HK1176851B - Therapeutic agent delivery system for localized application of therapeutic substances to a biological conduit - Google Patents

Description

Therapeutic agent delivery system for topical application of therapeutic substances to biological conduits

Technical Field

The present invention relates to systems, devices and methods for treating biological conduits (e.g., blood vessels) by local delivery of therapeutic agents.

Background

Various techniques and instruments have been developed for ablating or repairing tissue in biological conduits (e.g., without limitation, blood vessels and similar body passageways). One common purpose of such techniques and instruments is to remove atherosclerotic plaque from the arteries of a patient. Atherosclerosis is characterized by the accumulation of fatty deposits (atheroma) in the intimal layer (beneath the endothelial cell layer) of a patient's blood vessel. The relatively soft, cholesterol-rich atherosclerotic material initially deposited typically hardens over time into calcified atherosclerotic plaques. This atheroma can obstruct blood flow and is therefore commonly referred to as stenotic lesions (stenoses) or stenosis (stenoses), and the obstructive material is referred to as stenotic material. If left untreated, this stenosis can cause angina, hypertension, myocardial infarction, stroke, leg pain, and the like.

Rotational atherectomy (Rotational atherectomy) has become a common technique for removing such stenotic material. This procedure is most commonly used to perform calcified lesion openings in coronary arteries. Rotational atherectomy is generally not used alone, but is followed by balloon angioplasty (balloon angioplasty), often followed by the implantation of a stent to help maintain patency of the open artery. For non-calcified lesions, balloon angioplasty alone is often used to open the artery and a stent is implanted to maintain patency of the open artery. However, studies have shown that a significant proportion of patients who have undergone balloon angioplasty and have had stents implanted in their arteries experience stent restenosis, a long-term formation of stent blockage due to excessive growth of scar tissue within the stent. In this case, Atherectomy (Atherectomy) is the preferred method of removing excess scar tissue from the stent (balloon angioplasty is not effective in the stent), thereby restoring arterial permeability.

Several rotational atherectomy devices have been developed in an attempt to remove stenotic material. In one such device (see U.S. patent 4,990,134 (Auth)), a file covered with an abrasive material (e.g., diamond particles) is secured to the distal end of a flexible drive shaft. As the file advances through the stenosis, it rotates at high speeds (typical speed ranges are 150,000 and 190,000 rpm). However, when the file clears the stenotic tissue, it can block blood flow. Once the rasp is advanced through the stenosis, the artery is expanded to a diameter equal to or slightly greater than the maximum outer diameter of the rasp. Often more than one size of file must be used to open the artery to the desired diameter.

U.S. patent No. 5,314,438 (Shturman) discloses another rotational atherectomy device with a drive shaft in which a portion of the drive shaft is enlarged in diameter and at least a segment of this enlarged surface is covered with an abrasive material to define an abrasive portion of the drive shaft. When the grinding part rotates at high speed, it can clear the narrow tissue in the artery. While this atherectomy device has certain advantages over the Auth device in flexibility, it is only possible to open the artery to a diameter approximately equal to the diameter of the enlarged abrasive surface of the drive shaft, since the device is not eccentric in nature.

U.S. Pat. No. 6,494,890 (Shturman) discloses a rotational atherectomy device with a drive shaft having an enlarged eccentric portion, wherein at least a segment of such an enlarged surface is covered with an abrasive material. When the grinding part rotates at high speed, it can clear the narrow tissue in the artery. Such devices are capable of dilating an artery to a diameter greater than the resting diameter of the enlarged eccentric, in part due to orbital rotational movement at high operating speeds. Since the enlarged eccentric portion contains the drive axis that is not bonded together, the enlarged eccentric portion of the drive shaft can bend when extending into a stenosis or during high speed operation. This curvature allows a larger diameter to be opened during high speed operation, but less control is required of the diameter at which the artery actually abrades. The disclosure of U.S. Pat. No. 6,494,890 is incorporated herein by reference in its entirety.

