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4D corneal tissue engineering: achieving time-dependent tissue self-curvature through localized control of cell actuators
While tissue engineering is widely used to construct complex tridimensional biocompatible structures, researchers are now attempting to extend the technique into the fourth dimension. Such fourth dimension consists in the transformation of 3D materials over time, namely, by changing their shape, composition, and/or function when subjected to specific external stimuli. Herein, producing a 4D biomaterial with an internal mechanism of stimulus, using contractile cells as bioâactuators to change tissue shape and structure, is explored. Specifically, producing corneaâshaped, curved stromal tissue equivalents via the controlled, cellâdriven curving of collagenâbased hydrogels. This is achieved by modulating the activity of the bioâactuators in delimited regions of the gels using a contractionâinhibiting peptide amphiphile. The selfâcurved constructs are then characterized in terms of cell and collagen fibril reorganization, gel stiffness, cell phenotype, and the ability to sustain the growth of a corneal epithelium in vitro. Overall, the results show that the structural and mechanical properties of selfâcurved gels acquired through a 4D engineering method are more similar to those of the native tissue, and represent a significant improvement over planar 3D scaffolds. In this perspective, the study demonstrates the great potential of cell bioâactuators for 4D tissue engineering applications