Local delivery of rapamycin for treatment of proliferative sequelae associated with PTCA procedures, including delivery using a modified stent

Abstract
Methods of preparing intravascular stents with a polymeric coating containing macrocyclic lactone (such as rapamycin or its analogs), stents and stent graphs with such coatings, and methods of treating a coronary artery with such devices. The macrocyclic lactone-based polymeric coating facilitates the performance of such devices in inhibiting restenosis.
Description
FIELD OF THE INVENTION

Delivery of rapamycin locally, particularly from an intravascular stent, directly from micropores in the stent body or mixed or bound to a polymer coating applied on stent, to inhibit neointimal tissue proliferation and thereby prevent restenosis. This invention also facilitates the performance of the stent in inhibiting restenosis.


BACKGROUND OF THE INVENTION

Re-narrowing (restenosis) of an artherosclerotic coronary artery after percutaneous transluminal coronary angioplasty (PTCA) occurs in 10–50% of patients undergoing this procedure and subsequently requires either further angioplasty or coronary artery bypass graft. While the exact hormonal and cellular processes promoting restenosis are still being determined, our present understanding is that the process of PTCA, besides opening the artherosclerotically obstructed artery, also injures resident coronary arterial smooth muscle cells (SMC). In response to this injury, adhering platelets, infiltrating macrophages, leukocytes, or the smooth muscle cells (SMC) themselves release cell derived growth factors with subsequent proliferation and migration of medial SMC through the internal elastic lamina to the area of the vessel intima. Further proliferation and hyperplasia of intimal SMC and, most significantly, production of large amounts of extracellular matrix over a period of 3–6 months results in the filling in and narrowing of the vascular space sufficient to significantly obstruct coronary blood flow.


Several recent experimental approaches to preventing SMC proliferation have shown promise althrough the mechanisms for most agents employed are still unclear. Heparin is the best known and characterized agent causing inhibition of SMC proliferation both in vitro and in animal models of balloon angioplasty-mediated injury. The mechanism of SMC inhibition with heparin is still not known but may be due to any or all of the following: 1) reduced expression of the growth regulatory protooncogenes c-fos and c-myc, 2) reduced cellular production of tissue plasminogen activator; are 3) binding and dequestration of growth regulatory factors such as fibrovalent growth factor (FGF).


Other agents which have demonstrated the ability to reduce myointimal thickening in animal models of balloon vascular injury are angiopeptin (a somatostatin analog), calcium channel blockers, angiotensin converting enzyme inhibitors (captopril, cilazapril), cyclosporin A, trapidil (an antianginal, antiplatelet agent), terbinafine (antifungal), colchicine and taxol (antitubulin antiproliferatives), and c-myc and c-myb antinsense oligonucleotides.


Additionally, a goat antibody to the SMC mitogen platelet derived growth factor (PDGF) has been shown to be effective in reducing myointimal thickening in a rat model of balloon angioplasty injury, thereby implicating PDGF directly in the etiology of restenosis. Thus, while no therapy has as yet proven successful clinically in preventing restenosis after angioplasty, the in vivo experimental success of several agents known to inhibit SMC growth suggests that these agents as a class have the capacity to prevent clinical restenosis and deserve careful evaluation in humans.


Coronary heart disease is the major cause of death in men over the age of 40 and in women over the age of fifty in the western world. Most coronary artery-related deaths are due to atherosclerosis. Atherosclerotic lesions which limit or obstruct coronary blood flow are the major cause of ischemic heart disease related mortality and result in 500,000–600,000 deaths in the United States annually. To arrest the disease process and prevent the more advanced disease states in which the cardiac muscle itself is compromised, direct intervention has been employed via percutaneous transiuminal coronary angioplasty (PTCA) or coronary artery bypass graft (CABG) PTCA is a procedure in which a small balloon-tipped catheter is passed down a narrowed coronary artery and then expanded to re-open the artery. It is currently performed in approximately 250,000–300,000 patients each year. The major advantage of this therapy is that patients in which the procedure is successful need not undergo the more invasive surgical procedure of coronary artery bypass graft. A major difficulty with PTCA is the problem of post-angioplasty closure of the vessel, both immediately after PTCA (acute reocclusion) and in the long term (restenosis).


The mechanism of acute reocclusion appears to involve several factors and may result from vascular recoil with resultant closure of the artery and/or deposition of blood platelets along the damaged length of the newly opened blood vessel followed by formation of a fibrin/red blood cell thrombus. Recently, intravascular stents have been examined as a means of preventing acute reclosure after PTCA.


Restenosis (chronic reclosure) after angioplasty is a more gradual process than acute reocclusion: 30% of patients with subtotal lesions and 50% of patients with chronic total lesions will go on to restenosis after angioplasty. While the exact mechanism for restenosis is still under active investigation, the general aspects of the restenosis process have been identified.


In the normal arterial will, smooth muscle cells (SMC) proliferate at a low rate (<0.1%/day; ref). SMC in vessel wall exists in a contractile phenotype characterized by 80–90% of the cell cytoplasmic volume occupied with the contractile apparatus. Endoplasmic reticulum, golgi bodies, and free ribosomes are few and located in the perinuclear region. Extracellular matrix surrounds SMC and is rich in heparin-like glycosylaminoglycans which are believed to be responsible for maintaining SMC in the contractile phenotypic state.


Upon pressure expansion of an intracoronary balloon catheter during angioplasty, smooth muscle cells within the arterial wall become injured. Cell derived growth factors such as platelet derived growth factor (PDGF), basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), etc. released from platelets (i.e., PDGF) adhering to the damaged arterial luminal surface, invading macrophages and/or leukocytes, or directly from SMC (i.e., BFGF) provoke a proliferation and migratory response in medial SMC. These cells undergo a phenotypic change from the contractile phenotyope to a synthetic phenotype characterized by only few contractile filament bundles but extensive rough endoplasmic reticulum, golgi and free ribosomes. Proliferation/migration usually begins within 1–2 days post-injury and peaks at 2 days in the media, rapidly declining thereafter (Campbell et al., In: Vascular Smooth Muscle Cells in Culture, Campbell, J. H. and Campbell, G. R., Eds, CRC Press, Boca. Ratioh, 1987, pp. 39–55); Clowes, A. W. and Schwartz, S. M., Circ. Res. 56:139–145, 1985).


