Inhibition Of Experimental Neointimal Hyperplasia By A Novel Helical Bare Metal Stent In Porcine Model

Although percutaneous stent placement is designed to maintain patency of the treated arteries, the neointimal hyperplasia (NIH) and the subsequent vascular remodeling may cause long-term in-stent stenosis and dominate the problem of stent failure. This is also true in the infrainguinal peripheral arterial disease, where the bare metal stent (BMS) is predominately used.There are two main principles regarding to solve the NIH problem in the stent system. One principle is from the tissue-engineering point of view, and focused on the new materials or new ways to build the stents. An enormous investigations of stent design are available, differing with regard to drug elution, coating, strut thickness, biocompatible material and even biodegradation. However, until now there is no proof of any impact of the stent design on restenosis rate in peripheral vascular region. The other main principle is the fluid dynamics which had been well recognized in the development of arterial diseases (e.g. atherosclerosis) and vascular graft failure (also due to intimal hyperplasia), but forgotten until recently in the endovascular stent industry.It is widely accepted that the normal vascular wall, especially the endothelium layer, has inherent properties that can resist the intimal hyperplasia, and it is the local flow patterns in the arteries that strongly influences this ability. The arterial geometry is commonly three-dimensional, or non-planar, and the properties of the blood flow in such geometry include swirling, relatively uniform distribution of wall shear, and inhibition of flow disturbance. Spiral blood-flow patterns have been observed in human infrainguinal blood vessels, and the spiral folds has been found on the endoluminal surfaces.Endovascular stents do modulate the hemodynamics within the stented segment. The most widely studied impact of stent placement on fluid dynamics and negative remodeling is the creation of a area of low (<5dyn/cm2) wall shear stress, which can subsequently lead to greater intimal hyperplasia and recurrent stenosis. Keeping these findings in mind, a self-expanding small amplitude helical stent has been developed to alter the arterial geometry into spiral mode after its implantation and shown to generate physiological-type swirling flow and modify the distribution of wall shear stress. The purpose of our study was to investigate the influence of helical stent design on neointima-induced stenosis and its possible mechanism in a porcine model. PART ⅠAnimal Model Investigation For The Influence Of helical stent On The Intra-stent Wall Shear Stress And Neointimal FormationObjective:To observe the hemodynamics changes after helical stent implantation as well as its influence on the neointimal formation in comparison with conventional straight stent. Methods:Novel helical and conventional straight stents were implanted into common carotid arteries in Yucatan mini pigs. Hemodynamics changes were addressed by angiography and ultrasonic Doppler analysis. Histomorphometry and quantitative angiographic analysis were performed30days after stent implantation. Results:Helical stent was associated with high technology success rate and satisfied short-term safety. Stent-induced swirling flow patterns were confirmed using angiography and ultrasonic duplex. Average follow-up diameter of the stented vessel was proved significantly decreased by quantitative angiographic analysis. Histomorphometry demonstrated significantly reduced neointimal formation within helical stent comparing with conventional straight stent. A moderate correlation was found between neointimal thickness and estimated wall shear stress values. Conclusion:Helical stent has the abilities to induce a three-dimension swirling blood flow and relatively increase the wall shear stress inside the stented segment, which can inhibit the neointimal formation and reduce in-stent restenosis.PART IIEffectiveness And Safety Observation After Helical Stent Implantation Into Porcine Carotid ArteriesObjective:To observe the effectiveness and safety of helical stent after its90-and180-day implantations. Methods:Novel helical stents were implanted into common carotid arteries in Yucatan mini pigs. Postoperative safety was followed up. Histomorphometry and quantitative angiographic analysis were performed and compared among different time points (30-,90-and180-day). Results:Helical stent was associated with satisfied mid-and long-term safty. Average follow-up diameter in angiography was shown significantly decreased after180days in comparison with90days. Histomorphometry indicated the media layer area was gradually reduced over time. The least neointimal hyperplasia was observed at90-day follow-up. Conclusion: Helical stent has satisfied mid-and long-term safety. The neointimal development reaches its peak value at about30days after implantation, and retains a relative low level around90days. Late-stent positive remodeling and late neointimal hyperplasia might be associated with exorbitant radial force of the helical stent.PART ⅢPreliminary study on the biological mechanism behind the inhibition of neointimal hyperplasia of the novel helical stentObjective:To study the biological mechanism behind the inhibition of neointimal hyperplasia of the novel helical stent. Methods:Using computational hemodynamic analysis, the wall shear stress and near-wall oxygen distribution was calculated. Endothelization was addressed by scanning electron microscope30days after stent implantation. The expressions of VEGF-A, HIF-la and HIF-2a were qualified by real-time PCR. Results:In the computational hemodynamic model, the wall shear stress was asymmetrically distributed around the inter surface of the helical stented segment, and was gradually increased from the proximal to the distal. The middle and distal section showed a more localized area of poor oxygenation than the proximal portion. After30-day stent implantation, the expression of VEGF-A、HIF-1α、HIF-2α was significant lower in the helical case than in the straight case. Conclusion:Helical stent can induce higher intra-stent wall shear stress, which might be the hemodynamic mechanism of the neointimal inhibition. Better oxygen distribution and subsequent induced lower expression of the VEGF-A、HIF-1α、HIF-2α might be the genetic mechanism behind the positive results.