Patent Application
20070191766
The present invention relates to the delivery of a therapeutic agent or other material to a target site of an organic vessel. More specifically, it relates to devices, systems, and methods for the delivery or transplant of a therapeutic agent to the interior of an organic vessel and the transplant of cells to an organic vessel.
Stents are implantable medical devices used to maintain the diameter of a vessel after the vessel has been opened or a blockage removed. For example, a stent may be placed in a coronary artery after an angioplasty procedure is performed. Stenting is a growing field of treatment and research in medicine, and various types of stents have found use in a wide range of treatments.
In many applications, it is desirable for implanted stents to become covered in endothelial cells as early as possible after implantation of the stent. This may be particularly true with respect to arterial stenting, and especially coronary arterial stenting. Implanted stents that have not re-endothelialized (i.e., become covered to some degree with endothelial cells) are associated with adverse clinical events such as stent thrombosis. After a stent is implanted it may take several weeks for endothelial cells to propagate from healthy areas within the vessel to the region of the implanted stent and cover the stent.
Stents may be covered with various therapeutic agents to aid acceptance of the stent or to serve other therapeutic goals. For example, stents may be covered with drugs that act to inhibit restenosis (re-blocking) of a vessel. However, it is not always feasible to put desired coatings on stents. It may be desirable, for example, to coat the stent with an agent that would encourage re-endothelialization. Unfortunately many such substances may not be capable of surviving the treatment, packaging, and sterilization that must be performed on stents prior to delivery or insertion.
The present invention regards systems, devices, and methods that may allow substances to be moved to and placed on the surface of medical devices, including stents, that have been implanted in the body.
A device embodying the present invention may comprise a flexible surface with nanotubes disposed on the inflatable surface. The device may also be a balloon-type catheter, with nanotubes disposed on a surface of the balloon. These devices and others may be used to deposit material on or transplant material to the surface of an implanted medical device implanted in the body of a patient. There are numerous other devices and methods that fall within the scope of the invention.
A balloon catheter or other device with a flexible or expandable region comprising nanotubes is provided. The nanotubes may be disposed on the outside of the balloon, such that when the balloon is placed inside a vessel such as a coronary artery and inflated, the nanotubes may contact an exposed surface of the vessel. The nanotubes may then be actuated, for example by vibration, in order to harvest endothelial cells from a healthy region of the vessel. The balloon may then be deflated and repositioned at an intended delivery site, such as the implant site of a stent. When the balloon is expanded at the delivery site, the nanotubes may be actuated such that the harvested endothelial cells are deposited at the intended delivery site.
A cross-section of balloon 110 is shown in
Devices according to the present invention may comprise an interior balloon, an exterior balloon, and nanotubes disposed on the exterior surface of the exterior balloon.
The nanotubes may comprise a piezoelectric actuator. The device illustrated in
When balloon 110 is inflated, nanotubes 120 may contact site 310 as shown. Nanotubes 120 may then be actuated by a practitioner in order to harvest material from site 310. For example, if site 310 comprises healthy endothelial cells, nanotubes 120 may be actuated in order to harvest healthy endothelial cells for later transplant at a site within the vessel. Such actuation may comprise applying a vacuum to the interior of balloon 110. When a vacuum is applied, healthy endothelial cells or other material may be removed from site 310 and deposited within nanotubes 120. The nanotubes 120 may comprise a piezoelectric material or be otherwise in communication with a piezoelectric actuator, such that they may be actuated by applying a voltage to electrically conductive element 220. Electrically conductive element 220 is electrically connected 221 to nanotubes 120. Various types and methods of connections are possible, with connections 221 shown as an example. When a voltage is applied to nanotubes 120 via an electrically conductive element 220 and connections 221, the nanotubes 120 may be deformed such that they draw material from a site 310 into the interior of the nanotubes 120.
Balloon 110 may be deflated, for example by applying a vacuum or otherwise removing fluid from the interior of balloon 110, after material is collected. Balloon 110 may then be repositioned, for example at or near the location of an implanted medical device such as a stent, in order to deposit the harvested material.
