Endoluminal Scaffolds for Vascular Reconstruction and Exclusion of Aneurysms From the Cerebral Circulation
The latest class of neuroendovascular devices being evaluated is intended to treat cerebral aneurysms. In addition to inducing flow stasis–mediated thrombosis of aneurysms and thus at times being referred to as flow diverters, these devices reconstitute pathologic arterial segments to near-physiologic normalcy. The successful implementation of such an endoluminal scaffold for vascular reconstruction in the cerebral circulation requires careful consideration of various factors drawn from engineering, physics, and biological sciences. Here we review some of these factors.
The key engineering issues in the manufacturing of a neuroendovascular device such as an endoluminal scaffold for vascular reconstruction (ESVR) are the choice of materials, design of the construct, and manufacturing methods, for example, laser cutting versus braiding or knitting. A priori knowledge of biocompatibility limits the choice to a small number of materials from a very large arsenal of alloys. Furthermore, the construct needs to have the mechanical stability and strength to provide enough outward radial force to remain in the implanted location without migrating while providing superior apposition to the luminal wall of highly tortuous cerebral vessels. It is also desirable to make the device of 1 type of material to avoid galvanic corrosion over time. Given these constraints, we selected a cobalt-chromium alloy that is widely used as a surgical implant material owing to its biocompatibility, excellent fatigue properties, high corrosion resistance, and mechanical strength.1,2 It also exhibits kink resistance and flexibility, and its extruded wire form is used to weave the ESVR. Our experience with the use of this material in the elastase-induced aneurysm model in rabbits has been very favorable,3 with no undesirable acute (or chronic) biological response and preserved structural integrity in the long term.
We have evaluated ESVRs composed of wires ranging from 30 to 50 μm in diameter with a variable number of ends (see Figure 1; number of ends designated as N) and various weave angles (β) to achieve a nominal porosity index ranging from 65% to 70%. The porosity of the ESVR is defined as
The term “coverage” or “cover factor” (100−porosity percent) is also occasionally used to represent this parameter. The length of the ESVR should be selected such that the total length (L) spans the width of the aneurysm neck plus at least 1.5 times the parent vessel diameter on each side (Δ) to ensure sufficient proximal and distal landing zones to anchor the ESVR in the parent artery. This requirement is balanced with the need to make the device short enough to be able to deliver it through tortuous cerebral arteries and minimize disturbance of adjacent vessels. Based on our experience and simple geometric considerations, it is possible to easily deliver an ESVR through a catheter with an inner luminal diameter of <800 μm.
The porosity of loosely woven ESVRs does not uniquely define the porous medium. Although pore size could be used as an additional parameter required for uniqueness, the pore size of braided devices changes with changes in the diameter of the device compared with its stress-free condition. Therefore, we elected to use the mathematical variable pore density, which depends on wire thickness, number of ends, and the porosity index. It is essentially the inverse of the area of the opening within each repeatable cell of the device. Figure 2 demonstrates the concept of the lack of uniqueness of porosity alone to define a device. In this example, if one considers the white diamonds as holes and the black ones as metal, the porosity of the 2 panels in Figure 2 is the same, that is, 50%. However, the figure on the left has a 16-fold higher pore density than the 1 on the right. The concept of pore density, or pore size, is very important for the biological response of the artery to the implant, because pore density determines the properties of the scaffold over which cellular elements proliferate and populate.
Changes in Flow Physics Due to an ESVR
We used particle image velocimetry and elastomeric replicas of the elastase-induced aneurysm model in rabbits to investigate flow in the parent artery and within the aneurysm. We investigated 6 different configurations of ESVRs4 and studied the influence of porosity and pore density parameters on the flow field (Figure 3). Our studies showed a complex interaction between parent-vessel flow and intra-aneurysmal flow. This interaction is partially responsible for the replenishment of fresh blood into the aneurysmal sac during each heart beat. Thus, the prevailing hemodynamics maintain a good supply of oxygen and nutrients to the pathologic entity. Therefore, decoupling parent-vessel flow from that of the aneurysm is essential for curative remodeling of the pathologic entity, and a properly designed ESVR should appropriately modify the local hemodynamics to exclude the pathologic entity from the circulation.4 We developed 4 indices of device performance based on well-known flow physics. Two of the indices are related to the vorticity function and were reduced by calculating the instantaneous intra-aneurysmal hydrodynamic circulation.
Equation 2a represents the vorticity in the x-y plane with velocity vectors u and v along the x and y axis, respectively. Equation 2b is the hydrodynamic circulation, where A is the area of a contour element around which the circulation is calculated, and is the vector normal to this element. The selected indices of performance were peak hydrodynamic circulation (which usually occurs during systole) and mean hydrodynamic circulation throughout the cardiac beat.
Here, E is kinetic energy, ρ is density, V is volume, and v is velocity. Because no changes in volume or density are expected, the square of the velocity alone can be evaluated.
