Macromolecular design of a bivalirudin peptide-loaded Carbopol 940 hydrogel for local thrombin inhibition and prevention of neointimal hyperplasia.

Neointimal hyperplasia (NIH) at vascular anastomosis sites remains a significant cause of graft failure after cardiovascular surgery. Here, we developed a bivalirudin-incorporated Carbopol 940 hydrogel (C-Biv) that provides sustained local thrombin inhibition, thereby preventing early thrombosis and subsequent smooth muscle proliferation. Bivalirudin is a 20-amino-acid thrombin-inhibiting peptide, and C-Biv was designed as a macromolecular network to modulate its local release and bioactivity at vascular anastomosis sites. Carbopol 940, a crosslinked polyacrylic acid, was selected for its high viscosity, pH-sensitive swelling, and established biocompatibility as a macromolecular carrier. Rheological characterization identified 0.5% (w/v) Carbopol 940 as the optimal formulation, achieving a viscosity comparable to that of medical lubricating gels (approximately 150 Pa·s). Drug-release analysis showed an initial burst of 60% bivalirudin within 24 h, followed by gradual release up to 72 h. The hydrogel exhibited excellent cytocompatibility (>90% cell viability in L929, A7r5, and HUVECs) and no measurable cytotoxicity as assessed by live/dead staining. In a rat abdominal aortic repair model, C-Biv application significantly reduced arterial wall thickening (showing a trend at 4 weeks: 373.4% in the PR group vs 152.6% in the C-Biv group, p = 0.0854; and a significant reduction at 12 weeks: 262.8% vs 126.9%, p = 0.0456) and decreased PCNA- and α-SMA-positive cell accumulation by over 40% at 4 and 12 weeks, without altering systemic biochemical parameters. These findings indicate that local delivery of bivalirudin via a biocompatible Carbopol 940 matrix effectively suppresses thrombin-mediated vascular remodeling, providing a practical and safe strategy for preventing postoperative vascular stenosis.