Engineers dimeric thymosin β4-loaded nanofibrous vascular grafts using biodegradable elastomer sheaths for muscular artery regeneration, specifically tested in aging animals. Dimeric TB4 provided sustained pro-angiogenic and anti-inflammatory signaling, promoting perivascular adipose stem cell recruitment and macrophage M2 polarization. In aging animal models, the TB4-functionalized grafts achieved patent, non-thrombotic arterial regeneration superior to unmodified scaffolds. Demonstrates that dimeric TB4 formulation on nanofibrous scaffolds addresses the specific challenge of vascular regeneration in the aged body.
Abstract
Regenerating nonthrombotic and compliant artery, especially in the aging body, remains a major surgical challenge, mainly owing to the inadequate knowledge of the major cell sources contributing to arterial regeneration and insufficient bioactivity of delivered peptides in grafts. Ultrathin nanofibrous sheaths stented with biodegrading elastomer present opening channels and reduced material residue, enabling fast cell recruitment and host remodeling, while incorporating peptides offering developmental cues are challenging. In this study, a recombinant human thymosin β4 dimer (DTβ4) that contains two complete Tβ4 molecules is produced. The adult perivascular adipose is found as the dominant source of vascular progenitors which, when stimulated by the DTβ4-loaded nanofibrous sheath, enables 100% patency rates, near-complete structural as well as adequate functional regeneration of artery, and effectively ameliorates aging-induced defective regeneration. As compared with Tβ4, DTβ4 exhibits durable regenerative activity including recruiting more progenitors for endothelial cells and smooth muscle cells, when incorporated into the ultrathin polycaprolactone sheath. Moreover, the DTβ4-loaded interface promotes smooth muscle cells differentiation, mainly through promoting M2 macrophage polarization and chemokines. Incorporating artificial DTβ4 into ultrathin sheaths of fast degrading vascular grafts creates an effective interface for sufficient muscular remodeling thus offering a robust tool for vessel replacement.