Finally, daughter synthetic cells migrate to the intimal layer of arterial smooth muscle and continue to proliferate. Proliferation and migration continues until the damaged luminal endothelial layer regenerates at which time proliferation ceases within the intima, usually within 7–14 days postinjury. The remaining increase in intimal thickening which occurs over the next 3–6 months is due to an increase in extracellular matrix rather than cell number. Thus, SMC migration and proliferation is an acute response to vessel injury while intimal hyperplasia is a more chronic response. (Liu et al., Circulation, 79:1374–1387, 1989).


Patients with symptomatic reocclusion require either repeat PTCA or CABG. Because 30–50% of patients undergoing PTCA will experience restenosis, restenosis has clearly limited the success of PTCA as a therapeutic approach to coronary artery disease. Because SMC proliferation and migration are intimately involved with the pathophysiological response to arterial injury, prevention of SMC proliferation and migration represents a target for pharmacological intervention in the prevention of restenosis.


SUMMARY OF THE INVENTION

Novel Features and Applications to Stent Technology Currently, attempts to improve the clinical performance of stents have involved some variation of either applying a coating to the metal, attaching a covering or membrane, or embedding material on the surface via ion bombardment. A stent designed to include reservoirs is a new approach which offers several important advantages over existing technologies.


Local Drug Delivery from a Stent to Inhibit Restenosis


In this application, it is desired to deliver a therapeutic agent to the site of arterial injury. The conventional approach has been to incorporate the therapeutic agent into a polymer material which is then coated on the stent. The ideal coating material must be able to adhere strongly to the metal stent both before and after expansion, be capable of retaining the drug at a sufficient load level to obtain the required dose, be able to release the drug in a controlled way over a period of several weeks, and be as thin as possible so as to minimize the increase in profile. In addition, the coating material should not contribute to any adverse response by the body (i.e., should be non-thrombogenic, non-inflammatory, etc.). To date, the ideal coating material has not been developed for this application.


An alternative would be to design the stent to contain reservoirs which could be loaded with the drug. A coating or membrane of biocompatable material could be applied over the reservoirs which would control the diffusion of the drug from the reservoirs to the artery wall.


One advantage of this system is that the properties of the coating can be optimized for achieving superior biocompatibility and adhesion properties, without the addition requirement of being able to load and release the drug. The size, shape, position, and number of reservoirs can be used to control the amount of drug, and therefore the dose delivered.





BRIEF DESCRIPTION OF THE DRAWINGS

The invention will be better understood in connection with the following figures in which



FIGS. 1 and 1A are top views and section views of a stent containing reservoirs as described in the present invention;



FIGS. 2
a and 2b are similar views of an alternate embodiment of the stent with open ends;



FIGS. 3
a and 3b are further alternate figures of a device containing a grooved reservoir; and



FIG. 4 is a layout view of a device containing a reservoir as in FIG. 3.





DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

Pharmacological attempts to prevent restenosis by pharmacologic means have thus far been unsuccessful and all involve systemic administration of the trial agents. Neither aspirin-dipyridamole, ticlopidine, acute heparin administration, chronic warfarin (6 months) nor methylprednisolone have been effective in preventing restenosis although platelet inhibitors have been effective in preventing acute reocclusion after angioplasty. The calcium antagonists have also been unsuccessful in preventing restenosis, although they are still under study. Other agents currently under study include thromboxane inhibitors, prostacyclin mimetics, platelet membrane receptor blockers, thrombin inhibitors and angiotensin converting enzyme inhibitors. These agents must be given systemically, however, and attainment of a therapeutically effective dose may not be possible; antiproliferative (or anti-restenosis) concentrations may exceed the known toxic concentrations of these agents so that levels sufficient to produce smooth muscle inhibition may not be reached (Lang et al., 42 Ann. Rev. Med., 127–132 (1991); Popma et al., 84 Circulation, 1426–1436 (1991)).


Additional clinical trials in which the effectiveness for preventing restenosis of dietary fish oil supplements, thromboxane receptor antagonists, cholesterol lowering agents, and serotonin antagonists has been examined have shown either conflicting or negative results so that no pharmacological agents are as yet clinically available to prevent post-angioplasty restenosis (Franklin, S. M. and Faxon, D. P., 4 Coronary Artery Disease, 2-32-242 (1993); Serruys, P. W. et al., 88 Circulation, (part 1) 1588–1601, (1993).


Conversely, stents have proven useful in preventing reducing the proliferation of restenosis. Stents, such as the stent 10 seen in layout in FIG. 4, balloon-expandable slotted metal tubes (usually but not limited to stainless steel), which when expanded within the lumen of an angioplastied coronary artery, provide structural support to the arterial wall. This support is helpful in maintaining an open path for blood flow. In two randomized clinical trials, stents were shown to increase angiographic success after PTCA, increase the stenosed blood vessel lumen and to reduce the lesion recurrence at 6 months (Serruys et al., 331 New Eng Jour. Med, 495, (1994); Fischman et al., 331 New Eng Jour. Med, 496–501 (1994). Additionally, in a preliminary trial, heparin coated stents appear to possess the same benefit of reduction in stenosis diameter at follow-up as was observed with non-heparin coated stents. Additionally, heparin coating appears to have the added benefit of producing a reduction in sub-acute thrombosis after stent implantation (Serruys et al., 93 Circulation, 412–422, (1996). Thus, 1) sustained mechanical expansion of a stenosed coronary artery has been shown to provide some measure of restenosis prevention, and 2) coating of stents with heparin has demonstrated both the feasibility and the clinical usefulness of delivering drugs to local, injured tissue off the surface of the stent.


