4D Corneal Tissue Engineering: Achieving Time‐Dependent Tissue Self‐Curvature through Localized Control of Cell Actuators

Abstract

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 bio-actuators to change tissue shape and structure, is explored. Specifically, producing cornea-shaped, curved stromal tissue equivalents via the controlled, cell-driven curving of collagen-based hydrogels. This is achieved by modulating the activity of the bio-actuators in delimited regions of the gels using a contraction-inhibiting peptide amphiphile. The self-curved 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 self-curved 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 bio-actuators for 4D tissue engineering applications.

Designing Scaffolds for Corneal Regeneration

“…[90] The addition of peptide amphiphiles (PAs) to collagen has been shown to control contraction to enable a curvature to be generated. [77] Different types of collagen scaffolds have been developed for corneal tissue engineering including hydrogels, films and sponges. Collagen hydrogels usually have a very high water content (up to 99.7% v/v) but unlike many other hydrophilic hydrogels that are incompressible, the water content of collagen hydrogels can be reduced under compression, thus allowing the collagen concentration and hydrogel stiffness to be controlled.…”

Prospects and Challenges of Translational Corneal Bioprinting

“…The constructs also integrated well in a rabbit corneal model. In another study, Miotto et al [42] were able to induce self-curving of collagen-based hydrogels via contraction-inhibiting peptide amphiphiles in certain regions of the gels. However, the contraction was facilitated by alpha SMA expressing corneal stromal cells (i.e., Myo-SFs), which can cause corneal scarring and reduced transparency.…”

Advanced Bottom‐Up Engineering of Living Architectures

“…Beyond their flexibility for designing self‐assembled hydrogels with tunable biochemical and mechanical features, peptide amphiphiles can be also explored for developing biomimetic constructs. In an innovative study, researchers have exploited a C 16 G 3 RGDS peptide amphiphile for programing cell‐driven contraction of compressed collagen hydrogels in defined regions . Here, cells served as bioactuators capable of mechanically transforming hydrogels into curved structures, thus remodeling the dense collagen stroma toward a more native‐like organization found in human cornea.…”