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1.
脑超声造影中超声强度对血脑屏障通透性的影响   总被引:5,自引:1,他引:5  
目的探讨不同机械指数的诊断性超声在超声造影中对血脑屏障通透性的影响,以了解脑超声造影检查中超声强度的安全应用范围。方法50只清洁级SD大鼠,经尾静脉注射剂量为1ml/kg的“脂氟显”超声造影剂,辅以不同机械指数的超声进行辐照,观察超声照射后血脑屏障通透性的变化。结果在MI等于0.4时,血脑屏障通透性与对照组相比无统计学差异,当MI≥0.8时,血脑屏障通透性增加,且随着超声能量的进一步提高血脑屏障的通透性增加。结论高机械指数的体表超声在超声造影中可导致血脑屏障通透性增加,但应用适当强度的超声在进行大脑超声造影时仍是安全的。  相似文献   

2.
We have developed a method to use low-intensity focused ultrasound pulses combined with an ultrasound contrast agent to produce temporary blood-brain barrier disruption (BBBD). This method could provide a means for the targeted delivery of drugs or imaging agents into the brain. In all our previous work, we used Optison as the ultrasound contrast agent. The purpose of this study was to test the feasibility of using the contrast agent Definity for BBBD. A total of 36 non-overlapping locations were sonicated through a craniotomy in experiments in the brains of nine rabbits (four locations per rabbit; ultrasound [US] frequency: 0.69 MHz; burst: 10 ms; pulse repetition frequency (PRF): 1 Hz; duration: 20 s). The peak negative pressure amplitude ranged from 0.2 to 1.5 MPa. An additional 11 locations were sonicated using Optison at pressure amplitude of 0.5 MPa. Definity and Optison dosages were the same as those used clinically for ultrasound imaging: 10 and 50 microl/kg, respectively. The probability for BBBD (determined using MRI contrast agent enhancement) as a function of pressure amplitude was similar to that found earlier with Optison. For both agents, the probability was estimated to be 50% at 0.4 MPa using probit regression. Histologic examination revealed small, isolated areas of extravasated erythrocytes in some locations. At 0.8 MPa and higher, these areas were sometimes accompanied by tiny (dimensions of 100 microm or less) regions of damaged brain parenchyma. The magnitude of the BBBD was larger with Optison than with Definity at 0.5 MPa (signal enhancement: 13.3% +/- 4.4% vs. 8.4% +/- 4.9%; p = 0.04). In addition, more areas with extravasated erythrocytes were observed with Optison (5.0 +/- 3.5 vs. 1.4 +/- 1.9 areas with extravasation in histology section with largest effect; p = 0.03). We concluded that BBBD is possible using Definity at the dosage of contrast agent and the acoustic parameters tested in this study. The probability for BBBD as a function of pressure amplitude and the type of acute tissue effects were similar to what has been observed using Optison. However, under the experimental conditions used in this study, Optison produced a larger effect for the same acoustic pressure amplitude.  相似文献   

3.
The feasibility of blood-brain barrier (BBB) opening in the hippocampus of wild-type mice using focused ultrasound (FUS) through the intact skull and skin was investigated. Needle hydrophone measurements through ex vivo skulls revealed minimal attenuation ( approximately 18% of the pressure amplitude), a well-focused beam pattern and minute focus displacement through the parietal bone. In experiments in vivo, the brains of three mice were sonicated transcranially. Pulsed ultrasound sonications at 1.5 MHz and acoustic pressures ranging from 0.8 to 2.7 MPa were used at 20% duty cycle. Before sonication, a bolus of 10 microL of an ultrasound contrast agents (Optison) was injected intravenously. Contrast-enhanced high-resolution magnetic resonance imaging (9.4 T) revealed BBB opening and allowed for the monitoring of the slow permeation of gadolinium in the hippocampus. The region of the brain where BBB opening occurred increased with the pressure amplitude. These findings thus demonstrated the feasibility of locally opening the BBB in mice using FUS through intact skull and skin and serve as the first step in determining and assessing feasibility of drug delivery to specific regions in the mouse brain using FUS.  相似文献   

