Modeling of Microvascular Permeability Changes after Electroporation

Vascular endothelium selectively controls the transport of plasma contents across the blood vessel wall. The principal objective of our preliminary study was to quantify the electroporation-induced increase in permeability of blood vessel wall for macromolecules, which do not normally extravasate from blood into skin interstitium in homeostatic conditions. Our study combines mathematical modeling (by employing pharmacokinetic and finite element modeling approach) with in vivo measurements (by intravital fluorescence microscopy). Extravasation of fluorescently labeled dextran molecules of two different sizes (70 kDa and 2000 kDa) following the application of electroporation pulses was investigated in order to simulate extravasation of therapeutic macromolecules with molecular weights comparable to molecular weight of particles such as antibodies and plasmid DNA. The increase in blood vessel permeability due to electroporation and corresponding transvascular transport was quantified by calculating the apparent diffusion coefficients for skin microvessel wall (D [μm2/s]) for both molecular sizes. The calculated apparent diffusion coefficients were D = 0.0086 μm2/s and D = 0.0045 μm2/s for 70 kDa and 2000 kDa dextran molecules, respectively. The results of our preliminary study have important implications in development of realistic mathematical models for prediction of extravasation and delivery of large therapeutic molecules to target tissues by means of electroporation.

血管内皮（vascular endothelium）可选择性调控血浆成分跨血管壁的转运过程。本预实验的核心目标是定量分析电穿孔（electroporation）诱导的血管壁通透性升高情况，这类大分子在稳态条件下通常不会从血液渗入皮肤间质。
本研究将数学建模（采用药代动力学与有限元建模（finite element modeling）方法）与体内实验测量（通过活体荧光显微镜术（intravital fluorescence microscopy））相结合。
我们针对两种不同分子量（70 kDa与2000 kDa）的荧光标记葡聚糖分子，探究了电穿孔脉冲处理后的外渗情况，以此模拟分子量与抗体、质粒DNA（plasmid DNA）等颗粒相当的治疗性大分子的外渗过程。
通过计算两种分子量葡聚糖对应的皮肤微血管壁表观扩散系数（apparent diffusion coefficients，记为D，单位为μm²/s），定量分析了电穿孔诱导的血管通透性升高及相应的跨血管运输过程。
对于70 kDa与2000 kDa的葡聚糖分子，其表观扩散系数分别为D=0.0086 μm²/s与D=0.0045 μm²/s。
本预实验结果对于构建合理的数学模型具有重要参考价值，该模型可用于预测电穿孔介导的大型治疗性分子的外渗过程与靶组织递送效率。