WO2017040371A1 - Devices and methods for ablation of vascular defects - Google Patents

Abstract

A double-lumen balloon catheter assembly has embedded electrodes for endovascular application of radiofrequeney electrical energy precisely at the neck region of a saccular aneurysm to remove the endothelial cellular layer (the intima) prior to treatment by conventional embolization methods such as packing the aneurysm with coils. The electrodes are embedded in the wall of the balloon and deform elasticaliy as the balloon is inflated to place the electrodes at the aneurysm neck. The electrodes then return the balloon to its original shape after inflation pressure is removed. Since the position of the electrodes is fixed on the balloon, and they are configured only to apply energy to the aneurysm neck, the catheter assembly substantially avoids involvement of the intima at locations other than the aneurysm neck.

Description

DEVICES AND METHODS FOR ABLATION OP VASCULAR DEFECTS CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of U.S. provisional application no.62/211,757, filed August 29, 2015, the entire contents of which are incorporated herein by reference.

BACKGROUND OF OF THE INVENTION

[0002] Field of the Invention

[0003] The present invention relates to endovascular treatment of vascular diseases, and more particularly, to devices and methods for selectively and precisely applying energy in a localized circumferential fashion at the origin of a saccular aneurysm or other vascular defect to damage the endothelial cellular layer (that is, the intima) at the origin of the defect while substantially avoiding involvement of other locations and cellular layers of the vascular wall.

[0004] Description of Related Art

[0005] An aneurysm is a balloon-like bulge of a vessel wall that may occur anywhere in the body.

Aneurysms can grow in size and eventually leak, dissect or rupture, which can have devastating effects on normal functioning or may even be fatal. Aneurysms in the brain can be particularly serious. Autopsy reports have shown that intracranial aneurysms are present in roughly 5% of the population. (1*3) This suggests that there are many cases of intracranial aneurysms that go undetected and present a potential health threat. Methods of screening for intracranial aneurysms have improved over the years, and treatment is usually indicated even though an individual is otherwise in good health. Thus, improved procedures for treating aneurysms, especially those in the brain, are constantly being sought.

[0006] Subarachnoid hemorrhage (SAH) is the most serious presentation of post-rupture of intracranial aneurysms. It is estimated that the annual incidence of SAH from

non-traumatic causes ranges from two to 23 cases per 100,000, which translates to 6,500 to 74,000 cases of SAH every year in the United States. Approximately 80% of non-traumatic SAH cases are due to ruptured intracranial aneurysms. (4-7) Untreated ruptured intracranial aneurysms are associated with a high mortality rate and risk of rebleeding. (8) The fatality rate in cases of intracranial aneurysm rupture remains high (from 27% to 44%], even though it showed a decrease in a three-decade period ending in the 1990s due to continuous improvements in patient management strategies. (9)

[0007] Two popular approaches for the treatment of intracranial aneurysms seek to obliterate the aneurysm. One approach involves neurosurgery and the other employs endovascular procedures, in a typical neurosurgical approach, an operator gains access to the subarachnoid space via craniotomy and attaches a microsurgical clip to the affected blood vessel to exclude the aneurysm from blood circulation. Harvey Cushing and Walter Dandy are credited with introducing microsurgical clips to treat intracranial aneurysms (10 ), and it was the accepted standard of care up to the mid-1990s. Conventional endovascular therapy takes a different approach, aiming to obliterate an aneurysm by occluding its dome with coils, a procedure often referred to by those skilled in the art as "coiling." A device known widely as the Guglielmi detachable coil (11) was approved by the FDA for the treatment of intracranial aneurysms in 1995. Conceptually, coiling involves filling the aneurysm dome with soft coils to cause embolization within the aneurysm. [0008] However, therapies other than coiling continued to be explored for several reasons. One is because of the potential for coil-occluded intracranial aneurysms to recur over time after the procedure. (12) And post-treatment angiographic examination has indicated that recurrence is more likely for more dangerous large intracranial aneurysms than for smaller lesions. (13) There can also be complications with intracranial aneurysm coiling procedures, the two most common being thromboembolic events, which occur in 7.3% of unruptured aneurysms and 13.3% of ruptured aneurysms, and intraoperative rupture with a prevalence of 2.0% in unruptured aneurysms and 3.7% in ruptured aneurysms that had clotted prior to the coiling procedure. (14, 15) Mortality rates in intracranial aneurysm cases involving coiling-caused intraoperative rupture and thromboembolic events are 3.7% and 16.7%, respectively. (IS) Reducing these mortality rates caused by coiling procedures is one goal of those working in the art

[0009] The potential for recurrence of an intracranial aneurysm treated by coiling is typically assessed by the extent of a phenomenon known as recanalization. by which pathways for blood become reestablished in the coil-occluded, embolized aneurysm. Recanalization occurs in 20.8% of cases, requiring retreatment in 10.3%. (16) The risk of rerupture of initially ruptured intracranial aneurysms treated with coils runs in parallel with the degree of the initial occlusion of aneurysm cavity. That is, the more densely the aneurysm is packed with coils, the higher the probability of rerupture. (17) Due to the possibility of recanalization of coil-embolized aneurysms, their postoperative follow up by methods that can detect the presence of pathways in the embolized aneurysm, such as digital subtraction and/or magnetic resonance angiography, is strongly indicated. (18)

[0010] Over the years, there have been significant advances in imaging technologies and

interventional tools for supporting endovascular therapy of intracranial aneurysms, including the introduction of biplane flat panel digital and magnetic resonance angiography equipment, development of microcatheters, softer detachable coils, and compliant balloons, stents and flow diverters. All of these have contributed to

improvements in management strategies for endovascular treatment of intracranial aneurysms. (9)

