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超声造影剂微气泡的包膜黏弹特性的定量表征研究

郭各朴 张春兵 屠娟 章东

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超声造影剂微气泡的包膜黏弹特性的定量表征研究

郭各朴, 张春兵, 屠娟, 章东

Quantitative characterization of viscoelasticity of microbubbles in ultrasound contrast agent

Guo Ge-Pu, Zhang Chun-Bing, Tu Juan, Zhang Dong
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  • 包膜黏弹特性显著影响微气泡超声造影剂的诊断及治疗应用效果. 本文结合原子力显微镜技术及声衰减特性测量提出了一种对微气泡造影剂包膜黏弹特性定量表征的新方法. 首先采用原子力显微镜技术进行机械特性分析得到包膜微气泡的有效硬度及体弹性模量; 然后测量声衰减特性, 基于微气泡动力学理论, 计算包膜微气泡的体黏度系数. 为验证方法的有效性, 实验制备了直径为1-5 μm的白蛋白包膜微气泡造影剂, 原子力显微镜测量的有效硬度和体弹性模量分别为0.149±0.012 N/m和8.31±0.667 MPa, 并与粒径无关. 声衰减特性测量和动力学理论拟合的包膜微气泡的体黏度系数为0.374±0.003 Pa·s. 该方法可推广至其他种类包膜微气泡的黏弹特性表征, 对超声造影剂的制备及其诊断和治疗应用有积极意义.
    Ultrasound contrast agent (UCA) microbubbles have been commonly used in clinic to enhance the acoustic backscattering signals in ultrasound imaging diagnosis. With increasing demand for the continuous improvement of imaging resolution and sensitivity, new type UCAs (e.g., targeted microbubbles and multifunctional microbubbles) have attracted growing interest in both medical and scientific communities. Many efforts have been made to modify microbubble shell properties, which can strongly affect microbubble dynamic behaviors, so as to enable to create some new functionalities of UCAs. However, accurate characterization of the shell mechanical properties of UCAs has been recognized to be rather challenging. In previous work, microbubble’s mechanical properties are normally estimated by fitting measured dynamic response signals with coated-microbubble models. Inevitable uncertainty will be introduced in fitting results because there are more than one unknown shell parameters are adopted in these dynamic models. In the present paper, a comprehensive approach is developed to quantitatively characterize the visco-elasticity of the encapsulated microbubbles. By combining the techniques of atomic force microscopy (AFM), single particle optical sensing (SPOS), acoustic attenuation measurement, and the coated-bubble dynamics simulation, the size distribution, shell thickness, shell elasticity and viscosity of UCA microbubbles are determined one by one in sequence. To examine the validity of this approach, a kind of albumin-shelled microbubbles with diameters ranging from 1 to 5 μm are fabricated in our lab. Based on AFM technology, the microbubble effective shell stiffness and bulk elasticity modulus are measured to be 0.149±0.012 N/m and 8.31±0.667 MPa, respectively. It is noteworthy that the shell elastic property is shown to be independent of the initial size of microbubbles. Furthermore, the size distribution and acoustic attenuation measurements are also performed of these bubbles. Then, combined with microbubble dynamic model simulations, the UCA shell viscosity is calculated to be 0.374±0.003 Pa·s. Compared with previous estimation method, the current technology can be used as an effective tool to assess UCA shell visco-elasticity with improved accuracy and certainty. It is also shown that the feasibility to optimize the design and fabrication of UCAs can satisfy different requirements in ultrasound diagnostic and therapeutic applications.
    • 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:81127901,81227004,81171659,11374155,11174141,11104140,11161120324)和国家高技术研究发展计划计划(2012AA022702))资助的课题.
    • Funds: Projects supported by the National Basic Research Program of China (Grant No. 2011CB707900), the National Natural Science Foundation of China (Grant Nos. 81127901, 81227004, 81171659, 11374155, 11174141, 11104140, 11161120324), and the National High-Tech Research and Development Program (Grant No. 2012AA022702).
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    [3]

    Ferrara K W, Borden M A, Zhang H 2009 Acc. Chem. Res. 42 881

    [4]

