Abstract:
Multiple-balloon catheters, and methods of treatment therewith, are provided including an inflatable inner balloon at least partially enclosed by an expandable outer balloon that has holes. The annular space between the inner balloon and the outer balloon is configured to promote delivery of the fluid evenly through holes in the outer balloon to avoid problems of underloading and/or overloading. Preferably, the annular space is in communication with the holes, and the annular space is configured to receive and then to release and distribute the fluid via the holes in a substantially uniform manner such that even amounts of fluid are released in the distal and proximal holes. The inner balloon may have various configurations including being tapered relative to the outer balloon. The outer balloon may also be tapered accordingly. The device may also include raised portions disposed in the annular space and configured to define channels having various configurations.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application claims priority and the benefit of provisional U.S. patent application Ser. No. 61/043,208, filed Apr. 8, 2008, which is incorporated herein by reference in its entirety. 
    
    
     TECHNICAL FIELD 
     The present application relates to medical catheters configured to release a therapeutic agent. More particularly, the present application relates to medical multiple balloon catheters useful in the local administration of a therapeutic agent within a body vessel, as well as methods for the local administration of a therapeutic agent. 
     BACKGROUND 
     Localized administration of therapeutic agents within a body vessel can be advantageous for treatment of a variety of medical conditions. Although such medical conditions can be treated by the general systemic administration of a therapeutic agent, systemic administration of some therapeutic agents can not only result in the unnecessary absorption of the therapeutic agent by tissue outside an intended point of treatment, but also require administration of a greater dose of the therapeutic agent than necessary to compensate for the dissipated therapeutic agent. Accordingly, the treatment of many conditions requires local delivery of the therapeutic agent to a particular portion of internal body tissue, without dissipating the therapeutic agent to the tissue surrounding the particular portion of tissue. 
     To aid site-specific localized treatment, percutaneous delivery systems such as medical catheters can be used to deliver a therapeutic agent to the target site within a body vessel with minimal invasiveness. Medical catheters permit the delivery of the therapeutic agent from the medical catheter placed within the body vessel proximate the desired treatment site. The delivery of the therapeutic agent from the medical catheter can occur before, during and/or after a procedure such as percutaneous transluminal coronary angioplasty (PTCA), a technique used to dilate stenotic portions of blood vessels. The medical catheter can be adapted to perform a PTCA procedure and locally deliver the therapeutic agent to the site of the procedure. During PTCA, a medical balloon catheter is threaded into and through a body vessel lumen along a wire guide and positioned at a stenosis or other point of treatment, where the balloon is inflated to dilate the target site of the body vessel lumen. After treatment, the balloon is deflated and the catheter is removed from the target site and the patient&#39;s lumen, thereby allowing blood to freely flow through the unrestricted lumen. 
     At times after PCTA the treated portions of the body vessel can have a reoccurrence of constrictions or blockages. This phenomenon is called restenosis, which is the reoccurrence of stenosis at the treated site within the body vessel that can be caused by the body responding to the surgical procedure. Restenosis of the body vessel commonly develops over several months after the procedure, which can require another angioplasty procedure or a surgical by-pass operation. Proliferation and migration of smooth muscle cells (SMC) from the media layer of the lumen to the intima can cause an excessive production of extra cellular matrices (ECM), which is believed to be one of the leading contributors to the development of restenosis. The extensive thickening of tissues narrows the lumen of the blood vessel, constricting or blocking the blood flow through the vessel. 
     Therapeutic agents can limit or prevent restenosis. The therapeutic agents can be locally delivered with PTCA from a catheter and/or by placement of a stent configured to release the therapeutic agent after the PTCA procedure. Procedures involving medical balloon catheters can also be used in combination with the placement of stents, synthetic vascular grafts or administration of therapeutic agents, during the PTCA procedure to reduce or eliminate the incidence of restenosis. 
     Medical balloon catheters have been developed to administer the therapeutic agent locally to tissue while dilating a body vessel. For instance, a medical balloon catheter can include two concentrically arrayed coaxial balloons at the distal end of a double balloon catheter, also called a balloon-inside-a-balloon design. The outer balloon can include one or more perforations or holes to locally administer a therapeutic agent, while the inner balloon provides the dilatation and/or sealing of the body vessel lumen. 
     Nevertheless, localized administration of therapeutic agents evenly within a body vessel with a double balloon catheter can be difficult. In particular, during administration of the therapeutic agent, more of the therapeutic agent can diffuse out of the outer balloon holes at the proximal end of the outer balloon than from the outer balloon holes positioned nearer the distal end of the outer balloon. This can result in administering the therapeutic agent unevenly along the length of the outer balloon, possibly due to fluid pressure losses between the annular spaces along the length of the balloon due to the wall shear stresses on the fluid flowing between the balloons. Thus, there remains a need for a multiple balloon catheter for expanding a body vessel and locally administering medication evenly to the body vessel for an intended medical application. Also, there remains a need for a multiple balloon catheter for expanding a body vessel and locally administering medication to the body vessel evenly along the length of the balloon catheter to avoid overloading of the therapeutic agent at the proximal end and/or underloading of the therapeutic agent at the distal end of the catheter. 
     SUMMARY 
     The present disclosure describes multiple-balloon fluid delivery catheter configurations that release a fluid in a desired manner by providing preferred configurations of the annular space between an inner balloon and an outer balloon around the catheter. The multiple-balloon catheters or weeping balloon catheters may include a catheter shaft having a perforated, expandable outer balloon disposed around at least a portion of an inflatable inner balloon. The balloons in the respective inflated and expanded configurations define an annular lumen. The annular lumen is in communication with a fluid delivery lumen extending along the catheter shaft and the holes of the outer balloon. Fluid passed through the fluid delivery lumen in the catheter shaft and the annular lumen may be released through the holes of the outer balloon. 
