PubMed Health⌕ Search

Biomedical subjects

Katherine W Ferrara

Publications and source records attributed to Katherine W Ferrara.

34 records · Page 2Linked to original sources
PubMed2004

Ultrasonic analysis of peptide- and antibody-targeted microbubble contrast agents for molecular imaging of alphavbeta3-expressing cells.

The goal of targeted ultrasound contrast agents is to significantly and selectively enhance the detection of a targeted vascular site. In this manuscript, three distinct contrast agents targeted to the alphavbeta3 integrin are examined. The alphavbeta3 integrin has been shown to be highly expressed on metastatic tumors and endothelial cells during neovascularization, and its expression has been shown to correlate with tumor grade. Specific adhesion of these contrast agents to alphavbeta3-expressing cell monolayers is demonstrated in vitro, and compared with that of nontargeted agents. Acoustic studies illustrate a backscatter amplitude increase from monolayers exposed to the targeted contrast agents of up to 13-fold (22 dB) relative to enhancement due to control bubbles. A linear dependence between the echo amplitude and bubble concentration was observed for bound agents. The decorrelation of the echo from adherent targeted agents is observed over successive pulses as a function of acoustic pressure and bubble density. Frequency-domain analysis demonstrates that adherent targeted bubbles exhibit high-amplitude narrowband echo components, in contrast to the primarily wideband response from free microbubbles. Results suggest that adherent targeted contrast agents are differentiable from free-floating microbubbles, that targeted contrast agents provide higher sensitivity in the detection of angiogenesis, and that conventional ultrasound imaging techniques such as signal subtraction or decorrelation detection can be used to detect integrin-expressing vasculature with sufficient signal-to-noise.

Antibodies↗
PubMed2004

Radiation-force assisted targeting facilitates ultrasonic molecular imaging.

Ultrasonic molecular imaging employs contrast agents, such as microbubbles, nanoparticles, or liposomes, coated with ligands specific for receptors expressed on cells at sites of angiogenesis, inflammation, or thrombus. Concentration of these highly echogenic contrast agents at a target site enhances the ultrasound signal received from that site, promoting ultrasonic detection and analysis of disease states. In this article, we show that acoustic radiation force can be used to displace targeted contrast agents to a vessel wall, greatly increasing the number of agents binding to available surface receptors. We provide a theoretical evaluation of the magnitude of acoustic radiation force and show that it is possible to displace micron-sized agents physiologically relevant distances. Following this, we show in a series of experiments that acoustic radiation force can enhance the binding of targeted agents: The number of biotinylated microbubbles adherent to a synthetic vessel coated with avidin increases as much as 20-fold when acoustic radiation force is applied; the adhesion of contrast agents targeted to alpha(v)beta3 expressed on human umbilical vein endothelial cells increases 27-fold within a mimetic vessel when radiation force is applied; and finally, the image signal-to-noise ratio in a phantom vessel increases up to 25 dB using a combination of radiation force and a targeted contrast agent, over use of a targeted contrast agent alone.

Avidin↗
PubMed2004

Acoustic signatures of submicron contrast agents.

Previous studies have revealed that hard-shelled submicron contrast agents exhibit large relative expansions and strong acoustical echoes that can be observed experimentally, and predicted by theoretical simulations. In this paper, we study harmonic imaging and pulse-pair imaging techniques designed to assist in the differentiation of these contrast agents from tissue. For harmonic imaging, we apply a high-sensitivity, narrowband strategy that differentiates the microbubble from tissue based on the generation of strong harmonic echoes. For pulse-pair imaging, we apply high spatial resolution, wideband strategies using phase inversion, which relies on the frequency differences observed in response to phase-inverted pulses, and signal subtraction, which takes advantage of the amplitude differences in response to identical pulses. The bubble-to-phantom signal amplitude ratio in the absence of motion approaches 20 dB using phase inversion and 30 dB using signal subtraction; both techniques are robust for up to 50 microm of simulated motion. With the experience gained in these studies, we hope to advance the development of multi-pulse or shaped-pulse techniques that are optimized for specific clinical applications.

