Abstract:
A method and apparatus for an intervention device for the surgical repair of aneurysm includes therewith a therapeutic delivery vehicle. The therapeutic delivery vehicle provides a time release of therapeutic agents, such as doxycycline, to the aneurysm site to reduce the presence of elastin attacking proteins in that location. Time release is affected by encasing the therapeutic agent in a time delivery vehicle. The time delivery vehicle may be diffusion based, or may introduce the therapeutic by both physical breakdown and diffusion mechanisms. The time delivery vehicle is further encapsulated in a porous membrane, such that materials in the pouch above a selected size remain within the porous membrane as the therapeutic agent is dispensed from the time delivery vehicle, but the therapeutic agent can pass through the pores to reach the aneurysmal site.

Description:
BACKGROUND OF THE INVENTION  
         [0001]    1. Field of the Invention  
           [0002]    Embodiments of the present invention generally relate to the field of the treatment of body lumens, more particularly to the field of the treatment of blood vessels, and more particularly to the treatment of blood vessel aneurysms with stents, lined stents such as stent grafts, and the use of pharmaceutical agents therewith for the treatment of localized, blood vessel phenomena, such as aneurysm.  
           [0003]    2. Description of the Related Art  
           [0004]    Aneurysm, i.e., the enlargement of a blood vessel at a specific location therein to the point where rupture of the blood vessel is imminent, has been treated in the past by surgical intervention techniques, whereby the affected portion of the blood vessel is removed, or bypassed, so that the flow lumen is replaced by a synthetic graft. This treatment regimen is highly invasive for the patient undergoing it, and typically requires a multiple day post-operative hospital stay, as well as several months of recovery time until the patient has fully recovered from the surgery. Additionally, some patients may not capable of undergoing such a procedure.  
           [0005]    To address the limitations imposed by surgical intervention to replace the aneurysmal blood vessel region with an artificial graft, a technique has been developed by which the aneurysmal blood vessel site been treated by placing what is known in the art as a stent graft, within the blood vessel in a position by which the tubular body of the stent graft spans the interior of the weakened area of the blood vessel wall. The stent graft, properly positioned, will allow blood to flow through the hollow tubular interior thereof, and also prevent blood, under systemic pressure, from reaching the weakened blood vessel wall at the aneurysmal site spanned by the tubular body thereof. However, there is still the opportunity for blood to reach the weakened wall location, such as through leakage of blood between the seal at the end of the stent graft and the vessel wall and thus into the weakened region, diffusion of blood through the graft material itself, or re-supply of blood into the aneurysmal sac from adjacent blood vessels. In each case, there is a renewed risk that the blood vessel may rupture. Furthermore, there remains a risk of additional deterioration of the blood vessel wall at the aneurysmal location even in the absence of blood leakage into the region isolated by the stent graft or the renewed supply of blood to the isolated region.  
           [0006]    Typically, surgical intervention for aneurysm repair is not indicated until the blood vessel diameter, at the aneurysmal site, is 150 to 200% of its normal diameter. Below this threshold, the normal course of treatment has been to monitor the site, and if the diameter of the blood vessel wall at the aneurysmal site continues to expand beyond an undesirable threshold diameter, intervene surgically. Recently, it has been found that the application of certain antibiotics, such as doxycycline, can reduce the severity and/or progression of an aneurysm, and thereby reduce the likelihood of the need for surgical intervention to repair the aneurysm. It is postulated that the antibiotic reduces the level of an elastin attacking protein in the bloodstream and blood vessel wall, thereby reducing the severity of protein based attack on the elastin cells in the blood vessel wall and thus reduces the severity and the progression of the aneurysm. Typical antibiotic treatment requires the use of systemic antibiotics, either orally, intramuscularly or intravenously introduced, in a dosage sufficient to ensure that the quantity of antibiotic reaching the aneurysm is sufficient to affect the elastin attacking protein level at the aneurysm site. Thus, far more antibiotic must be used than that needed to treat the aneurysm, because a substantial portion of the antibiotic is directed by the blood stream to locations other than the aneurysmal site. The systemic use of antibiotics to treat localized treatment sites can lead to serious side effects, including the occurrence of drug resistant bacteria, gastrointestinal disruption, and the like. The longer the course of antibiotics is taken, and the higher the dosage, the higher the risk of serious side effects.  