     The configuration of the annular lumen are preferably selected to provide a substantially equal rate, volume, pressure, or any combination, of fluid flow through the holes of the outer balloon at a fixed fluid delivery pressure at the proximal end of the catheter shaft. By varying the configuration of at least one of the inner balloon, the outer balloon, and/or attachments therebetween, the annular lumen is then configured to promote delivery of the fluid evenly through the plurality of holes in the outer balloon. Preferably, there will not be more fluid released at the proximal end of the porous region of the outer balloon compared to the distal end of the porous region the outer balloon. This ensures that the point of treatment within the body vessel is receiving equal amounts of fluid along the outer balloon, thereby preventing wasteful release of excess fluid within the body vessel. 
     In one embodiment, a multiple-balloon intraluminal fluid delivery catheter for delivering a fluid into a body vessel includes a catheter shaft, an outer balloon and an inner balloon. The catheter shaft extends along a longitudinal axis from a proximal end to a distal end. The catheter shaft can include at least one of an inflation lumen to deliver an inflation fluid, a fluid delivery lumen to deliver the fluid, and/or a wire guide lumen for receiving a wire guide. The inner balloon includes a middle region having a first end and a second end. The second end can be disposed closer to the distal end of the outer balloon than the proximal end of the outer balloon. The inner balloon is mounted on the catheter shaft and in communication with the inflation lumen. The inner balloon is movable between a deflated configuration and an inflated configuration. In the inflated configuration, the inner balloon can have a maximum cross-sectional area at the second end, which can be sized to dilate a portion of the body vessel. 
     The outer balloon is mounted around at least a portion of the inner balloon. The outer balloon has a proximal end and a distal end and a middle portion therebetween. The outer balloon is movable between a compressed configuration and an expanded configuration. In the expanded configuration the outer balloon can have a maximum cross-sectional area sized to sealably contact a portion of the body vessel. The outer balloon also includes a plurality of holes. The holes are disposed along the circumferential surface of the balloon, and preferably along the middle portion. The holes can be uniform in size and frequency, but also can vary in size and frequency. The inner balloon and the outer balloon can be independently movable to the inflated configuration and the expanded configuration, respectively. 
     The inner balloon and the outer balloon are configured and oriented such that an annular lumen is defined when the inner balloon is in the inflated configuration and the outer balloon is in the expanded configuration. The annular lumen is in communication with the fluid delivery lumen and the plurality of holes. The annular lumen is configured to promote the delivery of the fluid through the plurality of holes. The annular lumen can have a portion disposed between the middle region of the inner balloon and the middle portion of the outer balloon. The annular lumen portion can have an increasingly smaller cross-sectional area along the longitudinal axis in a distal direction. 
     Various configurations are provided to vary the cross sectional area of the annular lumen between the inner balloon and outer balloon in order to promote delivery of the fluid evenly through the plurality of holes. 
     In one aspect, the first end of the inner balloon can be proximal to the second end of the inner balloon, and in the inflated configuration the inner balloon can include an increasingly larger cross-sectional area along the middle region from the first end to the second end. Alternatively, the inner balloon in the inflated configuration can include an increasingly larger cross-sectional area along the middle region from the first end to the second end. Alternatively, the inner balloon in the inflated configuration can have an asymmetrical taper along the middle region. Alternatively, the inner balloon in the inflated configuration can have a uniform taper along the middle region. Alternatively, the inner balloon in the inflated configuration can have a series of steps of increasingly larger cross-sectional areas. The steps may be disposed along the middle region. 
     In another aspect, the outer balloon in the expanded configuration can include a tapering surface having an increasingly smaller, or larger, cross-sectional area along the middle portion from the proximal end to the distal end, depending on the initial orientation of the balloon. In one example, the inner balloon in the inflated configuration can be cylindrical having a uniform cross-sectional area along the middle region from the first end to the second end. In another example, the inner balloon in the inflated configuration can include a tapering surface having an increasingly smaller, or larger, cross-sectional area along the middle region from the first end to the second end, depending on the initial orientation of the balloon. The taper of the tapering surface of the outer balloon can be greater, or smaller, than the taper of the tapering surface of the inner balloon, depending on the initial orientation of the balloon. 
     In another aspect, the multiple-balloon catheter can also include a plurality of raised portions disposed in the annular lumen and attached to at least one of an inner surface of the outer balloon and an outer surface of the inner balloon. At least a portion of the raised portion is sealably contactable against the inner surface and the outer surface when the inner balloon is in the inflated configuration and the outer balloon is in the expanded configuration. The raised portions are spaced apart such that a channel is defined therebetween, with the channel being configured to promote delivery of the fluid evenly through the plurality of holes. In one example, each of the raised portions can have a lateral cross-sectional area at a first point and a lateral cross-sectional area at a second point distal to the first point. The lateral cross-sectional area at the second point can be greater than the lateral cross-sectional area at the first point such that the channel becomes narrower in the distal direction. In another example, each of the raised portions can be interconnected by a web along the outer surface of the inner balloon. The web can have a cross-sectional area at a first point and a cross-sectional area at a second point distal to the first point. The cross-sectional area at the second point can be greater than the cross-sectional area at the first point such that the channel becomes narrower in the distal direction. 
     In another embodiment, methods of delivering a therapeutic agent or other fluid to a point of treatment within a body vessel with the multiple-balloon catheter described herein. The multiple-balloon catheter is inserted within the body vessel over a wire guide. The multiple-balloon catheter can incorporate a rapid exchange system or an over-the-wire system. The multiple-balloon catheter is translated through the body vessel to the point of treatment over the wire guide that slidably extends through the wire guide lumen. The inner balloon is then inflated to the inflated configuration to place or urge the outer balloon in contact with a wall of said body vessel. Inflation fluid can be delivered to the catheter shaft, through the inflation lumen, to enter into the inner balloon. The therapeutic agent is introduced through the fluid delivery lumen of the catheter shaft at a pressure effective to deliver the therapeutic agent to the body vessel wall through the annular lumen and the plurality of holes of the outer balloon. Preferably, the therapeutic agent is locally administered to the body vessel evenly along the length of the outer balloon to avoid overloading of the therapeutic agent through the proximal end and/or underloading of the therapeutic agent through the distal end of the holes of the outer balloon. 
