Baruch B. Lieber

Physical factors effecting cerebral aneurysm pathophysiology.

Many factors that are either blood-, wall-, or hemodynamics-borne have been associated with the initiation, growth, and rupture of intracranial aneurysms. The distribution of cerebral aneurysms around the bifurcations of the circle of Willis has provided the impetus for numerous studies trying to link hemodynamic factors (flow impingement, pressure, and/or wall shear stress) to aneurysm pathophysiology. The focus of this review is to provide a broad overview of such hemodynamic associations as well as the subsumed aspects of vascular anatomy and wall structure. Hemodynamic factors seem to be correlated to the distribution of aneurysms on the intracranial arterial tree and complex, slow flow patterns seem to be associated with aneurysm growth and rupture. However, both the prevalence of aneurysms in the general population and the incidence of ruptures in the aneurysm population are extremely low. This suggests that hemodynamic factors and purely mechanical explanations by themselves may serve as necessary, but never as necessary and sufficient conditions of this disease’s causation. The ultimate cause is not yet known, but it is likely an additive or multiplicative effect of a handful of biochemical and biomechanical factors.

Hemodynamics of Flow Diverters

Cerebral aneurysms are pathological focal evaginations of the arterial wall at and around the junctions of the circle of Willis. Their tenuous walls predispose aneurysms to leak or rupture leading to hemorrhagic strokes with high morbidity and mortality rates. The endovascular treatment of cerebral aneurysms currently includes the implantation of fine-mesh stents, called flow diverters, within the parent artery bearing the aneurysm. By mitigating flow velocities within the aneurysmal sac, the devices preferentially induce thrombus formation in the aneurysm within hours to days. In response to the foreign implant, an endothelialized arterial layer covers the luminal surface of the device over a period of days to months. Organization of the intraneurysmal thrombus leads to resorption and shrinkage of the aneurysm wall and contents, eventually leading to beneficial remodeling of the pathological site to a near-physiological state. The devices primary function of reducing flow activity within aneurysms is corollary to their mesh structure. Complete specification of the device mesh structure, or alternately device permeability, necessarily involves the quantification of two variables commonly used to characterize porous media-mesh porosity and mesh pore density. We evaluated the flow alteration induced by five commercial neurovascular devices of varying porosity and pore density (stents: Neuroform, Enterprise, and LVIS; flow diverters: Pipeline and FRED) in an idealized sidewall aneurysm model. As can be expected in such a model, all devices substantially reduced intraneurysmal kinetic energy as compared to the nonstented case with the coarse-mesh stents inducing a 65-80% reduction whereas the fine-mesh flow diverters induced a near-complete flow stagnation (∼98% reduction). We also note a trend toward greater device efficacy (lower intraneurysmal flow) with decreasing device porosity and increasing device pore density. Several such flow studies have been and are being conducted in idealized as well as patient-derived geometries with the overarching goals of improving device design, facilitating treatment planning (what is the optimal device for a specific aneurysm), and predicting treatment outcome (will a specific aneurysm treated with a specific device successfully occlude over the long term). While the results are generally encouraging, there is poor standardization of study variables between different research groups, and any consensus will only be reached after standardized studies are conducted on collectively large datasets. Biochemical variables may have to be incorporated into these studies to maximize predictive values.

