Bioadhesive Perivascular Microparticle-Gel Drug Delivery System for Intimal Hyperplasia Prevention: In Vitro Evaluation and Preliminary Biocompatibility Assessment

Abstract

Intimal hyperplasia (IH) is an undesirable pathology occurring after peripheral or coronary bypass surgery. It involves the proliferation and migration of vascular smooth muscle cells, leading to a reduction in the diameter of the vascular lumen, which can lead to stenosis and graft failure. Topically applied atorvastatin (ATV) has been shown to slow down this process. To be effective, the drug delivery system should remain at the perivascular site for 5–8 weeks, corresponding to the progression of IH, and be capable of releasing an initial dose of the drug followed by a sustained release. Ideally, bioadhesion would anchor the gel to the application site. To meet these needs, we encapsulated ATV in a 2-component system: a hyaluronic acid–dopamine bioadhesive gel for rapid release and biodegradable microparticles for sustained release. The system was characterized by scanning electron microscopy, rheology, bioadhesion on porcine arteries, and a release profile. The rheological properties were adequate for perivascular application, and we demonstrated superior bioadhesion and cohesion compared to the control HA formulations. The release profile showed a burst, generated by free ATV, followed by sustained release over 8 weeks. A preliminary evaluation of subcutaneous biocompatibility in rats showed good tolerance of the gel. These results offer new perspectives on the perivascular application towards an effective solution for the prevention of IH.