Abstract:
A catheter and methods for luminal therapy are provided wherein a catheter has an outer balloon with a multiplicity of apertures for infusing one or more therapeutic agents into a vessel wall, an intermediate balloon having a multiplicity of apertures offset from the apertures of outer balloon to serve as a baffle that reduces jetting and promotes uniform distribution of therapeutic agent exiting through the outer balloon, and an impermeable inner balloon disposed within the intermediate balloon that enables the intermediate and outer balloons to be forced into engagement with the vessel wall to dilate the vessel and disrupt plaque lining the vessel wall and to also facilitate the uniform delivery of the therapeutic agent. The outer balloon may include protrusions that contact the vessel wall to disrupt the plaque, bumpers to reduce washout during infusion of therapeutic agents; the intermediate balloon may include a texture, ribs or protrusions on its outer surface to prevent adhesion to the outer balloon during dilation of the vessel; and the catheter may include a guide wire lumen sized to accept an energy delivery device to delivery energy that enhances uptake of the therapeutic agent or prolongs therapeutic effectiveness of the is agent.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
       [0001]    This application is a continuation under 35 U.S.C. §120 of U.S. patent application Ser. No. 14/477,638, filed Sep. 4, 2014, which is a divisional of U.S. patent application Ser. No. 14/084,518, filed Nov. 19, 2013, now U.S. Pat. No. 8,827,953, issued Sep. 9, 2014, which claims the benefit of priority of U.S. Provisional Patent Application Ser. No. 61/752,902, filed Jan. 15, 2013, the entire contents of each of which are incorporated herein by reference. 
     
    
     FIELD OF THE INVENTION 
       [0002]    The present invention relates generally to the delivery of intraluminal therapy, such as treatment of vascular lesions. In some preferred embodiments, apparatus and methods are provided for treating calcified lesions in peripheral vasculature to prevent arterial dissections, atheroembolizations, perforations and restenosis following an angioplasty and/or stent procedures. 
       BACKGROUND OF THE INVENTION 
       [0003]    A need exists for simple and efficacious delivery of intraluminal therapies. Such therapies range from delivery of anti-mitotic agents to reduce the restenosis following angioplasty, to delivery of angiogenic factors, delivery of therapeutic agents to reduce intravascular thrombus, delivery of therapeutic agents to improve arterial compliance through the structural alteration of intimal and medial calcification, delivery of fluent cross-linkable materials that may be hardened in situ to provide support for a vessel (e.g., as is described in U.S. Pat. No. 5,749,915 to Slepian, the entire contents of which is incorporated herein by reference), or to exclude or reduce the development of a nascent vascular aneurysms. Previously-known methods and apparatus typically involve use of multiple catheters and devices to accomplish such treatments, which adds time, cost and complexity, increased exposure to ionizing radiation and risk of morbidity to previously-known therapeutic procedures. It therefore would be advantageous to provide methods and apparatus that simplify such previously-known procedures, reduce time, cost and complexity, and improve acute procedural success and long-term patient outcomes. 
         [0004]    Percutaneous transluminal angioplasty of coronary and peripheral arteries (PTCA and PTA, respectively) are widely accepted as the revascularization procedures of choice in patients with ischemic cardiovascular syndromes (i.e., chronic and acute coronary ischemic syndromes and chronic limb ischemia, including claudication and critical limb ischemia). However, use of these conventional percutaneous treatments has an important limitation: restenosis—the exuberant proliferation of smooth muscle cells that grow to re-occlude the treated vessel segment, causing the reoccurrence of symptoms and necessitating potential reintervention. 
         [0005]    Various adjuncts to angioplasty seek to reduce restenosis; these include atherectomy (e.g., extractional, rotational, orbital, laser), bare metal and bare nitinol stents and, more recently, drug eluting stents (DES). The latter technology has been demonstrated to significantly reduce coronary artery restenosis when compared to angioplasty or bare metal stents, however, its use requires chronic administration of adjunct pharmacotherapies to prevent subacute stent thrombosis, the sudden and life threatening clotting of the stent. Unfortunately, not all patients tolerate these essential pharmacotherapies due to impaired tolerance, allergic reactions or contraindication to such drug use (i.e., history of previous bleeding) and/or their associated expense. 
         [0006]    In peripheral arteries, the use of bare nitinol stents have been shown to be superior to balloon angioplasty alone and has emerged as the “default” percutaneous strategy for the treatment of chronic limb ischemic syndromes, particularly in complex disease patterns involving the femoropopliteal artery. Despite their common use, nitinol stents present a substantial concern of in-stent restenosis (ISR), the proliferation of smooth muscle cells within the stent leading to occlusion of the stent lumen. ISR poses additional risk to the patient by necessitating additional vessel reintervention to re-establish vessel blood flow. 
         [0007]    Currently, there is no established treatment for the vexing problem of ISR, which occurs in about 30%-50% of nitinol stents over a 1-2 year follow-up period, a rate that may increase depending on the patient demographic (i.e., diabetics) and vessel morphology (small vessel diameter, length of diseased vessel treated and the presence of vessel wall calcification). Importantly, there are presently no recognized effective and durable therapies to treat ISR; as such, emerging technologies focus on preventing restenosis through the application of anti-restenotic therapeutic agents into the diseased vessel wall layers via the vessel&#39;s luminal surface. 