[0011] These advances have led to two types of neurovascular remodeling techniques developed in an effort to improve the safety and efficacy of endovascular coiling treatments, particularly of wide-neck and complex intracranial aneurysms. Wide neck aneurysms are especially prone to rupture of the aneurysm dome during coiling procedures, and complex aneurysms, involving multiple chambers, require each chamber to be coiled individually without involving previously coiled chambers or dislocation of coils to the parent vessel. One such technique developed to improve outcomes in these cases involves

balloon-assisted coiling (BAG) whereby a non-detachable single balloon, placed in a parent vessel either across the neck of the aneurysm, or a non-detachable double balloon, placed distally and proximally to the aneurysm origin, is temporarily inflated during deployment of each coil in an intracranial aneurysm. (19) Unfortunately, several studies suggest that BAC techniques did not contribute to a better clinical outcome than unassisted coiling, even though some studies have shown that BAC techniques have given superior anatomical results in occluding endovascularly treated intracranial aneurysms. And as balloon catheters have improved, they have been utilized with increasing frequency just as sentinel tools that are inflated only when intracranial aneurysms rupture during coiling. (20)

[0012] A second remodeling technique for endovascular treatment of intracranial aneurysms is stent-assisted coiling (SAC). (21) Several cohort studies comparing SAC procedures and traditional coiling alone have been published, but the results have been controversial. For example, two systematic reviews concluded that SAC seemed to have more adverse events than traditional coiling. (22, 23) However, the studies reported by Reavey-Cantwelt et al. (23) were based solely on the outcomes of SAC procedures alone. More recently, results of a meta-analysis of ten retrospective cohort studies concluded that SAC has a significantly lower recurrence rate than traditional coiling (16.2% vs 34.4%) of intracranial aneurysms, and analysis of complication events did not reveal any significant difference between the two methods. (24) On the other hand, a qualitative, systematic review of 17 articles on SAC treatment of ruptured aneurysms concluded that adverse events appear more common and clinical outcomes are likely worse than traditional coiling without stent assistance. (25)

[0013] Aside from coiling, it has also been proposed to use intracranial stents for endovascular flow diversion away from an aneurysm and back into a parent vessel Early in vitro and in vivo studies showed this concept to be theoretically valid, but clinical application was limited because of the high porosity of first-generation intracranial stents. With technological improvements, intracranial flow diverters have become available for parent vessel reconstruction endoluminally, and early clinical experiences have been

encouraging. According to recently reported meta-analysis of 29 studies concluded that treatment of intracranial aneurysms with flow-diverter devices is feasible and effective with high complete occlusion rates. (26) However, the "rates of... morbidity and mortality [with this procedure] are not negligible." Ibid.

[0014] In summary, there is a need to improve known methods of endovascular treatment of intracranial aneurysms, in view of the lack of consensus as to the safety and efficacy of known alternatives, traditional, unassisted coil embolization remains a preferred procedure for endovascular treatment of intracranial aneurysms. However, all types of coil embolization are subject to the recurrence of aneurysms over time because of recanalization. [0015] It has been shown that coil-embolized aneurysms recanalize due to ear!y endothelial invasion of a clot inside the aneurysm cavity. (27, 28) These studies also showed that denuding the endothelium prior to the procedure caused increased migration and proliferation of macrophages and fibroblasts at the denuded area, which lead to local deposition of collagen and thereby minimize chances of recanalization.

[0016] An approach seeking to take advantage of that discovery is discussed in Pub. No.

US 2005/0085836, which discloses devices of various shapes for damaging the endothelium by mechanically denuding it prior to coiling. The publication also discloses alternatives to mechanically damaging the endothelium, one of which is using a coil, balloon, sponge, catheter, or other appropriate endovascular tool for delivering a chemical agent toxic to the endothelium. Another alternative applies heat or cold through a microballoon to damage the endothelium. Still another uses a denudation device comprising an endovascular tool with one or more electrodes for applying electricity or radiofrequency to the endothelium, and another suggests denuding the endothelium using a laser connected to an endovascular tool via fiber optic cable.

[0017] Although Pub. No. US 2005/0085836 notes the desirability of removing the endothelium at the neck of an aneurysm where it meets the vessel wail, the disclosed devices are all designed to remove the endothelium from the inside surface of the aneurysm sac In fact, the publication recognizes that the disclosed devices can scrape the vessel wall and even perforate the aneurysm if the user does not exercise sufficient care during the procedure. However, those skilled in the art will recognize that endovascular procedures by their nature are not amenable to the fine positional control required to completely avoid possible harmful vascular damage when using these devices, particularly when treating aneurysms in the subarachnoid space. All of the disclosed device configurations would make it difficult to effectively remove endothelium from the neck of the aneurysm without potentially causing deleterious damage to other components of the vascular wall, including the wail of the aneurysm.

[0018] What is needed is an effective way to remove the endothelial cellular layer around the circumference of the origin of vascular defects such as aneurysms, dissections, arteriovenous malformations, vascular tumors, and the like, in a way that eliminates or minimizes involvement of the defect itself to preserve the integrity of the remaining vessel wall components at the origin of the defect

SUMMARY OF THE INVENTION

[0019] It is an object of the present invention to provide improved devices and methods for treating a vascular defect by enabling more precise removal of endothelial ceils at the site of the defect

[0020] A more specific object of the subject matter disclosed herein is selective endovascular removal of an endothelial layer of a vascular wall to enhance biological processes responsible for promotion of local thickening of a defect in the wall. The devices and methods described herein enable removal of at least a portion of the endothelial layer around the circumference of a vascular defect just at its origin, without substantially affecting other components of the vascular wail.

[0021] In accordance with those objects, an aspect of the invention provides a double-lumen balloon catheter assembly comprising a supporting catheter having a central lumen and an inflatable balloon forming a sealed balloon lumen between an inner surface of the balloon and the outer surface of the supporting catheter. Inflation fluid is introduced to the balloon lumen under pressure to inflate the balloon, and energy applying means extends circumferentially around the balloon proximate to its outer surface for removing an endothelial cellular layer (the intima) just at the region of the vascular defect without substantially affecting other components of the vascular wall when the energy applying means is actuated while the inflated balloon is in contact with the region. In a more specific form, the energy applying means includes at least two electrodes comprising zig-zag shaped plastically deformable rings molded in place within the balloon wall to exert a radially inward force as the balloon is inflated for collapsing the balloon when pressure is released from the balloon lumen. Method aspects of the invention include using this type of double-lumen balloon catheter assembly for removing the endothelial cellular layer (the intima) by using an RF generator to supply a predetermined amount of electrical energy to the electrodes for a predetermined time.

