During endovascular aneurysm repair (EVAR), if the stent-graft device is too long for a given patient the redundant (extra) length adopts a convex configuration in the aneurysm. Based on clinical experience, we hypothesize that redundant stent-graft configurations increase the downward force acting on the device, thereby increasing the risk of device dislodgement and failure. This work numerically studies both steady-state and physiologic pulsatile blood flow in redundant stent-graft configurations. Computational fluid dynamics simulations predicted a peak downward displacement force for the zero-, moderate- and severe-redundancy configurations of 7.36, 7.44 and 7.81 N, respectively for steady-state flow; and 7.35, 7.41 and 7.85 N, respectively for physiologic pulsatile flow. These results suggest that redundant stent-graft configurations in EVAR do increase the downward force acting on the device, but the clinical consequence depends significantly on device-specific resistance to dislodgement.

This thesis focuses on special arterial fluid mechanics techniques developed for patient-specific computer modeling of blood flow in cerebral arteries with aneurysm and stent. These techniques are used in conjunction with the core computational technique, which is the space–time version of the variational multiscale (VMS) method and is called “DST/SST-VMST.” The special techniques include using NURBS for the spatial representation of the surface over which the stent mesh is built, mesh generation techniques for both the finite- and zero-thickness representations of the stent, techniques for generating refined layers of mesh near the arterial and stent surfaces, and models for representing double stent. We compute the unsteady flow patterns in the aneurysm and investigate how those patterns are influenced by the presence of single and double stents. We also compare the flow patterns obtained with the finite- and zero-thickness representations of the stent.

With each heartbeat, major arteries experience circumferential expansion due to internal pressure changes. This pulsatile force is called cyclic strain and has been implicated in playing a pivotal role in the genetic regulation of vascular physiology and pathology. This dissertation investigates the hypothesis that in human umbilical vein endothelial cells (HUVEC), pathological levels of cyclic strain activate the c-Myc promoter, leading to c-Myc transcription and downstream gene induction. To determine expression and time-dependency of c-Myc in HUVEC, mRNA and protein expression of c-Myc under physiological (6-10% cyclic strain) and pathological conditions (20% cyclic strain) were studied. Both c-Myc mRNA and protein expression increased more than three-fold in HUVEC (P4-P5) cyclically-strained at 20%. This expression occurred in a time-dependent manner, peaking in the 1.5-2 hour range and falling to basal levels by 3 hours. Subsequently, the mechanism of c-Myc transcription was investigated by using specific inhibitors to modulate c-Myc transcriptional activation. These compounds, obtained from the University of Arizona Cancer Center, attenuated cyclic-strain-induced c-Myc transcription by about 50%. Having established this reduction in expression, it was investigated how these effects modulate downstream genes that are regulated by c-Myc. The results indicate that direct targeting of the c-Myc promoter may decrease stretch-induced gene expression of vascular endothelial growth factor (VEGF), proliferating cell nuclear antigen (PCNA) and heat shock protein 60 (HSP60). These findings may help in the development of a novel therapeutic opportunity in vascular diseases.

Vascular stents have become a standard for treating atherosclerosis due to distinct advantages in trauma and cost with other surgical techniques. Unfortunately, the therapy is hindered by the risk of a new blockage (termed restenosis) developing in the treated artery. Clinical studies have indicated that stent design is a major risk factor for restenosis, with failure rates varying from 20 to 40% for bare metal stents. Subsequently, there has been a significant effort devoted to reducing failure rates by covering stents in polymer coatings in which anti-proliferative drugs are embedded, however complications have arisen (e.g. incomplete endothelization, lack of success in peripheral arteries, lack of long-term follow-up studies) that have limited the success of this technology. It has been thought that restenosis is directly related to the mechanical conditions that vascular stents create. Moreover, it has been hypothesized that stents that induce higher non-physiologic stresses result in a more aggressive pathobiological response that can lead to restenosis development. In this study, a combination of computational modeling and in vivo analysis were conducted to investigate the artery stent-induced wall stresses, and subsequent biological inflammatory response. In particular, variations in stent design were investigated as a means of examining specific stent design criteria that minimize the mechanical impact of stenting. Collectively, these data indicate that stent designs that subject the artery wall to higher stress values result in significantly more neointimal tissue proliferation, therefore, confirming the aforementioned hypothesis. Moreover, this work provides valuable insight into the role that biomechanics can play in improving the success rate of this percutaneous therapy and overall patient care.

