Medical devices comprising rapamycin

专利摘要:
A medical device for securing biological tissue to biological tissue and biological tissue tosynthetic material comprises a fastening element and a therapeutic dosage of rapamycinreleasably affixed to at least a portion of the fastening element for the prevention of neointimalhyperplasia in the biological tissue proximate the fastening element. The fasteningelement can comprise a staple or a suture.
公开号:EP1449545A1
申请号:EP04250847
申请日:2004-02-18
公开日:2004-08-25
发明作者:Noah M. Roth；Scott Lyle Rush；Theresa Scheuble
申请人:Cordis Corp；
IPC主号:A61L31-00

专利说明:
[0001] The present invention relates to the local administration of drug/drugcombinations for the prevention and treatment of vascular disease, and more particularly tointraluminal medical devices for the local delivery of drug/drug combinations for theprevention and treatment of vascular disease caused by injury and methods for maintainingthe drug/drug combinations on the intraluminal medical devices. The present inventionalso relates to medical devices, including stents, grafts, anastomotic devices, perivascularwraps, sutures and staples having drugs, agents and/or compounds affixed thereto to treatand prevent disease and minimize or substantially eliminate a biological organism'sreaction to the introduction of the medical device to the organism. In addition, the drugs,agents and/or compounds may be utilized to promote healing.
[0002] A stent is commonly used as a tubular structure left inside the lumen of a duct torelieve an obstruction. Commonly, stents are inserted into the lumen in a non-expandedform and are then expanded autonomously, or with the aid of a second device in situ. Atypical method of expansion occurs through the use of a catheter-mounted angioplastyballoon which is inflated within the stenosed vessel or body passageway in order to shearand disrupt the obstructions associated with the wall components of the vessel and toobtain an enlarged lumen.
[0003] Many individuals suffer from circulatory disease caused by a progressive blockageof the blood vessels that profuse the heart and other major organs. More severe blockageof blood vessels in such individuals often leads to hypertension, ischemic injury, stroke, ormyocardial infarction. Atherosclerotic lesions, which limit or obstruct coronary bloodflow, are the major cause of ischemic heart disease. Percutaneous transluminal coronaryangioplasty is a medical procedure whose purpose is to increase blood flow through anartery. Percutaneous transluminal coronary angioplasty is the predominant treatment forcoronary vessel stenosis. The increasing use of this procedure is attributable to itsrelatively high success rate and its minimal invasiveness compared with coronary bypasssurgery. A limitation associated with percutaneous transluminal coronary angioplasty isthe abrupt closure of the vessel, which may occur immediately after the procedure and restenosis, which occurs gradually following the procedure. Additionally, restenosis is achronic problem in patients who have undergone saphenous vein bypass grafting. Themechanism of acute occlusion appears to involve several factors and may result fromvascular recoil with resultant closure of the artery and/or deposition of blood platelets andfibrin along the damaged length of the newly opened blood vessel.
[0004] Restenosis after percutaneous transluminal coronary angioplasty is a more gradualprocess initiated by vascular injury. Multiple processes, including thrombosis,inflammation, growth factor and cytokine release, cell proliferation, cell migration andextracellular matrix synthesis each contribute to the restenotic process.
[0005] While the exact mechanism of restenosis is not completely understood, the generalaspects of the restenosis process have been identified. In the normal arterial wall, smoothmuscle cells proliferate at a low rate, approximately less than 0.1 percent per day. Smoothmuscle cells in the vessel walls exist in a contractile phenotype characterized by eighty toninety percent of the cell cytoplasmic volume occupied with the contractile apparatus.Endoplasmic reticulum, Golgi, and free ribosomes are few and are located in theperinuclear region. Extracellular matrix surrounds the smooth muscle cells and is rich inheparin-like glycosylaminoglycans, which are believed to be responsible for maintainingsmooth muscle cells in the contractile phenotypic state (Campbell and Campbell, 1985).
[0006] Upon pressure expansion of an intracoronary balloon catheter during angioplasty,smooth muscle cells within the vessel wall become injured, initiating a thrombotic andinflammatory response. Cell derived growth factors such as platelet derived growth factor,basic fibroblast growth factor, epidermal growth factor, thrombin, etc., released fromplatelets, invading macrophages and/or leukocytes, or directly from the smooth musclecells provoke a proliferative and migratory response in medial smooth muscle cells. Thesecells undergo a change from the contractile phenotype to a synthetic phenotypecharacterized by only a few contractile filament bundles, extensive rough endoplasmicreticulum, Golgi and free ribosomes. Proliferation/migration usually begins within one totwo days' post-injury and peaks several days thereafter (Campbell and Campbell, 1987;Clowes and Schwartz, 1985).
[0007] Daughter cells migrate to the intimal layer of arterial smooth muscle and continueto proliferate and secrete significant amounts of extracellular matrix proteins. Proliferation,migration and extracellular matrix synthesis continue until the damaged endotheliallayer is repaired at which time proliferation slows within the intima, usually within sevento fourteen days post-injury. The newly formed tissue is called neointima. The furthervascular narrowing that occurs over the next three to six months is due primarily tonegative or constrictive remodelling.
[0008] Simultaneous with local proliferation and migration, inflammatory cells adhere tothe site of vascular injury. Within three to seven days post-injury, inflammatory cells havemigrated to the deeper layers of the vessel wall. In animal models employing eitherballoon injury or stent implantation, inflammatory cells may persist at the site of vascularinjury for at least thirty days (Tanaka et al., 1993; Edelman et al., 1998). Inflammatorycells therefore are present and may contribute to both the acute and chronic phases ofrestenosis.
[0009] Numerous agents have been examined for presumed anti-proliferative actions inrestenosis and have shown some activity in experimental animal models. Some of theagents which have been shown to successfully reduce the extent of intimal hyperplasia inanimal models include: heparin and heparin fragments (Clowes, A.W. and Kamovsky M.,Nature 265: 25-26, 1977; Guyton, J.R. et al., Circ. Res., 46: 625-634, 1980; Clowes, A.W.and Clowes, M.M., Lab. Invest. 52: 611-616, 1985; Clowes, A.W. and Clowes, M.M.,Circ. Res. 58: 839-845, 1986; Majesky et al., Circ. Res. 61: 296-300, 1987; Snow et al.,Am. J. Pathol. 137: 313-330, 1990; Okada, T. et al., Neurosurgery 25: 92-98, 1989),colchicine (Currier, J.W. et al., Circ. 80: 11-66, 1989), taxol (Sollot, S.J. et al., J. Clin.Invest. 95: 1869-1876, 1995), angiotensin converting enzyme (ACE) inhibitors (Powell,J.S. et al., Science, 245: 186-188, 1989), angiopeptin (Lundergan, C.F. et al. Am. J.Cardiol. 17(Suppl. B):132B-136B, 1991), cyclosporin A (Jonasson, L. et al., Proc. Natl.,Acad. Sci., 85: 2303, 1988), goat-anti-rabbit PDGF antibody (Ferns, G.A.A., et al., Science253: 1129-1132, 1991), terbinafine (Nemecek, G.M. et al., J. Pharmacol. Exp. Thera. 248:1167-1174, 1989), trapidil (Liu, M.W. et al., Circ. 81: 1089-1093, 1990), tranilast(Fukuyama, J. et al., Eur. J. Pharmacol. 318: 327-332, 1996), interferon-gamma (Hansson, G.K. and Holm, J., Circ. 84: 1266-1272, 1991), rapamycin (Marx, S.O. et al., Circ. Res.76: 412-417, 1995), steroids (Colburn, M.D. et al., J. Vase. Surg. 15: 510-518, 1992), seealso Berk, B.C. et al., J. Am. Coll. Cardiol. 17: 111B-117B, 1991 ), ionizing radiation(Weinberger, J. et al., Int. J. Rad. Onc. Biol. Phys. 36: 767-775, 1996), fusion toxins (Farb,A. et al., Circ. Res. 80: 542-550, 1997) antisense oligionucleotides (Simons, M. et al.,Nature 359: 67-70, 1992) and gene vectors (Chang, M.W. et al., J. Clin. Invest. 96: 2260-2268,1995). Anti-proliferative action on smooth muscle cells in vitro has beendemonstrated for many of these agents, including heparin and heparin conjugates, taxol,tranilast, colchicine, ACE inhibitors, fusion toxins, antisense oligionucleotides, rapamycinand ionizing radiation. Thus, agents with diverse mechanisms of smooth muscle cellinhibition may have therapeutic utility in reducing intimal hyperplasia.
[0010] However, in contrast to animal models, attempts in human angioplasty patients toprevent restenosis by systemic pharmacologic means have thus far been unsuccessful.Neither aspirin-dipyridamole, ticlopidine, anti-coagulant therapy (acute heparin, chronicwarfarin, hirudin or hirulog), thromboxane receptor antagonism nor steroids have beeneffective in preventing restenosis, although platelet inhibitors have been effective inpreventing acute reocclusion after angioplasty (Mak and Topol, 1997; Lang et al., 1991;Popma et al., 1991). The platelet GP II_b/III_a receptor antagonist that is sold under the trademark Reopro is still under study but has not shown definitive results for the reduction inrestenosis following angioplasty and stenting. Other agents, which have also beenunsuccessful in the prevention of restenosis, include the calcium channel antagonists,prostacyclin mimetics, angiotensin converting enzyme inhibitors, serotonin receptorantagonists, and anti-proliferative agents. These agents must be given systemically,however, and attainment of a therapeutically effective dose may not be possible; anti-proliferative(or anti-restenosis) concentrations may exceed the known toxic concentrationsof these agents so that levels sufficient to produce smooth muscle inhibition may not bereached (Mak and Topol, 1997; Lang et al., 1991; Popma et al., 1991).
[0011] Additional clinical trials in which the effectiveness for preventing restenosisutilizing dietary fish oil supplements or cholesterol lowering agents has been examinedshowing either conflicting or negative results so that no pharmacological agents are as yet clinically available to prevent post-angioplasty restenosis (Mak and Topol, 1997; Franklinand Faxon, 1993: Serruys, P.W. et al., 1993). Recent observations suggest that theanti lipid/antioxidant agent, probucol, may be useful in preventing restenosis but this workrequires confirmation (Tardif et al., 1997; Yokoi, et al., 1997). Probucol is presently notapproved for use in the United States and a thirty-day pretreatment period would precludeits use in emergency angioplasty. Additionally, the application of ionizing radiation hasshown significant promise in reducing or preventing restenosis after angioplasty in patientswith stents (Teirstein et al., 1997). Currently, however, the most effective treatments forrestenosis are repeat angioplasty, atherectomy or coronary artery bypass grafting, becauseno therapeutic agents currently have Food and Drug Administration approval for use forthe prevention of post-angioplasty restenosis.
[0012] Unlike systemic pharmacologic therapy, stents have proven useful in significantlyreducing restenosis. Typically, stents are balloon-expandable slotted metal tubes (usually,but not limited to, stainless steel), which, when expanded within the lumen of an angio-plastiedcoronary artery, provide structural support through rigid scaffolding to the arterialwall. This support is helpful in maintaining vessel lumen patency. In two randomizedclinical trials, stents increased angiographic success after percutaneous transluminalcoronary angioplasty, by increasing minimal lumen diameter and reducing, but noteliminating, the incidence of restenosis at six months (Serruys et al., 1994; Fischman et al.,1994).
[0013] Additionally, the heparin coating of stents appears to have the added benefit ofproducing a reduction in sub-acute thrombosis after stent implantation (Serruys et al.,1996). Thus, sustained mechanical expansion of a stenosed coronary artery with a stent hasbeen shown to provide some measure of restenosis prevention, and the coating of stentswith heparin has demonstrated both the feasibility and the clinical usefulness of deliveringdrugs locally, at the site of injured tissue.
[0014] As stated above, the use of heparin coated stents demonstrates the feasibility andclinical usefulness of local drug delivery; however, the manner in which the particular drugor drug combination is affixed to the local delivery device will play a role in the efficacy of this type of treatment. For example, the processes and materials utilized to affix thedrug/drug combinations to the local delivery device should not interfere with the operationsof the drug/drug combinations. In addition, the processes and materials utilized should bebiocompatible and maintain the drug/drug combinations on the local device throughdelivery and over a given period of time. For example, removal of the drug/drugcombination during delivery of the local delivery device may potentially cause failure ofthe device.
[0015] Accordingly, there exists a need for drug/drug combinations and associated localdelivery devices for the prevention and treatment of vascular injury causing intimalthickening which is either biologically induced, for example, atherosclerosis, or mechanicallyinduced, for example, through percutaneous transluminal coronary angioplasty. Inaddition, there exists a need for maintaining the drug/drug combinations on the localdelivery device through delivery and positioning as well as ensuring that the drug/drugcombination is released in therapeutic dosages over a given period of time.
[0016] A variety of stent coatings and compositions have been proposed for theprevention and treatment of injury causing intimal thickening. The coatings may becapable themselves of reducing the stimulus the stent provides to the injured lumen wall,thus reducing the tendency towards thrombosis or restenosis. Alternately, the coating maydeliver a pharmaceutical/therapeutic agent or drug to the lumen that reduces smoothmuscle tissue proliferation or restenosis. The mechanism for delivery of the agent isthrough diffusion of the agent through either a bulk polymer or through pores that arecreated in the polymer structure, or by erosion of a biodegradable coating.
[0017] Both bioabsorbable and biostable compositions have been reported as coatings forstents. They generally have been polymeric coatings that either encapsulate a pharmaceutical/therapeuticagent or drug, e.g. rapamycin, taxol etc., or bind such an agent to thesurface, e.g. heparin-coated stents. These coatings are applied to the stent in a number ofways, including, though not limited to, dip, spray, or spin coating processes.
[0018] One class of biostable materials that has been reported as coatings for stents ispolyfluoro homopolymers. Polytetrafluoroethylene (PTFE) homopolymers have been usedas implants for many years. These homopolymers are not soluble in any solvent atreasonable temperatures and therefore are difficult to coat onto small medical deviceswhile maintaining important features of the devices (e.g. slots in stents).
[0019] Stents with coatings made from polyvinylidenefluoride homopolymers andcontaining pharmaceutical/therapeutic agents or drugs for release have been suggested.However, like most crystalline polyfluoro homopolymers, they are difficult to apply as highquality films onto surfaces without subjecting them to relatively high temperatures thatcorrespond to the melting temperature of the polymer.
[0020] It would be advantageous to develop coatings for implantable medical devices thatwill reduce thrombosis, restenosis, or other adverse reactions, that may include, but do notrequire, the use of pharmaceutical or therapeutic agents or drugs to achieve such affects,and that possess physical and mechanical properties effective for use in such devices evenwhen such coated devices are subjected to relatively low maximum temperatures. It wouldalso be advantageous to develop implantable medical devices in combination with variousdrugs, agents and/or compounds which treat disease and minimize or substantiallyeliminate a living organisms' reaction to the implantation of the medical device. In certaincircumstances, it may be advantageous to develop implantable medical devices incombination with various drugs, agents and/or compounds which promote wound healing.
[0021] The drug/drug combination therapies, drug/drug combination carriers andassociated local delivery devices of the present invention provide a means for overcomingthe difficulties associated with the methods and devices currently in use, as brieflydescribed above. In addition, the methods for maintaining the drug/drug combinationtherapies, drug/drug combination carriers on the local delivery device ensure that thedrug/drug combination therapies reach the target site.
[0022] In accordance with one aspect, the present invention is directed to a medicaldevice for securing biological tissue to biological tissue and biological tissue to synthetic material. The medical device comprises a fastening element and a therapeutic dosage ofrapamycin releasably affixed to at least a portion of the fastening element for theprevention of neo-intimal hyperplasia in the biological tissue proximate the fasteningelement.
[0023] The medical devices, drug coatings and methods for maintaining the drug coatingsor vehicles thereon of the present invention utilizes a combination of materials to treatdisease, and reactions by living organisms due to the implantation of medical devices forthe treatment of disease or other conditions. The local delivery of drugs, agents orcompounds generally substantially reduces the potential toxicity of the drugs, agents orcompounds when compared to systemic delivery while increasing their efficacy.
[0024] Drugs, agents or compounds may be affixed to any number of medical devices totreat various diseases. The drugs, agents or compounds may also be affixed to minimize orsubstantially eliminate the biological organism's reaction to the introduction of the medicaldevice utilized to treat a separate condition. For example, stents may be introduced to opencoronary arteries or other body lumens such as biliary ducts. The introduction of thesestents cause a smooth muscle cell proliferation effect as well as inflammation.Accordingly, the stents may be coated with drugs, agents or compounds to combat thesereactions. Anastomosis devices, routinely utilized in certain types of surgery, may alsocause a smooth muscle cell proliferation effect as well as inflammation. Stent-grafts andsystems utilizing stent-grafts, for example, aneurysm bypass systems may be coated withdrugs, agents and/or compounds which prevent adverse affects caused by the introductionof these devices as well as to promote healing and incorporation. Therefore, the devicesmay also be coated with drugs, agents and/or compounds to combat these reactions. Inaddition, devices such as aneurysm bypass systems may be coated with drugs, agentsand/or compounds that promote would healing, thereby reducing the risk of endoleaks orother similar phenomena.
[0025] The drugs, agents or compounds will vary depending upon the type of medicaldevice, the reaction to the introduction of the medical device and/or the disease sought tobe treated. The type of coating or vehicle utilized to immobilize the drugs, agents or compounds to the medical device may also vary depending on a number of factors,including the type of medical device, the type of drug, agent or compound and the rate ofrelease thereof.
[0026] In order to be effective, the drugs, agents or compounds should preferably remainon the medical devices during delivery and implantation. Accordingly, various coatingtechniques for creating strong bonds between the drugs, agents or compounds may beutilized. In addition, various materials may be utilized as surface modifications to preventthe drugs, agents or compounds from coming off prematurely.
[0027] The drug/drug combinations and delivery devices of the present invention may beutilized to effectively prevent and treat vascular disease, and in particular, vascular diseasecaused by injury. Various medical treatment devices utilized in the treatment of vasculardisease may ultimately induce further complications. For example, balloon angioplasty is aprocedure utilized to increase blood flow through an artery and is the predominanttreatment for coronary vessel stenosis. However, as stated above, the procedure typicallycauses a certain degree of damage to the vessel wall, thereby potentially exacerbating theproblem at a point later in time. Although other procedures and diseases may cause similarinjury, exemplary embodiments of the present invention will be described with respect tothe treatment of restenosis and related complications following percutaneous transluminalcoronary angioplasty and other similar arterial/venous procedures, including the joining ofarteries, veins and other fluid carrying conduits.