Realistic Vascular Replicator for TAVR Procedures

AbstractTranscatheter aortic valve replacement (TAVR) is an over-the-wire procedure for treatment of severe aortic stenosis (AS). TAVR valves are conventionally tested using simplified left heart simulators (LHS). While those provide baseline performance reliably, their aortic root geometries are far from the anatomical in situ configuration, often overestimating the valves’ performance. We report on a novel benchtop patient-specific arterial replicator designed for testing TAVR and training interventional cardiologists in the procedure. The Replicator is an accurate model of the human upper body vasculature for training physicians in percutaneous interventions. It comprises of fully-automated Windkessel mechanism to recreate physiological flow conditions. Calcified aortic valve models were fabricated and incorporated into the Replicator, then tested for performing TAVR procedure by an experienced cardiologist using the Inovare valve. EOA, pressures, and angiograms were monitored pre- and post-TAVR. A St. Jude mechanical valve was tested as a reference that is less affected by the AS anatomy. Results in the Replicator of both valves were compared to the performance in a commercial ISO-compliant LHS. The AS anatomy in the Replicator resulted in a significant decrease of the TAVR valve performance relative to the simplified LHS, with EOA and transvalvular pressures comparable to clinical data. Minor change was seen in the mechanical valve performance. The Replicator showed to be an effective platform for TAVR testing. Unlike a simplified geometric anatomy LHS, it conservatively provides clinically-relevant outcomes and complement it. The Replicator can be most valuable for testing new valves under challenging patient anatomies, physicians training, and procedural planning.n

Physical Simulators and Replicators in Endovascular Neurosurgery Training

The increased adoption of endovascular neurosurgery procedures to treat cerebrovascular pathologies has led to the commercialization of a wide array of medical devices which, in turn, necessitates a more sophisticated training environment for physicians and fellows than the traditional “see one, do one, teach one” concept. Improvements in simulation technology and a changing healthcare culture are facilitating a wider assimilation of benchtop simulation models in lieu of cadaver or animal models in physician training as well as treatment planning. Medical device manufacturers as well as regulators are also increasingly utilizing such simulators for device development and assessment of efficacy. Low-fidelity physical simulacra in the form of simplistic vascular replicas with or without coarse pumping systems have been available for basic neuroendovascular simulations for several years. Additive manufacturing, or 3D printing, has ushered in the use of anatomically accurate vascular replicas derived from patient imaging. Other considerations that improve the fidelity of simulating the neuroendovascular compartment include flows and pressures, catheter friction, blood-analog fluid, X-ray attenuation, etc. This chapter briefly describes these components of high-fidelity physical simulators, called replicators, for endovascular neurosurgery training.

In vitro angiographic comparison of the flow-diversion performance of five neurovascular stents:

Background and purpose Data differentiating flow diversion properties of commercially available low- and high-porosity stents are limited. This in vitro study applies angiographic analysis of intra-aneurysmal flow to compare the flow-diversion performance of five neurovascular devices in idealized sidewall and bifurcation aneurysm models. Methods Five commercial devices (Enterprise, Neuroform, LVIS, FRED, and Pipeline) were implanted in silicone sidewall and bifurcation aneurysm models under physiological average flow of blood analog fluid. High-speed angiographic images were acquired pre- and post-device implantation and contrast concentration-time curves within the aneurysm were recorded. The curves were quantified with five parameters to assess changes in contrast transport, and thus aneurysm hemodynamics, due to each device. Results Inter-device flow-diversion performance was more easily distinguished in the sidewall model than the bifurcation model. There were no obvious overall statistical trends in the bifurcation parameters but the Pipeline performed marginally better than the other devices. In the sidewall geometry, overall evidence suggests that the LVIS performed better than the Neuroform and Enterprise. The Pipeline and FRED devices were statistically superior to the three stents and Pipeline was superior to FRED in all sidewall parameters evaluated. Conclusions Based on this specific set of experiments, lower-porosity flow diverters perform significantly better in reducing intra-aneurysmal flow activity than higher-porosity stents in sidewall-type geometries. The LVIS device is potentially a better flow diverter than the Neuroform and Enterprise devices, while the Pipeline is potentially better than the FRED.