Numerous agents are being actively studied as antiproliferative agents for use in restenosis and have shown some activity in experimental animal models. These include: heparin and heparin fragments (Clowes and Karnovsky, 265 Nature, 25–626, (1977); Guyton, J. R. et al. 46 Circ. Res., 625–634, (1980); Clowes, A. W. and Clowes, M. M., 52 Lab. Invest., 611–616, (1985); Clowes, A. W. and Clowes, M. M., 58 Circ. Res., 839–845 (1986); Majesky et al., 61 Circ Res., 296–300, (1987); Snow et al., 137 Am. J. Pathol., 313–330 (1990); Okada, T. et al., 25 Neurosurgery, 92–898, (1989) colchicine (Currier, J. W. et al., 80 Circulation, 11–66, (1989), taxol (ref), agiotensin converting enzyme (ACE) inhibitors (Powell, J. S. et al., 245 Science, 186–188 (1989), angiopeptin (Lundergan, C. F. et al., 17 Am. J. Cardiol. (Suppi. B); 132B–136B (1991), Cyclosporin A (Jonasson, L. et. al., 85 Proc. Nati, Acad. Sci., 2303 (1988), goat-anti-rabbit PDGF antibody (Ferns, G. A. A., et al., 253 Science, 1129–1132 (1991), terbinafine (Nemecek, G. M. et al., 248 J. Pharmacol. Exp. Thera., 1167–11747 (1989), trapidil (Liu, M. W. et al., 81 Circulation, 1089-1093 (1990), interferon-gamma (Hansson, G. K. and Holm, 84 J. Circulation, 1266–1272 (1991), steroids (Colburn, M. D. et al., 15 J. Vasc. Surg., 510–518 (1992), see also Berk, B. C. et al., 17 J. Am. Coll. Cardiol., 111B–117B (1991), ionizing radiation (ref), fusion toxins (ref) antisense oligonucleotides (ref), gene vectors (ref), and rapamycin (see below).


Of particular interest in rapamycin. Rapamycin is a macrolide antibiotic which blocks IL-2-mediated T-cell proliferation and possesses antiinflammatory activity. While the precise mechanism of rapamycin is still under active investigation, rapamycin has been shown to prevent the G.sub.1 to 5 phase progression of T-cells through the cell cycle by inhibiting specific cell cyclins and cyclin-dependent protein kinases (Siekierka, Immunol. Res. 13: 110–116, 1994). The antiproliferative action of rapamycin is not limited to T-cells; Marx et al. (Circ Res 76:412–417, 1995) have demonstrated that rapamycin prevents proliferation of both rat and human SMC in vitro while Poon et al. have shown the rat, porcine, and human SMC migratin can also be inhibited by rapamycin (J Clin Invest 98: 2277–2283, 1996). Thus, rapamycin is capable of inhibiting both the inflammatory response known to occur after arterial injury and stent implantation, as well as the SMC hyperproliferative response. In fact, the combined effects of rapamycin have been demonstrated to result in a diminished SMC hyperproliferative response in a rat femoral artery graft model and in both rat and porcine arterial balloon injury models (Gregory et al., Transplantation 55:1409–1418, 1993; Gallo et al., in press, (1997)). These observations clearly support the potential use of rapamycin in the clinical setting of post-angioplasty restenosis.


Although the ideal agent for restenosis has not yet been identified, some desired properties are clear: inhibition of local thrombosis without the risk systemic bleeding complications and continuous and prevention of the dequale of arterial injury, including local inflammation and sustained prevention smooth muscle proliferation at the site of angioplasty without serious systemic complications. Inasmuch as stents prevent at least a portion of the restenosis process, an agent which prevents inflammation and the proliferation of SMC combined with a stent may provide the most efficacious treatment for post-angioplasty restenosis.


Experiments


Agents: Rapamycin (sirolimus) structural analogs (macrocyclic lactones) and inhibitors of cell-cycle progression.


Delivery Methods: These can vary:






    • Local delivery of such agents (rapamycin) from the struts of a stent, from a stent graft, grafts, stent cover or sheath.

    • Involving comixture with polymers (both degradable and nondegrading) to hold the drug to the stent or graft.

    • or entrapping the drug into the metal of the stent or graft body which has been modified to contain micropores or channels, as will be explained further herein.

    • or including covalent binding of the drug to the stent via solution chemistry techniques (such as via the Carmeda process) or dry chemistry techniques (e.g. vapour deposition methods such as rf-plasma polymerization) and combinations thereof.

    • Catheter delivery intravascularly from a tandem balloon or a porous balloon for intramural uptake.

    • Extravascular delivery by the pericardial route.

    • Extravascular delivery by the advential application of sustained release formulations.


      Uses:

    • for inhibition of cell proliferation to prevent neointimal proliferation and restenosis.

    • prevention of tumor expansion from stents.

    • prevent ingrowth of tissue into catheters and shunts inducing their failure.





1. Experimental Stent Delivery Method—Delivery from Polymer Matrix:


Solution of Rapamycin, prepared in a solvent miscible with polymer carrier solution, is mixed with solution of polymer at final concentration range 0.001 weight % to 30 weight % of drug. Polymers are biocompatible (i.e., not elicit any negative tissue reaction or promote mural thrombus formation) and degradable, such as lactone-based polyesters or copolyesters, e.g., polylactide, polycaprolacton-glycolide, polyorthoesters, polyanhydrides; poly-amino acids; polysaccharides; polyphosphazenes; poly(ether-ester) copolymers, e.g., PEO-PLLA, or blends thereof. Nonabsorbable biocompatible polymers are also suitable candidates. Polymers such as polydimethylsiolxane; poly(ethylene-vingylacetate); acrylate based polymers or copolymers, e.g., poly(hydroxyethyl methylmethacrylate, polyvinyl pyrrolidinone; fluorinated polymers such as polytetrafluoroethylene; cellulose esters.


