超声造影剂微泡非线性动力学响应的机理及相关应用

于洁; 郭霞生; 屠娟; 章东

doi:10.7498/aps.64.094306

摘要

随着生命科学及现代医学的发展, 一体化无创精准诊疗已经日益成为人们关注的焦点问题, 而关于超声造影剂微泡的非线性效应的相关机理、动力学建模及其在超声医学领域中的应用研究也得到了极大的推动. 本文对下列课题进行了总结和讨论, 包括: 1)基于Mie散射技术和流式细胞仪对造影剂微泡参数进行定征的一体化解决方案; 2)通过对微泡包膜的黏弹特性进行非线性修正, 构建新的包膜微泡动力学模型; 3)探索造影剂惯性空化阈值与其包膜参数之间的相关性; 以及4)研究超声联合造影剂微泡促进基因/药物转染效率并有效降低其生物毒性的相关机理.

关键词:

Abstract

Ultrasound contrast agent (UCA) reflers to the agent that has specific acoustic properties to enhance the contrast in ultrasound imaging by composition of gas-filled microbubbles with micrometer-diameters. In a diagnostic ultrasound field, microbubbles in fluid create an acoustic impedance mismatch between fluid and surrounding tissue to increase the reflection of sound and achieve a better contrast. Ongoing developments improve diagnostic possibilities of UCA remarkably, whereas their potential therapeutic applications have also been investigated for a couple of decades. The nonlinear response of UCA microbubbles has clinical reflevance from both diagnostic and therapeutic perspectives. The aim of this review is to introduce the latest reflearch progress of our group regarding the mechanism and applications of the nonlinear dynamic response to UCA, which include (1) an all-in-one solution characterizing coated bubble parameters with the help of the light scattering technique and flow cytometry, which makes it possible to quickly integrate the size distribution with dynamic motions of thousands of microbubbles and easily verify the validities of different shelled bubble dynamic models; (2) the development of a new bubble dynamics model that takes into account both nonlinear shell elasticity and viscosity, which can not only be capable of simulating the “compression-only” behavior of microbubbles excited by large amplitude ultrasound but also eliminate the dependence of bubble shell parameters on bubble size; (3) the estimation of UCA inertial cavitation thresholds of two types of commercial UCA microbubbles (viz., SonoVue microbubbles coated with lipid shells and KangRun microbubbles coated with albumin shells) and the evaluation of the relationship between microbubble inertial cavitation thresholds and their shell parameters; and (4) the reflearches of DNA transfection efficiency and the reduction of cytotoxicity in gene delivery facilitated by UCA excited by 1-MHz focused ultrasound pulses, and the results indicate that the measured DNA transfection efficiency and sonoporation pore size generally increase with the enhancement of inertial cavitation dose, while the cell viability decreases linearly with the increase of International Classification of Diseases (ICD). These studies are of significance for better understanding the mechanism of ultrasound-induced microbubble nonlinear dynamics and investigating the effective quantification technique for microbubble cavitation activity, which are important for further optimizing therapeutic ultrasound effects and avoiding the side-effects.

Keywords:

ultrasound contrast agent microbubbles /
nonlinear responses /
inertial cavitation /
gene/drug delivery

作者及机构信息

1.
近代声学教育部重点实验室, 南京大学物理学院, 南京 210093;

2.
江苏省中医院, 南京 210029

基金项目: 国家重点基础研究发展计划(批准号: 2011CB707900)、国家自然科学基金(批准号: 61072027, 81127901, 81227004, 11374155, 11174141, 11274170, 11474001和11474161)和国家高技术研究发展计划(批准号: 2012AA022702)资助的课题.

Authors and contacts

1.
Institute of Acoustics, Key Laboratory of Modern Acoustics (MOE), School of Physics, Nanjing University, Nanjing 210093, China;

2.
Jiangsu Province Hospital of TCM, Nanjing 210029, China

Funds: Project supported by the State Key Development Program for Basic Research of China (Grant No. 2011CB707900), the National Natural Science Foundation of China (Grant Nos. 61072027, 81127901, 81227004, 11374155, 11174141, 11274170, 11474001, 11474161), and the National High Technology Research and Development Program of China (Grant No. 2012AA022702).