All ESVRs performed well and significantly reduced the intra-aneurysmal hydrodynamic circulation and energy indices compared with the control (no device) case (Figure 3). Wall shear stress in the vicinity of the aneurysm neck, which has been implicated in aneurysm growth, was also significantly reduced. The devices reduced the mean hydrodynamic circulation to ≈12.5±2.5% of the control value and the mean kinetic energy to 21.6±5.8% of that in the control. Devices E and C effected the lowest mean hydrodynamic circulation, mean energy (Figure 3), and peak energy compared with the others. In summary, devices E and C scored the best results in 3 of the 4 indices and almost scored the best in terms of the peak circulation index. Moreover, the change in peak circulation did not reach significance for any of the ESVRs. Thus, it was reasonable to conclude that these particular devices (E and C) would be the best performers in vivo.
We constructed elastase-induced aneurysms in rabbits5,6 and implanted 3 different ESVRs. The devices selected were 2 that scored the best (devices C and E, Figure 3) and device B that had the same porosity but a different pore density than did device E. Twenty one (n=9), 90 (n=9), and 180 (n=12) days after implantation, the aneurysms were evaluated by angiography, the animals were euthanized, and the vasculatures containing the implants were harvested for histologic evaluation. Figure 4 shows angiograms acquired before treatment and at the 180-day follow-up of an animal treated with device C. As shown, the aneurysm was successfully occluded by the device. The relative performance of the 3 devices as measured purely by intra-aneurysmal flow reduction indices in vitro was clearly reflected in the aneurysm occlusion rates in vivo.3
We also quantified the changes in intra-aneurysmal hemodynamics due to ESVR implantation from angiographic data.7,8 The aneurysm is delineated as a region of interest and, by defining a position vector to track the aneurysm as it moves, the aneurysmal contrast washout curve is recorded. This washout curve is then fit to the following model, which isolates the convective and diffusive modes of aneurysmal flow exchange.
ρconv and ρdiff represent the relative magnitudes of convective and diffusive transport, respectively, whereas τconv and τdiff are the corresponding time constants. The parameters σ and μ characterize the method of contrast injection. Figure 5A shows the washout curves obtained before and immediately after implantation of a device. The marked reduction in amount of contrast entering the aneurysm and its relatively sluggish washout can be noted on this figure. Figure 5B and 5C shows the fits of the mathematical model to these 2 curves. As would be expected, an increase in amplitude of the diffusive component (ρdiff) and a decrease in the amplitude of the convective component (ρconv) of the model can be noted. The inset table lists the values of the washout curve amplitudes and optimized values of the 3 more important model parameters obtained after fitting the pre- and postimplant washout curves. By quantifying the washout of contrast from the aneurysm with these optimized parameters, the performance of various ESVRs can be statistically compared. Also, the optimized time constants were found to have a linear correlation to the mean kinetic energy obtained by particle image velocimetry.9 Such quantification could also be used to estimate the long-term occlusion potential of the aneurysm immediately after device implantation (while the patient is being treated). The inset in Figure 5 shows such an index, called the washout coefficient (W). For all animals combined, a value of this index of <30 predicted >97% angiographic occlusion of the aneurysm at follow-up, with a sensitivity and specificity of 73% and 82%, respectively.8
Biological Response to an ESVR
We have successfully implanted 3 configurations of ESVRs with varying porosities and pore densities (device C: 65%, 14 pores/mm2; device B: 70%, 12 pores/mm2; and device E: 70%, 18 pores/mm2) across 30 in vivo aneurysms. Device E yielded an angiographic occlusion rate of 97±1% (mean± SE of the mean for 3 cases) at 21 days with equivalent values at 90 and 180 days. The lower-porosity device C, which did not perform well at 90-day follow-up (percentage aneurysm occlusion=62±10%), was able to occlude the aneurysm at 180 days (95±5% occlusion based on 4 cases).3 These results suggest that the thrombus deposition in the aneurysm and its conversion to stable scar tissue can be a lengthy process in this species (rabbit) and is much longer than in other experimental aneurysms, such as the canine10 or porcine11 model.
These findings were confirmed by our histologic results, which showed that at 21-day follow-up, the aneurysm dome was filled with red untransformed thrombus. At 90-day follow-up, the thrombus in the aneurysm only starts to show transformation to scar tissue and even at 180-day follow-up, remnants of fresh thrombus are visible. Because the thrombotic and thrombolytic profile of the rabbit is considered close to that of humans,12 it is reasonable to believe that the remodeling process in humans spans a similar period. A recent preliminary evaluation of flow diverters in aneurysm patients also suggests this to be the case.13 Figure 6A shows an aneurysm section 180 days after implantation of device C. Because the devices are designed from thin wires and exert the minimum requisite radial force, they elicit a minimal yet stable neointimal response (Figure 6B); there was no “in-stent stenosis” in any of the implants. Arterial side branches remained patent in all animals at all time points (Figure 6C and 6D).
Source of Funding
This work was supported by the National Institutes of Health under grant No. R01NS045753.
- Received July 6, 2010.
- Accepted July 16, 2010.
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