In Situ Blood Vessel and Aneurysm Treatment

Treatment of aneurysmal blood vessels with local delivery of therapeutic agents thereby reduces or lessens the severity of an aneurysm, and, where used in conjunction with the placement of an excluding device, provides for more rapid recovery of the blood vessel from any disturbance occurring during placement of the excluding device. Therapeutic agents are placed in the aneurysmal site in a time-release carrier medium, such that the therapeutic agent is released into the aneurysmal site over a period of time without the need to provide systemic introduction of the therapeutic agent. The carrier may be introduced through the patient's dermis, such as with the use of a laparoscope, or intravascularly, through the use of a catheter. The carrier may be in a solid matrix, viscous liquid or liquid form.

DETAILED DESCRIPTION OF THE INVENTION

Referring initially toFIG. 1, there is shown an aneurysmal blood vessel10, in particular, there is shown an aorta12undergoing an aneurysmal event, such that the aorta or blood vessel wall14is enlarged at an aneurysmal site16and the diameter of the aorta12at the aneurysmal site16is on the order of over 150% to 300% of the diameter of a healthy aorta12, or a diameter of five cm or greater. The aneurysmal site16forms an aneurysmal bulge or sac18. If left untreated, the aneurysmal sac18may continue to deteriorate, increase in size, and eventually tear or burst.

Non-surgical intervention to treat aneurysm is a recent development, and, as previously discussed herein, involves the use of systemic therapeutic agents, such as antibiotics (such as doxycycline) or other MMP2 and MMP9 or other MMPs inhibitors to reduce the attack on the blood vessel elastin or collagen at the aneurysmal site16. It is believed that by reducing the incidence of these MMP2 and MMP9 proteins, the aneurysmal site16will not progress and thus continue to expand and weaken, and in fact may heal of its own accord. However, such prior art techniques are problematic, in that they produce unwanted and undesirable side effects.

The present invention provides treatment of aneurysmal blood vessels, such as aorta12, without the need for systemic therapy. Generally, the invention provides mechanism for sustained, time release of therapeutic agents at the local aneurysmal site, thereby enabling greater control of dosage to the aneurysmal site16, as well as eliminating the problems associated with systemic therapy treatment. The therapeutic agents are disposed within a carrier20(see, e.g.,FIG. 2), and are released thereby through eluding, diffusing or other release mechanisms. The carrier may be in a solid, gel or liquid form, and may be located both within and outside of the blood vessel at the aneurysmal site16.

A carrier material provided is adapted to exhibit a combination of physical characteristics such as biocompatibility, and, preferably, biodegradability and bioabsorbability, while providing a delivery vehicle for release of one or more therapeutic agents that aid in the treatment of aneurysmal tissue. The carrier material used is biocompatible such that it results in no induction of inflammation or irritation when implanted, degraded or absorbed.

Preferred polymeric carriers include poly(ethylene-vinyl acetate), polyurethanes, poly(D,L-lactic acid) oligomers and polymers, poly(L-lactic acid) oligomers and polymers, poly (glycolic acid), copolymers of lactic acid and glycolic acid, poly (caprolactone), poly (valerolactone), polyanhydrides, copolymers of poly (caprolactone) or poly (lactic acid) with a polyethylene glycol (e.g., MePEG), and blends, admixtures, or co-polymers of any of the above. Other preferred polymers include polysaccharides such as hyaluronic acid, chitosan and fucans, and copolymers of polysaccharides with degradable polymers.

Additionally, polymers as described herein can also be blended or copolymerized in various compositions as required.

The polymeric carriers as discussed can be fashioned in a variety of forms with desired release characteristics and/or with specific desired properties. For example, the polymeric coatings may be fashioned to release the therapeutic agent or agents upon exposure to a specific triggering event such as pH. Representative examples of pH-sensitive polymers include poly(acrylic acid) and its derivatives (including for example, homopolymers such as poly(aminocarboxylic acid); poly(acrylic acid); poly(methyl acrylic acid), copolymers of such homopolymers, and copolymers of poly(acrylic acid) and acrylmonomers such as those discussed above. Other pH sensitive polymers include polysaccharides such as cellulose acetate phthalate; hydroxypropylmethylcellulose phthalate; hydroxypropyl methylcellulose acetate succinate; cellulose acetate trimellilate; and chitosan. Yet other pH sensitive polymers include any mixture of a pH sensitive polymer and a water-soluble polymer.

