Nikfar Mehdi, Razizadeh Meghdad, Paul Ratul, Zhou Yuyuan, Liu Yaling
Department of Mechanical Engineering and Mechanics, Lehigh University, Bethlehem, Pennsylvania 18015, USA.
Department of Bioengineering, Lehigh University, Bethlehem, Pennsylvania 18015, USA.
Biomicrofluidics. 2021 Aug 2;15(4):044102. doi: 10.1063/5.0059165. eCollection 2021 Jul.
Intracellular drug delivery by rapid squeezing is one of the most recent and simple cell membrane disruption-mediated drug encapsulation approaches. In this method, cell membranes are perforated in a microfluidic setup due to rapid cell deformation during squeezing through constricted channels. While squeezing-based drug loading has been successful in loading drug molecules into various cell types, such as immune cells, cancer cells, and other primary cells, there is so far no comprehensive understanding of the pore opening mechanism on the cell membrane and the systematic analysis on how different channel geometries and squeezing speed influence drug loading. This article aims to develop a three-dimensional computational model to study the intracellular delivery for compound cells squeezing through microfluidic channels. The Lattice Boltzmann method, as the flow solver, integrated with a spring-connected network via frictional coupling, is employed to capture compound capsule dynamics over fast squeezing. The pore size is proportional to the local areal strain of triangular patches on the compound cell through mathematical correlations derived from molecular dynamics and coarse-grained molecular dynamics simulations. We quantify the drug concentration inside the cell cytoplasm by introducing a new mathematical model for passive diffusion after squeezing. Compared to the existing models, the proposed model does not have any empirical parameters that depend on operating conditions and device geometry. Since the compound cell model is new, it is validated by simulating a nucleated cell under a simple shear flow at different capillary numbers and comparing the results with other numerical models reported in literature. The cell deformation during squeezing is also compared with the pattern found from our compound cell squeezing experiment. Afterward, compound cell squeezing is modeled for different cell squeezing velocities, constriction lengths, and constriction widths. We reported the instantaneous cell center velocity, variations of axial and vertical cell dimensions, cell porosity, and normalized drug concentration to shed light on the underlying physics in fast squeezing-based drug delivery. Consistent with experimental findings in the literature, the numerical results confirm that constriction width reduction, constriction length enlargement, and average cell velocity promote intracellular drug delivery. The results show that the existence of the nucleus increases cell porosity and loaded drug concentration after squeezing. Given geometrical parameters and cell average velocity, the maximum porosity is achieved at three different locations: constriction entrance, constriction middle part, and outside the constriction. Our numerical results provide reasonable justifications for experimental findings on the influences of constriction geometry and cell velocity on the performance of cell-squeezing delivery. We expect this model can help design and optimize squeezing-based cargo delivery.
通过快速挤压实现细胞内药物递送是最新且简单的基于细胞膜破坏的药物封装方法之一。在这种方法中，细胞在微流体装置中因在通过狭窄通道挤压过程中的快速变形而使细胞膜穿孔。虽然基于挤压的药物加载已成功地将药物分子加载到各种细胞类型中，如免疫细胞、癌细胞和其他原代细胞，但到目前为止，对于细胞膜上的孔开放机制以及不同通道几何形状和挤压速度如何影响药物加载尚无全面的了解。本文旨在建立一个三维计算模型来研究复合细胞通过微流体通道挤压时的细胞内递送。采用格子玻尔兹曼方法作为流动求解器，通过摩擦耦合与弹簧连接网络集成，以捕捉快速挤压过程中复合胶囊的动力学。通过从分子动力学和粗粒化分子动力学模拟得出的数学相关性，孔径与复合细胞上三角形斑块的局部面应变成正比。我们通过引入一种新的挤压后被动扩散数学模型来量化细胞质内的药物浓度。与现有模型相比，所提出的模型没有任何依赖于操作条件和装置几何形状的经验参数。由于复合细胞模型是新的，通过在不同毛细管数下模拟简单剪切流中的有核细胞并将结果与文献中报道的其他数值模型进行比较来对其进行验证。挤压过程中的细胞变形也与我们复合细胞挤压实验中发现的模式进行了比较。之后，针对不同的细胞挤压速度、收缩长度和收缩宽度对复合细胞挤压进行建模。我们报告了瞬时细胞中心速度、细胞轴向和垂直尺寸的变化、细胞孔隙率以及归一化药物浓度，以揭示基于快速挤压的药物递送背后的物理原理。与文献中的实验结果一致，数值结果证实收缩宽度减小、收缩长度增大和细胞平均速度促进细胞内药物递送。结果表明，细胞核的存在增加了挤压后的细胞孔隙率和加载药物浓度。给定几何参数和细胞平均速度，在三个不同位置可实现最大孔隙率：收缩入口、收缩中部和收缩外部。我们的数值结果为关于收缩几何形状和细胞速度对细胞挤压递送性能影响的实验结果提供了合理的解释。我们期望这个模型能够帮助设计和优化基于挤压的货物递送。
