Study Of A Novel Endovascular Stent For Intracranial Aneurysm Treatment With An Experimental In Vivo Model

Intracranial aneurysm was an dengerous disease with high mobidity and mortality. Clipping and endovascular coiling were all effective but also with some deficients. Researches showed that the key point for the cure of aneurysm is the reconstruction of parent artery. Thus significant flow changes after treatment is needed. The porous stent implantation for aneurysm therapy aims to the reconstruction of parent artery. It is not only efficient to those special aneurysms, such as wide-necked aneurysms, tiny aneurysm and dissection aneurysm, but also safe in procedure. This technique has been supported by several clinical and experimental evidences, but the researches in this field are still debated. To reduce intraaneurysmal circulation to induce the thrombus formation, also to keep the opening of the normal branch vessels, we designed three types of novel endovascular stent (NES) for aneurysm therapy. In this study we would implant the novel stents across the neck of the in vivo aneurysm model and to investigate the change of circulation in the aneurysms. The effectiveness of the stent to induce thrombosis and affect branch vessels would be assessed, as well as the growth of neointima and the reaction of vessels to the stents. Our study would provide evidences for the clinical use of NES in the future.PartⅠEstablishment of multiple carotid side-wall aneurysm models in caninePURPOSE: To establish multiple carotid side-wall aneurysms model in canine and investigate hemodynamic and histopathologic characteristics of the model. METHODS: Bilateral multiple side-wall aneurysm models were surgically established on the carotid arteries of 17 dogs. The dogs were randomized to 3 groups: to be heparinized during procedure, after procedure, and not to be heparinized. Angiography was performed 1w or 2w, and 1m to evaluate the hemodynamic characteristics. Histopatholgic study was performed 2w and 1m in 12 aneurysms. RESULTS: 38 experimental aneurysms were confirmed. Angiograms showed whirl-like, vortex flow of blood within the dome of the aneurysms. 1 and 6 aneurysms were obliterated with thrombus in group of post-procedure heparinized and non-heparinized respectively. There's no significant difference in thrombosis rate between group of post-procedure heparinized and intra-procedure heparinized (Nemenyi: P=0.149). Histopatholgic study showed aneurysms became stable with the reduced inflammations after 1m. CONCLUSIONS: Multiple side-wall aneurysm models on canine carotid could be established by surgery. To heparinize post-procedure and intra-procedure during model establishment could get the same anti-coagulation results. This model was good be used to study the therapy technique of aneurysm for its well controlled.PartⅡMeasurement and analysis of Intraaneurysm pressure during the novel endovascular stent implanting proceduresPURPOSE: To investigate the pressure changes in the aneurysm dome during NES implantation and to analyze the effect of stent for intraaneurysm pressure. METHODS: Endovascular therapy was performed to 9 dogs with successful aneurysm model established. First, to navigate a microcatheter into aneurysm dome with its hub connected to a biological signal analysator to record the pressure changes. Then the novel stents were implanted across the aneurysm neck. The pressure changes and the pressure in the parent artery were recorded during the procedure. The pressure values at different time and between different stents were analyzed. RESULTS: 16 aneurysms were treated and all with delayed circulation, also 12 with reduced volume. Pressure values in 15 aneurysms were recorded successfully. The mean pressure in the aneurysm at time point of prior to stent deployment, during deployment, after deployment and in the parent artery was 103.41mmHg, 113.39 rnmHg, 103.60 mmHg and 105.02 mmHg respectively. The intraaneurysm pressure during stent deployment was highest (LSD: P<0.05). The pressure changes due to different stents were with no difference (P=0.970). CONCLUSIONS: The NES implantation was safe and simple. It could change the circulation in the aneurysms quickly. The pressure changes recorded via microcatheter were equal to that in parent artery and different types of stents didn't change the pressure in the aneurysm. The balloon expandable stent would increase intraaneurysm pressure transiently during its deployment. PartⅢFollow up of a novel endovascular stent implantation and angiographic quantitative analysis of the hemodynamicsPURPOSE: To follow up the results of NES implantation for aneurysm. To investigate the quantitative analysis method for hemodynamics study. METHODS: Angiography was performed to 9 dogs undergone stent implantation therapy at time of prior to procedure, right after procedure, 2w after