Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA.
Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA.
Lab Chip. 2021 Sep 14;21(18):3509-3519. doi: 10.1039/d1lc00348h.
Microfluidic organ-on-a-chip (Organ Chip) cell culture devices are often fabricated using polydimethylsiloxane (PDMS) because it is biocompatible, transparent, elastomeric, and oxygen permeable; however, hydrophobic small molecules can absorb to PDMS, which makes it challenging to predict drug responses. Here, we describe a combined simulation and experimental approach to predict the spatial and temporal concentration profile of a drug under continuous dosing in a PDMS Organ Chip containing two parallel channels separated by a porous membrane that is lined with cultured cells, without prior knowledge of its log value. First, a three-dimensional finite element model of drug loss into the chip was developed that incorporates absorption, adsorption, convection, and diffusion, which simulates changes in drug levels over time and space as a function of potential PDMS diffusion coefficients and log values. By then experimentally measuring the diffusivity of the compound in PDMS and determining its partition coefficient through mass spectrometric analysis of the drug concentration in the channel outflow, it is possible to estimate the effective log range of the compound. The diffusion and partition coefficients were experimentally derived for the antimalarial drug and potential SARS-CoV-2 therapeutic, amodiaquine, and incorporated into the model to quantitatively estimate the drug-specific concentration profile over time measured in human lung airway chips lined with bronchial epithelium interfaced with pulmonary microvascular endothelium. The same strategy can be applied to any device geometry, surface treatment, or microfluidic model to simulate the spatial and temporal gradient of a drug in 3D without prior knowledge of the partition coefficient or the rate of diffusion in PDMS. Thus, this approach may expand the use of PDMS Organ Chip devices for various forms of drug testing.
微流控器官芯片（Organ Chip）细胞培养设备通常使用聚二甲基硅氧烷（PDMS）制造，因为它具有生物相容性、透明性、弹性和氧气透过性；然而，疏水性小分子可以被 PDMS 吸收，这使得难以预测药物反应。在这里，我们描述了一种结合模拟和实验的方法来预测在含有两个平行通道的 PDMS Organ Chip 中连续给药时药物的空间和时间浓度分布，其中一个通道通过多孔膜与另一个通道隔开，膜上排列着培养细胞，而无需事先了解其 logP 值。首先，我们开发了一个药物进入芯片的三维有限元模型，该模型包含吸收、吸附、对流和扩散，模拟了药物在时间和空间上的变化，作为潜在 PDMS 扩散系数和 logP 值的函数。然后，通过实验测量该化合物在 PDMS 中的扩散系数，并通过对通道流出物中药物浓度的质谱分析确定其分配系数，就可以估计该化合物的有效 logP 值范围。我们通过实验推导出抗疟药物和潜在 SARS-CoV-2 治疗药物阿莫地喹的扩散和分配系数，并将其纳入模型，以定量估计在人类肺气道芯片中测量的药物特异性时间浓度分布，该芯片衬有支气管上皮细胞，与肺微血管内皮细胞接口。该策略可以应用于任何器件几何形状、表面处理或微流控模型，在无需事先了解 PDMS 中的分配系数或扩散率的情况下模拟药物在 3D 中的时空梯度。因此，这种方法可能会扩大 PDMS Organ Chip 设备在各种形式的药物测试中的应用。
