Patent Application
20070288084
The term “stents” refers to devices that are used to maintain patency of a body lumen or interstitial tract. There are two categories of stents; those which are balloon expandable (e.g., stainless steel) and those which are self-expanding (e.g., nitinol). Stents are currently used in peripheral, coronary, and cerebrovascular vessels, the alimentary, hepatobiliary, and urologic systems, the liver parenchyma (e.g., porto-systemic shunts), and the spine (e.g., fusion cages). In the future, stents will be used in smaller vessels (currently minimum stent diameters are limited to about 2 millimeters). For example, they will be used in the interstitium to create conduits between the ventricles of the heart and coronary arteries, or between coronary arteries and coronary veins. In the eye, stents are being developed for the Canal of Schlem to treat glaucoma.
As used herein the phrase, “bioactive materials” refers to any organic, inorganic, or living agent that is biologically active or relevant. For example, a bioactive material can be a protein, a polypeptide, a polysaccharide (e.g. heparin), an oligosaccharide, a mono- or disaccharide, an organic compound, an organometallic compound, or an inorganic compound. It can include a living or senescent cell, bacterium, virus, or part thereof. It can include a biologically active molecule such as a hormone, a growth factor, a growth factor producing virus, a growth factor inhibitor, a growth factor receptor, an anti-inflammatory agent, an antimetabolite, an integrin blocker, or a complete or partial functional insense or antisense gene. It can also include a man-made particle or material, which carries a biologically relevant or active material. An example is a nanoparticle comprising a core with a drug and a coating on the core.
Bioactive materials also can include drugs such as chemical or biological compounds that can have a therapeutic effect on a biological organism. Bioactive materials include those that are especially useful for long-term therapy such as hormonal treatment. Examples include drugs for contraception and hormone replacement therapy, and for the treatment of diseases such as osteoporosis, cancer, epilepsy, Parkinson's disease and pain. Suitable biological materials can include, e.g., anti-inflammatory agents, anti-infective agents (e.g., antibiotics and antiviral agents), analgesics and analgesic combinations, antiasthmatic agents, anticonvulsants, antidepressants, antidiabetic agents, antineoplastics, anticancer agents, antipsychotics, and agents used for cardiovascular diseases such as anti-restenosis and anti-coagulant compounds. Exemplary drugs include, but are not limited to, antiproliferatives such as paclitaxel and rampamycin, everolimus, tacrolimus, des-aspartate angiotensin 1, exochelins, nitric oxide, apocynin, gamma-tocopheryl, pleiotrophin, estradiol, heparin, aspirin and 5-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA) reductase inhibitors such as atorvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin, etc.
Bioactive materials also can include precursor materials that exhibit the relevant biological activity after being metabolized, broken-down (e.g. cleaving molecular components), or otherwise processed and modified within the body. These can include such precursor materials that might otherwise be considered relatively biologically inert or otherwise not effective for a particular result related to the medical condition to be treated prior to such modification.
Combinations, blends, or other preparations of any of the foregoing examples can be made and still be considered bioactive materials within the intended meaning herein. Aspects of the present invention directed toward bioactive materials can include any or all of the foregoing examples.
As used herein, the term “degradable” includes a feature of a material that allows its complete or near complete disappearance from an area over time. In addition to the conventional meaning of degradable, this term should also be read to include erodable and absorbable materials.
U.S. Pat. Nos. 5,292,331 and 5,135,536 to Boneau and Hilstead respectively, and the references cited therein, make it clear that stents can be configured and constructed in many different ways. The present invention is applicable to all known stent configurations, and it will be readily apparent from the following discussion of several exemplary configurations how the invention can be applied to any other type of stent construction.
As stated earlier, it is often beneficial for an implanted stent to release a bioactive material to reduce the physiological trauma associated with the stent's implantation and to aid in the treatment, inhibition and/or prevention of restenosis, abrupt reclosure or re-occlusion (all hereinafter referred to as “reclosure”). The stents of the present invention are designed to allow for varying amounts of bioactive material release along the stent due to increased surface area of various portions of the stent. These portions of the stent that increase surface area for bioactive material deposition are degradable so that they do not add long term bulk to the stent once the release of bioactive materials is no longer required. The increased surface area can be provided anywhere along the length of the stent. In one embodiment, the increased surface area is provided at the ends of the stent to provide more bioactive material release at the ends. Providing for increased release of bioactive materials at the ends of a stent can be beneficial to ease the transition between stented and unstented portions of a vessel and to also provide therapeutic benefit to those portions of the vessel damaged during the implantation procedure, but beyond the ends of the stent.
