Simulated capillary blood flow measurement using a nonlinear ultrasonic contrast agent.

This paper proposes a system for measuring slow, small volume blood flow, such as that found in the capillary beds. The method relies on the injection of a strongly nonlinear echocardiographic contrast agent, whose echoes are then analyzed by a modified Doppler process. The contrast agent is necessary to increase the signal-to-clutter ratio from the small blood volume, and to distinguish the blood movement from other moving structures, such as vessel walls or surrounding tissue. The nonlinear properties of this saccharide-based contrast agent are described, as evidenced by experimental evaluation. The contrast agent and signal processing modality are then tested in a blood flow simulator, at velocities as low as 1.5 mm/s, with good results. In addition, an analysis for applying this technique in vivo is presented, accounting for the dynamic and acoustic parameters of the physiological environment. Finally, some specific applications for this method are discussed, including its limitations.     

Parenchymal enhancement and tumor visualization using a new sonographic contrast agent.

The purpose of this study was to assess the ability of a sonographic contrast agent to increase parenchymal echogenicity and improve tumor visibility. The agent is an emulsion that changes at body temperature from nonechogenic submicrometer liquid droplets to echogenic 1 to 5 microns microbubbles, capable of transversing the pulmonary and capillary circulations. Peripheral venous injections (dosages of 0.05 to 0.8 ml/kg) were administered to five woodchucks (three with multiple hepatomas), 12 rabbits (with renal VX-2 tumors), and four dogs. Ultrasonograms were acquired from kidney, liver, tumors (including tumor vessels) and normal vessels. Uptake and washout curves were generated via videodensitometry. Finally, Doppler shifts from a cuff transducer around the celiac trunk were analyzed to provide an in vivo dose-response curve. Vascular enhancement, including hepatoma and VX-2 tumor vessels, was seen for 2 to 3 min. Maximum enhancement was 18.7 dB for a 0.6 ml/kg dose. Enhancement of normal liver and kidney parenchyma was observed in all three species for up to 20 min. Small hepatomas became more echogenic centrally, but larger tumors showed no increase in central echogenicity. In conclusion, improved tumor visibility and parenchymal enhancement was demonstrated in animals.     

经静脉声学造影定量心肌局部血流量的实验研究

目的：研究应用自制声学造影剂进行心肌造影超声心动图（MCE）定量显示不同冠状动脉血流量时局部心肌血流量（MB）变化的能力，以及与放射性微球的心肌血流量间的关系。了解其用于评价微循环的价值。方法：开胸犬6条，取乳头肌短轴观，采用经静脉连续滴注造影剂的方法，分别在基础状态，静脉给予潘生丁造成的充血状态，左冠状动脉回旋支（LCx）不同程度狭窄状态下通过逐渐递增触发间歇进行MC，以公式y=A(1-e^βt）拟合感兴趣区的时间－强度化曲线，以A(反映心肌局部血容量）与β（反映心肌局部血流速度）的乘积代表MBF。在最后狭窄状态，于MCE结束后左房内注入放射性微球测量局部心肌血流量，结果：（1）应用递增触发间歇的方法可清晰准确显示局部心肌显影程度的变化。（2）充血状态下，随冠状动脉血流量下降，A．β（LCx）亦减低，每条犬的LCx冠状动脉血流量变化与LCx供血区的A．β（LCx）变化呈正相关(r值分别为0.92,0.83,0.96,0.66,0.83,0.82,P值分别为0.04,0.03,0.003,0.01,0.03,0.03)。（3）A．β（LCx）／A．β（LAD）与放射微球测得MBF（LCx）／MBF（LAD）相关（Y＝0．76X＋0．0.07,r=0.82,P=0.01)，结论：经静脉连续滴注自制声学造影剂对开胸犬行MCE可获得清淅的心肌造影图像，并能够定量反映开胸犬的心肌局部血流量变化。     

