超声造影剂微气泡的包膜黏弹特性的定量表征研究

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.

Quantitative characterization of viscoelasticity of microbubbles in ultrasound contrast agent

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.