U.S. Pat. No. 5,681,336 (Clement) discloses an eccentric tissue clearing file in which a layer of abrasive particles is secured to the outer surface of the file with a suitable adhesive. This configuration is limited, however, because, as Clement at column 3, lines 53-55, the rotational speed of the asymmetrical rasps "is lower than the rotational speed of the high speed cutting device to counteract heat or imbalance. This indicates that for a given size and mass of solid file, rotation at the high speeds used in atherectomy (e.g., 20,000-. Basically, the deviation of the center of mass from the axis of rotation of the drive shaft results in the creation of significant centrifugal forces, thereby creating excessive pressure on the artery wall, and creating excessive heat and larger particles.

Another method of treating occluded blood vessels may include the use of stents. The stent may be placed at the site of a stenosis and expanded to widen the vessel, leaving it in place like a vascular implant.

Regardless of the technique used to open an occluded conduit (e.g., a blood vessel) and restore normal fluid flow within the conduit, a problem remains: restenosis. A certain proportion of treated catheters and blood vessels reocclude (restenosis) after a period of time; this occurs in up to 30-40% of cases. When restenosis occurs, the original procedure can be repeated or an alternative method can be used to restore fluid, e.g., blood, flow.

A related common feature of each of the above treatments is that each causes some trauma to the vessel wall. Restenosis occurs for a number of reasons; each cause is associated with trauma. Small clots may form on the arterial wall. Small tears in the vessel wall expose the blood to foreign materials and proteins that are highly likely to form thrombi. The formed clot grows gradually and even contains growth hormone released by platelets within the clot. In addition, growth hormone released by other cells (e.g., macrophages) can cause smooth muscle cell and fibroblast proliferation abnormalities in the affected area. Inflammation can cause new tissue growth due to trauma in the wall of the conduit in the above manner.

It is known that certain therapeutic substances can have a positive effect on the prevention and/or inhibition of restenosis. There are difficulties in applying these substances to the affected area at therapeutic doses. For example, the area to be treated is very small and localized. The flow of fluid, such as blood, in the conduit is continuous, forming a flow boundary along the catheter wall that must be broken so that the therapeutic substance can reach the local area of interest within a dosage range that is considered therapeutically effective. This technique does not adequately provide a mechanism to break this flow boundary to reach the target area; instead, generally, the therapeutic substance is placed in the main stream of the conduit at a much higher dose than the therapeutic dose, by intravenous or intraluminal injection, since most of the therapeutic substance simply flows downstream, either being absorbed systemically or being discharged as waste. For example, intravenous medication is delivered systemically intravenously, or locally, without reaching the target area, such as by intraluminal injection. Such unnecessary systemic drug exposure can have unknown and unnecessary adverse consequences in areas, tissues and/or organs remote from the target area. Clearly, systemic infusion and exposure are not suitable for treating diseases or conditions having a single targeted intraluminal area.

The potential use of topical application of therapeutic doses of therapeutic substances is not limited to the treatment of coronary arteries. In addition to coronary delivery, other atherosclerotic sites, such as the renal, iliac, femoral, distal leg, and carotid arteries, as well as arteriovenous shunts used in saphenous vein grafts, vascular grafts, and hemodialysis, are biological conduits suitable for local therapeutic substance delivery methods and mechanisms. Potential applications are not limited to blood vessels only; any biological conduit having a target region suitable for treatment may benefit from this treatment method and mechanism.

The present invention overcomes these deficiencies.

Disclosure of Invention

The present invention provides a system, device and method for the local application of therapeutic substances within biological conduits. In various embodiments, a dissolvable bag (dissolvable bag) or pill (bolus) of at least one therapeutic agent is introduced and squeezed and/or sealed within the tubing wall. In other embodiments, at least one therapeutic agent is formed into soluble barbs (barbs) that are hydraulically ejected from the catheter and anchored in the wall of the conduit.

In this manner, the application of at least one therapeutic dose of a therapeutic substance to the affected area is achieved while reducing unwanted systemic exposure and attendant adverse side effects. Ultimately, the need to administer doses in excess of the therapeutic effect is eliminated.

The figures and description that follow more particularly exemplify these and other embodiments of the invention.

Drawings

The invention may be more completely understood in consideration of the following detailed description of various embodiments of the invention in connection with the accompanying drawings. These drawings include:

FIG. 1 is a side view of one embodiment of the present invention;

FIG. 2A is a side partial cross-sectional view of one embodiment of the present invention;

FIG. 2B is a side partial cross-sectional view of one embodiment of the present invention;

FIG. 2C is a side partial cross-sectional view of one embodiment of the present invention;

FIG. 3 is a side partial cross-sectional view of one embodiment of the present invention;

FIG. 4 is a side partial cross-sectional view of one embodiment of the present invention;

FIG. 5 is a side partial cross-sectional view of one embodiment of the present invention;

FIG. 6 is a side partial cross-sectional view of one embodiment of the present invention; and

FIG. 7 is a side partial cross-sectional view of one embodiment of the present invention.

