Pharmacological manipulation of macrophage autophagy effectively rejuvenates the regenerative potential of biodegrading vascular graft in aging body

Abstract

Declined regenerative potential and aggravated inflammation upon aging create an inappropriate environment for arterial regeneration. Macrophages are one of vital effector cells in the immune microenvironment, especially during biomaterials mediated repairing process. Here, we revealed that the macrophage autophagy decreased with aging, which led to aggravated inflammation, thereby causing poor vascular remodeling of artificial grafts in aging body. Through loading the autophagy-targeted drugs, rapamycin and 3-MA (3-methyladenine), in PCL (polycaprolactone) sheath of the PGS (poly glycerol sebacate) - PCL vascular graft, the essential role of macrophage autophagy was confirmed in regulating macrophage polarization and biomaterial degradation. Moreover, the utilization of rapamycin promoted anti-inflammatory polarization of macrophage by activating autophagy, which further promoted myogenic differentiation of vascular progenitor cells and accelerated endothelialization. Our study elucidated the contribution of pharmacological manipulation of macrophage autophagy in promoting regeneration of small caliber artery, which may pave a new avenue for clinical translation of vascular grafts in aging body.

Incorporation of Controlled Release Systems Improves the Functionality of Biodegradable 3D Printed Cardiovascular Implants

“…The drug-loaded graft demonstrated a positive effect on the phenotype of macrophages having switched to the M2 phenotype (lower Alizarin red staining) when compared to control grafts without rapamycin, resulting in anticalcification properties of the rapamycin-loaded vascular graft. 105 Other potential candidates of interest for drug release in cardiovascular implants are bioactive agents such as growth factors which can regulate cellular differentiation and migration inside the structure. Fibroblast growth factor (FGF), insulin growth factor-I (IGF-I), platelet-derived growth factor (PDGF), transforming growth factor-β1 (TGF-β1), and vascular endothelial growth factor (VEGF) are the most promising agents.…”

Prosthetic vascular grafts engineered to combat calcification: Progress and future directions

“…Sirolimus‐eluting stents reduce restenosis occurrence after percutaneous coronary revascularization in comparison to bare metal stents (Moses et al, 2003). W. Chen et al (2022) demonstrated that rapamycin released from a PCL sheath around a PGS‐PCL vascular graft can polarize macrophages to the M2 phenotype. This graft was implanted interpositionally in the rat abdominal aorta.…”

Effect of static tensile stress on enzymatic degradation of poly(glycerol sebacate)

“…[10][11][12] Because the mechanical properties of PGS are similar to those of some natural soft tissues and it has satisfactory biocompatibility, PGS has been widely used in various tissue engineering applications such as myocardium, blood vessels, trachea, retina, skin, nerves, valves, and cartilage. [13][14][15][16][17][18][19] The degradation performance of PGS has attracted much attention. It is reported that the mass of PGS in PBS solution at 37 C under stirring conditions decreased by 17% for 60 days.…”