[0028] While the invention will be described with respect to the treatment of restenosisand related complications following percutaneous transluminal coronary angioplasty, it isimportant to note that the local delivery of drug/drug combinations may be utilized to treata wide variety of conditions utilizing any number of medical devices, or to enhance thefunction and/or life of the device. For example, intraocular lenses, placed to restore visionafter cataract surgery is often compromised by the formation of a secondary cataract. Thelatter is often a result of cellular overgrowth on the lens surface and can be potentiallyminimized by combining a drug or drugs with the device. Other medical devices whichoften fail due to tissue in-growth or accumulation of proteinaceous material in, on and around the device, such as shunts for hydrocephalus, dialysis grafts, colostomy bagattachment devices, ear drainage tubes, leads for pace makers and implantable defibrillatorscan also benefit from the device-drug combination approach. Devices which serve toimprove the structure and function of tissue or organ may also show benefits whencombined with the appropriate agent or agents. For example, improved osteointegration oforthopaedic devices to enhance stabilization of the implanted device could potentially beachieved by combining it with agents such as bone-morphogenic protein. Similarly othersurgical devices, sutures, staples, anastomosis devices, vertebral disks, bone pins, sutureanchors, hemostatic barriers, clamps, screws, plates, clips, vascular implants, tissueadhesives and sealants, tissue scaffolds, various types of dressings, bone substitutes,intraluminal devices, and vascular supports could also provide enhanced patient benefitusing this drug-device combination approach. Perivascular wraps may be particularlyadvantageous, alone or in combination with other medical devices. The perivascular wrapsmay supply additional drugs to a treatment site. Essentially, any type of medical devicemay be coated in some fashion with a drug or drug combination which enhances treatmentover use of the singular use of the device or pharmaceutical agent.
[0029] In addition to various medical devices, the coatings on these devices may be usedto deliver therapeutic and phannaceutic agents including: antiproliferative/antimitoticagents including natural products such as vinca alkaloids (i.e. vinblastine, vincristine, andvinorelbine), paclitaxel, epidipodophyllotoxins (i.e. etoposide, teniposide), antibiotics(dactinomycin (actinomycin D) daunorubicin, doxorubicin and idarubicin), anthracyclines,mitoxantrone, bleomycins, plicamycin (mithramycin) and mitomycin, enzymes (L-asparaginasewhich systemically metabolizes L-asparagine and deprives cells which do nothave the capacity to synthesize their own asparagine); antiplatelet agents such as G(GP)II_b/III_a inhibitors and vitronectin receptor antagonists; antiproliferative/antimitoticalkylating agents such as nitrogen mustards (mechlorethamine, cyclophosphamide andanalogs, melphalan, chlorambucil), ethylenimines and methylmelamines(hexamethylmelamine and thiotepa), alkyl sulfonates-busulfan, nirtosoureas (carmustine(BCNU) and analogs, streptozocin), trazenes-dacarbazinine (DTIC);antiproliferative/antimitotie antimetabolites such as folic acid analogs (methotrexate),pyrimidine analogs (fluorouracil, floxuridine, and cytarabine), purine analogs and related inhibitors (mercaptopurine, thioguanine, pentostatin and 2-chlorodeoxyadenosine{cladribine}); platinum coordination complexes (cisplatin, carboplatin), procarbazine,hydroxyurea, mitotane, aminoglutethimide; hormones (i.e. estrogen); anticoagulants(heparin, synthetic heparin salts and other inhibitors of thrombin); fibrinolytic agents (suchas tissue plasminogen activator, streptokinase and urokinase), aspirin, dipyridamole,ticlopidine, clopidogrel, abciximab; antimigratory; antisecretory (breveldin); anti-inflammatory:such as adrenocortical steroids (cortisol, cortisone, fludrocortisone,prednisone, prednisolone, 6a-methylprednisolone, triamcinolone, betamethasone, anddexamethasone), non-steroidal agents (salicylic acid derivatives i.e. aspirin; para-aminophenolderivatives i.e. acetominophen; indole and indene acetic acids (indomethacin,sulindac, and etodalac), heteroaryl acetic acids (tolmetin, diclofenac, and ketorolac),arylpropionic acids (ibuprofen and derivatives), anthranilic acids (mefenamic acid, andmeclofenamic acid), enolic acids (piroxicam, tenoxicam, phenylbutazone, andoxyphenthatrazone), nabumetone, gold compounds (auranofin, aurothioglucose, goldsodium thiomalate); immunosuppressives: (cyclosporine, tacrolimus (FK-506), sirolimus(rapamycin), azathioprine, mycophenolate mofetil); angiogenic agents: vascular endothelialgrowth factor (VEGF), fibroblast growth factor (FGF); angiotensin receptor blockers; nitricoxide donors; anti-sense oligionucleotides and combinations thereof; cell cycle inhibitors,mTOR inhibitors, and growth factor receptor signal transduction kinase inhibitors;retenoids; cyclin/CDK inhibitors; HMG co-enzyme reductase inhibitors (statins); andprotease inhibitors.
[0030] As stated previously, the implantation of a coronary stent in conjunction withballoon angioplasty is highly effective in treating acute vessel closure and may reduce therisk of restenosis. Intravascular ultrasound studies (Mintz et al., 1996) suggest thatcoronary stenting effectively prevents vessel constriction and that most of the late luminalloss after stent implantation is due to plaque growth, probably related to neointimalhyperplasia. The late luminal loss after coronary stenting is almost two times higher thanthat observed after conventional balloon angioplasty. Thus, inasmuch as stents prevent atleast a portion of the restenosis process, a combination of drugs, agents or compoundswhich prevents smooth muscle cell proliferation, reduces inflammation and reducescoagulation or prevents smooth muscle cell proliferation by multiple mechanisms, reduces inflammation and reduces coagulation combined with a stent may provide the mostefficacious treatment for post-angioplasty restenosis. The systemic use of drugs, agents orcompounds in combination with the local delivery of the same or different drug/drugcombinations may also provide a beneficial treatment option.
[0031] The local delivery of drug/drug combinations from a stent has the followingadvantages; namely, the prevention of vessel recoil and remodelling through thescaffolding action of the stent and the prevention of multiple components of neointimalhyperplasia or restenosis as well as a reduction in inflammation and thrombosis. This localadministration of drugs, agents or compounds to stented coronary arteries may also haveadditional therapeutic benefit. For example, higher tissue concentrations of the drugs,agents or compounds may be achieved utilizing local delivery, rather than systemicadministration. In addition, reduced systemic toxicity may be achieved utilizing localdelivery rather than systemic administration while maintaining higher tissueconcentrations. Also in utilizing local delivery from a stent rather than systemicadministration, a single procedure may suffice with better patient compliance. Anadditional benefit of combination drug, agent, and/or compound therapy may be to reducethe dose of each of the therapeutic drugs, agents or compounds, thereby limiting theirtoxicity, while still achieving a reduction in restenosis, inflammation and thrombosis.Local stent-based therapy is therefore a means of improving the therapeutic ratio(efficacy/toxicity) of anti-restenosis, anti-inflammatory, anti-thrombotic drugs, agents orcompounds.
[0032] There are a multiplicity of different stents that may be utilized followingpercutaneous transluminal coronary angioplasty. Although any number of stents may beutilized in accordance with the present invention, for simplicity, a limited number of stentswill be described in exemplary embodiments of the present invention. The skilled artisanwill recognize that any number of stents may be utilized in connection with the presentinvention. In addition, as stated above, other medical devices may be utilized.
[0033] Embodiments of the invention will now be described by way of example withreference to the accompanying drawings, in which: Figure 1 is a view along the length of a stent (ends not shown) prior to expansionshowing the exterior surface of the stent and the characteristic banding pattern. Figure 2 is a perspective view along the length of the stent of Figure 1 havingreservoirs in accordance with the present invention. Figure 3 indicates the fraction of drug released as a function of time from coatingsof the present invention over which no topcoat has been disposed. Figure 4 indicates the fraction of drug released as a function of time from coatingsof the present invention including a topcoat disposed thereon. Figure 5 indicates the fraction of drug released as a function of time from coatingsof the present invention over which no topcoat has been disposed. Figure 6 indicates in vivo stent release kinetics of rapamycin from poly(VDF/HFP). Figure 7 is a cross-sectional view of a band of the stent of Figure 1 having drugcoatings thereon in accordance with a first exemplary embodiment of the invention. Figure 8 is a cross-sectional view of a band of the stent of Figure 1 having drugcoatings thereon in accordance with a second exemplary embodiment of the invention. Figure 9 is a cross-sectional view of a band of the stent of Figure 1 having drugcoatings thereon in accordance with a third exemplary embodiment of the presentinvention. Figures 10 to 13 illustrate an exemplary one-piece embodiment of an anastomosisdevice having a fastening flange and attached staple members in accordance with thepresent invention. Figure 14 is a side view of an apparatus for joining anatomical structures together,according to an exemplary embodiment of the invention. Figure 15 is a cross-sectional view showing a needle portion of the Figure 14apparatus passing through edges of anatomical structures, according to an exemplaryembodiment of the invention. Figure 16 is a cross-sectional view showing the Figure 14 apparatus pulledthrough an anastomosis, according to an exemplary embodiment of the invention. Figure 17 is a cross-sectional view showing a staple of the Figure 14 apparatusbeing placed into proximity with the anatomical structures, according to an exemplaryembodiment of the invention Figure 18 is a cross-sectional view showing a staple of the Figure 14 apparatusbeing engaged on both sides of the anastomosis, according to an exemplary embodiment ofthe invention. Figure 19 is a cross-sectional view showing a staple after it has been crimped tojoin the anatomical structures, according to an exemplary embodiment of the invention. Figure 20 is a cross-sectional view of a balloon having a lubricious coating affixedthereto in accordance with the present invention. Figure 21 is a cross-sectional view of a band of the stent in Figure 1 having alubricious coating affixed thereto in accordance with the present invention. Figure 22 is a partial cross-sectional view of a self-expanding stent in a deliverydevice having a lubricious coating in accordance with the present invention. Figure 23 is a cross-sectional view of a band of the stent in Figure 1 having amodified polymer coating in accordance with the present invention. Figure 24 is a side elevation of an exemplary stent-graft in accordance with thepresent invention. Figure 25 is a fragmentary cross-sectional view of another alternate exemplaryembodiment of a stent-graft in accordance with the present invention. Figure 26 is a fragmentary cross-sectional view of another alternate exemplaryembodiment of a stem-graft in accordance with the present invention. Figure 27 is an elevation view of a fully deployed aortic repair system inaccordance with the present invention. Figure 28 is a perspective view of a stent for a first prosthesis, shown for clarity inan expanded state, in accordance with the present invention. Figure 29 is a perspective view of a first prosthesis having a stent covered by agasket material in accordance with the present invention. Figure 30 is a diagrammatic representation of an uncoated surgical staple inaccordance with the present invention. Figure 31 is a diagrammatic representation of a surgical staple having amultiplicity of through-holes in accordance with the present invention. Figure 32 is a diagrammatic representation of a surgical staple having a coating onthe outer surface thereof in accordance with the present invention. Figure 33 is a diagrammatic representation of a section of suture material having acoating thereon in accordance with the present invention. Figure 34 is a diagrammatic representation of a section of suture material having acoating impregnated into the surface thereof in accordance with the present invention.
[0034] Referring to the drawings, Figure 1 shows a stent 100 which may be utilized inaccordance with an exemplary embodiment of the present invention. The expandablecylindrical stent 100 comprises a fenestrated structure for placement in a blood vessel, ductor lumen to hold the vessel, duct or lumen open, more particularly for protecting a segmentof artery from restenosis after angioplasty. The stent 100 can be expanded circumferentiallyand maintained in an expanded configuration, that is circumferentially or radiallyrigid. The stent 100 is axially flexible and when flexed at a band, the stent 100 avoids anyexternally protruding component parts.
[0035] The stent 100 generally comprises first and second ends with an intermediatesection between them. The stent 100 has a longitudinal axis and comprises a plurality oflongitudinally disposed bands 102, wherein each band 102 defines a generally continuouswave along a line segment parallel to the longitudinal axis. A plurality of circumferentiallyarranged links 104 maintain the bands 102 in a substantially tubular structure. Essentially,each longitudinally disposed band 102 is connected at a plurality of periodic locations, by ashort circumferentially arranged link 104 to an adjacent band 102. The wave associatedwith each of the bands 102 has approximately the same fundamental spatial frequency inthe intermediate section, and the bands 102 are so disposed that the wave associated withthem are generally aligned so as to be generally in phase with one another. As illustrated inthe figure, each longitudinally arranged band 102 undulates through approximately twocycles before there is a link to an adjacent band 102.
[0036] The stent 100 may be fabricated utilizing any number of methods. For example,the stent 100 may be fabricated from a hollow or formed stainless steel tube that may bemachined using lasers, electric discharge milling, chemical etching or other means. Thestent 100 is inserted into the body and placed at the desired site in an unexpanded form. Inone exemplary embodiment, expansion may be effected in a blood vessel by a balloon catheter, where the final diameter of the stent 100 is a function of the diameter of theballoon catheter used.
[0037] It should be appreciated that a stent 100 in accordance with the present inventionmay be embodied in a shape-memory material, including, for example, an appropriate alloyof nickel and titanium or stainless steel. Structures formed from stainless steel may bemade self-expanding by configuring the stainless steel in a predetermined manner, forexample, by twisting it into a braided configuration. In this embodiment after the stent 100has been formed it may be compressed so as to occupy a space sufficiently small as topermit its insertion in a blood vessel or other tissue by insertion means, wherein theinsertion means include a suitable catheter, or flexible rod. On emerging from the catheter,the stent 100 may be configured to expand into the desired configuration where theexpansion is automatic or triggered by a change in pressure, temperature or electricalstimulation.
[0038] Figure 2 illustrates an exemplary embodiment of the present invention utilizingthe stent 100 illustrated in Figure 1. As illustrated, the stent 100 may be modified tocomprise one or more reservoirs 106. Each of the reservoirs 106 may be opened or closedas desired. These reservoirs 106 may be specifically designed to hold the drug/drugcombinations to be delivered. Regardless of the design of the stent 100, it is preferable tohave the drug/drug combination dosage applied with enough specificity and a sufficientconcentration to provide an effective dosage in the lesion area. In this regard, the reservoirsize in the bands 102 is preferably sized to adequately apply the drug/drug combinationdosage at the desired location and in the desired amount.
[0039] In an alternate exemplary embodiment, the entire inner and outer surface of thestent 100 may be coated with drug/drug combinations in therapeutic dosage amounts. Adetailed description of a drug for treating restenosis, as well as exemplary coatingtechniques, is described below. It is, however, important to note that the coatingtechniques may vary depending on the drug/drug combinations. Also, the coatingtechniques may vary depending on the material comprising the stent or other intraluminalmedical device.
[0040] Rapamycin is a macrocyclic triene antibiotic produced by Streptomyceshygroscopicus as disclosed in US-3929992. It has been found that rapamycin among otherthings inhibits the proliferation of vascular smooth muscle cells in vivo. Accordingly,rapamycin may be utilized in treating intimal smooth muscle cell hyperplasia, restenosis,and vascular occlusion in a mammal, particularly following either biologically or mechanicallymediated vascular injury, or under conditions that would predispose a mammal tosuffering such a vascular injury. Rapamycin functions to inhibit smooth muscle cellproliferation and does not interfere with the re-endothelialization of the vessel walls.
[0041] Rapamycin reduces vascular hyperplasia by antagonizing smooth muscleproliferation in response to mitogenic signals that are released during an angioplastyinduced injury. Inhibition of growth factor and cytokine mediated smooth muscleproliferation at the late G1 phase of the cell cycle is believed to be the dominantmechanism of action of rapamycin. However, rapamycin is also known to prevent T-cellproliferation and differentiation when administered systemically. This is the basis for itsimmunosuppresive activity and its ability to prevent graft rejection.
[0042] As used herein, rapamycin includes rapamycin and all analogs, derivatives andcongeners that bind to FKBP 12, and other immunophilins and possesses the samepharmacologic properties as rapamycin including inhibition of TOR.
[0043] Although the anti-proliferative effects of rapamycin may be achieved throughsystemic use, superior results may be achieved through the local delivery of the compound.Essentially, rapamycin works in the tissues, which are in proximity to the compound, andhas diminished effect as the distance from the delivery device increases. In order to takeadvantage of this effect, one would want the rapamycin in direct contact with the lumenwalls. Accordingly, in a preferred embodiment, the rapamycin is incorporated onto thesurface of the stent or portions thereof. Essentially, the rapamycin is preferablyincorporated into the stent 100, illustrated in Figure 1, where the stent 100 makes contactwith the lumen wall.
[0044] Rapamycin may be incorporated onto or affixed to the stent in a number of ways.In the exemplary embodiment, the rapamycin is directly incorporated into a polymericmatrix and sprayed onto the outer surface of the stent. The rapamycin elutes from thepolymeric matrix over time and enters the surrounding tissue. The rapamycin preferablyremains on the stent for at least three days up to approximately six months, and morepreferably between seven and thirty days.
[0045] Any number of non-erodible polymers may be utilized in conjunction withrapamycin. In one exemplary embodiment, the rapamycin or other therapeutic agent maybe incorporated into a film-forming polyfluoro copolymer comprising an amount of a firstmoiety selected from the group consisting of polymerized vinylidenefluoride andpolymerized tetrafluoroethylene, and an amount of a second moiety other than the firstmoiety and which is copolymerized with the first moiety, thereby producing the polyfluorocopolymer, the second moiety being capable of providing toughness or elastomericproperties to the polyfluoro copolymer, wherein the relative amounts of the first moiety andthe second moiety are effective to provide the coating and film produced therefrom withproperties effective for use in treating implantable medical devices.
[0046] The present invention provides polymeric coatings comprising a polyfluorocopolymer and implantable medical devices, for example, stents coated with a film of thepolymeric coating in amounts effective to reduce thrombosis and/or restenosis when suchstents are used in, for example, angioplasty procedures. As used herein, polyfluorocopolymers means those copolymers comprising an amount of a first moiety selected fromthe group consisting of polymerized vinylidenefluoride and polymerized tetrafluoroethylene,and an amount of a second moiety other than the first moiety and which iscopolymerized with the first moiety to produce the polyfluoro copolymer, the secondmoiety being capable of providing toughness or elastomeric properties to the polyfluorocopolymer, wherein the relative amounts of the first moiety and the second moiety areeffective to provide coatings and film made from such polyfluoro copolymers withproperties effective for use in coating implantable medical devices.