Connective Tissue↗
PubMed2003

Contrast-enhanced US of microcirculation of superficially implanted tumors in rats.

PURPOSE: To determine the ability of contrast material-enhanced ultrasonography (US) to assess replenishment time in a rat kidney and adenocarcinoma tumor model. MATERIALS AND METHODS: Mammary adenocarcinoma cells were implanted into the subcutaneous tissues of the flank of 11 rats. Resultant tumors were imaged serially with contrast-enhanced US and compared with images of the rat kidney, a highly perfused normal organ. The US acquisition and processing methods yield images of perfused tumor regions and the times required to achieve 80% replenishment. Findings at contrast-enhanced computed tomography (CT) and light microscopy of hematoxylin-eosin-stained tumor tissue were compared. Paired Student t test was performed to compare the accuracy of US with that of histologic examination and CT in the detection of viable tumor regions. RESULTS: Replenishment of the kidney cortex microvasculature requires 1-5 seconds compared with a replenishment time of 6-14 seconds in tumors. Over the time course of tumor growth, the mean perfusion time becomes progressively longer, and a wider range of perfusion times is detected. Comparison of findings at US, CT, and histologic examination suggested that all three methods yield correlated estimates of the percentage of viable perfused tumor cells. Results of the t test suggested that the viable tumor percentages observed at US are not significantly different from those observed at CT and histologic examination (US vs CT, P =.92; US vs histologic examination, P =.94). CONCLUSION: Repeated measurements of microvascular flow rate can be accomplished in a rat animal model with a minimally invasive technique.

Adenocarcinoma↗
PubMed2003

Effect of coupled oscillations on microbubble behavior.

Ultrasound contrast agents are encapsulated microbubbles whose nonlinear acoustic scattering signatures have been the foundation of their use in diagnostic imaging. The coupled oscillations of microbubbles along their lines of center are investigated theoretically using radial equations in the monopole approximation and an energy balance, which is obtained for the system. Coupled microbubble pairs of different initial radii are investigated numerically relative to the normal modes for the linearized system. For microbubble pairs of different size bubbles driven below the mode of the smaller bubble and above the mode of the larger bubble, it is shown that oscillations of the smaller agent are affected substantially more by the coupling than those of the larger one. For separation distances of 10 and 500 microns, a difference of approximately 10 dB occurs in the second harmonic output of a 1.0-micron radius agent coupled with a 2.2-micron radius agent forced at 2.0 MHz and 0.3 MPa. The subharmonic spectral peak is shown to decrease approximately 19 dB for the coupling of 1.5- and 2.2-micron radius agents at 10- and 500-micron distances under the same acoustic forcing conditions. These coupling effects on the radiated pressure and its spectral power are highlighted for contrast agent imaging applications.

Humans↗
PubMed2003

Sentinel node detection using contrast-enhanced power Doppler ultrasound lymphography.

RATIONALE AND OBJECTIVES: To establish the feasibility of using contrast-enhanced interstitial ultrasound (US) lymphography as an alternative to current sentinel node detection methods. METHODS: Aqueous US contrast microbubble suspensions of varying diameter were evaluated in vitro to characterize response to insonation. Contrast media were then injected subcutaneously into the distal extremities of 11 normal dogs to target the cervical and popliteal lymph nodes (nodes, n = 40). First-order (sentinel) lymph nodes and second-order sublumbar nodes were imaged intermittently from 0 to at least 120 minutes following contrast injection using continuous power Doppler mode. Lymphoscintigraphy studies were performed on 4 dogs to verify lymphatic drainage patterns and sentinel lymph nodes. RESULTS: Contrast enhancement occurred in 34/40 (85%) sentinel nodes overall and in 30/32 (94%) nodes when submicron or near-micron diameter bubble formulations were used. In many instances, enhancement persisted throughout the imaging period. Contrast response was most pronounced using a high mechanical index and tissue artifact was reduced or eliminated when using a high pulse repetition frequency. CONCLUSIONS: Contrast-enhanced interstitial US lymphography could serve as an alternative to current sentinel node detection methods. Preliminary findings suggest that submicron or near-micron-diameter bubbles may be suitable for lymphatic imaging applications.