Detailed Description

While the invention is amenable to various modifications and alternative forms, specifics thereof have been shown by way of example in the drawings and will be described in detail. It should be noted, however, that the intention is not to limit the invention to the particular embodiments described. On the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the invention.

For the purposes of describing the invention, the following terms and definitions are used:

by "physical disorder" is meant any condition that has an adverse effect on the functioning of the body.

The term "treating" includes preventing, alleviating, delaying, stabilizing and/or eliminating a physical disorder, such as a vascular disorder. In certain embodiments, treatment includes repair of damage due to a physical disorder (e.g., a vascular disorder) and/or intervention due to the same, including but not limited to mechanical intervention.

"therapeutic agent" includes any substance that exerts a certain effect, including but not limited to therapeutic, prophylactic or diagnostic effects. Thus, the therapeutic agent may comprise anti-inflammatory drugs, anti-infective drugs, analgesics, antiproliferative drugs, and the like, including but not limited to anti-restenosis drugs. Therapeutic agents also include mammalian stem cells. Therapeutic agents as used herein also include other drugs, genetic material and biological material. Genetic material refers to DNA or RNA, including but not limited to DNA/RNA encoding useful proteins, including viral and non-viral vectors, intended for insertion into the human body. Viral vectors include adenovirus, entero-avirus, adeno-associated virus, retrovirus, alpha virus, lentivirus, herpes simplex virus, in vitro modified cells (e.g., stem cells, fibroblasts, myoblasts, satellite cells, pericytes, cardiomyocytes, skeletal muscle cells, macrophages), replication competent viruses, and hybrid vectors. Non-viral vectors include artificial chromosomes and minichromosomes, plastid DNA vectors, cationic polymers, graft copolymers, neutral polymers PVP, SP1017, lipids or liposomes (lipoplexe), nanoparticles and microparticles with and without target sequences such as Protein Transduction Domains (PTDs). Biological materials include cells, yeasts, bacteria, proteins, peptides, cytokines, and hormones. Examples of peptides and proteins include growth factors (FGF, FGF-1, FGF-2, VEGF, endothelial mitogenic growth factors, epidermal growth factors, transforming growth factors-alpha and-beta, platelet-derived endothelial growth factors, platelet-derived growth factors, tumor necrosis factor-alpha, hepatocyte growth factor and insulin-like growth factors), transcription factors, protein kinases, CD inhibitors, thymidine kinases and osteogenic proteins. These dimeric proteins may be provided as homodimers, heterodimers, or combinations thereof, alone or with other molecules.

Therapeutic agents further include cells (if desired) produced in humans (autologous or allogeneic) or animal-derived (xenogeneic), genetically engineered, or otherwise delivered the protein of interest to the site of transplantation. Cells that fall within the definition of therapeutic agent herein also include whole bone marrow, bone marrow mononuclear cells, progenitor cells (e.g., endothelial progenitor cells), stem cells (e.g., mesenchymal cells, hematopoietic cells, neural cells), pluripotent stem cells, fibroblasts, macrophages, and satellite cells.