         [0008]    Anti-proliferative drugs (i.e., paclitaxel, sirolimus) retard smooth muscle migration into an area of angioplasty-induced vessel injury and reduce restenosis. Drug delivery catheters have been designed to facilitate the delivery of such therapeutic agents into the vessel wall via its luminal surface. For example, U.S. Pat. No. 5,112,305 to Barath et al. describes a catheter having a single balloon including a multiplicity of protrusions. The protrusions include apertures that enable a drug to be introduced into the balloon and infused through the apertures into the vessel wall. U.S. Pat. No. 5,049,132 to Shaffer et al. and U.S. Pat. No. 6,733,474 to Kusleika each describe a catheter having an impermeable inner balloon and an outer balloon having pores through which a drug may be infused into the vessel wall. U.S. Pat. No. 5,681,281 to Vigil et al. similarly shows a catheter having an impermeable inner balloon and an outer balloon having a multiplicity of apertured protrusions for injecting a drug into a vessel wall. U.S. Pat. No. 5,213,576 to Abiuso et al. describes a catheter having nested balloons with offset apertures, to reduce jetting and provide more uniform distribution of a drug infused into a vessel through the catheter. 
         [0009]    All of the previously-known systems described in the foregoing patents have had drawbacks that have prevented commercialization of those designs. For example, catheters having a single apertured balloon, such as described in the above patent to Shaffer et al., cannot provide uniform distribution of a drug or other material around the circumference or along the axis of the vessel due to jetting through the apertures. Catheters with apertured protrusions, such as described in the above patents to Barath et al. and Vigil et al, are difficult to manufacture and are believed to be prone to having the apertures clogged with debris when the balloon is embedded into the plaque lining the vessel wall. Also, the use of excessively high pressures within the balloon to clear the apertured protrusions may lead to excessively non-uniform drug infusion and potential vessel dissection. 
         [0010]    On the other hand, in a catheter such as described in Abiuso et al., nested balloons having offset apertures cause the inner balloon to serve as a baffle that reduces jetting through the apertures in the outer balloon, thereby providing a much more uniform infusion through the outer balloon. However, as the Abiuso catheter lacks an inner impermeable balloon to move the drug infusing layers into apposition with the vessel wall, there is the potential for much of the drug to be washed into systemic circulation during deployment of the nested balloons. Moreover, because Abiuso lacks a dilatation balloon, it has no ability to disrupt calcified plaque, and accordingly, must be used with a separate dilatation balloon requiring additional catheter exchanges, contrast and radiation exposure and vessel irritation. 
         [0011]    Recent clinical data has identified a variety of atherosclerotic plaque morphologies in coronary and peripheral vessels, which prevent the effective penetration of drug therapies into the various vessel layers. Specifically, the presence of dense fibro-calcific and calcified intimal and medial plaques, are associated with peri-procedural failure (due to vessel recoil and/or vessel wall dissection) and subsequent restenosis as these plaques are effective barriers to the penetration and uptake of therapeutic drugs delivered luminally. As such, the instructions for use (IFU) of many current approved devices and inclusion/exclusion angiographic criteria of on-going regulatory trial designs specifically exclude patients from device treatment with angiographic evidence of severely calcified vessels. Given the large and growing patient population with diabetes and chronic kidney disease and conditions associated with heavy vessel wall calcification, this represents a substantial patient population in which emerging therapies may be ineffective. 
         [0012]    In view of the many drawbacks of previously-known systems and methods, it would be desirable to provide apparatus and methods that overcome such drawbacks. In particular, it would be desirable to provide devices suitable for intraluminal therapies, such as intravascular drug infusion systems and methods, which reduce the number of equipment exchanges needed to both disrupt intravascular plaque and to infuse an anti-stenotic agent into a vessel wall to reduce occurrence of restenosis. 
         [0013]    It further would be desirable to provide devices and methods suitable for intraluminal therapies, such as intravascular drug infusion systems and methods, that permit a clinician to dilate a vessel to disrupt calcified plaque and then to infuse an anti-mitotic agent into the vessel wall through the disrupted plaque. 
         [0014]    It still further would be desirable to provide devices and methods suitable for intraluminal therapies, such as intravascular drug infusion systems and methods, wherein a balloon of the catheter may include a multiplicity of apertures, such that the apertures are resistant to clogging during use of the balloon to dilate the vessel and disrupt the plaque. 
         [0015]    Previously known systems also describe the use of various energy sources to deliver energy to fluent material infused into a vessel to pave a vessel or create an in situ stent. Such systems are described, for example, in U.S. Pat. No. 5,662,712 to Pathak et al. and U.S. Pat. No. 5,899,917 to Edwards et al. A drawback of these systems, however, is that each forms a new mechanical structure disposed within the vessel that is separate and distinct from the vessel wall. Because the arteries, and to a lesser extent, the veins, expand and contract during each cardiac cycle due to pressure pulsations, such attempts to form a rigid mechanical support that is not integrated with the vessel wall are inherently problematic. 
         [0016]    It therefore further would be desirable to use existing vasculature structure to enhance or perpetuate the anti-mitotic effect of drugs infused via an intravascular route. In particular, it would be desirable to employ application of energy, e.g., such as ultraviolet (UV) light energy, monopolar or bipolar generated radiofrequency (RF) generated heat, or focused or unfocused ultrasonic energy, to potentiate the delivery and effectiveness of anti-mitotic agents when administered from the luminal surface into the media and adventitial layers in the presence of vascular calcification. 
       SUMMARY OF THE INVENTION 
       [0017]    In view of the aforementioned drawbacks of previously-known systems and methods, the present invention provides apparatus and methods that reduce the number of equipment exchanges needed to both disrupt intravascular plaque and to infuse therapeutic agents, such as anti-proliferative drugs or regenerative therapy agents, into a vessel wall to reduce occurrence of restenosis and/or promote angiogenesis, or to exclude a weakened vessel portion or reduce enlargement of a nascent aneurysm. 
