WO2014022867A1 - Endovascular multi-balloon cathethers with optical diffuser for treatment of vascular stenoses - Google Patents

Abstract

An interventional vascular therapeutic device (100) including a catheter shaft (110) having a pair of occlusion balloons (132, 134), a dilatation balloon (136) disposed on the catheter shaft between the occlusion balloons, a first inflation lumen (112) and a second inflation lumen (113) cofigured to supply inflation fluid to a proximally disposed one and a distal on of the occlusion balloons, a third inflation lumen (115) configured to supply inflation fluid to the dilatation balloon, a primary lumen (111) extending the entire length of the catheter configured to slidably receive a guidewire, and an infusion lumen (114) extending from a proximal end of the catheter shaft toward the distal end of the catheter shaft and terminating at an infusion exit port (140) located between the occlusion balloons. The device including an optical fiber (480) configured to be inserted into the primary lumen in exchange for the guidewire.

Description

ENDOVASCULAR MULTI-BALLOON CATHETERS WITH OPTICAL DIFFUSER FOR TREATMENT OF VASCULAR STENOSES

Description

Cross-Reference to Related Application 01] This application claims the benefit of priority of U.S.

Provisional Application No. 61/679,591, entitled "Endovascular Multi-Balloon Catheters with Optical Diffuser for Treatment of Vascular Stenoses," filed on August 3, 2012 and U.S. Provisional Application No. 61/794,725, entitled "Endovascular Multi-Balloon Catheters with Optical Diffuser for Treatment of Vascular Stenoses," filed on March 15, 2013, and is related to U.S. Patent No. 7,514,399 to Utecht et al. and U.S. Provisional Application No. 61/679,365, entitled "Compositions and Methods of Using the Compositions for Plaque Softening," filed on August 3, 2012, the disclosures of all of which are incorporated herein by reference.

Technical Field

[0002] The present disclosure relates to catheters and, more particularly, to endovascular multi-balloon catheters having an optical diffuser for treatment of vascular stenoses.

Background

[0003] Vascular plaque causes several medical conditions, including but not limited to, coronary artery disease, carotid artery disease, and peripheral artery disease, resulting in hypertension, ischemic injury, stroke, or myocardial infarction and sometimes death.

[0004] While the exact mechanism of plaque build-up in vasculature is not completely understood, the general aspects of this atherosclerotic process have been identified. In the normal arterial wall, vascular smooth muscle cells (VSMC) proliferate at a low rate, approximately less than 0.1 percent per day. These VSMC cells in the vessel walls exist in a contractile phenotype characterized by eighty to ninety percent of the cell cytoplasmic volume occupied with the contractile apparatus. Endoplasmic reticulum, Golgi, and free ribosomes are few and are located in the perinuclear region. Extracellular matrix surrounds the VSMC, and is rich in heparin- like glycosylaminoglycans, which are believed to be responsible for maintaining smooth muscle cells in the contractile phenotypic state.

[0005] Atherogenesis is the developmental process of atheromatous plaques, resulting in atherosclerotic narrowing of the cardiovasculature over time. The build-up of an atheromatous plaque is a slow process, developed over a period of several years through a complex series of cellular events occurring within the arterial wall, and in response to a variety of local vascular circulating factors. Atheromatous plaques form in the arterial tunica intima, a region of the vessel wall located between the endothelium and the tunica media. The bulk of these lesions are made of excess fat, collagen, and elastin. At first, as the plaques grow, only wall thickening occurs without any significant narrowing. Stenosis is a late event, which may never occur and is often the result of repeated plaque rupture and healing responses, not just the atherosclerotic process by itself. Such vascular stenoses are alternatively referred to as vascular lesions.

[0006] Intracellular micro-calcifications form within the VSMC of the surrounding muscular layer, specifically in the muscle cells adjacent to the atheromas. As the atherosclerotic diseases progresses, these VSMC become abnormally proliferative, secreting substances (e.g., growth factors, tissue-degradation enzymes and other proteins). In time, as cells die, this leads to extracellular calcium deposits between the muscular wall and outer portion of the atheromatous plaques. The outer, older portions of the plaque become more calcific, less metabolically active and more physically rigid over time.

[0007] Two plaque types can be distinguished, namely: (a) fibro- lipid / fatty plaques; and (b) fibrous / calcified plaques.

[0008] The fibro-lipid (fibro-fatty) plaque is characterized by an accumulation of lipid-laden cells underneath the intima of the arteries, typically without narrowing the lumen due to compensatory expansion of the bounding muscular layer of the artery wall. Beneath the endothelium there is a "fibrous cap" covering the atheromatous "core" of the plaque. The core consists of lipid-laden cells (macrophages and smooth muscle cells) with elevated tissue cholesterol and cholesterol ester content, fibrin, proteoglycans, collagen, elastin, and cellular debris. In advanced plaques, the central core of the plaque usually contains extracellular cholesterol deposits (released from dead cells), which form areas of cholesterol crystals with empty, needle-like clefts. At the periphery of the plaque are younger "foamy" cells and capillaries. These type of plaques are sometimes referred to as vulnerable plaques, and usually produce the most damage to the individual when they rupture, often leading to fatal myocardial infarction when present within the coronary arteries.

[0009] The fibrous plaque is also localized under the intima, within the wall of the artery resulting in thickening and expansion of the wall and, sometimes, spotty localized narrowing of the lumen with some atrophy of the muscular layer. The fibrous plaque contains collagen fibers (eosinophilic), precipitates of calcium (hematoxylinophilic) and, rarely, lipid-laden cells. Atheromas within the vessel wall are soft and fragile with little elasticity. In addition, the calcification deposits between the outer portion of the atheroma and the muscular wall of the blood vessel, as they progress, lead to a loss of elasticity and stiffening of the blood vessel as a whole.

The calcification deposits, after they have become sufficiently advanced, are partially visible on coronary artery computed tomography or electron beam tomography (EBT) as rings of increased radiographic density, forming halos around the outer edges of the atheromatous plaques, within the artery wall. On CT, greater than 130 units on the Hounsfield scale (some argue for 90 units) has been the radiographic density usually accepted as clearly representing tissue calcification within arteries. A carotid intima- media thickness scan (CIMT can be measured by B-mode ultrasonography) measurement has been recommended by the American Heart Association as the most useful method to identify atherosclerosis.

Intravascular ultrasound (IVUS) and optical coherence tomography (OCT) are the current most sensitive intravascular methods for detecting and measuring more advanced atheroma within living individuals. However, these imaging systems are seldom used for assessment of atheroma in view of their cost, which is not reimbursed in many medical environments, as well as invasive risks.

Angiography, since the 1960s, has been the traditional way of evaluating atheroma. However, angiography is only motion or still images of dye mixed with the blood within the arterial lumen and do not directly visualize atheroma. Rather, the wall of arteries, including atheroma with the arterial wall, generally remain invisible, with only limited shadows which define their contoured boundaries based upon x-ray absorption. The limited exception to this rule is that with very advanced atheroma, with extensive calcification within the wall, a halo-like ring of radiodensity can be seen in older patient, especially when arterial lumens are visualized end-on. On cine-floro, cardiologists and radiologists typically look for these calcification shadows to recognize arteries before they inject any contrast agent during angiograms.