[0047] The coatings may comprise pharmaceutical or therapeutic agents for reducingrestenosis, inflammation, and/or thrombosis, and stents coated with such coatings mayprovide sustained release of the agents. Films prepared from certain polyfluoro copolymercoatings of the present invention provide the physical and mechanical properties requiredof conventional coated medical devices, even where maximum temperature, to which thedevice coatings and films are exposed, are limited to relatively low temperatures. This isparticularly important when using the coating/film to deliver pharmaceutical/therapeuticagents or drugs that are heat sensitive, or when applying the coating onto temperature-sensitivedevices such as catheters. When maximum exposure temperature is not an issue,for example, where heat-stable agents such as itraconazole are incorporated into thecoatings, higher melting thermoplastic polyfluoro copolymers may be used and, if veryhigh elongation and adhesion is required, elastomers may be used. If desired or required,the polyfluoro elastomers may be crosslinked by standard methods described in, e.g.,Modern Fluoropolymers, (J. Shires ed.), John Wiley & Sons, New York, 1997, pp. 77-87.
[0048] The present invention comprises polyfluoro copolymers that provide improvedbiocompatible coatings or vehicles for medical devices. These coatings provide inertbiocompatible surfaces to be in contact with body tissue of a mammal, for example, ahuman, sufficient to reduce restenosis, or thrombosis, or other undesirable reactions.While many reported coatings made from polyfluoro homopolymers are insoluble and/orrequire high heat, for example, greater than about one hundred twenty-five degreescentigrade, to obtain films with adequate physical and mechanical properties for use onimplantable devices, for example, stents, or are not particularly tough or elastomeric, filmsprepared from the polyfluoro copolymers of the present invention provide adequateadhesion, toughness or elasticity, and resistance to cracking when formed on medicaldevices. In certain exemplary embodiments, this is the case even where the devices aresubjected to relatively low maximum temperatures.
[0049] The polyfluoro copolymers used for coatings according to the present inventionare preferably film-forming polymers that have molecular weight high enough so as not tobe waxy or tacky. The polymers and films formed therefrom should preferably adhere tothe stent and not be readily deformable after deposition on the stent as to be able to be displaced by hemodynamic stresses. The polymer molecular weight should preferably behigh enough to provide sufficient toughness so that films comprising the polymers will notbe rubbed off during handling or deployment of the stent. In certain exemplaryembodiments the coating will not crack where expansion of the stent or other medicaldevices occurs.
[0050] Coatings of the present invention comprise polyfluoro copolymers, as definedabove. The second moiety polymerized with the first moiety to prepare the polyfluorocopolymer may be selected from those polymerized, biocompatible monomers that wouldprovide biocompatible polymers acceptable for implantation in a mammal, whilemaintaining sufficient elastomeric film properties for use on medical devices claimedherein. Such monomers include, without limitation, hexafluoropropylene (HFP), tetrafluoroethylene(TFE), vinylidenefluoride, 1-hydropentafluoropropylene, perfluoro(methylvinyl ether), chlorotrifluoroethylene (CTFE), pentafluoropropene, trifluoroethylene,hexafluoroacetone and hexafluoroisobutylene.
[0051] Polyfluoro copolymers used in the present invention typically comprise vinylidinefluoridecopolymerized with hexafluoropropylene, in the weight ratio in the range offrom about 50 to about 92 wt-% vinylidinefluoride to about 50 to about 8 wt-% HFP.Preferably, polyfluoro copolymers used in the present invention comprise from about 50 toabout 85 wt-% vinylidinefluoride copolymerized with from about 50 to about 15 wt-%HFP. More preferably, the polyfluoro copolymers will comprise from about 55 to about70 wt-% vinylidinefluoride copolymerized with from about 45 to about 30 wt-% HFP.Even more preferably, polyfluoro copolymers comprise from about 55 to about 65 wt-%vinylidinefluoride copolymerized with from about 45 to about 35 wt-% HFP. Such polyfluorocopolymers are soluble, in varying degrees, in solvents such as dimethylacetamide(DMAc), tetrahydrofuran, dimethyl formamide, dimethyl sulphoxide and n-methylpyrrolidone. Some are soluble in methylethylketone (MEK), acetone, methanol and othersolvents commonly used in applying coatings to conventional implantable medical devices.
[0052] Conventional polyfluoro homopolymers are crystalline and difficult to apply ashigh quality films onto metal surfaces without exposing the coatings to relatively high temperatures that correspond to the melting temperature (T_m) of the polymer. The elevatedtemperature serves to provide films prepared from such PVDF homopolymer coatings thatexhibit sufficient adhesion of the film to the device, while preferably maintaining sufficientflexibility to resist film cracking upon expansion/contraction of the coated medical device.Certain films and coatings according to the present invention provide these same physicaland mechanical properties, or essentially the same properties, even when the maximumtemperatures to which the coatings and films are exposed is less than about a maximumpredetermined temperature. This is particularly important when the coatings/filmscomprise pharmaceutical or therapeutic agents or drugs that are heat sensitive, for example,subject to chemical or physical degradation or other heat-induced negative affects, or whencoating heat sensitive substrates of medical devices, for example, subject to heat-inducedcompositional or structural degradation.
[0053] Depending on the particular device upon which the coatings and films of thepresent invention are to be applied and the particular use/result required of the device,polyfluoro copolymers used to prepare such devices may be crystalline, semi-crystalline oramorphous.
[0054] Where devices have no restrictions or limitations with respect to exposure of sameto elevated temperatures, crystalline polyfluoro copolymers may be employed. Crystallinepolyfluoro copolymers tend to resist the tendency to flow under applied stress or gravitywhen exposed to temperatures above their glass transition (T_g) temperatures. Crystallinepolyfluoro copolymers provide tougher coatings and films than their fully amorphouscounterparts. In addition, crystalline polymers are more lubricious and more easily handledthrough crimping and transfer processes used to mount self-expanding stents, for example,nitinol stents.
[0055] Semi-crystalline and amorphous polyfluoro copolymers are advantageous whereexposure to elevated temperatures is an issue, for example, where heat-sensitive pharmaceuticalor therapeutic agents are incorporated into the coatings and films, or where devicedesign, structure and/or use preclude exposure to such elevated temperatures. Semi-crystallinepolyfluoro copolymer elastomers comprising relatively high levels, for example, from about thirty to about forty-five weight percent of the second moiety, for example,HFP, copolymerized with the first moiety, for example, VDF, have the advantage ofreduced coefficient of friction and self-blocking relative to amorphous polyfluorocopolymer elastomers. Such characteristics may be of significant value when processing,packaging and delivering medical devices coated with such polyfluoro copolymers. Inaddition, such polyfluoro copolymer elastomers comprising such relatively high content ofthe second moiety serves to control the solubility of certain agents, for example, rapamycin,in the polymer and therefore controls permeability of the agent through the matrix.
[0056] Polyfluoro copolymers utilized in the present inventions may be prepared byvarious known polymerization methods. For example, high pressure, free-radical, semi-continuousemulsion polymerization techniques such as those disclosed in Fluoro-elastomers-dependenceof relaxation phenomena on compositions, POLYMER 30, 2180,1989, by Ajroldi, et al., may be employed to prepare amorphous polyfluoro copolymers,some of which may be elastomers. In addition, free-radical batch emulsion polymerizationtechniques disclosed herein may be used to obtain polymers that are semi-crystalline, evenwhere relatively high levels of the second moiety are included.
[0057] As described above, stents may comprise a wide variety of materials and a widevariety of geometries. Stents may be made of biocomptible materials, including biostableand bioabsorbable materials. Suitable biocompatible metals include, but are not limited to,stainless steel, tantalum, titanium and nickel titanium based alloys (including nitinol), andcobalt alloys (including cobalt-chromium nickel alloys). Suitable nonmetallic biocompatiblematerials include, but are not limited to, polyamides, polyolefins (i.e. polypropylene,polyethylene etc.), nonabsorbable polyesters (i.e. polyethylene terephthalate),and bioabsorbable aliphatic polyesters (i.e. homopolymers and copolymers of lactic acid,glycolic acid, lactide, glycolide, para-dioxanone, trimethylene carbonate, ∈-caprolactone,and blends thereof).
[0058] The film-forming biocompatible polymer coatings generally are applied to thestent in order to reduce local turbulence in blood flow through the stent, as well as adversetissue reactions. The coatings and films formed therefrom also may be used to administer a pharmaceutically active material to the site of the stent placement. Generally, the amountof polymer coating to be applied to the stent will vary depending on, among other possibleparameters, the particular polyfluoro copolymer used to prepare the coating, the stentdesign and the desired effect of the coating. Generally, the coated stent will comprise fromabout 0.1 to about fifteen weight percent of the coating, preferably from about 0.4 to aboutten weight percent. The polyfluoro copolymer coatings may be applied in one or morecoating steps, depending on the amount of polyfluoro copolymer to be applied. Differentpolyfluoro copolymers may be used for different layers in the stent coating. In fact, incertain exemplary embodiments, it is highly advantageous to use a diluted first coatingsolution comprising a polyfluoro copolymer as a primer to promote adhesion of asubsequent polyfluoro copolymer coating layer that may include pharmaceutically activematerials. The individual coatings may be prepared from different polyfluoro copolymers.
[0059] Additionally, a top coating may be applied to delay release of the pharmaceuticalagent, or they could be used as the matrix for the delivery of a different pharmaceuticallyactive material. Layering of coatings may be used to stage release of the drug or to controlrelease of different agents placed in different layers.
[0060] Blends of polyfluoro copolymers may also be used to control the release rate ofdifferent agents or to provide a desirable balance of coating properties, i.e. elasticity,toughness, etc., and drug delivery characteristics, for example, release profile. Polyfluorocopolymers with different solubilities in solvents may be used to build up different polymerlayers that may be used to deliver different drugs or to control the release profile of a drug.For example, polyfluoro copolymers comprising 85.5/14.5 (wt/wt) of poly(vinylidine-fluoride/HFP)and 60.6/39.4 (wt/wt) of poly(vinylidinefluoride/HFP) are both soluble inDMAc. However, only the 60.6/39.4 PVDF polyfluoro copolymer is soluble in methanol.So, a first layer of the 85.5/14.5 PVDF polyfluoro copolymer comprising a drug could beover coated with a topcoat of the 60.6/39.4 PVDF polyfluoro copolymer made with themethanol solvent. The top coating may be used to delay the drug delivery of the drugcontained in the first layer. Alternately, the second layer could comprise a different drug toprovide for sequential drug delivery. Multiple layers of different drugs could be providedby alternating layers of first one polyfluoro copolymer, then the other. As will be readily appreciated by those skilled in the art, numerous layering approaches may be used toprovide the desired drug delivery.
[0061] Coatings may be formulated by mixing one or more therapeutic agents with thecoating polyfluoro copolymers in a coating mixture. The therapeutic agent may be presentas a liquid, a finely divided solid, or any other appropriate physical form. Optionally, thecoating mixture may include one or more additives, for example, nontoxic auxiliarysubstances such as diluents, carriers, excipients, stabilizers or the like. Other suitableadditives may be formulated with the polymer and pharmaceutically active agent orcompound. For example, a hydrophilic polymer may be added to a biocompatiblehydrophobic coating to modify the release profile, or a hydrophobic polymer may be addedto a hydrophilic coating to modify the release profile. One example would be adding ahydrophilic polymer selected from the group consisting of polyethylene oxide, polyvinylpyrrolidone, polyethylene glycol, carboxylmethyl cellulose, and hydroxymethyl cellulose toa polyfluoro copolymer coating to modify the release profile. Appropriate relative amountsmay be determined by monitoring the in vitro and/or in vivo release profiles for thetherapeutic agents.
[0062] The best conditions for the coating application are when the polyfluoro copolymerand pharmaceutic agent have a common solvent. This provides a wet coating that is a truesolution. Less desirable, yet still usable, are coatings that contain the pharmaceutical agentas a solid dispersion in a solution of the polymer in solvent. Under the dispersionconditions, care must be taken to ensure that the particle size of the dispersedpharmaceutical powder, both the primary powder size and its aggregates and agglomerates,is small enough not to cause an irregular coating surface or to clog the slots of the stent thatneed to remain essentially free of coating. In cases where a dispersion is applied to thestent and the smoothness of the coating film surface requires improvement, or to beensured that all particles of the drug are fully encapsulated in the polymer, or in caseswhere the release rate of the drug is to be slowed, a clear (polyfluoro copolymer only)topcoat of the same polyfluoro copolymer used to provide sustained release of the drug oranother polyfluoro copolymer that further restricts the diffusion of the drug out of thecoating may be applied. The topcoat may be applied by dip coating with mandrel to clear the slots. This method is disclosed in US-6153252. Other methods for applying the topcoatinclude spin coating and spray coating. Dip coating of the topcoat can be problematic if thedrug is very soluble in the coating solvent, which swells the polyfluoro copolymer, and theclear coating solution acts as a zero concentration sink and redissolves previouslydeposited drug. The time spent in the dip bath may need to be limited so that the drug isnot extracted out into the drug-free bath. Drying should be rapid so that the previouslydeposited drug does not completely diffuse into the topcoat.
[0063] The amount of therapeutic agent will be dependent upon the particular drugemployed and medical condition being treated. Typically, the amount of drug representsabout 0.001 % to about 70% of the total coating weight, more typically about 0.001 % toabout 60% of the total coating weight. It is possible that the drug may represent as little as0.0001 % of the total coating weight.
[0064] The quantity and type of polyfluoro copolymers employed in the coating filmcomprising the pharmaceutic agent will vary depending on the release profile desired andthe amount of drug employed. The product may contain blends of the same or differentpolyfluoro copolymers having different molecular weights to provide the desired releaseprofile or consistency to a given formulation.
[0065] Polyfluoro copolymers may release dispersed drug by diffusion. This can result inprolonged delivery (over, say approximately one to two-thousand hours, preferably two toeight-hundred hours) of effective amounts (0.001 mg/cm²-min to 1000 mg/cm²-min) of thedrug. The dosage may be tailored to the subject being treated, the severity of the affliction,the judgment of the prescribing physician, and the like.
[0066] Individual formulations of drugs and polyfluoro copolymers may be tested inappropriate in vitro and in vivo models to achieve the desired drug release profiles. Forexample, a drug could be formulated with a polyfluoro copolymer, or blend of polyfluorocopolymers, coated onto a stent and placed in an agitated or circulating fluid system, forexample, twenty-five percent ethanol in water. Samples of the circulating fluid could betaken to determine the release profile (such as by HPLC, UV analysis or use of radiotagged molecules). The release of a pharmaceutical compound from a stent coating into theinterior wall of a lumen could be modelled in appropriate animal system. The drug releaseprofile could then be monitored by appropriate means such as, by taking samples atspecific times and assaying the samples for drug concentration (using HPLC to detect drugconcentration). Thrombus formation can be modelled in animal models using the Inplateletimaging methods described by Hanson and Harker, Proc. Natl. Acad. Sci. USA85:3184-3188 (1988). Following this or similar procedures, those skilled in the art will beable to formulate a variety of stent coating formulations.
[0067] While not a requirement of the present invention, the coatings and films may becrosslinked once applied to the medical devices. Crosslinking may be affected by any ofthe known crosslinking mechanisms, such as chemical, heat or light. In addition,crosslinking initiators and promoters may be used where applicable and appropriate. Inthose exemplary embodiments utilizing crosslinked films comprising pharmaceuticalagents, curing may affect the rate at which the drug diffuses from the coating. Crosslinkedpolyfluoro copolymers films and coatings of the present invention also may be usedwithout drug to modify the surface of implantable medical devices. EXAMPLESExample 1:
[0068] A PVDF homopolymer (Solef® 1008 from Solvay Advanced Polymers, Houston,TX, T_m about 175°C) and polyfluoro copolymers of poly(vinylidenefluoride/HFP), 92/8and 91/9 wt-% vinylidenefluoride/HFP as determined by F¹⁹NMR, respectively (eg:Solef® 11010 and 11008, Solvay Advanced Polymers, Houston, TX, Tm about 159°C and160°C, respectively) were examined as potential coatings for stents. These polymers aresoluble in solvents such as, but not limited to, DMAc, N,N-dimethylformamide (DMF),dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), tetrahydrofuran (THF) andacetone. Polymer coatings were prepared by dissolving the polymers in acetone, at 5 wt-%as a primer, or by dissolving the polymer in 50/50 DMAc/acetone, at 30 wt-% as a topcoat.Coatings that were applied to the stents by dipping and dried at 60°C in air for severalhours, followed by 60°C for three hours in a <100 mm Hg vacuum, resulted in white foamy films. As applied, these films adhered poorly to the stent and flaked off, indicating theywere too brittle. When stents coated in this manner were heated above 175°C, i.e. abovethe melting temperature of the polymer, a clear, adherent film was formed. Since coatingsrequire high temperatures, for example, above the melting temperature of the polymer, toachieve high quality films. As mentioned above, the high temperature heat treatment isunacceptable for the majority of drug compounds due to their thermal sensitivity. Example 2:
[0069] A polyfluoro copolymer (Solef® 21508) comprising 85.5 wt-% vinylidenefluoridecopolymerized with 14.5 wt-% HFP, as determined by F¹⁹ NMR, was evaluated. Thiscopolymer is less crystalline than the polyfluoro homopolymer and copolymers describedin Example 1. It also has a lower melting point reported to be about 133°C. Once again, acoating comprising about 20 wt-% of the polyfluoro copolymer was applied from apolymer solution in 50/50 DMAc/MEK. After drying (in air) at 60°C for several hours,followed by 60°C for three hours in a <100 mtorr Hg vacuum, clear adherent films wereobtained. This eliminated the need for a high temperature heat treatment to achieve highquality films. Coatings were smoother and more adherent than those of Example 1. Somecoated stents that underwent expansion show some degree of adhesion loss and "tenting" asthe film pulls away from the metal. Where necessary, modification of coatings containingsuch copolymers may be made, e.g. by addition of plasticizers or the like to the coatingcompositions. Films prepared from such coatings may be used to coat stents or othermedical devices, particularly where those devices are not susceptible to expansion to thedegree of the stents.