The polymer used may be obtained from various chemical companies known to those with skill in the art. However, because of the presence of unreacted monomers, low molecular weight oligomers, catalysts, and other impurities, it may be desirable (and, depending upon the materials used, may be necessary) to increase the purity of the polymer used. The purification process yields polymers of better-known, purer composition, and therefore increases both the predictability and performance of the mechanical characteristics of the coatings. The purification process will depend on the polymer or polymers chosen. Generally, in the purification process, the polymer is dissolved in a suitable solvent. Suitable solvents include (but are not limited to) methylene chloride, ethyl acetate, chloroform, and tetrahydrofuran. The polymer solution usually is then mixed with a second material that is miscible with the solvent, but in which the polymer is not soluble, so that the polymer (but not appreciable quantities of impurities or unreacted monomer) precipitates out of solution. For example, a methylene chloride solution of the polymer may be mixed with heptane, causing the polymer to fall out of solution. The solvent mixture then is removed from the copolymer precipitate using conventional techniques. For information regarding stents and coatings, see U.S. Pat. No. 6,387,121 to Alt; U.S. Pat. No. 6,451,373 to Hossainy, et al.; and U.S. Pat. No. 6,364,903 to Tseng, et al.

Liquid or Gel Based Carriers and their Placement

Referring toFIG. 2, there is shown an embodiment of the invention, wherein the carrier20is of a gel or liquid form, and is located within the aorta wall14. Specifically, in this embodiment, the carrier20is a liquid based carrier medium, preferably a gel such as a low viscosity sol gel or liposome type gel, in which the therapeutic agent is trapped for time release therefrom This gel-based carrier is injected into the aorta wall14and maintained therein to dispense or elude, over time, the therapeutic agent. Preferably, the carrier20is placed by injection into the Tunica Media34, which forms the muscular layer of the blood vessel wall14intermediate of the Tunica Intima36, the inner surface38of which is in intimate contact with blood flowing through the aorta or other blood vessel, and the Tunica Adventitia40, which forms the outer surface of aorta12or other blood vessel. By locating the carrier20within the Tunica Media34, within which the elastin cells which provide elasticity and strength to the blood vessel wall14are located, the therapeutic agent in the gel is in intimate contact with the cells of greatest interest in aneurysm treatment, and thus should have the greatest possible efficacy in treatment of the underlying cause of the aneurysm.

In this embodiment, the material-forming carrier20preferably may be collagen, biodegradable polymer, fibrin, glue, a type of monodisperse hydrogel or sol gel, formed as a viscous slurry of nanoparticles. The nanoparticles are synthesized from poly-N-isopropylacrylamide (pNIPAm) lightly cross-linked with N,N-methylenebis(acrylamide)(BIS). The therapeutic agent is included during synthesis, and becomes trapped in the resulting material. After precipitation polymerization in aqueous media, the particles are centrifuged from the surrounding water, resulting in a relatively high viscosity gelatinous material. The viscosity may be modified by the addition of water, to lower the viscosity to enable delivery of the sol gel in a liquid form such as through a needle.

Referring now toFIGS. 2 and 3, a mechanism for locating the carrier20and therapeutic agent therein in the Tunica Media is generically shown. A laparoscope42is operated by the hand44of a practitioner, to position a syringe46having the carrier20in gel form therein, in the proximity of an aneurysmal blood vessel wall14location. The syringe46includes a needle49thereon, which is configured to be manipulated into the region of the blood vessel wall14between the Tunica Intima36and Tunica Adventitia40as shown inFIG. 5. Once the needle is so located, a quantity of carrier20is injected, through an aperture48at the end of the needle48, into the Tunica Media34. Preferably, the needle49is manipulated, by the practitioner, to multiple localized sites on the aorta wall14, such that carrier20may be located and maintained in multiple locations or sites50within the Tunica Media. After a sufficient, as determined by the practitioner or physician, quantity of the carrier is so positioned, the needle48and then the laparoscope are removed and the incision through which the laparoscope42was positioned is sutured shut.