Polymer/drug mixture is applied to the surfaces of the stent by either dip-coating, or spray coating, or brush coating or dip/spin coating or combinations thereof, and the solvent allowed to evaporate to leave a film with entrapped rapamycin.


2. Experimental Stent Delivery Method—Delivery from Microporous Depots in Stent Through a Polymer Membrane Coating:


Stent, whose body has been modified to contain micropores or channels is dipped into a solution of Rapamycin, range 0.001 wt % to saturated, in organic solvent such as acetone or methylene chloride, for sufficient time to allow solution to permeate into the pores. (The dipping solution can also be compressed to improve the loading efficiency.) After solvent has been allowed to evaporate, the stent is dipped briefly in fresh solvent to remove excess surface bound drug. A solution of polymer, chosen from any identified in the first experimental method, is applied to the stent as detailed above. This outer layer of polymer will act as diffusion-controller for release of drug.


3. Experimental Stent Delivery Method—Delivery via Lysis of a Covalent Drug Tether:


Rapamycin is modified to contain a hydrolytically or enzymatically labile covalent bond for attaching to the surface of the stent which itself has been chemically derivatized to allow covalent immobilization. Covalent bonds such as ester, amides or anhydrides may be suitable for this.


4. Experimental Method—Pericardial Delivery:


A: Polymeric Sheet


Rapamycin is combined at concentration range previously highlighted, with a degradable polymer such as poly(caprolactone-gylcolid-e) or non-degradable polymer, e.g., polydimethylsiloxane, and mixture cast as a thin sheet, thickness range 10.mu. to 1000.mu. The resulting sheet can be wrapped perivascularly on the target vessel. Preference would be for the absorbable polymer.


B: Conformal Coating:


Rapamycin is combined with a polymer that has a melting temperature just above 37° C., range 40°–45° C. Mixture is applied in a molten state to the external side of the target vessel. Upon cooling to body temperature the mixture solidifies conformably to the vessel wall. Both non-degradable and absorbable biocompatible polymers are suitable.


As seen in the figures it is also possible to modify currently manufactured stents in order to adequately provide the drug dosages such as rapamycin. As seen in FIGS. 1a, 2a and 3a, any stent strut 10, 20, 30 can be modified to have a certain reservoir or channel 11, 21, 31. Each of these reservoirs can be open or closed as desired. These reservoirs can hold the drug to be delivered. FIG. 4 shows a stent 40 with a reservoir 45 created at the apex of a flexible strut. Of course, this reservoir 45 is intended to be useful to deliver rapamycin or any other drug at a specific point of flexibility of the stent. Accordingly, this concept can be useful for “second generation” type stents.


In any of the foregoing devices, however, it is useful to have the drug dosage applied with enough specificity and enough concentration to provide an effective dosage in the lesion area. In this regard, the reservoir size in the stent struts must be kept at a size of about 0.0005″ to about 0.003″. Then, it should be possible to adequately apply the drug dosage at the desired location and in the desired amount.


These and other concepts will are disclosed herein. It would be apparent to the reader that modifications are possible to the stent or the drug dosage applied. In any event, however, the any obvious modifications should be perceived to fall within the scope of the invention which is to be realized from the attached claims and their equivalents.

Claims
  • 1. A metallic stent having a coating applied thereto, wherein: said coating comprises a mixture of a biocompatible polymeric carrier and a therapeutic agent;said polymeric carrier comprises at least one nonabsorbable polymer;said therapeutic agent is rapamycin, or a macrocyclic lactone analog thereof, present in an amount effective to inhibit neointimal proliferation; andsaid stent provides a controlled release of said therapeutic agent over a period of several weeks.
  • 2. The metallic stent according to claim 1 wherein said therapeutic agent is a macrocyclic lactone analog of rapamycin.
  • 3. The metallic stent according to claim 1 wherein said biocompatible polymeric carrier comprises a fluorinated polymer.
  • 4. The metallic according to claim 3 wherein said biocompatible polymeric carrier further comprises an acrylate-based polymer or copolymer.
  • 5. A method of inhibiting neointimal proliferation in a coronary artery resulting from percutaneous transluminal coronary angioplasty comprising implanting a metallic stent according to any one of claims 1 to 4 in the lumen of said coronary artery.
CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of Ser. No. 10/951,385, filed Sep. 28, 2004, now pending, which is a continuation of Ser. No. 10/408,328, filed Apr. 7, 2003, now issued as U.S. Pat. No. 6,808,536, which is a continuation of application Ser. No. 09/874,117, filed Jun. 4, 2001, now issued as U.S. Pat. No. 6,585,764, which is a continuation of application Ser. No. 09/061,568, filed Apr. 16, 1998, now issued as U.S. Pat. No. 6,273,913, which in turn claims benefit of provisional application Ser. No. 60/044,692, filed Apr. 18, 1997. The disclosures of these prior applications are incorporated herein by reference in their entirety.