4.
Ultrasound-stimulated microbubbles are currently under investigation as a means of transiently disrupting the blood-brain barrier (BBB) and it has been shown that the strength of this effect is highly dependent on ultrasound exposure conditions. The objective of this study was to investigate the potential for contrast agent destruction in the brain under conditions relevant to BBB disruption with a view to determining its possible influence on effective exposure parameters. An ultrasound imaging array was mounted within the aperture of a 1.68-MHz focused therapy transducer. Pulse lengths of 10 ms were used at repetition rates of 0.1–2.0 Hz and pressures from 0.30–0.88 MPa. Contrast imaging was performed after the bolus injection of Definity™, and contrast time-intensity curves were then analyzed for regions-of-interest exposed to the therapy beam. Individual therapy pulses resulted in microbubble destruction, with the degree of agent depletion and replenishment time increasing with transmit pressure. As the pulse repetition rate was increased, agent reperfusion between pulses was incomplete and the concentration within the beam was progressively diminished, to a degree dependent on both pressure and repetition rates. These results demonstrate that microbubble concentration can be substantially influenced by destruction induced by therapeutic ultrasound pulses. The kinetics of this effect may therefore be a significant factor influencing the efficiency of BBB disruption, suggesting that monitoring of the spatial and temporal distribution of contrast agents may be warranted to guide and optimize BBB disruption therapy in both preclinical and clinical contexts. (E-mail: goertz@sri.utoronto.ca)  相似文献   

5.
The blood-brain barrier (BBB) inhibits the entry of the majority of chemotherapeutic agents into the brain. Previous studies have illustrated the feasibility of drug delivery across the BBB using focused ultrasound (FUS) and microbubbles. Here, we investigated the effect of FUS-enhanced delivery of doxorubicin on survival in rats with and 9L gliosarcoma cells inoculated in the brain. Each rat received either: (1) no treatment (control; N = 11), (2) FUS only (N = 9), (3) IV liposomal doxorubicin (DOX only; N = 17), or (4) FUS with concurrent IV injections of liposomal doxorubicin (FUS+DOX; N = 20). Post-treatment by magnetic resonance imaging (MRI) showed that FUS+DOX reduced tumor growth compared with DOX only. Further, we observed a modest but significant increase in median survival time after a single treatment FUS+DOX treatment (p = 0.0007), whereas neither DOX nor FUS had any significant impact on survival on its own. These results suggest that combined ultrasound-mediated BBB disruption may significantly increase the antineoplastic efficacy of liposomal doxorubicin in the brain.  相似文献   

6.
The permeability of the blood-brain barrier (BBB) can be enhanced by focused ultrasound (FUS) in localized regions with applications of ultrasound contrast agent (UCA). The purpose of this study was to evaluate the dose distribution of Evans blue (EB) in the targeted brain by sonication with treatment strategy. FUS exposure was applied with an ultrasound frequency of 1 MHz, a 5% duty cycle and a repetition frequency of 1 Hz. Single sonication with two doses of UCA and two sonications at the same location or an interval of 3 mm to induce BBB disruption for assessing dose distribution. The permeability of the BBB was measured quantitatively based on EB extravasation. Gadolinium deposition was monitored by contrast enhanced MR imaging for dose distribution of the focal plane. Hematoxylin and eosin staining was performed for histologic observation. No significant difference was found for EB in the focal regions between the single sonication with UCA at a dose of 300 μL/kg and repeated sonication with UCA at a lower dose of 150 μL/kg. There was a sharper dose distribution in the brain with repeated sonication at the same location, compared with the brain receiving two sonications at an interval of 3 mm. Compared with a single sonication with UCA at a dose of 150 μL/kg, the histologic evaluation of the sonicated regions indicated that more erythrocytes were seen in the brain treated with single sonication at a higher dose of 300 μL/kg or repeated sonication at a dose of 150 μL/kg. This study demonstrated that the dose distribution of molecular delivery could be regulated by sonication with treatment planning.  相似文献   

