Large-scale perfused tissues via synthetic 3D soft microfluidics

Sergei Grebenyuk (), Abdel Rahman Abdel Fattah, Manoj Kumar, Burak Toprakhisar, Gregorius Rustandi, Anja Vananroye, Idris Salmon, Catherine Verfaillie, Mark Grillo and Adrian Ranga ()
Additional contact information
Sergei Grebenyuk: KU Leuven
Abdel Rahman Abdel Fattah: KU Leuven
Manoj Kumar: KU Leuven
Burak Toprakhisar: KU Leuven
Gregorius Rustandi: KU Leuven
Anja Vananroye: KU Leuven
Idris Salmon: KU Leuven
Catherine Verfaillie: KU Leuven
Mark Grillo: Grillo Consulting Inc.
Adrian Ranga: KU Leuven

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract The vascularization of engineered tissues and organoids has remained a major unresolved challenge in regenerative medicine. While multiple approaches have been developed to vascularize in vitro tissues, it has thus far not been possible to generate sufficiently dense networks of small-scale vessels to perfuse large de novo tissues. Here, we achieve the perfusion of multi-mm3 tissue constructs by generating networks of synthetic capillary-scale 3D vessels. Our 3D soft microfluidic strategy is uniquely enabled by a 3D-printable 2-photon-polymerizable hydrogel formulation, which allows for precise microvessel printing at scales below the diffusion limit of living tissues. We demonstrate that these large-scale engineered tissues are viable, proliferative and exhibit complex morphogenesis during long-term in-vitro culture, while avoiding hypoxia and necrosis. We show by scRNAseq and immunohistochemistry that neural differentiation is significantly accelerated in perfused neural constructs. Additionally, we illustrate the versatility of this platform by demonstrating long-term perfusion of developing neural and liver tissue. This fully synthetic vascularization platform opens the door to the generation of human tissue models at unprecedented scale and complexity.

Date: 2023
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DOI: 10.1038/s41467-022-35619-1

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