US Referenced Citations (437)
Number Name Date Kind
861659 Johnston Jul 1907 A
3051677 Rexford Aug 1962 A
3279996 Long et al. Oct 1966 A
3526005 Bokros Sep 1970 A
3599641 Sheridan Aug 1971 A
3657744 Ersek Apr 1972 A
3744596 Sander Jul 1973 A
3779805 Alsbeg Dec 1973 A
3929992 Sehgal et al. Dec 1975 A
3932627 Margraf Jan 1976 A
3948254 Zaffaroni Apr 1976 A
3952334 Bokros et al. Apr 1976 A
3968800 Vilasi Jul 1976 A
4069307 Higuchi et al. Jan 1978 A
4076285 Martinez Feb 1978 A
4292965 Nash et al. Oct 1981 A
4299226 Banka Nov 1981 A
4300244 Bokros Nov 1981 A
4312920 Pierce et al. Jan 1982 A
4321711 Mano Mar 1982 A
4323071 Simpson et al. Apr 1982 A
4390599 Broyles Jun 1983 A
4413359 Akiyama et al. Nov 1983 A
4423183 Close Dec 1983 A
4441216 Ionescu et al. Apr 1984 A
4503569 Dotter Mar 1985 A
4512338 Balko et al. Apr 1985 A
4550447 Seiler, Jr. et al. Nov 1985 A
4553545 Maass et al. Nov 1985 A
4560374 Hammerslag Dec 1985 A
4562596 Kornberg Jan 1986 A
4565740 Golander et al. Jan 1986 A
4580568 Gianturco Apr 1986 A
4613665 Larm Sep 1986 A
4642111 Sakamoto et al. Feb 1987 A
4655771 Wallsten Apr 1987 A
4656083 Hoffman et al. Apr 1987 A
4676241 Webb et al. Jun 1987 A
4678466 Rosenwald Jul 1987 A
4687482 Hanson Aug 1987 A
4689046 Bokros Aug 1987 A
4731054 Billeter et al. Mar 1988 A
4733665 Palmaz Mar 1988 A
4739762 Palmaz Apr 1988 A
4740207 Kreamer Apr 1988 A
4749585 Greco et al. Jun 1988 A
4753652 Langer et al. Jun 1988 A
4760849 Kropf Aug 1988 A
4768507 Fischell et al. Sep 1988 A
4776337 Palmaz Oct 1988 A
4786500 Wong Nov 1988 A
4787899 Lazarus Nov 1988 A
4800882 Gianturco Jan 1989 A
4810784 Larm Mar 1989 A
4856516 Hillstead Aug 1989 A
4871357 Hsu et al. Oct 1989 A
4872867 Joh Oct 1989 A
4876109 Mayer et al. Oct 1989 A
4886062 Wiktor Dec 1989 A
4907336 Gianturco Mar 1990 A
4916193 Tang et al. Apr 1990 A
4954126 Wallsten Sep 1990 A
4969458 Wiktor Nov 1990 A
4990131 Dardik et al. Feb 1991 A
4990155 Wilkoff Feb 1991 A
4994071 MacGregor Feb 1991 A
4994298 Yasuda Feb 1991 A
4998923 Samson et al. Mar 1991 A
5015253 MacGregor May 1991 A
5019090 Pinchuk May 1991 A
5019096 Fox, Jr. et al. May 1991 A
5029877 Fedeli Jul 1991 A
5034265 Hoffman et al. Jul 1991 A
5035706 Gianturco et al. Jul 1991 A
5041100 Rowland et al. Aug 1991 A
5041126 Gianturco Aug 1991 A
5047020 Hsu Sep 1991 A
5049132 Shaffer et al. Sep 1991 A
5049403 Larm et al. Sep 1991 A
5053048 Pinchuk Oct 1991 A
5059166 Fischell et al. Oct 1991 A
5061275 Wallsten et al. Oct 1991 A
5061750 Feijen et al. Oct 1991 A
5064435 Porter Nov 1991 A
5092877 Pinchuk Mar 1992 A
5102417 Palmaz Apr 1992 A
5104404 Wolff Apr 1992 A
5116365 Hillstead May 1992 A
5122154 Rhodes Jun 1992 A
5131908 Dardik et al. Jul 1992 A
5133732 Wiktor Jul 1992 A
5134192 Feijen et al. Jul 1992 A
5135536 Hillstead Aug 1992 A
5163952 Froix Nov 1992 A
5163958 Pinchuk Nov 1992 A
5171217 March et al. Dec 1992 A
5171262 MacGregor Dec 1992 A
5176660 Truckai Jan 1993 A
5176972 Bloom et al. Jan 1993 A
5178618 Kandarpa Jan 1993 A
5180366 Woods Jan 1993 A
5182317 Winters et al. Jan 1993 A
5185408 Tang et al. Feb 1993 A
5192307 Wall Mar 1993 A
5195984 Schalz Mar 1993 A
5213576 Abiuso et al. May 1993 A
5213898 Larm et al. May 1993 A
5217483 Tower Jun 1993 A
5222971 Willard et al. Jun 1993 A
5226913 Pinchuk Jul 1993 A
5234456 Silvestrini Aug 1993 A
5246445 Yachia et al. Sep 1993 A
5258020 Froix Nov 1993 A
5258021 Duran Nov 1993 A
5262451 Winters et al. Nov 1993 A
5266073 Wall Nov 1993 A
5272012 Opolski Dec 1993 A
4733665 Palmaz Jan 1994 A
5275622 Lazarus et al. Jan 1994 A
5282823 Schwartz et al. Feb 1994 A
5282824 Gianturco Feb 1994 A
5283257 Gregory et al. Feb 1994 A
5288711 Mitchell et al. Feb 1994 A
5290305 Inoue Mar 1994 A
5292331 Boneau Mar 1994 A
5292802 Rhee et al. Mar 1994 A
5304121 Sahatjian Apr 1994 A
5304200 Spaulding Apr 1994 A
5306250 March et al. Apr 1994 A
5308862 Ohlstein May 1994 A
5308889 Rhee et al. May 1994 A