7.
诊断性超声造影对胎盘屏障通透性影响的实验研究   总被引:3,自引:0,他引:3  
目的探讨不同机械指数的诊断性超声造影对胎盘屏障通透性的影响,以了解超声造影检查中超声强度的安全性。 方法14~16d(孕中期)清洁级SD孕鼠,经尾静脉注射剂量为1ml/kg的“声诺维”超声造影剂,不同机械指数(MI:0.13、1.0、1.4)的超声对孕鼠子宫进行连续及间歇辐照,时间5min,在荧光显微镜下观察胎盘及胎鼠组织伊文思蓝(Evans blue,EB)自发红色荧光情况。 结果诊断剂量超声造影,大体观察胎盘呈深蓝色,胎鼠呈半透明浅粉色。在荧光显微镜下,胎盘内可见明显的EB自发的红色荧光斑块,在胎鼠体内未见EB荧光显像。 结论高机械指数及低机械指数诊断性超声造影均不会导致孕鼠胎盘屏障通透性增加。  相似文献   

8.
This work investigated the effect of ultrasonic frequency on the threshold for blood-brain barrier (BBB) disruption induced by ultrasound pulses combined with an ultrasound contrast agent. Experiments were performed in rabbits using pulsed sonications at 2.04 MHz with peak pressure amplitudes ranging from 0.3 to 2.3 MPa. BBB disruption was evaluated using contrast-enhanced magnetic resonance imaging. The threshold for BBB disruption was estimated using probit regression. Representative samples with similar amounts of contrast enhancement were examined in light microscopy. Results from these experiments were compared with data from previous studies that used ultrasound frequencies between 0.26 and 1.63 MHz. We found that the BBB disruption threshold (value where the probability for disruption was estimated to be 50%) expressed in terms of the peak negative pressure amplitude increased as a function of the frequency. It appeared to be constant, however, when the exposures were expressed as a function of the mechanical index (peak negative pressure amplitude estimated in situ divided by square root of frequency). Regression of data from all frequencies resulted in an estimated mechanical index threshold of 0.46 (95% confidence intervals: 0.42 to 0.50). Histologic examination of representative samples with similar amounts of blood-brain barrier disruption found that the number of regions containing extravasated red blood cells per unit area was substantially lower on average for lower ultrasound frequencies. This data suggests that the mechanical index is a meaningful metric for ultrasound-induced blood-brain barrier disruption, at least for when other parameters that are not taken into account by the mechanical index are not varied. It also suggests that lower frequency sonication produces less red blood cell extravasation per unit area. (E-mail: njm@bwh.harvard.edu)  相似文献   

9.
Disruption of the blood-brain barrier (BBB) may be transiently achieved via high-frequency focused spherical ultrasound in the presence of microbubbles. In this experimental animal study, we sought to determine whether focal reversible opening of the BBB may be achieved using low-frequency (i.e., 20–30 kHz) planar ultrasonic waves. In the presence of microbubbles, we were able to obtain BBB opening using non-focused ultrasound irradiation with a frequency as low as 28 kHz. We also achieved a tight regulation of the ultrasound patterns by using a mechanical scanning device equipped with a pinhole. Histologic examination of the brains supported the feasibility of our system. The areas of BBB disruption obtained with this method were large enough to cover a typical circumscribed cerebral tumor mass. The inherent advantages of our BBB opening method include an improved portability, the possibility to obtain fairly wide areas of BBB opening and a low incidence of hemorrhagic complications. In addition, our system has the potential to reduce the need for image guidance for treating superficial brain lesions. (E-mail: haoliliu@mail.cgu.edu.tw).  相似文献   

