Three-dimensional biomimetic scaffolds for hepatic differentiation of size-controlled embryoid bodies
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Three-dimensional biomimetic scaffolds for hepatic differentiation of size-controlled embryoid bodies Yichun Wang1,a)
, Joong Hwan Bahng1, Nicholas A. Kotov2
1
Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan 48109, USA; and Biointerfaces Institute, University of Michigan, Ann Arbor, Michigan 48109, USA 2 Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan 48109, USA; Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan 48109, USA; Department of Material Science & Engineering, University of Michigan, Ann Arbor, Michigan 48109, USA; and Biointerfaces Institute, University of Michigan, Ann Arbor, Michigan 48109, USA a) Address all correspondence to this author. e-mail: [email protected] Received: 26 October 2018; accepted: 12 February 2019
Three-dimensional (3D) biomimetic scaffolds are critical for tissue engineering to support stem cell culture and organoid formation. Embryonic stem (ES) cells hold promising potential for tissue regeneration and ES cellderived specific lineages are expected to be strongly influenced by the size of embryoid bodies (EBs). However, the fundamental knowledge needed to achieve the goal of highly reproducible, efficient, and scalable differentiation of how EB size affects differentiation is missing. Here, we used 3D biomimetic scaffolds with highly uniform porous structure to regulate size of EBs and differentiated them toward hepatic fate. The results showed EBs formed within the scaffolds were precisely controlled by pore sizes of the scaffolds. We found that EBs equals to or larger than 180 ± 27 lm maintained the ability to differentiate to hepatic lineage. The 3D biomimetic scaffold provides the effective tools toward accurate regulation of EB sizes for tissue engineering.
Introduction Embryonic stem (ES) cells with pluripotency offer a powerful approach for differentiating into all adult cell types and are a promising source of progenitors for cell replacement therapy and tissue regeneration [1, 2]. ES cells can be derived to differentiate into a wide spectrum of cell types, such as neural cells, cardiomyocytes, hepatic, and endothelial cells, by forming embryoid bodies (EBs) [1]. The size of EBs is a key factor in determining cell fate and promoting differentiation toward cardiomyocytes [3], chondrocytes [4], or neural lineages [5]. A number of engineered microstructures have been developed that can control over size of EBs, such as hanging drop (HD) [6], multiwell plates [7], micropatterning hydrogel [8, 9, 10], laser direct-write [11], micropatterned chips [12, 13, 14], and three-dimensional (3D) printed scaffold [15, 16]. The HD method allowed single cells spontaneously to self-assemble but the formed EBs are not spherical because of the cell spreading on the flat substrate. Various micropatterned methods provided external forces or confined geometry to control the diameters and homogeneity of EB formation, but the yield of EBs so far has shown limitations of precise diameters. In
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