Long-term remodeling of compliance matched tissue engineered vascular grafts is sex specific

This study investigated how biological sex influences the long-term remodeling of compliance-matched tissue-engineered vascular grafts. Multilayer electrospun grafts were fabricated from polyester sulfobetaine urethane urea, polyester urethane urea, and gelatin, with the relative thicknesses of high- and low-gelatin layers adjusted to produce compliance-matched TEVGs and stiffer hypocompliant TEVGs. Benchtop mechanical characterization confirmed that compliance-matched grafts had a mean compliance of 0.0011 ± 0.0002 mmHg^-1, statistically indistinguishable from native rat abdominal aorta at 0.0013 ± 0.0004 mmHg^-1, whereas hypocompliant grafts were significantly less compliant at 0.0007 ± 0.00009 mmHg^-1. Grafts were implanted as abdominal aortic interposition grafts in male and female Sprague Dawley rats and monitored for six months. Immediately after implantation, compliance-matched grafts remained within the native aortic compliance range and were significantly more compliant than hypocompliant grafts, although their compliance decreased during the first month and subsequently became similar to the hypocompliant group. All implanted grafts remained patent through six months. Long-term remodeling depended on both graft mechanics and biological sex. Compliance-matched grafts showed greater degradation and less calcification than hypocompliant grafts. In males, compliance matching increased expression of contractile vascular smooth muscle cell genes including Acta2, Myh11, and Cnn1. In females, compliance matching reduced residual CD68-positive macrophage presence compared with hypocompliant grafts. Independent of graft type, female animals exhibited greater intimal thickening, reduced luminal mature VSMC markers, greater fibrillar collagen deposition, increased scaffold degradation, and decreased calcification compared with males. Overall, the study shows that initial mechanical compliance matching can improve several long-term TEVG remodeling outcomes even when the graft does not maintain native-like compliance, while also demonstrating that the biological response to graft mechanics is strongly sex dependent.