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Gradient hydrogels for screening stiffness effects on patient‐derived glioblastoma xenograft cellfates in 3D
Author(s) -
Zhu Danqing,
Trinh Pavin,
Li Jianfeng,
Grant Gerry A.,
Yang Fan
Publication year - 2021
Publication title -
journal of biomedical materials research part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.849
H-Index - 150
eISSN - 1552-4965
pISSN - 1549-3296
DOI - 10.1002/jbm.a.37093
Subject(s) - temozolomide , stiffness , self healing hydrogels , matrix metalloproteinase , cancer research , glioblastoma , downregulation and upregulation , materials science , cancer cell , cancer , u87 , medicine , biomedical engineering , chemistry , biochemistry , polymer chemistry , composite material , gene
Abstract Brain cancer is a devastating disease given its extreme invasiveness and intricate location. Glioblastoma multiforme (GBM) is one of the most common forms of brain cancer, and cancer progression is often correlated with significantly altered tissue stiffness. To elucidate the effect of matrix stiffness on GBM cell fates, previous research is largely limited to 2D studies using immortalized cell lines, which has limited physiological relevance. The objective of the study is to develop gradient hydrogels with brain‐mimicking stiffness range as a 3Din vitro GBM model for screening of the effects of matrix stiffness on GBM. To increase the physiological relevance, patient‐derived tumor xenograft (PDTX) GBM cells were used. Our gradient platform allows formation of cell‐containing hydrogels with stiffness ranging from 40 Pa to 1,300 Pa within a few minutes. By focusing on a brain‐mimicking stiffness range, this gradient hydrogel platform is designed for investigating brain cancer. Increasing stiffness led to decreased GBM proliferation and less spreading, which is accompanied by downregulation of matrix‐metalloproteinases (MMPs). Using temozolomide (TMZ) as a model drug, we demonstrate that increasing stiffness led to higher drug resistance by PDTX GBM cells in 3D, suggesting matrix stiffness can directly modulate how GBM cells respond to drug treatment. While the current study focuses on stiffness gradient, the setup may also be adapted for screening other cancer niche cues such as how biochemical ligand gradient modulates brain cancer progression and drug responses using reduced materials and time.