Porous hydrogel arrays for hepatoma cell spheroid formation and drug resistance investigation

Drug resistance is one of the major obstacles in the drug therapy of cancers. Efforts in this area in pre-clinical research have focused on developing novel platforms to evaluate and decrease drug resistance. In this paper, inspired by the structure of hives where swarms live and breed, we propose porous hydrogel arrays with a uniform pore structure for the generation of hepatoma cell spheroids and the investigation of drug resistance. The porous hydrogel arrays were fabricated using polyethylene glycol diacrylate (PEGDA) hydrogel to negatively replicate a well-designed template. Benefiting from the elaborate processing of the template, the prepared porous hydrogel arrays possessed a uniform pore structure. Due to their anti-adhesion properties and the excellent biocompatibility of the PEGDA hydrogel, the hepatoma cells could form well-defined and uniform hepatoma cell spheroids in the porous hydrogel arrays. We found that the resistant hepatoma cell spheroids showed more significant Lenvatinib resistance and a migratory phenotype compared with a two-dimensional (2D) cell culture, which reveals the reason for the failure of most 2D cell-selected drugs for in vivo applications. These features give such porous hydrogel arrays promising application prospects in the investigation of tumor cell spheroid culture and in vitro drug resistance.