[0070] The coating process above was repeated, this time with a coating comprising the85.5/14.6 (wt/wt) (vinylidenefluoride/HFP) and about 30 wt-% of rapamycin (Wyeth-AyerstLaboratories, Philadelphia, PA), based on total weight of coating solids. Clear filmsthat would occasionally crack or peel upon expansion of the coated stents resulted. It isbelieved that inclusion of plasticizers and the like in the coating composition will result incoatings and films for use on stents and other medical devices that are not susceptible tosuch cracking and peeling. Example 3:
[0071] Polyfluoro copolymers of still higher HFP content were then examined. Thisseries of polymers were not semi crystalline, but rather are marketed as elastomers. Onesuch copolymer is Fluorel™ FC2261Q (from Dyneon, a 3M-Hoechst Enterprise, Oakdale,MN), a 60.6/39.4 (wt/wt) copolymer of vinylidenefluoride/HFP. Although this copolymerhas a T_g well below room temperature (T_g about -20°C) it is not tacky at room temperatureor even at 60°C. This polymer has no detectable crystallinity when measured byDifferential Scanning Calorimetry (DSC) or by wide angle X-ray diffraction. Films formedon stents as described above were non-tacky, clear, and expanded without incident whenthe stents were expanded.
[0072] The coating process above was repeated, this time with coatings comprising the60.6/39.4 (wt/wt) (vinylidenefluoride/HFP) and about 9, 30 and 50 wt-% rapamycin(Wyeth-Ayerst Laboratories, Philadelphia, PA), based on total weight of coating solids,respectively. Coatings comprising about 9 and 30 wt-% rapamycin provided white,adherent, tough films that expanded without incident on the stent. Inclusion of 50 wt-%drug, in the same manner, resulted in some loss of adhesion upon expansion.
[0073] Changes in the comonomer composition of the polyfluoro copolymer also canaffect the nature of the solid state coating, once dried. For example, the semicrystallinecopolymer sold under the trade mark Solef 21508, containing 85.5% vinylidenefluoridepolymerized with 14.5% by weight HFP forms homogeneous solutions with about 30%rapamycin (drug weight divided by total solids weight, for example, drug plus copolymer)in DMAc and 50/50 DMAc/MEK. When the film is dried (60°C/16 hours followed by60°C/3 hours in vacuum of 100 mm Hg) a clear coating, indicating a solid solution of thedrug in the polymer, is obtained. Conversely, when an amorphous copolymer, Fluorel™FC2261 Q, of PDVF/HFP at 60.6/39.5 (wt/wt) forms a similar 30% solution of rapamycinin DMAc/MEK and is similarly dried, a white film, indicating phase separation of the drugand the polymer, is obtained. This second drug containing film is much slower to releasethe drug into an in vitro test solution of 25% ethanol in water than is the former clear filmof crystalline Solef 21508 copolymer. X-ray analysis of both films indicates that the drugis present in a non-crystalline form. Poor or very low solubility of the drug in the high HFP containing copolymer results in slow permeation of the drug through the thin coating film.Permeability is the product of diffusion rate of the diffusing species (in this case the drug)through the film (the copolymer) and the solubility of the drug in the film. Example 4: In vitro release results of rapamycin from coating.
[0074] Figure 3 is a plot of data for the 85.5/14.5 vinylidenefluoride/HFP polyfluorocopolymer, indicating fraction of drug released as a function of time, with no topcoat.Figure 4 is a plot of data for the same polyfluoro copolymer over which a topcoat has beendisposed, indicating that most effect on release rate is with a clear topcoat. As showntherein, TC150 refers to a device comprising one hundred fifty micrograms of topcoat,TC235 refers to 235 µg of topcoat, etc. The stents before topcoating had an average of750 µg of coating containing 30% rapamycin. Figure 5 is a plot for the 60.6/39.4vinylidenefluoride/HFP polyfluoro copolymer, indicating fraction of drug released as afunction of time, showing significant control of release rate from the coating without theuse of a topcoat. Release is controlled by loading of drug in the film. Example 5: In vivo stent release kinetics of rapamycin from poly(VDF/HFP).
[0075] Nine New Zealand white rabbits (2.5-3.0 kg) on a normal diet were given aspirintwenty-four hours prior to surgery, again just prior to surgery and for the remainder of thestudy. At the time of surgery, animals were premedicated with Acepromazine (0.1-0.2mg/kg) and anaesthetised with a Ketamine/Xylazine mixture (40 mg/kg and 5 mg/kg,respectively). Animals were given a single intraprocedural dose of heparin (150 IU/kg,i.v.).
[0076] Arteriectomy of the right common carotid artery was performed and a 5 F catheterintroducer (Cordis Corporation) placed in the vessel and anchored with ligatures. Iodinecontrast agent was injected to visualize the right common carotid artery, brachlocephalictrunk and aortic arch. A steerable guide wire (0.014 inch/180 cm, Cordis, Inc.) wasinserted via the introducer and advanced sequentially into each iliac artery to a locationwhere the artery possesses a diameter closest to 2 mm using the angiographic mappingdone previously. Two stents coated with a film made of poly(VDF/HFP):(60.6/39.4) with30% rapamycin were deployed in each animal where feasible, one in each iliac artery, using 3.0 mm balloon and inflation to 8-10 ATM for thirty seconds followed after a oneminute interval by a second inflation to 8-10 ATM for thirty seconds. Follow-upangiographs visualizing both iliac arteries are obtained to confirm correct deploymentposition of the stent.
[0077] At the end of procedure, the carotid artery was ligated and the skin is closed with3/0 vicryl suture using a one layered interrupted closure. Animals were given butoropanol(0.4 mg/kg, s.c.) and gentamycin (4 mg/kg, i.m.). Following recovery, the animals werereturned to their cages and allowed free access to food and water.
[0078] Due to early deaths and surgical difficulties, two animals were not used in thisanalysis. Stented vessels were removed from the remaining seven animals at the followingtime points: one vessel (one animal) at ten minutes post implant; six vessels (three animals)between forty minutes and two hours post-implant (average, 1.2 hours); two vessels (twoanimals) at three days post implant; and two vessels (one animal) at seven days post-implant.In one animal at two hours, the stent was retrieved from the aorta rather than theiliac artery. Upon removal, arteries were carefully trimmed at both the proximal and distalends of the stent. Vessels were then carefully dissected free of the stent, flushed to removeany residual blood, and both stent and vessel frozen immediately, wrapped separately infoil, labelled and kept frozen at -80C. When all samples had been collected, vessels andstents were frozen, transported and subsequently analysed for rapamycin in tissue andresults are illustrated in Figure 4. Example 6: Purifying the polymer.
[0079] The Fluorel™ FC2261Q copolymer was dissolved in MEK at about ten weightpercent and was washed in a 50/50 mixture of ethanol/water at a 14:1 of ethanol/water toMEK solution ratio. The polymer precipitated out and was separated from the solventphase by centrifugation. The polymer again was dissolved in MEK and the washingprocedure repeated. The polymer was dried after each washing step at 60°C in a vacuumoven (<200 mtorr) over night. Example 7: In vivo testing of coated stents in porcine coronary arteries.
[0080] Stents available from Cordis Corporation under the trade mark CrossFlex werecoated with the "as received" Fluorel™ FC2261Q PVDF copolymer and with the purifiedpolyfluoro copolymer of Example 6, using the dip and wipe approach. The coated stentswere sterilized using ethylene oxide and a standard cycle. The coated stents and bare metalstents (controls) were implanted in porcine coronary arteries, where they remained fortwenty-eight days.
[0081] Angiography was performed on the pigs at implantation and at twenty-eight days.Angiography indicated that the control uncoated stent exhibited about twenty-one percentrestenosis. The polyfluoro copolymer "as received" exhibited about 26% restenosis(equivalent to the control) and the washed copolymer exhibited about 12.5% restenosis.
[0082] Histology results reported neointimal area at twenty-eight days to be 2.89±0.2,3.57±0.4 and 2.75±0.3, respectively, for the bare metal control, the unpurified copolymerand the purified copolymer.
[0083] Since rapamycin acts by entering the surrounding tissue, it s preferably onlyaffixed to the surface of the stent making contact with one tissue. Typically, only the outersurface of the stent makes contact with the tissue. Accordingly, in one exemplaryembodiment, only the outer surface of the stent is coated with rapamycin.
[0084] The circulatory system, under normal conditions, has to be self-sealing, otherwisecontinued blood loss from an injury would be life threatening. Typically, all but the mostcatastrophic bleeding is rapidly stopped though a process known as hemostasis. Hemostasisoccurs through a progression of steps. At high rates of flow, hemostasis is acombination of events involving platelet aggregation and fibrin formation. Plateletaggregation leads to a reduction in the blood flow due to the formation of a cellular plugwhile a cascade of biochemical steps leads to the formation of a fibrin clot.
[0085] Fibrin clots, as stated above, form in response to injury. There are certaincircumstances where blood clotting or clotting in a specific area may pose a health risk. For example, during percutaneous transluminal coronary angioplasty, the endothelial cellsof the arterial walls are typically injured, thereby exposing the sub-endothelial cells.Platelets adhere to these exposed cells. The aggregating platelets and the damaged tissueinitiate further biochemical process resulting in blood coagulation. Platelet and fibrinblood clots may prevent the normal flow of blood to critical areas. Accordingly, there is aneed to control blood clotting in various medical procedures. Compounds that do notallow blood to clot are called anti-coagulants. Essentially, an anti-coagulant is an inhibitorof thrombin formation or function. These compounds include drugs such as heparin andhirudin. As used herein, heparin includes all direct or indirect inhibitors of thrombin orFactor Xa.
[0086] In addition to being an effective anti-coagulant, heparin has also beendemonstrated to inhibit smooth muscle cell growth in vivo. Thus, heparin may beeffectively utilized in conjunction with rapamycin in the treatment of vascular disease.Essentially, the combination of rapamycin and heparin may inhibit smooth muscle cellgrowth via two different mechanisms in addition to the heparin acting as an anti-coagulant.
[0087] Because of its multifunctional chemistry, heparin may be immobilized or affixedto a stent in a number of ways. For example, heparin may be immobilized onto a variety ofsurfaces by various methods, including the photolink methods disclosed in US-3959078,US-4722906, US-5229172, US-5308641, US-5350800 and US-5415938. Heparinizedsurfaces have also been achieved by controlled release from a polymer matrix, for example,silicone rubber, as disclosed in US-5837313, US-6099562 and US-6120536.
[0088] Unlike rapamycin, heparin acts on circulating proteins in the blood and heparinneed only make contact with blood to be effective. Accordingly, if used in conjunctionwith a medical device, such as a stent, it would preferably be only on the side that comesinto contact with the blood. For example, if heparin were to be administered via a stent, itwould only have to be on the inner surface of the stent to be effective.
[0089] In an exemplary embodiment of the invention, a stent may be utilized incombination with rapamycin and heparin to treat vascular disease. In this exemplary embodiment, the heparin is immobilized to the inner surface of the stent so that it is incontact with the blood and the rapamycin is immobilized to the outer surface of the stent sothat it is in contact with the surrounding tissue. Figure 7 illustrates a cross-section of aband 102 of the stent 100 illustrated in Figure 1. As illustrated, the band 102 is coated withheparin 108 on its inner surface 110 and with rapamycin 112 on its outer surface 114.
[0090] In an alternate exemplary embodiment, the stent may comprise a heparin layerimmobilized on its inner surface, and rapamycin and heparin on its outer surface. Utilizingcurrent coating techniques, heparin tends to form a stronger bond with the surface it isimmobilized to then does rapamycin. Accordingly, it may be possible to first immobilizethe rapamycin to the outer surface of the stent and then immobilize a layer of heparin to therapamycin layer. In this embodiment, the rapamycin may be more securely affixed to thestent while still effectively eluting from its polymeric matrix, through the heparin and intothe surrounding tissue. Figure 8 illustrates a cross-section of a band 102 of the stent 100illustrated in Figure 1. As illustrated, the band 102 is coated with heparin 108 on its innersurface 110 and with rapamycin 112 and heparin 108 on its outer surface 114.
[0091] There are a number of possible ways to immobilize, i.e., entrapment or covalentlinkage with an erodible bond, the heparin layer to the rapamycin layer. For example,heparin may be introduced into the top layer of the polymeric matrix. In otherembodiments, different forms of heparin may be directly immobilized onto the top coat ofthe polymeric matrix, for example, as illustrated in Figure 9. As illustrated, a hydrophobicheparin layer 116 may be immobilized onto the top coat layer 118 of the rapamycin layer112. A hydrophobic form of heparin is utilized because rapamycin and heparin coatingsrepresent incompatible coating application technologies. Rapamycin is an organic solvent-basedcoating and heparin, in its native form, is a water-based coating.
[0092] As stated above, a rapamycin coating may be applied to stents by a dip, spray orspin coating method, and/or any combination of these methods. Various polymers may beutilized. For example, as described above, poly(ethylene-co-vinyl acetate) and polybutylmethacrylate blends may be utilized. Other polymers may also be utilized, but not limitedto, for example, polyvinylidene fluoride-co-hexafluoropropylene and polyethylbutyl methacrylate-co-hexyl methacrylate. Also as described above, barrier or top coatings mayalso be applied to modulate the dissolution of rapamycin from the polymer matrix. In theexemplary embodiment described above, a thin layer of heparin is applied to the surface ofthe polymeric matrix. Because these polymer systems are hydrophobic and incompatiblewith the hydrophilic heparin, appropriate surface modifications may be required.
[0093] The application of heparin to the surface of the polymeric matrix may beperformed in various ways and utilizing various biocompatible materials. For example, inone embodiment, in water or alcoholic solutions, polyethylene imine may be applied on thestents, with care not to degrade the rapamycin (e.g., pH < 7, low temperature), followed bythe application of sodium heparinate in aqueous or alcoholic solutions. As an extension ofthis surface modification, covalent heparin may be linked on polyethylene imine usingamide-type chemistry (using a carbondiimide activator, e.g. EDC) or reductive aminationchemistry (using CBAS-heparin and sodium cyanoborohydride for coupling). In anotherexemplary embodiment, heparin may be photolinked on the surface, if it is appropriatelygrafted with photo initiator moieties. Upon application of this modified heparinformulation on the covalent stent surface, light exposure causes cross-linking andimmobilization of the heparin on the coating surface. In yet another exemplaryembodiment, heparin may be complexed with hydrophobic quaternary ammonium salts,rendering the molecule soluble in organic solvents (e.g. benzalkonium heparinate, tri-dodecylmethylammoniumheparinate). Such a formulation of heparin may be compatiblewith the hydrophobic rapamycin coating, and may be applied directly on the coatingsurface, or in the rapamycin/hydrophobic polymer formulation.
[0094] It is important to note that the stent, as described above, may be formed from anynumber of materials, including various metals, polymeric materials and ceramic materials.Accordingly, various technologies may be utilized to immobilize the various drugs, agent,compound combinations thereon. Specifically, in addition to the polymeric matricesdescribed above biopolymers may be utilized. Biopolymers may be generally classified asnatural polymers, while the above-described polymers may be described as syntheticpolymers. Exemplary biopolymers, which may be utilized include, agarose, alginate,gelatin, collagen and elastin. In addition, the drugs, agents or compounds may be utilized in conjunction with other percutaneously delivered medical devices such as grafts andprofusion balloons.
[0095] In addition to utilizing an anti-proliferative and anti-coagulant, anti-inflammatoriesmay also be utilized in combination therewith. One example of such acombination would be the addition of an anti-inflammatory corticosteroid such asdexamethasone with an anti-proliferative, such as rapamycin, cladribine, vincristine, taxol,or a nitric oxide donor and an anti-coagulant, such as heparin. Such combination therapiesmight result in a better therapeutic effect, i.e., less proliferation as well as lessinflammation, a stimulus for proliferation, than would occur with either agent alone. Thedelivery of a stent comprising an anti-proliferative, anti-coagulant, and an anti-inflammatoryto an injured vessel would provide the added therapeutic benefit of limitingthe degree of local smooth muscle cell proliferation, reducing a stimulus for proliferation,i.e., inflammation and reducing the effects of coagulation thus enhancing the restenosis-limitingaction of the stent.
[0096] In other exemplary embodiments of the inventions, growth factor inhibitor orcytokine signal transduction inhibitor, such as the ras inhibitor, R115777, or P38 kinaseinhibitor, RWJ67657, or a tyrosine kinase inhibitor, such as tyrphostin, might be combinedwith an anti-proliferative agent such as taxol, vincristine or rapamycin so that proliferationof smooth muscle cells could be inhibited by different mechanisms. Alternatively, an anti-proliferativeagent such as taxol, vincristine or rapamycin could be combined with aninhibitor of extracellular matrix synthesis such as halofuginone. In the above cases, agentsacting by different mechanisms could act synergistically to reduce smooth muscle cellproliferation and vascular hyperplasia. This invention is also intended to cover othercombinations of two or more such drug agents. As mentioned above, such drugs, agents orcompounds could be administered systemically, delivered locally via drug deliverycatheter, or formulated for delivery from the surface of a stent, or given as a combination ofsystemic and local therapy.
[0097] In addition to anti-proliferatives, anti-inflammatories and anti-coagulants, otherdrugs, agents or compounds may be utilized in conjunction with the medical devices. For example, immunosuppressants may be utilized alone or in combination with these otherdrugs, agents or compounds. Also gene therapy delivery mechanisms such as modifiedgenes (nucleic acids including recombinant DNA) in viral vectors and non-viral genevectors such as plasmids may also be introduced locally via a medical device. In addition,the present invention may be utilized with cell based therapy.
[0098] In addition to all of the drugs, agents, compounds and modified genes describedabove, chemical agents that are not ordinarily therapeutically or biologically active mayalso be utilized in conjunction with the present invention. These chemical agents,commonly referred to as pro-drugs, are agents that become biologically active upon theirintroduction into the living organism by one or more mechanisms. These mechanismsinclude the addition of compounds supplied by the organism or the cleavage of compoundsfrom the agents caused by another agent supplied by the organism. Typically, pro-drugs aremore absorbable by the organism. In addition, pro-drugs may also provide some additionalmeasure of time release.
[0099] The coatings and drugs, agents or compounds described above may be utilized incombination with any number of medical devices, and in particular, with implantablemedical devices such as stents and stent-grafts. Other devices such as vena cava filters andanastomosis devices may be used with coatings having drugs, agents or compounds therein.The exemplary stent illustrated in Figures 1 and 2 is a balloon expandable stent. Balloonexpandable stents may be utilized in any number of vessels or conduits, and are particularlywell suited for use in coronary arteries. Self-expanding stents, on the other hand, areparticularly well suited for use in vessels where crush recovery is a critical factor, forexample, in the carotid artery. Accordingly, it is important to note that any of the drugs,agents or compounds, as well as the coatings described above, may be utilized incombination with self-expanding stents which are known in the art.