           [0007]    One additional proposed mechanism for treating blood vessels which are in an aneurysmal state, but for which surgery is not yet indicated, is to introduce “micro-spheres” containing a quantity of the therapeutic agent such as doxycycline, into the blood stream. Such microspheres are constructed to provide a time release of the pharmaceutical agent, and thus provide long term dosing of the aneurysmal site. These microspheres are typically configured to have a diameter on the order of at least 50 microns, such that sufficient therapeutic agent can be carried therein to enable a relatively long-term release of the therapeutic agent from the microsphere and into the bloodstream. However, microspheres of this size can cause substantial complications, such as the blockage of smaller capillaries or distal thrombosis. Additionally, only a small portion of the therapeutic agent released from the microspheres actually reaches the aneurysm, because the majority of the agent becomes distributed throughout the body by the patients&#39; blood. Therefore, although the microspheres provide the patient with longer term regular dosing of the therapeutic agent, and thus free the patient from the need to regularly ingest or inject the agent, they do not eliminate the issue of the need for excess agent to treat a small locale, and the unintended consequences which may arise as a result.  
           [0008]    Although the intravenous introduction of microspheres has been used to treat aneurysm, the intravenous use of such microspheres to treat the aneurysmal site after the placement of a stent graft therein is not possible, because the body of the stent graft will seal off the aneurysmal portion of the blood vessel wall from the microspheres, thereby preventing therapeutic delivery to the aneurysmal site. However, there still exists a need, post stent graft placement, to treat the aneurysmal site with therapeutic agents such as doxycycline, so as to reduce the severity and/or the progression of the aneurysm and thereby reduce the risk of aneurysm rupture, tear or other failure.  
           [0009]    Therefore, there exists a need in the art for a localized drug delivery system, which will allow timed delivery of therapeutic agents to an aneurysmal site in a blood vessel, after placement of a bypassing element or prosthesis, such as placing a stent graft in the blood vessel to span the aneurysmal site, without the need for systemic application of the therapeutic agent.  
         SUMMARY OF THE INVENTION  
         [0010]    The present invention generally concerns methods and apparatus for the localized application of pharmaceutical and therapeutic agents. In one embodiment, the invention includes an encapsulation member, within which is provided a time release carrier containing, and capable of dosing over time, a therapeutic agent. In one embodiment, the encapsulation member is a pouch which is attached to the outer, i.e., blood vessel wall side, of a stent graft passing through an aneurysmal blood vessel, the stent graft thus isolating the aneurysmal region of the blood vessel from blood flow through the blood vessel and the pouch enabling delivery of the pharmaceutical agent to the aneurysmal blood vessel site. The encapsulation member is placed, by the method of locating a stent, stent graft, or other intervention device for spanning an aneurysm site through the interior of a blood vessel, and including the pouch on the exterior of the intervention device such that the pouch is positioned to release therapeutic agents into the space between the intervention device and the wall of the aneurysmal blood vessel.  
           [0011]    The encapsulation member preferably is a pouch, constructed of a porous, biocompatible material, within which the therapeutic agent is located within a time-release carrier, such as microspheres. The pore size of the pouch material is less than that of the microsphere diameter, such that the microspheres remain encapsulated within the pouch as they release their therapeutic agent. Where the microspheres are degradable, the pores prevent release of the microsphere material from the pouch until they are of a sufficiently small size that their presence in the bloodstream will not result in systemic complications.  
           [0012]    Preferably, the encapsulation member is attached to the stent graft at the proximal end thereof, i.e., at the end thereof into which blood flow enters the inner diameter of the stent graft to bypass the aneurysmal wall, and thus, as the stent graft is placed, any blood flow there past may come into contact with the aneurysmal blood vessel wall location. After the stent graft is in place, the encapsulation member will be surrounded with fluid in the space between the stent graft and the wall of the aneurysmal blood vessel, and thus the therapeutic agent will disperse through the fluid to provide the therapeutic agent to the wall of the aneurysmal location and treat the aneurysm to reduce the extension of the blood vessel wall and thereby reduce likelihood of rupture thereof. 
       
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0013]    So that the manner in which the above recited features of the present invention can be understood in detail, a more particular description of the invention, briefly summarized above, may be had by reference to embodiments, some of which are illustrated in the appended drawings. It is to be noted, however, that the appended drawings illustrate only typical embodiments of this invention and are therefore not to be considered limiting of its scope, for the invention may admit to other equally effective embodiments.  
