Endogenous Stem Cell‐Based In Situ Tissue Regeneration Using Electrostatically Interactive Hydrogel with a Newly Discovered Substance P Analog and VEGF‐Mimicking Peptide

Abstract The use of chemoattractants to promote endogenous stem cell‐based in situ tissue regeneration has recently garnered much attention. This study is the first to assess the endogenous stem cell migration using a newly discovered substance P (SP) analog (SP1) by molecular dynamics simulations as an efficient chemoattractant. Further, a novel strategy based on electrostatic interaction using cationic chitosan (Ch) and anionic hyaluronic acid (HA) to prepare an SP1‐loaded injectable C/H formulation without SP1 loss is developed. The formulation quickly forms an SP1‐loaded C/H hydrogel in situ through in vivo injection. The newly discovered SP1 is found to possess human mesenchymal stromal cells (hMSCs) migration‐inducing ability that is approximately two to three times higher than that of the existing SP. The designed VEGF‐mimicking peptide (VP) chemically reacts with the hydrogel (C/H‐VP) to sustain the release of VP, thus inducing vasculogenic differentiation of the hMSCs that migrate toward the C/H‐VP hydrogel. Similarly, in animal experiments, SP1 attracts a large number of hMSCs toward the C/H‐VP hydrogel, after which VP induces vasculogenic differentiation. Collectively, these findings indicate that SP1‐loaded C/H‐VP hydrogels are a promising strategy to facilitate endogenous stem cell‐based in situ tissue regeneration.