[0014] Interventional vascular procedures, such as percutaneous transluminal angioplasty (PTA) for peripheral vascular disease and percutaneous transluminal coronary angioplasty (PTCA) for coronary artery disease, are typically performed using an inflatable balloon dilatation catheter to restore increased luminal diameter at the vascular lesion. During a typical PTA procedure, the dilatation catheter is positioned within the blood vessel at the location of the narrowing caused by the lesion, and the balloon is expanded with inflation fluid to dilate the vessel lumen. Following the dilatation, it is common to introduce a second balloon catheter which carries and deploys an expandable metal stent which serves to maintain vessel patency.

[0015] Restenosis, the recurrence of vascular stenosis after corrective surgery, is an accelerated form of atherosclerosis. Recent evidence has supported a unifying hypothesis of vascular injury in which coronary artery restenosis along with coronary vein graft and cardia allograft atherosclerosis can be considered to represent a much accelerated form of the same pathogenic process that results in spontaneous atherosclerosis. Similarly, restenosis is problematic with peripheral vasculature.

[0016] Upon pressure expansion of an intracoronary balloon catheter during PTA, for example, smooth muscle cells and endothelial cells within the vessel wall become injured, initiating a thrombotic and inflammatory response. Cell derived growth factors such as platelet derived growth factor, basic fibroblast growth factor, epidermal growth factor, thrombin, etc., released from platelets, invading macrophages and/or leukocytes, or directly from the smooth muscle cells provoke a proliferative and migratory response in medial smooth muscle cells. These cells undergo a change from the contractile phenotype to a synthetic phenotype characterized by only a few contractile filament bundles, extensive rough endoplasmic reticulum, Golgi and free ribosomes. Proliferation and migration usually begin within one to two days' post-injury and peaks several days thereafter.

[0017] Daughter cells migrate to the intimal layer of arterial smooth muscle and continue to proliferate and secrete significant amounts of extracellular matrix proteins. Proliferation, migration and extracellular matrix synthesis continue until the damaged endothelial layer is repaired at which time proliferation slows within the intima, usually within seven to fourteen days post- injury. The newly formed tissue is called neointima. The further vascular narrowing that occurs over the next three to six months is due primarily to negative or constrictive remodeling.

[0018] Simultaneous with local proliferation and migration, inflammatory cells adhere to the site of vascular injury. Within three to seven days post-injury, inflammatory cells have migrated to the deeper layers of the vessel wall. In animal models employing either balloon injury or stent implantation, inflammatory cells may persist at the site of vascular injury for at least thirty days. Inflammatory cells therefore are present and may contribute to both the acute and chronic phases of restenosis.

[0019] Restenosis can occur following coronary artery bypass graft surgery (CABG), endarterectomy, heart transplantation, and with increased frequency following percutaneous balloon angioplasty (PTA and PTC A), atherectomy, laser ablation or endovascular stenting. Unfortunately, up to one-third of patients receiving a revascularization procedure will redevelop artery- blockage (i.e., restenosis) within a little as six months after treatment. Restenosis is ultimately responsible for recurrence of symptoms (or death), often requiring repeat revascularization surgery. Despite over three decades of research and significant improvements in the primary success rate of the various medical and surgical treatment of atherosclerosis disease, including angioplasty, bypass grafting and endarterectomy, secondary failure due to late restenosis continues to occur with as much as one-third to one-half of treated patients.

[0020] However, patients with calcified plaque present a much more difficult challenge for intervention. Indeed, presentation of diffuse, calcified vascular plaque within coronary arteries is often one of the most critical exclusion criteria for PTCA patient candidates, and these patients are instead required to receive invasive coronary artery bypass graft (CABG) surgery to alleviate the coronary blood flow deficiencies. On the other hand, patients presenting diffuse, calcified vascular plaque in their peripheral arteries and veins may still be eligible for PTA vascular intervention, but these patients typically require a preliminary interventional procedure involving plaque removal, such as by use of atherectomy catheters.

[0021] In the event that an atherectomy procedure is required, the interventional physician must first deploy an embolic protection device (EPD) within the vessel being treated at a location which is distal (i.e., downstream relative to blood flow) to the atherectomy treatment site. Despite the adjunctive use of such an EPD, plaque particulates which are dislodged by the atherectomy device can occasionally escape the EPD and travel downstream within the vasculature causing a stroke, heart attack or otherwise permanently compromise distal vascular blood flow. In any event, the use of atherectomy devices produces substantial trauma to the blood vessel, and can produce serious complications such as thrombosis, as well as poor vascular healing response leading to premature restenosis. Finally, to the extent that the interventional physician performs a PTA procedure within a blood vessel containing a lesion formed of calcified plaque, even after preliminary atherectomy, it is known that dilating such a treatment site is more likely to produce increased vascular damage to the vascular tissue, such as micro-dissections of the residual calcified plaque which propagates into the adjacent vascular tissue.

[0022] Over the past three decades, interventional revascularizations are often followed by the deployment of vascular stent implants. Unfortunately, these devices are sometimes prone to produce thrombus which can embolize causing strokes, myocardial infarct, and the like. Additionally, stents may tend to fatigue over time, leading to strut fracture which causes further damage to adjacent vascular tissue, as well as increased risk of severe thrombosis complications. Use of stents in certain peripheral vascular, such as the superficial femoral artery (SFA) which decends below the waist to the knees, is particularly poorly suited for stenting, in view of the substantial forces which act upon the SFA during walking as well as sitting, such as substantial vessel / stent elongation, vessel / stent compression and vessel / stent torsional motion.

[0023] During angioplasty, intra-arterial balloon catheter inflation and stent deployment results in de-endothelialization, disruption of the internal elastic lamina, and injury to medial smooth muscle cells. A significant number of patients have a biological reaction of the arterial wall characterized by smooth muscle cell proliferation that results in luminal narrowing. While restenosis likely results from the interdependent actions of the ensuing inflammation, thrombosis, and smooth muscle cell accumulation, the final common pathway evolves as a result of medial VSMC dedifierentiation from a contractile to a secretory phenotype. This involves, principally, VSMC secretion of matrix metalloproteinases degrading the surrounding basement membrane, proliferation and chemotactic migration into the intima, and secretion of a large extracellular matrix, forming the neointimal fibroproliferative lesion. Much of the VSMC phenotypic dedifferentiation after arterial injury mimics that of neoplastic cells (i.e., abnormal proliferation, growth-regulatory molecule and protease secretion, migration and basement invasion).