         [0018]    The present invention further provides devices and methods suitable for intraluminal therapies, such as intravascular drug infusion systems and methods, that permit a clinician to dilate a vessel to disrupt calcified plaque and then to infuse therapeutic agents into the vessel wall through the disrupted plaque without the need to exchange catheters. 
         [0019]    In accordance with another aspect of the present invention, a balloon catheter is provided including an outer balloon having a multiplicity of apertures for infusing one or more therapeutic agents into the vessel wall, an intermediate balloon having a multiplicity of apertures offset from the apertures of outer balloon to serve as a baffle that reduces jetting and promotes uniform distribution of therapeutic agents through the outer balloon, and an impermeable inner balloon disposed within the intermediate balloon that enables the intermediate and outer balloons to be forced into engagement with the vessel wall to dilate the vessel and disrupt plaque lining the vessel wall. 
         [0020]    The intermediate balloon optionally may include a texture, ribs or protrusions on its outer surface that contacts the inner surface of the outer balloon to prevent the intermediate and outer balloons from adhering to one another during dilation of the vessel. Such a feature ensures that an annular space is maintained between the intermediate and outer balloons to facilitate uniform distribution of therapeutic agents during use of the catheter to perform therapy. 
         [0021]    The outer balloon also may include bumpers at its proximal and distal ends to facilitate delivery of therapeutic agents. The outer balloon optionally may include a multiplicity of protrusions and apertures, such that the apertures are interposed between the protrusions so as to reduce the risk that the apertures become clogged during use of the balloon to dilate the vessel and disrupt the plaque. 
         [0022]    In accordance with yet another aspect of the present invention, a catheter of the present invention is constructed to include a central lumen that accommodates not only a conventional guide wire for positioning the catheter, but also permits a wire carrying an energy source, such as an ultraviolet light source (“UV”), ultrasound transducer, electrically-powered resistive heater, or monopolar or bipolar radiofrequency (RF) heating element, to be substituted for the guide wire to deliver energy to the vessel wall segment where the therapeutic agent was infused. In a preferred embodiment, the material comprising the distal end region of the catheter shaft, and preferably also the materials comprising the inner, intermediate and outer balloons, are selected to reduce absorption energy delivered to the material infused into the vessel wall. 
         [0023]    Methods of using the apparatus of the present invention also are provided, wherein the inventive catheter is first used, by inflating the inner balloon with a conventional balloon inflation system, to dilate a vessel and disrupt calcified plaque disposed on the luminal lining. The inner balloon is then depressurized, and one or more suitable fluent therapeutic agents are infused into a space between the inner balloon and the intermediate balloon. The therapeutic agent passes through the multiplicity of apertures, designed of specific variable diameters and positioned in specific patterns along the inner-most and outer-most balloons, into the annular space between the intermediate and outer balloons, and then through the apertures in the outer balloon to uniformly contact the disrupted plaque. Immediately, or after a predetermined interval, an energy delivery source, (e.g., a wire delivering a UV light source, ultrasound transducer or resistive heater), may be exchanged for the guide wire in the central lumen of the catheter. The energy source is activated to enhance uptake of the therapeutic agent through plaque, intima, media of the vessel wall so that the therapeutic agent becomes deposited in the media, adventitia and/or vaso vasorum of the vessel wall, or to activate a property of the fluent material to cause it to harden or otherwise transition to effectuate a therapeutic or diagnostic purpose. 
         [0024]    In accordance with one aspect of the present invention, the application of energy from the energy source to the therapeutic agent infused into the vessel wall causes the agent to polymerize in the adventitia or vaso vasorum, thereby reducing washout of the drug caused by circulation through the vaso vasorum. In this manner, the therapeutic agent will be localized within the vessel wall, and serve as a reservoir that prolongs the therapeutic effect of the agent, for example, by reducing occurrence of late-term restenosis of the vessel. Alternatively, the agent may polymerize to form a durable rigid or semi-rigid support within the vessel wall, that serves as an in situ stent that reduces reduction (restenosis) or enlargement (growth of an aneurysm) of the vessel diameter, as suited for a particular therapy. Alternatively, energy from the energy source may be delivered to the vessel media, adventitia and/or vaso vasorum prior to the application of the therapeutic agent or substance. 
         [0025]    The apparatus and methods of the present invention therefore facilitate ease of use by reducing the number of catheters required for the effective pre-dilatation of a diseased vessel segment and facilitates the penetration and controlled, uniform delivery of one or more therapeutic agents into the vessel layers using a baffled balloon, which may include a multiplicity of bumpers or protrusions configured to disrupt calcified plaque while avoiding clogging of the infusion apertures. Finally, the catheter provides a central lumen dimensioned to accept an externally powered energy source, and the distal region of the catheter preferably comprises materials that facilitate transmission of such energy to the therapeutic agent while reducing absorption by the catheter materials. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0026]    Further features of the invention, its nature and various advantages will be apparent from the accompanying drawings and the following detailed description of the preferred embodiments, in which: 
           [0027]      FIG. 1  is a plan view of the illustrative catheter constructed in accordance with the principles of the present invention. 
           [0028]      FIGS. 2A and 2B  are, respectively, detailed plan and sectional views of the distal region of the catheter of  FIG. 1 . 
           [0029]      FIGS. 3A and 3B  are, respectively, detailed plan and sectional views of the distal region of an alternative catheter constructed in accordance with the principles of the present invention. 
