Engineering a Brain Cancer Chip for High-throughput Drug Screening

Abstract

Glioblastoma multiforme (GBM) is the most common and malignant of all human primary brain cancers, in which drug treatment is still one of the most effective treatments. However, existing drug discovery and development methods rely on the use of conventional two-dimensional (2D) cell cultures, which have been proven to be poor representatives of native physiology. Here, we developed a novel three-dimensional (3D) brain cancer chip composed of photo-polymerizable poly(ethylene) glycol diacrylate (PEGDA) hydrogel for drug screening. This chip can be produced after a few seconds of photolithography and requires no silicon wafer, replica molding, and plasma bonding like microfluidic devices made of poly(dimethylsiloxane) (PDMS). We then cultured glioblastoma cells (U87), which formed 3D brain cancer tissues on the chip, and used the GBM chip to perform combinatorial treatment of Pitavastatin and Irinotecan. The results indicate that this chip is capable of high-throughput GBM cancer spheroids formation, multiple-simultaneous drug administration, and a massive parallel testing of drug response. Our approach is easily reproducible, and this chip has the potential to be a powerful platform in cases such as high-throughput drug screening and prolonged drug release. The chip is also commercially promising for other clinical applications, including 3D cell culture and micro-scale tissue engineering.

Complementary, Semiautomated Methods for Creating Multidimensional PEG-Based Biomaterials

“…10 Moreover, the dynamics of microenvironments have been captured in some 3D models by using photoinitiated polymerization to change the hydrogel modulus and ligand density 11 and by creating patterns within a hydrogel to control the spatial arrangement of biochemical cues within the matrix to direct cell phenotype. 12 Lastly, more complex material designs that include microfluidics have been used to capture the bone marrow, 13 liver, 14 and heterogeneous tumor microenvironments, [15][16] or to study the response of lung inflammation 17 and glioblastoma 18 to drugs. While these systems capture fluid flow and spatial gradients, they are generally labor-intensive 18 and low-throughput, 17 which makes expansion to large-scale studies a significant challenge.…”

Cancer-on-a-chip systems at the frontier of nanomedicine

“…Alternatively, Wang and colleagues fabricated a 3D co-culture microfluidic device to monitor tumor cell invasion in a real-time manner, and proposed that cancer-associated fibroblasts could have a key role in the promotion of the invasive capacity of NSCLC cells by upregulating the expression of glucose-regulated protein 78 [51]. Akay and co-workers demonstrated the potential of a brain-cancer-on-a-chip device in the formation of spheroids from U87 glioblastoma cells, which was further used for high-throughput screening of simultaneously administrated drugs, pitavastatin and irinotecan [52]. Niu and colleagues established a microfluidic co-cultured platform to simulate the bladder cancer microenvironment [53].…”

Three‐Dimensional Models of the Human Brain Development and Diseases

“…[46] Aside from compartmentalized microfluidic devices, researchers have been engineering other novel designs of brain-on-a-chip models to recapitulate numerous aspects of the human brain physiology in vitro. [51–53] …”