A parallel-plate capacitively-coupled plasma deposition system was designed and built for the growth of polyethylene glycol-like films. Deposition rate, bonding structure and dissolution and swelling behavior was characterized as a function of input RF power, reactor pressure and substrate temperature to provide information on the relationship between input plasma parameters and film properties. For the conditions studied in this thesis, deposition rates increased at increasing input powers and operating pressures and decreasing substrate temperatures. The PEG-like coatings resembled higher molecular weight solution-polymerized PEG films with a higher crosslinked structure. Manipulation of plasma deposition conditions allowed control of film crosslink density and resulted in tunable dissolution and swelling properties of the PEG-like polymer. At higher applied powers, lower operating pressures, and higher substrate temperatures, films had a higher crosslink density, thus leading to slower dissolution rates and smaller extents of swelling. Void space openings of swelled-state, PEG-like films were determined using electrophoretic drift and diffusion-controlled transport of fluorophore-tagged PAMAM dendrimers into the bulk of the coating. PAMAM dendrimers were used because of their well-defined sizes and negatively-charged succinamic acid surface groups as a means to probe pore sizes of the plasma films. It was estimated that the upper bound of pore size diameters in the plasma polymer was approximately equal to ~5.5-6.0 nm. Positron annihilation lifetime spectroscopy was used to determine average pore sizes and was estimated to equal ~0.60-0.65 nm.

Atherosclerosis is the number one cause of death in the United States and one of the most common treatments is the implantation of a stent. In order to eliminate the two most common complications - restenosis and thrombosis - a novel covered stent is investigated. A covered stent membrane should be able to undergo large stretch, prevent restenosis, and be relatively non-thrombogenic. Polyvinyl alcohol (PVA) cryogels are examined as a candidate material for covered stent membranes. Mechanical testing included uniaxial tensile testing, puncture testing, and the fabrication and expansion of PVA cryogel covered stents. Uniaxial testing showed PVA cryogels to have sufficient ultimate stretch which was similar to bare metal stents during deployment. Puncture testing revealed that PVA cryogels are not likely to puncture in vivo. No tears were seen in the PVA cryogel membrane after expansion of the covered stents. Finite element analysis was used to determine a PVA cryogel membrane's effect on artery wall stress. PVA cryogel covered stents reduced both artery wall stress and tissue prolapse when compared to equivalent uncovered stents. Migration assays were used to determine if PVA cryogels are able to block the smooth muscle cell migration seen during restenosis. PVA cryogels significantly reduced cellular migration in modified Boyden chambers - suggesting that they would be able to prevent restenosis in vivo. Thrombogenicity was tested in vitro with a gravity-fed flow loop using porcine blood and in vivo with a sheep model. PVA cryogels were found to be less thrombogenic than polyester controls with the flow loop system. The sheep study demonstrated the feasibility of implanting PVA cryogel covered stents and good early patency. After explantation, the PVA cryogel membranes were intact - providing in vivo evidence for the durability of PVA cryogel covered stents. Overall, this work provides evidence that covered stents made with PVA cryogels are a feasible device in terms of their mechanics, ability to prevent restenosis, and low thrombogenicity. This work represents a major advancement in the development of PVA cryogel covered stents and provides necessary safety and feasibility data for future clinical trials.

Thèse d'exercice : Médecine. Médecine générale : Paris 12 : 2005. / Titre provenant de l'écran-titre. Bibliogr. f. 46-63.