[0100] Anastomosis is the surgical joining of biological tissues, specifically the joining oftubular organs to create an intercommunication between them. Vascular surgery ofteninvolves creating an anastomosis between blood vessels or between a blood vessel and avascular graft to create or restore a blood flow path to essential tissues. Coronary artery bypass graft surgery (CABG) is a surgical procedure to restore blood flow to ischemic heartmuscle whose blood supply has been compromised by occlusion or stenosis of one or moreof the coronary arteries. One method for performing CABG surgery involves harvesting asaphenous vein or other venous or arterial conduit from elsewhere in the body, or using anartificial conduit, such as one made of polyester (for example that sold under the trademark Dacron) or polytetrafluoroethylene (for example that sold under the trade markGoretex) tubing, and connecting this conduit as a bypass graft from a viable artery, such asthe aorta, to the coronary artery downstream of the blockage or narrowing. It is preferableto utilize natural grafts rather than synthetic grafts. A graft with both the proximal anddistal ends of the graft detached is known as a "free graft." A second method involvesrerouting a less essential artery, such as the internal mammary artery, from its nativelocation so that it may be connected to the coronary artery downstream of the blockage.The proximal end of the graft vessel remains attached in its native position. This type ofgraft is known as a "pedicled graft". In the first case, the bypass graft must be attached tothe native arteries by an end-to-side anastomosis at both the proximal and distal ends of thegraft. In the second technique at least one end-to-side anastomosis must be made at thedistal end of the artery used for the bypass. In the description of the exemplary embodimentgiven below reference will be made to the anastomoses on a free graft as the proximalanastomosis and the distal anastomosis. A proximal anastomosis is an anastomosis on theend of the graft vessel connected to a source of blood, for example, the aorta and a distalanastomosis is an anastomosis on the end of the graft vessel connected to the destination ofthe blood flowing through it, for example, a coronary artery. The anastomoses will alsosometimes be called the first anastomosis or second anastomosis, which refers to the orderin which the anastomoses are performed regardless of whether the anastomosis is on theproximal or distal end of the graft.
[0101] At present, essentially all vascular anastomoses are performed by conventionalhand suturing. Suturing the anastomoses is a time-consuming and difficult task, requiringmuch skill and practice on the part of the surgeon. It is important that each anastomosisprovide a smooth, open flow path for the blood and that the attachment be completely freeof leaks. A completely leak-free seal is not always achieved on the very first try. Consequently, there is a frequent need for resuturing of the anastomosis to close any leaksthat are detected.
[0102] The time consuming nature of hand sutured anastomoses is of special concern inCABG surgery for several reasons. Firstly, the patient is required to be supported oncardiopulmonary bypass (CPB) for most of the surgical procedure, the heart must beisolated from the systemic circulation (i.e. "cross-clamped"), and the heart must usually bestopped, typically by infusion of cold cardioplegia solution, so that the anastomosis site onthe heart is still and blood-free during the suturing of the anastomosis. Cardiopulminarybypass, circulatory isolation and cardiac arrest are inherently very traumatic, and it hasbeen found that the frequency of certain post-surgical complications varies directly with theduration for which the heart is under cardioplegic arrest (frequently referred to as the"crossclamp time"). Secondly, because of the high cost of cardiac operating room time, anyprolongation of the surgical procedure can significantly increase the cost of the bypassoperation to the hospital and to the patient. Thus, it is desirable to reduce the duration ofthe crossclamp time and of the entire surgery by expediting the anastomosis procedurewithout reducing the quality or effectiveness of the anastomoses.
[0103] The already high degree of manual skill required for conventional manuallysutured anastomoses is even more elevated for closed-chest or port-access thoracoscopicbypass surgery, a newly developed surgical procedure designed to reduce the morbidity ofCABG surgery as compared to the standard open-chest CABG procedure. In the closed-chestprocedure, surgical access to the heart is made through narrow access ports made inthe intercostal spaces of the patient's chest, and the procedure is performed under thoracoscopicobservation. Because the patient's chest is not opened, the suturing of the anastomosesmust be performed at some distance, using elongated instruments positioned throughthe access ports for approximating the tissues and for holding and manipulating the needlesand sutures used to make the anastomoses. This requires even greater manual skill than thealready difficult procedure of suturing anastomoses during open-chest CABG surgery.
[0104] In order to reduce the difficulty of creating the vascular anastomoses during eitheropen or closed-chest CABG surgery, it would be desirable to provide a rapid means for making a reliable end-to-side anastomosis between a bypass graft or artery and the aorta orthe native vessels of the heart. A first approach to expediting and improving anastomosisprocedures has been through stapling technology. Stapling technology has beensuccessfully employed in many different areas of surgery for making tissue attachmentsfaster and more reliably. The greatest progress in stapling technology has been in the areaof gastrointestinal surgery. Various surgical stapling instruments have been developed forend-to-end, side-to-side, and end-to-side anastomoses of hollow or tubular organs, such asthe bowel. These instruments, unfortunately, are not easily adaptable for use in creatingvascular anastomoses. This is partially due to the difficulty in miniaturizing the instrumentsto make them suitable for smaller organs such as blood vessels. Possibly even moreimportant is the necessity of providing a smooth, open flow path for the blood. Knowngastrointestinal stapling instruments for end-to-side or end-to-end anastomosis of tubularorgans are designed to create an inverted anastomosis, that is, one where the tissue foldsinward into the lumen of the organ that is being attached. This is acceptable ingastrointestinal surgery, where it is most important to approximate the outer layers of theintestinal tract (the serosa). This is the tissue which grows together to form a strong,permanent connection. However, in vascular surgery this geometry is unacceptable forseveral reasons. Firstly, the inverted vessel walls would cause a disruption in the bloodflow. This could cause decreased flow and ischemia downstream of the disruption, or,worse yet, the flow disruption or eddies created could become a locus for thrombosis whichcould shed emboli or occlude the vessel at the anastomosis site. Secondly, unlike theintestinal tract, the outer surfaces of the blood vessels (the adventitia) will not growtogether when approximated. The sutures, staples, or other joining device may therefore beneeded permanently to maintain the structural integrity of the vascular anastomosis.Thirdly, to establish a permanent, nonthrombogenic vessel, the innermost layer (theendothelium) should grow together for a continuous, uninterrupted lining of the entirevessel. Thus, it would be preferable to have a stapling instrument that would createvascular anastomoses that are everted, that is folded outward, or which create direct edge-to-edgecoaptation without inversion.
[0105] At least one stapling instrument has been applied to performing vascularanastomoses during CABG surgery. This device, first adapted for use in CABG surgery by Dr Vasilii I Kolesov and later refined by Dr Evgenii V Kolesov (US-4350160), was used tocreate an end-to-end anastomosis between the internal mammary artery (IMA) or a veingraft and one of the coronary arteries, primarily the left anterior descending coronary artery(LAD). Because the device could only perform end-to-end anastomoses, the coronaryartery first had to be severed and dissected from the surrounding myocardium, and theexposed end everted for attachment. This technique limited the indications of the device tocases where the coronary artery was totally occluded, and therefore there was no loss ofblood flow by completely severing the coronary artery downstream of the blockage to makethe anastomosis. Consequently, this device is not applicable where the coronary artery isonly partially occluded and is not at all applicable to making the proximal side-to-endanastomosis between a bypass graft and the aorta.
[0106] One attempt to provide a vascular stapling device for end-to-side vascularanastomoses is described in US-5234447 (Kaster et al). Kaster et al provide a ring-shapedstaple with staple legs extending from the proximal and distal ends of the ring to join twoblood vessels together in an end-to-side anastomosis. However, Kaster et al does notprovide a complete system for quickly and automatically performing an anastomosis. Themethod of applying the anastomosis staple disclosed by Kaster et al involves a great deal ofmanual manipulation of the staple, using hand operated tools to individually deform thedistal tines of the staple after the graft has been attached and before it is inserted into theopening made in the aortic wall. One of the more difficult manoeuvres in applying theKaster et al staple involves carefully everting the graft vessel over the sharpened ends ofthe staple legs, then piercing the evened edge of the vessel with the staple legs.Experimental attempts to apply this technique have proven to be very problematic becauseof difficulty in manipulating the graft vessel and the potential for damage to the graft vesselwall. For speed, reliability and convenience, it is preferable to avoid the need for complexmanoeuvres while performing the anastomosis. Further bending operations must then beperformed on the staple legs. Once the distal tines of the staple have been deformed, it maybe difficult to insert the staple through the aortotomy opening. Another disadvantage of theKaster et al device is that the distal tines of the staple pierce the wall of the graft vessel atthe point where it is evened over the staple. Piercing the wall of the graft vessel potentiallyinvites leaking of the anastomosis and may compromise the structural integrity of the graft vessel wall, serving as a locus for a dissection or even a tear which could lead to catastrophicfailure. Because the Kaster et al staple legs only apply pressure to the anastomosisat selected points, there is a potential for leaks between the staple legs. The distal tines ofthe staple are also exposed to the blood flow path at the anastomotic site where it is mostcritical to avoid the potential for thrombosis. There is also the potential that exposure of themedial layers of the graft vessel where the staple pierces the wall could be a site for theonset of intimal hyperplasia, which would compromise the long-term patency of the graftas described above. Because of these potential drawbacks, it is desirable to make theattachment to the graft vessel as atraumatic to the vessel wall as possible and to eliminateas much as possible the exposure of any foreign materials or any vessel layers other than asmooth uninterrupted intimal layer within the anastomosis site or within the graft vessellumen.
[0107] A second approach to expediting and improving anastomosis procedures isthrough the use of anastomotic fittings for joining blood vessels together. One attempt toprovide a vascular anastomotic fitting device for end-to-side vascular anastomoses isdescribed in US-4366819 (Kaster) for an Anastomotic Fitting. This device is a four-partanastomotic fitting having a tubular member over which the graft vessel is evened, a ringflange which engages the aortic wall from within the aortic lumen, and a fixation ring and alocking ring which engage the exterior of the aortic wall. Another similar AnastomoticFitting is described in US-4368736 (Kaster). This device is a tubular fitting with a flangeddistal end that fastens to the aortic wall with an attachment ring, and a proximal end with agraft fixation collar for attaching to the graft vessel. These devices have a number ofdrawbacks. Firstly, the anastomotic fittings described expose the foreign material of theanastomotic device to the blood flow path within the arteries. This is undesirable becauseforeign materials within the blood flow path can have a tendency to cause hemolysis,platelet deposition and thrombosis. Immune responses to foreign material, such as rejectionof the foreign material or auto-immune responses triggered by the presence of foreignmaterial, tend to be stronger when the material is exposed to the bloodstream. As such, it ispreferable that as much as possible of the interior surfaces of an anastomotic fitting thatwill be exposed to the blood flow path be covered with vascular tissue, either from thetarget vessel or from the graft vessel, so that a smooth, continuous, hemocompatible endothelial layer will be presented to the bloodstream. The anastomotic fitting described byKaster in the '819 patent also has the potential drawback that the spikes that hold the graftvessel onto the anastomotic fitting are very close to the blood flow path, potentially causingtrauma to the blood vessel that could lead to leaks in the anastomosis or compromise of themechanical integrity of the vessels. Consequently, it is desirable to provide an anastomosisfitting that is as atraumatic to the graft vessel as possible. Any sharp features such asattachment spikes should be placed as far away from the blood flow path and theanastomosis site as possible so that there is no compromise of the anastomosis seal or thestructural integrity of the vessels.
[0108] A device for end-to-end anastomosis that is sold by 3M under the trade markUnilink (disclosed in US-4624257, US-4917090 and US-4917091) is designed for use inmicrosurgery, such as for reattaching vessels severed in accidents. This device provides ananastomosis clamp that has two eversion rings which are locked together by a series ofimpaling spikes on their opposing faces. However, this device is awkward for use in end-to-sideanastomosis and tends to deform the target vessel; therefore it is not currently usedin CABG surgery. Due to the delicate process needed to insert the vessels into the device, itwould also be unsuitable for port-access surgery.
[0109] In order to solve these and other problems, it is desirable to provide ananastomosis device which performs an end-to-side anastomosis between blood vessels orother hollow organs and vessels. It is also desirable to provide an anastomosis devicewhich minimizes the trauma to the blood vessels while performing the anastomosis, whichminimizes the amount of foreign materials exposed to the blood flow path within the bloodvessels and which avoids leakage problems, and which promotes rapid endothelializationand healing. It is also desirable that the invention provide a complete system for quicklyand automatically performing an anastomosis with a minimal amount of manualmanipulation.
[0110] Anastomosis devices may be utilized to join biological tissues, and moreparticularly, joining tubular organs to create a fluid channel. The connections between thetubular organs or vessels may be made side to side, end to end and/or end to side. Typically, there is a graft vessel and a target vessel. The target vessel may be an artery,vein or any other conduit or fluid carrying vessel, for example, coronary arteries. The graftvessel may comprise a synthetic material, an autologus vessel, a homologus vessel or axenograft. Anastomosis devices may comprise any suitable biocompatible materials, forexample, metals, polymers and elastomers. In addition, there are a wide variety of designsand configurations for anastomosis devices depending on the type of connection to bemade. Similarly to stents, anastomosis devices cause some injury to the target vessel,thereby provoking a response from the body. Therefore, as in the case with stents, there isthe potential for smooth muscle cell proliferation which can lead to blocked connections.Accordingly, there is a need to minimize or substantially eliminate smooth muscle cellproliferation and inflammation at the anastomotic site. Rapamycin and/or other drugs,agents or compounds may be utilized in a manner analogous to stents as described above.In other words, at least a portion of the anastomosis device may be coated with rapamycinor other drug, agent or compound.
[0111] Figures 10 to 13 illustrate an exemplary anastomosis device 200 for an end to sideanastomosis. The exemplary anastomosis device 200 comprises a fastening flange 202 andattached staple members 204. As stated above, the anastomosis device may comprise anysuitable biocomopatible material. Preferably, the anastomosis device 200 comprises adeformable biocompatible metal, such as a stainless steel alloy, a titanium alloy or a cobaltalloy. Also as stated above, a surface coating or surface coating comprising a drug, agentor compound may be utilized to improve the biocompatibility or other materialcharacteristics of the device as well as to reduce or substantially eliminate the body'sresponse to its placement therein.
[0112] In the exemplary embodiment, the fastening flange 202 resides on the interiorsurface 206 of the target vessel wall 208 when the anastomosis is completed. In order tosubstantially reduce the risk of hemolysis, thrombogenesis or foreign body reactions, thetotal mass of the fastening flange 202 is preferably as small as possible to reduce theamount of foreign material within the target vessel lumen 210.
[0113] The fastening flange 202 is in the form of a wire ring with an internal diameter,which when fully expanded, is slightly greater than the outside diameter of the graft vesselwall 214 and of the opening 216 made in the target vessel wall 208. Initially, the wire ringof the fastening flange 202 has a rippled wave-like shape to reduce the diameter of the ringso that it will easily fit through the opening 216 in the target vessel wall 208. The pluralityof staple members 204 extend substantially perpendicular from the wire ring in theproximal direction. In the illustrative exemplary embodiment, there are nine staplemembers 204 attached to the wire ring fastening flange 202. Other variations of theanastomosis device 200 might typically have from four to twelve staple members 204depending on the size of the vessels to be joined and the security of attachment required inthe particular application. The staple members 204 may be integrally formed with the wirering fastening flange 202 or the staple members 204 may be attached to the fastening flange202 by welding, brazing or any other suitable joining method. The proximal ends 218 ofthe staple members 204 are sharpened to easily pierce the target vessel wall 208 and thegraft vessel wall 214. Preferably, the proximal ends 218 of the staple members 204 havebarbs 220 to improve the security of the attachment when the anastomosis device 200 isdeployed. The anastomosis device 200 is prepared for use by mounting the device onto thedistal end of an application instrument 222. The fastening flange 202 is mounted on ananvil 224 attached to the distal end of the elongated shaft 226 of the application instrument222. The staple members 204 are compressed inward against a conical holder 228 attachedto the instrument 222 proximal to the anvil 224. The staple members 204 are secured inthis position by a cap 230 which is slidably mounted on the elongated shaft 226. The cap230 moves distally to cover the sharpened, barbed proximal ends 218 of the staplemembers 204 and to hold them against the conical holder 228. The application instrument222 is then inserted through the lumen 232 of the graft vessel 214. This may be done byinserting the application instrument 222 through the graft vessel lumen 232 from theproximal to the distal end of the graft vessel 214, or it may be done by backloading theelongated shaft 226 of the application instrument 222 into the graft vessel lumen 232 fromthe distal end to the proximal end, whichever is most convenient in the case. The anvil 224and conical holder 228 on the distal end of the application instrument 222 with theanastomosis device 200 attached is extended through the opening 216 into the lumen 210of the target vessel.
[0114] Next, the distal end 234 of the graft vessel wall 214 is everted against the exteriorsurface 236 of the target vessel wall 208 with the graft vessel lumen 232 centred over theopening 216 in the target vessel wall 208. The cap 230 is withdrawn from the proximalends 218 of the staple members 204, allowing the staple members 204 to spring outward totheir expanded position. The application instrument 222 is then drawn in the proximaldirection so that the staple members pierce the target vessel wall 208 surrounding theopening 216 and the everted distil end 234 of the graft vessel 214.
[0115] The application instrument 222 has an annular staple former 238 which surroundsthe outside of the graft vessel 214. Slight pressure on the everted graft vessel wall from theannular staple former 238 during the piercing step assists in piercing the staple members204 through the graft vessel wall 214. Care should be taken not to apply too much pressurewith the annular staple former 238 at this point in the process because the staple members204 could be prematurely deformed before they have fully traversed the vessel walls. Ifdesired, an annular surface made of a softer material, such as an elastomer, can be providedon the application instrument 222 to back up the vessel walls as the staple members 204pierce through them.
[0116] Once the staple members 204 have fully traversed the target vessel wall 208 andthe graft vessel wall 214, the staple former 238 is brought down with greater force whilesupporting the fastening flange 202 with the anvil 224. The staple members 204 aredeformed outward so that the sharpened, barbed ends 218 pierce back through the everteddistil end 234 and into the target vessel wall 208 to form a permanent attachment. Tocomplete the anastomosis, the anvil 224 is withdrawn through the graft vessel lumen 232.As the anvil 224 passes through the wire ring fastening flange 202, it straightens out thewave-like ripples so that the wire ring flange 202 assumes its full expanded diameter.Alternately, the wire ring fastening flange 202 may be made of a resilient material so thatthe flange 202 may be compressed and held in a rippled or folded position until it isreleased within the target vessel lumen 210, whereupon it will resume its full expandeddiameter. Another alternate construction would be to move the anastomosis device of ashape-memory alloy so that the fastening flange may be compressed and inserted throughthe opening in the target vessel, whereupon it would be returned to its full expanded diameter by heating the device 200 to a temperature above the shape-memory transitiontemperature.