           [0030]      FIGS. 4A and 4B  are, respectively, detailed plan and sectional views of the distal region of another alternative catheter constructed in accordance with the principles of the present invention. 
           [0031]      FIGS. 5A to 5C  illustrate steps of the using the catheter of  FIG. 1  to dilate a plaque-lined vessel and to infuse an anti-mitotic or other therapeutic agent or drug. 
           [0032]      FIG. 6  is a detailed sectional view of the balloons described in  FIG. 5 . 
           [0033]      FIG. 7  is a detailed sectional view corresponding to encircled region  7  in  FIG. 5B . 
           [0034]      FIG. 8  is a detailed sectional view corresponding to encircled region  8  in  FIG. 5C . 
           [0035]      FIG. 9  illustrates a step of inserting an energy delivery wire into the central lumen of the catheter of the present invention during or after the step illustrated in  FIG. 5C . 
           [0036]      FIGS. 10A and 10B  are, respectively, plan and sectional views of an alternative embodiment of the catheter of the present invention. 
           [0037]      FIG. 11  is a detailed sectional view corresponding to encircled region  11  in  FIG. 10B . 
       
    
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
       [0038]    Referring to  FIG. 1 , balloon catheter  20  constructed in accordance with the principles of the present invention is described. Catheter  20  includes proximal end  21 , distal region  22  and elongated shaft  23 . Proximal end  21 , which is manipulated by the clinician, preferably includes hemostatic port  24  that permits conventional guide wire  25  to be extended through a lumen of catheter  20 , balloon inflation port  26  and infusion agent port  27 . Catheter preferably has a length and diameter suitable for use in the desired cardiac or peripheral vessel, e.g., 130 to 150 cm in length with a diameter of 2.5 mm to 60 mm, in the case of an abdominal aortic or thoracic aneurysm and balloon lengths from 2 cm to 20 cm. Ports  24 ,  26  and  27  are conventional elements, and together with proximal end  21  of catheter  20  may comprise materials conventionally used in the construction of intravascular catheters, e.g., polyethylene or polyterephthalate. Although catheter  20  is depicted as an over-the-wire (“OTW”) catheter, it is to be understood that the inventive aspects of the catheter of the present invention readily may be employed in a rapid exchange (“RX”) catheter or in a catheter having a working lumen and an auxiliary lumen for guidewire insertion such as that described in U.S. Pat. No. 7,018,358 to Joergensen, the entire contents of which is incorporated herein by reference. 
         [0039]    Referring now to  FIGS. 2A and 2B , distal region  22  of one embodiment of catheter  20  of the present invention is described.  FIG. 2A  depicts the exterior of distal region  22  with outer balloon  30  in an expanded state suitable for dilating a vessel, while for purposes of clarity,  FIG. 2B  depicts a sectional view of the inner components of distal region  22  with intermediate balloon  31  and inner balloon  32  in partially expanded states suitable for infusing a therapeutic agent into a vessel wall. Outer balloon  30  preferably comprises a noncompliant or semi-compliant material such as polyethylene or polyterephthalate. Outer balloon  30  is sized and shape for insertion as appropriate for the intended therapy and bodily lumen. For example, outer balloon  30  may have a diameter in an expanded state of about 2.5-4.0 mm for insertion in smaller lumens, such as coronary vessels, about 4-7 mm for insertion in larger lumens such as peripheral vessels, or as much as 4-6 cm if the catheter is designed for use in providing therapy in the thoracic or abdominal aorta. Intermediate balloon  31  and inner balloon  32  preferably comprise a semi-compliant or compliant material such as polyterephthalate or nylon. As described in further detail below, in a preferred embodiment, inner balloon  32  is configured to expand intermediate balloon  31  and outer balloon  30  until outer balloon  30  reaches its maximum designed diameter. In an alternative embodiment, outer balloon  30  also may comprise a compliant material, while intermediate balloon  31  and inner balloon  32  also may comprise a non-compliant material. 
         [0040]    Still referring to  FIGS. 2A and 2B , outer balloon  30  has exterior surface  34  and multiplicity of through-wall apertures  35 . In the embodiment depicted in  FIG. 2A , apertures  35  illustratively are arranged in a pattern where each row is offset by a predetermined angle, e.g., about 45°, from an adjacent row; however, other patterns will readily occur to a person of ordinary skill in the design of balloon catheters. For example, each row or pattern of apertures on the outer balloon may be aligned uniformly with adjacent rows; there may be a single row of apertures on the outer balloon; there may be two rows of apertures on opposite sides of the outer balloon, etc. In addition, apertures  35  are depicted as being circular in shape which may vary in diameter along the length of the balloon, but could have any other desired shapes, such as rectangular, triangular or elliptical. Outer balloon  30 , intermediate balloon  31  and inner balloon  32  preferably are affixed to catheter shaft  23  at shoulders  36  and  37  via thermal bonds or glue welds. 
