Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
LaBS, Department of Chemistry, Materials and Chemical Engineering, Politecnico di Milano, Milan, 20133, Italy.
Small. 2019 Nov;15(46):e1902393. doi: 10.1002/smll.201902393. Epub 2019 Sep 9.
In vitro prediction of physiologically relevant transport of therapeutic molecules across the microcirculation represents an intriguing opportunity to predict efficacy in human populations. On-chip microvascular networks (MVNs) show physiologically relevant values of molecular permeability, yet like most systems, they lack an important contribution to transport: the ever-present fluid convection through the endothelium. Quantification of transport through the MVNs by current methods also requires confocal imaging and advanced analytical techniques, which can be a bottleneck in industry and academic laboratories. Here, it is shown that by recapitulating physiological transmural flow across the MVNs, the concentration of small and large molecule therapeutics can be directly sampled in the interstitial fluid and analyzed using standard analytical techniques. The magnitudes of transport measured in MVNs reveal trends with molecular size and type (protein versus nonprotein) that are expected in vivo, supporting the use of the MVNs platform as an in vitro tool to predict distribution of therapeutics in vivo.
在体外预测治疗分子在微循环中的生理相关转运，为预测人体疗效提供了一个诱人的机会。芯片上的微血管网络 (MVN) 显示出具有生理相关性的分子通透性值，但与大多数系统一样，它们缺乏对运输的重要贡献：始终存在的通过内皮的流体对流。目前的方法通过 MVN 进行的转运定量还需要共聚焦成像和先进的分析技术，这在工业和学术实验室中可能成为一个瓶颈。本文表明，通过在 MVN 上再现生理跨壁流动，可以直接在细胞间液中取样小分子和大分子治疗药物的浓度，并使用标准分析技术进行分析。在 MVN 中测量的转运量与体内预期的分子大小和类型（蛋白质与非蛋白质）的趋势一致，支持将 MVN 平台用作体外工具来预测治疗药物在体内的分布。
