Bioprinting of hydrogel beads to engineer pancreatic tumor-stroma microtissues for drug screening

Beisi Huang; Xiaoyun Wei; Keke Chen; Ling Wang; Mingen Xu

doi:10.18063/ijb.676

Bioprinting of hydrogel beads to engineer pancreatic tumor-stroma microtissues for drug screening

Int J Bioprint. 2023 Feb 1;9(3):676. doi: 10.18063/ijb.676. eCollection 2023.

Authors

Beisi Huang¹, Xiaoyun Wei¹, Keke Chen¹, Ling Wang^{1

2}, Mingen Xu^{1

2}

Affiliations

¹ School of Automation, Hangzhou Dianzi University, Hangzhou 310018, China.
² Key Laboratory of Medical Information and 3D Bioprinting of Zhejiang Province, Hangzhou Dianzi University, Hangzhou 310018, China.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) having features of dense fibrotic stromal and extracellular matrix (ECM) components has poor clinical outcome. In vitro construction of relevant preclinical PDAC models recapitulating the tumor-stroma characteristics is therefore in great need for the development of pancreatic cancer therapy. In this work, a three-dimensional (3D) heterogeneous PDAC microtissue based on a dot extrusion printing (DEP) system is reported. Gelatin methacryloyl (GelMA) hydrogel beads encapsulating human pancreatic cancer cells and stromal fibroblasts were printed, which demonstrated the capacity of providing ECM-mimetic microenvironments and thus mimicked the native cell-cell junctions and cell-ECM interactions. Besides, the spherical structure of the generated hydrogel beads, which took the advantage of encapsulating cells in a reduced volume, enabled efficient diffusion of oxygen, nutrients and cell waste, thus allowing the embedded cells to proliferate and eventually form a dense pancreatic tumor-stroma microtissue around hundred microns. Furthermore, a tunable stromal microenvironment was easily achieved by adjusting the density of stromal cells in the hydrogel beads. Based on our results, the produced heterogeneous pancreatic microtissue recapitulated the features of cellular interactions and stromal-like microenvironments, and displayed better anti-cancer drug resistance than mono-cultured pancreatic cancer spheroids. Together, the DEP system possesses the ability to simply and flexibly produce GelMA hydrogel beads, providing a robust manufacturing tool for the pancreatic cancer drug screening platform fabrication. In addition, the engineered pancreatic tumor-stroma microtissue based on bioprinted GelMA hydrogel beads, other than being ECM-biomimetic and stroma-tunable, can be used for observation in situ and may serve as a new drug screening platform.

Keywords: 3D bioprinting; Drug screening; GelMA hydrogel beads; Tumor-stroma microtissues; Tunable stromal microenvironment.