Protease‐Sensitive, VEGF‐Mimetic Peptide, and IKVAV Laminin‐Derived Peptide Sequences within Elastin‐Like Recombinamer Scaffolds Provide Spatiotemporally Synchronized Guidance of Angiogenesis and Neurogenesis

Abstract

Spatiotemporal control of vascularization and innervation is a desired hallmark in advanced tissue regeneration. For this purpose, we design a 3D model scaffold, based on elastin-like recombinamer (ELR) hydrogels. This contains two interior and well-defined areas, small cylinders, with differentiated bioactivities with respect to the bulk. Both are constructed on a protease sensitive ELR with a fast-proteolyzed domain, but one bears a VEGF-mimetic peptide (QK) and the other a laminin-derived pentapeptide (IKVAV), to promote angiogenesis and neurogenesis, respectively. The outer bulk is based on a slow proteolytic sequence and RGD cell adhesion domains. In vitro studies show the effect of QK and IKVAV peptides on the promotion of endothelial cell and axon spreading, respectively. The subcutaneous implantation of the final 3D scaffold demonstrates the ability to spatiotemporally control angiogenesis and neurogenesis in vivo. Specifically, the inner small cylinder containing the QK peptide promotes fast endothelialization, whereas the one with IKVAV peptide promotes fast neurogenesis. Both, vascularization and innervation take place in advance of the bulk scaffold infiltration. This scaffold shows that it is possible to induce vascularization and innervation in predetermined areas of the scaffold well ahead to the bulk infiltration. That significantly increases the efficiency of the regenerative activity.

Spatial-Controlled Coating of Pro-Angiogenic Proteins on 3D Porous Hydrogels Guides Endothelial Cell Behavior

“…During the last decades, cell–ECM interaction research has shown that when cell-adhesive molecules were spatially presented to the cells in different manners, they induced different patterns of cellular behavior [ 40 , 41 ]. In the case of CoC hydrogels, cell adhesion was achieved thanks to the contribution of the Caf1-YIGSR coating in the channel during the first coating step ( Figure 4 ).…”

Hydrogels to Recapture Extracellular Matrix Cues That Regulate Vascularization

“…In addition, VEGF-mimetic peptide and elastin-like polypeptide-based hydrogels, in combination with integrin binding motifs and urokinase-protease-sensitive sequences, synergistically induced cell infiltration and angiogenesis without the formation of fibrotic tissue in vivo. 61 Moreover, the combination of different integrin-adhesion ligands presenting a high binding affinity and selectivity for α v β 3 , α 5 β 1 , or α 4 β 1 facilitated the dynamic capture and adhesion of endothelial colony forming cells under shear flow mimicking blood flow. 62…”

Engineering of M2 Macrophages‐Derived Exosomes via Click Chemistry for Spinal Cord Injury Repair

“…[22] Likewise, Fernando et al reported a 3D hydrogel scaffold containing the IKVAV peptide promoted axon spreading neurogenesis in mice. [23] However, to the best of our knowledge, no previous study has prepared engineered exosomes grafted with IKVAV and taken their advantages for SCI repair.…”