To overcome this phenomenon, and in an attempt to prevent restenosis, several companies have developed stents that are permanently implanted in coronary or peripheral vessels and release (elute) drugs that inhibit or prevent cell proliferation and therefore prevent the narrowing created by VSMC proliferation. However, while drug eluting stents reduce VSMC proliferation and restenosis on the one hand, they also prevent recovery of an endothelial cell monolayer for an extended period of time (e.g., several months or longer), thereby making the vessel wall thrombogenic for an extended period. The resulting clinical outcome is late clotting of drug-eluting stents (DES), resulting in chronic health risks, such as late-stage thrombosis. To prevent stent thrombosis, patients are typically recommended to take anticoagulant and antiplatelet drugs (e.g., aspirin and Plavix) for at least one year, assuming that endothelial cell recovery and vessel healing will happen within this one year window. Unfortunately, however, increasing numbers of patients receiving DES implants are being required to continue various platelet anti-aggregation, anti-coagulant therapy for several years if not indefinitely, with enormous additional healthcare cost and with considerable future health complications and patient inconvenience.

[0025] In addition to DES implants, a variety of other interventional catheter devices have been developed to locally administer the desired therapeutic agents to the vascular treatment site. Although most of the available drug delivery catheters rely on simple fluid transfer for delivery of compounds into the vasculature, they can be classified into three main groups, namely: (a) passive diffusion catheters; (b) pressure-driven balloon catheters; and (c) mechanically-assisted injection catheters.

[0026] Balloon catheters that facilitate passive diffusion of the pharmacological agent to reach only the innermost layers of the artery wall (e.g., intima and media) include dual (i.e., double) balloon occlusion catheters, channel balloon catheters, microporous balloon catheters and hydrogel balloon catheters.

[0027] Dual-balloon occlusion catheters have an infusion port separated by two balloons that expand under low-pressure inflation to a predetermined diameter. When inflated, the balloons isolate a treatment zone within the vascular treatment site, enabling the physician to infuse a specified fluid which contains the therapeutic agent and maintain a high local concentration compared to systemic infusion. The fluid infused may contain a pharmaceutical agent, or an infusion of cell / gene therapy materials carried in suspension, which can then be introduced through a port into the retaining space created between the dual, inflated balloons. Early dual- occlusion balloon system for drug delivery are taught, for example, by U.S. Patent No. 4,636,195 to Wolinsky and U.S. Patent No. 4,824,436 to Wolinsky, utilize a dual-balloon arrangement located at the distal end of the catheter, with the balloons being longitudinally spaced apart, including a proximal occlusion balloon and a distal occlusion balloon. During use, the proximal and distal balloons are located on opposite sides of a vascular lesion, and a space is defined therebetween. While the occlusion balloons are inflated, the desired therapeutic agent can be infused through another lumen provided in the catheter to enter the occluded vascular space. Thus, the dual balloon system creates a cylindrical space for infusion of a drug which is isolated from blood flow through the artery or vein. This system offers a safety advantage, since relatively minor damage to the vessel intima and media results from the low occlusion balloon pressures.

Helical or spiral-shaped balloon catheters are modified dual-balloon structures having a coil-shaped balloon wrapped around a perfusion channel forming a through-lumen to permit passive perfusion of blood flow while the helical balloon is inflated into contact with inner surface of the vessel wall. The proximal and distal ends of the helical balloon are designed to occlude the region of the artery which overlies the balloon structure, while providing a closed helical space into which therapeutic fluid can be introduced through an infusion port. An exemplary helical balloon catheter suitable for localized vascular drug delivery is described in U.S. Patent No. 5,554,119 to Harrison et al., which corresponds to the DISPATCH™ catheter developed and manufactured by SciMed Life Systems, Inc. The advantage of this system is that the central lumen which is defined by the perfusion channel that is concentrically disposed within the perfusion balloon, thereby permitting a continuous blood flow during balloon inflation to eliminate ischemia in downstream tissue. Thus, this passive blood perfusion feature supports longer inflation times, giving the therapeutic fluid more time to interact with the vessel wall. Although both helical and dual-balloon occlusion catheters may suffer some compromise in the event of significant branch vessels which intersect with the vascular treatment site of the parent vessel, careful positioning of the device may be sufficient to block alternative blood flow conduits.

[0029] Additional catheter designs have been proposed for local delivery of drug to a vascular sitewhich involve the use of a perforated or weeping balloon membrane. This approach was disclosed by Wolinsky, H., in an article entitled, Use of a Perforated Balloon Catheter to Deliver Concentrated Heparin Into the Wall of a Normal Canine Artery, 15 JACC 475 (Feb. 1990). In this case, the catheter utilized a balloon with several micro-porous apertures, and the drug was incorporated directly into the same fluid (e.g., saline fluid) which is used to inflate the balloon. However, one of the major concerns of any device with perforated apertures is the potential adverse effect caused by the relatively high velocity jet of fluid which impacts the wall of the blood vessel, and which may cause micro-dissections of the vascular tissue.

[0030] Hydrogel-coated balloons are angioplasty balloon catheters whose exterior is coated with an adsorbent polymer-based coating which has been saturated or loaded with a selected therapeutic agent. Following balloon inflation, the drug- impregnated polymer physically contacts with the vessel wall. Comparatively, the local therapeutic drug dose is required to be significantly higher on the coated surface of this device relative to the levels needed to support delivery within a confined cylindrical space provided by a double or spiral balloon catheter. For example, histological analysis of artery wall segments after hydrogel balloon delivery of a viral-mediated β-galactosidase reporter gene showed gene expression predominantly in medial cells, suggesting this as a method for penetrating beneath the intimal cell layer. However, it is not clear to what tissue depth within the vascular wall the therapeutic drug can be delivered using this approach. Moreover, with many DEB systems it is difficult to predictably and repeatedly ensure precisely what amount of drug is successfully delivered to the vascular tissue, as opposed to residual drug which simply adheres to the balloon coating or otherwise dissipates in the blood flow upon deflation of the DEB balloon element.

[0031] In summary, the following considerations are among the most critical with respect to patients receiving interventional vascular treatment for treatment of vascular stenoses, namely: (a) maintaining acute vascular patency upon removal of the PTA dilatation system, particularly if no stent is deployed; (b) limiting arterial restenosis after balloon angioplasty or stenting; (c) hindering intimal hyperplasia and stenosis relative to sapphenous vein bypass (SVG) grafts; (d) promoting restored blood flow in both arterial and venous vasculature, such as with lower limb ischemia patients; (e) preventing thrombus formation at the vascular treatment site; and (f) stabilizing plaque to reduce lesion progression, embolization and diminish the risk of later rupture.

[0032] As noted above, it would also be highly desirable to provide interventional revascularization therapies for patients suffering from calcified plaque. Diagnosis of extensive calcified plaque will typically either result in the patient being entirely excluded from intended interventional therapy, or otherwise requires adjunctive use of atherectomy devices and embolic protection devices, all of which present considerable additional cost, as well as introducing risk of trauma to vascular tissue. [0033] Additionally, it would be desirable to provide interventional revascularization therapies for patients requiring PTA or PTCA procedures, but without the necessity of having to implant a prosthetic stent which may restenose or otherwise fracture due to prolonged fatigue at certain high-stress anatomy of the vasculature, or which may fail to properly heal due to complications associated with pharmaceutical agents delivered by DES implants and / or the polymeric coatings used on the DES implants to provide the desired release kinetics of therapeutic agents.

