An in vitro system for the study of ultrasound contrast agents using a commercial imaging system.

An in vitro system for the investigation of the behaviour of contrast microbubbles in an ultrasound field, that provides a full diagnostic range of settings, is yet to be presented in the literature. The evaluation of a good compromise of such a system is presented in this paper. It is based on (a) an HD13000 ATL scanner (Bothell, WA, USA) externally controlled by a PC and (b) on the use of well-defined reference materials. The suspensions of the reference ultrasonic scattering material are placed in an anechoic tank. The pulse length ranges from 2 to 10 cycles, the acoustic pressure from 0.08 to 1.8 MPa, the transmit frequency from 1 to 4.3 MHz, and the receive frequency from 1 to 8 MHz. The collection of 256 samples of RF data, at an offset distance from the transducer face, was performed at 20 MHz digitization rate, which corresponds to approximately 1 cm depth in water. Two particle suspensions are also presented for use as reference scatterers for contrast studies: (a) a suspension of Orgasol (ELF Atochem, Paris, France) particles (approximately 5 microm mean diameter) and (b) a suspension of Eccosphere (New Metals & Chemicals Ltd, Essex, UK) particles (approximately 50 microm mean diameter). A preliminary experiment with the contrast agent Definity (DuPont Pharmaceutical Co, Waltham, MA) showed that the above two materials are suitable for use as a reference for contrast backscatter.     

A stimulus-responsive contrast agent for ultrasound molecular imaging

Complement activation by targeting ligands is an important issue that governs the fate of targeted colloidal contrast agents for molecular imaging. Here, we extend previous work on a stimulus-responsive microbubble construct, in which the ligand is normally buried by a polymeric overbrush and transiently revealed by ultrasound radiation force, to show reduced complement activation and focused adhesion to cells using a physiological peptide ligand. Attachment of C3/C3b in vitro and production of soluble C3a anaphylotoxin in vitro and in vivo decreased significantly for the buried-ligand architecture vs. the conventional exposed-ligand motif and no-ligand control. Additionally, the buried-ligand architecture prevented adhesion of Arg-Gly-Tyr (RGD)-bearing microbubbles to integrin-expressing human umbilical vein endothelial cells (HUVEC) when driven by buoyancy in a static chamber, but it did not affect adhesion efficiency when activated by ultrasound radiation force pulses. These results show, for the first time, the molecular mechanism for reduced immunogenicity for the buried-ligand architecture and feasibility of targeting with this motif using a physiological ligand-receptor pair.     

Iron oxide nanoparticle-containing microbubble composites as contrast agents for MR and ultrasound dual-modality imaging

Magnetic resonance (MR) and ultrasound (US) imaging are widely used diagnostic modalities for various experimental and clinical applications. In this study, iron oxide nanoparticle-embedded polymeric microbubbles were designed as multi-modal contrast agents for hybrid MR-US imaging. These magnetic nano-in-micro imaging probes were prepared via a one-pot emulsion polymerization to form poly(butyl cyanoacrylate) microbubbles, along with the oil-in-water (O/W) encapsulation of iron oxide nanoparticles in the bubble shell. The nano-in-micro embedding strategy was validated using NMR and electron microscopy. These hybrid imaging agents exhibited strong contrast in US and an increased transversal relaxation rate in MR. Moreover, a significant increase in longitudinal and transversal relaxivities was observed after US-induced bubble destruction, which demonstrated triggerable MR imaging properties. Proof-of-principle in?vivo experiments confirmed that these nanoparticle-embedded microbubble composites are suitable contrast agents for both MR and US imaging. In summary, these magnetic nano-in-micro hybrid materials are highly interesting systems for bimodal MR-US imaging, and their enhanced relaxivities upon US-induced destruction recommend them as potential vehicles for MR-guided US-mediated drug and gene delivery.     

