声致穿孔跨细胞基因递送技术中微泡和细胞膜相互作用的力学机理

Gene delivery technique aiming at cell reprogramming is a powerful tool in biological medical engineering. Presently many gene delivery techniques based on biological or physical methods have defect in biological safety. The sonoporation technique developed recently is promising to overcome this important difficulty. Although this technique is proved to be feasible and has been extensively applied to various kinds of cells, there are still lots of open questions in its mechno-biological mechanisms in poration, which limits its development and clinic applications. The complicated multiscale problems involved in the interaction between jets or shear flows and cellular membranes is frontier in the academic researches. The present project proposes, by combining molecular dynamical simulation and three dimensional immersed finite element, taking the advantage of microscopic information about the gating of mechanosensitive channels, deformation and poration of cellular membrane based on molecular dynamical simulation, establishes a mesoscopic model for poration, and includes the model to macroscopic hydrodynamic equations. By investigating this multiscale hydrodynamic model, we will focus on the dynamics of stable cavitation and tandem bubble cavitation, trying to clarify the controversy on the mechanism of sonoporation, and to provide theoretical guide for experimental design and optimization through analyzing the influences of different physical and geometric parameters on the dynamic process.

基于基因递送技术，进行细胞重编程是生物医学工程的强大工具。现有的基因递送技术存在生物安全性方面的隐患，近年来发展的声致空化方法有助于克服这一重大缺陷。尽管目前声致空化已经被证明可以广泛地运用于不同种类的细胞，且行之有效，但由于人们对该方法中的力学机制尚存在很多争议之处，极大地影响了该方法的进一步发展和临床应用。声致穿孔涉及射流和剪切流场与细胞膜相互作用的复杂多尺度问题，是学术界研究的热点。本项目提出结合分子动力学模拟和三维浸没有限元法，利用分子动力学模拟得到不同流体环境下细胞膜力敏通道的开启、细胞膜的变形和破裂过程，从中提取微观信息，力图建立细胞膜穿孔过程的介观力学模型，并用于宏观流体力学方程，研究稳态空化和串联气泡空化等情况。通过对多尺度流体模型的研究，致力于澄清目前学术界关于声致穿孔力学机制的争议，并通过分析不同物理和几何参数对动力学过程的影响，为实验系统的设计和优化提供理论依据。

基于基因递送技术，进行细胞重编程是生物医学工程的强大工具。本项目以声致空化技术为背景，着力开展理论研究，分析其中的多尺度力学机理。项目取得了预期的成果，主要体现在激波冲击细胞膜的分子动力学模拟、红细胞在微管道中的运动及其力敏通道开启情况、DNA分子在受限液滴中的构象及其调控、纳米颗粒在复杂凝胶网络中的运动等方面。值得一提的是，本项目提出了一种新型的跨膜递送方法，值得进一步开展研究，以实现大规模产业化。本项目已经发表了学术论文7篇，有2篇在审稿中，申请发明专利1项，培养了一系列研究生，积极开展了国内外学术交流活动。