[0034] Finally, it would be desirable to provide interventional revascularization therapies which can reliably restore vessel patency to both arteries and veins, including previous CABG patients whose sapphenous vein bypass grafts have become occluded over time.

Summary

[0035] The present disclosure accordingly is directed to a system for providing a more comprehensive, universally-applicable vascular intervention which enables treatment of a broader category of patients suffering from atherosclerotic disease. The present disclosure includes an interventional catheter which controllably delivers certain chemical formulations, based upon various naphthalimide-based carrier solutions as disclosed in more detail in U.S. Patent No. 7,514,399 to Utecht et al. and U.S. Provisional Application No. 61/679,365, entitled "Compositions and Methods of Using the Compositions for Plaque Softening," filed on August 3, 2012, the disclosures of which are incorporated herein by reference. The chemical formulations are locally infused by the catheter into the desired vascular treatment site in order to facilitate treatment of a vessel requiring revascularization (e.g., an artery or vein having narrowed luminal regions, such as stenoses restricting blood flow).

[0036] In particular, the present disclosure is intended to restore and maintain the vessel patency of stenosed vasculature, including treatment of vasculature lesions comprising atherosclerotic plaque which may or may not be calcified, and to effectively softens calcified plaque, thereby enabling pecutaneous transluminal angioplasty (e.g., PTA and PTCA) to be performed on the treated plaque in order to reestablish and maintain the desired vessel patency.

[0037] Additionally, the present disclosure specifically contemplates use of these naphthalimide-based carrier solutions to enable adjunctive drug delivery of various therapeutic agents, which can be releasably tethered to the carrier solution to ensure diffusion of an effective dose of the desired therapeutic agent throughout the intramural space of the vascular wall (e.g., intima, media and adventitia), following which the agents are released into the vascular tissue to improve healing and inhibit restenosis following revascularization.

[0038] Finally, the present disclosure specifically contemplates use of specific naphthalimide-polyethylene glycol (naphthalimide- PEG) compositions previously disclosed in more detail in U.S. Patent No. 7,514,399 to Utecht et al. and U.S. Provisional Application No. 61/679,365, entitled "Compositions and Methods of Using the Compositions for Plaque Softening," filed on August 3, 2012. The naphthalimide-polyethylene glycol (naphthalimide-PEG) composition may be a biocompatible, light-activated polyethylene- glycol (PEG) based solution with the viscosity of saline. This naphthalimide-PEG composition is water-soluble and has a low molecular weight which enables diffusion through atherosclerotic plaque and calcium and into the vessel wall, including the media. This naphthalimide-PEG composition is supplied in an 8ml vial containing 7ml of solution.

[0039] This naphthalimide-PEG composition can be activated at the vascular treatment site, such as by photoactivation, thereby cleaving off the naphthalimide molecules which are readily eliminated from the body. Upon activation, the PEG linkers are photochemically produced as a reactive intermediate during release, and these PEG linkers will bind at their opposite active ends to available collagen protein naturally present within the numerous collagen fibrils which comprise the vascular wall tissue. As a result, the cross-linked collagen fibrils will be reinforced and stabilized.

[0040] Prior to photoactivation and collagen cross-linking, it is important that the physician has already reestablished the vessel lumen to a desired luminal diameter which more closely approximates a normal diameter. Consequently, the fully diffused naphthalimide-PEG composition will immediately produce collagen cross-linking which instantaneously fixates the vessel wall and effectively provides an endogenous vascular stent. This process is otherwise also herein referred to as a Natural Vascular Scaffolding (NVS) therapy, and the therapeutic catheter which is used to perform this procedure is referred to as the NVS catheter.

[0041] By eliminating the necessity of delivering an implantable prosthetic stent following PTA therapy, it is expected that vessel trauma otherwise associated with stent deployment, which can be very substantial, is thereby avoided. Moreover, providing NVS therapy in lieu of stenting is expected to reduce the need to administer anti -platelet aggregation agents (e.g., PLAVIX) to inhibit thrombus formation, as well as to reduce the need to administer anti-proliferative agents (e.g., Taxol, Sirolimus, Everolimus, Zotarolimus, Biolimus, etc.) to inhibit in-stent restenosis. Finally, the ability to diffuse the NVS carrier solutions directly into all layers of the vessel (e.g., arterial layers of intima, media, and adventitia), together with a tethered drug which becomes bio-available as a function of the rate of hydrolysis of the linker, is believed to more effectively deliver drugs directly into the vascular tissue requiring therapy. Particular attention, for example, is being given to ensure that the all tissue layers of the artery wall, including the intima, media, and adventitia, receive appropriate drug therapy.

[0042] Conventional PTA balloon dilatation procedures are performed on patients using standard PTA catheters which include a dilatation balloon disposed at the distal end of the catheter. During the PTA procedure, the distal end of the PTA catheter is advanced to the vascular stenosis over a pre-advanced guidewire, and the dilatation balloon is positioned across the vascular stenosis or lesion (i.e., vascular blockage produced by plaque deposition which restricts blood flow). Once the dilatation balloon is aligned with the vascular stenosis, it is inflated to compress the plaque against the vessel wall, thereby reestablishing the vessel lumen. Once the vessel lumen is restored, the PTA catheter is withdrawn from the patient.

[0043] In the event that further interventional treatment is required, such as delivery of an implantable vascular stent, the guidewire used during the PTA procedure is left in place such that it remains within the vessel, extending across the treated region of the vessel where the stenosis was dilated. However, at this point of the revascularization procedure, the present disclosure contemplates removal of the initial PTA catheter, and substitution with an NVS therapeutic catheter in place of a stent delivery catheter. Next, an NVS therapeutic catheter is introduced over the pre-advanced guidewire to position the distal end of the NVS catheter precisely at the region of the vessel previously treated by the PTA catheter.

[0044] Further advantages and embodiments will become evident from the attached drawings.

Brief Description of the Drawings

[0045] In the figures:

[0046] FIG. 1 is an illustration of an exemplary catheter in accordance with various aspects of the disclosure;

[0047] FIG. 2 is a cross-sectional view of the catheter along II-II of FIG. 1;

[0048] FIG. 3 is an illustration of a distal end of the catheter of

FIG. 1;

[0049] FIG. 4 is an illustration of an exemplary light fiber for use with the catheter of FIG. 1; and

[0050] FIG. 5 is a longitudinal cross sectional view of the distal portion of a balloon catheter assembly having multiple balloons in accordance with various aspects of the disclosure.

Detailed Description

[0051] An exemplary NVS therapeutic catheter 100 is depicted in

FIG. 1. The NVS therapeutic catheter comprises a catheter shaft 110 incorporating five lumens 111, 112, 113, 114, and 115 extending longitudinally the majority of the length of the catheter shaft. The entire catheter shaft measures approximately 138 centimeters in length. The NVS therapeutic catheter is compatible with a 7F Cook Ansel Introducer Sheath. The main catheter shaft is composed of a polymeric composition which provides suitable column strength and flexibility to controllably advance through tortuous vasculature to the target vascular treatment site. An exemplary polymeric composition for the catheter shaft is a Pebax™ 7233 polyetheramide block copolymer, formed by a single extrusion, with a radially- symmetrical, five-lumen construction, and having a light transmission efficiency of better than 90% from the central-most lumen through the outer wall. A cross-sectional view of an exemplary, co-extruded catheter shaft having five lumens is depicted in FIG. 2.

