高分子材料超声对比剂的制备及显影特征

背景：目前所用的超声对比剂均为内含不同气体成分的微气泡,其外壳材料多数为表面活性剂类、人血蛋白质类、脂类等。随着高分子化学的发展,高分子材料对比剂成为超声对比剂研究领域的热点。目的：探讨各种超声对比剂制备中遇到的困难以及解决方法,从而最终寻找合理的高分子材料超声对比剂。方法：采用电子检索的方式,在万方数据库（http：//www.wanfangdata.com.cn/）中检索2005-01/2010-12有关高分子材料应用于超声造影方面的研究文章,关键词为＂高分子材料,超声,对比剂＂。排除重复研究、普通综述或Meta分析类文章,筛选纳入26篇文献进行评价。结果与结论：近年来随着高分子科学与多学科融合的分子医学的兴起和快速发展,显像对比剂受到了越来越广泛的关注。高分子材料超声对比剂由于具有好的生物相容性,粒径大小均匀,良好的抗压性能,较长的显影持续时间等特点,已成为目前研究的热点。其中靶向微泡对比剂经静脉注射可到达特定靶区,低功率超声作用下可提高局部组织显影的分辨率。携带治疗药物或基因的靶向微泡对比剂在低频（1MHz）超声作用下可以产生瞬态空化效应,迫使细胞膜的通透性增加,从而有效提高了药物或基因的转染率。如今,靶向微泡携抗肿瘤药物联合超声作用正逐渐成为治疗肿瘤的一种新模式,是近期医学研究的一个热点。超声联合靶向微泡技术在临床诊断和治疗中显示出了较大的优势,但其准确的生物学机制目前医学界还未清楚,超声治疗参数需进一步优化。     

高分子材料超声对比剂的制备及显影特征

背景:目前所用的超声对比剂均为内含不同气体成分的微气泡,其外壳材料多数为表面活性剂类、人血蛋白质类、脂类等。随着高分子化学的发展,高分子材料对比剂成为超声对比剂研究领域的热点。目的:探讨各种超声对比剂制备中遇到的困难以及解决方法,从而最终寻找合理的高分子材料超声对比剂。方法:采用电子检索的方式,在万方数据库(http://www.wanfangdata.com.cn/)中检索2005-01/2010-12有关高分子材料应用于超声造影方面的研究文章,关键词为"高分子材料,超声,对比剂"。排除重复研究、普通综述或Meta分析类文章,筛选纳入26篇文献进行评价。结果与结论:近年来随着高分子科学与多学科融合的分子医学的兴起和快速发展,显像对比剂受到了越来越广泛的关注。高分子材料超声对比剂由于具有好的生物相容性,粒径大小均匀,良好的抗压性能,较长的显影持续时间等特点,已成为目前研究的热点。其中靶向微泡对比剂经静脉注射可到达特定靶区,低功率超声作用下可提高局部组织显影的分辨率。携带治疗药物或基因的靶向微泡对比剂在低频(1MHz)超声作用下可以产生瞬态空化效应,迫使细胞膜的通透性增加,从而有效提高了药物或基因的转染率。如今,靶向微泡携抗肿瘤药物联合超声作用正逐渐成为治疗肿瘤的一种新模式,是近期医学研究的一个热点。超声联合靶向微泡技术在临床诊断和治疗中显示出了较大的优势,但其准确的生物学机制目前医学界还未清楚,超声治疗参数需进一步优化。     

新型荧光-超声双功能复合成像剂的制备和表征

目的:将量子点和微泡通过静电吸附自组装技术复合在一起,得到一种新型双功能复合成像剂,并对其荧光-超声成像功能进行评价.方法:①基于表面活性剂的微泡的制备:对司盘60和吐温80表面活性剂混合乳液进行超声处理,分离并洗涤得到包裹全氟丙烷气体的微泡.②复合成像剂的制各:静电吸附自组装得到聚电解质和量子点包覆的复合微泡.③复合成像剂的表征:使用激光共聚焦显微镜以确定量子点是否成功吸附于微泡的外表面;测量荧光光谱以证明复合成像剂的荧光成像功能;进行动物体内超声造影实验以证明复合成像剂的超声造影成像功能.结果:①激光共聚焦显微镜结果证明量子点吸附于微泡的表面.②荧光光谱证明复合成像剂具有荧光成像的功能.③动物体内造影证明复合成像剂具有良好的超声成像功能.结论:通过层层自组装技术可得到具有荧光-超声双功能成像效果的复合成像剂,并在实验动物体内超声造影得到验证.     

