planes twice for short time spans - first, immediately after microbubble destruction to record the initial rise of the TICs, and second, a sufficient time thereafter to assess final values of the TIC. Data from both periods are combined to fit a model function from which parameters are extracted such as perfusion rate and blood volume. This approach was evaluated by in vitro measurements on a perfusion-mimicking phantom for both, individual images such as would be used for volume reconstruction in 3-D and compound images obtained from full angle spatial compounding (FASC, 360 degrees ). An error analysis is conducted to derive the deviation of the extracted parameters of the proposed method compared with the conventional one. These deviations are entailed by a reduction in acquisition time of the proposed method, which can be adjusted by several parameters, depending on the prevailing flow. Optimization strategies are proposed to find optimal values for those settings.

Limited-angle spatial compound imaging of skin with high-frequency ultrasound (20 MHz).

In dermatology, high-frequency ultrasound (HFUS) is used for high-resolution skin imaging. The conventional B-scan type approach is to perform lateral scans perpendicular to the direction of sound propagation. Ultrasound spatial compounding enables improvement of the image contrast, suppression of speckle and noise, and reduction of imaging artifacts in comparison with conventional B-mode imaging, but it has not yet found its way into HFUS skin imaging applications. In this paper, the potential of HFUS spatial compounding for skin imaging is systematically evaluated. A new HFUS system with a sophisticated scanner for limited-angle (up to +/-40 degrees) spatial compound imaging was developed and implemented. Echo signals are acquired using a 20 MHz spherically focused single-element transducer with an axial and lateral resolution of 69 mum and 165 mum, respectively, in the focus. A calibration scheme for the estimation of unknown system parameters and precise image reconstruction has been developed. The implemented system has been evaluated using measurements of geometrically well-defined structures, speckle phantoms, and in vivo measurements. The results show the advantage of the proposed spatial compound skin imaging concept compared with conventional B-mode imaging in terms of image contrast, isotropy, and independence from the orientation of surfaces.

Three-dimensional reconstruction of fine vascularity in ultrasound breast imaging using contrast-enhanced spatial compounding: in vitro analyses.

RATIONALE AND OBJECTIVES: Ultrasound image quality can be improved by imaging an object (here: the female breast) from different viewing angles in one image plane. With this technique, which is commonly referred to as spatial compounding, a more isotropic resolution is achieved while speckle noise and further artifacts are reduced. We present results obtained from a combination of spatial compounding with contrast-enhanced ultrasound imaging in three dimensions to reduce contrast specific artifacts (depth dependency, shadowing, speckle) and reconstruct vascular structures. MATERIALS AND METHODS: We used a conventional ultrasound scanner and a custom made mechanical system to rotate an ultrasound curved array probe around an object (360 degrees, 36 transducer positions). For 10 parallel image planes, ultrasound compound images were generated of a flow-mimicking phantom consecutively supplied with water and contrast agent. These compound images were combined to form a volume dataset and postprocessed to obtain a sonographic subtraction angiography. RESULTS: Image quality was significantly improved by spatial compounding for the native (ie, without contrast agent), and, in particular, for the contrast-enhanced case. After subtracting the native images from the contrast-enhanced ones, only structures supplied with contrast agent remain. This technique yields much better results for compound images than for conventional ultrasound images because speckle noise and an anisotropic resolution affect the latter. CONCLUSIONS: With the presented approach contrast specific artifacts can be eliminated efficiently, and a subtraction angiography can be computed. A speckle reduced three-dimensional reconstruction of submillimeter vessel structures was achieved for the first time. In the future, this technique can be applied in vivo to image the vascularity of cancer in the female breast.

Full angle spatial compounding for improved replenishment analyses in contrast perfusion imaging: in vitro studies.