Animals↗
PubMed2002

Targeted imaging using ultrasound.

The discipline of medical imaging is expanding to include both traditional anatomic modalities and new techniques for the functional assessment of the presence and extent of disease. Current FDA-approved ultrasound contrast agents are micron-sized bubbles with a stabilizing shell. Microbubble contrast agents can be used to estimate microvascular flow rate in a manner similar to dynamic contrast-enhanced magnetic resonance imaging (MRI). The concentration of these agents within the vasculature, reticulo-endothelial, or lymphatic systems produces an effective passive targeting of these areas. Liquid-filled nanoparticles and liposomes have also demonstrated echogenicity and are under evaluation as ultrasound contrast agents. Actively targeted ultrasound relies on specially designed contrast agents to localize the targeted molecular signature or physiologic system. These agents typically remain within the vascular space, and therefore possible targets include molecular markers on thrombus, endothelial cells, and leukocytes. The purpose of this review is to summarize the requirements, challenges, current progress, and future directions of targeted imaging with ultrasound.

Animals↗
PubMed2002

Dynamics of therapeutic ultrasound contrast agents.

Novel therapeutic contrast agents offer great potential for localized drug delivery. Localized delivery should significantly improve the efficacy of drug delivery and reduce any toxic exposure to the healthy tissue. This work describes a preliminary theoretical description of agents, such as those developed by the ImaRx Corporation, enclosed by a relatively thick fluid shell. A theoretical extension is made to a generalized Rayleigh-Plesset formulation that allows it to be solved for an encapsulating liquid shell of arbitrary thickness and density. The equation is used to investigate the role of shell thickness, density and viscosity on the radial dynamics and velocity of the inner and outer radii. Comparisons are made with experimental measurements of the maximum radial expansions for agents with triacetin shells. For a seven-cycle driving acoustic pulse with a center frequency of 1.5 MHz and peak amplitude of 1.6 MPa, the equation predicts maximum expansions from 5.5 to 1.3 times the initial radius for agents 1 to 10 microm, respectively, in initial radius with a 500-nm (28.0 cP) encapsulating shell. These predictions have reasonable agreement with the maximum radial expansions obtained from optical experimental data of fragmenting and intact agents. Approximate agreement between theory and experiment for a similar range of agent sizes is also demonstrated for a pulse with the same pressure amplitude at 2.5 MHz. At 2.5 MHz, smaller radial expansion amplitudes from 1.1 to 4.1 times the initial radius were found for agents 1 to 10 microm in initial radius, respectively. Discrepancies are attributed to shape instabilities and their associated fragmentation effects not incorporated in the equation. A significant difference in the inner and outer wall velocities is predicted for agents with a 500-nm triacetin shell. A 2.5 microm initial radius agent driven with a seven-cycle pulse at 2.5 MHz and 1.6 MPa achieves a maximum negative inner wall velocity of 364 m/s and outer wall velocity of 63 m/s. For parameters that correspond to large differences between the inner and outer wall velocities, fragmentation is typically observed experimentally.

Contrast Media↗
PubMed2002

A new high resolution color flow system using an eigendecomposition-based adaptive filter for clutter rejection.

We present a new signal processing strategy for high frequency color flow mapping in moving tissue environments. A new application of an eigendecomposition-based clutter rejection filter is presented with modifications to deal with high blood-to-clutter ratios (BCR). Additionally, a new method for correcting blood velocity estimates with an estimated tissue motion profile is detailed. The performance of the clutter filter and velocity estimation strategies is quantified using a new swept-scan signal model. In vivo color flow images are presented to illustrate the potential of the system for mapping blood flow in the microcirculation with external tissue motion.