[0052] Proximally disposed Luer hubs 120 communicate with each lumen 111, 112, 113, 114, and 115 of the main shaft through dedicated extension tubing 121, 122, 123, 124, and 125 comprising suitable polymeric materials, such as elastomeric PVC or nylon single lumen tubing. The extension tubing may be thermally bonded or adhesively bonded to a proximal manifold which unitizes the catheter components to effect independent fluid or component access to the three distal, inflatable balloons 132, 134, and 136, as well as the guide wire lumen 111, and the injection port to the NVS composition infusion lumen 114.

[0053] A first catheter lumen 111 is provided along the full length of the NVS catheter sufficient in size to slidably accommodate a guidewire having a diameter of 0.018 inches, over which the catheter is delivered, following removal of the pre- dilatation PTA catheter. At the distal end of the shaft, the catheter incorporates dual occlusion balloons, comprising proximal occlusion balloon (PROX OB in FIG. 1) 132 and distal occlusion balloon (DIST OB in FIG. 1) 134, which are formed of a relatively high compliance polymeric material, such as Pellethane™ 80 AE elastomeric polyurethane polymer. In the example of treating larger vascular anatomy, such as the SFA, these occlusion balloons 132 and 134 are sized to occlude vessel lumens from approximately 4 to 9 mm diameter over a length of up to 10mm. The proximal occlusion balloon 132 and the distal occlusion balloon 134 are provided inflation fluid by an independent second catheter lumen 112 and a third catheter lumen 113, which respectively extend from the proximal end 102 of the catheter to their respective occlusion balloons 132 and 134. When inflated, the occlusion balloons cooperatively function to temporarily isolate the treated region of the vessel from blood flow.

[0054] A fourth catheter lumen (Injection lumen in FIG. 1) 114 extending the majority of the length of the NVS catheter is provided for injection of the NVS composition into the treated region of the vessel. An infusion outlet port (Injection site in FIG. 1) 140 is provided at the distal end 142 of the fourth lumen 114, and is located approximately 3 mm distal from the proximal occlusion balloon 132 but proximal of the distal occlusion balloon 134. This infusion outlet port is used to infuse the NVS composition into the treated region of the vessel.

[0055] The Natural Vascular Scaffolding (NVS) composition is referred to as 10-8-10PAS or BL-8. The chemical composition of the Natural Vascular Scaffolding (NVS) solution is 2-[2-[2-(2- aminoethoxy)ethoxy]ethyl]-6-[2-[2-[2-[[2-[2-[2-(2- aminoethoxy)ethoxy]ethyl]-l,3-dioxo-benzo[de]isoquinolin-6- yl]amino]ethoxy]ethoxy]ethylamino]benzo[de]isoquinoline-l,3-dione, (C₄2H52N6Oio),MW 800 g/mol, suspended at a concentration of 2.0 mg/ml in phosphate buffered saline (PBS) at pH 7.4. NVS solution is an orange-colored solution with a viscosity very close to that of water. The NVS solution is delivered into the tissue layers of the arterial wall, where subsequent photo-activation occurs and results in an adhesive or tissue reinforcement effect among adjacent tissues containing collagen and related proteins, through the generation of a small, reactive species polyether (Molecular Weight = 148).

The NVS solution contains 2.0 mg/mL of the NVS composition, and it is administered at a dose of 250 of NVS Solution per cm of treatment region relative to superior femoral arteries (SFA) having vessel diameters ranging from 4.0 - 8.0 mm..

A primary dilatation balloon (TZB or Treatment Zone Balloon in FIG. 1) 136 is located at the distal end 104 of the catheter shaft, and is positioned between the dual occlusion balloons 132 and 134. The primary dilatation balloon is comprised of a relatively semi-compliant polymeric balloon material, such as Vestamid™ L2101F nylon-12 polymer, with a nominal compliance of approximately ten percent (10%) over a pressure range of 7 to 12 atmospheres. The primary dilatation balloon 136 is provided inflation fluid by a fifth lumen (TZB lumen in FIG. 1) 115 extending nearly the full length of the catheter.

As depicted in FIG. 3, to facilitate accurate placement of the NVS therapeutic catheter, two radiopaque marker bands 350 and 352 are located at each shoulder of the primary dilatation balloon 136 to delineate the working length of the working section of the balloon and aid in its proper placement relative to the vascular treatment site. Additionally, radiopaque marker bands 354 and 356 are each located in the center of each respective occlusion balloon to further assist in catheter placement.

As a clinical example using the present disclosure, an interventional NVS procedure involving the SFA would preferably provide NVS therapeutic catheters having different lengths, perhaps ranging from 80 to 100 mm, and with various diameters ranging from 4 to 7 mm. [0060] Use of the NVS therapeutic catheter 100 is as follows.

The proximal occlusion balloon 132 is first inflated, followed by injection of a saline flush through the fourth lumen 114 to temporarily purge blood from the region of the vessel to be treated. Thereafter, the distal occlusion balloon 134 is inflated, to effectively isolate the treated region of the vessel from blood flow. While the dual occlusion balloons 132 and 134 are temporarily inflated, the NVS composition is infused into the isolated region of the vessel to be treated, and the temporary interruption of blood flow in the treated region of the vessel permits sufficient time for the NVS composition to diffuse fully into the vascular tissues (e.g., intima, media and adventitia). The time required for adequate tissue perfusion of the vessel wall will vary depending upon the size of the vessel being treated, as well as the particular NVS composition being used, but perfusion / soak times ranging between 3 to 6 minutes should be sufficient for most circumstances.

[0061] Once diffusion of the injected NVS composition is sufficiently complete, the primary dilatation balloon, which is located between the dual occlusion balloons, is inflated to reestablish the desired lumen diameter and cylindrical shape at the region of the vessel being treated. Ideally, the reestablished lumen vessel diameter should be at least as great as the diameter of normal vasculature in the immediate vicinity.

[0062] In some cases, this method may further comprise after the step of isolating, a step of expanding a vessel lumen having a first diameter, which is smaller than a normal lumen diameter for the vessel at a location adjacent to the isolated section, to a second diameter which is equal to or greater than the normal lumen diameter. The second lumen diameter can be maintained during an activating step. The second diameter of the lumen can comprise a diameter which exceeds the normal diameter by up to thirty percent. The lumen diameter can be expanded by balloon angioplasty. The step of expanding can be performed at least one of prior to, during, and subsequent to the applying step. After the step of expanding, the method may further comprise a step of activating the NVS composition with a sufficient amount of an activating agent, such as photoactivation.