For contrast enhanced perfusion imaging semi-quantitative methods (such as the bolus-, replenishment- or depletion-method) are commonly used to analyze the dynamic changes in concentration of contrast agent induced by insonification. In order to apply these methods and to decrease artifacts from tissue nonlinearity, perfusion imaging is conducted using decreased transmit power. However, echo signals from deeper structures are often too weak to be successfully analyzed. Furthermore, shadowing artifacts may occur as a result of high concentration of contrast agent in the beam path. Thus, those semi-quantitative methods often fail or yield ambiguous diagnoses. Imaging an object (e.g., the female breast) from multiple viewing angles (spatial compounding) may overcome these issues. In addition, spatial compounding achieves an isotropic resolution and reduces speckle and further common artifacts. In this paper we present results obtained from a combination of spatial compounding with contrast enhanced perfusion imaging. Applying the replenishment method, we extracted perfusion-related parameters and compared the conventional parametric images with the compound parametric images. We found that the compounded parametric images outperform the conventional images due to reduced noise and suppression of artifacts.

In vivo ultrasound biomicroscopy of skin: spectral system characteristics and inverse filtering optimization.

High-frequency ultrasound (HFUS) in the 20 MHz to 100 MHz range has to meet the opposite requirements of good spatial resolution and of high penetration depth for in vivo ultrasound biomicroscopy (UBM) of skin. The attenuation of water, which serves as sound propagation medium between utilized single element transducers and the skin, becomes very eminent with increasing frequency. Furthermore, the spectra of acquired radio frequency (rf) echo signals change over depth because of the diffracted sound field characteristics. The reduction of the system's center frequency and bandwidth causes a significant loss of spatial resolution over depth. In this paper, the spectral characteristics of HFUS imaging systems and the potential of inverse echo signal filtering for the optimization of pulse-echo measurements is analyzed and validated. A Gaussian model of the system's transfer function, which takes into account the frequency-dependent attenuation of the water path, was developed. Predictions of system performance are derived from this model and compared with measurement results. The design of a HFUS skin imaging system with a 100 MHz range transducer and a broadband driving electronics is discussed. A time-variant filter for inverse rf echo signal filtering was designed to compensate the system's depth-dependent imaging properties. Results of in vivo measurements are shown and discussed.

Ultrasonographic contrast-agent imaging of sub-millimeter vessel structures with spatial compounding: in vitro analyses.

In clinical diagnostics, ultrasonographic contrast-agent imaging gives access to medical parameters such as perfusion and vascularization. In addition to the artifacts that are typical for ultrasonic imaging, e.g., speckle noise and depth-dependent sensitivity and resolution, contrast-agent imaging shows more pronounced depth dependence and may suffer from shadowing artifacts that arise from high attenuation of the ultrasound waves by the contrast agent at high concentrations. By imaging an object from different viewing angles in one 2D image plane and summing the images obtained (spatial compounding), image quality can be increased and artifacts can be suppressed. In the present study, we combined both techniques to overcome the limitations of contrast-agent imaging. We used a commercially available ultrasound scanner and a custom-made high-precision mechanical system to rotate the ultrasound transducer fully around the object under investigation. Using this set-up, ultrasound data were acquired in reflection mode to generate a 360 degrees compound scan of a flow-mimicking phantom supplied with contrast agent.

Preoperative ultrasonic assessment of thin melanocytic skin lesions using a 100-MHz ultrasound transducer: a comparative study.

BACKGROUND: It has been shown that tumor thickness (TT) of melanocytic skin lesions (MSL) of less than 1 mm vertical thickness assessed by 20 MHz are often incorrectly evaluated. OBJECTIVE: We aimed to evaluate the accuracy of 100-MHz ultrasound for the determination of TT of thin MSL, compared with conventional 20-MHz ultrasound and histologic findings. METHODS: Thirty-seven patients with 50 suspicious MSL, including tumor diameter up to 1 cm and maximum vertical TT of less than 1 mm, were recruited. The agreement between the histologically and ultrasographically measured TT was analyzed using Bland and Altman plots. RESULTS: Compared to histology, 20-MHz ultrasound (33.9 microm) as well as 100-MHz (16 microm) resulted in overestimation of TT that was twofold higher for 20-MHz ultrasound. The latter also revealed wider 95% limits of agreement (4.9 to 63 microm) than 100-MHz ultrasound (3.5 to 28.7 microm). CONCLUSION: Analysis of agreement clearly demonstrated that the performance of 100-MHz ultrasound is superior to conventional 20-MHz ultrasound, even though a relatively small positive bias was observed in 100-MHz ultrasound, indicating a systematic error. We consider 100-MHz ultrasound a useful tool for the noninvasive determination of TT of thin MSL in vivo.