Sonographic detection of kidney infarctions using ultrasound contrast media

Contrast-enhanced CT is currently the gold standard for the diagnosis of kidney infarction. Particularly in patients with renal insufficiency, however, the use of iodine contrast media is limited. Sonographic examination using ultrasound contrast media may be an alternative for these patients. CASE REPORTS: We examined three patients with suspected ischaemic kidney infarction with ultrasound contrast media. Scanning was performed with low mechanical index, and SonoVue was used as by contrast-enhancing agent. In all three patients, kidney infarctions were clearly shown. In two patients, the lesions were confirmed by contrast-enhanced CT, in one no CT was performed because of impaired renal function. CONCLUSION: Kidney infarctions can reliably be detected by contrast-enhanced ultrasound using SonoVue as contrast agent. This is particularly valuable in patients with renal impaired renal function and other contraindications against iodine contrast media.     

Microbubble contrast agent detection using binary coded pulses

Real-time visualization of microbubbles in the microvasculature of deep tissues remains a challenge for existing nonlinear microbubble imaging techniques. A technique with high sensitivity to nonlinear signals is required to compensate for the effects of limited power used to avoid bubble destruction and the high attenuation of the overlying tissues for deeper targets. The use of coded pulses in ultrasound imaging is well established as a means of improving the signal-to-noise ratio (SNR) within B-mode ultrasound imaging, but the feasibility of this approach for detecting microbubbles has not been well studied. In this work we investigate the use of binary phase encoding together with phase and amplitude modulation (PIAM) for the detection of nonlinear signals from microbubbles. A series of simulation experiments were conducted using a modified Rayleigh-Plesset model together with Golay and Barker coding techniques to investigate (i) the ability of binary encoded PIAM to detect nonlinear signals, (ii) the effect of the SNR and insonating pressure on the detection process, (iii) the sensitivity of different pulse encoding approaches and (iv) the effects of bubble resonance behavior on the detection process. The results show that the binary encoding approach combined with PIAM is able to detect nonlinear signals from microbubbles. It was found that nonlinear scattering from the microbubbles degrades the sensitivity of the binary encoded approach such that at high SNR there is no advantage in using these pulses over existing short-pulse PIAM. However, at lower SNR (<20 dB) the increased pulse length provides improved sensitivity without significant loss of spatial resolution, even under conditions in which the detection failed completely for existing approaches. The results also show that both the insonating acoustic pressure and resonance behavior of bubbles have an effect on the detection sensitivity and spatial resolution for the binary encoded approach.     

自制声学造影剂定量局部心肌血流效果的实验研究

目的　探讨自制声学造影剂进行心肌造影超声心动图 (myocardialechocardiography ,MCE)检查中自制声学造影剂定量局部心肌血流 (myocardialbloodflow ,MBF)的能力。 方法　MCE检测开胸犬不同状态的局部MBF ,并与放射性微球测得的心肌血流量的比较。①造影剂制备 :将 1%人体白蛋白、5 %葡萄糖和氟碳气体以一定的比例混合 ,分别以 70s ,14 0s和 2 10s进行声振 ,比较各组造影剂中微泡的大小和浓度。②MCE定量MBF :开胸犬 6条 ,分别在基础状态、静脉给予潘生丁造成的充血状态、左冠状动脉回旋支 (LCx)不同程度狭窄状态下计算MCE得出的局部MBF。③在最后狭窄状态 ,于MCE结束后左房内注入放射性微球测量局部心肌血流量。结果　①以 70s ,14 0s和 2 10s声振制成造影剂微泡的直径分别为 ( 9.0 1± 3.14 ) μm ,( 6 .45± 2 .39) μm ,( 4 .86± 2 .0 9) μm ,浓度分别为 ( 1.71± 0 .2 2 )× 10 8个 /ml,( 3.77± 0 .92 )× 10 8个 /ml,( 8.95± 0 .81)× 10 8个 /ml ,故使用与文献中造影剂直径和浓度最接近的 2 10s声振造影剂进行MCE。②在无冠脉狭窄及狭窄程度较轻时 ,随触发间歇时间的延长 ,心肌最后均可达完全显影 ,但所需时间不同。③A·β(LCx) /A·β(LAD) 与放射微球测得MBF(LCx) /MBF(LAD) 相关 (Y =0     