靶向声学造影技术的研究现状与进展

超声造影剂 (ultrasoundcontrastagents ,UCA)是利用声波对气体反射比液体大近 10 0 0倍的原理 ,使用含气微泡后超声回声增强得到更高的对比分辨力 ,从而有利于疾病的诊断。至今 ,有关超声造影剂的研究已有近 3 0年的历史[1] 。过去几年中 ,靶向微泡的开发已取得可观进展。这种微泡对于靶向病变组织有一定亲和力 ,可以附着于某种疾病的特殊标记物 ,靶向微泡在病变组织的积聚可实现分子和细胞过程的无创性超声成像。本综述主要讨论靶向微泡分子成像的早期实验和对比增强超声分子成像具体应用的靶向方法。一、靶向炎症的对比超声成像血池中…     

微泡造影剂在肝脏疾病诊治中的研究进展

新型造影剂的发展,使肝脏的超声造影正发生巨大的变化.当静脉注射不同类型的超声造影剂时,微泡通过肺循环,在特定的影像程序下,不仅可以增强多普勒信号、改善灰阶超声图像的质量,而且可以实时地观察微血管及组织的血流灌注.通过在微泡上偶联肿瘤特异性抗体等方法使微泡具有靶向功能,大大提高了对肿瘤诊断的准确性,同时还可以携带药物与基因用于肿瘤的治疗.随着靶向超声微泡技术的发展,靶向超声微泡必将为超声显像与临床治疗提供一种有效的方法.     

靶向超声分子成像技术在心血管疾病诊断中的研究进展

靶向超声分子成像技术是利用超声微泡表面的固有生物学特性构建成靶向超声微泡,或将靶向于病变组织特定分子的特异配体连接至超声微泡外壳,经静脉将靶向超声微泡注入体内,使其选择性地聚集于靶组织,通过对比超声检查产生靶组织细胞水平、分子水平显影1-2。该技术是目前分子影像学领域的研究热点,其具有高特异性、高敏感性、高空间时间分辨率、早期定量评价、分子显像、无创、无放射污染、相对安全性、仪器便携等优点3-7。近年来,其在涉及炎症、血栓、血管新生等心血管疾病的分子成像中得到广泛应用。本文就靶向超声分子成像技术在心血管疾病诊断中的研究进展予以综述。     

高分子微泡超声对比剂制备条件的优化

背景：前期实验采用左旋聚乳酸一甲基端聚乙二醇包裹液态氟碳全氟戊烷成功制备了高分子微泡超声对比剂,其在体内外低机械指数二次谐波超声造影模式下显影良好。 目的：优化高分子微泡超声对比剂的制备条件,以制备产量大、粒径适宜且分布均匀的微泡。方法：采用单乳化法制备包裹液态氟碳全氟戊烷的高分子微泡超声对剂,以微泡产量与粒径大小及分布为评价指标,分别对高分子聚合物质量与液态氟碳体积比（4／1、2／1、1／1、1／2）、电动内切匀浆的转速（18000,26000,35000r／min）、匀浆时间（15,30,60,120s）3个制备条件进行优化。以优化条件制备的高分子微泡超声对比剂进行新西兰大白兔肾脏超声造影,TCA软件分析造影的始增时间、达峰时间、峰值降半时间及峰值强度等参数。 结果与结论：高分子微泡超声对比剂的优化条件为：高分子聚合物质量与液态氟碳体积比为2／1,匀浆转速为26000r／min,匀浆时间为60s,此时微泡产量为（1．8±0．4）×109／mL,粒径（3．7±1．3）μm且分布较均匀。新西兰大白兔肾脏造影的始增时间为（3．1±O．6）s,达峰时间为（2．9±0．5）s,峰值降半时间为（4．0±0．7）S,峰值强度为（4．7±1．1）×10-5AU,说明高分子微泡体内造影效果好。     

超声介导微泡造影剂在临床诊断及治疗中的作用

超声介导靶向微泡造影属于＂超声分子影像学＂的范畴,是指将微泡造影剂通过血管途径进入靶组织,应用超声造影技术来观察靶区在组织水平、细胞及亚细胞水平的成像,借以反映病变区组织在分子基础方面的变化。特异性靶向超声微泡表面携带有对靶分子具有特异识别能力的分子探针（单克隆抗体或其他配体）,     

靶向超声造影成像的研究进展

靶向超声造影成像是一门新兴的将超声造影技术与靶向超声微泡造影剂相结合,对体内组织器官微观病变进行分子水平探测与成像的方法.靶向超声造影是目前超声造影的前沿性课题,随着超声造影剂在临床的不断应用与实践,使得超声诊断学与治疗学发生了跳跃式的前进.     