[0022] Other general and specific aspects, details, embodiments, and adaptations of a device and methods for ablation of vascular defects in furtherance of the objects of the subject matter herein are described below in the context of certain specific embodiments of the claimed subject matter.

[0023] This Summary is provided solely to introduce in a simplified form a selection of concepts that are described in detail further below. It is not intended necessarily to identify key or essential features of the subject claimed herein, nor is it intended to be used an aid in determining the scope of the claimed subject matter.

BRIEF DESCRIPTION OP THE DRAWINGS

[0024] The objects of the invention will be better understood from the detailed description of its preferred embodiments which follows below, when taken in conjunction with the accompanying drawings, in which like numerals and letters refer to like features throughout The following is a brief identification of the drawing figures used in the accompanying detailed description. [0025] FIGURE 1 is a schematic representation of a double-lumen balloon catheter assembly with embedded electrodes that comprises one embodiment of a device for implementation of the invention described and claimed herein, taken along the longitudinal axis of the catheter.

[0026] FIGURE 2 is a cross section of the balloon catheter assembly along the line 11-11 in

FIGURE 1.

[0027] FIGURE 3 depicts the balloon catheter assembly constructed according to the depiction in FIGURES 1 and 2 positioned in the neck of a saccular aneurysm prior to full inflation of the balloon for performing a procedure in accordance with one method aspect of the subject matter herein.

[0028] FIGURE 4 depicts the balloon catheter assembly after positioning with the balloon inflated to contact the neck of the aneurysm.

[0029] FIGURE 5 is an enlarged view of the area denoted as such in FIGURE 4 showing the

position of the electrodes at the aneurysm neck for applying radiofrequency energy thereto.

[0030] One skilled in the art will readily understand that the drawings are not strictly to scale, but nevertheless will find them sufficient, when taken with the detailed descriptions of preferred embodiments that follow, to make and use the present invention.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS.

[0031] The detailed description that follows is intended to provide specific examples of

particular embodiments illustrating various ways of implementing the claimed subject matter, it is written to take into account the level of knowledge of one of ordinary skill in the art to which the claimed subject matter pertains. Accordingly, certain details may be omitted as being unnecessary for enabling such a person to realize the embodiments described herein. In addition, to the extent that spatially relative terms such as "top," "bottom " "right^* "left;" "under," "over," "proximal" "distal," etc., may be used herein for convenience, but they in no way limit the structure or procedure described, unless the context indicates otherwise.

[0032] In addition, terms used throughout are meant to have the ordinary and customary

meaning that would be ascribed to them by one of ordinary skill in the art However, some of the terms used in the description herein will be explicitly defined and that definition is meant to apply throughout For example, the term "substantially" is sometimes used to indicate a degree of similarity of one item, such as a properly, structural feature, or parameter, to another. This means that the items are sufficiently similar in value to achieve the purpose ascribed to them in the context of the description accompanying the use of the term. Exact equivalence of many items discussed herein is not possible because of factors such as engineering tolerances and normal variations in operating conditions, but such deviations from an exact identity still fall within the meaning herein of being "substantially" the same. Likewise, omission of the term "substantially" when equating two such items does not imply that they are identical unless the context suggests otherwise. Similar considerations apply to the term "about" which is sometimes used herein to indicate that the nominal value of a parameter can vary a certain amount as long as it produces the intended effect or result

[0033] General Principles

[0034] The devices and methods described herein selectively remove an endothelial layer of a vascular wall to enhance biological processes responsible for promotion of local thickening of a defect in the wall In particular, the disclosed devices enable removal of the endothelial cellular layer (the intima) just at the origin of the vascular defect without substantial!y affecting other components of the vascular wall implicating areas of defects other than their origin has heretofore been a shortcoming of otherwise effective prior art devices and methods that attempt to take advantage of the known benefits of removing endothelial cells as one aspect of endovascular procedures seeking to repair vascular defects.

[0035] More particularly, the devices and methods described herein use endovascular ablation of a vascular defect, described herein with reference to a device for endovascular treatment of saccular aneurysms, although the disclosed devices and methods are generally applicable to various types of vascular delects, including but not limited to dissections, arteriovenous malformations, and tumors. To that end, a unique energy emitting double-lumen balloon catheter temporarily seals the a defect at its origin using a low pressure, compliant, atraumatic balloon, while mechanical, thermal, electromagnetic or chemical energy is applied selectively and precisely around the circumference of the lesion at its origin.

[0036] Embodiments of the Double-Lumen Balloon Catheter

[0037] A preferred embodiment employs electrodes embedded in the balloon to apply electrical power at a predetermined level for a period of time at a frequency or frequencies that cause ablation of endothelial cells. In a particularly preferred embodiment the devices and methods use radiofrequency (RP) ablation. RF ablation is a known technique having various applications, and some of the principles underlying its effectiveness in causing tissue necrosis are described in Pub. No. US 2015/0305801, the contents of which, particularly as they relate to RF ablation, are incorporated herein by reference as if set out in full. [0038] A preferred form of a device for accomplishing the ends described herein, and treatment methods performed using the device, will be described with reference to FIGURES 1-5. Beginning with FIGURES 1 and 2, FIGURE 1 schematically depicts a cross-section of a double-lumen balloon catheter assembly 10 taken along a longitudinal axis A. (Section lines are generally omitted from FIGURE 1 for the sake of clarity.) FIGURE 2 is a cross-section of the catheter 10 taken at line ll-II of FIGURE 1. The catheter assembly 10 includes a supporting microcatheter 12 with a central lumen 14 extending from a proximal end (not shown) to an open distal end 16. The central lumen 1.4 serves several functions that will be described below in detail in connection with an endovascular procedure performed using the assembly 10.

