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集合多种诊断和治疗功能的声/磁造影剂微泡的研究与开发已经成为当前医学超声、生物医学工程及临床应用领域共同关注的热点问题. 超顺磁氧化铁纳米颗粒具有独特的磁性特征和良好的生物相容性, 可被用作核磁共振造影剂来提升影像对比度、空间分辨率及临床诊断准确性. 我们的前期工作表明, 通过将超顺磁氧化铁纳米颗粒挂载于常规超声造影剂微泡表面, 可以成功构建多模态诊断及治疗介质, 显著改变超声造影剂微泡的尺度分布及包膜粘弹系数等物理特性, 进而影响微泡造影剂的声散射特性及其声空化效应和热效应. 然而, 此前的研究仅考虑了声场强度和微泡浓度等影响因素, 对于脉冲超声时间特性对磁性微泡造影剂动力学响应的影响的相关研究仍有所欠缺. 本文通过热电偶对凝胶仿体血管模型中流动的双模态磁性微泡在不同占空比超声脉冲信号作用下, 产生温升效应开展了系统的实验测量, 并基于有限元模型对实验结果进行了仿真验证. 结果显示, 脉冲信号占空比的提升是增强血管中磁性微泡在聚焦超声作用下温升效果的关键性时间影响因素. 本文的研究成果将有助于更好地理解不同超声作用参数对双模态磁性微泡的热效应的影响机制, 对保障双模态磁性微泡在临床热疗应用中的安全性和有效性具有重要的指导意义.
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关键词:
- 超顺磁氧化铁纳米颗粒 /
- 聚焦超声 /
- 热效应 /
- 占空比
Development of acoustic/magnetic contrast agent microbubbles with various diagnostic and therapeutic functions has attracted more and more attention in medical ultrasound, biomedical engineering and clinical applications. Superparamagnetic iron oxide nanoparticles (SPIO) have unique magnetic characteristics and wonderful biocompatibility, so they can be used as MRI contrast agents to improve image contrast, spatial resolution and diagnostic accuracy. Our previous work shows that the multimodal diagnostic and therapeutic microbubble agents can be successfully constructed by embedding SPIO particles into the coating shell of conventional ultrasound contrast agent (UCA) microbubbles, which in turn changes the size distribution and shell properties of UCA microbubbles, thereby affecting their acoustic scattering, cavitation and thermal effects. However, previous studies only considered the influence factors such as acoustic pressure and microbubble concentration. The relevant investigation regarding the influence of ultrasound temporal characteristics on the dynamic response of magnetic microbubbles is still lacking. This work systematically measures the temperature enhancement effect of the SPIO-albumin microbubble solution flowing in the vascular gel phantom exposed to pulsed ultrasound with various temporal settings (e.g. duty cycle, PRF and single pulse length). Meanwhile, a two-dimensional finite element model is developed to simulate and verify the experimental observations. The results show that the increase of duty cycle of pulse signal should be the crucial factor affecting the temperature enhancement effect of flowing SPIO-albumin microbubble solution under the exposure to high-intensity focused ultrasound. The current results help us to better understand the influence of different acoustic setting parameters on the thermal effect of dual-modal magnetic UCA microbubbles, and provide useful guidance for ensuring the safety and effectiveness of the application of SPIO-albumin microbubbles in clinics.-
Keywords:
- superparamagnetic iron oxide /
- focused ultrasound /
- thermal effect /
- duty cycle
[1] 于洁, 郭霞生, 屠娟, 章东 2015 64 094306
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Google Scholar
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图 1 数值模拟仿真几何模型设计示意图
Fig. 1. Schematic diagram of geometric model design for numerical simulation.
图 4 实验装置示意图(凝胶中红色点表示测温针针尖位置, 垂直于纸面); 换能器焦点位于凝胶中聚酯管内, 测温针放置在管壁边缘
Fig. 4. Schematic diagram of the experimental device (the red dot in the gel indicates the position of the tip of the temperature probe, which is perpendicular to the paper). The transducer focus is located in the polyester tube in the gel, and the temperature probe is placed on the edge of the tube wall.
图 5 蛋白包膜微泡(a)和双模态磁性微泡(b)的透射电子显微镜图像
Fig. 5. Transmission electron microscope images of protein coated microbubbles (a) and bimodal magnetic microbubbles (b).
图 6 不同占空比条件下, 模拟血管中磁性微泡溶液在聚焦超声作用下的温度随时间变化情况(a)及最高温升情况(b). *表示p < 0.5
Fig. 6. Temperature change with time of magnetic microbubble solution in simulated blood vessels under the action of focused ultrasound under different duty cycles (a) and maximum temperature rise (b). * means p < 0.5
图 7 占空比保持不变时, 模拟血管中磁性微泡溶液在聚焦超声作用下的温度随时间变化情况(a)及最高温升情况(b)
Fig. 7. Temperature changes with time (a) and maximum temperature rise (b) of magnetic microbubble solution in simulated blood vessels under the action of HIFU when the duty cycle remains unchanged.
表 1 模拟仿真计算中各区域材料参数设定
Table 1. Material parameter setting of each area in simulation calculation.