Site 310 may comprise a site to which previously-harvested cells or other material are to be delivered. For example, it may be the site of an implanted stent, to which harvested healthy endothelial cells are to be delivered. Balloon 110 may be positioned at or near the location of site 310. Balloon 110 may then be inflated as previously described, causing nanotubes 120 to be positioned at, near, or in contact with site 310. Nanotubes 120 may then be actuated such that material disposed within nanotubes 120 is deposited at site 310. For example, if nanotubes 120 were previously used to harvest endothelial cells from a healthy site within vessel 300, these cells may be deposited at site 310. Alternatively, nanotubes 120 may be actuated by, for example, applying pressure via fluid to the interior of balloon 110. When such pressure is applied, healthy endothelial cells or other material may be ejected from the interior of nanotubes 120 and deposited at site 310. Nanotubes 120 may comprise a piezoelectric material, such that they may be actuated by applying a voltage to electrically conductive element 220. Electrically conductive element 220 may be electrically connected 221 to nanotubes 120. It will be understood that various types and methods of connection are possible, with connections 221 shown as an example. When a voltage is applied to nanotubes 120 via electrically conductive element 220 and connections 221, nanotubes 120 may be deformed such that they eject material from within nanotubes 120 to site 310. It may be preferred for balloon 110 to be approximately 20% longer than the intended treatment site 310 in order to insure sufficient material is deposited. For example, when healthy endothelial cells are being transplanted to an implanted stent, it may be desirable for cells to cover not only the stent but also the areas around or near the stent in order to encourage endothelialization of the entire area.
Piezoelectric material 420 may also be used to eject material from the nanotubes. Nanotube 410 comprises piezoelectric material 420 connected to external voltage source 440. When a voltage is applied, piezoelectric material 420 may be deformed such that material is ejected from nanotube opening 430. For example, piezoelectric material 420 may expand along the longitudinal axis of nanotube 410 when a voltage is applied, causing outward pressure within nanotube 410. Material within nanotube 410 may thereby be ejected. Similarly, the entirety of nanotube 410 may comprise a piezoelectric material, such that application of a voltage causes nanotube 410 to be deformed. For example, application of a voltage may cause nanotube 410 to decrease in diameter, resulting in an increased pressure within nanotube 410. Other configurations of piezoelectric material are possible.
Devices according to the present invention may comprise a therapeutic agent or other substance disposed on or within the nanotubes. The device may then be used to deliver the substance to an intended delivery site within a vessel. For example, a growth factor such as Vascular Endothelial Growth Factor (VEGF) may be disposed on the nanotubes, after which the balloon may be placed at the intended delivery site as previously described. The balloon may then be inflated and the nanotubes actuated so as to deposit the growth factor or other substance at the delivery site. As an example, the device may deposit VEGF on the surface of a stent to encourage endothelialization of the stent.
Referring to
Devices according to the present invention may also be used to transplant material from one site within a vessel to another site within a vessel.
A medical device such as a stent may be implanted within the vessel of a patient.
As used herein, the “proximal” end of a device or portion of a device refers to the end closest to a practitioner operating the device. Similarly, the “distal” end of a device or portion of a device refers to the end farthest from the operator of the device.
The term “therapeutic agent” as used throughout includes one or more “therapeutic drugs” or “genetic material.” The term “therapeutic agent” used herein includes pharmaceutically active compounds, nucleic acids with and without carrier vectors such as lipids, compacting agents (such as histones), virus (such as adenovirus, adenoassociated virus, retrovirus, lentivirus and a-virus), polymers, hyaluronic acid, proteins, cells and the like, with or without targeting sequences. The therapeutics administered in accordance with the invention includes the therapeutic agent(s) and solutions thereof.
The therapeutic agent may be any pharmaceutically acceptable agent such as a non-genetic therapeutic agent, a biomolecule, a small molecule, or cells.