Therapeutic agents also include non-genetic material such as: antithrombotic agents (such as heparin, heparin derivatives, and urokinase); antiproliferative agents (such as enoxaparin, angiostatin or monoclonal antibodies that prevent smooth muscle proliferation, hirudin and acetylsalicylic acid, amlodipine and doxazosin); anti-inflammatory agents, such as glucocorticoids, betamethasone, dexamethasone, prednisolone, corticosterone, budesonide, estrogens, sulfasalazine, and mesalamine; antineoplastic/antiproliferative/antimitotic agents, such as paclitaxel, 5-fluorouracil, cisplatin, vinblastine, vincristine, epothilones, methotrexate, azathioprine, doxorubicin, and mitomycin; endostatin, angiostatin and thymidine kinase inhibitors, taxol and its analogs or derivatives; anesthetics, such as lidocaine, bupivacaine, and ropivacaine; anticoagulants, such as heparin, antithrombin compounds, platelet receptor antagonists, antithrombin antibodies, antiplatelet receptor antibodies, aspirin, dipyridamole, protamine, hirudin, prostaglandin inhibitors, platelet inhibitors, and tick anticoagulant peptides; vascular cell growth promoters such as growth factors, vascular endothelial growth factors, growth factor receptors, transcription activators and transformation promoters (translational promoters); vascular cell growth inhibitors, such as antiproliferative agents, growth factor inhibitors, growth factor receptor antagonists, transcription inhibitors, transformation inhibitors, replication inhibitors, inhibitory antibodies, antibodies to growth factors, bifunctional molecules consisting of one growth factor and one cytotoxin, bifunctional molecules consisting of one antibody and one cytotoxin; a cholesterol lowering agent; a vasodilator; and agents that interfere with endogenous vasoactive mechanisms; antioxidants, such as probucol; antibacterial agents such as penicillin, cefoxitin, oxacillin, tobramycin; angiogenic substances, such as acidic and basic fibroblast growth factor, estrogens (including estradiol (E2), estriol (E3), and 17- β estradiol); and drugs against heart failure such as digoxin, beta-blockers, angiotensin-converting enzyme, inhibitors (including captopril and enalapril). The bioactive material may be used in combination with (a) a bioactive material, including solvents, carriers or excipients, such as sucrose acetate isobutyrate, ethanol, N-methylpyrrolidone, dimethyl sulfoxide, benzyl benzoate and benzyl acetate.

Furthermore, "therapeutic agent" includes, particularly in the preferred methods of treatment of the present invention, the method comprising administering at least one therapeutic agent to a blood vessel of a mammal that has been subjected to procedural trauma (such as by angioplasty or rotational atherectomy) to inhibit restenosis. Preferably, the therapeutic agent is a cytoskeletal inhibitor or a smooth muscle inhibitor, including, for example, taxol and functional analogs, equivalents or derivatives thereof, such as taxotere, paclitaxel for injection (abraxane TM), coroxane TM, or a cytochalasin, such as cytochalasin B, cytochalasin C, cytochalasin A, cytochalasin D, or analogs or derivatives thereof.

Other specific examples of "therapeutic agents" that may be applied to a body lumen using various embodiments of the present invention include, but are not limited to:

l-arginine;

an adipocyte;

transgenic cells, such as autologous endothelial cells transfected with the beta-galactosidase gene, seeded on the surface of injured arteries;

erythromycin;

penicillin;

heparin;

aspirin;

hydrocortisone;

dexamethasone;

forskolin;

GP IIb/IIIa inhibitors;

cyclohexane;

a Rho kinase inhibitor;

rapamycin;

histamine;

nitroglycerin;

a vitamin E;

vitamin C;

stem cells;

a growth hormone;

hirudin;

hirulog;

argatroban;

Vapirprost；

a prostacyclin;

(ii) a glucan;

erythropoietin;

endothelial growth factor;

an epidermal growth factor;

a core binding factor A;

vascular endothelial growth factor;

fibroblast growth factor;

thrombin;

a thrombin inhibitor; and

glucosamine, and many other therapeutic substances.

The therapeutic agent delivery system of the present invention can be used to apply a therapeutic agent to any surface of a body lumen that can be catheterized. Such body lumens include, inter alia, blood vessels, the urethra, coronary blood vessels, the esophagus, the trachea, the colon, and the bile ducts.

Fig. 1 illustrates one embodiment of a delivery system 100 for local delivery and application of at least one therapeutic agent 10 to a biological conduit 160. The system 100 includes a pouch 20 composed of a dissolvable or biodegradable material and containing at least one therapeutic agent 10, the pouch 20 secured to an outer surface of an expandable stent 30; alternatively, an inflatable balloon may be used in place of the stent 30. The pockets 20 may be continuously wrapped radially around the outer surface of the expandable stent 30, or in a preferred embodiment, more than one pocket 20 is placed radially around the outer surface of the expandable stent 30. The stent 30 is expanded within the biological conduit in any known manner to press the dissolvable bag 20 containing the therapeutic agent 10 against the inner wall W of the biological conduit. The bag 20 may be made of two separate soluble or biodegradable materials: the first dissolvable or biodegradable material 40 is on the conduit wall W side of the bag 20 and the second dissolvable or biodegradable material 50 is on the stent side of the bag 20. Preferably, the first dissolvable or biodegradable material dissolves or biodegrades before the second dissolvable or biodegradable material. This differential arrangement in materials is such that when the first material dissolves or biodegrades, the at least one therapeutic agent 10 contacts the wall W of the conduit 160 while the at least one therapeutic agent 10 is retained in place by the scaffold or the second soluble or biodegradable material.

