Scalable microvascular networks-on-chip enable 8-week unidirectional perfusion for long-term vascular toxicity screening

bioRxiv (Cold Spring Harbor Laboratory)

Abstract

ABSTRACT Cardiovascular toxicity is a leading cause of late-stage drug attrition, yet current in vitro vascular models lack the longevity and scalability needed to capture clinically relevant responses in mature vasculature. We developed a vascular microphysiological system comprising 32 parallel, self-assembled microvascular networks from primary human endothelial cells and stromal fibroblasts. Networks were unidirectionally perfused by gravity-driven, pump-free flow. They remained functionally perfusable for at least 57 days, the longest duration reported for self-assembled microvascular networks, and underwent progressive maturation characterised by perivascular fibroblast organisation, basement membrane deposition, and matrix remodelling. Variance decomposition confirmed high reproducibility, with intra-plate variability of 3–7% and no operator-dependent effects on network morphometry. Exploiting this extended culture window, we reveal maturation-dependent shifts in endothelial inflammatory responsiveness and cytotoxic susceptibility. Distinct acute and chronic toxicity profiles of clinically used tyrosine kinase inhibitors are resolved, and a concentration- and time-dependent spectrum of sorafenib-induced microvascular responses is produced. These results show that vascular longevity and progressive maturation are key requirements for assessing vascular toxicity, and provide a scalable platform for evaluating acute and chronic drug responses in mature human microvascular tissues.

Authors 7

1. Sander Ruiter Aachen Mimetas BV

   Mimetas (Netherlands)

   Affiliation as printed

   MIMETAS BV, Oegstgeest, The Netherlands

2. Iris Schilt Aachen Mimetas BV

   Mimetas (Netherlands)

   Affiliation as printed

   MIMETAS BV, Oegstgeest, The Netherlands

3. Camila Clavijo Aachen Mimetas BV

   Mimetas (Netherlands)

   Affiliation as printed

   MIMETAS BV, Oegstgeest, The Netherlands

4. Thomas Olivier Aachen Mimetas BV

   Mimetas (Netherlands)

   Affiliation as printed

   MIMETAS BV, Oegstgeest, The Netherlands

5. Paul Vulto Aachen Mimetas BV

   Mimetas (Netherlands)

   Affiliation as printed

   MIMETAS BV, Oegstgeest, The Netherlands

6. Todd P. Burton Aachen Mimetas BV

   Mimetas (Netherlands)

   Affiliation as printed

   MIMETAS BV, Oegstgeest, The Netherlands

7. Lenie J. van den Broek corresponding Aachen Mimetas BV

   Mimetas (Netherlands)

   Affiliation as printed

   MIMETAS BV, Oegstgeest, The Netherlands