Feasibility of contrast-enhanced sonography during resection of cerebral tumours: initial results of a prospective study.

The aim of this study was to adapt the ultrasonographical techniques developed for brain perfusion imaging to an intraoperative setting for topographic diagnosis of cerebral tumours. During surgery, the patients underwent contrast-enhanced ultrasonography (phase inversion harmonic imaging, bolus kinetic, fitted model function). Endocavity curved array (6.5EC10, 6.5 MHz) was used intraoperatively. The ultrasound contrast agent SonoVue (Bracco) was administered IV as a bolus injection. Off-line, time-intensity curves as well as perfusion maps were calculated and parameters such as peak intensity were locally extracted to characterise perfusion. Seven patients with brain tumours of different histologic types were subjected to contrast-enhanced ultrasonography during surgery. Tissue differentiation with contrast agent was superior to conventional B-mode ultrasound imaging. Intraoperative contrast-enhanced ultrasonography enabled visualisation of cerebral tumours in high spatial resolution.

An ultrasound research interface for a clinical system.

Under a contract with the National Cancer Institute, we have developed a research interface to an ultrasound system. This ultrasound research interface (URI) is an optional feature providing several basic capabilities not normally available on a clinical scanner. The URI can store high-quality beamformed radio-frequency data to file for off-line processing. Also, through an integrated user interface, the user is provided additional control over the B-mode receive aperture and color flow ensemble size. A third major capability is the ability to record and playback macro files. In this paper, we describe the URI and illustrate its use on three research examples: elastography, computed tomography, and spatial compounding.

[Pre- and intraoperative ultrasound imaging in neurosurgery]. / Prä- und intraoperative Ultraschallbildgebung in der Neurochirurgie.

Advanced applications of ultrasound in neurosurgery have been evaluated in two projects of the Ruhr Center of Excellence for Medical Engineering (KMR), Bochum, Germany. Engineers, neurologists, and neurosurgeons are cooperating within an interdisciplinary project structure, in order to practically approach neurosurgical problems by elaborating novel ultrasound-based technologies. On one hand, procedures have been implemented for an ultrasound-based registration of bone structures, applicable, amongst others, to the high-accuracy navigation of pedicle screws. On the other hand, concepts have been developed regarding a pre- and intraoperative application of ultrasound contrast agents for the detection of cerebral tumors and for the monitoring of surgery. In this article, both projects are discussed on the basis of the results obtained thus far and, furthermore, potentials of these concepts are presented that may complement or extend the scopes of the neurosurgical practice.

Investigation of the influence of blood flow rate on large vessel cooling in hepatic radiofrequency ablation.

Radiofrequency (RF) ablation using high-frequency current has become an important treatment method for patients with non-resectable liver tumors. Tumor recurrence is associated with tissue cooling in the proximity of large blood vessels. This study investigated the influence of blood flow rate on tissue temperature and lesion size during monopolar RF ablation at a distance of 10 mm from single 4- and 6-mm vessels using two different approaches: 1) an ex vivo blood perfusion circuit including an artificial vessel inserted into porcine liver tissue was developed; and 2) a finite element method (FEM) model was created using a novel simplified modeling technique for large blood vessels. Blood temperatures at the inflow/outflow of the vessel and tissue temperatures at 10 and 20 mm from the electrode tip were measured in the ex vivo set-up. Tissue temperature, blood temperature and lesion size were analyzed under physiological, increased and reduced blood-flow conditions. The results show that changes in blood flow rate in large vessels do not significantly affect tissue temperature and lesion size far away from the vessel. Monopolar ablation could not produce lesions surrounding the vessel due to the strong heat-sink effect. Simulated tissue temperatures correlated well with ex vivo measurements, supporting the FEM model.