Turning now to fig. 2A-2C, another embodiment of a delivery system 200 for local delivery and application of at least one therapeutic agent 10 to a biological conduit 160. The system 200 includes a catheter 60 disposed within the tube 160 and includes a lumen therethrough and a plurality of holes 70 in fluid communication with the tube 160. The delivery sheath 80 is slidably disposed within the lumen of the catheter 60. The space between the delivery sheath 80 and the catheter 60 defines a therapeutic agent delivery lumen 90. The delivery lumen 90 is in fluid communication with the plurality of orifices 70.

The system 200 further includes an inflatable balloon secured to the distal end of the delivery sheath 80, the inflatable balloon 110 being inflated using inflation media and inflation means well known in the art. Balloon 110 is at least partially covered by an expandable stent 120, which is covered by an expandable tube 130 made of plastic or similar material. A syringe 170 containing at least one therapeutic agent 10 is in fluid communication with the therapeutic agent delivery lumen 90.

In use, the conduit 60 is placed in the pipe 160 and the delivery sheath 80 is placed in the conduit 60. The delivery sheath 80 is axially displaced distally until the tip of the balloon 110 is outside the lumen of the catheter 60. The exposed tip of balloon 110 is then inflated with an inflation medium and at least one therapeutic agent 10 is delivered under pressure down therapeutic agent delivery lumen 90 until therapeutic agent 10 reaches a number of holes 70, from which therapeutic agent 10 is delivered to biological conduit 160. At this point, the delivery sheath 80 may continue to be displaced distally, or alternatively, the catheter 60 may be displaced proximally. In either case, the remaining portion of balloon 110 is displaced distally out of the lumen of catheter 60 and fully inflated, trapping the at least one therapeutic agent between the wall W of catheter 160 and the expandable tube 130 covering stent 120. Balloon 110 can now be deflated and withdrawn, leaving stent 120, tube 130 and therapeutic agent 10 in place for therapeutic purposes.

Fig. 3 provides another embodiment of a delivery system 300 for local delivery and application of at least one therapeutic agent 10 to biological conduit 160. The system 300 includes a syringe 170, as is well known in the art, in which at least one therapeutic agent 10 is stored. The system 300 further includes an elongate, flexible catheter 302, an expandable stent 304 (which is expanded by means well known in the art, including a balloon on the catheter 302, or by self-expanding means), and an elongate, flexible delivery sheath 306 (which includes a tubular wall, the sheath wall 307 including a lumen therethrough in fluid communication with the syringe 170 and terminating in a flexible nozzle 308 in fluid communication with the lumen of the sheath wall 307). The system 300 further includes a distal expandable tubular region 310 with the flexible nozzle 308 disposed on an outer surface of the distal expandable tubular region 310, and a prong 312 of the delivery sheath 306 defining the distal expandable tubular region 310 and the flexible nozzle 308.

In use, the catheter 302, stent 304 and delivery sheath 306 are secured to a target area within the biological conduit 160. Stent 304 is expanded, as is distal expandable tubular region 306, to press distal expandable tubular region 306 and flexible nozzle 308 against wall W of biological lumen 160. The operator may then actuate the syringe 170 to deliver at least one therapeutic agent 10 through the lumen of the cannula wall 307 to the flexible nozzle 308 (where the therapeutic agent 10 is delivered), forming a radial delivery balloon 314 around the expanded stent 304. At this point, catheter 302 and sheath 306 may be removed, allowing the therapeutic agent to exert its therapeutic effect. In some embodiments, the distal expandable tubular region 310 may be detached from the delivery sheath 306 to form a barrier, retaining the therapeutic agent within the radial delivery balloon 314 and pressing the therapeutic agent evenly against the wall W of the biological conduit 160. Or proximally withdrawing the delivery sheath 306 in its entirety.