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[41]	De Jong N, Emmer M, Van Wamel A, Versluis M 2009 Med. Biol. Eng. Comput. 47 861
[42]	Guo X S, Li Q, Zhang Z, Zhang D, Tu J 2013 J. Acoust. Soc. Am. 134 1622
[43]	Dayton P A, Morgan K E, Klibanov A L, Brandenburger G H, Ferrara K W 1999 IEEE Trans. Ultrason. Ferr. 46 220
[44]	Matula T J, Swalwell J, Tu J, Cui W C, Chen W Z 2011 IEEE International Ultrasonics Symposium (IUS) Orlando, FL, USA, October 18-21, 2011 p156
[45]	Tu J, Guan J F, Qiu Y Y, Matula T J 2009 J. Acoust. Soc. Am. 126 2954
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[50]	Yu H, Xu L 2014 J. Control. Release 174 151
[51]	Miller D L, Thomas R M 1995 Ultrasound Med. Biol. 21 1059
[52]	Flynn H G, Church C C 1988 J. Acoust. Soc. 84 985
[53]	Newman C, Bettinger T 2007 Gene Ther. 14 465
[54]	Chen S Y, Shohet R V, Bekeredjian R, FrenkelP, Grayburn P A 2003 J. Am. Coll. Cardiol. 42 301
[55]	Sheyn D, Kimelman-Bleich N, Pelled G, Zilberman Y, Gazit D, Gazit Z 2008 Gene Ther. 15 257
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[60]	Marston P L 1991 Appl. Optics 30 3479
[61]	Bohren C F, Huffman D R 1998 Absorption and scattering of light by small particles (Weinheim, Germany: Wiley-VCH Verlag GmbH)
[62]	Paul S, Katiyar A, Sarkar K, Chatterjee D, Shi W T, Forsberg F 2010 J. Acoust. Soc. Am. 127 3846
[63]	Tsiglifis K, Pelekasis N A 2008 J. Acoust. Soc. Am. 123 4059
[64]	Li Q, Matula T J, Tu J, Guo X S, Zhang D 2013 Phys. Med. Biol. 58 985
[65]	Chang P P, Chen W S, Mourad P D, Poliachik S L, Crum L A 2001 IEEE Trans. Ultrason. Ferr. 48 161
[66]	Chen W S, Matula T J, Brayman A A, Crum L A 2003 J. Acoust. Soc. Am. 113 643
[67]	Tu J, Matula T J, Brayman A A, Crum L A 2006 Ultrasound Med. Biol. 32 281
[68]	Apfel R E, Holland C K 1991 Ultrasound Med. Biol. 17 179
[69]	Deng C X, Xu Q H, Apfel R E, Holland C K 1996 Ultrasound Med. Biol. 22 939
[70]	Deshpande M C, Prausnitz M R 2007 J. Control. Release 118 126
[71]	Mitragotri S 2005 Nat. Rev. Drug Discov. 4 255
[72]	Tsivgoulis G, Alexandrov A V 2007 Neurotherapeutics 4 420
[73]	Miller D L, Pislaru S V, Greenleaf J E 2002 Somat Cell Mol Genet 27 115
[74]	Qiu Y, Luo Y, Zhang Y, Cui W, Zhang D, Wu J, Zhang J, Tu J 2010 J. Control. Release 145 40
[75]	Zhang C B, Cao H L, Li Q, Tu J, Guo X S, Liu Z, Zhang D 2013 Ultrasound Med. Biol. 39 161
[76]	Park J, Fan Z Z, Deng C X 2011 J. Biomech. 44 164
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[79]	Tran T A, Roger S, Le Guennec J Y, Tranquart F, Bouakaz A 2007 Ultrasound Med. Biol. 33 158

