Ultrashort Self-Assembling Peptide Hydrogels Provide Mechanical and Adhesive Support for Tissue Engineering and Coral Restoration

Ultrashort peptides that self-assemble into hydrogel matrices can provide mechanical and adhesion cues by a slight change in their sequence. Here we report two examples of specific sequence designs for tissue engineering and coral restoration applications.<br/>Cells’ interactions with their microenvironment influence their morphological features and regulate crucial cellular functions including proliferation, differentiation, metabolism, and gene expression. Most biological data available are based on <i>in vitro</i> two-dimensional (2D) cellular models, which fail to recapitulate the three-dimensional (3D) <i>in vivo</i> systems. This can be attributed to the lack of cell–matrix interaction and the limitless access to nutrients and oxygen, in contrast to <i>in vivo</i> systems. Despite the emergence of a plethora of 3D matrices to address this challenge, there are few reports offering a proper characterization of these matrices or studying how the cell–matrix interaction influences cellular metabolism in correlation with gene expression. In this study, two tetrameric ultrashort self-assembling peptide sequences, FFIK and FIIK, were used to create <i>in vitro</i> 3D models using well-described human dermal fibroblast cells. The peptide sequences are derived from naturally occurring amino acids that are capable of self-assembling into stable hydrogels without UV or chemical cross-linking. Our results showed that 2D cultured fibroblasts exhibited distinct metabolic and transcriptomic profiles compared to 3D cultured cells. The observed changes in the metabolomic and transcriptomic profiles were closely interconnected and influenced several important metabolic pathways including the TCA cycle, glycolysis, MAPK signaling cascades, and hemostasis. Data provided here may lead to clearer insights into the influence of the surrounding microenvironment on human dermal fibroblast metabolic patterns and molecular mechanisms, underscoring the importance of utilizing efficient 3D <i>in vitro</i> models to study such complex mechanisms.<br/>Coral reef survival is threatened globally. One way to restore this delicate ecosystem is to enhance coral growth by the controlled propagation of coral fragments. To be sustainable, this technique requires the use of biocompatible underwater adhesives. Hydrogels based on rationally designed ultrashort self-assembling peptides (USP) are of great interest for various biological and environmental applications, due to their biocompatibility and tunable mechanical properties. Implementing superior adhesion properties to the USP hydrogel compounds is crucial in both water and high ionic strength solutions and is relevant in medical and marine environmental applications such as coral regeneration. Some marine animals secrete large quantities of the aminoacids dopa and lysine to enhance their adhesion to wet surfaces. Therefore, the addition of catechol moieties to the USP sequence containing lysine (IIZK) should improve the adhesive properties of USP hydrogels. However, it is challenging to place the catechol moiety (Do) within the USP sequence at an optimal position without compromising the hydrogel self-assembly process and mechanical properties. Here, we demonstrate that, among three USP hydrogels, DoIIZK is the least adhesive and that the adhesiveness of the IIZDoK hydrogel is compromised by its poor mechanical properties. The best adhesion outcome was achieved using the IIZKDo hydrogel, the only one to show equally sound adhesive and mechanical properties. A mechanistic understanding of this outcome is presented here. This property was confirmed by the successful gluing of coral fragments by means of IIZKDo hydrogel that are still thriving after more than three years since the deployment. The validated biocompatibility of this underwater hydrogel glue suggests that it could be advantageously implemented for other applications, such as surgical interventions.