     The above, as well as other advantages of the present invention, will become readily apparent to those skilled in the art from the following detailed description of a preferred embodiment when considered in the light of the accompanying drawings. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  is a perspective view of a multiple-balloon catheter. 
         FIG. 2A  is a transverse cross-sectional view along line  2 A- 2 A of the multiple-balloon catheter shown in  FIG. 1 . 
         FIG. 2B  is a transverse cross-sectional view along line  2 B- 2 B of the multiple-balloon catheter shown in  FIG. 1 . 
         FIG. 2C  is a transverse cross-sectional view along line  2 C- 2 C of the multiple-balloon catheter shown in  FIG. 1 . 
         FIG. 3  is longitudinal cross-sectional view of the distal portion of the multiple-balloon catheter. 
         FIG. 4  is longitudinal cross-sectional view of the distal portion of a multiple-balloon catheter within a body vessel. 
         FIG. 5  is a side view of another multiple-balloon catheter, depicting an inner balloon having a stepped configuration. 
         FIG. 6  is a side view of another multiple-balloon catheter, depicting an outer balloon having a taper. 
         FIG. 7A  is a side view of another multiple-balloon catheter, depicting raised portions in between the inner and outer balloons. 
         FIG. 7B  is a partial sectional view taken along line  7 B- 7 B in  FIG. 7A , depicting raised portions and channels. 
         FIG. 7C  is a partial sectional view taken along line  7 C- 7 C in  FIG. 7A , which is distal to line  7 B- 7 B, depicting raised portions and channels. 
     
    
    
     DETAILED DESCRIPTION 
     As used herein, the term “implantable” refers to an ability of a medical device to be positioned at a location within a body, such as within a body vessel. Furthermore, the terms “implantation” and “implanted” refer to the positioning of a medical device at a location within a body, such as within a body vessel. 
     The term “biocompatible” refers to a material that is substantially non-toxic in the in vivo environment of its intended use, and that is not substantially rejected by the patient&#39;s physiological system (i.e., is non-antigenic). This can be gauged by the ability of a material to pass the biocompatibility tests set forth in International Standards Organization (ISO) Standard No. 10993 and/or the U.S. Pharmacopeia (USP) 23 and/or the U.S. Food and Drug Administration (FDA) blue book memorandum No. G95-1, entitled “Use of International Standard ISO-10993, Biological Evaluation of Medical Devices Part-1: Evaluation and Testing.” Typically, these tests measure a material&#39;s toxicity, infectivity, pyrogenicity, irritation potential, reactivity, hemolytic activity, carcinogenicity and/or immunogenicity. A biocompatible structure or material, when introduced into a majority of patients, will not cause an undesirably adverse, long-lived or escalating biological reaction or response, and is distinguished from a mild, transient inflammation which typically accompanies surgery or implantation of foreign objects into a living organism. 
     As used herein, the term “body vessel” means any body passage lumen that conducts fluid, including but not limited to blood vessels, esophageal, intestinal, biliary, urethral and ureteral passages. 
     The medical devices of the embodiments described herein can be oriented in any suitable absolute orientation with respect to a body vessel. The recitation of a “first” direction is provided as an example. Any suitable orientation or direction can correspond to a “first” direction. For example, the first direction can be a radial direction in some embodiments. 
       FIG. 1  illustrates an exemplary embodiment of a medical device comprising a multiple-balloon catheter  10  or weeping balloon catheter. The multiple-balloon catheter  10  extends from a proximal end  12  to a distal end  14 . Therebetween, the multiple-balloon catheter  10  includes a manifold  16  located toward a proximal region  18  of the multiple-balloon catheter  10  and a multiple-balloon assembly  20  at a distal region  19  of the multiple-balloon catheter  10 . The manifold  16  is operatively joined to a catheter shaft  22  in the proximal region  18 , with the catheter shaft  22  extending from a proximal end  26  to a distal end  28 . The manifold  16  can include a lateral injection port  32  and an inflation port  34 . The catheter shaft  22  can include an inflation lumen  30 , a fluid delivery lumen  33  spaced from the inflation lumen  30 , and a wire guide lumen  38 . The catheter shaft  22  can also include one or more conventional fittings and/or adapters between the manifold  16  and the proximal end  26  of the catheter shaft  22 . The multiple-balloon catheter  10  can be a “short wire” system having a wire guide port  23  within an intermediate region of the catheter shaft  22 , providing access to a wire guide lumen  38  extending through the catheter shaft  22  from the wire guide port  23  to the distal end  14  of the multiple-balloon catheter shaft  10 , as shown in  FIG. 1 . Optionally, the multiple-balloon catheter  10  can be an “over the wire” system with the wire guide port  23  positioned as part of the manifold  16 . That is, the manifold  16  can include the wire guide port  23  in addition to the inflation port  34  and the injection port  32 . 
     The distal region  19  of the multiple-balloon catheter  10  includes a perforated second balloon  42  radially disposed around at least a portion of a first balloon  40 . The first balloon  40  is preferably non-porous and in fluid communication with the inflation port  34  through the body of the catheter shaft  22 . The second balloon  42  includes a plurality of holes  46  and is in fluid communication with the injection port  32  through the catheter shaft  22  and separated from both the first balloon  40  and the inflation port  34 . 
     In a preferred embodiment shown in  FIG. 1 , the first balloon  40  is a tapered inner balloon, having a portion with an increasingly larger cross-sectional area moving distally along the longitudinal axis  24 , and the second balloon  42  is an outer cylindrical balloon. Optionally, multiple inner balloons, each having a uniform cross-sectional area, a tapering cross-sectional area, or both, can be arranged within the outer balloon, where much like the stepped configuration embodiment, described in more detail below, the general cross-sectional area of each balloon is increasingly larger moving along the longitudinal axis in the distal direction to generally define a taper. 