Pressure and Flow Rate Changes During Contrast Injections in Cerebral Angiography: Correlation to Reflux Length

Cerebral angiography involves the antegrade injection of contrast media through a catheter into the vasculature to visualize the region of interest under X-ray imaging. Depending on the injection and blood flow parameters, the bolus of contrast can propagate in the upstream direction and proximal to the catheter tip, at which point contrast is said to have refluxed. In this in vitro study, we investigate the relationship of fundamental hemodynamic variables to this phenomenon. Contrast injections were carried out under steady and pulsatile flow using various vessel diameters, catheter sizes, working fluid flow rates, and injection rates. The distance from the catheter tip to the proximal edge of the contrast bolus, called reflux length, was measured on the angiograms; the relation of this reflux length to different hemodynamic parameters was evaluated. Results show that contrast reflux occurs when the pressure distal to the catheter tip increases to be greater than the pressure proximal to the catheter tip. The ratio of this pressure difference to the baseline flow rate, called reflux resistance here, was linearly correlated to the normalized reflux length (reflux length/vessel diameter). Further, the ratio of blood flow to contrast fluid momentums, called the Craya–Curtet number, was correlated to the normalized reflux length via a sigmoid function. A sigmoid function was also found to be representative of the relationship between the ratio of the Reynolds numbers of blood flow to contrast and the normalized reflux length. As described by previous reports, catheter based contrast injections cause substantial increases in local flow and pressure. Contrast reflux should generally be avoided during standard antegrade angiography. Our study shows two specific correlations between contrast reflux length and baseline and intra-injection parameters that have not been published previously. Further studies need to be conducted to fully characterize the phenomena and to extract reliable indicators of clinical utility. Parameters relevant to cerebral angiography are studied here, but the essential principles are applicable to all angiographic procedures involving antegrade catheter injections.

Phototherapy Enhanced Exclusion of Aneurysms From the Cerebral Circulation

Accumulated experience using flow diverters in humans suggests that complete cure of the aneurysm is usually a protracted process that can last up to twelve months [1]. While it is well established that a properly designed flow diverter serves as a scaffold for neointimal proliferation, the process of its formation over the aneurysm neck is delayed until the aneurysm cavity itself is occluded by a thrombus, negating flow of fresh blood through the neck, and thus allowing the neointimal formation to bridge the aneurysm neck. The notion that induction of some injury to the luminal surface of the aneurysmal tissue, particularly to the endothelium, may result in a healing response that is faster than just placing a flow diverter and waiting for thrombus formation within the aneurysm has been tried in the past using various experimental models. Some of the injuries to the aneurysm tissue that have been tried in the past include mechanical scraping, thermal heating and UV irradiation. All these attempts, while showing that hastening the thrombus formation is feasible, have not resulted in any success due to the fact that the processes that were tried suffered from lack of proper control to be implemented in actual aneurysmal tissue that is weakened and diseased a priori.Copyright

Preliminary In Vitro Estimates of Intra-Aneurysmal Void Sizes After Endovascular Coiling

Endovascular coiling has become a well-established treatment method for cerebral aneurysms. The primary drawback of the technique is aneurysm recanalization requiring periodic angiographic follow-ups and possible aneurysm re-treatment. A recent review [1] estimates that 20% of treated aneurysms re-canalize and that half of those aneurysms (10%) are re-treated. Aneurysm recanalization is, in turn, largely caused by compaction of the coil mass due to hemodynamic impingement forces every cardiac cycle. Currently, the only quantitative measure used to characterize effectiveness of the treatment is the aneurysm packing density (ratio of total volume of coils inserted into the aneurysm and the volume of the aneurysm). Lower packing densities have been correlated with higher coil compaction rates [2], so aneurysms are generally coiled to maximal packing. A wider aneurysm neck is also correlated with higher coil-compaction rates. Coiling in such wide-neck aneurysms is performed either with the support of a balloon that is removed post-coiling or with the support of an intracranial stent that is implanted. Such assist devices also improve aneurysm packing densities [3].Copyright

In Vitro Simulation of Flow Diverter Induced Clotting in Aneurysms Using Rennet Activated Milk Flow

Flow diverters are currently being evaluated in patients with cerebral aneurysms. Blood cells (such as platelets) contact the device mesh as they enter the aneurysm and pro-coagulant factors released by these activated cells accumulate within the aneurysm because of the intra-aneurismal flow stasis created by the device. The efficacy of any flow diverter is thus related to the rate at which blood coagulation factors accumulate within the aneurysm and get converted to thrombus.Copyright