Exemplary non-genetic therapeutic agents include anti-thrombogenic agents such heparin, heparin derivatives, prostaglandin (including micellar prostaglandin E1), urokinase, and PPack (dextrophenylalanine proline arginine chloromethylketone); anti-proliferative agents such as enoxaprin, angiopeptin, sirolimus (rapamycin), tacrolimus, everolimus, zotarolimus, monoclonal antibodies capable of blocking smooth muscle cell proliferation, hirudin, and acetylsalicylic acid; anti-inflammatory agents such as dexamethasone, rosiglitazone, prednisolone, corticosterone, budesonide, estrogen, estrodiol, sulfasalazine, acetylsalicylic acid, mycophenolic acid, and mesalamine; anti-neoplastic/anti-proliferative/anti-mitotic agents such as paclitaxel, epothilone, cladribine, 5-fluorouracil, methotrexate, doxorubicin, daunorubicin, cyclosporine, cisplatin, vinblastine, vincristine, epothilones, endostatin, trapidil, halofuginone, and angiostatin; anti-cancer agents such as antisense inhibitors of c-myc oncogene; anti-microbial agents such as triclosan, cephalosporins, aminoglycosides, nitrofurantoin, silver ions, compounds, or salts; biofilm synthesis inhibitors such as non-steroidal anti-inflammatory agents and chelating agents such as ethylenediaminetetraacetic acid, O,O′-bis(2-aminoethyl)ethyleneglycol-N,N,N′,N′-tetraacetic acid and mixtures thereof; antibiotics such as gentamycin, rifampin, minocyclin, and ciprofolxacin; antibodies including chimeric antibodies and antibody fragments; anesthetic agents such as lidocaine, bupivacaine, and ropivacaine; nitric oxide; nitric oxide (NO) donors such as linsidomine, molsidomine, L-arginine, NO-carbohydrate adducts, polymeric or oligomeric NO adducts; anti-coagulants such as D-Phe-Pro-Arg chloromethyl ketone, an RGD peptide-containing compound, heparin, antithrombin compounds, platelet receptor antagonists, anti-thrombin antibodies, anti-platelet receptor antibodies, enoxaparin, hirudin, warfarin sodium, Dicumarol, aspirin, prostaglandin inhibitors, platelet aggregation inhibitors such as cilostazol and tick antiplatelet factors; vascular cell growth promotors such as growth factors, transcriptional activators, and translational promotors; vascular cell growth inhibitors such as growth factor inhibitors, growth factor receptor antagonists, transcriptional repressors, translational repressors, replication inhibitors, inhibitory antibodies, antibodies directed against growth factors, bifunctional molecules consisting of a growth factor and a cytotoxin, bifunctional molecules consisting of an antibody and a cytotoxin; cholesterol-lowering agents; vasodilating agents; agents which interfere with endogenous vascoactive mechanisms; inhibitors of heat shock proteins such as geldanamycin; angiotensin converting enzyme (ACE) inhibitors; beta-blockers; bAR kinase (bARKct) inhibitors; phospholamban inhibitors; protein-bound particle drugs such as ABRAXANE™; and any combinations and prodrugs of the above.
Exemplary biomolecules include peptides, polypeptides and proteins; oligonucleotides; nucleic acids such as double or single stranded DNA (including naked and cDNA), RNA, antisense nucleic acids such as antisense DNA and RNA, small interfering RNA (siRNA), and ribozymes; genes; carbohydrates; angiogenic factors including growth factors; cell cycle inhibitors; and anti-restenosis agents. Nucleic acids may be incorporated into delivery systems such as, for example, vectors (including viral vectors), plasmids or liposomes.