[0063] It is further contemplated that the NVS catheter can be used for both the primary PTA dilation procedure, by inflating the primary dilation balloon to restore the desired lumen diameter, followed by deflating the primary dilation balloon and proceeding to occlude, infuse, and photoactivate the vessel, as previously described, to perform the NVS therapy. However, severely narrowed vessels may require that the initial PTA procedure be performed by an separate and independent PTA catheter having a sufficiently low profile to cross the lesion.

[0064] Thereafter, the guidewire 170 is withdrawn from the first lumen 111 of the catheter to permit a light fiber 480 to be substituted into the first (i.e., guidewire) lumen. An exemplary light fiber 480 is depicted in FIG. 4. An exemplary light fiber comprises a plastic optical fiber (POF) comprising a core of materials such as nylon, polymethylmethacrylate (PMMA, or acrylic polymer) and having a nominal diameter of approximately 0.20 inches, coated with a fluoropolymer cladding material of nominal 10 micron wall thickness. The POF is of sufficient length that it may be proximally attached, via an SMA 905 connector, to a laser powered light source of approximately 430 to 470 nm wavelength, which is deemed to sufficiently photoactivate the NVS compositions previously disclosed. The light fiber 480 is designed to extend distally to allow light emanation within the primary dilatation balloon 136 of the catheter 100 described above. It is contemplated that the light fiber 480 can alternatively be permanently integrated into the catheter shaft. Additionally, it is also contemplated that it is possible to substitute the fiber and light diffuser with an LED array disposed at the distal end of the NVS delivery catheter.

[0065] The light required for the photo-activation of the NVS solution is delivered by the light fiber 480, which in one embodiment was machined from a Mitsubishi SK-20 Medical Grade light fiber (Mitsubishi Rayon Co., Ltd., Tokyo, Japan), comprised of a polymethyl methacrylate core with a fluorinated polymer cladding material, and having a diameter of 0.020 inches. The proximal end of the fiber 480 is provided with a Sub-Miniature Version A (SMA) optical connector to enable connection to an external light source. The distal end of the fiber 480 is laser etched to provide a radial light emission pattern comparable in size to full length of the PTA dilatation balloon.

[0066] The light fiber 480 utilizes a helical laser etching pattern

(approximately 10-30 coils/cm) to disrupt the interface between the core and the cladding. The disruptions in the interface provide a mechanism for light to escape the central fiber core. An excimer laser is utilized to etch the desired patterns on short (1cm) fibers. The excimer laser ablates the outer sheath and provides aggressive light harvesting potential. A femtosecond laser is utilized to etch the desired pattern on longer light fibers, producing a more subtle disruption between the core and the cladding. This subtle disruption is more useful in the production of longer light fibers. Regardless of the laser technology used, the etching pattern of the cut is designed to more aggressively harvest the light near the distal end of the fiber where the flux of light through the core has been diminished. [0067] The exemplary light fiber 480 of the present disclosure incorporates a light diffuser 490 disposed at the distal end 482 of the fiber, formed by creating an array of closely-spaced, helically- arranged, circular etchings or pits 492 through the outer cladding of the fiber optic. These helical etchings 492 are produced by use of a programmable work station in combination with a femtosecond laser (e.g., a laser power of 10 uJ / pulse, operating at a pulse rate of 51.86 Hz pulse rate, producing a wavelength of approximately 1,150 nm), which manipulates the rotation and longitudinal rotation of the fiber relative to the laser beam, as well as modulating the laser pulses applied to the fiber, to provide helical etchings having a pattern with a variable pitch 494 which results in higher density etchings progressing from the proximal to the distal end of the diffuser. The variable helical etching pattern is provided to accommodate the attenuation of light energy over the length of the diffuser, thereby generating a more uniform flux density of light emission along the region of the vessel being treated, and thus a more uniform degree of photoactivation and cross-linking within the collagen of the vessel. The objective using this etching technique would be to produce optical diffusers which can operate at a relatively high radial emission efficiency, such as ninety percent (90%). By way of comparison, it is expected that alternative laser technology, such as eximer lasers, would not be as effective for this optical fiber etching process, since eximer lasers are more prone to drift, are less precise and produce a wider cutting kerf than the femtosecond lasers.

[0068] During operation, these pitted laser etchings provide discontinuities at the cladding core interface which produce back- scatter of beams propagating longitudinally through the optic fiber core. Normally, any back-scatter rays which are produced at the respective etched pit will produce some rays which continue to reflect within the core along its length occasionally reflecting between opposing cladding surfaces. To the extent, however, that back-scatter rays which are produced at the respective etched pit exceed a critical angle relative to the interface between the outer surface of the core and cladding, then that portion of back-scatter rays will escape from the fiber optic core emerging out from the opposite side of the pitted etching which initially produced the back- scatter. By arranging these helically-arranged pitted etchings at appropriate locations, with increasing pitch and etching density progressing from the proximal end of the fiber optic diffuser to the distal end of the diffuser, the effective radial emissions along the length of the diffuser are kept relative uniform, preferably within a tolerance of no more than about ±10%.

The light fiber 480 is sized to extend the length of the catheter shaft, and the light diffuser 490 which is located at the distal end 482 of the light fiber. More particularly, the light diffuser 490 is spaced an appropriate distance from the proximal end 484 of the light fiber, such that upon insertion into the first catheter lumen 111, the light diffuser 490 will be coextensively disposed to align with the region of the vessel to be treated. The relative length of the light diffuser 490 is preferably selected to be of a length approximating the length of lesions to be treated in stenosed vasculature, such as diffuser lengths varying from 40 to 100 mm, but greater lengths may be needed for treatment of diffuse lesions in various anatomy, such as the superficial femoral artery (SFA). With such a NVS system, it would be suitable for use in treating the SFA, as well as the popliteal artery above the knee, relative to symptomatic de novo or restenotic lesions that are 40 - 90 mm in length with reference vessel diameters between 4 - 7 mm. [0070] At this stage, a reusable, external light source comprising a blue diode emitter which is capable of producing approximately 3 Watts of power, with alternatively power ranges from 2.0 - 5.0 Watts, is coupled to the proximal end of the NVS catheter 100 to deliver light to the distal end of the catheter via the light fiber 480. The light source generates an output of light at approximately 450 nm (i.e., nominally between 420 - 490 nm), which is laterally scattered by the light diffuser 490 and passes through the translucent primary inflation balloon 136, and ultimately diffuses into the adjacent tissue of the vessel wall, with a sufficient quantum of light energy (e.g., radial emissions having a flux density of 100 mWatts / cm for an artery having a dimension of 8 cm length x 7 mm diameter) to photoactivate the NVS composition, which cleaves the NVS molecule, and releases the PEG linkers which are photochemically produced as a reactive intermediate and will bind to collagen within the vascular tissue. The photoactivation period will vary depending upon the size of the vessel being treated, as well as the particular NVS composition being used, but activation times ranging from 30 to 90 seconds should be sufficient for most circumstances, and more preferably at about 60 seconds. Thereafter, the light source is turned off.