Low-cost laser speckle contrast imaging of blood flow using a webcam

Laser speckle contrast imaging has become a widely used tool for dynamic imaging of blood flow, both in animal models and in the clinic. Typically, laser speckle contrast imaging is performed using scientific-grade instrumentation. However, due to recent advances in camera technology, these expensive components may not be necessary to produce accurate images. In this paper, we demonstrate that a consumer-grade webcam can be used to visualize changes in flow, both in a microfluidic flow phantom and in vivo in a mouse model. A two-camera setup was used to simultaneously image with a high performance monochrome CCD camera and the webcam for direct comparison. The webcam was also tested with inexpensive aspheric lenses and a laser pointer for a complete low-cost, compact setup ($90, 5.6 cm length, 25 g). The CCD and webcam showed excellent agreement with the two-camera setup, and the inexpensive setup was used to image dynamic blood flow changes before and after a targeted cerebral occlusion.OCIS codes: (120.6150) Speckle imaging, (120.3890) Medical optics instrumentation, (170.3880) Medical and biological imaging, (040.1490) Cameras     

新型造影剂全氟显子宫输卵管超声造影的临床分析

目的：探讨新型造影剂全氟显低机械指数实时谐波子宫输卵管超声造影（Hysterosalpingo-contrast sonography,HyCoSy）对输卵管通畅性的临床应用价值。方法：选择不孕症妇女48例,采用造影剂全氟显,先行经腹部B超引导下HyCoSy,实时观察造影剂在子宫、输卵管的流动及显影情况,判断输卵管的通畅性,次日行X线碘油造影（X-ray hysterosalpingography,X-HSG）,将其结果对照分析。结果：HyCoSy与X-HSG检查结果的总符合率为93.7%、特异度为97.9%、灵敏度（不通畅为87.5%、通而不畅92.0%）,其一致性较强（Kappa值为0.900）,有统计学意义（P<0.001）。结论：新型造影剂全氟显低机械指数实时谐波超声造影术对输卵管显像清晰,判断准确,且操作简便、安全、经济,可作为临床不孕症患者输卵管通畅性检查的一种有效方法。     

Power,spectral, and color flow Doppler enhancement by a new ultrasonographic contrast agent.

The ability of EchoGen contrast agent (Sonus Pharmaceuticals, Bothell, WA) to enhance aortic, renal, and scrotal spectral Doppler, color flow, and power Doppler sonography at doses from 0.01 ml/kg to 0.65 ml/kg was evaluated in dogs. Videotaped images were digitized and analyzed for Doppler signal strength at known postinjection times. Contrast agent increased aortic spectral Doppler peak height, spectral width, and brightness. Contrast agent increased renal and testicular color flow and power Doppler sonographic signal and enhanced the visualization of vascular anatomy. Intensity and duration of these effects increased with increasing dose of contrast agent. Enhancement effect varied in different organs. At higher doses, blooming and Doppler shift artifacts were observed and are believed to be due to machine limitation.     