施引文献

[1]	Pace N G, Cowley A, Campbell A M 1997 J. Acoust. Soc. Am. 102 1474
[2]	Goldberg B B, Raichlen J S, Forsberg F 2001 Ultrasound contrast agents: basic principles and clinical applications (2nd Ed.) (London: Martin Dunitz)
[3]	Hernot S, Klibanov A L 2008 Adv. Drug Deliver. Rev. 60 1153
[4]	Lindner J R 2009 Nat Rev Cardiol 6 475
[5]	Stride E P, Coussios C C 2010 P. I. Mech. Eng. H 224 171
[6]	Mitragotri S 2005 Nat. Rev. Drug Discov. 4 255
[7]	Ferrara K, Pollard R, Borden M 2007 Annu.Rev. Biomed. Eng. 9 415
[8]	Kennedy J E 2005 Nat. Rev. Cancer 5 321
[9]	Everbach E C, Francis C W 2000 Ultrasound Med. Biol. 26 1153
[10]	Escoffre J M, Mannaris C, Geers B, Novell A, Lentacker I, Averkiou M, Bouakaz A 2013 IEEE T. Ultrason. Ferr. 60 78
[11]	Faez T, Emmer M, Kooiman K, Versluis M, Van der Steen A, De Jong N 2013 IEEE T. Ultrason. Ferr. 60 7
[12]	Dejong N, Hoff L 1993 Ultrasonics 31 175
[13]	Dejong N, Cornet R, Lancee C T 1994 Ultrasonics 32 455
[14]	Dejong N, Cornet R, Lancee C T 1994 Ultrasonics 32 447
[15]	Church C C 1995 J. Acoust. Soc. Am. 97 1510
[16]	Rayleigh 1917 Philos Mag 34 94
[17]	Plesset M S 1949 J. Appl. Mech.-T. Asme 16 277
[18]	Roy R A, Madanshetty S I, Apfel R E 1990 J. Acoust. Soc. Am. 87 2451
[19]	Hoff L, Sontum P C, Hovem J M 2000 J. Acoust. Soc. Am. 107 2272
[20]	Chomas J E, Dayton P, Allen J, Morgan K, Ferrara K W 2001 IEEE Trans. Ultrason. Ferr. 48 232
[21]	Tu J, Swalwell J E, Giraud D, Cui W C, Chen W Z, Matula T J 2011 IEEE Trans. Ultrason. Ferr. 58 955
[22]	Morgan K E, Allen J S, Dayton P A, Chomas J E, Klibanov A L, Ferrara K W 2000 IEEE Trans. Ultrason. Ferr. 47 1494
[23]	Chatterjee D, Sarkar K 2003 Ultrasound Med. Biol. 29 1749
[24]	Sarkar K, Shi W T, Chatterjee D, Forsberg F 2005 J. Acoust. Soc. Am. 118 539
[25]	Doinikov A A, Dayton P A 2007 J. Acoust. Soc. Am. 121 3331
[26]	Sijl J, Dollet B, Ouvervelde M, Garbin V, Rozendal T, De Jong N, Lohse D, Versluis M 2010 J. Acoust. Soc. Am. 128 3239
[27]	Emmer M, Van Wamel A, Goertz D E, De Jong N 2007 Ultrasound Med. Biol. 33 941
[28]	Viti J, Mori R, Guidi F, Versluis M, De Jong N, Tortoil P 2012 IEEE Trans. Ultrason. Ferr. 59 2818
[29]	Van der Meer S M, Marmottant P G, Hilgenfeldt S, Versluis M, Lohse D, Chin C T, Bouakaz A, Mastik F, Emmer M 2005 2005 IEEE Ultrasonics Symposium 1-4 974
[30]	De Jong N, Emmer M, Chin C T, Bouakaz A, Mastik F, Lohse D, Versluis M 2007 Ultrasound Med. Biol. 33 653
[31]	Sijl J, Overvelde M, Dollet B, Garbin V, De Jong N, Lohse D, Versluis M 2011 J. Acoust. Soc. Am. 129 1729
[32]	Emmer M, Van Wamel A, Goertz D E, Versluis M, De Jong N 2006 2006 IEEE Ultrasonics Symposium 1-5 1545
[33]	Overvelde M, Garbin V, Sijl J, Dollet B, De Jong N, Lohse D, Versluis M 2010 Ultrasound Med. Biol. 36 2080
[34]	Hay T A, Ilinskii Y A, Zabolotskaya E A, Hamilton M F 2013 J. Acoust. Soc. Am. 134 1454
[35]	Shams M M, Dong M Z, Mahinpey N 2014 Aiche J. 60 2660
[36]	Shen Y Y, Longo M L, Powell R L 2008 J. Colloid Interf. Sci. 327 204
[37]	Faez T, Emmer M, Docter M, Sijl J, Versluis M, De Jong N 2011 Ultrasound Med. Biol. 37 958
[38]	Van der Meer S M, Dollet B, Voormolen M M, Chin C T, Bouakaz A, De Jong N, Versluis M, Lohse D 2007 J. Acoust. Soc. Am. 121 648
[39]	Marmottant P, Van der Meer S, Emmer M, Versluis M, De Jong N, Hilgenfeldt S, Lohse D 2005 J. Acoust. Soc. Am. 118 3499