Alternatively, the carrier20may be positioned in the blood vessel, or the region between the Tunica Intima36and Tunica Media40intraveneously. Referring toFIG. 13, there is shown a catheter200, which is configured to have a syringe portion202(shown in phantom) at the distal end204thereof, such that the needle208of the syringe portion202may be retracted within catheter200during introduction of the catheter200up an artery of a patient, but the needle206thereof may be extended, once the distal end204of catheter200is positioned within the stent graft80at the aneurysmal site16. Additionally, catheter200includes an extension mechanism, such that the syringe may be actuated, typically by depressing the plunger thereof when the needle is properly positioned for placement of the carrier20. Extending of the needle, and depressing of the plunger, are easily accomplished by extending wires (not shown) within the sheath of catheter200, and linearly moving the wires while holding the sheath portion of the catheter stationary. Once the distal end204of catheter200is located adjacent to the aorta or blood vessel aneurysmal site16, the needle208is extended therefrom, and inserted through into the region between the Tunica Intima36and Tunica Media40such that carrier20in viscous sol gel or other needle dispensable form, is dispensed through needle208and apertures210. After a desired quantity of carrier20, as determined by the practitioner or physician, is injected into the blood vessel wall, the needle208is withdrawn into the catheter200, and the catheter200is withdrawn from the artery and the incision into the artery is closed, such as by suturing.

Solid Carriers and their Placement

Referring now toFIG. 4, there is shown the aorta12ofFIG. 1, having an intervention device, specifically a solid based carrier20′, located therein for the time-release delivery of therapeutic agents to the blood vessel wall. Therapeutic agents include, but are not limited to, agents which reduce the incidence of elastin attacking proteins, such as antibiotics, as well as anti-inflammatories and ace-inhibitors, etc. As shown inFIG. 2, the therapeutic agent carrier20′ in this embodiment is a relatively rigid sol gel produced material, which is attached to the aneurysmal site16with an adhesive22, such as a biocompatible acrylic adhesive.

Preparation of carriers for sol gel preparation is well known in the art, and when prepared, with the introduction of biological therapeutic agents, will result in a matrix from which the therapeutic agent will elude from over time. A typical sol gel preparation comprises hydrolysis and condensation of an orthosilicate such as tetramethyl orthosilicate TMOS) or tetraethyl orthosilicate (TEOS). For example, TMOS may be partially hydrolyzed in an acidic medium by addition of a controlled amount of water and the therapeutic agent is introduced in a suitable buffer to facilitate gelation. The buffer pH is chosen so as to allow the final solution to be close to neutrality in order to avoid denaturation of proteins. The resulting sol gel is a glass matrix, within which the therapeutic agent is entrapped and when exposed to fluids, such as blood in an aneurysmal sac18, will out and into the fluid over a period of time. By varying the pore size in the matrix, the speed of diffusion may be varied, by one skilled in the art, to match the duration of efficacy and rate of diffusion for treatment of an aneurysmal site16.

To position carrier20′ at the aneurysmal site16, carrier20′, with adhesive attached thereto, is located at the end of an introducing system, such as a wire or catheter, which is introduced by placement thereof in an artery, the femoral artery, and the catheter or wire is pushed up the artery until the end thereof, with the carrier thereon, is positioned against the wall of the blood vessel at the aneurysmal site16, such that adhesive22is in direct contact with the wall18. The adhesive may be self-curing, in a matter of seconds or minutes, such that by maintaining contact between the adhesive and wall, the adhesive22will cure and bond the carrier20′ to the wall. Alternatively, the adhesive could be curable by ultraviolet light, and in such case catheter will include a light source at the end thereof adjacent the location where carrier is carried, and such light source will be activated to cause curing of the adhesive in place and thus bonding of the carrier20′, in place against the blood vessel wall. Additionally, the adhesive22and the carrier20′ may be separately delivered to the aneurysmal site16by the catheter, such that the aneurysmal blood vessel wall14is first coated with the adhesive22, and the carrier20′ is then positioned in contact with the adhesive. Once bonding has occurred, the carrier20′ is released from the wire or catheter, and the catheter or wire is removed from the artery. Use of wires and catheters for the placement of intravascular devices is well known to those skilled in the art. Carrier20″ delivers the therapeutic agent to the aneurysmal site by virtue of diffusion of the therapeutic agent therefrom.