         [0041]    As best shown in  FIG. 2B , intermediate balloon  31  includes multiplicity of through-wall apertures  38  which may have varying diameters along the balloon length, and which preferably are offset from apertures  35  in outer balloon  30 . In this manner, a fluent therapeutic agent introduced into annular space  39  between the exterior of inner balloon  32  and interior surface of intermediate balloon  31  will pass into annular space  40  between the exterior of intermediate balloon  31  and the interior surface of outer balloon  30  without directly exiting through apertures  35  in the outer balloon. Accordingly, when a therapeutic agent is introduced into annular space  39  via infusion lumen  41  and infusion port  27  on proximal end  21  (see  FIG. 1 ), the agent passes from annular space  39  to annular space  40 , from which it uniformly exits outer balloon  30  via apertures  35 . Inflation port  26  on proximal end  21  (see  FIG. 1 ) is coupled to interior space  42  of inner balloon  32  via inflation lumen  43  that extends through catheter shaft  23 . Apertures  35  may be the same size or a different size than apertures  38 . Preferably, apertures  35  and  38  are laser drilled and have a diameter between about 5 μm and about 50 μm. In one embodiment, apertures  35  have a diameter of about 5 μm and apertures  38  have a diameter of about 10 μm. In addition, a subset of the multiplicity of apertures  35  or  38  may be differently sized from another subset of the multiplicity. For example, a distal portion of a row of apertures  35  each may have a first diameter and a proximal portion of the row each may have a second diameter, different from the first. In one embodiment, in a row of sixteen apertures, eight distal apertures each has a diameter of about 15-25 μm and eight proximal apertures each has a diameter of about 7-17 μm. 
         [0042]    As depicted in  FIG. 2B , after use of catheter  20  for dilating the vessel wall, inner balloon  32  may be inflated to any lower desired pressure to reduce the volume of therapeutic agent delivered into annular space  39  and to facilitate the rate of delivery to the vessel wall. Alternatively, inner balloon  32  may be deflated entirely after the vessel dilatation step. 
         [0043]    Still referring to  FIG. 2B , catheter shaft  23  includes lumen  44 , preferably centrally located in catheter shaft  23 , to permit guide wire  25  to be extended through catheter  20  to facilitate positioning of distal region  22  at a desired location in a patient&#39;s vasculature or organ. Distal region  22  also may include radiopaque markers disposed along catheter shaft  23 , for example, in the vicinity of shoulders  36  and  37 , to facilitate positioning of the catheter under fluoroscopic imaging. In accordance with one aspect of the present invention, lumen  44  preferably is sized to permit a wire containing an energy source, e.g., an ultraviolet light source (or light fiber), ultrasound transducer, or resistive heater, to be advanced into distal region  22  to deposit energy into the therapeutic agent or drug, to facilitate uptake by the vessel wall or provide another therapeutic effect, as described herein below. For such embodiments, balloons  30 - 31  and catheter shaft  23  preferably comprise materials that permit light energy of selected frequencies to pass through the catheter without significant absorption or loss of energy. 
         [0044]    Referring now to  FIGS. 3A and 3B , distal region  22 ′ of an alternative balloon catheter is constructed similarly to distal region  22  of  FIGS. 2A and 2B , wherein like components are identified by like-primed reference numbers. Thus, for example, apertures  35 ′ in  FIGS. 3A and 3B  correspond to apertures  35  of  FIGS. 2A and 2B , etc. As will be observed by comparing  FIGS. 2A ,  2 B and  3 A,  3 B, outer balloon  30 ′ includes proximal bumper  45  around the circumference of its proximal end and distal bumper  46  around the circumference of its distal end, and apertures  35 ′ are aligned in uniform rows. Bumpers  45 ,  46  extend from exterior surface  34 ′ so as to create a pocket between bumpers  45  and  46  and between exterior surface  34 ′ and the luminal surface when bumpers  45 ,  46  are urged into contact with the luminal surface. In this manner, bumpers  45 ,  46  facilitate delivery of therapeutic agents to the luminal surface via the pocket such that the agents are delivered uniformly along the length of the balloon, reduce clogging of the apertures when the bumpers are urged into contact with the luminal surface, and reduce the risk that fluent material delivered to the vessel surface will be washed into systemic circulation. 
         [0045]    Referring now to  FIGS. 4A and 4B , distal region  22 ″ of yet another alternative balloon catheter is constructed similarly to distal region  22  of  FIGS. 2A and 2B  except that outer balloon  30 ″ further includes multiplicity of solid protrusions  47  extending from exterior surface  34 ″ and interposed between multiplicity of through-wall apertures  35 ″. In the embodiment depicted in  FIG. 4A , protrusions  47  and apertures  35 ″ illustratively are arranged in a regular pattern; however, other patterns will readily occur to a person of ordinary skill in the design of balloon catheters. Preferably, apertures  35 ″ are offset from protrusions  47  so as to reduce clogging of the apertures when the protrusions are urged into contact with the luminal surface. In addition, while protrusions  47  are illustratively depicted as substantially circular cylinders having rounded extremities, other configurations, such as rectangular, conical or pyramidal structures also could be used. Protrusions  47  extend from exterior surface  34 ″ so as to create a pocket between exterior surface  34 ″ and the luminal surface when protrusions  47  are urged into contact with the luminal surface. In this manner, protrusions  47  facilitate delivery of therapeutic agents to the luminal surface via the pocket, and reduce the risk that fluent material delivered to the vessel surface will be washed into systemic circulation. 
         [0046]    Referring now to  FIGS. 5A to 5C , a method of using the catheter of  FIGS. 1 and 2  to perform an interventional procedure is described. As will be readily understood to one of ordinary skill in the art, while the method is described for use with the catheter of  FIGS. 1 and 2 , the alternative catheters of  FIGS. 3 and 4  may be used in a similar manner to that described below. 