[0039] The assembly 10 further includes a balloon 20 with an outer surface 22 and an inner surface 24, the latter being bonded to the supporting microcatheter 12 proximate to its distal end 16 at a distal bonding site 26. A proximal end of the balloon 20 is bonded to the supporting microcatheter 12 at a proximal bonding site 27. A sealed balloon lumen 28 bounded by the supporting microcatheter 12 and the inner balloon surface 22 thus extends between the bonding sites 24 and 26. The balloon is inflated though inflation conduits 30 formed within the wall of the supporting microcatheter 12 for

communication with a fluid source (not shown) further toward the proximal end of the supporting microcatheter 12. The inflation conduits 30 communicate with the balloon lumen 28 at one or more ports (not shown) to inflate the balloon with fluid introduced to the conduits 30.

[0040] The balloon 20 includes endothelial altering means, which in the present embodiment comprise two electrodes 40 and 42, section lined in FIGURE 1, that are embedded in the wall of the balloon between its outer surface 20 and inner surface 22. Conductors 44, 46, also embedded in the balloon wall, connect the electrodes 40, 42, respectively, to an RF generator (not shown) for a purpose to be described. Other than embedding electrodes in the balloon wall as endothelial altering means, the balloon catheter construction shown in FIGURES 1 and 2 is conventional and uses conventional materials for providing a balloon catheter for endovascular treatment of aneurysms. The same materials and assembly techniques will provide a sufficiently compliant supporting microcatheter and balloon that will enable practicing of the endovascular treatments described herein, but any suitable materials and manufacturing procedures can be used as long as they are consistent with the purposes described herein.

[0041] In that regard, a suitable manner of embedding the electrodes and conductors 42, 44, 46, and 48 in the balloon wall involves arranging them in the desired locations and configurations in a balloon mold and filling the moid with molten balloon material so that it surrounds the electrodes and conductors, thus molding them in place as the balloon material cures in the mold. The configuration of title electrodes 42, 44 is an important feature of this embodiment of the catheter assembly 10. As seen in FIGURE 1, they have a zig-zag shape in the circumferential direction around the balloon 20, so that as the balloon inflates, its circumference expands and elastically deforms the electrodes (see FIGURE 4}. As the electrodes deform, they straighten, and as they do so, they exert a radially inward force on the balloon, which causes the balloon to return to the condition shown in FIGURE 1 when it is deflated.

[0042] The present embodiment uses zig-zag shaped electrodes to provide a spring force for collapsing the balloon when it is deflated. The term "zig-zag" is used herein to denote a shape that includes a series of short turns, angles, or alterations in a course, in this case, the circumferential direction around the balloon, in the depicted embodiment; the zig-zag shape has substantially sharp corners, but the inside and/or outside corners of an electrode can be rounded within the meaning of "zig-zag." Those skilled in the art will understand that zig-zagged electrodes are merely one manner of providing spring means for exerting a radially inward force on the balloon as it is inflated, and that other constructions can be employed for the same purpose.

[0043] Endovascular Procedures Using the Double-Lumen Balloon Catheter

[0044] FIGURES 3-5 depict a typical endovascular procedure for repairing a saccular aneurysm using the double-lumen balloon catheter assembly 10. FIGURE 3 is a schematic illustration of a saccular aneurysm SA in a vascular wall VW. In a conventional manner, a guide wire (not shown) is advanced through a guide catheter GC that has been placed adjacent to the mouth of the aneurysm SA. The catheter assembly 10 is then introduced over the guide wire, also in a conventional manner, until the distal end of the

microcatheter 12 is in the desired position with the electrodes 40, 42 at the neck of aneurysm, as shown in FIGURE 4. (The electrodes are shown in solid lines in FIGURES 4 and S to more clearly indicate their position during the procedure.) Optionally, the microcatheter 12 can include a radio opaque marker at or near the distal end to assist positioning. It will be appreciated that the balloon 20 is shown partially inflated in FIGURE 4 for purposes of illustration, but it is passed through the guide catheter GC in its deflated state, shown in FIGURE 1. After the microcatheter has been positioned in its desired location, the guide wire is removed. These techniques for positioning balloon catheters during endovascular aneurysm procedures are well known by those skilled in the art and do not require a detailed explanation.

[0045] Once it is determined that the distal end of the microcatheter 12 is in the desired location, the balloon is inflated, again in a conventional manner, by using a fluid or gas supplied via the ports 30 to the balloon inflation lumen 28. FIGURE 1 shows a preferred orientation of the balloon 20 relative to the microcatheter 12, with the pair of electrodes 42 and 44 centered along the axial extent of the balloon. However, the electrode pair can be at other axial locations of the balloon in different constructions of the catheter assembly 10.

FIGURE S shows an electrode pair 42' and 44' located non-centrally in the balloon in the axial direct to illustrate this possible constructional variation of the balloon. Optionally, an injection of contrast agent mixed with normal saline (typically a 1 :1 solution) may be performed after balloon inflation to verify that the balloon has adequately sealed the aneurysm neck. It will be understood that the position of the balloon is adjusted during inflation as necessary to ensure that the aneurysm neck is properly sealed with the electrodes in position for performing the ablation procedure (described further below) when the balloon reaches the desired size. If the neck is not adequately sealed, appropriate adjustments may be made and one or more additional injections of contrast agent may be made.