10.
As a potentially viable method of brain drug delivery, the safety profile of blood-brain barrier (BBB) opening using focused ultrasound (FUS) and ultrasound contrast agents (UCA) needs to be established. In this study, we provide a short-term (30-min or 5-h survival) histological assessment of murine brains undergoing FUS-induced BBB opening. Forty-nine mice were intravenously injected with Definity microbubbles (0.05 μL/kg) and sonicated under the following parameters: frequency of 1.525 MHz, pulse length of 20 ms, pulse repetition frequency of 10 Hz, peak rarefactional acoustic pressures of 0.15–0.98 MPa and two 30-s sonication intervals with an intermittent 30-s delay. The BBB opening threshold was found to be 0.15–0.3 MPa based on fluorescence and magnetic resonance imaging of systemically injected tracers. Analysis of three histological measures in hematoxylin and eosin–stained sections revealed the safest acoustic pressure to be within the range of 0.3–0.46 MPa in all examined time periods post sonication. Across different pressure amplitudes, only the samples 30 min post opening showed significant difference (p < 0.05) in the average number of distinct damaged sites, microvacuolated sites, dark neurons and sites with extravasated erythrocytes. Enhanced fluorescence around severed microvessels was also noted and found to be associated with the largest tissue effects, whereas mildly diffuse BBB opening with uniform fluorescence in the parenchyma was associated with no or mild tissue injury. Region-specific areas of the sonicated brain (thalamus, hippocampal fissure, dentate gyrus and CA3 area of hippocampus) exhibited variation in fluorescence intensity based on the position, orientation and size of affected vessels. The results of this short-term histological analysis demonstrated the feasibility of a safe FUS-UCA–induced BBB opening under a specific set of sonication parameters and provided new insights on the mechanism of BBB opening. (E-mail: ek2191@columbia.edu)  相似文献   

11.
The purpose was to assess whether standard ultrasound (US) perfusion-imaging by means of contrast-enhanced transcranial color-coded sonography (TCCS) affects the blood-brain barrier (BBB) in patients with small-vessel disease (SVD). One week after a screening MRI to exclude a preexisting BBB disruption, unilateral TCCS phase inversion harmonic imaging (PIHI) was performed in an axial diencephalic plane after intravenous bolus application of 2.5 mL SonoVue (IGEA, Bracco, Italy). Magnetic resonance imaging (MRI) was performed immediately after US. In five patients, PIHI was performed applying a mean mechanical index (MI) of 0.7 +/- 0.1 for a time period of 2.5 min. MRI was started 12 +/- 2 min after US contrast injection. Comparisons of initial and post-US MRI by four blinded readers did not show any signs of BBB disruption. It is concluded that standard contrast-enhanced US perfusion imaging in patients with SVD did not lead to MRI-detectable BBB changes. This gives further evidence for safety of diagnostic US. Future investigations with larger sample sizes and higher-field MRI might give further insights into potential bioeffects of diagnostic, as well as therapeutic, contrast-enhanced transcranial US.  相似文献   

12.
Previously, it was shown that low-intensity focused ultrasound pulses applied along with an ultrasound contrast agent results in temporary blood-brain barrier (BBB) disruption. This effect could be used for targeted drug delivery in the central nervous system. This study examined the effects of burst length, pulse repetition frequency (PRF), and ultrasound contrast agent dose on the resulting BBB disruption. One hundred nonoverlapping brain locations were sonicated through a craniotomy in experiments in 26 rabbits (ultrasound frequency: 0.69 MHz, burst: 0.1, 1, 10 ms, PRF: 0.5, 1, 2, 5 Hz, duration: 20 s, peak negative pressure amplitude: 0.1 to 1.5 MPa, Optison dosage 50, 100, 250 microl/kg). For each sonication, BBB disruption was evaluated using contrast-enhanced magnetic resonance imaging. The BBB disruption threshold (the pressure amplitude yielding a 50% probability for BBB disruption) was determined using probit regression for the three burst lengths tested. Tissue effects were examined in light microscopy for representative locations with similar amounts of contrast enhancement from each group. While changing the PRF or the Optison dosage did not result in a significant difference in the magnitude of the BBB disruption (p > 0.05), reducing the burst length resulted in significantly less contrast enhancement (p < 0.01). The BBB disruption thresholds were estimated to be 0.69, 0.47 and 0.36 MPa for 0.1, 1 and 10 ms bursts, respectively. No difference was detected in histology between any experimental groups. This data suggests that over the range of parameters tested, BBB disruption is not affected by PRF or ultrasound contrast agent dose. However, both the BBB disruption magnitude and its threshold depend on the burst length.  相似文献   