[40]	Doinikov A A, Haac J F, Dayton P A 2009 Ultrasonics 49 269
[41]	De Jong N, Emmer M, Van Wamel A, Versluis M 2009 Med. Biol. Eng. Comput. 47 861
[42]	Guo X S, Li Q, Zhang Z, Zhang D, Tu J 2013 J. Acoust. Soc. Am. 134 1622
[43]	Dayton P A, Morgan K E, Klibanov A L, Brandenburger G H, Ferrara K W 1999 IEEE Trans. Ultrason. Ferr. 46 220
[44]	Matula T J, Swalwell J, Tu J, Cui W C, Chen W Z 2011 IEEE International Ultrasonics Symposium (IUS) Orlando, FL, USA, October 18-21, 2011 p156
[45]	Tu J, Guan J F, Qiu Y Y, Matula T J 2009 J. Acoust. Soc. Am. 126 2954
[46]	Wu J, Nyborg W L 2008 Adv. Drug Deliver. Rev. 60 1103
[47]	Kobayashi N, Yasu T, Yamada S, Kudo N, Kuroki M, Kawakami M, Miyatake K, Saito M 2002 Ultrasound Med. Biol. 28 949
[48]	Maruvada S, Hynynen K 2004 Ultrasound Med. Biol. 30 67
[49]	Feril L B, Kondo T, Zhao Q L, Ogawa R, Tachibana K, Kudo N, Fujimoto S, Nakamura S 2003 Ultrasound Med. Biol. 29 331
[50]	Yu H, Xu L 2014 J. Control. Release 174 151
[51]	Miller D L, Thomas R M 1995 Ultrasound Med. Biol. 21 1059
[52]	Flynn H G, Church C C 1988 J. Acoust. Soc. 84 985
[53]	Newman C, Bettinger T 2007 Gene Ther. 14 465
[54]	Chen S Y, Shohet R V, Bekeredjian R, FrenkelP, Grayburn P A 2003 J. Am. Coll. Cardiol. 42 301
[55]	Sheyn D, Kimelman-Bleich N, Pelled G, Zilberman Y, Gazit D, Gazit Z 2008 Gene Ther. 15 257
[56]	Duvshani-Eshet M, Benny O, Morgenstern A, Machluf M 2007 Mol. Cancer Ther. 6 2371
[57]	Duvshani-Eshet M, Machluf M 2007 Cancer Gene Ther. 14 306
[58]	Collins C G, Tangney M, Larkin J O, Casey G, Whelan M C, Cashman J, Murphy J, Soden D, Vejda S, Mckenna S, Kiely B, Collins J K, Barrett J, Aarons S, O’Sullivan G C 2006 Cancer Gene Ther. 13 1061
[59]	Craig R, Cutrera J, Zhu S, Xia X, Lee Y H, Li S 2008 Mol. Ther. 16 901
[60]	Marston P L 1991 Appl. Optics 30 3479
[61]	Bohren C F, Huffman D R 1998 Absorption and scattering of light by small particles (Weinheim, Germany: Wiley-VCH Verlag GmbH)
[62]	Paul S, Katiyar A, Sarkar K, Chatterjee D, Shi W T, Forsberg F 2010 J. Acoust. Soc. Am. 127 3846
[63]	Tsiglifis K, Pelekasis N A 2008 J. Acoust. Soc. Am. 123 4059
[64]	Li Q, Matula T J, Tu J, Guo X S, Zhang D 2013 Phys. Med. Biol. 58 985
[65]	Chang P P, Chen W S, Mourad P D, Poliachik S L, Crum L A 2001 IEEE Trans. Ultrason. Ferr. 48 161
[66]	Chen W S, Matula T J, Brayman A A, Crum L A 2003 J. Acoust. Soc. Am. 113 643
[67]	Tu J, Matula T J, Brayman A A, Crum L A 2006 Ultrasound Med. Biol. 32 281
[68]	Apfel R E, Holland C K 1991 Ultrasound Med. Biol. 17 179
[69]	Deng C X, Xu Q H, Apfel R E, Holland C K 1996 Ultrasound Med. Biol. 22 939
[70]	Deshpande M C, Prausnitz M R 2007 J. Control. Release 118 126
[71]	Mitragotri S 2005 Nat. Rev. Drug Discov. 4 255
[72]	Tsivgoulis G, Alexandrov A V 2007 Neurotherapeutics 4 420
[73]	Miller D L, Pislaru S V, Greenleaf J E 2002 Somat Cell Mol Genet 27 115
[74]	Qiu Y, Luo Y, Zhang Y, Cui W, Zhang D, Wu J, Zhang J, Tu J 2010 J. Control. Release 145 40
[75]	Zhang C B, Cao H L, Li Q, Tu J, Guo X S, Liu Z, Zhang D 2013 Ultrasound Med. Biol. 39 161
[76]	Park J, Fan Z Z, Deng C X 2011 J. Biomech. 44 164
[77]	Ohl C D, Wolfrm B 2003 Bba-Gen. Subjects 1624 131
[78]	Qiu Y Y, Zhang C B, Tu J, Zhang D 2012 J.Biomech 45 1339
[79]	Tran T A, Roger S, Le Guennec J Y, Tranquart F, Bouakaz A 2007 Ultrasound Med. Biol. 33 158

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