Referring now toFIG. 5, there is shown a further embodiment of the invention, wherein carrier20″ is composed of a micro-encapsulation element, such as a plastic, resin, or the like, which has substantially rigidity and is positioned at the aneurysmal site16by the use of tethers60,62, each of which projects through the wall of the aorta12at the aneurysmal site16, and terminates in a hook64,66, at the distal end of each of the tethers60,62. Each of hooks64,66include thereon a barb68at the tether receiving end70thereof, and a relatively sharp point72, such that point72may be used, in conjunction with a remotely operated catheter, wire or the like (not shown), to puncture the aorta wall14at the aneurysmal site16. Once point72has punctures aorta wall14, hook64(or66) is pushed through the aorta wall, such that barb38engages against the outer surface of aorta wall14, thereby securing the tether against retraction through the hole created by sharp point72. Each tether60,62is secured within or on the carrier20, such as by being molded therein when the carrier20″ is made.

In the embodiments according to the invention shown and described with respect toFIGS. 4 and 5, carrier20′,20″ is a rigid or substantially rigid, yet porous or leaching, material. One such carrier20′ or20″″ is the rigid sol gel derived material previously described herein. Additionally, carrier may be provided as PLGA, poly Lactide, poly Lactic acid, poly glycolide, PCL, Poly(Lactide-glycolide) copolymer, Poly(Lactide-glycolide-caprolactone) copolymer, Poly(Lactide-caprolactone) copolymer, Poly(glycolide-caprolactone) copolymer, other biodegradable polymers, having the therapeutic integrally formed therein, as a porous polymer, such that the therapeutic agent may dissolved or otherwise captured in the pores thereof, or, as a polymer for which the therapeutic agent has a physical or chemical affinity, such that the therapeutic agent may be held thereby for later release into the aneurysmal site. To manufacture the carrier from a co-polymer such as PLGA (poly(DL-co-glycolic-acid), which is a co-polymer the solid form of PLGA are mixed with an solvent, such that they are dissolved therein, and the therapeutic agent, and a solvent therefore, are mixed with the dissolved PLGA. Tethers60,62are then located to span across yet within the mixture. Alternatively, the tethers60,62may extend from a mesh which is disposed in and becomes encased in the carrier matrix when the copolymer solidifies, such that the mesh helps encapsulate the carrier20when used at the aneurysmal site16. The mixture is then heated (or subjected to vacuum), to drive off the solvents, leaving behind a solid form of PLGA having the therapeutic agent held and dispersed therein. When placed in a fluid, such as blood, the PLGA will break down, releasing the therapeutic agent as it disintegrates or the agent can diffuse slowly out of the carrier.

Where a porous polymer is used as the carrier, the carrier is prepared by placing the porous polymer in a bath of the therapeutic dissolved in a solvent therefore, such as water. After a sufficient period of time for diffusion of the therapeutic agent into the carrier, the carrier is removed from the agent-solvent bath, and is ready for use. Alternatively, the polymer can be mixed with the therapeutic agent before the formation of porous structure. As a result, the therapeutic agent is distributed evenly in the matrix. Finally, where the carrier is configured from a material having a physical or chemical bonding attraction to the therapeutic agent, the carrier is likewise located in a liquid form of the therapeutic agent, such as the agent dissolved in a solvent, or the therapeutic agent is physically forced into the carrier material, such as by rolling the carrier material in a solid form of the therapeutic agent.

Referring now toFIG. 6, still a further embodiment according to the invention is shown. In this embodiment, a carrier, e.g., carrier20′″ is again provided, with the tethers60,62(which are optional) and hooks64,66as shown inFIG. 3, except the carrier20′″ is located outside of the aorta12, i.e., on the exterior of the aorta12. This positioning is enabled by making an incision through the patient's dermis, and directing a laparoscope or other such tool through the muscle and intervening tissue to the aorta site, and positioning the carrier20′″ against the aorta wall14on the exterior thereof, while also inserting the hooks64,66into the aorta such that the barb68portions thereof are positioned in the aorta12so as to prevent carrier from pulling away therefrom. This positions the carrier20′″ against the aorta wall14, to enable the therapeutic agent therein to elude, escape or diffuse therefrom and into the aorta wall14for therapeutic treatment thereof. Again, in this embodiment, carrier may be any of the rigid carrier compositions described herein. Alternatively, the carrier20″′ may be positioned exterior to the aorta12without tethers, and maintained in place as the location has limited fluid flow therepast.