Fig. 4 illustrates another embodiment of a delivery system 400 for local delivery and application of at least one therapeutic agent 10 to biological conduit 160. The system 400 includes a flexible, elongate catheter 402 slidably secured within the tube 160 and having a lumen therethrough. An inflatable delivery sheath 404 is slidably disposed within the lumen of the catheter 402. The inflatable delivery sleeve 404 includes separate lumens therethrough, an inflation lumen 406 and a therapeutic agent delivery lumen 408. The inflatable delivery sleeve 404 also includes a distal inflatable balloon 410 in fluid communication with the inflation lumen 406 and an inflator 412. The inflation lumen 408 terminates distally in an aperture 414 disposed in the inflatable balloon 410 and is in fluid communication with the syringe 170 or, equivalently, a device containing at least one therapeutic agent 10.

In use, the catheter 402 is placed in the tube 160 and the inflatable delivery sheath 404 is displaced distally within the lumen of the catheter 402 until the deflated balloon 410 extends distally from the distal end of the catheter 402. The inflation pump 412 is activated to pump inflation medium through the inflation lumen 406, thereby inflating the balloon 410. The operator may then actuate the syringe 170 to deliver at least one therapeutic agent 10 into the therapeutic agent delivery lumen 408 and through the aperture 414, forming a thin therapeutic agent pocket 416 radially around the inflated balloon 410, and the balloon 410 pressing the therapeutic agent 10 into the wall W of the conduit 160. Balloon 410 may then be deflated, withdrawn into the lumen of catheter 402 and the device withdrawn.

Fig. 5-7 illustrate another embodiment of a delivery system 500 for local delivery and application of at least one therapeutic agent 10 to biological conduit 160. The system 500 includes a flexible elongate catheter 502 through which a lumen passes. The system 500 further includes a delivery sheath 504 slidably disposed within the lumen of the catheter 502. A plurality of radially disposed balloons 506 are disposed near the distal end of the delivery sheath 504. The bladder 506 is defined within the transfer sleeve 504 by a thin base film 508 and a thin cover film 510, each of the thin base film 508 and the thin cover film 510 having a very low breaking strength such that the films 508, 510 are easily ruptured. The delivery sheath 504 also includes a fluid injection lumen 511 having a terminal end 512 at a distal end thereof, and the fluid injection lumen 511 is in fluid communication with a reservoir 514, such as saline or the like, operatively connected to and in fluid communication with a pump 416 for pumping fluid into the lumen 511. A control system 518 may be employed to control the length of pumping time, pump pressure, and the amount of liquid pumped through the interior chamber 511.

In the system 500, at least one therapeutic agent barb 520 is disposed in each of the bladders 506, held therein by the membranes 508, 510. The barb 520 may include a cryotherapeutic agent 10 or may be a soluble or biodegradable material formed in a barb shape to facilitate entry into the wall W of a conduit, wherein the therapeutic agent 10 is disposed in the barb 520.

In use, the catheter 502 is placed in the tube 160 and the delivery sheath 504 is slidably translated through the lumen of the catheter 502 until the balloon 506 emerges distally from the lumen of the catheter 502. The operator may then activate pump 516, either manually or through control system 518, in order to inject fluid from reservoir 515, reservoir 515 generating a rapid burst of fluid pressure into fluid injection lumen 510. The terminal end 512 of the fluid injection lumen 510 functions, in part, to force the injection fluid to seek an exit port from the fluid injection lumen 510. The base membrane 508 is weak so that pressure from the injected liquid breaks the base membrane 508, forcing the barbs 520 radially outward into the pocket 506. The cover 510 is also easily broken by the barbs 520 and the radially outward pressure of the liquid. As such, the barbs 520 pop out of the bladder 506 into the wall W of the conduit 160, as shown in FIG. 6.

Fig. 7 illustrates an alternative embodiment of the system 500, in which several barbs 520 may be provided in the bladder 506. Thus, a series of barbs 520 in a radially stacked arrangement (radial stacked arrangement) is provided. In this embodiment, the injection of liquid through the liquid injection lumen 510 may present the barbs 520 radially outward most of the time through the protective membrane 510. If desired, a second wave (or third wave, etc.) of injection fluid may be delivered from reservoir 514 to inner chamber 510, thereby injecting the next set of barbs 520. In this manner, a continuous shock wave of injected liquid can be used to deliver the series of barbs 520 to the wall of the tube 160.