         [0014]    [0014]FIG. 1 is a schematic view of a human, showing an aneurysmal aorta therein;  
         [0015]    [0015]FIG. 2 is a sectional view of the aorta shown in FIG. 1, showing a repair vehicle, specifically shown a stent graft, therein;  
         [0016]    [0016]FIG. 3 is an enlarged view of a portion of the stent graft of FIG. 2; and  
         [0017]    [0017]FIG. 4 is an enlarged view, partially in section, of an encapsulation member used in conjunction with the repair vehicle of FIG. 2. 
     
    
     DETAILED DESCRIPTION  
       [0018]    Referring initially to FIG. 1, there is shown an intravascular repair vehicle, specifically a stent graft  10 , positioned in a blood vessel, in this embodiment, an aorta  12 , and spanning, within the aorta  12 , an aneurysmal portion  14  of the aorta  12 . The aneurysmal portion  14  is formed of a bulging of the aorta wall  16 , in a location where the strength and resiliency or the aorta wall  16  is weakened. As a result, an aneurysmal sac  18  is formed of distended vessel wall tissue. The stent graft  10  is positioned spanning the sac  18  and thereby provide both a secure passageway for blood flow through the aorta  12  and to seal off the aneurysmal portion  14  of the aorta  12  from additional blood flow from the aorta  12 . The placement of the stent graft in the aorta  12  is a technique well known to those skilled in the art, and essentially includes the opening of a blood vessel in the leg, and the insertion of the stent graft  10  contained in a catheter into the vessel and through the vessel until deployed to be located in a spanning position across the aneurysmal portion  14  of aorta  12 . The bifurcated stent graft  10  has a pair of branched sections bifurcating from a trunk portion thereof. This style of stent graft  10  is typically positioned in place by first inserting a catheter with the trunk portion into place through an artery in one leg, providing a first branched section to the aneurysmal location through the same artery and attaching it to the trunk portion at the aneurysmal site, and then inserting a catheter with the second branched section into place through an artery in the other leg of the patient, positioning it adjacent to the trunk portion, and likewise connecting it thereto. The procedure, and attachment mechanisms for assembling the stent graft in place in this configuration, is well known in the art, and is also disclosed in U.S. Pat. No. 6,203,568, incorporated herein by reference.  
         [0019]    Referring now to FIG. 2, a bifurcated stent graft  10  is shown, being configured as a generally tubular member having distal ends  20 ,  22 , a proximal end  24  and a cylindrical body portion  26 . Although the bifurcated stent graft  10  is shown, in FIG. 2, in its fully assembled and positioned state, it is to be understood that the bifurcated stent graft  10  typically comprises at least three sections, a trunk portion  28 , located in the lower portion of the descending aorta, and two minor diameter leg portions  30 ,  32 , constructed integrally as one piece or with one leg joined thereto as shown. In one embodiment, the bifurcated stent graft  10  is configured such that each portion  28 ,  30  and  32  thereof includes a liner  27  externally supported by a tubular metal web  31  that expands to a pre-established diameter when placed in the aorta  12 .  
         [0020]    When assembled in place, the entire stent graft  10  spans the aneurysmal portion  14  of the aorta  12 , including the sac  18 , to seal such portion of the aorta  12  from blood flowing through the aorta  12 . The metal web  31  includes a plurality of ring frame members each of which preferably includes a plurality of diamond shaped elements  34 , typically provided as discrete lengths of diamond outlines such that a single length of such material can span the circumference of the stent graft  10  at the particular location where the hoop forms a portion of the metal web  31 , and such diamond outlines are interconnected to form a continuous cylinder resulting in continuous support frame within which the liner  27  is supported. The diamond shaped elements  34  are preferably interconnected, as shown in FIG. 3, at the interstices  35  thereof, such as by tying them, welding them, or otherwise attaching them to one another. The diamond shaped elements  34  can be understood to form a ring or hoop, such as proximal ring  38  shown as those spanned by a dashed line in FIG. 2 formed of the extension of the diamond shaped elements about the circumference of the stent graft at the proximal end  24  thereof. Additionally, a first ring  41  again shown as those spanned by a second dashed line, circumscribes the stent graft  10  at the next inwardly disposed set of diamond shaped elements  34  disposed on the stent graft  10 . Within the metal web  31  is disposed and supported the liner  27 , which is affixed to the metal web  31  by mechanisms such as weaving or braiding the liner  27  to the metal web  31 , or by mechanisms such as heat welding, bonding, gluing or ultrasonic welding. A bifurcated stent graft  10  of this construction is further disclosed in U.S. Pat. No. 6,203,568, previously incorporated herein by reference. When positioned in place in a blood vessel such as aorta  12 , the stent graft will be in intimate contact with the blood vessel wall  16  for a length sufficient to ensure that blood will not readily flow between the stent graft  10  and the blood vessel wall  16 . Typically, the stent graft  10  is in intimate contact with the blood vessel wall over the span of several rings from each of proximal end  24  and distal ends  20 ,  22 .  