Each of the embodiments according to the invention shown and described with reference toFIGS. 1 to 6provide time release delivery of the therapeutic agent directly to the aneurysmal site16, without the need for systemic application of the therapeutic agent and the attendant risk of side effects therefrom. Further, each of the embodiments of the carrier20,20′,20″ or20′″ specifically enable timed release of the therapeutic agent, and their structure and positioning enables them to be replaced periodically, if considered necessary and prudent, through the removal thereof from the aneurysmal site by a catheter extended through the aorta12, or by a laparoscope extended thereto through the body and the reintroduction of a new carrier20,20′,20″ or20′″ having fresh therapeutic agent therein, to the aneurysmal site16.

Although the placement of a sol gel derived solid matrix carrier, e.g.20′ is described herein as being performed with an adhesive, this type of carrier is likewise readily affixed to the blood vessel wall14adjacent the aneurysmal site16with the tethers60,62and hooks64,66as described herein with respect toFIGS. 4 to 6. Likewise, the embodiments of the carrier described herein with respect toFIGS. 4 to 6may also be affixed to the blood vessel wall14adjacent to the aneurysmal site16by the adhesive22.

Although the invention has been described herein as applicable to situations wherein the carrier is placed in the aneurysmal site16, without application of an excluding device, the use of the carrier is equally applicable to situations where an excluding device is used to internally by-pass the aneurysmal site16through the blood vessel itself.

Use of the Carrier in Conjunction with an Excluding Device

Referring now toFIG. 7, the aneurysmal site of the aorta12ofFIG. 1is shown having a stent graft80placed therein to span the aneurysmal site16. In this embodiment, stent graft80is a modular stent graft, having a main body portion82having an ipsilateral extension83thereon, and a contralateral limb portion84which is separately introduced and placed in the aorta12from main body portion82. To locate the stent graft80in the aorta12, a sheath86as shown inFIG. 8, having the main body portion82of the stent graft80therein, is first inserted into the femoral artery and then pushed up the artery until the sheath extends past the aneurysmal site16. The sheath is then removed, while the stent graft main body portion is deployed therefrom, such that the proximal end88of the main body portion82is positioned above (or beyond) the aneurysmal site16, and the distal end90of the ipsilateral extension8is positioned below the aneurysmal site16within the artery60as shown inFIG. 7. The contra lateral limb portion84of the stent graft80is then deployed through the artery92, on a wire, sheath86or the like, such that the contralateral limb portion84is located inside a portion of the main body portion82and extends therefrom down the artery92to its distal end94as also shown inFIG. 7(only a portion of which is shown).

Referring still toFIG. 7, stent graft80includes both a stent portion96, which reinforcingly engages with graft portion98. Stent portion96is configured as a plurality of hoops or rings, which may be compressed for placement in the aorta12, and once properly in position, actuated to expand and thereby press against or into the adjacent blood vessel wall14. Thus, an actuation means, such as a sheath or manipulating wires, or the like (not shown), which when manipulated cause the generally cylindrical profile of the stent portion96to expand, and press against the aorta wall14at least at the proximal end and distal ends thereof, thereby sealing off the aneurysmal site from blood flow. Graft portion is a flexible element having sufficient strength to allow blood to pass therethrough without rupture. Typical materials for graft portion98include biocompatible plastics such as implantable quality woven polyester. Such polyester material may also include, therewith, components such as collagen, albumin, of an absorbable polymer or of a biocompatible fiber.

Referring again toFIG. 7, the aneurysmal sac18is isolated from the interior of aorta12by the positioning of stent graft80, and there is positioned therein carrier20,20′ or20″. Carrier20,20′ or20″ may be configured of any of the structural embodiments discussed herein with respect toFIGS. 2 through 6.