[0046] The preferred location of the balloon electrodes 40, 42 is shown in FIGURE 5, which is an enlarged view of the aneurysm neck region as indicted in FIGURE 4. The balloon is inflated until its outer wall 22 is firmly pressed against the aneurysm neck region NR. The electrodes, which are connected by the conductors 44, 46 to a conventional RF generator used for tissue ablation (see, for example, Pub. No. US 2015/0305801), subject the aneurysm neck to electrical energy. According to conventional understanding, RF ablation involves passing current through tissue to cause ion agitation, which is converted by friction into heat The resultant cellular heating causes coagulation necrosis and consequent cell death. Because ion agitation, and thus tissue heating, is greatest in areas of highest current density (that is, closest to the active electrode tips), necrosis is limited to a relatively small volume of tissue. Accordingly, by precise placement of the electrodes 40 and 42 relative to each other and the aneurysm, the applied electrical energy

(represented notionally by the field lines in FIGURE 5) is substantially limited to ablation in the aneurysm neck region NR. [0047] In one actual double-lumen balloon catheter assembly, used in the animal efficacy studies discussed below, the microcatheter 12 was made of polyurethane, making it highly elastic and compliant, coated with polyvinylpyrrolidone, polyacrylamide and heparin for their hydrophilic and nonthrombogenic properties, and had a wall thickness of 0.S mm. The microcatheter had a central lumen 14 with a 0.5 mm diameter for a guide wire and fluids (for example, contrast material and saline), and an inflation conduit 30 with a 0.25 mm diameter located within the wall of the catheter for the inflation fluid used to inflate and deflate the balloon 20. The balloon itself was also highly elastic and compliant polyurethane, having its outer surface coated with polyvinylpyrrolidone, polyacrylamide and heparin to facilitate navigation of the balloon in small caliber vessels to minimize the possibility of damaging the endothelial layer of a vessel or forming clots while the system was not active [that is, in the absence of energy application}. The outer diameter of the deflated balloon was 2.7 mm. The inner diameter of the deflated balloon was 1.7 mm. The axial length of the balloon was 5 mm. The balloon was capable of inflation to a 10 mm outer diameter. The hollow space between the inner surface of the balloon and the outer surface of the microcatheter (the balloon lumen 28) was 0.1 mm in the radial direction.

[0048] The electrodes 40, 42 in the double-lumen balloon catheter assembly were embedded in the balloon wall in a two-dimensional zig-zag shape as shown in FIGURE 1 for delivering RF energy to the neck region of an aneurysm as discussed above. Each electrode was a 95% platinum/5% iridium alloy ring with a circular cross-section (see FIGURE 5) having a diameter of 0.25 mm. The electrodes were identically shaped and nested as shown in FIGURE 1 with a space d = 1.0 mm between them. The distance g between the radially outer surface of each electrode and the balloon outer surface 22 was 0.1 mm. The conductors 44, 46 were made of the same material as the electrodes and were likewise embedded in the balloon wail with a distal end of each connected to a respective electrode, as described previously, and their proximal ends connected to an RF generator. [0049] In a typical application, the balloon is inflated until the balloon-to-aneurysm neck ratio is equal to 1:1, meaning that the balloon is inflated so that its diameter matches the diameter of the aneurysm neck, without exerting sufficient pressure to damage the highly fragile aneurysm neck and causing the aneurysm to rupture. In the studies described herein, the balloon was inflated up to a pressure of 2.0 ATM. The RF generator was then activated to apply one Watt of power at a frequency of 70 KHz for 80 seconds, resulting localized heating of the vascular tissue to a temperature of 80 °C.. A timer was placed in the circuit to automatically shut off the RF generator after the allotted time. The balloon was deflated, and shrunk to its undeformed state under the spring force provided by the electrodes. At that time, the catheter assembly can be withdrawn, or the aneurysm can be packed with coils via a conventional microcatheter inserted through the lumen 14 of the support catheter 12.

[0050] It will be appreciated that the gap "g" shown in FIGURE 5 between the electrodes within the balloon and the surface of the aneurysm is an important parameter for proper implementation of this procedure. The balloon should be manufactured so that the size of this gap has a value determined in consideration of the amount of electrical power to be applied so that the effect of the energy is to destroy the intima in an area substantially limited to the aneurysm neck region N R without affecting tissue in other areas of the surrounding vascular wall. In this fashion, a double-lumen balloon catheter constructed and used as described herein enables a safe, highly effective endovascular procedure for the treatment of aneurysms and other vascular defects of the types already mentioned.

[0051] Animal Efficacy Study Using RF Frequency to Ablate Aneurysm Neck

[00S2] A study was conducted on rabbits to evaluate the feasibility and efficacy of using the radiofrequency energy emitting double-lumen balloon catheter described above for ablation of elastase-induced wide necked saccular aneurysms. [0053] I. Materials and Methods

[0054] Animal Selection and Care Compliance, The study was conducted in 24 New Zealand white male rabbits (3-4 kg) by a research team including an interventional cardiologist, an interventional neuroradiologist, and a vascular pathologist in accordance with approved protocol by the Institutional Animal Care and Use Committee of Charles River

Laboratories. The animals were maintained under the National Institutes of Health's Guide to the Care and Use of Laboratory Animals. Vendor surveillance reports indicated chat the rabbits were from colonies seronegative for Encephalitozoon cuniculi, cilia- associated respiratory bacillus, and Treponema paraJuiscuniculi and were negative for Salmonella spp., Klebsiella spp., Citrobacter spp., helminth endoparasites, and arthropod ectoparasites. The rabbits were housed in a vivarium that was not SPP for Bordetella bronchiseptica, but Pasteurella multocida was a controlled pathogen. Rabbits were singly housed in stainless-steel cages in animal rooms with constant environmental conditions (61 to 72 °P [16.1 to 22.2 °CJ; relative humidity, 30% to 70%; 12:12-hour light:dark cycle) and were fed with a fixed-formula rabbit diet (2031 Tekiad Global High Fiber Rabbit Diet, Harlan Laboratories, Madison, WTJ, supplemented with alfalfa hay once daily.

Postoperative care included buprenorphine (0.005 mg/ kg SC) twice daily for at least 2 days and enrofloxarin (S mg/kg SC) once daily for 5 days.