5314444 Gianturco May 1994 A
5314472 Fontaine May 1994 A
5328471 Slepian Jul 1994 A
5334301 Heinke et al. Aug 1994 A
5336518 Narayanan et al. Aug 1994 A
5338770 Winters et al. Aug 1994 A
5342348 Kaplan Aug 1994 A
5342387 Summers Aug 1994 A
5342621 Eury Aug 1994 A
5354257 Roubin et al. Oct 1994 A
5354308 Simon et al. Oct 1994 A
5356433 Rowland et al. Oct 1994 A
5366504 Andersen et al. Nov 1994 A
5368566 Crocker Nov 1994 A
5370683 Fontaine Dec 1994 A
5370691 Samson Dec 1994 A
5375612 Cottenceau et al. Dec 1994 A
5376112 Duran Dec 1994 A
5378475 Smith et al. Jan 1995 A
5380299 Fearnot et al. Jan 1995 A
5382261 Palmaz Jan 1995 A
5383853 Jung et al. Jan 1995 A
5383928 Scott et al. Jan 1995 A
5387235 Chuter Feb 1995 A
5389106 Tower Feb 1995 A
5393772 Yue et al. Feb 1995 A
5395390 Simon et al. Mar 1995 A
5397355 Marin et al. Mar 1995 A
5399352 Hanson Mar 1995 A
5403341 Solar Apr 1995 A
5405377 Cragg Apr 1995 A
5409696 Narayanan et al. Apr 1995 A
5411549 Peters May 1995 A
5415619 Lee et al. May 1995 A
5417969 Hsu et al. May 1995 A
5419760 Narcisco, Jr. May 1995 A
D359802 Fontaine Jun 1995 S
5421955 Lau et al. Jun 1995 A
5423885 Williams Jun 1995 A
5429618 Keogh Jul 1995 A
5429634 Narciso, Jr. Jul 1995 A
5439446 Barry Aug 1995 A
5441515 Khosravi et al. Aug 1995 A
5441516 Wang et al. Aug 1995 A
5441947 Dodge et al. Aug 1995 A
5443458 Evry Aug 1995 A
5443477 Marin et al. Aug 1995 A
5443496 Schwartz et al. Aug 1995 A
5443498 Fontaine Aug 1995 A
5443500 Sigwart Aug 1995 A
5447724 Helmus et al. Sep 1995 A
5449372 Schmaltz et al. Sep 1995 A
5449373 Pinchasik et al. Sep 1995 A
5449382 Dayton Sep 1995 A
5464450 Buscemi et al. Nov 1995 A
5464540 Friesen et al. Nov 1995 A
5464650 Berg et al. Nov 1995 A
5474563 Myler et al. Dec 1995 A
5486357 Narayanan Jan 1996 A
5496365 Sgro Mar 1996 A
5500013 Buscemi et al. Mar 1996 A
5510077 Dinh et al. Apr 1996 A
5512055 Domb et al. Apr 1996 A
5516781 Morris et al. May 1996 A
5519042 Morris et al. May 1996 A
5523092 Hanson et al. Jun 1996 A
5527354 Fontaine et al. Jun 1996 A
5545208 Wolff et al. Aug 1996 A
5551954 Buscemi et al. Sep 1996 A
5554182 Dinh et al. Sep 1996 A
5554954 Takahashi Sep 1996 A
5556413 Lam Sep 1996 A
5562922 Lambert Oct 1996 A
5563146 Morris Oct 1996 A
5569197 Helmus Oct 1996 A
5569295 Lam Oct 1996 A
5569462 Martinson et al. Oct 1996 A
5569463 Helmus et al. Oct 1996 A
5571089 Crocker Nov 1996 A
5571166 Dinh et al. Nov 1996 A
5574059 Regunathan et al. Nov 1996 A
5575818 Pinchuk Nov 1996 A
5578075 Dayton Nov 1996 A
5580873 Bianco et al. Dec 1996 A
5580874 Bianco et al. Dec 1996 A
5591140 Narayanan et al. Jan 1997 A
5591197 Orth et al. Jan 1997 A
5591224 Schwartz et al. Jan 1997 A
5591227 Dinh et al. Jan 1997 A
5599352 Dinh et al. Feb 1997 A
5603722 Phan et al. Feb 1997 A
5604283 Wada et al. Feb 1997 A
5605696 Eury et al. Feb 1997 A
5607463 Schwartz et al. Mar 1997 A
5607475 Cahalan et al. Mar 1997 A
5609629 Fearnot et al. Mar 1997 A
5616608 Kinsella et al. Apr 1997 A
5620984 Bianco et al. Apr 1997 A
5621102 Bianco et al. Apr 1997 A
5622975 Singh et al. Apr 1997 A
5624411 Tuch Apr 1997 A
5628785 Schwartz et al. May 1997 A
5629077 Turnlund et al. May 1997 A
5629315 Bianco et al. May 1997 A
5632763 Glastra May 1997 A
5632771 Boatman et al. May 1997 A
5632776 Kurumatani et al. May 1997 A
5632840 Campbell May 1997 A
5635201 Fabo Jun 1997 A
5637113 Tartaglia et al. Jun 1997 A
5643312 Fischell et al. Jul 1997 A
5643939 Ohlstein Jul 1997 A
5646160 Morris et al. Jul 1997 A
5648357 Bianco et al. Jul 1997 A
5649952 Lam Jul 1997 A
5649977 Campbell Jul 1997 A
5651174 Schwartz et al. Jul 1997 A
5652243 Bianco et al. Jul 1997 A
5653747 Dereume Aug 1997 A
5653992 Bezwada et al. Aug 1997 A
5662609 Slepian Sep 1997 A
5665591 Sonenshein et al. Sep 1997 A
5665728 Morris et al. Sep 1997 A
5667764 Kopia et al. Sep 1997 A
5669924 Shaknovich Sep 1997 A
5670506 Leigh et al. Sep 1997 A