Liquid and Viscous Carrier Applications with Exclusion Device

Where a carrier20″″ is configured as a viscous sol gel carrier, the carrier may be readily introduced to the aneurysmal site16after placement of the stent graft80, by injecting the carrier through a needle extending from the artery, i.e., blood flow side of the stent graft80to the aneurysmal sac18side thereof. To provide the placement of the carrier20″″, a catheter100as shown inFIG. 9is configured to have a syringe portion102(shown in phantom) at the distal end104thereof, such that the needle108of the syringe portion102may be retracted within catheter100during introduction of the catheter up an artery of a patient, but the needle106thereof may be extended, once the distal end104of catheter100is positioned within the stent graft80at the aneurysmal site16. Additionally, catheter100includes an extension mechanism, such that the syringe may be actuated, typically by depressing the plunger thereof when the needle is properly positioned for placement of the carrier20″″. Extending of the needle, and depressing of the plunger, are easily accomplished by extending wires (not shown) within the sheath of catheter, and linearly moving the wires while holding the sheath portion of the catheter stationary. Once the distal end104of catheter100is located in stent graft80, needle108is extended therefrom, and inserted through the graft portion of stent graft80such that one or more apertures (not shown) in needle108are exposed to aneurysmal sac18, and carrier20″″, in viscous sol gel or other needle dispensable form, is dispensed through needle108and apertures110into aneurysmal sac16. After a desired quantity of the carrier20″″ as determined by the practitioner or physician, is injected into the aneurysmal sac18, the needle108is withdrawn into the catheter100, and the catheter100is withdrawn from the patient and the incision into the artery and the dermis is dosed, such as by suturing.

Alternatively, it is also contemplated herein that the liquid or gel based carrier may be introduced into the aneurysmal sac18by external means, such as by directing a laparoscope having a syringe thereon, through the dermis and to a position adjacent to, and exterior of, the aneurysmal sac18, and extending a needle on the syringe through the aorta wall14to a position within aneurysmal sac18. Thence the gel or liquid carrier is introduced through the needle, and the needle is withdrawn. This methodology may also be used to dispense microsphere carriers, such as those manufactured from a copolymer such as PLGA, so long as the microsphere diameter is less than that of the needle aperture. Thus carrier20″″, with the capability for time release of therapeutic agents therein, may be externally positioned in the aneurysmal sac18and maintained therein by the excluding character of stent graft80. Alternately, the carrier/drug can be delivered inside the vessel wall, outside the aneurysm sac or in the adventitial layer of the vessel wall.

Although a carrier such as sol gel is readily introducible to the aneurysmal sac18after the placement of an excluding device such as stent graft80, carriers having solid form which is larger than can readily pass through the needle can also be used in conjunction with an excluding device, but alternate placement is necessary. Referring first toFIGS. 10 to 12, there is shown a first mechanism for placing solid carriers, such as PLGA, plastic, resin or other base carriers (e.g.20) into aneurysmal sac18where an exclusion device is placed to span the aneurysmal site16. As shown inFIG. 10, a carrier e.g.20is positioned within the aneurysmal region of aorta12, at the aneurysmal sac18, by virtue of catheter120which has been inserted into a leg artery such that carrier e.g.20was pushed up the artery to aneurysmal sac18before the stent graft80is deployed. Then, as shown inFIG. 11, a stent graft80is positioned within aorta12to span the aneurysmal site16, while catheter120maintains the carrier e.g.20in position in aneurysmal sac18. The placement of stent graft80in aorta12is well know in the art, and has been generally set forth previously herein. Once the stent graft80is properly positioned in aorta12, carrier e.g.20is released from the catheter120, and catheter is120is removed from aorta12and the leg artery, and the incisions are dosed. Thus, a carrier e.g.20having a size or consistency which prevents placement into an aneurysmal sac18through a needle may be readily placed with catheter120maintained in place during stent graft80deployment. Further, this methodology of deployment may also be used with flowable sol gel or liquid agents, by maintaining them in a dispensing apparatus in end of the catheter120maintained in the aneurysmal sac18during stent graft80deployment, and dispensing them into the then isolated aneurysmal sac18region before removing catheter120. In each instance, whether carrier e.g.20is in liquid, solid or gel form, the carrier will remain within aneurysmal sac18, or trapped between the stent graft80and the adjacent contacted regions of aorta wall14, as stent graft80isolates aneurysmal sac18from the remainder of aorta12. Thus, the carrier e.g.20need not be otherwise attached to the aneurysmal location. Additionally, after the efficacy of carrier e.g.20is extinguished, such as when the level of therapeutic agent eluded or dispensed therefrom reaches a threshold minimum value, the carrier e.g.20can be replaced by again introducing catheter120into aorta12, manipulating it into the isolated aneurysmal sac18, and placing a new carrier e.g.20therein. Where carrier e.g.20is one which degrades over time, such as PLGA, certain sol gel type or other soluble type carriers e.g.20the new or replacement carrier e.g.20may be positioned in aneurysmal sac18without the need to remove the earlier placed carrier e.g.20. Where the carrier e.g.20is non degradable, such as a plastic carrier, the earlier carrier e.g.20typically should first be retrieved by the catheter120, before a replacement carrier e.g.20is placed therein.

