TY - JOUR
T1 - Application of Transmural Flow Across In Vitro Microvasculature Enables Direct Sampling of Interstitial Therapeutic Molecule Distribution
AU - Offeddu, Giovanni S.
AU - Possenti, Luca
AU - Loessberg-Zahl, Joshua T.
AU - Zunino, Paolo
AU - Roberts, John
AU - Han, Xiaogang
AU - Hickman, Dean
AU - Knutson, Charles G.
AU - Kamm, Roger D.
PY - 2019/11/13
Y1 - 2019/11/13
N2 - 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.
AB - 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.
KW - biotherapeutics and biologics
KW - hydraulic conductivity
KW - organ-on-chip
KW - permeability
KW - transendothelial transport
KW - n/a OA procedure
UR - http://www.scopus.com/inward/record.url?scp=85071939578&partnerID=8YFLogxK
U2 - 10.1002/smll.201902393
DO - 10.1002/smll.201902393
M3 - Article
C2 - 31497931
AN - SCOPUS:85071939578
SN - 1613-6810
VL - 15
JO - Small
JF - Small
IS - 46
M1 - 1902393
ER -