Stents of the present invention also can help treat areas of a vessel that are damaged by stent implantation that do not necessarily require long-term stenting. The present invention treats these areas by including degradable sections at the ends of the stent. These degradable sections can contain bioactive materials and can release these bioactive materials at damaged portions of the vessel, stent them for a time, and eventually erode, leaving a non-stented portion of the vessel. The present invention also can include degradable portions with or without bioactive materials at other locations. For instance, when a stent is placed a vessel branch, the portion of the stent that might otherwise gate the ostium of the branch can be quickly degradable to avoid this problem. As stated, described degradable portions of the present invention can include bioactive materials and/or radiopaque materials to aid in device implantation. In one embodiment, the majority of the stent can be degradable with only a portion remaining for long term treatment site identification.
The embodiment of the stents of the present invention depicted in
In
There are many approaches that can be adopted to create a stent with both degradable and nondegradable portions. For example, a degradable portion of a stent could be formed around a nondegradable portion by insert molding and/or solvent casting. Degradable and nondegradable portions could also be sandwiched together by, without limitation, cladding, press fitting or clamping.
In addition to providing increased surface area for bioactive material deposition, the degradable tabs of the present invention also provide for temporarily increased mass of the stent. This temporarily increased mass (which is not structurally required) is beneficial for enhanced radiopacity in stent positioning. For example, the degradable tabs or other degradable features placed at different portions along the length of a stent can be used to position the stent appropriately in an area of a vessel bifurcation or other specific treatment sites. Further, the degradable tabs and stent sections of the present invention can lack bioactive materials altogether and only be used for enhanced radiopacity, can include bioactive materials within the degradable material, can have bioactive materials coated onto the surface of the degradable material or can include bioactive materials within and coated onto the surface of the degradable material. Further, nondegradable portions of the stent also can have bioactive materials included on their surface.
As stated earlier, embodiments of the present invention can increase the surface area of a stent at any point along the body or end crowns of the stent. Increasing the surface area of a stent for additional bioactive material deposition and subsequent release at one or more ends of a stent may ease the transition between stented and unstented portions of a vessel by providing for additional bioactive materials that combat restenosis at the transition site.
The tabs of the present invention, whether found within crowns or extending from the ends of crowns can take on a variety of shapes and sizes. Further, the stents of the present invention can be used in any blood vessel, including, for example and without limitation, the coronary vasculature (which includes, without limitation, the right, left common, left anterior descending and circumflex arteries and their branches) and the peripheral vasculature (including without limitation branches of the carotid, aorta, femoral, renal, popliteal, and related arteries). While the stents of the present invention mainly have been described in terms of their use in a blood vessels, they can also be used in other lumens of the body, for example and without limitation, respiratory ducts, gastrointestinal ducts, bile ducts, the urinary system, the digestive tube, and the tubes of the reproductive system in both men and women.
The degradable tabs and sections of the present invention can be formed with a variety of appropriate materials. Some of these materials include, for example and without limitation, degradable polymers such as, without limitation, poly[lactide-co-glycolide], polyanhydrides, and polyorthoesters, whose carboxylic groups are exposed on the external surface as their smooth surface erodes. In addition, polymers containing labile bonds, such as, without limitation, polyanhydrides and polyesters, are well known for their hydrolytic reactivity. Their hydrolytic degradation rates can generally be altered by simple changes in the polymer backbone.
In accordance with the present invention, degradable tabs and sections can be constructed from polymers or monomers using linkages susceptible to biodegradation, such as ester, peptide, anhydride, orthoester, and phosphoester bonds.
