Modeling Endothelialized Hepatic Tumor Microtissues for Drug Screening

Abstract

Compared to various traditional 2D approaches, the scaffold‐based 3D tumor models have emerged as an effective strategy to investigate the complex mechanisms behind cancer progression and responses to drug treatments, by providing biomimetic extracellular matrix and stromal‐like microenvironments including the vascular elements. Herein, the development of a 3D endothelialized hepatic tumor microtissue model based on the fusion of multicellular aggregates of human hepatocellular carcinoma cells and human umbilical vein endothelial cells cocultured in poly(lactic‐ co ‐glycolic acid)‐based porous microspheres (PLGA PMs) is reported. In contrast to the conventional 2D culture, the cells within the PLGA PMs exhibit significantly higher half‐maximal inhibitory concentration values against anticancer drugs, including doxorubicin and cisplatin. Furthermore, the feasibility of coculturing other cell types, such as fibroblasts (L929) and HepG2 cells, is investigated. Together, the findings emphasize the significance of engineered 3D hepatic tumor microtissue models using PLGA PM‐based multicellular aggregates for drug screening applications.

Advances in hydrogel-based vascularized tissues for tissue repair and drug screening

“…Notably, HUVECs specifically express vascular endothelial cadherin (VE-Cad) and CD31, which is helpful in effectively identify them as ECs [ 78 , 107 , 130 ]. In our previous study, CD31 and VE-Cad staining were operated both in vitro and in vivo , indicating the growth, maturation, and organization of HUVECs [ 23 , 78 ]. Similarly, EPCs, showing the possibility of differentiating into mature functional ECs, are characterized by the expression of hematopoietic progenitor cell antigen (CD34) and vascular endothelial growth factor receptor-2 (VEGFR-2) markers [ 140 , 141 ].…”

“…The traditional assessment of drug candidates in vitro and in vivo primarily relies on the 2D cell monolayer culture on a petri dish and 3D animal models, respectively [ 23 , 193 ]. However, the toxicity prediction is far from accurate due to the rarely physiological microenvironment in 2D plates [ 159 ].…”

“…However, the toxicity prediction is far from accurate due to the rarely physiological microenvironment in 2D plates [ 159 ]. In addition, the ethical issues and high costs also hamper the application of animal experiments towards drug evaluation [ 23 ]. In this regard, several efforts have been dedicated to creating functional organs to accelerate the process of drug development [ 23 , 83 , 99 , 121 , 142 , 156 , 159 , [194] , [195] , [196] , [197] ].…”

“…In addition, the ethical issues and high costs also hamper the application of animal experiments towards drug evaluation [ 23 ]. In this regard, several efforts have been dedicated to creating functional organs to accelerate the process of drug development [ 23 , 83 , 99 , 121 , 142 , 156 , 159 , [194] , [195] , [196] , [197] ]. In recent few years, hydrogel-based tissue models have garnered tremendous interest in artificial organs due to their tunable physiochemical properties, favorable permeability, and high biocompatibility [ 83 , 121 , 142 , 194 , 195 ].…”

“…In tissue engineering, the designed 3D matrices based on biomaterials are regarded as an effective tool to provide a suitable microenvironment to predict cell activities, as well as orchestrate vascularized tissue formation [ 5 , 23 , 24 ]. Theoretically, the ideal scaffold materials would be the natural decellularized ECM (dECM), which could be harvested from the native tissues after acellular disposal treatment [ 25 , 26 ].…”