5672638 Verhoeven et al. Sep 1997 A
5674242 Phan et al. Oct 1997 A
5679400 Tuch Oct 1997 A
5679659 Verhoeven et al. Oct 1997 A
5684061 Ohnishi et al. Nov 1997 A
5691311 Maraganore et al. Nov 1997 A
5693085 Buirge et al. Dec 1997 A
5697967 Dinh et al. Dec 1997 A
5697971 Fischell et al. Dec 1997 A
5700286 Tartaglia et al. Dec 1997 A
5707385 Williams Jan 1998 A
5709874 Hanson et al. Jan 1998 A
5713949 Jayaraman Feb 1998 A
5716981 Hunter et al. Feb 1998 A
5725549 Lam Mar 1998 A
5725567 Wolff et al. Mar 1998 A
5728150 McDonald et al. Mar 1998 A
5728420 Keogh Mar 1998 A
5731326 Hart et al. Mar 1998 A
5733327 Igaki et al. Mar 1998 A
5733920 Mansuri et al. Mar 1998 A
5733925 Kunz et al. Mar 1998 A
5735897 Buirge Apr 1998 A
5739138 Bianco et al. Apr 1998 A
5755734 Richter et al. May 1998 A
5755772 Evans et al. May 1998 A
5759205 Valentini Jun 1998 A
5769883 Buscemi et al. Jun 1998 A
5776184 Tuch Jul 1998 A
5780476 Underiner et al. Jul 1998 A
5782908 Cahalan et al. Jul 1998 A
5788979 Alt et al. Aug 1998 A
5792106 Mische Aug 1998 A
5792772 Bianco et al. Aug 1998 A
5798372 Davies et al. Aug 1998 A
5799384 Schwartz et al. Sep 1998 A
5800507 Schwartz Sep 1998 A
5800508 Goicoechea et al. Sep 1998 A
5807861 Klein et al. Sep 1998 A
5811447 Kunz et al. Sep 1998 A
5820917 Tuch Oct 1998 A
5820918 Ronan et al. Oct 1998 A
5824048 Tuch Oct 1998 A
5824049 Ragheb et al. Oct 1998 A
5827587 Fukushi Oct 1998 A
5833651 Donovan et al. Nov 1998 A
5837008 Berg et al. Nov 1998 A
5837313 Ding et al. Nov 1998 A
5843120 Israel et al. Dec 1998 A
5843166 Lentz et al. Dec 1998 A
5843172 Yan Dec 1998 A
5849034 Schwartz Dec 1998 A
5851217 Wolff et al. Dec 1998 A
5851231 Wolff et al. Dec 1998 A
5858990 Walsh Jan 1999 A
5861027 Trapp Jan 1999 A
5865814 Tuch Feb 1999 A
5871535 Wolff et al. Feb 1999 A
5873904 Ragheb et al. Feb 1999 A
5876433 Lunn Mar 1999 A
5877224 Brocchini et al. Mar 1999 A
5879697 Ding et al. Mar 1999 A
5882335 Leone et al. Mar 1999 A
5891108 Leone et al. Apr 1999 A
5893840 Hull et al. Apr 1999 A
5897911 Loeffler Apr 1999 A
5900246 Lambert May 1999 A
5902266 Leone et al. May 1999 A
5916910 Lai Jun 1999 A
5922393 Jayaraman Jul 1999 A
5932243 Fricker et al. Aug 1999 A
5932299 Katoot Aug 1999 A
5932580 Levitzki et al. Aug 1999 A
5951586 Berg et al. Sep 1999 A
5957971 Schwartz Sep 1999 A
5968091 Pinchuk et al. Oct 1999 A
5972027 Johnson Oct 1999 A
5976534 Hart et al. Nov 1999 A
5977163 Li et al. Nov 1999 A
5980553 Gray et al. Nov 1999 A
5980566 Alt et al. Nov 1999 A
5980972 Ding Nov 1999 A
5981568 Kunz et al. Nov 1999 A
5985307 Hanson et al. Nov 1999 A
5997468 Wolff et al. Dec 1999 A
6004346 Wolff et al. Dec 1999 A
6015432 Rakos et al. Jan 2000 A
6039721 Johnson et al. Mar 2000 A
6059813 Vrba et al. May 2000 A
6071305 Brown et al. Jun 2000 A
6074659 Kunz et al. Jun 2000 A
6080190 Schwartz Jun 2000 A
6096070 Ragheb et al. Aug 2000 A
6120536 Ding et al. Sep 2000 A
6120847 Yang et al. Sep 2000 A
6136798 Cody et al. Oct 2000 A
6140127 Sprague Oct 2000 A
6146358 Rowe Nov 2000 A
6153252 Hossainy et al. Nov 2000 A
6159488 Nagier et al. Dec 2000 A
6171232 Papandreou et al. Jan 2001 B1
6171609 Kunz Jan 2001 B1
6177272 Nabel et al. Jan 2001 B1
6179817 Zhong Jan 2001 B1
6193746 Strecker Feb 2001 B1
6214901 Chudzik et al. Apr 2001 B1
6225346 Tang et al. May 2001 B1
6240616 Yan Jun 2001 B1
6245537 Williams et al. Jun 2001 B1
6251920 Grainger et al. Jun 2001 B1
6254632 Wu et al. Jul 2001 B1
6254634 Anderson et al. Jul 2001 B1
6258121 Yang et al. Jul 2001 B1
6268390 Kunz Jul 2001 B1
6273913 Wright et al. Aug 2001 B1
6284305 Ding et al. Sep 2001 B1
6287320 Slepian Sep 2001 B1
6287628 Hossainy et al. Sep 2001 B1
6299604 Ragheb et al. Oct 2001 B1
6306144 Sydney et al. Oct 2001 B1
6306166 Barry et al. Oct 2001 B1
6306176 Whitbourne Oct 2001 B1
6306421 Kunz et al. Oct 2001 B1
6309380 Larson et al. Oct 2001 B1
6309660 Hsu et al. Oct 2001 B1
6313264 Caggiano et al. Nov 2001 B1
