A microfluidic platform integrating functional vascularized organoids-on-chip

Authors:
Clément Quintard, Emily Tubbs , Gustav Jonsson , Jie Jiao , Jun Wang , Nicolas Werschler , Camille Laporte Amandine Pitaval , Thierno-Sidy Bah , Gideon Pomeranz , Caroline Bissardon , Joris Kaal , Alexandra Leopoldi , David A Long , Pierre Blandin , Jean-Luc Achard , Christophe Battail , Astrid Hagelkruys , Fabrice Navarro , Yves Fouillet , Josef M Penninger , Xavier Gidrol 
In:
Source: Nature
Publication Date: (2024)
Issue: 15: 1
Research Area:
Gastroenterology
Regenerative medicine
Cells used in publication:
Endothelial, umbilical vein, human (HUVEC)
Species: human
Tissue Origin: vein
Experiment

Mesenchymal spheroids

Primary human fibroblasts (FMA73) were extracted from skin explants obtained through the elective breast surgery of a healthy young woman following informed consent; this tissue was provided by Walid Rachidi, CEA Grenoble. GFP- and RFP-labelled HUVEC cells (Angio-Proteomie, cat. no. CAP0001GFP and cat. no. CAP0001RFP, respectively) were cultured in complete EndoGM medium (Angio-Proteomie, cat. no. CAP02). Passage 5–7 cells were used for the experiments. Fibroblasts cultured in Fibroblast Growth Medium-2 (Lonza, cat. no. CC-3132), and passage 6–8 cells were used for the experiments. We prepared fibroblasts and HUVEC co-culture, termed mesenchymal spheroid model here, in U-shaped 96-well ultra-low attachment microplates (Corning, cat. no. CLS4515). Fibroblasts and HUVEC cells were mixed at a ratio of 1:1 (5000 cells per well) in 150?µl of medium consisting of a mix of CnT-ENDO (Cellntec, cat. no. CnT-ENDO) / CnT-Prime Fibroblast medium (Cellntec, cat. no. CnT-PR-F) at a ratio 1:1. After pre-culturing for 1 day in the microplate, a spheroid was introduced into the device. The same medium mix of CnT-ENDO / CnT-Prime Fibroblast medium was used for the microfluidic perfusion of the fibroblasts and HUVEC co-culture spheroids. RFP-HUVEC cells were suspended in the hydrogel at a concentration of 6×106 cells per ml.

Abstract

The development of vascular networks in microfluidic chips is crucial for the long-term culture of three-dimensional cell aggregates such as spheroids, organoids, tumoroids, or tissue explants. Despite rapid advancement in microvascular network systems and organoid technologies, vascularizing organoids-on-chips remains a challenge in tissue engineering. Most existing microfluidic devices poorly reflect the complexity of in vivo flows and require complex technical set-ups. Considering these constraints, we develop a platform to establish and monitor the formation of endothelial networks around mesenchymal and pancreatic islet spheroids, as well as blood vessel organoids generated from pluripotent stem cells, cultured for up to 30 days on-chip. We show that these networks establish functional connections with the endothelium-rich spheroids and vascular organoids, as they successfully provide intravascular perfusion to these structures. We find that organoid growth, maturation, and function are enhanced when cultured on-chip using our vascularization method. This microphysiological system represents a viable organ-on-chip model to vascularize diverse biological 3D tissues and sets the stage to establish organoid perfusions using advanced microfluidics.