     According to  FIG. 3 , an annular balloon fluid delivery lumen  44  for receiving a therapeutic agent or fluid, such as a diagnostic media, from the injection port  32  via the fluid delivery lumen  33  can be formed between the first balloon  40  and the second balloon  42 . Both the first balloon  40  and the second balloon  42  can be sealed to the distal end of the catheter shaft  22 , within the distal portion of the catheter shaft  22  housing the distal portion of the wire guide lumen  38 . The multiple-balloon catheter  10  can be translated over a wire guide  36  that is shown extending from the wire guide port  23 , through the catheter shaft  22  and extending through the distal end  14  of the multiple-balloon catheter  10 . The multiple-balloon catheter  10  is typically provided separately from the wire guide  36 , an introducer sheath (not shown) or other devices typically used to insert the multiple-balloon catheter  10  within a body vessel. 
     The catheter shaft  22  of the multiple-balloon catheter  10  can have any suitable dimension, but is preferably shaped and configured for the intended use in a body vessel. The catheter shaft  22  preferably includes the wire guide lumen  38  configured to house a guide wire. The lumen  38  can have an inside diameter of about approximately 0.5 mm. The overall length of the catheter shaft  22  can be approximately 110-180 cm. The catheter shaft  22  can optionally be configured as a rapid exchange catheter, such as the catheter devices described in U.S. Pat. Nos. 5,690,642 and 5,814,061. The outside diameter of the catheter shaft  22  is typically approximately 1-1.5 mm, but can be up to about 3.5 mm. Further details regarding the manufacturing and/or assembling of the catheter shaft  22  are described in U.S. PCT Application Number US2008/75970 filed on Sep. 11, 2008, incorporated herein by reference in its entirety. 
       FIG. 2A  is a transverse cross-sectional view of the multiple-balloon assembly  20  along line  2 A- 2 A in  FIG. 1  showing a proximal end of the multiple-balloon assembly  20  of the multiple-balloon catheter  10 . The first balloon  40  includes a tubular member  41  defining the inflation lumen  30  and a tubular member  43  defining the wire guide lumen  38 . Preferably, the inflation lumen  30  and the fluid delivery lumen  33  (not shown in  FIG. 2A ) are in isolation from one another. The fluid delivery lumen  33  is in fluid communication with the annular balloon fluid delivery lumen  44 , which is shown between the second balloon  42  and the first balloon  40 . 
       FIG. 2B  is a transverse cross-sectional view of the multiple-balloon assembly  20  along line  2 B- 2 B in  FIG. 1  that is distally located from the line  2 A- 2 A, showing a proximal portion of the multiple-balloon assembly  20  of the multiple-balloon catheter  10  in the inflated configuration. The first balloon  40 , shown as tapered, defines the inflation lumen  30  extending radially around the tubular member  43  that defines the wire guide lumen  38 . The annular balloon fluid delivery lumen  44  is shown to be in between the second balloon  42  and the first balloon  40 . The cross-sectional area or diameter of the annular balloon fluid delivery lumen  44  is greater here than would be at a more distal position. 
       FIG. 2C  is a transverse cross-sectional view of the multiple-balloon assembly  20  along line  2 C- 2 C in  FIG. 1  that is distally located from the line  2 B- 2 B, showing the middle region  50  and the middle portion  70  of the multiple-balloon assembly  20  of the multiple-balloon catheter  10  in the inflated configuration. The first balloon  40 , shown as tapered, defines the inflation lumen  30  extending radially around the tubular member  43  that defines the wire guide lumen  38 . The holes  46  are in fluid communication with the annular balloon fluid delivery lumen  44 , which is shown between the second balloon  42  and the first balloon  40 . The cross-sectional area or diameter of the annular balloon fluid delivery lumen  44  is smaller here than would be at a more proximal position. 
     Referring to  FIG. 3 , the first balloon  40  having a proximal end  47  and a distal end  49  is mounted at the distal end of the catheter shaft  22 . The first balloon  40  is inflatable between a deflated configuration and an inflated configuration. The inflation lumen  30  defined by the tubular member  41  of the catheter shaft  22  is in communication with the first balloon  40 . The inflation of the first balloon  40  can be accomplished by any suitable means known in the art, e.g., by introducing an inflation fluid (e.g., air, saline, etc.) through the inflation lumen  30  into the first balloon  40 . 
     The first balloon  40  has a middle region  50 , which is defined between a first end  60  and a second end  62 . The first balloon  40  can also have a first portion  52  and a second portion  54  contiguous with the middle region  50 . The middle region  50  can be tapered or having an increasingly larger cross-sectional area or diameter in the inflated configuration along the longitudinal axis  24  moving distally away from the first end  60  to the second end  62 . The middle region  50  is preferably positioned proximate the working length or middle portion  70  of the second balloon. The first portion  52  also may have an increasingly larger cross-sectional area or diameter in the inflated configuration along the longitudinal axis  24  moving distally from the proximal end  47  to the first end  60 . The rate of incline of the first portion  52  may be the same as the middle region  50 , or preferably, the rate of incline may be larger than the middle region  50 , as shown in  FIG. 3 . The second portion  54 , to the contrary, has an increasingly smaller cross-sectional area or diameter in the inflated configuration along the longitudinal axis  24  moving distally from the second end  62  to the distal end  49 . 