Real-time photoacoustic imaging of prostate brachytherapy seeds using a clinical ultrasound system

Prostate brachytherapy is a popular prostate cancer treatment option that involves the permanent implantation of radioactive seeds into the prostate. However, contemporary brachytherapy procedure is limited by the lack of an imaging system that can provide real-time seed-position feedback. While many other imaging systems have been proposed, photoacoustic imaging has emerged as a potential ideal modality to address this need, since it could easily be incorporated into the current ultrasound system used in the operating room. We present such a photoacoustic imaging system built around a clinical ultrasound system to achieve the task of visualizing and localizing seeds. We performed several experiments to analyze the effects of various parameters on the appearance of brachytherapy seeds in photoacoustic images. We also imaged multiple seeds in an ex vivo dog prostate phantom to demonstrate the possibility of using this system in a clinical setting. Although still in its infancy, these initial results of a photoacoustic imaging system for the application of prostate brachytherapy seed localization are highly promising.     

基于嵌入式系统的超声造影剂振荡仪设计

【摘要】目的针对市场缺乏商业化超声造影剂制备设备的现状,研发了一种基于嵌入式系统的超声造影剂振荡仪。方法采用ARM系列S3C2410作为主控芯片,以LQ080V3DG作为主控触摸屏,利用光电传感器采集振荡频率,通过闭环控制算法实现振荡频率的精确控制。结果超声造影剂振荡仪最高振荡频率为10000r／min以上,单次振荡时间最长为120s,其工作性能稳定、操作方便、人机界面友好。结论基于本方案设计的振荡仪符合要求,能够制备粒径分布均匀的微气泡,具有良好的应用前景。     

Optical molecular imaging of lymph nodes using a targeted vascular contrast agent

We develop a highly specific antibody-dye conjugate for optical imaging of peripheral lymph nodes. The contrast agent consists of the monoclonal antibody recognizing endothelial ligands for the lymphocyte homing receptor L-selectin, MECA-79, and a near-infrared (near-IR) fluorescent indotricarbocyanine dye. The targeting and biodistribution behavior of MECA-79 is studied after radio-iodination and intravenous injection into mice demonstrating specific uptake in lymph nodes and accumulation in high endothelial venules (HEV). After conjugation of MECA-79 with indotricarbocyanine dye, the fluorescence imaging properties of the MECA-79 dye conjugate are examined by intravenous injection in nude mice and laser-induced fluorescence whole-body imaging in vivo. The MECA-79 antibody-dye conjugate accumulates in peripheral lymph nodes, whereas an isotype antibody-dye conjugate does not. Specific lymph node near-IR fluorescent signals become detectable within minutes after injection, and stable imaging persists for more than 24 h. The results demonstrate that vascular targeting of endothelial expression of glyocproteins is feasible to visualize the accumulation of near-IR fluorescent MECA-79 in lymph nodes, making this technology potentially useful to characterize processes of inflammation.     

Characterization of individual ultrasound microbubble dynamics with a light-scattering system

Ultrasound microbubbles are contrast agents used for diagnostic ultrasound imaging and as carriers for noninvasive payload delivery. Understanding the acoustic properties of individual microbubble formulations is important for optimizing the ultrasound imaging parameters for improved image contrast and efficient payload delivery. We report here a practical and simple optical tool for direct real-time characterization of ultrasound contrast microbubble dynamics based on light scattering. Fourier transforms of raw linear and nonlinear acoustic oscillations, and microbubble cavitations are directly recorded. Further, the power of this tool is demonstrated by comparing clinically relevant microbubble cycle-to-cycle dynamics and their corresponding Fourier transforms.     

Acoustic scattering from a contrast agent microbubble near an elastic wall of finite thickness

Interest in the problem under consideration in this study is motivated by targeted ultrasound imaging where one has to deal with microbubble contrast agents pulsating near blood vessel walls. A modified Rayleigh–Plesset equation is derived that describes the oscillation of a contrast agent microbubble near an elastic wall of finite thickness. It is assumed that the medium behind the wall is a fluid but it is shown that the equation obtained is easily transformable to the case that the medium behind the wall is an elastic solid. In contrast to the model of a rigid wall, which predicts decreasing natural frequency of a bubble near the wall, the elastic wall model reveals that the bubble natural frequency can both decrease and increase, and in cases of interest for medical applications, the bubble natural frequency usually increases. It is found that the influence of an elastic wall on the acoustic response of a bubble is determined by the ratio between a cumulative parameter, which integrally characterizes the mechanical properties of the wall and has the dimension of density, and the density of the liquid surrounding the bubble. It is shown that the acoustic influence of the arterial wall on the bubble is weak and apparently cannot be used to recognize the moment when the bubble approaches the wall. However, in experiments where the behavior of bubbles near various plastic walls is observed, changes in the bubble response, such as increasing natural frequency and decreasing oscillation amplitude, are detectable.     