    Kennedy J E 2005 Nature Rev. Cancer 5 321

    [5]

    Ferrara K, Pollard R, Borden M 2007 Annu. Rev. Biomed Eng. 9 415

    [6]

    Zhang C B, Liu Z, Guo X S, Zhang D 2011 Chin. Phys. B 20 024301

    [7]

    Kennedy J E 2005 Nature Rev. Cancer 5 321

    [8]

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    Liang J F, Chen W Z, Shao W H, Zhou C, Du L F, Jin L F 2013 Acta Phys. Sin. 62 084708 (in Chinese) [梁金福, 陈伟中, 邵纬航, 周超, 杜联芳, 金利芳 2013 物理学报 62 084708]

    [10]

    Chen Q, Zou X Y, Cheng J C 2006 Acta Phys. Sin. 55 6476 (in Chinese) [陈谦, 邹欣晔, 程建春 2006 物理学报 55 6476]

    [11]

    Hoff L, Sontum P C, Hovem J M 2000 J. Acoust. Soc. Am. 107 2272

    [12]

    Fouan D, Achaoui Y, Mensah S 2014 Appl. Phys. Lett. 104 114102

    [13]

    Sboros V, Moran C M, Pye S D, McDicken W N 2003 Ultrasound Med. Biol. 29 687

    [14]

    Chomas J E, Dayton P A, May D, Allen J, Klibanov A, Ferrara K 2000 Appl. Phys. Lett. 77 1056

    [15]

    Tu J, Guan J F, Qiu Y Y, Matula T J 2009 J. Acoust. Soc. Am. 126 2954

    [16]

    Sboros V, Glynos E, Pye S D, Moran C M, Butler M, Ross J A, Mcdicken V, Koutsos V 2007 Ultrasonics 46 349

    [17]

    Marmottant P, van der Meer S, Emmer M, Versluis M, de Jong N, Hilgenfeldt S, Lohse D 2005 J. Acoust. Soc. Am. 118 3499

    [18]

    Doinikov A A, Haac J F, Dayton P A 2009 Ultrasonics 49 269

    [19]

    Doinikov A A, Bouakaz A 2011 Ultrasoun. Ferro. Freq. Control 58 981

    [20]

    Liu K K 2006 J. Phys. D:Appl. Phys. 39 R189

    [21]

    Glynos, E, Koutsos, V, McDicken W N, Moran C M, Pye S D, Ross J A, Sboros V 2009 Langmuir 25 7514

    [22]

    Porter T R, Xie F, Kricsfeld A, Kilzer K 1995 J. Am. Col. Cardio. 26 33

    [23]

    de Jong N, Hoff L, Skotland T, Bom N 1992 Ultrasonics 30 95

    [24]

    Gorce J M, Schneider M 2000 Invest Radiol 35 661

    [25]

    Chen C C, Wu S Y, Finan J D, Morrison B, Konofagon E E 2013 IEEE Trans Ultrason Ferroelectr Freq Control 60 524

    [26]

    Doinilov A A, Haac J F, Dayton P A 2009 Ultrasonics 49 269

  • [1]

    Zhang X J, Cheng Y Q, Li L J, Wang X R 2005 Chin. J. Med. Imaging Technol. 21 819

    [2]

    Stride E P, Coussios C C 2010 Proc. Inst. Mech. Eng. H 224 171

    [3]

    Ferrara K W, Borden M A, Zhang H 2009 Acc. Chem. Res. 42 881

    [4]

    Kennedy J E 2005 Nature Rev. Cancer 5 321

    [5]

    Ferrara K, Pollard R, Borden M 2007 Annu. Rev. Biomed Eng. 9 415

    [6]

    Zhang C B, Liu Z, Guo X S, Zhang D 2011 Chin. Phys. B 20 024301

    [7]

    Kennedy J E 2005 Nature Rev. Cancer 5 321

    [8]

    Lu M Z, Wan M X, Shi Y, Song Y C 2002 Acta Phys. Sin. 51 928 (in Chinese) [陆明珠, 万明习, 施雨, 宋延淳 2002 物理学报 51 928]

    [9]