     Preferably, the middle region  50  in the inflated configuration is tapered in a manner effective to provide a desired resistance to fluid flow through the annular balloon fluid delivery lumen  44 , and/or to direct fluid flow through the annular balloon fluid delivery lumen  44  toward the holes  46  in the second balloon  42 . For example, the first balloon  40  may have an outer surface having a uniform taper from the second end to the first end, as shown in  FIG. 3  or  FIG. 4 . The angle of the taper may be selected to provide a desired rate of fluid flow through the holes  46  in the second balloon  42  as a function of the position of holes  46  relative to each other. For example, the first balloon  40  may be tapered in a manner providing for a substantially equal rate, volume, or both of fluid flow through all or substantially all of the holes  46  in the second balloon  42  at a given fluid pressure. The tapering rate of the middle region can be, for example, 0.125 mm per 10 mm in length to about 0.5 mm per 10 mm in length, although it is appreciated that the taping rate selected should be sufficient to optimize uniform delivery of fluid or therapeutic agent. In the alternative, the first balloon  40  may have an outer surface that has an asymmetric tapered configuration from the second end to the first end. This configuration can include tapering along the outer surface of the inner balloon that is parabolic, curved, a series of longitudinal portions having different degrees of tapering, or the like. 
     The maximum cross-sectional area or outer diameter  56  of the first balloon  40  can be large enough to dilate a portion of the body vessel when in the inflated configuration. The outer diameter  56  is preferably at the second end  62  of the middle region  50 . Regardless of the configuration of the first balloon  40 , when configured for use in a peripheral blood vessel, the maximum inflated outer diameter  56  of the first balloon  40  can be about 1.5 mm to about 8 mm, yet when configured for coronary vascular applications, the maximum inflated diameter  56  can have a range of from about 1.5 mm to about 4 mm. When configured for use in bile ducts, the maximum inflated outer diameter  56  of the first balloon  40  can be about 5-15 mm with a length of approximately 15-60 mm. Preferably, the geometry, material and configuration of the first balloon  40  is selected to withstand an internal inflation fluid pressure of about 5 ATM and, preferably, about 10 atmospheres without any leakage or rupture. The thickness of the first balloon  40  should be selected in order withstand a sufficient force that can inflate the first balloon  40  against the body vessel luminal wall without rupturing. 
     The second balloon  42  is mounted on the distal end of the catheter shaft  22 . The second balloon  42  is mounted around at least a portion of the first balloon  40 , but preferably mounted entirely around the first balloon  40 , with the second balloon  42  enclosing the first balloon  40 . The second balloon  42  includes a working length or a middle portion  70  between a proximal end  72  and a distal end  74 . The second balloon  42  is moveable between a compressed configuration and an expanded configuration. Preferably, the geometry, material and configuration of the second balloon  42  are selected to withstand an internal pressure of a therapeutic agent and the inflation of the first balloon  40  without any rupture. 
     Referring to both the first balloon  40  and the second balloon  42  in  FIG. 3 , the maximum inflated outer diameter  56  of the first balloon  40  can be at a point within the second balloon  42  that is closer to the distal end  74  of the second balloon  42  than the proximal end  72  of the second balloon  42 . Optionally, the maximum outer diameter  56  of the first balloon  40  can be smaller than, or substantially identical to, the maximum cross-sectional area or outer diameter  80  of the second balloon  42  in the expanded configuration. The maximum expanded outer diameter  80  of the second balloon  42  is preferably at the middle portion  70  of the second balloon  42 , the cross-sectional area being large enough to dilate a portion of the body vessel when in the expanded configuration. 
     The second balloon  42  is preferably shaped and configured for the intended use in a body vessel. When configured for use in a peripheral blood vessel, the expanded outer diameter  80  of the second balloon  42  can be about 1.5 mm to about 8 mm, yet when configured for coronary vascular applications, the expanded outer diameter  80  can have a range of from about 1.5 mm to about 4 mm. When configured for use in bile ducts, the expanded outer diameter  80  of the second balloon  42  can be about 5-15 mm with a length of approximately 15-60 mm. 
     According to  FIGS. 2B ,  2 C and  3 , the annular balloon fluid delivery lumen  44  is defined as the space between the first balloon  40  and the second balloon  42 . Preferably, the working region of the annular balloon fluid delivery lumen  44  is the space between the middle region  50  of the first balloon  40  and the middle portion  70  of the second balloon  42 . The annular balloon fluid delivery lumen  44  is in fluid communication with the fluid delivery lumen  33 , shown within a tubular member  35  of the catheter shaft  22 . 
     The annular balloon fluid delivery lumen  44  preferably has an increasingly smaller cross-sectional area along a first portion  90  of the longitudinal axis  24  moving distally. Typically, as the first balloon  40  inflates, the volume of the annular balloon fluid delivery lumen  44  decreases, increasing the resistance or pressure loss to fluid passing through the fluid delivery lumen  33  in the distal direction. However, because the proximal portion of the annular balloon fluid delivery lumen  44  has a much larger cross-sectional area than the cross-sectional area of the distal portion of the annular balloon fluid delivery lumen  44 , the proximal portion of annular balloon fluid delivery lumen  44  offers little resistance, or limited pressure loss, to fluid. Consequently, with a decrease in resistance the released therapeutic agent is permitted to move more easily in the distal direction along the second balloon  42  to reach the more distal holes  48 , while maintaining an effective velocity and pressure to allow more even distribution of the therapeutic agent from the all of the holes  48 . This also can permit the operator of the catheter to use a lower total pressure at the injection port  32  and/or less therapeutic agent or fluid. 
     Preferably, the change in cross-sectional area of the first portion  90  of the annular balloon fluid delivery lumen  44  is proportional to the tapering rate of the middle region  50  of the first balloon  40 . A second portion  92  of the annular balloon fluid delivery lumen  44 , contiguous with the first portion  90 , can have an increasingly larger cross-sectional area along the longitudinal axis  24  moving in the distal direction. The change in cross-sectional area of the second portion  92  of the annular balloon fluid delivery lumen  44  can be proportional to the tapering rate of the second portion  54  of the middle region  50  of the first balloon  40 . 