Potential of gold-bound microtubules as a new ultrasound contrast agent

Contrast agents based on gas-filled microspheres share the problem of time limited opacification due to low stability of microbubbles. The aim of this study was to test if gold-bound microtubules provide backscattering that allows microtubules to be potentially useful as an ultrasound (US) contrast agent. Gold colloids were immobilized on protein microtubule walls. Latex balloons were filled with gold-bound microtubules or conventional left heart contrast agent and were ultrasonographically imaged in fundamental and harmonic modes. Feasibility of anti-beta-tubulin antibody conjugation to gold-bound microtubules was confirmed using immune fluorescence analysis. Gold particles were successfully bound to microtubules. Contrast intensities in latex balloons filled with gold-bound microtubules (141 +/- 35) were comparable to those with Levovist (180 +/- 35) and did not decrease significantly during continuous US imaging for 20 min (135 +/- 34 vs. Levovist 5.0 +/- 2.0). Anti-beta-tubulin antibodies were successfully conjugated to gold-bound microtubules. Gold-bound microtubules provide a persistent contrast effect, suggesting their use as an ultrasonic contrast agent with the feasibility of antibody conjugation.     

Quantifying multimodal contrast agent biological activity using near‐infrared flow cytometry

Prior to imaging agent use in preclinical studies and clinical diagnostics, biological activity must be validated. The Lindmo assay has been used conventionally to quantify radiolabeled antibody (Ab) immunoreactivity, although published findings suggest it does not provide consistently accurate results. We developed and tested a near‐infrared (NIR) flow cytometry (FC) method for quantifying biological activity of a dual‐labeled Ab for use as a multimodal contrast agent in small animal and human positron emission tomography and NIR fluorescence imaging. Antibody specific for epithelial cell adhesion molecule was conjugated to DOTA–NHS–ester, labeled with IRDye 800CW and further labeled with ⁶⁴Cu or nonradioactive Cu prior to reacting with human prostate cancer cells for testing by the Lindmo or FC method, respectively. Immunoreactivity of the dual‐labeled agent was found to be 76.4 ± 15.7% by the Lindmo assay. When tested with and without Cu labeling using NIR FC, the biological activity was found to be 73.1 ± 7.7 and 79.4 ± 8.1%, respectively. No significant differences were found between these activity levels (p > 0.05), supporting NIR FC as an alternative method for measuring immunoreactivity and demonstrating that Cu labeling does not significantly affect the agent's ability to bind to its target. Biological activity was significantly reduced when the NIR dye‐to‐protein ratio was increased 3‐ to 4‐fold in agent preparations when tested by FC and the Lindmo assay. In summary, NIR FC is an alternative with similar specificity and sensitivity, and greater reproducibility relative to the Lindmo assay for quantifying biological activity of NIR fluorophore‐labeled, multimodal imaging agents. Copyright © 2012 John Wiley & Sons, Ltd.     

平行板流动腔在靶向超声造影剂研究中的进展

近年来,靶向超声分子成像的发展十分迅猛,靶向超声造影剂在靶组织中的特异聚积程度是实现超声分子成像的关键,决定这种特异聚积程度的最重要因素是靶向超声造影剂的靶向黏附效能.在评价靶向超声造影剂黏附效能的众多技术和方法中,新兴的平行板流动腔技术展示了其特有的优势,并被认为是体外评价靶向超声造影剂黏附效能最有用的方法,本文就平行板流动腔在靶向超声造影剂研究中的进展作一概述.     

Assessment of fetal and placental blood flow in primates using contrast enhanced ultrasonography.

