Assessing the angiogenic efficacy of pleiotrophin released from injectable heparin-alginate gels.

Abstract

With this work we design alginate-based hydrogels for therapeutically directing revascularization and repair processes in vivo. We immobilize pleiotrophin in injectable hydrogel formulations as the target factor to stimulate pro-angiogenic responses in endothelial cells. The optimized heparin-alginate/chitosan hydrogels, produced by internal cross-linking with calcium carbonate, show good biocompatibility and injectability, and allow to control the release of immobilized proteins in the subcutaneous tissue over a period of 7 days. In vitro assays, performed with translational hiPSC-derived endothelial cells, and the in vivo Matrigel plug assay are conducted to demonstrate the angiogenic effects of pleiotrophin on endothelial cells. Our results indicate that pleiotrophin stimulates endothelial cell morphogenesis in vitro and the migration of endothelial cells and macrophages as soon as 4 days after injections of the developed hydrogels, promoting the formation of structures similar to the healthy granulation tissue, which is an indicator of healing in ischemic wounds. These studies provide the rationale for further investigating this novel therapeutic for pursuing increased vascular density for efficient regeneration of ischemic tissues, by leveraging the host endothelial cell population to initiate angiogenic and reparative processes in vivo.