[0071] The PEG linkers, which have now disassociated from the naphthalimide molecules, present active sites at each end which readily cross-link with native collagen fibrils that are naturally prevalent within all tissue layers of the arterial wall. Because the primary inflation balloon 136 has dilated the vessel lumen to its desired diameter prior to photoactivation of the NVS composition, the cross-linking process fixates the proteins within the vessel wall, including the collagen fibrils which are now oriented in the desired geometric profile following dilatation. Thus, the cross-linking process will cause the post-angioplasty configuration of the vessel lumen to fixate at the desired orientation, and the reestablished vessel lumen will be maintained, even after removal of the NVS therapeutic catheter. Thus, the present disclosure is believed to prevent acute vessel recoil, as well as reduced trauma and potential for excessive post-dilation inflammatory response and restenosis.

[0072] Thereafter, the NVS delivery catheter and guidewire are removed, leaving a reinforced collagen scaffolding at the treated region of the vessel, thereby serving as an endogenous stent which presents no prosthetic structure that extends inwardly into the vessel lumen. Consequently, future interventions to treat the vessel can be practiced without concern of having to re-cross implantable prosthetic stents. Moreover, it is believed that the risk of thrombosis and in-stent restenosis are concomitantly reduced.

[0073] The use of NVS compositions designed to releasably tether therapeutic drugs to perform adjunctive, intramural drug delivery is practiced by similar clinical fashion. However, in such a case, the desired therapeutic agent has been releaseably coupled to the NVS composition by means of a specially-designed tether linkage. The tether linkage for drug delivery can comprise a PEG linker, or any other linker suitable for tethering the drug to the naphthalimide. Following photoactivation of the NVS composition, the tether linkage disassociates at one end from the respective naphthalimide molecule, and carries the tethered drug along with it to bind with native proteins (i.e., collagen) within the vascular tissues. Thus, the drug is temporarily anchored to the tissue site reached upon diffusion and photoactivation. Thereafter, the release kinetics for the drug are modulated by tailoring the specific hydrolysis rates of the respective tether linkage.

[0074] The protocol used in various vascular studies involved the following parameters, namely: 1) NVS solution concentration of 2.0 mg/mL;

2) NVS solution passive tissue soak time of 5 minutes;

3) NVS solution light activation time of 60 seconds; and

4) NVS solution photo-activation power of 225 mW/cm of vascular treatment region, which equates to power delivery of approximately

180 mW/cm 2 (11 J/cm 2 ) along a 2 cm length of 4 mm diameter arterial SFA segment.

[0075] The light absorbed by tissue is converted into thermal energy (heat) but the mass of tissue acts as an effective heat sink, limiting the temperature rise to <2°C during treatment..

[0076] Referring now to FIG. 5, a longitudinal cross-sectional view illustrates the distal region 200 of a balloon catheter assembly 500. A catheter shaft 30 encloses the first tubular member 202, the second tubular member 212 and the third tubular member 222 in a side-by-side configuration. The third tubular member 222 defines a guidewire lumen 226 configured to receive a guidewire. The proximal seal 242a joins an outer balloon 42 to the catheter shaft 30 proximal to the distal end 212b of the second tubular member 212 and the proximal seal 244a of the inner balloon 44. The outer balloon 42 is disposed circumferentially around the inner balloon 44, defining the balloon fluid delivery lumen 242 extends longitudinally from the proximal seal 242a to the distal seal 242b around the third tubular member 222. The outer balloon 42 includes a microporous portion 243 include a plurality of micropores 43, which are sized and distributed across the central portion of outer balloon 42 such that continued injection of NVS composition into the outer balloon will provide a uniform, gentle, weeping outflow into the lesion and associated vascular tissue. It should be appreciated that the NVS composition is designed to soften calcified plaque. [0077] An inner balloon 44 proximal seal 244a joins the inner balloon 44 around both the first tubular member 202 and the third tubular member 222, proximal to the distal end 202b of the first tubular member 202. The inner balloon 44 is disposed circumferentially around the third tubular member 222 and defines the balloon inflation lumen 244 extending longitudinally from the proximal seal 244a to the distal seal 244b around the third tubular member 222. Preferably, the distal seal 242b may overlap or be positioned around the distal seal 244b. Alternatively, the distal seal 244b of the inner balloon 44 is positioned proximal to the distal seal 242b of the outer balloon 42. Optionally, additional thermoformable material may be placed between the distal end 202b of the first tubular member 202 and the third tubular member 222. It some embodiments, it may be preferred that the distalmost portion of the third tubular member 222, which traverses the length of the inner and outer balloons 44, 42, is formed of a translucent polymeric material.

[0078] The inner balloon 44 and the outer balloon 42 may be formed from a semi-compliant expandable material. Preferably, the inner balloon 44 and the outer balloon 42 are formed from the materials having a similar Young's modulus and expandability. For example, the balloons may be formed from a polyamide (e.g., nylon 12) material, a polyamide block copolymer (e.g., PEBA) and blends thereof (e.g., nylon 12/PEBA and PEBA/PEBA blends). Alternative materials include polyolefins, polyolefin copolymers and blends thereof; polyesters (e.g., poly(ethylene terephthalate), PET); polyure thane copolymers with MDI, HMDI or TDI hard segment and aliphatic polyester, polyether or polycarbonate soft segment (e.g., Pellethane, Estane or Bionate); and polyester copolymers with 4GT (PBT) hard segment and aliphatic polyester or polyether soft segments (e.g., Hytrel, Pelprene or Arnitel). It some embodiments, it may be preferred to form both the inner and outer balloons from the save polymeric material, such as for example, Nylon 12.

[0079] The proximal seal and distal seal of each balloon (242a,

242b, 244a, 244b) may be formed in any suitable manner. Typically, the proximal and distal inner surfaces of the balloons 42, 44 are sealably attached to the catheter shaft 30 or a tubular member, as described above. Means of sealing the balloons 42, 44 include, for example, heat sealing, using an adhesive to form the seal, forced convection heating, radio frequency heating, ultrasonic welding, and laser bonding. Shrink tubing may be used as a manufacturing aid to compress and fuse the balloon 42, 44 to the catheter shaft 30 or a tubular member 202, 212, 222. The shrink tubing may be removed and disposed of after the balloon 42, 44 is sealed, or may remain on as part of the connected structure. If the catheter shaft 30 has an outer coating, the balloon 42, 44 may be bonded to the coating or directly to the catheter shaft 30.