procedure and 1m, 3m after procedure. A region of interest (ROI) delineating the aneurysm was selected, and the temporal variation in average density value was acquired and the time-density curve (TDC) was acquired. A mathematical model consists of convection and diffusion phenomenon was fitted to the TDC using least-squares minimization. Variations in model parameters were acquired and underwent statistics analysis. RESULTS: 7 aneurysms occluded and 8 with thrombus formation during follow up. The TDC intra-aneurysm could be fitted with mathematical model with physiological explanation. The mean indices value ofρ_diff,ρ_conv,τ_diffτ_conv changed significantly after stent implantation (Wilcoxon: P=0.001). The changes of indices before and after procedure among different stents were with no significance. The changes of indices value before and after procedure were correlated with the therapeutic results of the aneurysms. CONCLUSIONS: Use TDC to fit mathematical model is a valuable quantitative method to analyze the hemodynamic changes intraaneurysm. The NES could change the intraaneurysm hemodynamic state significantly. We might predict the likelihood of thrombus formation right after stent placement by analyzing the changes of these indices.PartⅣHistopathologic study of aneurysm after novel endovascular stent implantation in a canine modelPURPOSE: To investigate the mechanism of neointima growth on the aneurysm orifice after the treatment with NES, and to assess the effectiveness of this endovascular treatment technique. METHODS: One dog died 8 days after the treatment, 2 were sacrificed 1m after treatment, and 1 after 2m, 4 after 3 months. All aneurysms and arteries stented were harvested for gross histological examined. The 8-day-dog and one of 1m, one of 3m, were observed by scanning electron microscope (SEM). Other specimens were sent for histopathologic study. RESULTS: Gross histological examination of the 8-day-dog showed newly-formed thrombus in the aneurysm with type 12 stent across its orifice. Specimen examination of 1m showed thrombus obliteration in one aneurysm stented with type 12 stent and 1 with 15 stent, and there was partial thrombosis in aneurysm with type 9 stent. A carotid with a failing opened stent was occluded completely. Specimens of 3m showed aneurysms with stent of type 12 were occluded in one, partial thrombosis in one and opened in one. Those with type 9 stent were occluded in one and partial thrombosis in three. Except specimen of 8-day-dog, all specimens revealed neointima formation at the aneurysm orifice. The occluded ones showed intact neointimal covering and some aneurysm with too wide neck with partial covering for over-expanded strut intervals. Histopathologic examination revealed stretching of the media of the carotid by the strut and reactive smooth muscle cell proliferation around the strut. No intima hyperplasty was observed. SEM revealed neointima covering of luminal surface of stent, as well as strut across the orifice of aneurysm. The stent struts were covered by 2-3 membranous layers in specimens of 1m and 3 m. The neointima was mainly composed of collagenous fibers, and some endothelium cells covered them in a typical cobblestone pattern arrangement near the struts. CONCLUSIONS: Implantation of NES could promote the growth of neointimal even in the early stage of the implantation. The growth velocity was correlation with the porosity and the plane of the stent surface. The lower the porosity, the faster the neointima proliferate. The stent with the normal surface morphous would not induce intima hyperplasty.PartⅤStudy of the effects to small arterial branches of novel endovascular stentPURPOSE: To investigate the blood flow changes of small arterial branches after NES placement. METHODS: Eight NES stents were implanted within the proximal segments of vertebral arteries in 7 adult dogs during anticoagulative protection. Angiographic follow up were performed in 2w, 1m and 3m after procedure. Histopathologic and SEM examination were performed in 2m, 3m after procedure. RESULTS: Control angiograms demonstrated patency and unchanged flow of all stented branch arteries throughout the observation period, without any stenosis of parent artery. Histological findings verified 11 Small branches were related. The mean diameter of cervical muscle branches originating from the vertebral arteries within the stented segments were 740±123um. All the branches were patency no matter whether strut jail existed. Stented vessels showed compression of the media with atrophy. Scanning electron photomicrographs revealed the neointima proliferation slower near the branch vessels. The stent strut jailed the orifice of the branch vessel had not been covered by neointima in 3 months. CONCLUSIONS: All the three type of NES didn't affect the patency of small arterial branches in the follow up interval.