Hydrogel microdroplet based glioblastoma drug screening platform

Abstract

Glioblastoma is the most common primary malignant brain tumor with a five-year survival rate less than 5%. The standard of care involves surgical resection followed by treatment with the alkylating agent temozolomide (TMZ). GBM cells that evade surgery eventually become resistant to TMZ and lead to recurrence of tumors in patients. With only four drugs currently FDA-approved for GBM treatment, there is a need for a clinically relevant model capable of accelerating the identification of new therapies. Microgels are microscale ([~]10-1,000 m) hydrogel particles that can be used to encapsulate cells in a tailorable 3D matrix. Microdroplets offer short diffusion lengths relative to conventional hydrogel constructs (>1 mm) to limit spatial distributions of hypoxia and potentially screen therapeutics in a controlled and physiologically relevant environment. Here, we establish a method to encapsulate GBM cells in gelatin and polyethylene glycol (PEG) microgels. We show that microgel composition can affect cell morphology and further, that collections of GBM-laden hydrogels can be used to quantify the effect of single vs. metronomic doses of TMZ. GBM metabolic activity is maintained in microgel culture and GBM cells display drug response kinetics similar to previously established literature using macro-scale hydrogel constructs. Finally, we show microgels can be integrated with a liquid handler to enable high-throughput screening using cell-laden microgels.