Abstract
In this report, a strategy for constructing three-dimensional (3D) cellular architectures comprising viable cells is presented. The strategy uses a redox-responsive hydrogel that degrades under mild reductive conditions, and a confluent monolayer of cells (i.e., cell sheet) cultured on the hydrogel surface peels off and self-folds to wrap other cells. As a proof-of-concept, the self-folding of fibroblast cell sheet was triggered by immersion in aqueous cysteine, and this folding process was controlled by the cysteine concentration. Such folding enabled the wrapping of human hepatocellular carcinoma (HepG2) spheroids, human umbilical vein endothelial cells and collagen beads, and this process improved cell viability, the secretion of metabolites and the proliferation rate of the HepG2 cells when compared with a two-dimensional culture under the same conditions. A key concept of this study is the ability to interact with other neighbouring cells, providing a new, simple and fast method to generate higher-order cellular aggregates wherein different types of cellular components are added. We designated the method of using a cell sheet to wrap another cellular aggregate the ‘cellular Furoshiki’. The simple self-wrapping Furoshiki technique provides an alternative approach to co-culture cells by microplate-based systems, especially for constructing heterogeneous 3D cellular microstructures.
Highlights
In this report, a strategy for constructing three-dimensional (3D) cellular architectures comprising viable cells is presented
The shrinking ability of the cell sheet is mediated by the interplay between the wrapping behaviour of the cell sheet by redox responsive degradation and the state of other entities including cells on the cell sheet
Because the rate of degradation of the redox-responsive hydrogel is affected by the reductant concentration, the folding behaviour of the cell sheet detachment from the hydrogel was evaluated by varying the Cys concentration (1–50 mM)
Summary
A strategy for constructing three-dimensional (3D) cellular architectures comprising viable cells is presented. Recreation of the three-dimensional (3D) architecture of viable cells is an emerging technology[1,2] for developing tissue-like structures with functions in the field of tissue engineering and as a new cell-based tool in the early phase of drug discovery[3,4]. These bottom-up approaches[5,6,7] have attracted significant attention for use in the fabrication of 3D cellular microstructures, including the cell sheet[8], and multi-cellular aggregate technologies such as microstructure blocks[6], fibers[7], spheroids[9] and organoids[10]. In the field of tissue engineering, this system has been used to graft a cell sheet onto an organ surface, which attenuates deleterious host immune responses toward encapsulated cells used in autologous cell therapy applications[27,28,29]
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