Stent implantation is the most common treatment of coronary heart disease, one of the major causes of death worldwide. During a stenting procedure, the clinician inserts interventional devices inside the patient's vasculature. The navigation of the devices inside the patient's anatomy is monitored in real-time, under X-ray fluoroscopy. Three specific interventional devices play a key role in this procedure: the guide-wire, the angioplasty balloon and the stent. The guide-wire appears in the images as a thin curvilinear structure. The angioplasty balloon, that has two characteristic markerballs at its extremities, is mounted on the guide-wire. The stent is a 3D metallic mesh, whose appearance is complex in the fluoroscopic images. Stents are barely visible, but the proper assessment of their deployment is key to the procedure. The objective of the work presented in this thesis is twofold. On the first hand, we aim at designing, studying and validating image processing techniques that improve the visualization of stents. On the second hand, we study the processing of curvilinear structures (like guide-wires) for which we propose a new image processing technique. We present algorithms dedicated to the 2D and 3D visualization of stents. Since the stent is hardly visible, we do not intend to directly locate it by image processing means in the images. The position and motion of the stent are inferred from the location of two landmarks: the angioplasty balloon and of the guide-wire, which have characteristic shapes. To this aim, we perform automated detection, tracking and registration of these landmarks. The cornerstone of our 2D stent visualization enhancement technique is the use of the landmarks to perform motion compensated noise reduction. We evaluated the performance of this technique for 2D stent visualization over a large database of clinical data (nearly 200 cases). The results demonstrate that our method outperforms previous state of the art techniques in terms of image quality. A comprehensive validation confirmed that we reached the level of performance required for the commercial introduction of our algorithm. It is currently deployed in a large number of clinical sites worldwide. The 3D stent visualization that we propose, uses the landmarks to achieve motion compensated tomographic reconstruction. We show preliminary results over 22 clinical cases. Our method seems to outperform previous state of the art techniques both in terms of automation and image quality. The previous stent visualization methods involve the segmentation of the part of the guide-wire extending through the stent. We propose a generic tool to process such curvilinear structures that we call the Polygonal Path Image (PPI). The PPI relies on the concept of locally optimal paths. One of its main advantages is that it unifies the concepts of several previous state of the art techniques in a single formalism. Moreover the PPI enables to control the smoothness and the length of the structures to segment. Its parametrization is simple and intuitive. In order to fully benefit from the PPI, we propose an efficient scheme to compute it. We demonstrate its applicability for the task of automated guide-wire segmentation, for which it outperforms previous state of the art techniques

Techn. Universiẗat, Diss., 2005--München.

FDA approval of drug-eluting stents (DES) in 2002, was based on data obtained from several pivotal, short-term (< one year) randomized control trials that evaluated their efficacy in reducing in-stent restenosis when used in treatment of coronary artery lesions compared with bare metal stents (BMS). These trials excluded patients with complex coronary lesions. When the FDA approved use of DES in treatment of coronary artery lesions, the on-label indications only applied to a very limited subset of simple lesions. Immediate advantages of DES were observed in clinical practice for on-label indications, specifically in their ability to significantly reduce in-stent restenosis after PCI. The increased short-term safety and efficacy seen in on-label clinical cases soon led clinicians to expand the use DES to more complex lesions. These complex indications, not included in the pivotal FDA trials, are considered off-label. Off-label indications include bifurcation lesions, ostial lesions, lesions greater in length and diameter than those approved by the FDA, implantation in saphenous vein grafts, and lesions in the left main coronary artery. Currently, DES use for treatment of lesions presenting off-label indications may comprise as much as 60% of clinical cases. However, early evidence that DES may play a role in adverse safety outcomes, has led many to question the use of DES outside their on-label indications. This paper sought to evaluate some of the current research investigating first generation DES use in four different off-label indications: coronary artery bypass graft lesions, saphenous vein graft lesions, ostial lesions, and chronic total coronary occlusions. In particular, it looked at studies, which compared the efficacy and clinical outcomes of DES and BMS treatment of each of the different lesion types. The results of this evaluation were very promising in that of the four specific off-label indications evaluated, all of them showed to be superior in reduction of neointimal growth and subsequent in-stent restenosis. Additionally, DES treatment of left main coronary artery lesions, saphenous vein graft lesions, and chronic total coronary occlusions showed to be superior in reducing the incidence rate of major adverse cardiac events and target vessel revascularization over various follow-up durations. The only scenario that DES did not prove to be superior to BMSs was the treatment of ostial lesions. Long-term randomized control trials with large study populations should be performed to further elucidate the effects of DES treatment of specific off-label lesions.