Indocyanine-green-embedded PEBBLEs as a contrast agent for photoacoustic imaging

Nanoparticles 100 nm in diameter containing indocyanine green (ICG) have been developed as a contrast agent for photoacoustic (PA) imaging based on (photonic explorers for biomedical use by biologically localized embedding PEBBLE) technology using organically modified silicate (ormosil) as a matrix. ICG is an FDA-approved dye with strong optical absorption in the near-infrared (NIR) region, where light can penetrate deepest into biological tissue. A photoacoustic imaging system was used to study image contrast as a function of PEBBLE concentration in phantom objects. ICG-embedded ormosil PEBBLEs showed improved stability in aqueous solution compared with free ICG dye. The particles were conjugated with HER-2 antibody for breast cancer and prostate cancer cell targeting. Initial in vitro characterization shows high contrast and high efficiency for binding to prostate cancer cells. ICG can also be used as a photosensitizer (generating toxic oxygen by illumination) for photodynamic therapy. We have measured the photosensitization capability of ICG-embedded ormosil nanoparticles. This feature can be utilized to combine detection and therapeutic functions in a single agent.     

Development of a novel method for synthesis of a polymeric ultrasound contrast agent

Medical ultrasound is a highly valuable diagnostic tool, especially when compared with other imaging modalities. It is a noninvasive, real-time, portable, extremely safe method compared with X-ray and inexpensive relative to magnetic resonance imaging. However, ultrasound is limited in its ability to distinguish between diseased and normal tissue. This limitation has led to the development of contrast agents. We have produced novel poly (lactic-co-glycolic) acid air-filled microcapsules that work well as ultrasound contrast agents, giving up to 24 and 25 dB enhancement when insonated in the medical imaging range at 5 and 7.5 MHz, respectively. The capsules were fabricated by modifying a double emulsion method to encapsulate camphor in the oil phase and ammonium carbonate in the aqueous phase, and later sublime the encapsulated material, leaving voids capable of being filled with a gas in their place. The role of the surfactant, poly vinyl alcohol, solution temperature, was studied and found to play an important role in the morphology of the capsules, altering their acoustic response.     

Analysis of refill curve shape in ultrasound contrast agent studies

Contrast destruction and replenishment by Flash Echo Imaging (FEI) (also referred to as interval or intermittent imaging) has been qualitatively and quantitatively used for tissue blood refill measurements. Many features and capabilities of contrast refill in tissue blood flow and perfusion remain to be elucidated. To aid the development and full reliable utilization of the technique in medical practice, in this paper we undertake physical and mathematical modeling to evaluate different measures derivable from FEI and to provide a basis for the further study of sensitivity and stability of such measures for the detection and measurement of various flow properties and abnormalities. A phantom was developed and used to conduct a dynamic contrast study. Refill curves were investigated as a means of calculating the mean transit time (MTT) and investigating other information that can be determined from their shape. Exponential and error function fits and the area above these curves were used to estimate MTT. The bubble disruption zone was visually measured and theoretically modeled. Computer simulated refill curves based on the flow phantom for different velocity ranges were then computed and compared to the experimental refill curves. The simulated refill curves closely matched the experimental curves in both shape and MTT. The simulated refill curves matched the shape of the experimental results for different velocity ranges. Another simulation examined how a real circulatory system might influence refill. Different refill curve shapes were obtained for different vascular models. Models including the large arteries and veins showed a much faster initial slope than models where the large vessels were not included. Likewise, simulated "shunting" displayed a different slope than models without "shunting" and specific portions of the refill curve that could maximally distinguish shunting. This computer simulation could lead to some experimental hypotheses about differences between normal and cancerous blood flow.     