The carrier may also be placed into the aneurysmal sac18isolated behind stent graft80by virtue of providing an alternative structure in the stent graft80, such that a door130is provided in stent graft80to provide access between the interior of the blood vessel and the aneurysmal sac18. Referring now toFIG. 12, stent graft80is shown having a door130extending through the graft portion thereof, such that door130may be manipulated, by a hook132or other device on the end of a wire or catheter120, between an open position (shown inFIG. 12) and a dosed position (not shown). To place carrier e.g.20into the isolated aneurysmal sac18, door130is opened, such as by a locating a hook132adjacent thereto by introducing the hook on the end of a wire or of catheter120, and using such hook to manipulate the door120open. The hook is then withdrawn into its own sheath in the end of catheter120, or moved upwardly in aorta12to a non-interfering position with respect to door130, and then an additional wire (not shown) is directed from catheter120, holding carrier20″ thereon or therein, into aneurysmal sac18. Carrier20″ is then released from catheter120to be deposited in the aneurysmal sac18, and the wire is withdrawn through door130. Catheter120is then manipulated, in conjunction with hook132, to position hook132to dose door130. Catheter120is then withdrawn from the body, and the incisions through which they were placed are dosed.

Carrier e.g.20so placed may be any of the carrier configurations discussed herein, and when placed in aneurysmal sac18, is isolated from the blood flowing through aorta12and therefore will remain in place in aneurysmal sac18to release the therapeutic agents therein into any fluids in the aneurysmal sac18, and where in direct contact with wall14, directly thereto. Additionally, the presence of door130enables replacement of carrier e.g.20with an additional carrier e.g.20after the efficacy of the previously placed carrier becomes limited. Furthermore, the use of the door enables placement of solid carriers e.g.20′ into the aneurysmal sac18isolated by the stent graft80, as well as liquid or gel carriers e.g.20. Such liquid or gel based carriers may be dispensed into the aneurysmal sac18through a syringe or other dispensing media held in catheter120when the end thereof is extended into aneurysmal sac18through door130. Alternatively, the opening on the graft for the catheter to pass through can be covered by a cuff which can be placed on top of the opening after the carrier is delivered.

Although the invention herein has been described in terms of multiple individual embodiments, it should be understood that various of the embodiments hereof may be combined for effective aneurysm treatment. For example, an aneurysm may first be treated by positioning a carrier e.g.20in the aneurysmal site16without the presence of an excluding device, as described herein such as by the use of an intravascular catheter, a laparoscope, or the like. This may be done repeatedly over a period of time, replacing used carriers e.g.20with fresh carriers e.g.20, and if the aneurysm does not progress, no further intervention may be necessary. Additionally, different carrier and delivery regimes may be undertaken at the same aneurysmal site18, such that a sol-gel based carrier e.g.20is first adhered to the interior or exterior of the aneurysmal aorta wall14, and once the efficacy thereof is diminished, a different regime, such as introduction of sol gel or liquid carrier within the blood vessel itself, or a solid carrier e.g.20tethered to the blood vessel wall14at the aneurysmal site16may then be used. Further, an excluding device such as stent graft80may be introduced initially, before therapeutic agent treatment of the aneurysmal site16is initiated, such that carrier e.g.20may be placed therewith, or introduced therewith or in the same procedure, or, carrier e.g.20may be introduced later introduced such as through intravenous or laparoscopic introduction. Therefore, the invention provides multiple solutions to aneurysm treatment, with minimal invasiveness to the patient and with the capacity to modify the treatment plan in response to patient reaction to the treatment.