6316018 Ding et al. Nov 2001 B1
6335029 Kamath et al. Jan 2002 B1
6358556 Ding et al. Mar 2002 B1
6369039 Palasis et al. Apr 2002 B1
6379382 Yang Apr 2002 B1
6387121 Alt May 2002 B1
6403635 Kinsella et al. Jun 2002 B1
6407067 Schafer Jun 2002 B1
6517858 Le Moel et al. Feb 2003 B1
6517889 Jayaraman Feb 2003 B1
6545097 Pinchuk et al. Apr 2003 B2
6585764 Wright et al. Jul 2003 B2
6620194 Ding et al. Sep 2003 B2
6746773 Llanos et al. Jun 2004 B2
6776796 Falotico et al. Aug 2004 B2
6808536 Wright et al. Oct 2004 B2
20010007083 Roorda Jul 2001 A1
20010029351 Falotico et al. Oct 2001 A1
20010029660 Johnson Oct 2001 A1
20010032014 Yang et al. Oct 2001 A1
20010034363 Li et al. Oct 2001 A1
20010037145 Guruwaiya et al. Nov 2001 A1
20020010418 Lary et al. Jan 2002 A1
20020032477 Helmus et al. Mar 2002 A1
20020041899 Chudzik et al. Apr 2002 A1
20020061326 Li et al. May 2002 A1
20020068969 Shanley et al. Jun 2002 A1
20020071902 Ding et al. Jun 2002 A1
20020082680 Shanley et al. Jun 2002 A1
20020082685 Sirhan et al. Jun 2002 A1
20020091433 Ding et al. Jul 2002 A1
20020095114 Palasis Jul 2002 A1
20020099438 Furst Jul 2002 A1
20020103526 Steinke Aug 2002 A1
20020119178 Levesque et al. Aug 2002 A1
20020123505 Mollison et al. Sep 2002 A1
20020127327 Schwartz et al. Sep 2002 A1
20020133222 Das Sep 2002 A1
20020133224 Bajgar et al. Sep 2002 A1
20020165608 Llanos Nov 2002 A1
20020193475 Hossainy et al. Dec 2002 A1
20030065377 Davila et al. Apr 2003 A1
20030216699 Falotico Nov 2003 A1
20040049265 Ding et al. Mar 2004 A1
20040243097 Falotico et al. Dec 2004 A1
20040260268 Falotico et al. Dec 2004 A1
20050002986 Falotico et al. Jan 2005 A1
20050004663 Llanos et al. Jan 2005 A1
20050033261 Falotico et al. Feb 2005 A1
20050106210 Ding et al. May 2005 A1
20050187611 Ding et al. Aug 2005 A1
20050208200 Ding et al. Sep 2005 A1
20060088654 Ding et al. Apr 2006 A1
20060089705 Ding et al. Apr 2006 A1
Foreign Referenced Citations (74)
Number Date Country
3205942 Sep 1983 DE
19723723 Dec 1998 DE
0 145 166 Jun 1985 EP
0 177 330 Apr 1986 EP
0 183 372 Jun 1986 EP
0 221 570 May 1987 EP
0 421 729 Apr 1991 EP
0 540 290 May 1993 EP
0 568 310 Nov 1993 EP
0 604 022 Jun 1994 EP
0 621 015 Oct 1994 EP
0 623 354 Nov 1994 EP
0 712 615 May 1996 EP
0 716 836 Jun 1996 EP
0 734 721 Oct 1996 EP
0 747 069 Dec 1996 EP
0 761 251 Mar 1997 EP
0 800 801 Oct 1997 EP
0 540 290 Jan 1998 EP
0 830 853 Mar 1998 EP
0 815 803 Jul 1998 EP
0 850 651 Jul 1998 EP
0 938 878 Sep 1999 EP
0 938 878 Sep 1999 EP
0 950 386 Oct 1999 EP
0 968 688 Jan 2000 EP
0 633 032 Feb 2001 EP
1 192 957 Apr 2002 EP
1 588 726 Oct 2005 EP
1 588 727 Oct 2005 EP
566 807 Apr 1992 FR
0 662 307 Dec 1951 GB
1 205 743 Sep 1970 GB
2 135 585 Sep 1984 GB
0 734 698 Mar 1996 JP
660689 May 1979 SU
1457921 Feb 1989 SU
8903232 Apr 1989 WO
9112779 Sep 1991 WO
9215286 Sep 1992 WO
9401056 Jan 1994 WO
9421308 Sep 1994 WO
9421309 Sep 1994 WO
9424961 Nov 1994 WO
9600272 Jan 1996 WO
9626689 Sep 1996 WO
9632907 Oct 1996 WO
9634580 Nov 1996 WO
9725000 Jul 1997 WO
9733534 Sep 1997 WO
9808463 Mar 1998 WO
9813344 Apr 1998 WO
9819628 May 1998 WO
9823228 Jun 1998 WO
9823244 Jun 1998 WO
9834669 Aug 1998 WO
9836784 Aug 1998 WO
9847447 Oct 1998 WO
9856312 Dec 1998 WO
0021584 Apr 2000 WO
0027445 May 2000 WO
0027455 May 2000 WO
0032255 Jun 2000 WO
0038754 Jul 2000 WO
0187342 Nov 2001 WO
0187372 Nov 2001 WO
0187373 Nov 2001 WO
0187376 Nov 2001 WO
0226139 Apr 2002 WO
0226271 Apr 2002 WO
0226280 Apr 2002 WO
0226281 Apr 2002 WO
03015664 Feb 2003 WO
03057218 Jul 2003 WO
Related Publications (1)
Number Date Country
20060282160 A1 Dec 2006 US
Provisional Applications (1)
Number Date Country
60044692 Apr 1997 US
Continuations (4)
Number Date Country
Parent 10951385 Sep 2004 US
Child 11466983 US
Parent 10408328 Apr 2003 US
Child 10951385 US
Parent 09874117 Jun 2001 US
Child 10408328 US
Parent 09061586 Apr 1998 US
Child 09874117 US