[0055] Animal Anesthesia. The rabbits were premedicated with meloxicam (0.3 mg/kg SC), buprenorphine (0.005 mg/kg SC), and acepromazine (0.5 mg/kg SC), followed by ketamine (20 mg/kg 1M) and medetomidine (0.25 mg/kg 1M) for anesthesia induction. Endotracheal intubation by using 3.0 mm endotracheal tube was followed by the maintenance anesthesia with 1% to 2% isoflurane delivery in 100% oxygen. Heparin (100 U/kg) was administered IV. [0056] Aneurysm Model Creation, The fur at the neck was removed and the operation area was disinfected for the induction of the aneurysm. The right common carotid artery (RCCA) was surgically exposed over a length of 2 cm using a sterile technique and control of the vessel was obtained by a permanent ligation of its cranial part with 4-0 silk suture. A 2 mm beveled arteriotomy was made and a 5-French vascular sheath (Avanti introducer set; Cordis Endovascular Systems, Miami Lakes, FL) was introduced caudad into the lumen to the mid-portion of the vessel The same kind of second suture was used to tie the sheath to the RCCA. Nonionic contrast material was injected through the sheath to define the origin of the RCCA. With fluoroscopic guidance (OEC 9800 Plus, GE Medical Systems, Salt Lake City, UT), through the diaphragm of the sheath, a 3F Fogarty balloon (Baxter Healthcare Corp, Irvine, CA) catheter and a Tracker 10 microcatheter (Target

Therapeutics, Fremont; CA) were introduced into the RCCA.

[0057] The balloon was positioned within the brachiocephalic artery at the origin of the RCCA, and the tip of the microcatheter was positioned immediately cephalad to the balloon, to reside at the origin of the RCCA. The balloon was gently inflated to effect occlusion of the brachiocephalic artery and the origin of the RCCA. A solution of 25% by volume normal saline, 25% by volume iodinated contrast material (Omnipaque 300; Nycomed, Princeton, NJ), and 50% by volume porcine elastase (5.23 U/mgP, 40.1 mgP/mL; Worthington Biochemical Corp, Lakewood.NJ) and another solution of 25% by volume norma! saline, 25% by volume iodinated contrast material (Omnipaque 300; Nycomed, Princeton, NJ), and 50% by volume type 1 collagenase (1.5 mg; Sigma-Aldrich, St Louis, MO) were prepared on the bench. Under continuous fluoroscopic monitoring, the saline-contrast- elastase solution was infused into the lumen of the microcatheter until the lumen of the CCA was slightly expanded in size. The solution was maintained in place within the lumen of the RCCA for 10 minutes. This solution was suctioned by a syringe attached to the microcatheter, the lumen was irrigated by normal saline solution, then suctioned completely, and saline-contrast-coilagenase solution was infused and maintained in the similar fashion. Care was taken to stop the injection before the solutions leaked into the brachiocephalic artery around the Fogarty balloon. Subsequently, the balloon deflated and microcatheter and sheath were removed, the RCCA was ligatsd in its mid-portion and the skin was closed with a running suture. Aneurysms formed from the stump of the right common carotid artery.

[0058] Control Angiography. Animals of all groups were anesthetized as described above at four and 28 weeks after aneurysm creation. At four and 28 weeks after surgery, the animals of Group I underwent intravenous digital subtraction angiography (DSA) by the placement of a 24-gauge angiocath in the left ear vein and an external sizing marker over the chest in anesthetized animals. At 28 weeks after surgery, the animals of Groups 11, III, and IV underwent a similar DSA procedure. During two frames per second DSA, 7 mL of iodinated contrast material (Omnipaque 300; Nycomed, Princeton, Nj) was infused into the left ear vein. Filming was carried into the arterial phase. Magnified views of the aneurysm cavity and adjacent artery in the antero-posterior projection were transferred to film.

[0059] Stttdy Groups. The animals were divided equally into four groups with six animals in each.

Group 1 animals served as control group for aneurysm patency. Groups 11, HI and IV animals underwent aneurysm treatment four weeks after aneurysm creation,

respectively, by (a) densely packing the aneurysms with platinum coils, (b) a combination of dense coil-packing and deendothelialization of the aneurysm necks using the radiofrequency emitting double-lumen balloon catheter described above, and (c) de-endothelialization of the aneurysm necks using the radiofrequency emitting double- lumen balloon catheter only. [0060] Endovascular Treatment of Aneurysms, Under general anesthesia (described above), the animals of Group II, III and IV underwent the described treatments at four weeks after aneurysm creation using the following interventional procedures. The right femoral artery was surgically exposed and distaily ligated. A small arteriotomy was performed with microscissors. A 3F sheath was introduced into the vessel and fixated with a suture, then a 0.10 Transend wire was coaxially delivered through a prototype device as described herein into the aortic arch. A control series of angiography was done to get an impression of the anatomy of the vessels and the aneurysms. Then the prototype device was placed in the neck of the aneurysm and the animal was given 100 U/kg IV heparin. Depending on the size of the aneurysm, one to several coils were placed inside the lumen of the aneurysms in animals of Group II and III. (The necks of the aneurysms of the Group II rabbits were not deendothelialized, meaning they were not subjected to RP radiation using the double-lumen balloon catheter.) After each coil a control angiogram was done to determine the occlusion rate of the aneurysm sac In the case of incomplete occlusion more coils were placed until complete occlusion of the sac was achieved.

[0061] In addition to coiling, the aneurysms of Group HI animals were treated by radiofrequency energy application circumferentially with a mid-portion of the prototype device balloon as described above until it sealed the aneurysm neck, up to a pressure of 2.0 ATM. The RF generator was then turned on and heat was transmitted to the balloon until 80 °C was reached and maintained for up to 80 seconds (this includes the ramp-up time as the balloon was heated to the desired temperature). As RF energy was being delivered, the inflation pressure was maintained at a value determined by the size of the aneurysm neck (but no more than 2.0 ATM), and once the timer completed its countdown, the RF generator was automatically shut off. The aneurysms of Group IV animals were treated by radiofrequency energy application only, as described above. After retrieval of the prototype device, the femoral artery was LIgated. The wound was closed with a running suture and skin glue.