    Liang J F, Chen W Z, Shao W H, Zhou C, Du L F, Jin L F 2013 Acta Phys. Sin. 62 084708 (in Chinese) [梁金福, 陈伟中, 邵纬航, 周超, 杜联芳, 金利芳 2013 物理学报 62 084708]

    [10]

    Chen Q, Zou X Y, Cheng J C 2006 Acta Phys. Sin. 55 6476 (in Chinese) [陈谦, 邹欣晔, 程建春 2006 物理学报 55 6476]

    [11]

    Hoff L, Sontum P C, Hovem J M 2000 J. Acoust. Soc. Am. 107 2272

    [12]

    Fouan D, Achaoui Y, Mensah S 2014 Appl. Phys. Lett. 104 114102

    [13]

    Sboros V, Moran C M, Pye S D, McDicken W N 2003 Ultrasound Med. Biol. 29 687

    [14]

    Chomas J E, Dayton P A, May D, Allen J, Klibanov A, Ferrara K 2000 Appl. Phys. Lett. 77 1056

    [15]

    Tu J, Guan J F, Qiu Y Y, Matula T J 2009 J. Acoust. Soc. Am. 126 2954

    [16]

    Sboros V, Glynos E, Pye S D, Moran C M, Butler M, Ross J A, Mcdicken V, Koutsos V 2007 Ultrasonics 46 349

    [17]

    Marmottant P, van der Meer S, Emmer M, Versluis M, de Jong N, Hilgenfeldt S, Lohse D 2005 J. Acoust. Soc. Am. 118 3499

    [18]

    Doinikov A A, Haac J F, Dayton P A 2009 Ultrasonics 49 269

    [19]

    Doinikov A A, Bouakaz A 2011 Ultrasoun. Ferro. Freq. Control 58 981

    [20]

    Liu K K 2006 J. Phys. D:Appl. Phys. 39 R189

    [21]

    Glynos, E, Koutsos, V, McDicken W N, Moran C M, Pye S D, Ross J A, Sboros V 2009 Langmuir 25 7514

    [22]

    Porter T R, Xie F, Kricsfeld A, Kilzer K 1995 J. Am. Col. Cardio. 26 33

    [23]

    de Jong N, Hoff L, Skotland T, Bom N 1992 Ultrasonics 30 95

    [24]

    Gorce J M, Schneider M 2000 Invest Radiol 35 661

    [25]

    Chen C C, Wu S Y, Finan J D, Morrison B, Konofagon E E 2013 IEEE Trans Ultrason Ferroelectr Freq Control 60 524

    [26]

    Doinilov A A, Haac J F, Dayton P A 2009 Ultrasonics 49 269

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出版历程
  • 收稿日期:  2014-09-07
  • 修回日期:  2014-11-23
  • 刊出日期:  2015-06-05

超声造影剂微气泡的包膜黏弹特性的定量表征研究

  • 1. 南京大学声学研究所, 近代声学教育部重点实验室, 南京 210093;
  • 2. 南京中医药大学附属江苏省中医院, 南京 210056
    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:81127901,81227004,81171659,11374155,11174141,11104140,11161120324)和国家高技术研究发展计划计划(2012AA022702))资助的课题.

摘要: 包膜黏弹特性显著影响微气泡超声造影剂的诊断及治疗应用效果. 本文结合原子力显微镜技术及声衰减特性测量提出了一种对微气泡造影剂包膜黏弹特性定量表征的新方法. 首先采用原子力显微镜技术进行机械特性分析得到包膜微气泡的有效硬度及体弹性模量; 然后测量声衰减特性, 基于微气泡动力学理论, 计算包膜微气泡的体黏度系数. 为验证方法的有效性, 实验制备了直径为1-5 μm的白蛋白包膜微气泡造影剂, 原子力显微镜测量的有效硬度和体弹性模量分别为0.149±0.012 N/m和8.31±0.667 MPa, 并与粒径无关. 声衰减特性测量和动力学理论拟合的包膜微气泡的体黏度系数为0.374±0.003 Pa·s. 该方法可推广至其他种类包膜微气泡的黏弹特性表征, 对超声造影剂的制备及其诊断和治疗应用有积极意义.

English Abstract

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