         [0047]    In  FIG. 5A , guide wire  25  is placed in the vessel at the location of a lesion or plaque P, or nascent aneurysm, as determined using fluoroscopic imaging, contrast agents and conventional interventional techniques. Catheter  20  then is backloaded onto guide wire  25  by inserting the proximal end of the guide wire into the distal opening of lumen  44 . Catheter  20  is advanced through the patient&#39;s vasculature until distal region  22  is disposed in the region of interest, as determined using radiopaque markers on catheter shaft  23  and fluoroscopic imaging. When so disposed in patient&#39;s vessel V, distal end  22  of catheter  20  will appear as depicted in  FIG. 5A . In embodiments protrusions ( FIG. 4 ), during manufacture of the catheter, outer balloon  30 ′ or  30 ″ of the catheter may be wrapped or folded so that protrusions  47  are substantially flush with the remainder of the balloon material, thus preventing the protrusions from snagging or abrading the vessel intima during advancement along guide wire  25  to the location of interest. Alternatively, a delivery sheath (not shown) may be disposed over distal region  22 ,  22 ′, or  22 ″ of the catheter to present a smooth outer surface for the catheter, and the sheath then may be retracted proximally to expose the distal region once it is at the desired location in vessel V. 
         [0048]    Referring now to  FIGS. 5B ,  6 , and  7 , a conventional inflator is coupled to inflation port  26  and an inflation medium, such as saline or a saline diluted iodinated contrast agent, is delivered via inflation lumen  43  to inner balloon  32  to cause inner balloon  32  to expand intermediate balloon  31  and outer balloon  30 . As shown in  FIG. 6 , inner balloon  32  may expand intermediate balloon  31  and outer balloon  30  so that pocket  48  is created between outer balloon  30  and plaque P. In such an embodiment, pocket  48  may extend between bumpers  45  and  46  ( FIG. 3 ) or protrusions  47  ( FIG. 4 ) contact plaque P and the intima of the vessel V to dilate the vessel V and crack or disrupt plaque P. In addition, as shown in  FIG. 7 , inner balloon  32  may expand intermediate balloon  31  and outer balloon  30  into contact with plaque P and the intima of vessel V to dilate the vessel V and disrupt or cause cracks C in the plaque P. As inner balloon  32  expands, it contacts intermediate balloon  31  which contacts outer balloon  30  and causes outer balloon  30  to contact and crack or disrupt plaque P. 
         [0049]    In embodiments where the outer balloon includes protrusions ( FIG. 4 ), the protrusions engage plaque at discrete locations and place the plaque in tension, causing it to fracture. One or more therapeutic agents are infused through apertures  35 ,  35 ′,  35 ″ in outer balloon  30 ,  30 ′,  30 ″ and contacts the plaque along fracture zones that enable the therapeutic agent to be rapidly taken up by the vessel intima. Because apertures  35 ″ are interposed between the protrusions instead of extending through the protrusions as in prior art systems, compressed plaque at the point of contact of the protrusions is expected not to clog the apertures. It is expected that the foregoing arrangement of solid protrusions and interposed apertures will enable better uptake of therapeutic agents in calcified lesions than has heretofore been achieved. 
         [0050]    Referring to  FIGS. 6 and 7 , it is observed that vessel V comprises three layers: intima I, medial M, and adventitial A, which is supplied by vaso vasorum VV. It is known that the vaso vasorum VV supplies nourishment to vessel V and removes metabolic byproducts resulting from activity of the cells making up the vessel wall. In accordance with one aspect of the present invention, a therapeutic agent is infused into the wall of a vessel V, and preferably into the adventitia A and/or vaso vasorum VV, while also locally reducing flow in the vaso vasorum VV to reduce washout of the therapeutic agent from the adventitia A and vaso vasorum VV. In this manner, the vessel wall serves as a reservoir for the therapeutic agent, so that the infused therapeutic agent or drug is released from the adventitia A back into the medial M and intimal portions I of the vessel wall over a period of months to years, thereby prolonging the therapeutic effect of the infused agent or drug. 
         [0051]    The foregoing benefits may be achieved by a number of modes. In one embodiment, the therapeutic agent or drug may be designed so that when activated by supply of energy, e.g., irradiated by ultraviolet light, insonicated with ultrasound energy of a desired frequency, or heated by a resistive or other type of heater, the drug transitions from a fluent form to a gel-like or solid form. In this case, the therapeutic agent will assist in blocking or reducing flow through the vaso vasorum, and reduce the rate at which the therapeutic agent or drug is removed from the selected portion of the vessel wall. Alternatively or in addition, if the therapeutic agent transforms to a gel-like or solid form, it will be less susceptible to erosion. In an alternative embodiment, the deposited energy may cause a component of the therapeutic agent to heat up to cause polymerization or cross-linking of fluent bioactive materials and/or remodel or partially necrose portions of the adventitia or vaso vasorum, thereby locally blocking or reducing flow through the vaso vasorum and producing a reservoir of the therapeutic agent that provides prolonged release. As a further alternative embodiment, the deposited energy may function to enhance uptake of the therapeutic agent through the layers of the vessel wall. As a still further alternative embodiment, the energy may directly cause partial remodeling or necrosis of the adventitia and/or vaso vasorum to produce the reservoir effect noted above. 