Non-limiting examples of degradable components which are hydrolyzable are polymers and oligomers of glycolide, lactide, ε-caprolactone, other a-hydroxy acids, and other biologically degradable polymers that yield materials that are non-toxic or present as normal metabolites in the body. Non-limiting examples of poly(a-hydroxy acid)s include, without limitation, poly(glycolic acid), poly(DL-lactic acid) and poly(L-lactic acid). Other useful materials include, without limitation, poly(amino acids), poly(anhydrides), poly(orthoesters), and poly(phosphoesters). Polylactones such as poly(ε-caprolactone), poly(ε(3 caprolactone), poly(6-valerolactone) and poly(gamma-butyrolactone), for example, also can be used with the present invention.
These described polymers and materials can be obtained from sources such as Sigma Chemical Co., St. Louis, Mo., Polysciences, Warrenton, Pa., Aldrich, Milwaukee, Wis., Fluka, Ronkonkoma, N.Y., and BioRad, Richmond, Calif. or else synthesized from monomers obtained from these suppliers using standard techniques.
The degradable tabs and sections of the present invention also can include, for example and without limitation, magnesium or magnesium alloys (both hereinafter referred to as magnesium). Magnesium can include bioactive materials, when, for example, it is electroformed with a bioactive material in an electrocodeposition bath. Appropriate procedures for such electroforming are disclosed in, for example, co-pending U.S. patent application Ser. No. 11/220,328 filed on Sep. 6, 2005, which is hereby incorporated by reference for all it contains regarding electrocodeposition and electroforming. Alternatively, magnesium can be bioactive material free and instead have a bioactive material containing polymer applied over it.
Other appropriate materials for use as degradable materials in accordance with the present invention can include hydroxyapatite, aluminum-calcium-phosphorous oxide, bone meal, tricalcium phosphate ceramic implants and glass ceramics with high mechanical strength in the (50−x/2)CaO. SiO(2)-xB(2)O(3) (4.2<or =x <or =17.2) range as described by the School of Materials Science & Engineering, College of Engineering, Seoul National University, Seoul 151-742, Korea, which is incorporated by reference herein for its teachings regarding degradable glass ceramics. These glass ceramics consist of three phases: monoclinic wollastonite, calcium metaborate, and amorphous borosilicate matrix and form an apatite layer on its surface in simulated body fluid and with significant degradation.
Materials incorporated to enhance radiopacity can be, without limitation, mixed, coated, filled, encapsulated, complexed, dyed, and absorbed into a used degradable material. Non-limiting examples of appropriate radiopacity enhancing materials include a cyclic carbonate of ioxilan (IXC) mixed with radiopaque microspheres made from albumin molecules either containing or complexed with a radiopaque substances for clinical use; medical grade calcium sulfate; covalently bound iodine; water soluble contrast agents including, without limitation, metrizamide, iopamidol, iothalamate sodium, iodomide sodium, and meglumine; water insoluble contrast agents including, without limitation, tantalum, tantalum oxide, barium sulfate (PLA 96-BaSO4), gold, tungsten, and platinum powders; and MRI visible materials including, without limitation, gadolinium oxide.
It is to be understood that the present invention is not limited to the particular embodiments, materials, and examples described herein, as these can vary. Further, the tabs of the present invention can be made of material that is dissimilar to the material or materials that make up the other portions of the stent. It also is to be understood that the terminology used herein is used for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention. It must be noted that as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include the plural reference unless the context clearly dictates otherwise. Thus, for example, a reference to “a stent” or “a tab” is a reference to one or more stents or tabs and includes equivalents thereof known to those skilled in the art and so forth.
Unless defined otherwise, all technical terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs. Specific methods, devices, and materials are described, although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention.
Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.
Recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. “such as”) provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.
Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is herein deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.
Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations on those preferred embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventor expects skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.
Furthermore, numerous references have been made to patents and printed publications throughout this specification. Each of the above cited references and printed publications are herein individually incorporated by reference in their entirety.
In closing, it is to be understood that the embodiments of the invention disclosed herein are illustrative of the principles of the present invention. Other modifications that may be employed are within the scope of the invention. Thus, by way of example, but not of limitation, alternative configurations of the present invention may be utilized in accordance with the teachings herein. Accordingly, the present invention is not limited to that precisely as shown and described.
