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Small. 2019 Nov;15(46):e1902393. doi: 10.1002/smll.201902393. Epub 2019 Sep 9.

Application of Transmural Flow Across In Vitro Microvasculature Enables Direct Sampling of Interstitial Therapeutic Molecule Distribution.

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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.
BIOS Lab-on-a-Chip Group, University of Twente, Enschede, 7522, The Netherlands.
MOX, Department of Mathematics, Politecnico di Milano, Milan, 20133, Italy.
Amgen Discovery Research, Amgen Inc., 360 Binney Street, Cambridge, MA, 02141, USA.


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.


biotherapeutics and biologics; hydraulic conductivity; organ-on-chip; permeability; transendothelial transport


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