Estimating contrast agent motion from ultrasound images using an anisotropic diffusion-based optical flow technique

The purpose of this study was to suggest a novel optical flow method to estimate the motion patterns of contrast agents from an ultrasound image. We first recomposed the original image with relative structural and textural parts. We embedded an anisotropic diffusion model into a slightly non-convex total variation-L1 approximation scheme to provide more reliable estimates. An intermediate bilateral filter was adopted after each computation step to prevent over-smoothing effects. Ultrasound data were acquired during continuous injection of contrast agent into a tissue mimicking phantom. The results showed that our method provided robust performance for estimating contrast agent flow patterns.     

声学造影剂及二次谐波成像在肝癌中应用初探

目的：探讨微气泡型声学造影剂及二次谐波成像在肝癌中的应用特点。方法：２２例肝癌病人经外周静脉注射造影剂前后（剂量０．５～１．０ｍｌ）行基波成像、彩色多普勒成像及二次谐波成像检查。二次谐波成像用１．７／３．４ＭＨｚ（ＡＴＬ－ＨＤＩ５０００）或１．８／３．６ＭＨｚ（ＨＰ５５００）。结果：肝动脉期肝脏多数无明显增强，少数病灶内出现斑点状回声增强，门静脉增强后肝组织才明显增强，但肿瘤组织增强不明显。增强后有利于低回声病灶的显示而对高回声病灶或中高混杂回声病灶显示无益。增强后可显示更多的瘤血管。彩色多普勒成像增强程度不及二次谐波成像，但结果相似。结论：微气泡型声学造影剂主要反映肝组织总体供血量的变化，相对于正常肝组织来说肝癌总是少血管的。造影剂及谐波成像可以改善血管的显示，谐波成像的组织定征能力有待进一步研究。     

Selective imaging of adherent targeted ultrasound contrast agents

The goal of ultrasonic molecular imaging is the detection of targeted contrast agents bound to receptors on endothelial cells. We propose imaging methods that can distinguish adherent microbubbles from tissue and from freely circulating microbubbles, each of which would otherwise obscure signal from molecularly targeted adherent agents. The methods are based on a harmonic signal model of the returned echoes over a train of pulses. The first method utilizes an 'image-push-image' pulse sequence where adhesion of contrast agents is rapidly promoted by acoustic radiation force and the presence of adherent agents is detected by the signal change due to targeted microbubble adhesion. The second method rejects tissue echoes using a spectral high-pass filter. Free agent signal is suppressed by a pulse-to-pulse low-pass filter in both methods. An overlay of the adherent and/or flowing contrast agents on B-mode images can be readily created for anatomical reference. Contrast-to-tissue ratios from adherent microbubbles exceeding 30 dB and 20 dB were achieved for the two methods proposed, respectively. The performance of these algorithms is compared, emphasizing the significance and potential applications in ultrasonic molecular imaging.     

CT增强对比剂防渗漏导流报警系统研发的实验研究

目的研发一种能辅助CT增强扫描高压注射器及时、安全和准确杜绝对比剂外渗的导流报警系统,以有效避免并发症的发生。方法利用新型的压力传感器模块瞬时感应皮肤张力的变化,通过自毁式导流阀,准确实施对比剂外渗后的警示、导流和自毁功能,将对比剂外渗的危害控制在渗漏初期。并采用动物实验检测该系统的及时性、准确性和安全性。结果通过动物实验,有效验证了报警系统在高压注射器对比剂外渗的初期可瞬时、准确报警,及时切换通道实现导流、自毁。结论该系统设备结构简单、技术可靠,可及时、有效防止高压注射器对比剂外渗对肢体的损害,具有较好的临床应用前景。     

Development of a platform for co-registered ultrasound and MR contrast imaging in vivo

