Determining the Role of Microbubbles in Sonoporation through Numerical Simulations

100多年来，人们已经知道气泡和空洞坍塌的破坏能力。最初，研究的重点是海事应用，但今天感兴趣的领域要广泛得多。近年来，人们对超声穿孔产生了极大的兴趣，超声穿孔是一种通过应用超声波来增加细胞渗透性的过程，从而能够将大分子（如基因和药物）输送到细胞中，用于基因治疗或癌症治疗。已经提出了许多优于其他治疗技术的优点，因此，大量的实验研究（体外和体内）继续在理解和发展该程序方面取得进展。众所周知，在治疗区域的微泡的存在大大提高了程序的功效。然而，人们对微气泡的确切作用知之甚少。事实上，对多个气泡与相邻细胞物质相互作用的详细研究在实验中是极其困难的，特别是在体内环境中。为了帮助完全理解所涉及的流体力学过程，需要一种计算建模工具来提供精确的模拟，这种模拟可以以实验无法实现的精确和经济有效的方式进行控制。然而，这些过程的复杂性使得许多流行的计算和数学建模方法无法提供准确的动力学预测。考虑到这一点，该研究项目将开发一种计算建模工具，能够提供与声穿孔过程相关的气泡动力学（特别是可变形生物表面附近的多气泡动力学）的可靠和准确的定量预测。这项工作将扩展由作者和合作者开发的用于解决多相粘弹性流动问题的已有数学模型和数值方法。总体目标是确定（在定量意义上）在微泡增强声穿孔过程中发生的各种流体力学机制的相对重要性。这项调查解决了数学和计算研究在这一领域的缺乏，并将促进对声波过程的全面理解。该项目的重要见解和成果将在可行的临床程序的长期发展中发挥基础性作用。

For over 100 years the damaging capabilities of collapsing bubbles and cavities have been known. Originally, the focus of research was on maritime applications, but today the fields of interest are far more wide ranging. In recent years, there has been a great deal of interest in sonoporation - the process of increasing cell permeability through the application of ultrasound to enable the delivery of large molecules, such as genes and drugs, to cells for the purposes of gene therapy or cancer treatment. A number of benefits over other therapeutic techniques have been proposed, and, consequently, a large body of experimental research (both in vitro and in vivo) continues to make progress in understanding and developing the procedure. It is well-known that the presence of microbubbles in the treatment region greatly enhances the efficacy of the procedure. However, the precise role of the microbubbles is poorly understood. Indeed, a detailed study of the interaction of multiple bubbles with adjacent cellular matter is extremely difficult to perform experimentally, especially within in vivo environments. To aid a complete understanding of the fluid mechanical processes involved, a computational modelling tool is needed to provide accurate simulations which can be controlled in a precise and cost-effective manner unavailable to experiment. However, the complexity of these processes is such that many of the popular computational and mathematical modelling approaches fall short in providing accurate predictions of the dynamics. With this in mind, this research project will develop a computational modelling tool capable of providing robust and accurate quantitative predictions of bubble dynamics relevant to the sonoporation process (specifically, multi-bubble dynamics near a deformable biological surface). This work will extend a pre-existing mathematical model and numerical method developed by the author and collaborators for solving multiphase viscoelastic flow problems. The overall aim is to ascertain (in a quantitative sense) the relative importance of the various fluid mechanical mechanisms that occur during microbubble-enhanced sonoporation. This investigation addresses the dearth of mathematical and computational research in this area, and will facilitate a complete understanding of the sonoporation process. The important insights and output from this project will play a fundamental role in the long-term development of a viable clinical procedure.