Ultrasonographic contrast agents that stay within the vascular space and do not cross the placenta may permit differentiation between the maternal and fetal portions of the placenta and may be clinically useful for diagnosis of placental abnormalities. This study was performed to assess the effects of Levovist (Schering AG, Berlin) on the placental circulation and to determine whether hemodynamic effects on the fetus occur. Ten studies were performed in five pregnant macaques (median weight, 9.15 kg; range, 6.15 to 11 kg; median gestational age, 121 days; range, 34 days to term) under anesthesia. Gray scale, color, and duplex Doppler sonographic scans of the fetus and placenta were acquired using a 5 MHz curved array transducer. Fetal heart rate, resistive index, and systolic-diastolic ratios were measured in the fetal middle cerebral artery, aorta, umbilical artery, and uterine artery before and after administration of contrast agent. The following dose regimen was tested: 5 ml of physiologic saline solution followed by 0.1 ml/kg of 300 mg/ml Levovist (diagnostic dose), 0.5 ml/kg of 400 mg/ml Levovist (maximum dose), and 5 ml physiologic saline solution. The order of diagnostic dose and maximal dose was randomized among animals. Color enhancement of the basal portions of the placenta was documented after administration of contrast agent. Heart rate and middle cerebral artery systolic-diastolic ratio did not change between baseline and injections. A 7% decrease of the resistive index from baseline to maximum dose was measured in the uterine artery (not significant). A 7.7% decrease in the systolic-diastolic ratio from baseline to maximum dose was recorded in the umbilical artery. However, an identical change was measured after saline solution was injected. The resistive index in the aorta increased by 2.6% from baseline to maximum dose, a change that was not significant (P > 0.5). Ultrasonographic contrast enhancement of the maternal circulation in placenta is demonstrated to be without significant effects on the fetal circulation as measured in this limited population.     

Kinetic analysis of hyaluronidase activity using a bioactive MRI contrast agent

One of the attractions of molecular imaging using ‘smart’ bioactive contrast agents is the ability to provide non‐invasive data on the spatial and temporal changes in the distribution and expression patterns of specific enzymes. The tools developed for that aim could potentially also be developed for functional imaging of enzyme activity itself, through quantitative analysis of the rapid dynamics of enzymatic conversion of these contrast agents. High molecular weight hyaluronan, the natural substrate of hyaluronidase, is a major antiangiogenic constituent of the extracellular matrix. Degradation by hyaluronidase yields low molecular weight fragments, which are proangiogenic. A novel contrast material, HA‐GdDTPA‐beads, was designed to provide a substrate analog of hyaluronidase in which relaxivity changes are induced by enzymatic degradation. We show here a first‐order kinetic analysis of the time‐dependent increase in R₂ as a result of hyaluronidase activity. The changes in R₂ and the measured relaxivity of intact HA‐GdDTPA‐beads (r_2B) and HA‐GdDTPA fragments (r_2D) were utilized for derivation of the temporal drop in concentration of GdDTPA in HA‐GdDTPA‐beads as the consequence of the release of HA‐GdDTPA fragments. The rate of dissociation of HA‐GdDTPA from the beads showed typical bell‐shaped temperature dependence between 7 and 36 °C with peak activity at 25 °C. The tools developed here for quantitative dynamic analysis of hyaluronidase activity by MRI would allow the use of activation of HA‐GdDTPA‐beads for the determination of the role of hyaluronidase in altering the angiogenic microenvironment of tumor micro metastases. Copyright © 2006 John Wiley & Sons, Ltd.     

Sonographic detection of a stitch abscess

A 28-year-old man with a ruptured right Achilles tendon underwent primary end-to-end suture immediately after injury. Painful swelling developed 6 months later, and a lump with discharge from a sinus was observed during physical assessment. Sonographic examination with a 10-MHz linear-array transducer demonstrated a hypoechoic mass, 8 × 6 mm, within which were 2 markedly echogenic dots. A stitch abscess was strongly suspected and was confirmed surgically. © 1998 John Wiley & Sons, Inc. J Clin Ultrasound 26:225–227, 1998.     

自制包裹氟烷气体的表面活性剂类超声造影剂观察肝肿瘤血流实验研究

目的研究含氟烷气体的表面活性剂类超声造影剂对肿瘤血流信号增强的情况。方法5只荷肝VX2肿瘤的新西兰大白兔麻醉后，经腹部探测肝脏，显示肝肿瘤的血流信号。经耳缘静脉注射表面活性剂类超声造影剂，剂量0．1mg／kg，观察肿瘤周围血管及内部血流信号增强情况及持续时间。结果肝肿瘤周边及内部能量多普勒血流信号明显增强，且增强时间较长。结论表面活性剂类超声造影剂经外周静脉注射后血管二维及血流信号增强显著，值得进一步研究。