Imaging of the microvasculature is often performed using contrast agents in combination with either ultrasound (US) or magnetic resonance (MR) imaging. Contrast agents are used to enhance medical imaging by highlighting microvascular properties and function. Dynamic signal changes arising from the passage of contrast agents through the microvasculature can be used to characterize different pathologies; however, comparisons across modalities are difficult due to differences in the interactions of contrast agents with the microvasculature. Better knowledge of the relationship of contrast enhancement patterns with both modalities could enable better characterization of tissue microvasculature. We developed a co-registration platform for multi-modal US and MR imaging using clinical imaging systems in order to study the relationship between US and MR contrast enhancement. A preliminary validation study was performed in phantoms to determine the registration accuracy of the platform. In phantoms, the in-plane registration accuracy was measured to be 0.2 ± 0.2 and 0.3 ± 0.2 mm, in the lateral and axial directions, respectively. The out-of-plane registration accuracy was estimated to be 0.5 mm ±0.1. Co-registered US and MR imaging was performed in a rabbit model to evaluate contrast kinetics in different tissue types after bolus injections of US and MR contrast agents. The arrival time of the contrast agent in the plane of imaging was relatively similar for both modalities. We studied three different tissue types: muscle, large vessels and fat. In US, the temporal kinetics of signal enhancement were not strongly dependent on tissue type. In MR, however, due to the different amounts of agent extravasation in each tissue type, tissue-specific contrast kinetics were observed. This study demonstrates the feasibility of performing in vivo co-registered contrast US and MR imaging to study the relationships of the enhancement patterns with each modality.     

Quantitative functional lung imaging with synchrotron radiation using inhaled xenon as contrast agent.

Small airways play a key role in the distribution of ventilation and in the matching of ventilation to perfusion. The purpose of this study was to introduce an imaging method that allows measurement of regional lung ventilation and evaluation of the function of airways with a small diameter. The experiments were performed at the Medical Beamline of the European Synchrotron Radiation Facility. Monochromatic synchrotron radiation beams were used to obtain quantitative respiration-gated images of lungs and airways in two anaesthetized and mechanically ventilated rabbits using inhaled stable xenon (Xe) gas as a contrast agent. Two simultaneous images were acquired at two different energies, above and below the K-edge of Xe. Logarithmic subtraction of the two images yields absolute Xe concentrations. This technique is known as K-edge subtraction (KES) radiography. Two-dimensional planar and CT images were obtained showing spatial distribution of Xe concentrations within the airspaces, as well as the dynamics of filling with Xe. Bronchi down to 1 mm in diameter were visible both in the subtraction radiographs and in tomographic images. Absolute concentrations of Xe gas were calculated within the tube carrying the inhaled gas mixture, small and large bronchi, and lung tissue. Local time constants of ventilation with Xe were obtained by following the evolution of gas concentration in sequential computed tomography images. The results of this first animal study indicate that KES imaging of lungs with Xe gas as a contrast agent has great potential in studies of the distribution of ventilation within the lungs and of airway function, including airways with a small diameter.     

Gadolinium dimeglumine as a contrast agent for digital subtraction angiography: in vitro hounsfield unit measurement and clinical efficacy

The purpose of this study was to evaluate the feasibility and safety of using gadolinium-chelates for digital subtraction angiography (DSA) in patients with contraindications to iodinated contrast material, and to assess the clinically effective concentration of gadolinium (Gd). Gadopentetate dimeglumine and iopromide were used in density measurements. Using 20 mL disposable syringes, serial dilutions of Gd and iopromide with saline were performed. Computed tomography scanning was done and the attenuation of each was recorded as mean Hounsfield units using region of interest analysis. Clinical trials were done in twelve patients with the following types of angiogram or intervention: hemodialysis access, percutaneous biliary drainage, percutaneous nephrostomy, cerebral angiography and transarterial chemoembolization (TACE) in hepatocellular carcinoma. The density of 1 : 1 diluted Gd was nearly equal to that of 1 : 4 dilution of iopromide, and that of pure Gd was similar to or less than that of 1 : 1 dilution of iopromide. Serum creatinine level was not elevated in any of the patients. Gd is a safe alternative agent in patients with contraindications to iodinated contrast materials. Pure Gd without dilution is the most clinically useful concentration.