[0062] Angiographic Assessment of Aneurysm Morphology. Aneurysm morphology was studied by the interventional cardiologist and interventional neuroradiologist The width, height and neck diameter of the aneurysm cavities were determined in reference to the external sizing device. Measurements were performed with digital calipers (Digomatic Calipers; Mitutoyo Corp, Kanagowa, Japan). The width of the aneurysm cavity was determined at its point of maximum measurement, while the height was measured from the aneurysm dome to the mid-portion of a line connecting the proximal and distal portions of the aneurysm neck. The diameter of the parent artery was measured just proximal to the neck of the aneurysm.

[0063] Tissue Harvesting. Immediately after the last angiography at 28 weeks after aneurysm creation, all of the animals in all groups were euthanized with an overdose of intravenous sodium thiopental (10 mg/kg). The mediastinum was dissected, and the aortic arch and proximal great vessels, including the aneurysm segment of artery, were exposed, dissected free from surrounding tissues, and saline, followed by formalin, was rapidly injected through the indwelling catheter, removed en bloc and the results of the gross pathological analysis were documented photographically. The whole vessel segment was embedded in Technovit 7100 (Heraeus-Kulzer) thereby enabling slides with a thickness of 2 pm to be obtained by a rotational microtome, litis technique allowed visualization of both the soft tissue (with a special emphasis on a potential neo-endothelial layer) and the implanted metals on light microscopy. These slides were subsequently stained with hematoxylin-eosin and Elastica van Gieson stains for appraising the configuration of the arterial vessel wall. [0064] This technique was performed in three aneurysms of each of the groups. The remaining three aneurysms per group were further investigated with scanning electron microscopy to obtain an "in-vessel-view" of the aneurysms: the brachiocephalic trunk was longitudinally incised directly opposite the treated aneurysm and carefully spread apart After this procedure, the specimens were fixed in 3.9 % glutaraldehyde. They were dehydrated in a graded acetone series (30, 50, 70, 90, 3x100%) and critical-point-dried in carbon dioxide. The samples were fixed on scanning electron microscopy (SEM) stubs and sputter-coated with gold (SCD 030, Balzers Union, FL), then investigated in an ESEM XL 30 FEG (Environmental Scanning Electron Microscope XL 30 Field Emission Gun FEI Philips, Eindhoven, NL) in high vacuum mode with accelerating voltages of 2-10 kV.

[0065] Histological Assessment Histological and histometricai analyzes were performed by the vascular pathologist who paid particular attention to the cell type and the appearance of the extracellular matrix within the aneurysm cavity and its neck, and who was blinded with respect to the treatment that had been rendered.

[0066] 11. Results

[0067] All animals survived surgery and none showed clinical evidence of neurological insult Animals of all groups showed angiographic patency of parent arteries and aneurysms at four weeks after surgery. The same was found via follow-up angiography in the Group I animals at 28 weeks after aneurysm creation. Angiography of the animals of the remaining groups showed patent parent arteries. At 28 weeks after aneurysm creation it was found that the aneurysms of Group 11 animals were partially obliterated

angiographicaliy in four cases and the remaining two aneurysms were completely occluded. At the same time point, the aneurysms of Group III animals did not demonstrate presence of inflow of contrast material, whereas angiography of Group IV animals showed slow filling of the aneurysm domes. Angiographicaliy, the average dimensions of the aneurysm neck and cavity widths, height of the dome, dome-to-neck ratio and parent artery diameter were 5.2 ± 0.6 mm, 4.9 ± 0.9 mm, 9.1 ± 2.3 mm, 0.9 ± 0.2 and 4.7 ± 1.2 mm respectively.

[0068] Group I. Gross evaluation of harvested samples of Group i animals exhibited aneurysms at the long curve of the brachiocephalic artery. Histological evaluation of the aneurysms exhibited an abrupt termination of the internal elastic lamina at the margins of the sac and orifice, but the tunica media was undamaged and continued into the interior of the saccular part of the aneurysms. The sac walls exhibited a mild to moderately

inflammatory cellular (monocytes and neutrophils) and a mild fibromuscular response. The thickness of the wall at the neck, middle part and apex of the dome were 0.52 ± 0.09 mm, 0.44 ± 0.04 mm and 0.31 ± 0.06 mm respectively. An unorganized thrombus filled one-third of the distal half of aneurysm cavity at the proximity of its apex.

[0069] Group 11. Aneurysm domes of Group 11 animals demonstrated the presence of unorganized fresh thrombus and marked recanalization with laminated blood products of various ages. Spindle cells were found across the aneurysm necks. The necks were partially covered with fibrin. In the aneurysm dome only some of the coil loops were completely

endothelialized, some coil loops demonstrated a thin fibrinous layer; however, most of the coil loops close to the former aneurysm neck were bare and laid in direct contact to the flowing blood with presence of some fresh thrombus material close to the coils. A complete obliteration {i.e. neo-endothelialization over the aneurysm ostium) was not present in every aneurysm. The tissue-blood interface at the aneurysm neck was concave in ail five specimens.

[0070] Group III , Due to the over-inflation of the prototype device one of the animals of Group HI suffered rupture of the aneurysm neck, leading to massive hemorrhage. This animal was euthanized and excluded from the study, in order to have the same number of animals as in other groups one more animal underwent the same procedures as the other animals of this group. Al! specimens of this group showed complete obliteration of aneurysms from parent vessels. Histological analyzes of all specimens from this group showed neointimal coating of the former aneurysm neck above which, before the dome a collagen-rich granulation tissue was mostly present Coil loops demonstrated complete

neoendothelialization and an organized, old thrombus, loose connective tissue infiltration and spindle cells were noted within the domes of all aneurysms.

[0071] Group IV. In all specimens from Group IV the ostium of aneurysm was narrowed and the average thickness of its wall was 0.81 ± 0.12 mm due to the deposition of a collagen-rich, dense granulation tissue. Thickness of the wall at the middle part and apex of the dome were 0.5910.09 mm and 0.45 ± 0.08 mm respectively. A fresh, unorganized thrombus was present within the aneurysm cavity in all specimens of this group.