Non-limiting examples of proteins include serca-2 protein, monocyte chemoattractant proteins (“MCP-1”) and bone morphogenic proteins (“BMP's”), such as, for example, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 (Vgr-1), BMP-7 (OP-1), BMP-8, BMP-9, BMP-10, BMP-11, BMP-12, BMP-13, BMP-14, BMP-15. Preferred BMPS are any of BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, and BMP-7. These BMPs can be provided as homdimers, heterodimers, or combinations thereof, alone or together with other molecules. Alternatively, or in addition, molecules capable of inducing an upstream or downstream effect of a BMP can be provided. Such molecules include any of the “hedghog” proteins, or the DNA's encoding them. Non-limiting examples of genes include survival genes that protect against cell death, such as anti-apoptotic Bcl-2 family factors and Akt kinase; serca 2 gene; and combinations thereof. Non-limiting examples of angiogenic factors include acidic and basic fibroblast growth factors, vascular endothelial growth factor, epidermal growth factor, transforming growth factor ÿ and ÿ, platelet-derived endothelial growth factor, platelet-derived growth factor, tumor necrosis factor ÿ, hepatocyte growth factor, and insulin like growth factor. A non-limiting example of a cell cycle inhibitor is a cathespin D (CD) inhibitor. Non-limiting examples of anti-restenosis agents include p15, p16, p18, p19, p21, p27, p53, p57, Rb, nFkB and E2F decoys, thymidine kinase (“TK”) and combinations thereof and other agents useful for interfering with cell proliferation.
Exemplary small molecules include hormones, nucleotides, amino acids, sugars, and lipids and compounds have a molecular weight of less than 100 kD.
Exemplary cells include stem cells, progenitor cells, endothelial cells, adult cardiomyocytes, and smooth muscle cells. Cells can be of human origin (autologous or allogenic) or from an animal source (xenogenic), or genetically engineered. Non-limiting examples of cells include side population (SP) cells, lineage negative (Lin−) cells including Lin−CD34−, Lin−CD34+, Lin−cKit+, mesenchymal stem cells including mesenchymal stem cells with 5-aza, cord blood cells, cardiac or other tissue derived stem cells, whole bone marrow, bone marrow mononuclear cells, endothelial progenitor cells, skeletal myoblasts or satellite cells, muscle derived cells, go cells, endothelial cells, adult cardiomyocytes, fibroblasts, smooth muscle cells, adult cardiac fibroblasts +5-aza, genetically modified cells, tissue engineered grafts, MyoD scar fibroblasts, pacing cells, embryonic stem cell clones, embryonic stem cells, fetal or neonatal cells, immunologically masked cells, and teratoma derived cells.
Any of the therapeutic agents may be combined to the extent such combination is biologically compatible.
Any of the above mentioned therapeutic agents may be incorporated into a polymeric coating on a medical device or applied onto a polymeric coating on a medical device such as, for example, a stent. Such coated devices may be used with, in addition to, or in conjunction with devices according to the present invention. The polymers of the polymeric coatings may be biodegradable or non-biodegradable. Non-limiting examples of suitable non-biodegradable polymers include polystrene; polyisobutylene copolymers, styrene-isobutylene block copolymers such as styrene-isobutylene-styrene tri-block copolymers (SIBS) and other block copolymers such as styrene-ethylene/butylene-styrene (SEBS); polyvinylpyrrolidone including cross-linked polyvinylpyrrolidone; polyvinyl alcohols, copolymers of vinyl monomers such as EVA; polyvinyl ethers; polyvinyl aromatics; polyethylene oxides; polyesters including polyethylene terephthalate; polyamides; polyacrylamides; polyethers including polyether sulfone; polyalkylenes including polypropylene, polyethylene and high molecular weight polyethylene; polyUrethanes; polycarbonates, silicones; siloxane polymers; cellulosic polymers such as cellulose acetate; polymer dispersions such as polyUrethane dispersions (BAYHDROL®); squalene emulsions; and mixtures and copolymers of any of the foregoing.