Algorithms↗
PubMed2002

Dynamics and fragmentation of thick-shelled microbubbles.

Localized delivery could decrease the systemic side effects of toxic chemotherapy drugs. The unique delivery agents we examine consist of microbubbles with an outer lipid coating, an oil layer, and a perfluorobutane gas core. These structures are 0.5-12 microm in radius at rest. Oil layers of these acoustically active lipospheres (AALs) range from 0.3-1.5 microm in thickness and thus the agents can carry a large payload compared to nano-scale drug delivery systems. We show that triacetin-based drug-delivery vehicles can be fragmented using ultrasound. Compared with a lipid-shelled contrast agent, the expansion of the drug-delivery vehicle within the first cycle is similar, and a subharmonic component is demonstrated at an equivalent radius, frequency, and driving pressure. For the experimental conditions explored here, the pulse length required for destruction of the drug-delivery vehicle is significantly greater, with at least five cycles required, compared with one cycle for the contrast agent. For the drug-delivery vehicle, the observed destruction mechanism varies with the initial radius, with microbubbles smaller than resonance size undergoing a symmetric collapse and producing a set of small, equal-sized fragments. Between resonance size and twice resonance size, surface waves become visible, and the oscillations become asymmetrical. For agents larger than twice the resonance radius, the destruction mechanism changes to a pinch-off, with one fragment containing a large fraction of the original volume.

Contrast Media↗
PubMed2002

Optical and acoustical interrogation of submicron contrast agents.

Unlike conventional ultrasound contrast agents with a diameter of several microns, in this paper we explore the use of submicron contrast agents for the detection and localization of lymph nodes. The submicron agents are gas-filled, double-walled microspheres that rupture when exposed to ultrasound energy at megahertz frequencies. In this study, three experimental systems are combined with model predictions to assist in understanding the response of these unique agents to a range of signal transmission parameters. Optical experimental results for each agent delineate the relative expansion as a function of acoustical peak negative pressure, pulse length, and center frequency. The optical images demonstrate an order of magnitude expansion in radius during the pulse rarefaction, in which the expansion magnitude is dependent on the transmitted pressure and frequency. Simulations using a modified Rayleigh-Plesset model predict an increasing relative expansion for the microbubbles (initial bubble radius ranging from 0.3-1.3 microm) with increasing pressure and decreasing initial radius. Acoustically recorded frequency spectra reveal the presence of harmonics for a range of transmitted pulses. In addition, in-vivo results from a normal canine model demonstrate marked contrast enhancement of first order lymph nodes. We hope to offer an alternative to present intra-operative procedures for sentinel node detection.

Animals↗
PubMed2002

A new high resolution color flow system using an eigendecomposition-based adaptive filter for clutter rejection.

We present a new signal processing strategy for high frequency color flow mapping in moving tissue environments. A new application of an eigendecomposition-based clutter rejection filter is presented with modifications to deal with high blood-to-clutter ratios (BCR). Additionally, a new method for correcting blood velocity estimates with an estimated tissue motion profile is detailed. The performance of the clutter filter and velocity estimation strategies is quantified using a new swept-scan signal model. In vivo color flow images are presented to illustrate the potential of the system for mapping blood flow in the microcirculation with external tissue motion.

Algorithms↗
PubMed2002

The magnitude of radiation force on ultrasound contrast agents.

High-speed photography of insonified bubbles with a time resolution of 10 ns allows observations of translation due to radiation force, in addition to the visualization of radial oscillations. A modified version of the Rayleigh-Plesset equation is used to estimate the radius-time behavior of insonified microbubbles, and the accuracy of this model is verified experimentally. The translation of insonified microbubbles is calculated using a differential equation relating the acceleration of the bubble to the forces due to acoustic radiation and the drag imposed by the fluid. Simulations and experiments indicate that microbubbles translate significant distances with clinically relevant parameters. A 1.5 micron radius contrast agent can translate over 5 microns during a single 20-cycle, 2.25 MHz, 380 kPa acoustic pulse, achieving velocities over 0.5 m/s. Therefore, radiation force should be considered during an ultrasonic examination because of the possibility of influencing the position and flow velocity of the contrast agents with the interrogating acoustic beam.

