MODL-35. BIOENGINEERED HYDROGEL AND BLOOD BRAIN BARRIER-ON-A-CHIP SYSTEM TO STUDY GLIAL CELL ACTIVATION AND BLOOD BRAIN BARRIER DYSFUNCTION IN GLIOBLASTOMA

Abstract

Abstract Treatments for glioblastoma (GBM) are limited leading to short patient life expectancies after diagnosis. Current preclinical models of GBM fail to accurately replicate the function of the blood brain barrier (BBB) and the extreme heterogeneity of the GBM tumor hindering the drug development process. Therefore, there is a pressing need for improved model systems to study how different GBM subpopulations interact with glial cells and the BBB. To build such a model, we first focused on designing a 3D extracellular matrix-based hydrogel biomaterial that would support human astrocytes and a functional BBB. The hydrogel chosen for these studies is composed of functionalized hyaluronic acid (HA) and gelatin and has similar mechanical properties to the human brain. Using confocal imaging and qPCR, we have shown that astrocytes encapsulated in this hydrogel have greater branching and express fewer markers of activation compared to astrocytes grown in commonly used 3D biomaterials such as collagen I and Matrigel. Treatment with inflammatory cytokines and GBM cell derived extracellular vesicles (EVs) revealed that astrocytes in this environment display the activation and inflammatory phenotypes observed in vivo in GBM. Next, this hydrogel biomaterial was deployed in a bioengineered BBB-on-a-chip. We have shown that this system supports the formation of 3D microvessel structures with human brain endothelial cells, pericytes, and astrocytes that accurately mimic the function of the human BBB. Studies using this BBB-on-a-chip have shown that invasive glioma stem cells alter BBB permeability influencing the transport of certain therapeutics to the tumor site. We are now beginning to test how various subpopulations of GBM tumor cells behave in this model and how changes to glial cells and the BBB impact drug delivery and efficacy. This study shows that engineered in vitro models can provide critical insight into disease mechanisms and inform treatment design in GBM.