[0072] ill. Conclusions

[0073] This example study demonstrates that a device as described herein can be safely and effectively used for permanent sealing elastase-induced saccular aneurysm necks, particularly in combination with coil packing of the aneurysm sac. While not wishing to be bound by any particular theory, it is believed that application of RF energy in accordance with the description herein causes increased migration and proliferation of macrophages and fibroblasts at the deendothelialized area of the aneurysm neck, which leads to local deposition of collagen and thereby minimizes chances of recanalization.

[0074] Further Modifications And Embodiments [0075] Note that while the embodiments described above are described in the context of the intracranial arteries, similar techniques may be used in other vessels to seal defects (aneurysms, dissections, arteriovenous malformations and tumors) in different portions of a patient's anatomy.

[0076] In other embodiments the device disclosed herein, and specifically the endothelial

altering means, can be adapted to apply ultrasonic energy for endothelial ablation, or electromagnetic energy at frequencies other than radiofrequencies. In another embodiment the endothelial altering means could comprise a plastic ring with short brushes in the center of the balloon that mechanically remove endothelium after balloon inflation without affecting other components of a vascular wall, in still another variation the endothelial altering means could comprise a metal or plastic ring with short; hollow, flexible needles in the center of the balloon that enable delivery of a substance or substances to remove endothelium chemically without affecting other components of a vascular wall. In summary, the balloon mounted endothelial altering means of the present invention covers any structure suitable for endovascular use that can selectively remove endothelial cells of a vascular wall just at the origin of a vascular defect; without substantially affecting other components of the vascular wall, in order to enhance biological processes responsible for promotion of local thickening of a defect in the wall.

[0077] Summary And Conclusion

[0078] Those skilled in the art will readily recognize that only selected preferred embodiments of &e invention have been depicted and described, and it will be understood that various changes and modifications can be made other than those specifically mentioned above without departing from the spirit and scope of the invention, which is defined solely by the claims that follow. [0079] References

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Claims

WHAT IS CILAIMED lS:

1. A double-lumen balloon catheter assembly for ablating endothelial cells from a region proximate to the origin of a vascular defect; the assembly comprising:

a substantially cylindrical supporting catheter having a central lumen;

an inflatable balloon mounted on the supporting catheter and surrounding an outer surface thereof to form a sealed balloon lumen between an inner surface of the balloon and the outer surface of the supporting catheter;

at least one conduit for introducing fluid to the balloon lumen under pressure to inflate the balloon; and

energy applying means extending circumferentialiy around the balloon proximate to an outer surface thereof for removing an endothelial cellular layer (the intima) just at the region of the defect without substantially affecting other components of the vascular wail when the energy applying means is actuated while the inflated balloon is in contact with the region.

2. A catheter assembly as in claim 1, wherein the energy applying means includes electrodes embedded in a wall of the balloon and exerts a radially inward force as the balloon is inflated for collapsing the balloon when pressure is released from the balloon lumen.

3. A catheter assembly as in claim 2, wherein:

the energy applying means includes at least two electrodes comprising zig-zag shaped plastically deformab!e rings molded in place within the balloon wall, and conductors having distal ends connected to the electrodes for applying radiofrequency ( RF) electrical energy thereto; and the at least one conduit is formed within a wall of the supporting catheter.

4. A double-lumen balloon catheter assembly for ablating endothelial cells from a neck region of an aneurysm, the assembly comprising:

a substantially cylindrical supporting catheter having a central lumen; an inflatable balloon mounted on the supporting catheter and surrounding an outer surface thereof to form a sealed balloon lumen between an inner surface of the balloon and the outer surface of the supporting catheter;

at least one conduit within a wali of the supporting catheter for introducing fluid to the balloon lumen under pressure to inflate the balloon; and

two electrodes extending circumferentially around the balloon proximate to an outer surface thereof for removing an endothelial cellular layer (the intima) just at the neck region of the aneurysm without substantially affecting other components of the vascular wall when

radiofrequency (RF) electrical energy is applied to the electrodes while the inflated balloon is in contact with the neck region, wherein each electrode comprises a zig-zag shaped plastically deformable ring molded in place within the balloon wall for exerting a radially inward force as the balloon is inflated for collapsing the balloon when pressure is released from the balloon lumen; and conductors molded in place within the balloon wall and having distal ends connected to respective electrodes for applying radiofrequency (RF) electrical energy thereto.

5. A catheter assembly as in claim 4, wherein each electrode has a substantially circular cross-section.

6. A catheter assembly as in claim 5, wherein the electrodes are a 95% platinum/5% iridium alloy.

7. A catheter assembly as in claim 5, wherein the electrodes are spaced about 1.0 mm apart and about 0.1 mm from the outer surface of the balloon.

8. A catheter assembly as in claim 7, wherein the electrodes are a 95% platinum /5% iridium alloy.

9. A catheter assembly as in claim 4, wherein the balloon comprises polyurethane coated on the outer surface of the balloon with polyvinylpyrrolidone, polyacrylamide and heparin and the electrodes are a 95% platinum/5% iridium a!loy and are spaced about 1.0 mm apart and about 0.1 mm from the outer surface of the balloon.

10. An endovascular procedure for treating a saccular aneurysm using the catheter assembly described in claim 3 having proximal ends of the conductors connected to an RF generator, the method comprising:

endovascularly guiding a guide catheter to the vicinity of the aneurysm;

introducing the catheter assembly through the guide catheter to position the balloon within the neck of the aneurysm;

providing an inflation fluid under pressure through at least one conduit to inflate the balloon;

maneuvering the balloon so that the electrodes are positioned in a neck region of the aneurysm when the outer surface of the inflated balloon is in contact with the neck region; and removing an endothelial cellular layer (the intima) just in the neck region without substantially affecting other components of the vascular wall by actuating the RF generator to supply a predetermined amount of electrical energy to the electrodes for a predetermined time.