     The holes  46  for releasing fluid from the fluid delivery lumen  33  of the catheter shaft  22  can be disposed around the middle portion  70  of the second balloon  42 . The plurality of holes  46  can have any suitable size and shape suitable to provide a desired rate of fluid release from the annular balloon fluid delivery lumen  44 . Preferably, the plurality of holes  46  has a uniform dimension of about 10 micrometer (0.0004 inch) to about 1 mm (0.04 inch). This can permit the tapering rate of the annular balloon fluid delivery lumen  44  to reduce resistance to fluid delivery for a more even distribution of fluid. Alternatively, to reduce resistance to fluid delivery through the holes  46 , the plurality of holes  46  can have a cross sectional area that increases in the distal direction along the outer balloon, which is shown in  FIG. 1 . This can include holes that increase in size and/or frequency moving distally along the second balloon  42 . For example, the size of the holes can increase in the distal direction and/or the amount of holes can increase in the distal direction. The holes can be formed by any suitable method including mechanical punching, laser cutting, and the like 
     The first balloon  40  and the second balloon  42  can be formed and/or molded from a semi-compliant expandable, biocompatible material. Preferably, the first balloon  40  and the second balloon  42  are formed from the materials having a similar Young&#39;s modulus and expandability for better maintaining the space between the balloons during the entire inflation period. For example, the balloons  40 ,  42  can 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); polyurethane 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). The balloons  40 ,  42  can comprise any suitably non-elastic material such as ionomers, copolyesters, rubbers, or any medical grade polymers suitable for use in forming catheter balloons. 
     The proximal seal  82  and distal seal  84  of the first balloon  40  and the proximal seal  86  and distal seal  88  of the second balloon  42  can be formed in any suitable manner. Typically, the proximal and distal inner surfaces of the balloons  40 ,  42  are sealably attached to the catheter shaft  22  and/or tubular members to prevent any leakage of any fluid. Means of sealing the balloons  40 ,  42  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 can be used as a manufacturing aid to compress and fuse each balloon  40 ,  42  to the catheter shaft  22  or the tubular member defining the wire guide lumen  38 , the inflation lumen  30 , and/or the fluid delivery lumen  33 . The shrink tubing can be removed and disposed of after each balloon  40 ,  42  is sealed, or can remain on as part of the connected structure. If the catheter shaft  22  has an outer coating, each balloon  40 ,  42  can be bonded to the coating or directly to the catheter shaft  22 . 
     The therapeutic agent can be delivered through the fluid delivery lumen  33  and through the annular balloon fluid delivery lumen  44  at a pressure effective to deliver the therapeutic agent to the wall of the body vessel through the holes  46  in the second balloon  42 . The therapeutic agent can be delivered by direct local administration to the vessel site or injury through the holes  46  in the second balloon  42 . The antisense compound can have: (i) morpholino subunits linked together by phosphorodiamidate linkages, 2 atoms long, joining the morpholino nitrogen of one subunit to the 5′ exocyclic carbon of an adjacent subunit; and (ii) a sequence of bases attached to the subunits and containing a therapeutically beneficial antisense nucleotide sequence. While the compound need not necessarily 100% complementary to the target sequence, it is preferably effective to stably and specifically bind to the target sequence such that expression of the target sequence is modulated. The appropriate length of the oligomer to allow stable, effective binding combined with good specificity is about 8 to 42 nucleotide base units, and preferably about 12-25 base units. Mismatches, if present, are less destabilizing toward the end regions of the hybrid duplex than in the middle. Oligomer bases that allow degenerate base pairing with target bases are also contemplated, assuming base-pair specificity with the target is maintained. The compound preferably contains internal 3-base triplet complementary to the AUG site, and bases complementary to one or more bases 5′ and 3′ to the start site. One preferred compound sequence is the 20mer having the base sequence: 5′-ACG TTG AGG GGC ATC GTC GC-3′, where the CAT triplet in the sequences binds to the AUG start site, the 6 bases 3′ to the CAT sequence extend in the upstream (5′) direction on the target, and the 11 bases 5′ to the CAT sequence extend downstream on the target. This compound has enhanced solubility by virtue of having no self-annealing regions. Preferably, the therapeutic agent is a morpholino antisense compound having (i) from 8 to 42 nucleotides, including a targeting base sequence that is complementary to a region that spans the translational start codon of a c-myc mRNA; and (ii) uncharged, phosphorous-containing intersubunit linkages, in an amount effective to reduce the risk or severity of restenosis in the patient. These therapeutic agents are described in U.S. Pat. No. 7,094,765 and published U.S. patent application US 2006/0269587 A1, which are incorporated herein by reference in their entirety. While the therapeutic agent is described with respect to certain preferred antisense compounds, any suitable therapeutic agent in fluid form (i.e., a gas and/or a liquid) or in a fluid carrier can be delivered from the multi-balloon catheter assembly  20 . 
     Referring to  FIG. 4 , in operation, the multiple-balloon assembly  120  of the multiple-balloon catheter  110  can be implanted within a body vessel  102  by conventional medical procedures, such as the Seldinger technique, and subsequently translated through the body vessel  102  over the wire guide through the wire guide lumen  138  to position the distal region at a point of treatment  104  therein. Once implanted, the first balloon  140  can be inflated to a desired diameter by injecting a suitable inflation fluid, such as a pressurized air, gas or liquid, through the inflation port in the manifold. For example, the first balloon  140  can be inflated to expand a stenosis in a body vessel  102  such as a coronary artery. Preferably, the first balloon  140  is inflated until the second balloon  142  contacts a portion of a wall of the body vessel  102  at the point of treatment  104 . 
     A fluid containing a therapeutic agent and/or a diagnostic agent (e.g., x-ray contrast media) or any other fluid known to be used in a body vessel can be injected through the injection port, transported within the fluid delivery lumen  133  included in the catheter shaft  122  and introduced to the annular balloon fluid delivery lumen  144  between the second balloon  142  and the first balloon  140 . The therapeutic agent fluid can be pressurized to deliver the therapeutic agent to the wall of the body vessel  102  through the plurality of holes  148  in the second balloon  142  before, during or after inflation of the first balloon  140 . 