The present invention should not be considered limited to the particular examples described above, but rather should be understood to cover all aspects of the invention. Various modifications, equivalent steps, as well as numerous structures to which the present invention may be applicable will be readily apparent to those of skill in the art to which the present invention is directed upon review of the instant specification.

Claims (15)

1. A system for local delivery and application of at least one therapeutic agent pill to an inner wall of a biological conduit after opening the biological conduit through an occlusion within the biological conduit, the system comprising:

an expandable stent having an outer surface, said stent being capable of being delivered to a biological conduit and subsequently expanded within the conduit; and

a pouch comprising a first dissolvable or biodegradable material and a second dissolvable or biodegradable material, and containing a dose of at least one therapeutic agent,

wherein the bag is disposed on an outer surface of the expandable stent and the second dissolvable or biodegradable material is attached to and continuously wrapped radially around the outer surface of the expandable stent, wherein the first dissolvable or biodegradable material is compressed and disposed against the inner wall of the biological conduit due to the pressure of the expanded stent on the second dissolvable or biodegradable material,

wherein the first dissolvable or biodegradable material dissolves or biodegrades before the second dissolvable or biodegradable material such that when the first dissolvable or biodegradable material dissolves or biodegrades, the dose of the at least one therapeutic agent is thereby exposed on the inner wall of the biological conduit, and

wherein the pressure of the expanded stent against the second dissolvable or biodegradable material secures the dose of the at least one therapeutic agent in place to treat the wound until the second dissolvable or biodegradable material dissolves or biodegrades.

2. The system of claim 1, wherein at least one therapeutic agent comprises an anti-restenosis drug.

3. The system of claim 2, wherein the anti-restenosis drug comprises a cytoskeletal inhibitor.

4. The system of claim 2, wherein the anti-restenosis drug comprises a smooth muscle inhibitor.

5. The system of claim 2, wherein the anti-restenosis drug is selected from the group consisting of taxol, taxotere, paclitaxel, injectable paclitaxel, and coroxane.

6. The system of claim 1, wherein the at least one therapeutic agent is selected from the group consisting of anticoagulants, antiproliferatives, anti-inflammatories, cytostatics, cholesterol-lowering agents, vasodilators, antioxidants, antimicrobials, digoxin, beta-blockers, angiotensin-converting enzymes, captopril, anesthetics, and enalapril.

7. The system of claim 1, wherein the at least one therapeutic agent is selected from the group consisting of heparin, an antithrombin compound, a platelet receptor antagonist, an antithrombin antibody, an antiplatelet receptor antibody, dipyridamole, protamine, hirudin, a prostaglandin inhibitor, a platelet inhibitor, a vascular cell growth promoter, and urokinase.

8. The system of claim 1, wherein the at least one therapeutic agent is selected from the group consisting of enoxaparin, angiostatin, monoclonal antibodies that prevent smooth muscle cell proliferation, hirudin and acetylsalicylic acid, amlodipine, and doxazosin.

9. The system of claim 1, wherein at least one therapeutic agent is selected from the group consisting of glucocorticoids, betamethasone, dexamethasone, prednisolone, corticosterone, budesonide, estrogens, sulfasalazine, and mesalamine.

10. The system of claim 1, wherein the at least one therapeutic agent is selected from the group consisting of whole bone marrow, bone marrow mononuclear cells, progenitor cells, stem cells, pluripotent stem cells, fibroblasts, macrophages, and satellite cells.

11. The system of claim 10, wherein the progenitor cells further comprise endothelial progenitor cells.

12. The system of claim 10, wherein the stem cells are selected from the group consisting of mesenchymal cells, hematopoietic cells, and neural cells.

13. The system of claim 10, wherein at least one therapeutic agent is selected from the group consisting of cells of autologous origin, cells of allogeneic origin, cells of xenogeneic origin, and genetically engineered cells.

14. The system of claim 1, wherein at least one therapeutic agent is selected from the group consisting of DNA, RNA, viral vectors, and non-viral vectors.

15. The system of claim 1, wherein at least one therapeutic agent is selected from the group consisting of cells, yeast, bacteria, proteins, peptides, cytokines, and hormones.