[0117] In the above-described exemplary embodiment, the staple members 204 and/or thewire ring fastening flange 202 may be coated with any of the above-described agents, drugsor compounds such as rapamycin to prevent or substantially reduce smooth muscle wallproliferation.
[0118] Figure 14 illustrates an alternate exemplary embodiment of an anastomosis device.Figure 14 is a side view of an apparatus for joining at least two anatomical structures,according to another exemplary embodiment of the present invention. Apparatus 300includes a suture 302 having a first end 304 and a second end 306, the suture 302 beingconstructed for passage through anatomical structures in a manner to be describedsubsequently. Suture 302 may be formed from a wide variety of materials, for example,monofilament materials having minimal memory, including polypropylene or polyamide.Any appropriate diameter size may be used, for example, through 8-0. Other suture typesand sizes are also possible, of course, and are equally contemplated by the presentinvention.
[0119] A needle 308 preferably is curved and is disposed at the first end 304 of the suture302. A sharp tip 310 of needle 308 enables easy penetration of various anatomicalstructures and enables the needle 308 and the suture 302 to readily pass there through. Theneedle 308 may be attached to the suture 302 in various ways, for example, by swedging,preferably substantially matching the outer diameter of the needle 308 and the suture 302as closely as possible.
[0120] Apparatus 300 also includes a holding device 312 disposed at the second end 306of the suture 302. The holding device 312 includes first and second limbs 314, 316,according to the illustrated exemplary embodiment, and preferably is of greater stiffnessthan the suture 302. The first limb 314 may be connected to suture 302 in a number ofways, for example, by swedging, preferably substantially matching the outside diameter ofthe suture 302 and the holding device 312 as closely as possible. The holding device 312 includes a staple structure comprising a bendable material that preferably is soft andmalleable enough to crimp and hold its crimped position on the outside of an anastomosis.Such materials may include titanium or stainless steel. The holding device 312 may bereferred to as a staple, according to the illustrated embodiment, and the suture 302 and theneedle 308 a delivery system for staple 312.
[0121] Figure 14 illustrates one of the many possible initial configurations of holdingdevice 312, i.e. the configuration the holding device 312 is in upon initial passage throughthe anatomical structures and/or at a point in time beforehand. As will be described, theholding device 312 is movable from the initial configuration to a holding configuration, inwhich holding device 312 holds the anatomical structures together. According to theillustrated exemplary embodiments, the holding device 312 assumes the holdingconfiguration when it is bent or crimped, as shown in Figure 19 (further described below).
[0122] The holding device 312 preferably is substantially V-shaped or substantially U-shaped,as illustrated, but may assume a wide variety of shapes to suit particular surgicalsituations and/or surgeon preference. For example, one of limbs 314, 316 may be straightand the other curved, or limbs 314, 316 may be collinear. The holding device 312preferably is as smooth and round in cross-section as the needle 308. Further, the diametersof the needle 308, the suture 302, and the holding device 312 preferably are substantiallyidentical, especially the needle 308 and the holding device 312, to avoid creating holes inthe anatomical structures that are larger than the diameter of the staple 312. Such holeslikely would cause bleeding and/or leakage.
[0123] A method of using apparatus 300 is illustrated in Figures 15-19. First, asillustrated in Figure 15, the needle 308 passes through anatomical structures 318, 320,which are, for example, vascular structures. Specifically, according to the illustratedexemplary embodiment, the needle 308 passes through the edges 322, 324 of vascularstructures 318, 320. Then, as shown in Figure 16, the needle 308 pulls suture 302 into andthrough both structures 318, 320. The staple 312 then is pulled into desired proximity withstructures 318, 320, as shown in Figures 17-19, such that it is engaged on both sides of the illustrated anastomosis and associated lumen 326. According to one exemplaryembodiment, traction is placed on suture 302 to hook staple 312 into position.
[0124] As illustrated in Figure 19 and as referenced earlier, the staple 312 then is movedfrom its initial configuration to a holding or crimped configuration 328, in whichanatomical structures 318, 320 are joined together to effect an anastomosis between them.The staple 312 creates a substantially three hundred sixty -degree loop at the edge of theanastomosis, with crimped portion 330 outside lumen 321. A wide variety of tools and/ormechanisms may be used to crimp the staple 312 into its holding configuration, forexample, in the manner of closure of a vascular clip. The same tool, or an alternative tool,may then be used to separate the staple 312 from the suture 302, for example, by cutting.
[0125] Thus, the staple 312 holds vascular structures 318, 320 together from inside thevascular structures, as well as from outside, unlike the many prior art staples that secureopposed structures only externally. This achieves a number of advantages, as describedabove. Not only does a better approximation result, but crimping a staple is simpler thantying one or more knots and is also less likely traumatic on tissue. Staple closure with asingle crimp provides less tension on an anastomosis, for example, than a knot requiringseveral throws. Embodiments of the invention are especially advantageous in minimallyinvasive surgical situations, as knot-tying with, for example, a knot pusher in a minimallyinvasive setting through a small port is particularly tedious and can require up to four orfive throws to prevent slippage. Crimping a staple through the port, as with embodimentsof the invention, is far simpler and eliminates much of the difficulty.
[0126] According to one exemplary embodiment, the surgeon achieves a preciseapproximation of the vascular or other structures with preferably a limited number ofstaples or other holding devices, and then completes the anastomosis with biologic glue orlaser techniques. The holding devices, for example, two or more in number, may be used toorient or line up the structures initially and thus used as a "pilot" for guiding thecompletion of the anastomosis.
[0127] In the above described exemplary embodiment, the holding device 312 may becoated with any of the above-described drugs, agents or compounds such as rapamycin toprevent or substantially reduce smooth muscle cell proliferation.
[0128] As described above, various drugs, agents or compounds may be locally deliveredvia medical devices. For example, rapamycin and heparin may be delivered by a stent toreduce restenosis, inflammation, and coagulation. Various techniques for immobilizing thedrugs, agents or compounds are discussed above, however, maintaining the drugs, agents orcompounds on the medical devices during delivery and positioning is critical to the successof the procedure or treatment. For example, removal of the drug, agent or compoundcoating during delivery of the stent can potentially cause failure of the device. For a self-expandingstent, the retraction of the restraining sheath may cause the drugs, agents orcompounds to rub off the stent. For a balloon expandable stent, the expansion of theballoon may cause the drugs, agents or compounds to simply delaminate from the stentthrough contact with the balloon or via expansion. Therefore, prevention of this potentialproblem is important to have a successful therapeutic medical device, such as a stent.
[0129] There are a number of approaches that may be utilized to substantially reduce theabove-described concern. In one exemplary embodiment, a lubricant or mould releaseagent may be utilized. The lubricant or mould release agent may comprise any suitablebiocompatible lubricious coating. An exemplary lubricious coating may comprise silicone.In this exemplary embodiment, a solution of the silicone base coating may be introducedonto the balloon surface, onto the polymeric matrix, and/or onto the inner surface of thesheath of a self-expanding stent delivery apparatus and allowed to air cure. Alternately, thesilicone based coating may be incorporated into the polymeric matrix. It is important tonote, however, that any number of lubricious materials may be utilized, with the basicrequirements being that the material be biocompatible, that the material not interfere withthe actions/effectiveness of the drugs, agents or compounds and that the material notinterfere with the materials utilized to immobilize the drugs, agents or compounds on themedical device. It is also important to note that one or more, or all of the above-describedapproaches may be utilized in combination.
[0130] Referring now to Figure 20, there is illustrated a balloon 400 of a balloon catheterthat may be utilized to expand a stent in situ. As illustrated, the balloon 400 comprises alubricious coating 402. The lubricious coating 402 functions to minimize or substantiallyeliminate the adhesion between the balloon 400 and the coating on the medical device. Inthe exemplary embodiment described above, the lubricious coating 402 would minimize orsubstantially eliminate the adhesion between the balloon 400 and the heparin or rapamycincoating. The lubricious coating 402 may be attached to and maintained on the balloon 400in any number of ways including but not limited to dipping, spraying, brushing or spincoating of the coating material from a solution or suspension followed by curing or solventremoval step as needed.
[0131] Materials such as synthetic waxes, e.g. diethyleneglycol monostearate, hydrogenatedcastor oil, oleic acid, stearic acid, zinc stearate, calcium stearate, ethylenebis(stearamide), natural products such as paraffin wax, spermaceti wax, camuba wax, sodiumalginate, ascorbic acid and flour, fluorinated compounds such as perfluoroalkanes, perfluorofattyacids and alcohol, synthetic polymers such as silicones e.g. polydimethylsiloxane,polytetrafluoroethylene, polyfluoroethers, polyalkylglycol e.g. polyethyleneglycol waxes, and inorganic materials such as talc, kaolin, mica, and silica may be used toprepare these coatings. Vapour deposition polymerization e.g. parylene-C deposition, orRF-plasma polymerization of perfluoroalkenes and perfluoroalkanes can also be used toprepare these lubricious coatings.
[0132] Figure 21 illustrates a cross-section of a band 102 of the stent 100 illustrated inFigure 1. In this exemplary embodiment, the lubricious coating 500 is immobilized ontothe outer surface of the polymeric coating. As described above, the drugs, agents orcompounds may be incorporated into a polymeric matrix. The stent band 102 illustrated inFigure 21 comprises a base coat 502 comprising a polymer and rapamycin and a top coat504 or diffusion layer 504 also comprising a polymer. The lubricious coating 500 isaffixed to the top coat 502 by any suitable means, including but not limited to spraying,brushing, dipping or spin coating of the coating material from a solution or suspension withor without the polymers used to create the top coat, followed by curing or solvent removalstep as needed. Vapour deposition polymerization and RF-plasma polymerization may also be used to affix those lubricious coating materials that lend themselves to this depositionmethod, to the top coating. In an alternate exemplary embodiment, the lubricious coatingmay be directly incorporated into the polymeric matrix.
[0133] If a self-expanding stent is utilized, the lubricious coating may be affixed to theinner surface of the restraining sheath. Figure 22 illustrates a partial cross-sectional viewof self-expanding stent 200 within the lumen of a delivery apparatus sheath 14. Asillustrated, a lubricious coating 600 is affixed to the inner surfaces of the sheath 14.Accordingly, upon deployment of the stent 200, the lubricious coating 600 preferablyminimizes or substantially eliminates the adhesion between the sheath 14 and the drug,agent or compound coated stent 200.
[0134] In an alternate approach, physical and/or chemical cross-linking methods may beapplied to improve the bond strength between the polymeric coating containing the drugs,agents or compounds and the surface of the medical device or between the polymericcoating containing the drugs, agents or compounds and a primer. Alternately, otherprimers applied by either traditional coating methods such as dip, spray or spin coating, orby RF-plasma polymerization may also be used to improve bond strength. For example, asshown in Figure 23, the bond strength can be improved by first depositing a primer layer700 such as Vapour polymerized parylene-C on the device surface, and then placing asecondary layer 702 which comprises a polymer that is similar in chemical composition tothe one or more of the polymers that make up the drug-containing matrix 704, e.g.,polyethylene-co-vinyl acetate or polybutyl methacrylate but has been modified to containcross-linking moieties. This secondary layer 702 is then cross-linked to the primer afterexposure to ultra-violet light. It should be noted that anyone familiar with the art wouldrecognize that a similar outcome could be achieved using cross-linking agents that areactivated by heat with or without the presence of an activating agent. The drug-containingmatrix 704 is then layered onto the secondary layer 702 using a solvent that swells, in partor wholly, the secondary layer 702. This promotes the entrainment of polymer chains fromthe matrix into the secondary layer 702 and conversely from the secondary layer 702 intothe drug-containing matrix 704. Upon removal of the solvent from the coated layers, aninterpenetrating or interlocking network of the polymer chains is formed between the layers thereby increasing the adhesion strength between them. A top coat 706 is used asdescribed above.
[0135] A related difficulty occurs in medical devices such as stents. In the drug-coatedstents crimped state, some struts come into contact with each other and when the stent isexpanded, the motion causes the polymeric coating comprising the drugs, agents orcompounds to stick and stretch. This action may potentially cause the coating to separatefrom the stent in certain areas. The predominant mechanism of the coating self-adhesion isbelieved to be due to mechanical forces. When the polymer comes in contact with itself,its chains can tangle causing the mechanical bond, similar to Velcro®. Certain polymersdo not bond with each other, for example, fluoropolymers. For other polymers, however,powders may be utilized. In other words, a powder may be applied to the one or morepolymers incorporating the drugs, agents or other compounds on the surfaces of themedical device to reduce the mechanical bond. Any suitable biocompatible material whichdoes not interfere with the drugs, agents, compounds or materials utilized to immobilizethe drugs, agents or compounds onto the medical device may be utilized. For example, adusting with a water soluble powder may reduce the tackiness of the coatings surface andthis will prevent the polymer from sticking to itself thereby reducing the potential fordelamination. The powder should be water-soluble so that it does not present an embolirisk. The powder may comprise an anti-oxidant, such as vitamin C, or it may comprise ananti-coagulant, such as aspirin or heparin. An advantage of utilizing an anti-oxidant maybe in the fact that the anti-oxidant may preserve the other drugs, agents or compounds overlonger periods of time.
[0136] It is important to note that crystalline polymers are generally not sticky or tacky.Accordingly, if crystalline polymers are utilized rather than amorphous polymers, thenadditional materials may not be necessary. It is also important to note that polymericcoatings without drugs, agents and/or compounds may improve the operatingcharacteristics of the medical device. For example, the mechanical properties of themedical device may be improved by a polymeric coating, with or without drugs, agentsand/or compounds. A coated stent may have improved flexibility and increased durability.In addition, the polymeric coating may substantially reduce or eliminate galvanic corrosion between the different metals comprising the medical device. The same holds true foranastomosis devices.
[0137] Any of the above-described medical devices may be utilized for the local deliveryof drugs, agents and/or compounds to other areas, not immediately around the device itself.In order to avoid the potential complications associated with systemic drug delivery, themedical devices of the present invention may be utilized to deliver therapeutic agents toareas adjacent to the medical device. For example, a rapamycin coated stent may deliverthe rapamycin to the tissues surrounding the stent as well as areas upstream of the stent anddownstream of the stent. The degree of tissue penetration depends on a number of factors,including the drug, agent or compound, the concentrations of the drug and the release rateof the agent. The same holds true for coated anastomosis devices.
[0138] The drug, agent and/or compound/carrier or vehicle compositions described abovemay be formulated in a number of ways. For example, they may be formulated utilizingadditional components or constituents, including a variety of excipient agents and/orformulary components to affect manufacturability, coating integrity, sterilizability, drugstability, and drug release rate. Within exemplary embodiments of the present invention,excipient agents and/or formulary components may be added to achieve both fast-releaseand sustained-release drug elution profiles. Such excipient agents may include salts and/orinorganic compounds such as acids/bases or buffer components, anti-oxidants, surfactants,polypeptides, proteins, carbohydrates including sucrose, glucose or dextrose, chelatingagents such as EDTA, glutathione or other excipients or agents.
[0139] It is important to note that any of the above-described medical devices may becoated with coatings that comprise drugs, agents or compounds or simply with coatingsthat contain no drugs, agents or compounds. In addition, the entire medical device may becoated or only a portion of the device may be coated. The coating may be uniform or nonuniform.The coating may be discontinuous.
[0140] As described above, any number of drugs, agents and/or compounds may belocally delivered via any number of medical devices. For example, stents and anastomosis devices may incorporate coatings comprising drugs, agents and/or compounds to treatvarious disease states and reactions by the body as described in detail above. Other deviceswhich may be coated with or otherwise incorporate therapeutic dosages of drugs, agentsand/or compounds include stent-grafts, which are briefly described above, and devicesutilizing stent-grafts, such as devices for treating abdominal aortic aneurysms as well asother aneurysms, e.g. thoracic aorta aneurysms.
[0141] Stent-grafts, as the name implies, comprise a stent and a graft material attachedthereto. Figure 24 illustrates an exemplary stent-graft 800. The stent-graft 800 maycomprise any type of stent and any type of graft material as described in detailsubsequently. In the illustrated exemplary embodiment, the stent 802 is a self-expandingdevice. A typical self-expanding stent comprises an expandable lattice or network ofinterconnected struts. In preferred embodiments of the invention, the lattice is fabricated,e.g. laser cut, from an integral tube of material.
[0142] In accordance with the present invention, the stent may be variously configured.For example, the stent may be configured with struts or the like that form repeatinggeometric shapes. One skilled in the art will readily recognize that a stent may beconfigured or adapted to include certain features and/or to perform a certain function(s),and that alternate designs may be used to promote that feature or function.
[0143] In the exemplary embodiment of the invention illustrated in Figure 24, the matrixor struts of stent 802 may be configured into at least two hoops 804, each hoop 804comprising a number of struts 806 formed into a diamond shape, having approximatelynine diamonds. The stent 802 may further include a zigzag shaped ring 808 for connectingadjacent hoops to one another. The zigzag shaped rings 808 may be formed from a numberof alternating struts 810, wherein each ring has fifty-four struts.
[0144] An inner or outer surface of the stent 802 may be covered by or support a graftmaterial. Graft material 812 may be made from any number of materials known to thoseskilled in the art, including woven or other configurations of polyester, Dacron®, Teflon®, polyurethane porous polyurethane, silicone, polyethylene, terephthalate, expandedpolytetrafluoroethylene (ePTFE) and blends of various materials.
[0145] The graft material 812 may be variously configured, preferably to achievepredetermined mechanical properties. For example, the graft material may incorporate asingle or multiple weaving and/or pleating patterns, or may be pleated or unpleated. Forexample, the graft material may be configured into a plain weave, a satin weave, includelongitudinal pleats, interrupted pleats, annular or helical pleats, radially oriented pleats, orcombinations thereof. Alternately, the graft material may be knitted or braided. In theembodiments of the invention in which the graft material is pleated, the pleats may becontinuous or discontinuous. Also, the pleats may be oriented longitudinally,circumferentially, or combinations thereof.