     Optionally, the multiple-balloon assembly  120  of the multiple-balloon catheter  110  can include radiopaque material to provide a means for locating the multiple-balloon catheter  110  within a body vessel  102 . For example, the catheter shaft  122  can include one or more marker bands  108  annularly disposed around the outside of the catheter shaft  122  within the first balloon  140  to define the weeping region of the catheter  110 , or where the fluid is desirably release to the body vessel. If desired, radiopaque bands can be added to the catheter shaft  122 . Radiopaque marker bands  108  can be used by a clinician to fluoroscopically view and locate the distal portion of the multiple-balloon catheter  110  at a point of treatment  104  within a body vessel  102 . Various configurations of radiopaque marker bands  108  can be used. For example, radiopaque marker band  108  can be located on a distal end and/or on the catheter shaft  122  within the first balloon  140 . As shown, the radiopaque marker bands  108  can be stripes. Such radiopaque markers can be constructed by encapsulating a radiopaque material, such as a metallic ring, within the material of catheter shaft  122 . Alternatively a portion of the catheter shaft  122  can be made radiopaque for example by constructing the portion from a radiopaque polymer. For example a polymer can 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 can be selected to be adequately visible under fluoroscopy. 
     In another embodiment, methods of delivering a therapeutic agent to a body vessel are provided using any suitable catheter configuration, including the catheter of  FIG. 3  or the catheter of  FIG. 4 . Preferably, the methods include the step of inserting into a body vessel a multiple-balloon catheter. For example, the multiple-balloon catheter can include: (i) a catheter shaft extending from a proximal end to a distal end and defining an inflation lumen adjacently spaced from a fluid delivery lumen and a wire guide lumen; (ii) a deflated first balloon mounted on the distal end of the catheter shaft in communication with the inflation lumen, the first balloon having an increasingly larger cross-sectional area along a middle region between a first end and a second end; and (iii) a deflated second balloon mounted around at least a portion of the first balloon on the distal end of the catheter shaft in communication with the fluid delivery lumen, the second balloon having a middle portion including a plurality of holes in communication with the fluid delivery lumen for releasing a therapeutic agent from the fluid delivery lumen, where an annular balloon fluid delivery lumen is defined between the first balloon and the second balloon and in communication with the fluid delivery lumen. Optionally, the multiple-balloon catheter can be translated through the body vessel over a wire guide slidably extending through the wire guide lumen to a point of treatment. The first balloon can be inflated at the point of treatment to place the second balloon in contact with the wall of the body vessel. 
     With reference to  FIG. 5 , alternatively, the multiple-balloon catheter  150  can have a perforated outer balloon  152  radially disposed around an inner balloon  154  that has a stepped configuration. The middle region  155  of the inner balloon  154  includes a plurality of steps, for example, step  156 ,  158 ,  160 , although any number of steps can be included. Each step can have a portion with a uniform cross-sectional area, a tapering cross-sectional area, or both. The general cross-sectional area of each step is increasingly larger moving along the longitudinal axis in the distal direction to define generally a taper along the outer surface of the inner balloon. The shape of the stepped inner balloon  156  affects the shape of the working region of the annular balloon fluid delivery lumen  162 , providing a larger cross-sectional area at a proximal end  164  of than at a distal end  166  of the lumen  162  relative to the middle region  155 . The working region of the lumen described herein in the specification refers to the portion of the lumen disposed proximate to the holes of the outer balloon. The proximal end  164  of the annular fluid delivery lumen  162  provides little resistance to the therapeutic agent, thereby allowing the therapeutic agent to flow distally with an effective velocity pressure to release from the holes  168  of the perforated outer balloon  152 . This can also allow for an even distribution of fluid to the body vessel lumen between the more proximal and the more distal holes  168 . In all other respects, the multiple-balloon catheter  150  including the perforated outer balloon  152  and the stepped inner balloon  154  is substantially identical to the multiple-balloon catheters  10 ,  110  described herein. 
     Alternatively, with reference to  FIG. 6 , a second aspect of the present invention can include a multiple-balloon catheter  210  having a perforated tapered outer balloon  212  radially disposed around an inner second balloon  214 . The inner second balloon  214  can be cylindrical, but can also be tapered as described above with a suitable taper to form an increasingly larger annular lumen  216  between the first and second balloons  212 ,  214 . This application can be important where the body vessel is known to taper, especially after natural bends of the body vessel. The perforated tapered outer balloon  212  is sized to fit the tapering rate of the body vessel, for example, 0.5 mm per 20 mm in length, although other tapering rates are within the scope of the present invention. The perforated tapered outer balloon  212  is in fluid communication with the injection port and with the fluid delivery lumen  233  through the catheter shaft  218  and separated from both the inner balloon  214  and the inflation lumen  230 . The cross-sectional area or diameter of the tapered outer balloon  212  is increasingly smaller moving distally. The tapered outer balloon includes a plurality of holes  215 . Alternatively, the cross-sectional area or diameter of the tapered outer balloon can be increasingly larger moving distally, and this will depend on the orientation of the body vessel and the location of the point of insertion in the body. 