13.
The aim of this study was to evaluate the diagnostic value of ultrasound (US) as compared with magnetic resonance imaging (MRI) in the detection of placenta accreta. Sensitivity, specificity, summary receiver operating characteristic curves and areas under the curve (AUCs) were described and calculated using Meta-Disc Statistical Software, Version 1.4 (Unit of Clinical Biostatistics, Ramón y Cajal Hospital, Madrid, Spain). In the 13 studies included, US sensitivity was 83% (95% confidence interval [CI] 77%–88%), US specificity was 95% (95% CI: 93%–96%) and the diagnostic odds ratio (DOR) was 63.41 (95% CI: 29.04–138.48). In the MRI studies, sensitivity was 82% (95% CI: 72%–90%), specificity was 88% (95% CI: 81%–94%) and the DOR was 22.95 (95% CI: 3.19–165.11). Summary receiver operating characteristic analysis indicated that the diagnostic value of US in detection of placenta accreta is not significantly different from that of MRI. Both US and MRI were highly sensitive and specific in the detection of placenta accreta to support effective diagnostic methods.  相似文献   

14.
大鼠急性脑缺血再灌注后血脑屏障的变化   总被引:6,自引:0,他引:6  
目的研究大鼠急性脑缺血再灌注的血脑屏障变化以及MRI表现.方法 44只SD大鼠随机分为4组,采用大鼠线栓法建立急性脑缺血再灌注模型,A组、C组脑缺血2 h, B组、D组缺血6 h,A组、B组中每组10只分别于灌注前、再灌注后2 h和24 h行MRI检查,4只大鼠行组织学检查.C组、D组每组12只,分别于再灌注后2 h和24 h观察脑组织中伊文氏蓝染色情况并测量其含量. 结果 A、B两组再灌注前均无强化表现,再灌注后2 hA组10例中4例出现斑片状强化,B组10例均出现大片明显强化(P<0.05),B组中3例再灌注24 h T1WI出现高信号,相应大体标本断面可见出血灶,组织学观察显示B组脑组织损伤较A组严重.C组中8例可见右尾壳核斑片状蓝染区,而D组12例右尾壳核及额顶叶皮质区均见蓝染,测量两组右侧大脑半球伊文氏蓝含量与对侧相比均有显著性差异(P<0.05),两组之间右侧大脑半球伊文氏蓝含量相比有显著性差异(P<0.01),C组中再灌注2 h与再灌注24 h伊文氏蓝含量相比较有显著性差异(P<0.05),D组中再灌注2 h与再灌注24 h伊文氏蓝含量无差异(P>0.05).结论缺血再灌注时血脑屏障的损伤随着缺血时间的延长而加重,MRI增强扫描作为一个无创性、可重复性检查方法,有助于评价急性脑缺血再灌注后血脑屏障的状况.  相似文献   

15.
脑超声造影中超声造影剂剂量对血脑屏障通透性的影响   总被引:5,自引:3,他引:5  
目的探讨不同剂量超声造影剂在超声造影中对血脑屏障通透性的影响。方法60只清洁级SD大鼠,给予相同机械指数的超声进行辐照,并经尾静脉注射不同剂量的“脂氟显”超声造影剂,观察超声照射后血脑屏障通透性的变化。结果在造影剂剂量为50μl/kg时,血脑屏障通透性即与对照组相比产生显著性统计学差异,且随着超声造影剂剂量的增加其引起血脑屏障通透性也随之增加。结论在相同能量强度超声场中,超声造影剂微泡数目是引起不同生物学效应的重要因素。  相似文献   

16.
Polymersomes are a class of artificial vesicles prepared from amphiphilic polymers. Like lipid vesicles (liposomes), they too can encapsulate hydrophilic and hydrophobic drug molecules in the aqueous core and the hydrophobic bilayer respectively, but are more stable than liposomes. Although echogenic liposomes have been widely investigated for simultaneous ultrasound imaging and controlled drug delivery, the potential of the polymersomes remains unexplored. We prepared two different echogenic polymersomes from the amphiphilic copolymers polyethylene glycol–poly-DL-lactic acid (PEG-PLA) and polyethylene glycol–poly-L-lactic acid (PEG-PLLA), incorporating multiple freeze-dry cycles in the synthesis protocol to ensure their echogenicity. We investigated acoustic behavior with potential applications in biomedical imaging. We characterized the polymeric vesicles acoustically with three different excitation frequencies of 2.25, 5 and 10?MHz at 500?kPa. The polymersomes exhibited strong echogenicity at all three excitation frequencies (about 50- and 25-dB enhancements in fundamental and subharmonic, respectively, at 5-MHz excitation from 20?µg/mL polymers in solution). Unlike echogenic liposomes, they emitted strong subharmonic responses. The scattering results indicated their potential as contrast agents, which was also confirmed by clinical ultrasound imaging.  相似文献   