[0146] As illustrated in Figure 24, the graft material 812 may include a plurality oflongitudinal pleats 814 extending along its surface, generally parallel to the longitudinalaxis of the stent-graft 800. The pleats 814 allow the stent-graft 800 to collapse around itscentre, much as it would be when it is delivered into a patient. This provides a relativelylow profile delivery system, and provides for a controlled and consistent deploymenttherefrom. It is believed that this configuration minimizes wrinkling and other geometricirregularities. Upon subsequent expansion, the stent-graft 800 assumes its naturalcylindrical shape, and the pleats 814 uniformly and symmetrically open.
[0147] In addition, the pleats 814 help facilitate stent-graft manufacture, in that theyindicate the direction parallel to the longitudinal axis, allowing stent to graft attachmentalong these lines, and thereby inhibiting accidental twisting of the graft relative to the stentafter attachment. The force required to push the stent-graft 800 out of the delivery systemmay also be reduced, in that only the pleated edges of the graft make frictional contact withthe inner surface of the delivery system. One further advantage of the pleats 814 is thatblood tends to coagulate generally uniformly in the troughs of the pleats 814, discouragingasymmetric or large clot formation on the graft surface, thereby reducing embolus risk.
[0148] As shown in Figure 24, the graft material 812 may also include one or more, andpreferably a plurality of, radially oriented pleat interruptions 816. The pleat interruptions816 are typically substantially circular and are oriented perpendicular to longitudinal axis.Pleat interruptions 816 allow the graft and stent to bend better at selective points. Thisdesign provides for a graft material that has good crimpability and improved kinkresistance.
[0149] The foregoing graft materials may be braided, knitted or woven, and may be warpor weft knitted. If the material is warp knitted, it may be provided with a velour, or towellike surface; which is believed to speed the formation of blood clots, thereby promoting theintegration of a stent-graft or stent-graft component into the surrounding cellular structure.
[0150] A graft material may be attached to a stent or to another graft material by anynumber of structures or methods known to those skilled in the art, including adhesives,such as polyurethane glue; a plurality of conventional sutures of polyvinylidene fluoride,polypropylene, Dacron®, or any other suitable material; ultrasonic welding; mechanicalinterference fit; and staples.
[0151] The stent 802 and/or graft material 812 may be coated with any of the above-describeddrugs, agents and/or compounds. In one exemplary embodiment, rapamycin maybe affixed to at least a portion of the graft material 812 utilizing any of the materials andprocesses described above. In another exemplary embodiment, rapamycin may be affixedto at least a portion of the graft material 812 and heparin or other antithrombotics may beaffixed to at least a portion of the stent 802. With this configuration, the rapamycin coatedgraft material 812 may be utilized to minimize or substantially eliminate smooth musclecell hyperproliferation and the heparin coated stent may substantially reduce the chance ofthrombosis.
[0152] The particular polymer(s) utilized depends on the particular material upon which itis affixed. In addition, the particular drug, agent and/or compound may also affect theselection of polymer(s). As set forth above, rapamycin may be affixed to at least a portionof the graft material 812 utilizing the polymer(s) and processes described above. In another alternate exemplary embodiment, the rapamycin or any other drug, agent and/or compoundmay be directly impregnated into the graft material 812 utilizing any number of knowntechniques.
[0153] In yet another alternate exemplary embodiment, the stent-graft may be formedfrom two stents with the graft material sandwiched between them. Figure 25 is a simpleillustration of a stent-graft 900 formed from an inner stent 902, an outer stent 904 and graftmaterial 906 sandwiched between them. The stents 902, 904 and graft material 906 may beformed from the same materials as described above. As before, the inner stent 902 may becoated with an antithrombotic or anticoagulant such as heparin while the outer stent 904may be coated with an antiproliferative such as rapamycin. Alternately, the graft material906 may be coated with any of the above described drugs, agents and/or compounds, aswell as combinations thereof, or all three elements may be coated with the same ordifferent drugs, agents and/or compounds.
[0154] In yet another alternate exemplary embodiment, the stent-graft design may bemodified to include a graft cuff. As illustrated in Figure 26, the graft material 906 may befolded around the outer stent 904 to form cuffs 908. In this exemplary embodiment, thecuffs 908 may be loaded with various drugs, agents and/or compounds, including rapamycinand heparin. The drugs, agents and/or compounds may be affixed to the cuffs 908utilizing the methods and materials described above or through other means. For example,the drugs, agents and/or compounds may be trapped in the cuffs 908 with the graft material906 acting as the diffusion barrier through which the drug, agent and/or compound elutes.The particular material selected as well as its physical characteristics would determine theelution rate. Alternately, the graft material 906 forming the cuffs 908 may be coated withone or more polymers to control the elution rate as described above.
[0155] Stent-grafts may be utilized to treat aneurysms. An aneurysm is an abnormaldilation of a layer or layers of an arterial wall, usually caused by a systemic collagensynthetic or structural defect. An abdominal aortic aneurysm is an aneurysm in theabdominal portion of the aorta, usually located in or near one or both of the two iliacarteries or near the renal arteries. The aneurysm often arises in the infrarenal portion of the diseased aorta, for example, below the kidneys. A thoracic aortic aneurysm is an aneurysmin the thoracic portion of the aorta. When left untreated, the aneurysm may rupture, usuallycausing rapid fatal haemorrhaging.
[0156] Aneurysms may be classified or typed by their position as well as by the numberof aneurysms in a cluster. Typically, abdominal aortic aneurysms may be classified intofive types. A Type I aneurysm is a single dilation located between the renal arteries and theiliac arteries. Typically, in a Type 1 aneurysm, the aorta is healthy between the renalarteries and the aneurysm and between the aneurysm and the iliac arteries.
[0157] A Type II A aneurysm is a single dilation located between the renal arteries andthe iliac arteries. In a Type II A aneurysm, the aorta is healthy between the renal arteriesand the aneurysm, but not healthy between the aneurysm and the iliac arteries. In otherwords, the dilation extends to the aortic bifurcation. A Type II B aneurysm comprises threedilations. One dilation is located between the renal arteries and the iliac arteries. Like aType II A aneurysm, the aorta is healthy between the aneurysm and the renal arteries, butnot healthy between the aneurysm and the iliac arteries. The other two dilations are locatedin the iliac arteries between the aortic bifurcation and the bifurcations between the externaliliacs and the internal iliacs. The iliac arteries are healthy between the iliac bifurcation andthe aneurysms. A Type II C aneurysm also comprises three dilations. However, in a TypeII C aneurysm, the dilations in the iliac arteries extend to the iliac bifurcation.
[0158] A Type III aneurysm is a single dilation located between the renal arteries and theiliac arteries. In a Type III aneurysm, the aorta is not healthy between the renal arteries andthe aneurysm. In other words, the dilation extends to the renal arteries.
[0159] A ruptured abdominal aortic aneurysm is presently the thirteenth leading cause ofdeath in the United States. The routine management of abdominal aortic aneurysms hasbeen surgical bypass, with the placement of a graft in the involved or dilated segment.Although resection with a synthetic graft via transperitoneal or retroperitoneal approachhas been the standard treatment, it is associated with significant risk. For example,complications include perioperative myocardial ischemia, renal failure, erectile impotence, intestinal ischemia, infection, lower limb ischemia, spinal cord injury with paralysis, aorta-entericfistula, and death. Surgical treatment of abdominal aortic aneurysms is associatedwith an overall mortality rate of five percent in asymptomatic patients, sixteen to nineteenpercent in symptomatic patients, and is as high as fifty percent in patients with rupturedabdominal aortic aneurysms.
[0160] Disadvantages associated with conventional surgery, in addition to the highmortality rate, include an extended recovery period associated with the large surgicalincision and the opening of the abdominal cavity, difficulties in suturing the graft to theaorta, the loss of the existing thrombosis to support and reinforce the graft, the unsuitabilityof the surgery for many patients having abdominal aortic aneurysms, and the problemsassociated with performing the surgery on an emergency basis after the aneurysm hasruptured. Further, the typical recovery period is from one to two weeks in the hospital, anda convalescence period at home from two to three months or more, if complications ensue.Since many patients having abdominal aortic aneurysms have other chronic illnesses, suchas heart, lung, liver and/or kidney disease, coupled with the fact that many of these patientsare older, they are less than ideal candidates for surgery.
[0161] The occurrence of aneurysms is not confined to the abdominal region. Whileabdominal aortic aneurysms are generally the most common, aneurysms in other regions ofthe aorta or one of its branches are possible. For example, aneurysms may occur in thethoracic aorta. As is the case with abdominal aortic aneurysms, the widely acceptedapproach to treating an aneurysm in the thoracic aorta is surgical repair, involvingreplacing the aneurysmal segment with a prosthetic device. This surgery, as describedabove, is a major undertaking, with associated high risks and with significant mortality andmorbidity.
[0162] Over the past five years, there has been a great deal of research directed atdeveloping less invasive, percutaneous, e.g., catheter directed, techniques for the treatmentof aneurysms, specifically abdominal aortic aneurysms. This has been facilitated by thedevelopment of vascular stents, which can and have been used in conjunction with standardor thin-wall graft material in order to create a stent-graft or endograft. The potential advantages of less invasive treatments have included reduced surgical morbidity andmortality along with shorter hospital and intensive care unit stays.
[0163] Stent-grafts or endoprostheses are now FDA approved and commerciallyavailable. The delivery procedure typically involves advanced angiographic techniquesperformed through vascular accesses gained via surgical cutdown of a remote artery, suchas the common femoral or brachial arteries. Over a guidewire, the appropriate sizeintroducer will be placed. The catheter and guidewire are passed through the aneurysm,and, with the appropriate size introducer housing a stent-graft, the stent-graft will beadvanced along the guidewire to the appropriate position. Typical deployment of the stent-graftdevice requires withdrawal of an outer sheath while maintaining the position of thestent-graft with an inner-stabilizing device. Most stent-grafts are self-expanding; however,an additional angioplasty procedure, e.g., balloon angioplasty, may be required to securethe position of the stent-graft. Following the placement of the stent-graft, standardangiographic views may be obtained.
[0164] Due to the large diameter of the above-described devices, typically greater thantwenty French (3F = 1mm), arteriotomy closure requires surgical repair. Some proceduresmay require additional surgical techniques, such as hypogastric artery embolization, vesselligation, or surgical bypass, in order to adequately treat the aneurysm or to maintain flow toboth lower extremities. Likewise, some procedures will require additional, advancedcatheter directed techniques, such as angioplasty, stent placement, and embolization, inorder to successfully exclude the aneurysm and efficiently manage leaks.
[0165] While the above-described endoprostheses represent a significant improvementover conventional surgical techniques, there is a need to improve the endoprostheses, theirmethod of use and their applicability to varied biological conditions. Accordingly, in orderto provide a safe and effective alternate means for treating aneurysms, including abdominalaortic aneurysms and thoracic aortic aneurysms, a number of difficulties associated withcurrently known endoprostheses and their delivery systems must be overcome. Oneconcern with the use of endoprostheses is the prevention of endo-leaks and the disruptionof the normal fluid dynamics of the vasculature. Devices using any technology should preferably be simple to position and reposition as necessary, should preferably provide anacute fluid tight seal, and should preferably be anchored to prevent migration withoutinterfering with normal blood flow in both the aneurysmal vessel as well as branchingvessels. In addition, devices using the technology should preferably be able to beanchored, sealed, and maintained in bifurcated vessels, tortuous vessels, highly angulatedvessels, partially diseased vessels, calcified vessels, odd shaped vessels, short vessels, andlong vessels. In order to accomplish this, the endoprostheses should preferably beextendable and re-configurable while maintaining acute and long term fluid tight seals andanchoring positions.
[0166] The endoprostheses should also preferably be able to be delivered percutaneouslyutilizing catheters, guidewires and other devices which substantially eliminate the need foropen surgical intervention. Accordingly, the diameter of the endoprostheses in the catheteris an important factor. This is especially true for aneurysms in the larger vessels, such asthe thoracic aorta.
[0167] As stated above, one or more stent-grafts may be utilized to treat aneurysms.These stent-grafts or endoprostheses may comprise any number of materials andconfigurations. Figure 27 illustrates an exemplary system for treating abdominal aorticaneurysms. The system 1000 includes a first prosthesis 1002 and two second prostheses1004 and 1006, which in combination, bypass an aneurysm 1008. In the illustratedexemplary embodiment, a proximal portion of the system 1000 may be positioned in asection 1010 of an artery upstream of the aneurysm 1008, and a distal portion of the system1000 may be positioned in a downstream section of the artery or a different artery such asiliacs 1012 and 1014.
[0168] A prosthesis used in a system in accordance with the present invention typicallyincludes a support, stent or lattice of interconnected struts defining an interior space orlumen having an open proximal end and an open distal end. The lattice also defines aninterior surface and an exterior surface. The interior and/or exterior surfaces of the lattice,or a portion of the lattice, may be covered by or support at least one gasket material or graftmaterial.
[0169] In preferred embodiments of the invention, a prosthesis is moveable between anexpanded or inflated position and an unexpanded or deflated position, and any positionbetween them. In some exemplary embodiments of the invention, it may be desirable toprovide a prosthesis that moves only from fully collapsed to fully expanded. In otherexemplary embodiments of the invention, it may be desirable to expand the prosthesis, thencollapse or partially collapse the prosthesis. Such capability is beneficial to the surgeon toproperly position or re-position the prosthesis. In accordance with the present invention,the prosthesis may be self-expanding, or may be expandable using an inflatable device,such as a balloon or the like.
[0170] Referring back to Figure 27, the system 1000 is deployed in the infrarenal neck1010 of the abdominal aorta, upstream of where the artery splits into first and secondcommon iliac arteries 1012, 1014. Figure 27 shows the first prosthesis or stent gasket 1002positioned in the infrarenal neck 1010; two second prostheses, 1004, 1006, the proximalends of which matingly engage a proximal portion of stent gasket 1002, and the distal endsof which extend into a common iliac artery 1012 or 1014. As illustrated, the body of eachsecond prosthesis forms a conduit or fluid flow path that passes through the location of theaneurysm 1008. In preferred embodiments of the invention, the components of the system1000 define a fluid flow path that bypasses the section of the artery where the aneurysm islocated.
[0171] The first prosthesis includes a support matrix or stent that supports a sealingmaterial or foam, at least a portion of which is positioned across a biological fluid flowpath, e.g., across a blood flow path. In preferred embodiments of the invention, the firstprosthesis, the stent, and the sealing material are radially expandable, and define a hollowspace between a proximal portion of the prosthesis and a distal portion of the prosthesis.The first prosthesis may also include one or more structures for positioning and anchoringthe prosthesis in the artery, and one or more structures for engaging and fixing at least onesecond prosthesis in place, e.g., a bypass prosthesis.
[0172] The support matrix or stent of the first prosthesis may be formed of a wide varietyof materials, may be configured in a wide variety of shapes, and their shapes and uses are well known in the art. Exemplary prior art stents are disclosed in US-4733665,US-4739762 and US-4776337.
[0173] In preferred embodiments of the invention, the stent of the first prosthesis is acollapsible, flexible, and self-expanding lattice or matrix formed from a metal or metalalloy, such as nitinol or stainless steel. Structures formed from stainless steel may be madeself-expanding by configuring the stainless steel in a predetermined manner, for example,by twisting it into a braided configuration. More preferably, the stent is a tubular framethat supports a sealing material. The term tubular, as used herein, refers to any shapehaving a sidewall or sidewalls defining a hollow space or lumen extending between them;the cross-sectional shape may be generally cylindrical, elliptic, oval, rectangular, triangular,or any other shape. Furthermore, the shape may change or be deformable as a consequenceof various forces that may press against the stent or prosthesis.
[0174] The sealing material or gasket member supported by the stent may be formed of awide variety of materials, may be configured in a wide variety of shapes, and their shapesand uses are well known in the art. Exemplary materials for use with this aspect of theinvention are disclosed in US-4739762 and US-4776337.
[0175] The sealing material or gasket member may comprise any suitable material.Exemplary materials preferably comprise a biodurable and biocompatible material,including but are not limited to, open cell foam materials and closed cell foam materials.Exemplary materials include polyurethane, polyethylene, polytetrafluoroethylene; and othervarious polymer materials, preferably woven or knitted, that provide a flexible structure,such as a polyester such as that sold under the trade mark Dacron. Highly compressiblefoams are particularly preferred, preferably to keep the crimped profile low for betterdelivery. The sealing material or foam is preferably substantially impervious to bloodwhen in a compressed state.
[0176] The sealing material may cover one or more surfaces of the stent i.e., may belocated along an interior or exterior wall, or both, and preferably extends across theproximal end or a proximal portion of the stent. The sealing material helps impede any blood trying to flow around the first prosthesis, e.g., between the first prosthesis and thearterial wall, and around one or more bypass prostheses after they have been deployedwithin the lumen of the first prosthesis (described in more detail below).
[0177] In preferred embodiments of the invention, the sealing material stretches or coversa portion of the proximal end of the stent and along at least a portion of the outside wall ofthe stent.
[0178] In some embodiments of the invention, it may be desirable for the portion of thesealing material covering the proximal portion of the stent to include one or more holes,apertures, points, slits, sleeves, flaps, weakened spots, guides, or the like for positioning aguidewire, for positioning a system component, such as a second prosthesis, and/or forengaging, preferably matingly engaging, one or more system components, such as a secondprosthesis. For example, a sealing material configured as a cover or the like, and having ahole, may partially occlude the stent lumen.
[0179] These openings may be variously configured, primarily to conform to its use.These structures promote proper side by side placement of one or more, preferablymultiple, prostheses within the first prosthesis, and, in some embodiments of the invention,the sealing material may be configured or adapted to assist in maintaining a certain shapeof the fully deployed system or component. Further, these openings may exist prior todeployment of the prosthesis, or may be formed in the prosthesis as part of a deploymentprocedure. The various functions of the openings will be evident from the descriptionbelow. In exemplary embodiments of the invention, the sealing material is a foam coverthat has a single hole.
[0180] The sealing material may be attached to the stent by any of a variety of connectors,including a plurality of conventional sutures of polyvinylidene fluoride, polypropylene,Dacron®, or any other suitable material and attached thereto. Other methods of attachingthe sealing material to the stent include adhesives, ultrasonic welding, mechanicalinterference fit and staples.
[0181] One or more markers may be optionally disposed in or on the stent between theproximal end and the distal end. Preferably, two or more markers are sized and/orpositioned to identify a location on the prosthesis, or to identify the position of theprosthesis, or a portion thereof, in relation to an anatomical feature or another systemcomponent.
