Establishment of perfusable Blood-Brain Barrier (BBB) models for tackling Glioblastoma (GBM)

• Applicant: Professor Dr. Jürgen Groll, since 11/2022
• Subject Area: Biomaterials
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 496555966

The physiological protective function of the blood-brain barrier (BBB) hinders drug delivery into the brain, which represents a major challenge for therapeutics to effectively treat brain tumors such as glioblastoma (GBM) and brain metastases of several tumor entities. Targeting strategies to overcome the highly selective and restricted BBB permeability are a major focus of current research to cure brain cancer. Currently, the gold standard for testing novel therapeutics and BBB permeability is still using animal models accompanied by high costs and translation challenges to humans. The current in vitro alternatives are either perfusion-free simplified 2D test models based on semi-permeable membranes or perfusable Organ-on-a-Chip models, which partially emulate tissue function. However, they are plastic-based and lack accurate mimicry of the in vivo situation. More precise 3D in vitro models are demanded to accurately predict physiological BBB permeability and to improve the translation of pre-clinical success rates.Thus, this proposal offers to develop innovative 3D in vitro human BBB models combining channel perfusion and suitable 3D tissue size in a first application of an advanced GBM model. Herein, two novel in-house developed biofabrication-based methods for the generation of perfusable channels in 3D tissue models will be applied and further developed to match the characteristics for BBB modeling, like tissue hierarchy, perfusion, and the adaption to a more complex triple cell culture. In detail, both methods utilize melt electrowriting (MEW) to either fabricate a bilayered vascular graft or microchannel networks via sacrificial templating. Integration of these BBB structures within a hydrogel matrix will allow for the combination with tumor cells and, thus, to make a first application within an advanced GBM model. In general, this proposal paves the way for an innovative 3D in vitro BBB platform, with several possible applications not only related to GBM, but also other diseases like Multiple Sclerosis, Alzheimer's disease, and brain metastasis, e.g., of breast cancer cells. For the sake of simplicity, this first project will be initially performed with cell lines such as human microvascular brain endothelial cells, brain astrocytes, and pericytes. However, the results obtained in this proposal could be the basis for in follow-up studies to adapt the model to clinically more relevant cell sources (e.g., primary GBM cells and induced pluripotent stem cells (iPSCs) to establish the BBB) and integration of, e.g., immune cells will increase the model´s complexity.

• DFG Programme: Research Grants
• Ehemalige Antragstellerin: Dr. Carina Blum, until 11/2022