17.
18.
Magnetic resonance (MR) is currently used for diagnosis of osteosarcoma but not well even though contrast agents are administered. Here, we report a novel bone-targeted MR imaging contrast agent, Gd2-diethylenetriaminepentaacetate-bis(alendronate) (Gd2-DTPA-BA) for the diagnosis of osteosarcoma. It is the conjugate of a bone cell-seeking molecule (i.e., alendronate) and an MR imaging contrast agent (i.e., Gd-DTPA). Its physicochemical parameters were measured, including pKa, complex constant, and T1 relaxivity. Its bone cell-seeking ability was evaluated by measuring its adsorption on hydroxyapatite. Hemolysis was investigated. MR imaging and biodistribution of Gd2-DTPA-BA and Gd-DTPA were studied on healthy and osteosarcoma-bearing nude mice. Gd2-DTPA-BA showed high adsorption on hydroxyapatite, the high MR relaxivity (r1) of 7.613 mM−1 s−1 (2.6 folds of Gd-DTPA), and no hemolysis. The MR contrast effect of Gd2-DTPA-BA was much higher than that of Gd-DTPA after intravenous injection to the mice. More importantly, the MR imaging of osteosarcoma was significantly improved by Gd2-DTPA-BA. The signal intensity of Gd2-DTPA-BA reached 120.3% at 50 min, equal to three folds of Gd-DTPA. The bone targeting index (bone/blood) of Gd2-DTPA-BA in the osteosarcoma-bearing mice was very high to 130 at 180 min. Furthermore, the contrast enhancement could also be found in the lung due to metastasis of osteosarcoma. Gd2-DTPA-BA plays a promising role in the diagnoses of osteosacomas, including the primary bone tumors and metastases.  相似文献   

19.
MRI引导与监测聚焦超声靶向开放血脑屏障兔脑给药   总被引:1,自引:0,他引:1  
目的 探讨MRI引导与监测聚焦超声靶向开放血脑屏障(BBB)兔脑给药的效果.方法 25只新西兰大白兔随机均分为5组(0 h,2 h,4 h,8 h,24 h组),MRI引导聚焦超声辐照各组兔左脑,取靶点组织作为辐照组,取右脑相应解剖组织为对照组,分别于辐照后不同时间点静注欧乃影和甲氨喋呤(MTX),行T1加权相增强扫描,通过比较辐照组与对照组MRI信号强度增强率观察靶点BBB开放情况,并以靶点伊文氏蓝(EB)染色结果检验其准确性;以高效液相色谱法测定、比较辐照组与对照组MTX的浓度,计算靶点脑组织信号强度增强率与MTX浓度之间的线性相关系数.结果 兔脑靶点BBB开放处T1WI表现为点状或斑片状异常高信号影,与辐照前MRI定位时预设靶点位置吻合良好,并与EB蓝染结果一致,同时靶点脑组织信号强度增强率与MTX浓度之间的相关系数为0.96(P<0.01),两者有良好的相关性.结论 MRI能够引导与监测聚焦超声靶向开放BBB脑内给药,有望成为临床个体化治疗中枢神经系统疾病的理想监测手段.  相似文献   

20.
近年来,经直肠超声检查技术与超声新技术的联合应用在前列腺癌的临床诊断中发挥了越来越重要的作用,明显提高了对早期前列腺癌的诊断、鉴别诊断和临床分期的准确性及可靠性,为系统评价临床治疗效果提供了必要的参考依据。本文就现阶段医学超声新技术诊断早期前列腺癌的应用现状及进展进行综述。  相似文献   

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