靶向超声微泡在肿瘤诊断与治疗方面的研究进展

靶向超声微泡属于"超声分子影像学"的范畴.通过在微泡上偶联肿瘤特异性抗体等方法可以使微泡具有靶向功能,这能大大提高对肿瘤诊断的准确性,同时还可以携带药物与基因用于肿瘤的治疗.随着靶向超声微泡技术的发展,靶向超声微泡必将为超声显像与临床治疗提供一种有效的方法.     

Imaging Methods for Ultrasound Contrast Agents

Microbubble contrast agents were introduced more than 25 years ago with the objective of enhancing blood echoes and enabling diagnostic ultrasound to image the microcirculation. Cardiology and oncology waited anxiously for the fulfillment of that objective with one clinical application each: myocardial perfusion, tumor perfusion and angiogenesis imaging. What was necessary though at first was the scientific understanding of microbubble behavior in vivo and the development of imaging technology to deliver the original objective. And indeed, for more than 25 years bubble science and imaging technology have evolved methodically to deliver contrast-enhanced ultrasound. Realization of the basic bubbles properties, non-linear response and ultrasound-induced destruction, has led to a plethora of methods; algorithms and techniques for contrast-enhanced ultrasound (CEUS) and imaging modes such as harmonic imaging, harmonic power Doppler, pulse inversion, amplitude modulation, maximum intensity projection and many others were invented, developed and validated. Today, CEUS is used everywhere in the world with clinical indications both in cardiology and in radiology, and it continues to mature and evolve and has become a basic clinical tool that transforms diagnostic ultrasound into a functional imaging modality. In this review article, we present and explain in detail bubble imaging methods and associated artifacts, perfusion quantification approaches, and implementation considerations and regulatory aspects.     

Effect of Acoustic Parameters and Microbubble Concentration on the Likelihood of Encapsulated Microbubble Coalescence

Microbubble contrast agents are commonly used for therapeutic and diagnostic imaging applications. Under certain conditions, these contrast agents can coalesce on ultrasound application and form larger bubbles than the initial population. The formation of large microbubbles potentially influences therapeutic outcomes and imaging quality. We studied clinically relevant ultrasound parameters related to low-pressure therapy and contrast-enhanced ultrasound imaging to determine their effect on microbubble coalescence and subsequent changes in microbubble size distributions in vitro. Results indicate that therapeutic ultrasound at low frequencies, moderate pressures and high duty cycles are capable of forming bubbles greater than two times larger than the initial bubble distribution. Furthermore, acoustic parameters related to contrast-enhanced ultrasound imaging that are at higher frequency, low-pressure and low-duty cycle exhibit no statistically significant changes in bubble diameter, suggesting that standard contrast ultrasound imaging does not cause coalescence. Overall, this work suggests that the microbubble coalescence phenomenon can readily occur at acoustic parameters used in therapeutic ultrasound, generating bubbles much larger than those found in commercial contrast agents, although coalescence is unlikely to be significant in diagnostic contrast-enhanced ultrasound imaging. This observation warrants further expansion of parameter ranges and investigation of resulting effects.     

Ultrasound Molecular Imaging of Cardiovascular Disease

Molecular imaging with ultrasound contrast agents relies on the detection of microbubbles within diseased tissue. Microbubbles produce an acoustic signal owing to their resonant properties in an ultrasound field. Microbubble targeting is accomplished by either manipulating the microbubble shell for attachment of microbubbles to activated leukocytes, or by conjugation of disease-specific ligands to the microbubble surface. Inflammation, angiogenesis, and thrombus formation are central pathophysiologic processes in many cardiovascular diseases and produce phenotypic changes in the vascular compartment that can be imaged with targeted ultrasound contrast agents. In the future, targeted contrast ultrasound could aid in the diagnosis of atherosclerosis, myocardial ischemia, transplant rejection, and thrombosis syndromes and could be used for assessing angiogenesis.     