         [0052]    Referring now to  FIGS. 5C and 8 , after inner balloon  32  has been expanded to drive intermediate balloon  31 , and outer balloon  30  (and, if present, optional bumpers or protrusions) into contact with the vessel wall, inner balloon  32  is partially or completely deflated. Next, a vial or syringe containing a desired fluent therapeutic agent or drug, (e.g., an anti-mitotic drug such as paclitaxel or sirolimus, angiogenic vector, or stem cells), is coupled to infusion port  27  on proximal end  21  and activated to inject the agent through infusion lumen  41  into annular space  39  between inner balloon  32  and intermediate balloon  31  (see  FIG. 2B ). As indicated by the arrows in  FIG. 5C , the agent passes through apertures  38  in intermediate balloon  31  and into annular space  40  between intermediate balloon  31  and outer balloon  30 . Inner balloon  32  may be partially or completely reinflated to cause the therapeutic agent to pass through apertures  38  and into annular space  40  between intermediate balloon  31  and outer balloon  30  before exiting through apertures  35 . Because apertures  38  are offset from apertures  35  in outer balloon  30 , the agent circulates within annular space  40  before passing through apertures  35  and exiting outer balloon  30 . Additionally, because agent moves laterally towards apertures  35 , it will be more uniformly distributed around the circumference and along the axial length of the vessel than previously-known single balloon systems. This baffling effect provided by intermediate balloon  31  is expected to reduce jetting of therapeutic agent exiting through apertures  35  of outer balloon  30 , thus reducing the potential for vessel dissection. 
         [0053]    As depicted in further detail in  FIG. 8 , the therapeutic agent exits outer balloon into pockets  48  formed between cracks C in plaque and/or between bumpers, if provided. The therapeutic agent exits apertures  35  into pockets  48 , where it is expected to gain ready access to the vessel intima through cracks and fractures formed in plaque P during the dilatation step illustrated in  FIG. 5B . 
         [0054]    As will be apparent to one of ordinary skill in interventional procedures, the rate of infusion of therapeutic agent can be adjusted by varying the pressure at which the agent is supplied from the syringe or vial through infusion port  27 , or alternatively by adjusting the degree of inflation of inner balloon  32 . By adjusting the latter, the clinician can reduce the volume of annular space  39 , reducing the volume of therapeutic agent that must be used during the procedure. In addition, after infusing the therapeutic agent into annular space  39 , the clinician may increase the pressure in inner balloon  32  to pressurize annular spaces  39  and  40  and enhance the rate at which therapeutic agent exits apertures  35  and is infused into the vessel wall. Therapeutic agent deposited in pockets  48  preferably is taken up by the cells in the various layers of the wall of vessel V by normal cellular processes, as opposed to traumatically (e.g., by cleaving intercellular connections). 
         [0055]    In addition, as will be readily understood to one of ordinary skill in the art, while the balloon catheter is generally described as delivering a therapeutic agent, such as an anti-mitotic drug, to plaque, the disclosure is not limited thereto. The therapeutic agent may be selected to treat any condition where subintimal injection would be beneficial. For example, the therapeutic agent may be selected for treating a nascent or existing aneurysm when the balloon catheter is delivered proximate to an aneurysm. As another example, the therapeutic agent may be selected to induce angiogenesis, delivered either transluminally or into the sub-intimal space. The therapeutic agent may comprise, for example, one or more regenerative agents, anti-inflammatory agents, anti-allergenic agents, anti-bacterial agents, anti-viral agents, anticholinergic agents, antihistamines, antithrombotic agents, anti-scarring agents, antiproliferative agents, antihypertensive agents, anti-restenosis agents, healing promoting agents, vitamins, proteins, genes, growth factors, cells, stem cells, vectors, RNA, or DNA. 
         [0056]      FIG. 9  illustrates a final optional step in accordance with the method of present invention for infusing one or more therapeutic agents into the wall of vessel V.  FIG. 9  is similar to  FIG. 5C , except that in this step guide wire  25  is removed or retracted, and energy delivery device  50  carrying an energy deposition element is advanced through lumen  44  of catheter  20  and disposed in distal region  22 . The energy delivery element, located in the distal region of energy delivery device  50 , preferably includes one or more radiopaque markers to indicate positioning of the distal region under fluoroscopic imaging. Energy delivery device  50  preferably has a diameter between 0.018″ to 0.035″ and may comprise an optical fiber or source for delivering ultraviolet light, ultrasonic energy, or heat. Such devices, and the energy sources that are coupled to the proximal ends of such devices, are known in the art and accordingly are not described in detail here. Of particular importance, however, if a UV light or ultrasonic energy delivery device  50  is employed, catheter  20  preferably is constructed so that a substantial part of the energy is delivered to the vessel wall without being absorbed by the catheter material, and the energy absorbed by the vessel wall has some therapeutic benefit, e.g., activates the therapeutic agent. Energy emitted by energy delivery device  50  and absorbed by vessel V is represented by the solid arrows in  FIG. 9 . 
         [0057]    As discussed above with respect to  FIGS. 6 and 7 , energy delivery device  50  may provide a therapeutic effect either by facilitating uptake of the therapeutic agent by the vessel wall; by activating the therapeutic agent; by heating the therapeutic agent to effect a change to the vessel wall structure; or by directing delivering energy to selected layers of the vessel wall to cause polymerization or cross-linking of fluent therapeutic agents (e.g., as described in U.S. Pat. No. 5,749,915 to Slepian localized necrosis or remodeling of collagen contained within the vessel wall. 
         [0058]    In one embodiment, the deposited energy enhances uptake of the therapeutic agent through the layers of the vessel wall, for example, by activating moieties bound to the effective portion (e.g., anti-proliferative portion) of the therapeutic agent, (e.g., as described in U.S. Pat. No. 4,590,211 to Vorhees). Alternatively, the therapeutic agent or drug may be designed so that when irradiated by ultraviolet light, or insonicated with ultrasound energy of a desired frequency, the drug transitions from a fluent form to a gel-like or solid form. In this case, the therapeutic agent will assist in blocking or reducing flow through the vaso vasorum, and reduce the rate at which the therapeutic agent or drug is removed from the selected portion of the vessel wall. Alternatively or in addition, if the therapeutic agent transforms to a gel-like or solid form, it will be less susceptible to erosion, thereby locally prolonging the therapeutic effect of the agent. 