Non-limiting examples of suitable biodegradable polymers include polycarboxylic acid, polyanhydrides including maleic anhydride polymers; polyorthoesters; poly-amino acids; polyethylene oxide; polyphosphazenes; polylactic acid, polyglycolic acid and copolymers and mixtures thereof such as poly(L-lactic acid) (PLLA), poly(D,L,-lactide), poly(lactic acid-co-glycolic acid), 50/50 (DL-lactide-co-glycolide); polydioxanone; polypropylene fumarate; polydepsipeptides; polycaprolactone and co-polymers and mixtures thereof such as poly(D,L-lactide-co-caprolactone) and polycaprolactone co-butylacrylate; polyhydroxybutyrate valerate and blends; polycarbonates such as tyrosine-derived polycarbonates and arylates, polyiminocarbonates, and polydimethyltrimethylcarbonates; cyanoacrylate; calcium phosphates; polyglycosaminoglycans; macromolecules such as polysaccharides (including hyaluronic acid; cellulose, and hydroxypropylmethyl cellulose; gelatin; starches; dextrans; alginates and derivatives thereof), proteins and polypeptides; and mixtures and copolymers of any of the foregoing. The biodegradable polymer may also be a surface erodable polymer such as polyhydroxybutyrate and its copolymers, polycaprolactone, polyanhydrides (both crystalline and amorphous), maleic anhydride copolymers, and zinc-calcium phosphate.
Such coatings may be formed by any method known to one in the art. For example, an initial polymer/solvent mixture can be formed and then the therapeutic agent added to the polymer/solvent mixture. Alternatively, the polymer, solvent, and therapeutic agent can be added simultaneously to form the mixture. The polymer/solvent/therapeutic agent mixture may be a dispersion, suspension or a solution. The therapeutic agent may also be mixed with the polymer in the absence of a solvent. The therapeutic agent may be dissolved in the polymer/solvent mixture or in the polymer to be in a true solution with the mixture or polymer, dispersed into fine or micronized particles in the mixture or polymer, suspended in the mixture or polymer based on its solubility profile, or combined with micelle-forming compounds such as surfactants or adsorbed onto small carrier particles to create a suspension in the mixture or polymer. The coating may comprise multiple polymers and/or multiple therapeutic agents.
The coating can be applied to the medical device by various methods including dipping, spraying, rolling, brushing, electrostatic plating or spinning, vapor deposition, air spraying including atomized spray coating, and spray coating using an ultrasonic nozzle.
The coating is typically from about 1 to about 50 microns thick. In the case of balloon catheters, the thickness is preferably from about 1 to about 10 microns, and more preferably from about 2 to about 5 microns. Very thin polymer coatings, such as about 0.2-0.3 microns and much thicker coatings, such as more than 10 microns, are also possible. It is also within the scope of the present invention to apply multiple layers of polymer coatings onto a medical device used with, in addition to, or in conjunction with the present invention. Such multiple layers may contain the same or different therapeutic agents and/or the same or different polymers. Methods of choosing the type, thickness and other properties of the polymer and/or therapeutic agent to create different release kinetics are well known to one in the art.
The medical device may also contain a radio-opacifying agent within its structure to facilitate viewing the medical device during insertion and at any point while the device is implanted. Non-limiting examples of radio-opacifying agents are bismuth subcarbonate, bismuth oxychloride, bismuth trioxide, barium sulfate, tungsten, and mixtures thereof.
Non-limiting examples of medical devices according to the present invention include catheters, guide wires, balloons, filters (e.g., vena cava filters), stents, stent grafts, vascular grafts, intraluminal paving systems, implants and other devices used in connection with drug-loaded polymer coatings. Such medical devices may be implanted or otherwise utilized in body lumina and organs such as the coronary vasculature, esophagus, trachea, colon, biliary tract, urinary tract, prostate, brain, lung, liver, heart, skeletal muscle, kidney, bladder, intestines, stomach, pancreas, ovary, cartilage, eye, bone, and the like.
The examples described and illustrated herein are merely illustrative, as numerous other embodiments may be implemented without departing from the spirit and scope of the present invention. Moreover, while certain features of the invention may be shown on only certain embodiments or configurations, these features may be exchanged, added, and removed from and between the various embodiments or configurations while remaining within the scope of the invention. Likewise, methods described and disclosed may also be performed in various sequences, with some or all of the disclosed steps being performed in a different order than described while still remaining within the spirit and scope of the present invention.