材料 水 凝胶 磁性微泡溶液 密度/(kg·m–3) 1000 1043 1006 声速/(m·s–1) 1486 1542 1550 声衰减系数/(dB·cm–1) 0.0022 0.1998 1.0000 比热容/(J·kg–1·K–1) 4500 3580 导热系数/(W·m–1·K–1) 0.6 0.5 
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[1] 于洁, 郭霞生, 屠娟, 章东 2015 64 094306
Google Scholar
Yu J, Guo X S, Tu J, Zhang D 2015 Acta Phys. Sin. 64 094306
Google Scholar
[2] Wang H L, Thorling C A, Liang X W, Bridle K R, Grice J E, Zhu Y A, Crawford D H G, Xu Z P, Liu X, Roberts M S 2015 J. Mater. Chem. B 3 939
Google Scholar
[3] Niu C C, Wang Z G, Lu G M, Krupka T M, Sun Y, You Y F, Song W X, Ran H T, Li P, Zheng Y Y 2013 Biomaterials 34 2307
Google Scholar
[4] Shin T H, Choi Y, Kim S, Cheon J 2015 Chem. Soc. Rev. 44 4501
Google Scholar
[5] Duan L, Yang L, Jin J, Yang F, Liu D, Hu K, Wang Q X, Yue Y B, Gu N 2020 Theranostics 10 462
Google Scholar
[6] Guo G P, Lu L, Yin L L, Tu J, Guo X S, Wu J, Xu D, Zhang D 2014 Phys. Med. Biol. 59 6729
Google Scholar
[7] 赵丽霞, 王成会, 莫润阳 2021 70 014301
Google Scholar
Zhao L X, Wang C H, Mo R Y 2021 Acta Phys. Sin. 70 014301
Google Scholar
[8] Tu J, Yu ACH 2022 BME Frontiers 2022 9807347
[9] Yang Y Y, Li Q, Guo X S, Tu J, Zhang D 2020 Ultrason. Sonochem. 67 105096
Google Scholar
[10] Gu Y Y, Chen C Y, Tu J, Guo X S, Wu H Y, Zhang D 2016 Ultrason. Sonochem. 29 309
Google Scholar
[11] 郭各朴, 张春兵, 屠娟, 章东 2015 64 114301
Google Scholar
Guo G P, Zhang C B, Tu J, Zhang D 2015 Acta Phys. Sin. 64 114301
Google Scholar
[12] Guo G P, Tu J, Guo X S, Huang P T, Wu J, Zhang D 2016 J. Biomech. 49 319
Google Scholar
[13] Illing R O, Kennedy J E, Wu F, ter Haar G R, Protheroe A S, Friend P J, Gleeson F V, Cranston D W, Phillips R R, Middleton M R 2005 Br. J. Cancer 93 890
Google Scholar
[14] Poissonnier L, Chapelon J Y, Rouvière O, Curiel L, Bouvier R, Martin X, Dubernard J M, Gelet A 2007 Eur. Urol. 51 381
Google Scholar
[15] Hectors S J, Jacobs I, Heijman E, Keupp J, Berben M, Strijkers G J, Grüll H, Nicolay K 2015 NMR Biomed. 28 1125
Google Scholar
[16] Kennedy J E 2005 Nat. Rev. Cancer 5 321
Google Scholar
[17] Zhang L, Zhu H, Jin C B, Zhou K, Li K Q, Su H B, Chen W Z, Bai J, Wang Z B 2009 Eur. Radiol. 19 437
Google Scholar
[18] Sboros V 2008 Adv. Drug Delivery Rev. 60 1117
Google Scholar
[19] Kaneko Y, Maruyama T, Takegami K, Watanabe T, Mitsui H, Hanajiri K, Nagawa H, Matsumoto Y 2005 Eur. Radiol. 15 1415
Google Scholar
[20] Zhang S Y, Ding T, Wan M X, Jiang H J, Yang X, Zhong H, Wang S P 20 11 J. Acoust. Soc. Am. 129 2336
[21] Yang D X, Ni Z Y, Yang Y Y, Xu G Y, Tu J, Guo X S, Huang P T, Zhang D 2018 Ultrason. Sonochem. 49 111
Google Scholar
[22] Lee Y S, Hmilton M F 1995 J. Acoust. Soc. Am. 97 906
Google Scholar
[23] Pennes H H 1948 J. Appl. Physiol. 1 93
Google Scholar
[24] Qian K, Li C H, Ni Z Y, Tu J, Guo X S, Zhang D 2017 Ultrasonics 77 38
Google Scholar
[25] Tu J, Hwang J H, Fan T B, Guo X S, Crum L A, Zhang D 2012 Appl. Phys. Lett. 101 124102
Google Scholar
[26] Holt R G, Roy R A 2001 Ultra. Med. Biol. 27 1399
Google Scholar
[27] Coussios C C, Farny C H, Haar G T, Roy R A 2007 Int. J. Hyperthermia 23 105
Google Scholar
[28] Razansky D, Einziger P D, Adam D R 2006 IEEE Trans. Ultrason. Ferroelectr. Freq. Control 53 137
Google Scholar
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