     The inner balloon  214  is preferably non-porous and can be a variety of shapes such that the shape of the tapered outer balloon  212  relative to the shape of the inner balloon  214  affects the shape of the working region  252  of the annular balloon fluid delivery lumen  216 , providing a larger cross-sectional area at the proximal end  220  than at the distal end  222  of the working region  252  of the lumen  216 . The inner balloon can be cylindrical or can have a generally taper such as described in the above Figures. When in the inflated configuration the inner balloon  214  can include a tapering surface between proximal and distal conical ends of the balloon having an increasingly smaller cross-sectional area along the middle region  250  from the first end  262  to the second end  260 . The taper of the tapering surface of the outer balloon  212  along its middle portion or working length  270  from the first end  271  to the second end  273 , which is between proximal and distal conical ends of the balloon can be greater than the taper of the tapering surface of the inner balloon  214 , as shown in  FIG. 6 , in order for the cross-sectional area of the annular lumen  216  to become increasingly smaller. It is desirable that the proximal end  220  of the working region  252  of the annular fluid delivery lumen  216  provides little resistance to the therapeutic agent or fluid, thereby allowing the therapeutic agent to flow distally with an effective velocity pressure to release from the holes  215  of the perforated tapered outer balloon  212 . This can also allow for an even distribution of fluid to the body vessel lumen between the more proximal and the more distal holes  215 . In all other respects, the multiple-balloon catheter  210  including the perforated tapered outer balloon  212  and the tubular or tapered inner balloon  214  is substantially identical to the multiple-balloon catheters  10 ,  110  described herein. For instance, the middle portion  270  of the outer balloon  212  can include a plurality of holes  215  having a combined cross-sectional area that increases from the first end  271  to the second end  273  of the middle portion of the outer balloon. This can include holes that increase in size, density and/or frequency in order for the combined cross-sectional area to increase in the distal direction. Further, in the inflated configuration the inner balloon  214  has a maximum cross-sectional area at the first end  262  that is sized to dilate a portion of said body vessel. 
     In a third aspect of the present invention, with reference to  FIGS. 7A-C , the multiple-balloon catheter  310  can include one or more roughened or raised surface portions  312 . The raised portions  312  are formed integrally with one of the balloons  316 ,  318  or attached to either of the balloons, or both. The raised portions  312  are disposed within the annular fluid delivery lumen  314  between an outer balloon  316  and an inner balloon  318 . For example, the inner surface  320  of the outer balloon  316  and/or the outer surface  322  of the inner balloon  318  may include bumps, nodes or other surface features to form surface portions  312  that direct or channel fluid moving through the fluid delivery lumen toward one or more holes  324  in the outer balloon  316 . The raised portions can be uniform in height along the balloons or may vary in height such that the raised portions taper to a greater height in the distal direction. 
     In one embodiment, a perforated outer balloon  316  may be radially disposed around an inner balloon  318  having raised surface portions  312 , such as nodes, bumps, or some other form of raised irregularities, aligned linearly on the outer surface  322  of the inner balloon  318 . Preferably, the raised portions are disposed circumferentially around the annular lumen  314 , as shown in  FIGS. 7B and 7C .  FIG. 7B  is a partial sectional view taken along line  7 B- 7 B in  FIG. 7A , and  FIG. 7C  is a partial sectional view taken along line  7 C- 7 C in  FIG. 7A , which is distal to line  7 B- 7 B. The inner balloon  318  is preferably non-porous and in fluid communication with the inflation port through the body of the catheter shaft  326 . When the inner balloon  318  is inflated, the top surfaces of the raised surface portions  312  or irregularities sealably engage the underneath surface  320  of the outer balloon  316  to form channels  328  or passageways through which a therapeutic agent or fluid can be delivered, as shown in  FIGS. 7B and 7C . 
     Preferably, the channels  328  have a increasingly smaller cross-sectional area along a portion of the longitudinal axis moving distally to permit more uniform distribution of the fluid exiting the holes as described herein. The change in cross-sectional area of the channels could be various means as described herein, for example, a uniform taper, asymmetric taper, stepped configuration or the like. Each of the raised portions  312  can be interconnected by a web  330  along the outer surface  322  of the inner balloon  318 . The web  330  can have a cross-sectional area defined by the bottom of the channel to the surface of the inner balloon. The cross-sectional area may be uniform along the length of the balloons. Preferably, the web  330  has a cross-sectional area at a first point  332  and a cross-sectional area at a second point  334  distal to the first point  332 . The cross-sectional area at the second point  334  is greater than the cross-sectional area at the first point  332  such that the channel  328  becomes narrower, or has less depth, in the distal direction, as illustrated in  FIGS. 7B and 7C . 
     Optionally, each of the raised portions  312  can have a lateral cross-sectional area at the first point  332  and a lateral cross-sectional area at the second point  334  distal to the first point. The lateral cross-sectional area at the second point  334  being greater than the lateral cross-sectional area at the first point  332  to define channels  328  that become narrower, or have less width, along the distal direction. The width of the webs can also vary along the length of the channel. Alternatively, the cross-sectional area of the channels can change based on the depth, width, or both. 
     The formed channels can be straight or can taper, funneling the fluid from the proximal end  336  where the cross-sectional area of the channel  328  is larger to the distal end  338  where the cross-sectional area of the channel  328  is smaller. The channels  328  can be a variety of shapes such as V-shaped, U-shaped, sinusoidal or wavy, or other like shapes and can have a closed end and/or open end at the distal portion of the channel, or various combinations of both. For example, the channels  328  shown in  FIGS. 7B and 7C  are V-shaped and have a closed end. The channels  328  are preferably molded with the molding of the balloon, but can be separate structures that are attached to the surface with adhesions or heat welding. The channels  328  can not only direct the fluid to the holes  324  of the perforated outer balloon  316 , but also allow an increase in velocity and/or pressure of fluid to all of the holes  324  of the perforated outer balloon  316 . 
     The holes  324  are preferably created in the outer balloon where the channels are located. This can aid in the release of the fluid from the holes  324  and allow for an even distribution of fluid to the body vessel lumen between the more proximal and the more distal holes  324 . Although the raised surface portions  312  are described in relation to outer surface  322  of the inner balloon  318 , it is appreciated that the raised surface portions  312  can be a part of the inner surface  320  of the outer balloon  316  or part of both of the inner surface of the outer balloon and the outer surface of the inner balloon. In all other respects, the multiple-balloon catheter  310  including one or more roughened or raised surface portions  312  is similar or identical to the multiple-balloon catheters  10 ,  110  described herein. 
     Those of skill in the art will appreciate that other embodiments and variants of the structures and methods described above can be practiced within the scope of the present invention. It is therefore intended that the foregoing detailed description be regarded as illustrative rather than limiting, and that it be understood that it is the following claims, including all equivalents, that are intended to define the spirit and scope of this invention.