Contrast-enhanced harmonic endoscopic ultrasound

Second-generation intravenous blood-pool ultrasound contrast agents are increasingly used in endoscopic ultrasound (EUS) for characterization of microvascularization, differential diagnosis of benign and malignant focal lesions, and improving staging and guidance of therapeutic procedures. Although initially used as Doppler signal enhancers, second-generation microbubble contrast agents are now used with specific contrast harmonic imaging techniques, which benefit from the highly nonlinear behavior of the microbubbles. Contrast-specific modes based on multi-pulse technology are used to perform contrast-enhanced harmonic EUS based on a very low mechanical index (0.08 - 0.12). Quantification techniques based on dynamic contrast-enhanced ultrasound have been recommended for perfusion imaging and monitoring of anti-angiogenic treatment, mainly based on time-intensity curve analysis. Most of the clinical applications include the differential diagnosis of focal pancreatic masses, with adenocarcinoma having a distinct hypovascular (hypo-enhanced) appearance compared with neuroendocrine tumors, which are hypervascular (with strong arterial hyper-enhancement). However, pseudotumoral chronic pancreatitis and autoimmune pancreatitis also have an iso- or hypervascular appearance, making the differential diagnosis difficult. Even more promising is the use of dynamic contrast-enhanced harmonic EUS for the longitudinal monitoring of the effects of chemotherapy and/or anti-angiogenic therapy in advanced digestive cancers, which are difficult to examine by conventional cross-sectional imaging techniques.     

Ultrasound imaging and contrast agents: a safe alternative to MRI?

Microbubble contrast media are used to enhance ultrasound images. Because ultrasound is a real-time investigation, contrast-enhanced ultrasound offers possibilities for perfusion imaging. This review is conducted to evaluate the safety of contrast-enhanced ultrasound and its possible role in medical imaging. The safety of diagnostic ultrasound is still an important field of research. The wanted and unwanted effects of ultrasound and microbubble contrast media as well as the effects of ultrasound on these microbubbles are described. Furthermore, some of the possible applications and indications of contrast-enhanced ultrasound will be discussed. The shared advantages of MRI and ultrasound are the use of non-ionizing radiation and non-nephrotoxic contrast media. From this review it can be concluded that, for certain indications, contrast enhanced ultrasound could be a safe alternative to MRI and a valuable addition to medical imaging.     

Detection of parenchymal abnormalities in acute pyelonephritis by pulse inversion harmonic imaging with or without microbubble ultrasonographic contrast agent: correlation with computed tomography.

The purpose of this study was to evaluate the ability of pulse inversion harmonic imaging with or without microbubble ultrasonographic contrast agent in depicting renal parenchymal changes in acute pyelonephritis. The study population included 30 patients with acute pyelonephritis and 10 healthy volunteers. Pulse inversion harmonic imaging with or without contrast agent was compared with conventional ultrasonography and tissue harmonic imaging in terms of detection and conspicuity of renal abnormalities. The detection and conspicuity of renal parenchymal abnormalities in acute pyelonephritis on tissue harmonic imaging, pulse inversion harmonic imaging, and contrast-enhanced pulse inversion harmonic imaging were significantly better than those on conventional ultrasonography. In 2 of 10 healthy volunteers all 4 techniques yielded false-positive diagnoses of parenchymal abnormalities. In conclusion, tissue harmonic imaging and pulse inversion harmonic imaging are sensitive techniques for depicting renal parenchymal lesions in acute pyelonephritis. Despite relatively lower specificities and negative predictive values, these techniques are thought to be useful for the depiction of subtle parenchymal changes in acute pyelonephritis.     

Optimizing Sensitivity of Ultrasound Contrast-Enhanced Super-Resolution Imaging by Tailoring Size Distribution of Microbubble Contrast Agent

Ultrasound contrast-enhanced super-resolution imaging has recently attracted attention because of its extraordinary ability to image vascular features much smaller than the ultrasound diffraction limit. This method requires sensitive detection of separable microbubble events despite a noisy tissue background to indicate the microvasculature, and any approach that could improve the sensitivity of the ultrasound system to individual microbubbles would be highly beneficial. In this study, we evaluated the effect of varying microbubble size on super-resolution imaging sensitivity. Microbubble preparations were size sorted into different mean diameters and then were imaged at equal concentrations. Commercially manufactured Definity and Optison were also imaged for comparison. Both in vitro experiments in phantom vessels and in vivo experiments imaging rat tumors revealed that the sensitivity of contrast-enhanced super-resolution imaging can be improved by using microbubbles with a larger diameter.