Contrast Media↗
PubMed2002

Contrast-assisted destruction-replenishment ultrasound for the assessment of tumor microvasculature in a rat model.

Angiogenesis, the development of new blood vessels, is necessary for tumor growth. Anti-angiogenic therapies have recently received attention as a possible cancer treatment. The purpose of this study was to monitor the vascularity of induced tumors in rats using contrast-enhanced ultrasound during anti-angiogenic therapy. Six rats with subcutaneously implanted R3230 murine mammary adenocarcinomas were treated with an orally administered anti-angiogenic agent (SU11657) beginning 28 days after tumor implantation (20 mg/kg BW once daily). Three additional tumor-bearing control rats were treated with an equivalent volume of vehicle alone. Sonographic evaluation of tumor blood flow was performed using a modified Siemens Sonoline Elegra equipped with a 5.0 MHz linear transducer prior to drug administration, during the first 51 hours following initial drug administration, and on days 8 and 15 after initiation of therapy. Tumor volumes were estimated at each time point using a prolate ellipsoid method from linear dimensions measured on the B-mode ultrasound image in the three major axes. A destruction-replenishment technique was used for tumor blood flow evaluation using a constant rate infusion of intravenously delivered ultrasound contrast media (Definity). A destructive pulse was fired first, followed by a chain of non-destructive pulses that allowed for visualization of vascular contrast agent replenishment. Parametric maps of the time required for contrast agent replenishment and the time-integrated intensity were generated for both the tumor and kidney. Following ultrasound examination, contrast-enhanced computed tomography of each tumor was performed in the same imaging plane as that used to acquire the ultrasound images. Fifteen days after the start of treatment, tumors were excised, preserved in 10% formalin, and sectioned in a plane approximating the ultrasound and CT imaging planes. Sections were prepared for light microscopy with H & E, CD31 and factor VIII immunostain to evaluate overall morphology and vessel distribution. Ultrasound measurements of tumor volume, the spatial extent of contrast enhancement, and the time required for contrast replenishment within control tumors were significantly different from those of treated tumors. The time-integrated ultrasound contrast enhancement decreases and the time required for replenishment of the contrast agent within the tumor volume increases over the course of anti-angiogenic therapy. Parametric maps of integrated intensity are shown to correlate with the regions of viable tumor demonstrated on H & E and regions of elevated contrast intensity on CT. Contrast-enhanced ultrasound imaging of implanted tumors provides a tool to assess differences in the microcirculation of treated and control tumors in studies of anti-angiogenic agents.

Adenocarcinoma↗
PubMedDate not supplied

Ultrasound measurement of the effect of temperature on microperfusion in the eye.

Recent developments in ultrasound (US) technology have allowed the study of microperfusion in the anterior segment of the eye. Our aim was to determine the effect of the thermal environment on blood flow in the anterior segment. We measured blood flow in the major arterial circle of five rabbits. A 38-MHz US transducer was coupled to the eye with a normal saline water-bath with temperature controlled from 1 degrees C to 38 degrees C. The major arterial circle was localized and imaged using the swept-scan technique and M-mode data were then acquired for measurement of pulsatile flow. Peak systolic and mean velocity averaged 4.51 and 1.32 mm/s, respectively. Positive correlations were found between peak systolic (1.69%/ degrees C) and mean (1.76%/ degrees C) velocities and temperature. Vessel diameter (mean = 178 microm) did not show any significant change with temperature. High-resolution US flowmetry demonstrated decreasing flow rates in the iris with decreasing temperature.

Animals↗