A self-assembled dynamic extracellular matrix-like hydrogel system with multi-scale structures for cell bioengineering applications

Extracellular matrix (ECM) provides various types of direct interactions with cells and a dynamic environment, which can be remodeled through different assembly/degradation mechanisms to adapt to different biological processes. Herein, through introducing polyphosphate-modified hyaluronic acid and bioactive glass (BG) nano-fibril into a self-assembled hydrogel system with peptide-polymer conjugate, we can realize many new ECM-like functions in a synthetic polymer network. The hydrogel network formation is mediated by coacervation, followed by a gradual transition of peptide structure from α-helix to β-sheet. The ECM-like hydrogels can be degraded through a number of orthogonal mechanisms, including treatments with protease, hyaluronidase, alkaline phosphatase, and calcium ion. As 2D coating, the ECM-like hydrogels can be used to modify the planar surface to promote the adhesion of mesenchymal stromal cells, or to coat the cell surface in a layer-by-layer fashion to shield the interaction with the substrate. As ECM-like hydrogels for 3D cell culture, the system is compatible with injection and cell encapsulation. Upon incorporating fragmented electrospun bioactive glass nano-fibril into the hydrogels, the synergetic effects of soft hydrogel and stiff reinforcement nanofibers on recapitulating ECM functions result in reduced cell circularity in 3D. Finally, by injecting the ECM-like hydrogels into mice, gradual degradations over a time period of one month and high biocompatibility have been shown in vivo. The contribution of complex network dynamics and hierarchical structures to cell-biomatrix interaction can be investigated multi-dimensionally, as many mechanisms are orthogonal to each other and can be regulated individually.