[0182] First prosthesis is typically deployed in an arterial passageway upstream of ananeurysm, and functions to open and/or expand the artery, to properly position and anchorthe various components of the system, and, in combination with other components, seal thesystem or portions thereof from fluid leaks. For example, the sealing prosthesis may bedeployed within the infrarenal neck, between an abdominal aortic aneurysm and the renalarteries of a patient, to assist in repairing an abdominal aortic aneurysm.
[0183] Figures 27 to 29 show an exemplary sealing prosthesis of the present invention.Sealing prosthesis 1002 includes a cylindrical or oval self-expanding lattice, support, orstent 1016, typically made from a plurality of interconnected struts 1018. Stent 1016defines an interior space or lumen 1020 having two open ends, a proximal end 1022 and adistal end 1024. One or more markers 1026 may be optionally disposed in or on the stentbetween the proximal end 1022 and the distal end 1024.
[0184] Stent 1016 may further include at least two but preferably eight (as shown inFigure 28) spaced apart longitudinal legs 1028. Preferably, there is a leg extending fromeach apex 1030 of diamonds formed by struts 1018. At least one leg, but preferably eachleg, includes a flange 1032 adjacent its distal end which allows for the stent 1016 to beretrievable into its delivery apparatus after partial or nearly full deployment thereof so thatit can be turned, or otherwise repositioned for proper alignment.
[0185] Figure 29 shows the sealing material 1034 covering the proximal end 1022 ofstent gasket 1002. In the exemplary embodiment shown in Figure 29, sealing prosthesis1002 includes a sealing material 1034 having a first opening or hole 1036 and a secondopening or slit 1038. The gasket material covers at least a portion of the interior or exteriorof the stent, and most preferably covers substantially all of the exterior of the stent. For example, gasket material 1034 may be configured to cover stent 1016 from the proximalend 1022 to the distal end 1024, but preferably not covering longitudinal legs 1028.
[0186] The sealing material 1034 helps impede any blood trying to flow around bypassprostheses 1004 and 1006 after they have been deployed (as shown in Figure 27) and fromflowing around the stent gasket 1002 itself. For this embodiment, sealing material 1034 isa compressible member or gasket located along the exterior of the stent 1016 and at least aportion of the interior of the stent 1016.
[0187] The second prostheses 1004 and 1006 may comprise stent-grafts such as describedwith respect to Figure 24 and may be coated with any of the drugs, agents and/orcompounds as described above. In other words, the stent and/or the graft material may becoated with any of the above-described drugs, agents and/or compounds utilizing any of theabove-described polymers and processes. The stent gasket 1002 may also be coated withany of the above-described drugs, agents and/or compounds. In other words, the stentand/or sealing material may be coated with any of the above-described drugs, agents and/orcompounds utilizing any of the above-described polymers and processes. In particular,rapamycin and heparin may be of importance to prevent smooth muscle cellhyperproliferation and thrombosis. Other drugs, agents and/or compounds may be utilizedas well. For example drugs, agents and/or compounds which promote re-endotheliazationmay be utilized to facilitate incorporation of the prosthesis into the living organism. Also,embolic material may be incorporated into the stent-graft to reduce the likelihood of endoleaks.
[0188] It is important to note that the above-described system for repairing abdominalaortic aneurysms is one example of such a system. Any number of aneurysmal repairsystems comprising stent-grafts may be coated with the appropriate drugs, agents and/orcompounds, as well as combinations thereof. For example, thoracic aorta aneurysms maybe repaired in a similar manner. Regardless of the type of aneurysm or its position withinthe living organism, the components comprising the repair system may be coated with theappropriate drug, agent and/or compound as described above with respect to stent-grafts.
[0189] A difficulty associated with the treatment of aneurysms, specifically abdominalaortic aneurysms, is endoleaks. An endoleak is generally defined as the persistence ofblood flow outside of the lumen of the stent-graft, but within the aneurysmal sac oradjacent vascular segment being treated with the stent-graft. Essentially, endoleaks arecaused by one of two primary mechanisms, wherein each mechanism has a number ofpossible modalities. The first mechanism involves the incomplete sealing or exclusion ofthe aneurysmal sac or vessel segment. The second mechanism involves retrograde flow.In this type of endoleak, blood-flow into the aneurysmal sac is reversed due to retrogradeflow from patent collateral vessels, particularly the lumbar arteries or the inferiormesenteric artery. This type of endoleak may occur even when a complete seal has beenachieved around the stent-grafts. It is also possible that an endoleak may develop due tostent-graft failure, for example, a tear in the graft fabric.
[0190] Endoleaks may be classified by type. A type I endoleak is a peri graft leak at theproximal or distal attachment sites of the stent-grafts. Essentially, this type of endoleakoccurs when a persistent perigraft channel of blood flow develops due to an ineffective orinadequate seal at the ends of the stent-graft. There are a number of possible causes of atype I endoleak, including improper sizing of the stent-graft, migration of the stent-graft,incomplete stent-graft expansion and an irregular shape of the arterial lumen. A type IIendoleak is persistent collateral blood flow into the aneurysmal sac from a patent branch ofthe aorta. Essentially, the pressure in the aneurysmal sac is lower than the collateralbranches, thereby causing a retrograde blood flow. Sources of type II endoleaks includethe accessory renal arteries, the testicular arteries, the lumbar arteries, the middle sacralartery, the inferior mesenteric artery and the spinal artery. A type III endoleak may becaused by a structural failure of the abdominal aortic aneurysm repair system or itscomponents, for example, the stent-grafts. A type III endoleak may also be caused by ajunction failure in systems employing modular components. Sources of type III endoleaksinclude tears, rips or holes in the fabric of the stent-graft, improper sizing of the modularcomponents and limited overlap of the modular components. A type IV endoleak is bloodflow through the graft material itself. The blood flow through the pores of the graftmaterial or through small holes in the fabric caused by the staples or sutures attaching thegraft material to the stent. Blood flow through the pores typically occurs with highly porous graft fabrics. A type V endoleak or endotension is a persistent or recurrentpressurization of the aneurysmal sac without any radiologically detectable endoleak.Possible causes of a type V endoleak include pressure transmission by thrombus, highlyporous graft material, or the adjacent aortic lumen.
[0191] There are a number of possible treatment options for each type of endoleakdescribed above. The particular treatment option depends mainly upon the cause ofendoleak and the options are not always successful. The present invention is directed to amodification of existing endovascular abdominal aortic aneurysm repair systems ordevices, such as the exemplary devices described herein, that is intended to eliminate orsubstantially reduce the incidence of endoleaks.
[0192] The modification comprises coating at least a portion of the various componentscomprising an abdominal aortic aneurysm repair system with drugs, agents and/orcompounds which promote wound healing as described below. For example, portions ofthe exemplary system 1000, illustrated in Figure 27, may be coated with one or more drugs,agents and/or compounds that induce or promote the wound healing process, therebyreducing or substantially reducing the risk of endoleaks. It may be particularlyadvantageous to coat the ends of the two second prostheses 1004 and 1006 and the entirefirst prosthesis 1002, as these are the most likely regions for endoleaks. However, coatingthe entire stem-graft, i.e. graft material and stent, may prove beneficial depending upon thetype of endoleak. Since it is not always possible to stop endoleaks utilizing currentlyavailable methods, the use of wound healing agents, delivered locally, in accordance withthe present invention may serve to effectively stop or prevent acute and chronic endoleaks.It is important to note that the present invention may be utilized in combination with anyabdominal aortic aneurysm repair system, or with any other type of graft component whereleakage is a potential problem. The present invention may be utilized in conjunction withtype I, III, IV and V endoleaks.
[0193] Normal wound healing essentially occurs in three stages or phases, which have acertain degree of overlap. The first phase is cellular migration and inflammation. Thisphase lasts for several days. The second phase is the proliferation of fibroblasts for two to four weeks with new collagen synthesis. The third phase is remodelling of the scar andtypically lasts from one month to a year. This third phase includes collagen cross linkingand active collagen turnover.
[0194] As stated above, there are certain drugs, agents and/or compounds that may bedelivered locally to the repair site, via the repair system, that promotes wound healingwhich in turn may eliminate or substantially reduce the incidence of endoleaks. Forexample, increased collagen production early in wound healing leads to greater woundstrength. Accordingly, collagen may be combined with the repair system to increasewound strength and promote platelet aggregation and fibrin formation. In addition, certaingrowth factors may be combined with the repair system to promote platelet aggregation andfibrin formation as well as to increase wound strength.
[0195] Platelet-derived Growth Factor induces mitoses and is the major mitogen in serumfor growth in connective tissue. Platelet Factor 4 is a platelet released protein thatpromotes blood clotting by neutralizing heparin. Platelet-derived Growth Factor andPlatelet Factor 4 are important in inflammation and repair. They are active for humanmonocytes, neutrophils, smooth muscle cells, fibroblasts and inflammation cells.Transforming Growth Factor-β is a part of a complex family of polypeptide hormones orbiological factors that are produced by the body to control growth, division and maturationof blood cells by the bone marrow. Transforming Growth Factor-β is found in tissues andplatelets, and is known to stimulate total protein, collagen and DNA content in woundchambers implanted in vivo. Transforming Growth Factor-β in combination with collagenhas been shown to be extremely effective in wound healing.
[0196] A series of reactions take place in the body whenever a blood clot begins to form.A major initiator of these reactions is an enzyme system called the Tissue Factor/VIIacomplex. Accordingly, Tissue Factor/VIIa may be utilized to promote blood clot formationand thus enhance wound healing. Other agents which are known to initiate thrombusformation include thrombin, fibrin, plasminogin-activator initiator, adenosine diphosphateand collagen.
[0197] The use of these drugs, agents and/or compounds in conjunction with the variouscomponents of the repair system may be used to eliminate or substantially reduce theincidence of endoleaks through the formation of blood clots and wound healing.
[0198] The stent and/or graft material comprising the components of the system 1000may be coated with any of the above-described drugs, agents and/or compounds. Theabove-described drugs, agents and/or compounds may be affixed to a portion of the componentsor to all of the components utilizing any of the materials and processes describedabove. For example, the drugs, agents and/or compounds may be incorporated into apolymeric matrix or affixed directly to various portions of the components of the system.
[0199] The particular polymer(s) utilized depends on the particular material upon which itis affixed. In addition, the particular drug, agent and/or compound may also affect theselection of polymer(s).
[0200] As described above, other implantable medical devices that may be coated withvarious drugs, agents and/or compounds include surgical staples and sutures. Thesemedical devices may be coated with any of the above-described drugs, agents and/orcompounds to treat various conditions and/or to minimize or substantially eliminate theorganisms' reaction to the implantation of the device.
[0201] Figure 30 illustrates an uncoated or bare surgical staple 3000. The staple 3000may be formed from any suitable biocompatible material having the requisite strengthrequirements for a given application. Generally, surgical staples comprise stainless steel.Figure 31 illustrates an exemplary embodiment of a surgical staple 3000 comprising amultiplicity of through-holes 3002, which preferably contain one or more drugs, agentsand/or compounds as described above. The one or more drugs, agents and/or compoundsmay be injected into the through-holes 3002 with or without a polymeric mixture. Forexample, in one exemplary embodiment, the through-holes 3002 may be sized such that theone or more drugs, agents and/or compounds may be injected directly therein and elute at aspecific rate based upon the size of the through-holes 3002. In another exemplary embodiment,the one or more drugs, agents and/or compounds may be mixed with the appropriate polymer, which controls the elution rate, and injected into or loaded into the through-holes3002. In yet another alternate exemplary embodiment, the one or more drugs, agentsand/or compounds may be injected into or loaded into the though-holes 3002 and thencovered with a polymer to control the elution rate.
[0202] Figure 32 illustrates an exemplary embodiment of a surgical staple 3000comprising a coating 3006 covering substantially the entire surface thereof. In this embodiment,the one or more drugs, agents and/or compounds may be directly affixed to thestaple 3000 utilizing any number of known techniques including spraying or dipping, or theone or more drugs, agents and/or compounds may be mixed with or incorporated into apolymeric matrix and then affixed to the staple 3000. Alternately, the one or more drugs,agents and/or compounds may be directly affixed to the surface of the staple 3000 and thena diffusion barrier may be applied over the layer of one or more drugs, agents and/orcompounds.
[0203] Although any number of drugs, agents and/or compounds may be used inconjunction with the surgical staple 3000 to treat a variety of conditions and/or to minimizeor substantially eliminate the organism's reaction to the implantation of the staple 3000, ina preferred embodiment, the surgical staple 3000 is coated with an anti-proliferative. Theadvantage of such a device is that the anti-proliferative coating would function as aprophylactic defence against neo-intimal hyperplasia. As described above, neo-intimalhyperplasia often happens at the site of what the body perceives to be injuries, for example,anastomatic sites, either tissue to tissue or tissue to implant, which are often sites ofhyperplastic events. By utilizing a staple that comprises an anti-proliferative agent, theincidence of neo-intimal hyperplasia may be substantially reduced or eliminated.
[0204] Rapamycin is a known anti-proliferative that may be utilized on or in the surgicalstaple 3000 and may be incorporated into any of the above-described polymeric materials.An additional benefit of utilizing rapamycin is its action as an anti-inflammatory. The dualaction not only functions to reduce neo-intimal hyperplasia but inflammation as well.
[0205] In yet another alternate exemplary embodiment, the surgical staple 3000 may befabricated from a material, such as a polymeric material, which incorporates the one ormore drugs, agents, and/or compounds. Regardless of the particular embodiment, theelution rate of the one or more drugs, agents and/or compounds may be controlled asdescribed above.
[0206] Referring now to Figure 33, there is illustrated a section of suture material 4000.The suture 4000 may comprise any suitable material commonly utilized in the fabricationof both absorbable or non-absorbable sutures. As illustrated, the suture 4000 comprises acoating 4002 of one or more drugs, agents and/or compounds. As in the coating on thesurgical staple 3000, the one or more drugs, agents and/or compounds may be applieddirectly to the suture 4000 or it may be mixed or incorporated into a polymeric matrix andthen affixed to the suture 4000. Also as described above, the one or more drugs, agentsand/or compounds may be affixed to the suture 4000 and then a diffusion barrier or topcoating may be affixed to the one or more drugs, agents and/or compounds to control theelution or release rate.
[0207] Figure 34 illustrates a section of suture material 4000 impregnated with one ormore drugs, agents and/or compounds 4004. The one or more drugs, agents, and/orcompounds may be directly impregnated into the suture material 4000, incorporated into apolymeric matrix and then impregnated into the suture material 4000. Alternately, the oneor more drugs, agents and/or compounds may be impregnated into the suture material 4000and then covered with a polymeric material.
[0208] In yet another alternate exemplary embodiment, the suture 4000 may be formedfrom a material, for example, a polymeric material that incorporates the one or more drugs,agents and/or compounds. For example, the one or more drugs, agents, and/or compoundsmay be mixed within the polymer matrix and then extruded and/or formed by a dip methodto form the suture material.
[0209] The particular polymer(s) utilized depend on the particular material upon which itis affixed. In addition, the particular drug, agent, and/or compound may also affect the selection of polymers. Rapamycin may be utilized with poly(vinylidenefluoride)/hexafluoropropylene.

权利要求:
Claims (17)
[1]
A medical device for securing biological tissue to biological tissue andbiological tissue to synthetic material, the medical device comprising:
a fastening element; and
a therapeutic dosage of rapamycin releasably affixed to at least a portion of thefastening element for the prevention of neo-intimal hyperplasia in the biological tissueproximate the fastening element.
[2]
The medical device according to Claim 1, wherein the fastening elementcomprises a staple.
[3]
The medical device according to Claim 1, wherein the therapeutic dosageof rapamycin is incorporated into a polymeric matrix.
[4]
The medical device according to Claim 3, wherein the fastening elementcomprises a staple and the polymeric matrix is releasably affixed to an outer surface of thestaple.
[5]
The medical device according to Claim 2, wherein the staple comprises aplurality of holes.
[6]
The medical device according to Claim 5, wherein the therapeutic dosageof rapamycin is incorporated into the plurality of holes in the staple.
[7]
The medical device according to Claim 5, wherein the therapeutic dosageof rapamycin is incorporated into a polymeric matrix, and the polymeric matrix isincorporated into the plurality of holes in the staple.
[8]
The medical device according to Claim 3, wherein the polymeric matrixcomprises a polyfluoro copolymer comprising polymerized residue of a first moietyselected from the group consisting of vinylidenefluoride and tetrafluoroethylene, and polymerized residue of a second moiety other than the first moiety and which iscopolymerized with the first moiety, thereby producing the polyfluoro copolymer, whereinthe relative amounts of the polymerized residue of the first moiety and the polymerizedresidue of the second moiety are effective to produce the biocompatible vehicle withproperties effective for use in coating implantable medical devices when the coatedmedical device is subjected to a predetermined maximum temperature, and a solvent inwhich the polyfluoro copolymer is substantially soluble.
[9]
The medical device according to Claim 8, wherein the polyfluorocopolymer comprises from about 50 to about 92 wt-% of the polymerized residue of thefirst moiety copolymerized with from about 50 to about 8 wt-% of the polymerized residueof the second moiety.
[10]
The medical device according to Claim 8, wherein said polyfluorocopolymer comprises from about 50 to about 85 wt-% of the polymerized residue ofvinylidenefluoride copolymerized with from about 50 to about 15 wt-% of the polymerizedresidue of the second moiety.
[11]
The medical device according to Claim 8, wherein said copolymercomprises from about 55 to about 65 wt-% of the polymerized residue of thevinylidenefluoride copolymerized with from about 45 to about 35 wt-% of the polymerizedresidue of the second moiety.
[12]
The medical device according to Claim 8, wherein the second moiety isselected from the group consisting of hexafluoropropylene, tetrafluoroethylene, vinylidenefluoride,1-hydropentafluoropropyiene, perfluoro (methyl vinyl ether), chlorotrifluoroethylene,pentafluoropropene, trifluoroethylene, hexafluoroacetone and hexafluoroisobutylene.
[13]
The medical device according to Claim 8, wherein the second moiety ishexafluoropropylene.
[14]
The medical device according to Claim 1, wherein the fastening elementcomprises a suture.
[15]
The medical device according to Claim 14, wherein the therapeuticdosage of rapamycin is incorporated into a polymeric matrix.
[16]
The medical device according to Claim 15, wherein the polymeric matrixis releasably affixed to an outer surface of the suture.
[17]
The medical device according to Claim 15, wherein the polymeric matrixis impregnated into the suture.

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优先权:

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申请号 | 申请日 | 专利标题

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US371925||2003-02-20||

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US10/371,925|US20040167572A1|2003-02-20|2003-02-20|Coated medical devices|

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