         [0021]    Referring still to FIG. 2, there is shown a pouch  40 , connected to the proximal ring  38  of the bifurcated stent graft  10  on the outer surface thereof, i.e., positioned such that upon placement in an aneurysmal blood vessel location the pouch  40  is located between the stent graft  10  and the aneurysmal portion  14  of aorta  12 . The pouch  40  is preferably positioned on the stent graft  10  by sewing it to proximal ring  38 , thereby placing it in intimate contact with blood vessel wall  16 . Pouch  40  includes a porous shell  42  having a plurality of pores  44  (Shown in FIG. 4) therein, and opposed sides  43 ,  45  and ends  46 ,  48  forming a generally rectangular pouch  40 , end  48  being sewn to proximal ring  38  of trunk portion  28  of bifurcated stent graft  10 .  
         [0022]    Referring now to FIG. 4, pouch  40  is shown partially in cutaway, revealing a plurality of microspheres  50  packed therein, each of which preferably includes a pharmaceutical agent associated therewith. To maintain the microspheres  50  within the pouch  40 , yet allow transport of fluids through the pouch  40 , the porous shell  42  is manufactured from a porous biocompatible material having a plurality of pores  52  extending therethrough of a known diameter  54 . Microspheres  50 , when placed in the pouch  40 , are sized to have a diameter  56  greater than the pore diameter  54 . Preferably, pores  52  are on the order of five microns, and the microspheres  50  are initially ten to forty microns in diameter. Pouch  40  is preferably manufactured from a biocompatible material, such as Dacron, which is readily available with a pore size of approximately five microns. Pouch is preferably prepared by folding a sheet of the pouch material in half, and attaching together the opposed sides  43 ,  45  projecting from the crease occurring at the fold which forms end  46 , such as by sewing, laser welding, adhesives or the like to leave an open end. The microspheres  50 , or other pharmaceutical agent, is then loaded into the interior formed by securing the sides  43 ,  45 , and the open end  48  is then sealed by similar means as those used to close the sides. The closure of the sides  43 ,  45  and open end  48  must ensure any remaining gaps between the folded over sheet at the seams are no greater than the pore diameter  52 . Microspheres  50  for the present invention are preferably comprised of a biocompatible polymer, such as the copolymer, poly (DL-lactic-co-glycolic Acid), commonly known as PLGA, in which the pharmaceutical agent is encapsulated. When exposed to blood, the PLGA will break down into its co-constituents, thereby releasing the pharmaceutical agent trapped therein and thus releasing the agent within the pouch. The agent will then be dispersed from the pouch, either by virtue of diffusion processes, whereby the agent diffuses through the pores  52  of the pouch  40  and into contact with the adjacent blood vessel wall or blood or fluids thereadjacent, or by internal circulation of blood in the aneurysmal sac  18  causing blood or other fluids to flow through the pouch  40 , and thereby be present in the region of the aneurysmal sac  18  of the aorta  12  to reduce the concentration of elastin attacking proteins adjacent the aneurysmal portion  14  of the blood vessel wall  16  and thus reduce the likelihood of progression of the aneurysmal condition.  
