Background Rapid healing of endothelium on the coronary stent is a crucial method to prevent late stent thrombosis, a rare but life-threatening complication of drug eluting stents (DES). Here we developed a novel biomacromolecular coating for pro-healing DES and investigated their anti-proliferation as well as re- endothelialisation function.
Methods A dual function DES was designed in an asymmetric coating way: a layer-by-layer (LBL) self-assembly polymer of chitosan/heparin (CS/HEP) coated onto aluminal side of stents to accelerate re-endothelialisation and sirolimus onto vessel wall side to inhibit neointimal hyperplasia. Morphological, gene transcript (RT-PCR), endothelial and antithrombotic marker expression analyses were used to evaluate the effects of CS/HEP coating on adhesion, proliferation and differentiation of CD133+ endothelial progenitor cells (EPCs). Finally, the prohealing function as well as impact on coronary stenosis of this stent system were assessed in porcine model.
Results CS/HEP coating can significantly promote the adhesion, proliferation and differentiation of EPCs in vitro. CS/HEP upregulated expression of endothelial marker (ie, PECAM-1 and eNOS) and antithrombotic factor (ie, thrombomodulin). Interestingly, CS/HEP also promoted down-regulation of sirtuin-1, a gene related with endothelial cellular senescence. In porcine model, CS/HEP modified sirolimus eluting stent (CH-SES) showed rapid endothelialization superiority to bare metal stent (BMS) and SES, even in 1 week after stent implantation. Through electron microscopy analysis, the arteries treated with CH-SES were mostly fully endothelialized. As for effects on intimal hyperplasia, by angiography, intravascular ultrasound and histomorphometric analysis, there was no significant difference between CH-SES and SES in intimal thickness from 1 month to 3 and 6 months. Generally, SES took at least 3–4 weeks for the endothelial coverage of the stent struts, while the CH -SES only took 1–2 weeks for endothelial repair and kept antiproliferation function as SES.
Conclusion This natural chitosan/heparin biomacromolecular self-assembly coating was safe and efficient in stent implanted porcine model. The preliminary results hinted possible molecular basis of CS/HEP for rapid endothelial recovery. Meanwhile, coated with heparin, the CS -SES showed potent anti-coagulation function compared to traditional SES. To sum up, CS -SES may represent a promising self-rapid healing DES system to prevent in stent thrombosis as well as restenosis.