         [0059]    In a further alternative embodiment, the energy deposited by delivery device  50  may cause a component of the therapeutic agent to heat up and remodel collagen of, or partially necrose portions of, the adventitia or vaso vasorum. This effect also may cause a localized blockage that stops or reduces flow through the vaso vasorum and act to produce a localized reservoir of the therapeutic agent that provides prolonged release. As yet another alternative embodiment, the UV or ultrasonic energy may directly cause partial remodeling or necrosis of the adventitia and/or vaso vasorum to create localized blockage of the vaso vasorum to produce the reservoir effect noted above. 
         [0060]    Referring again to  FIG. 9 , energy delivery device  50  may be configured to deliver energy to vessel V during and after, or alternatively only a predetermined interval after, the therapeutic agent is delivered by catheter  20 . Once the process of delivering the therapeutic agent into the vessel wall is completed, and the appropriate amount of energy has been delivered to enhance or prolong the therapeutic effect of the therapeutic agent, energy delivery device  50  may be withdrawn. Next, suction may be drawn on infusion lumen  41  to remove any excess therapeutic agent from annular spaces  39  and  40  to collapse intermediate balloon  31  and retract outer balloon  30  away from the vessel wall. In an embodiment where the outer balloon includes protrusions, the outer balloon may be constructed so that, when deflated, the balloon preferentially will fold to enclose the protrusions and reduce the risk of abrading the vessel wall during removal. Alternatively, or in addition, an open-ended sheath (not shown) may be advanced over the exterior surface of catheter shaft  23  and the exterior of outer balloon  30  to facilitate removal of catheter  20 . Once catheter  20  is removed from the patient&#39;s vasculature, the access site may be closed using standard interventional techniques. 
         [0061]    Referring now to  FIGS. 10A ,  10 B and  11 , an alternative embodiment of apparatus constructed in accordance with the principles of the present invention is described. Catheter  60  includes elongated catheter shaft  61  having distal region  62  and outer balloon  63 . The proximal end of catheter shaft  61  is similar in construction to catheter  20  and preferably includes a hemostatic guide wire port, balloon inflation port and infusion port. As shown in  FIG. 10B  (which corresponds to an inflation state similar to  FIG. 2B ), distal region  62  includes outer balloon  63 , intermediate balloon  64  and inner balloon  65 . As for catheter  20  of the preceding embodiment, inner balloon  65  is fluid impermeable and is coupled via an inflation lumen to an inflation port on the proximal end. Likewise, intermediate balloon  64  includes a multiplicity of through-wall apertures  66  (see  FIG. 11 ) and is coupled via an infusion lumen to an infusion port disposed on the proximal end of the catheter. Outer balloon  63  includes one or more spiral protrusions  67  and a multiplicity of through-wall apertures  68 . 
         [0062]    Catheter  60  differs from the embodiment of  FIG. 1  in that the exterior surface of outer balloon  63  includes protrusions  67  arranged as a spiral ridge. In addition, whereas intermediate balloon  64  of the embodiment of  FIG. 1  may contain a textured surface to ensure that intermediate balloon  64  does not adhere to outer balloon  63 , intermediate balloon  64  in the embodiment of  FIGS. 10 and 11  includes a macroscopic feature to prevent such adhesion. In particular, intermediate balloon  64  includes spiral rib  69 , preferably comprised of the same material and potentially integrally formed with intermediate balloon  64 , disposed on its exterior-facing surface of the intermediate balloon. In this manner, spiral rib  69  contacts the inner surface of outer balloon to ensure that annular space  70  is maintained between intermediate balloon  64  and outer balloon  63  when inner balloon  65  is inflated to urge intermediate balloon  64  and outer balloon  63  into contact with a vessel wall to dilate the vessel and disrupt plaque. 
         [0063]    While in the embodiment of  FIGS. 10 and 11  protrusions  67  are configured as a spiral ridge having a rounded extremity, it should be understood that other patterns will readily occur to a person of ordinary skill in the design of balloon catheters, such as structures having rectangular, conical or pyramidal cross-sections, as may be desirable to fracture severe calcifications. Similarly, while apertures  68  are depicted as being circular, they may have any other desired shape, such as rectangular, triangular or elliptical. Preferably, apertures  68  are offset from protrusions  67  so as to reduce clogging of the apertures when the protrusions are urged into contact with the luminal surface. Likewise, apertures  66  in intermediate balloon  64  may be offset from apertures  68  in outer balloon  63  to achieve the benefits described above. 
         [0064]    Finally, although the macroscopic feature in intermediate balloon  64  is illustratively depicted as comprising spiral rib  69  having a substantially circular cross-section, this feature could have other cross-sections, such as rectangular, elliptical or triangular. In addition, spiral rib  69  need not form a continuous structure, but instead could comprise a multiplicity of discrete structures, similar in shape to protrusions  47  disposed on outer balloon  30 ″ of the embodiment of  FIG. 4 . For example, intermediate balloon  64  and outer balloon  63  may comprise the same material having the same protrusions disposed on their respective exterior surfaces. In this manner, construction of the distal end of the catheter of the present invention could be simplified, so long as the apertures in the intermediate and outer balloons are staggered or offset to provide the baffle action discussed above. 
         [0065]    While preferred illustrative embodiments of the invention are described above, it will be apparent to one skilled in the art that various changes and modifications may be made therein without departing from the invention. The appended claims are intended to cover all such changes and modifications that fall within the true spirit and scope of the invention.