Vascularisation and Perfusion of Brain Organoids with a Meningeal Barrier on an Organ-on-Chip Platform

• Applicant: Julian Gonzalez-Rubio
• Subject Area: Developmental Neurobiology ; Developmental Biology ; Experimental Models for the Understanding of Nervous System Diseases
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 573596563

Brain organoids are three-dimensional, lab-grown models of early human brain development that have revolutionized neuroscience research. However, their lack of vascularization causes severe hypoxia and necrosis at their core, limiting growth and maturation, and preventing the modelling of critical neurovascular interactions. Previous attempts to vascularize brain organoids often result in structural disruption from uncontrolled angiogenic invasion. Inspired by human embryogenesis - where vascular invasion occurs only after the developing brain is enclosed by meningeal layers - this project proposes a novel solution: enveloping the brain organoids in a meningeal barrier to protect them from aggressive vascularization. The organoids will then be implanted in a custom-designed, perfusable organ-on-chip platform containing a pre-established vascular network of endothelial and smooth muscle cells derived from induced pluripotent stem cells (iPSCs). The work plan consists of four key steps: (1) differentiating iPSCs into neural crest-derived meningeal cells and forming a stable meningeal-brain organoid construct; (2) engineering a 3D-printed chip capable of housing and perfusing brain organoids, with a design inspired by the arteriovenous loops performed in vascular microsurgeries in vivo; (3) establishing a capillary network in the chip’s hydrogel and integrating the meningeal-brain organoid into it; and (4) perfusing the system with blood-like media to examine the effects of oxygen and nutrient delivery on organoid maturation. The project will be conducted at the Cambridge Stem Cell Institute (University of Cambridge) under the guidance of Prof. Sanjay Sinha, an expert in iPSC vascular differentiation. It will also count on the co-supervision of Prof. Madeline Lancaster, the pioneer of brain organoid research and part of the prestigious Medical Research Council (MRC) - Laboratory of Molecular Biology. The applicant will benefit from the academic mentorship of Prof. Josef Penninger (Scientific Director of the Helmholtz Centre for Infection Research, Braunschweig, Germany), a leading expert in blood vessel organoids. The anticipated outcome is a reliable, human-specific model of the neurovascular unit, capable of long-term culture and suitable for modelling cerebrovascular diseases and neurodevelopmental disorders. This project will equip the applicant with critical expertise and an exceptional network, further advancing his path toward an independent research career.

• DFG Programme: WBP Fellowship
• International Connection: United Kingdom
• Host: Professor Sanjay Sinha, Ph.D.