         [0023]    The manufacture of the microspheres is accomplished by dissolving the copolymer, along with a desired quantity of the pharmaceutical agent, in a solvent such as an alcohol, and further adding water. The copolymer, combined with alcohol, water and pharmaceutical agent, forms an emulsion. This emulsion is heated, such as by placing the emulsion in a beaker, locating the beaker over a hot plate having a magnetically coupled stirring arrangement which couples to a stir rod in the beaker, and stirring the emulsion as the beaker and emulsion are heated to a temperature of the order of 70 to 80 degrees Celsius. As the solvents (alcohol and water) evaporate, the copolymer, having the pharmaceutical agent therein, precipitates out of solution as microspheres. Once a sufficient quantity of microspheres are precipitated, the emulsion is centrifuged, and the microspheres removed and dried. To provide microspheres having a certain diameter or desired range, the microspheres may be passed through filters or screens of known porosity, to separate microspheres into discrete groups of relatively equal size. Alternatively, the pharmaceutical agent can be encapsulated in a slab of the copolymer or other encapsulating material having time-release properties when exposed to blood or other body fluids. Such a slab is formed by dissolving copolymer in alcohol, along with the pharmaceutical agent, and then adding water and evaporating both the water and alcohol by heating the beaker or dish without stirring or agitating the beaker or dish in which the slab is prepared. The resultant slab is a matrix of copolymer having the pharmaceutical agent rapped therein, such that upon breakdown of the copolymer when exposed to blood, the pharmaceutical agent will be released. The resulting slab can be easily produced by those skilled in the art to have a thickness of between one-quarter to two and three quarter millimeters. Additionally, by modifying the mixture of the copolymers, as well as by the addition of plasticizers, and the like, the slab may be configured to have substantial flexibility, and thus be able to be twisted and bent when the stent graft  10  is placed in a catheter for delivery to the aneurysmal aorta  12 . The slab is cut, after formation, to fit within pouch  40 . The slab may, where sufficiently flexible, be cut to nearly the full size of the pouch  40 , or alternatively be cut into strips, or smaller pieces, which are then stuffed into pouch  40 . Preferably, the microspheres or slab are formed of PLGA, although other copolymers, such as PCL, are specifically contemplated.  
         [0024]    After the pouch  40  is filled with the carrier, either the microspheres  50  or the slab, which are inserted into an open end  48  of the pouch  40 , the end  48  is sown shut, and then attached to the stent graft  10 , preferably at the proximal ring  38  or next adjacent ring thereof. Preferably, the pouch  40  has a width, i.e., a length spanning the circumferential direction of the stent graft when sewn thereto, on the order of five millimeters, a length, i.e., in the direction extending on the stent graft in the direction away from the distal end, of approximately 10 millimeters, and a thickness on the order of less than 3 mm.  
         [0025]    The position of the pouch  40  adjacent the aneurysmal sac  18 , and sealed from the blood passing through the aorta  12  by the stent graft  10 , establishes the pouch  40  in a relatively sealed environment such that blood and other fluids in this region have a limited likelihood of being transmitted or passed from aneurysmal sac  18 . Thus, the pharmaceutical agent will be released into the blood or other fluid in this relatively isolated region, such that a maximum concentration sustainable in the blood will likely be reached, after which no further pharmaceutical agent will enter the blood unless pharmaceutical agent already in the blood is dissipated, such as by reaction with elastin attacking proteins. As a result, substantial quantities of the pharmaceutical agent will remain in place for a longer period of time, increasing the time efficacy of the delivery system. Furthermore, by placing pouch  40  at the proximal end  24  of the stent graft  10 , the pouch  40  will be positioned such that it is held in close contact with the blood vessel wall  14  at that location, and thus at least a portion of the therapeutic agent will be directly released from the pouch and into contact with the blood vessel wall  14  without the need to first pass through the blood or other fluid in the aneurysmal sac  18 . Therefore the therapeutic agent can be directly delivered, without intervening diffusion of release into the blood or other fluid, thereby increasing its efficacy ion treating the aneurysmal site.  
         [0026]    Preferably, multiple pouches  40  are used, each pouch being sewn at least one end thereof to the proximal or first ring of the stent graft  10 , such that the spacing between adjacent pouches  40  extending about the circumference of the stent graft is relatively equal. Preferably at least four such pouches are equally spaced about the circumference of the stent graft  10  when placed across the aneurysmal aorta  12  (three shown in FIG. 2). Alternatively, multiple pouches  40  can be located both about the circumference of the stent graft  10 , as well as longitudinally down its length.  
         [0027]    Although the invention has been described herein in terms of using a specific degradable matrix element for time release of the pharmaceutical (or therapeutic) agent, the invention specifically contemplates use of other matrix/carrier materials, such as PCL, alginate, ceramics and inorganic polymers, which may or may not be degradable when exposed to blood. Where a non-degradable matrix is used, the rate of release of the pharmaceutical agent is diffusion limited, as blood or other liquid must enter the pores of the matrix and physically contact the agent therein to cause release into the blood or fluid.  
         [0028]    Additionally, although the invention has been described in conjunction with the use of a stent graft to treat an aneurysmal aorta, the methods and apparatus herein are likewise applicable to treatment of other aneurysmal locations, as well as in conjunction with alternative repair vehicles. Finally, although the invention has been described in terms of using a time released pharmaceutical agent, the invention may also be practiced where other materials other than pharmaceuticals are used for time-release delivery. While the foregoing is directed to embodiments of the present invention, other and further embodiments of the invention may be devised without departing from the basic scope thereof.