[0080] When configured for use in a peripheral blood vessel, the inflated diameter of the outer balloon 42 may be about 1.5 mm (0.059-inches) to about 8 mm (0.3-inches), while a catheter intended for coronary vascular applications preferably has an expandable portion 14 with an inflated diameter range of from about 1.5 mm (0.059-inches) to about 4 mm (0.2 inches). When configured for use in bile ducts, the expanded diameter of the outer balloon 42 may be about 5-15 mm (0.2-0.59-inches) with a length of approximately 15- 60 mm (0.59-2.4 inches), and the outer diameter of the catheter shaft 30 may be up to about 3.5 mm (0.14-inches). The catheter shaft may be about 3-12 French between proximal to the balloons (i.e., an outer diameter of about 1 mm-4 mm (0.04-0.16-inches)), and preferably about 4-8 French. [0081] The exemplary embodiment of FIG. 5 is suitable for a use similar to that described above relative to the embodiments of FIGS. 1-4. However, the protocol by which the device of FIG. 5 is utilized differs from that of the device of FIGS. 1-4, as described in more detail below. For example, once the distal region 200 of the balloon catheter assembly 500 is properly positioned such that the dual concentric balloons 42, 44 are disposed directly beneath the vascular lesion to be treated, the preferred protocol using the device of FIG. 5 will deliver NVS composition to the lesion and vascular tissue prior to the final dilation using the inner balloon 44. A clinical advantage may be attained using the device of FIG. 5 according to this revised protocol because any calcified plaque present within the lesion being treated can be softened prior to dilating the inner balloon 44. Consequently, this improved protocol will reduce the incidence of vascular trauma and potential microdissection of vascular tissue. Accordingly, the NVS composition is delivered through tubular member 212 and into the annular space 242 defined between the outer surface of the inner balloon 44 and the inner surface of the outer balloon 42.

[0082] The remaining steps of the protocol include inflating the inner balloon to achieve the desired luminal gain at the lesion site, followed by an exchange of the guidewire with a fiberoptic provided with a light diffuser, such as that shown and described with respect to FIG. 4. Once the diffuser is properly positioned beneath the two balloons 42, 44, light energy is applied to the proximal end of the catheter, as discussed relative to the embodiments above, to photoactivate the NVS composition and reinforce native collagen. After photoactivation, the catheter assembly 500 is removed from the patient. [0083] Optionally, the balloon catheter assembly 10 may include radiopaque material to provide a means for locating the balloon catheter assembly 10 within a body vessel. For example, the third tubular member 222 may include one or more marker bands 252 annularly disposed around the outside of the third tubular member 222 within the inner balloon 44. If desired, radiopaque bands 252 may be added to the third tubular member 222. Radiopaque marker bands 252 may be used by a clinician to fluoroscopically view and locate the distal portion 200 of the balloon catheter assembly 10 at a treatment site within a body vessel. Various configurations of radiopaque marker bands 252 may be used. For example, radiopaque marker band 252 may be located on a distal end 4 and/or on the third tubular member 222 within the inner balloon 44. As shown, the radiopaque marker bands 252 may be stripes. Such radiopaque markers may be constructed by encapsulating a radiopaque material, such as a metallic ring, within the material of catheter shaft. Alternatively a portion of the catheter shaft may be made radiopaque for example by constructing the portion from a radiopaque polymer. For example a polymer may be mixed with a radiopaque filler such as barium sulfate, bismuth trioxide, bismuth subcarbonate or tungsten. The radiopaque material can comprise any suitable opacifying agent, further including bismuth, tantalum, or other suitable agents known in the art. The concentration of the agent in the coating may be selected to be adequately visible under fluoroscopy.

[0084] In lieu of the specially-designed balloon catheters described above, it is also possible to deliver the NVS solution and provide both revascularization and vascular reinforcement of the stenosed artery being treated, using catheters which are commercially available and approved for peripheral vascular use. [0085] For example, the NVS solution can be delivered to the stenosed artery using a TAP AS^® delivery catheter (distributed by Spectranetics Corporation, Colorado Springs, Colorado). The TAP AS^® catheter is indicated for general intravascular use in the peripheral vasculature in arteries with a luminal diameter of 1.8 mm and larger. The delivery catheter comprises a catheter shaft having two longitudinally-spaced apart occlusion balloons at the distal end of the catheter. The delivery catheter also includes an infusion lumen having an infusion delivery port disposed between the occlusion balloons to facilitate infusion of diagnostic or therapeutic agents into the vascular region to be treated while the occlusion balloons are inflated to isolate the treatment site from blood flow.

[0086] In use, the TAP AS^® delivery catheter is infuses the NVS solution to the isolated vascular treatment region, which is allowed to passively soak into the tissue of the vascular wall for a predetermined period of time (e.g., 5 minutes). Thereafter, the delivery catheter is removed from the artery and replaced with a marketed PTA balloon dilatation catheter indicated for use in the peripheral vasculature. Once the PTA dilatation catheter is positioned over the introduction guidewire at the vascular treatment site, the guidewire is removed and replaced with the NVS light fiber having a distal diffuser which is suitable to provide the light energy necessary for the photo-activation of the NVS solution which has permeated the vascular tissue. The PTA balloon is then inflated to restore the stenosed vascular region to the desired luminal diameter. The PTA dilatation is maintained in the inflated state while photo-activation is provided to the treatment site through the light fiber (e.g., photo-activation using 457 nm light at approximately 225mW / cm of treatment region for approximately 60 seconds) to facilitate crosslinking within the artery tissue. After the 60 second photo-activation period, the PTA balloon is deflated, and the light fiber is removed and replaced with the guidewire, upon which the PTA catheter is removed, and the treatment is complete.

[0087] It will be appreciated by the skilled person that the sequence of catheter-based procedures using commercially-available catheters approved for peripheral vascular intervention to perform delivery of the NVS solution, as well as PTA balloon dilatation, is capable of being varied to whatever the situation requires. For example, it is possible to first introduce a standard PTA catheter into the stenosed artery to dilate the lesion, followed by an exchange with a suitable catheter for infusion of the NVS solution (e.g., TAP AS^® delivery catheter), and then perform the photo- activation. Additionally, with arteries having more severe lesions, it is possible to first pre-dilate the stenosed artery with a PTA dilatation catheter (i.e., to establish a nominal lumen diameter sufficient to permit introduction of the NVS delivery catheter), followed by infusion of the NVS solution, and subsequent photo- activation.

[0088] It will be apparent to those skilled in the art that various modifications and variations can be made to the endovascular balloon catheters of the present disclosure without departing from the scope of the invention. Throughout the disclosure, use of the terms "a," "an," and "the" may include one or more of the elements to which they refer. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only.

Claims

Claims WHAT IS CLAIMED IS:

1. An interventional vascular therapeutic device, comprising:

an elongated catheter shaft having

a pair of occlusion balloons disposed in a spaced apart relationship at a distal end of the catheter shaft, a dilatation balloon disposed on the catheter shaft between the occlusion balloons,

a first inflation lumen configured to supply inflation fluid to a proximally disposed one of the occlusion balloons, a second inflation lumen configured to supply inflation fluid to a distally disposed one of the occlusion balloons,

a third inflation lumen configured to supply inflation fluid to the dilatation balloon,

a primary lumen extending substantially the entire length of the guidewire configured to slidably receive a guide wire, and

an infusion lumen extending from a proximal end of the catheter shaft toward the distal end of the catheter shaft and terminating at an infusion exit port located between the occlusion balloons; and

an optical fiber configured to be inserted into the primary lumen in exchange for the guidewire, the optical fiber being sized to extend to the dilatation balloon, the optical fiber being configured to be coupled at its proximal end to an external light source.