Method of fabricating a biocompatible stent

A method of forming an iridium oxide coating on a metal stent to achieve a firmattachment of a thin biocompatible coating of the iridium oxide such that the iridium oxide resists being dislodged from the stent upon expansion thereof in a vessel of the human body during implantation of the stent. The method includes submerging the stent in a coating solution having an adequate concentration of iridium chloride in a suitable liquid vehicle, and subjecting the coating solution with stent immersed therein to combined heating and application of ultrasonic energy at a temperature and energy level and for a time interval sufficient to form a coating of iridium oxide of desired thickness and surface roughness on the underlying metal surface of the stent. An biomedical implant with such underlying metal surface of primarily passive structure and an iridium oxide coating as a biologically active surface firmly attached to the underlying metal surface has catalytic properties similar to the normal catalytic activity in the cell cycle of a human body to assist in reducing inflammation associated with contact of the biomedical implant with tissue and blood of the body.

BACKGROUND OF THE INVENTION
 The present invention relates generally to stents which are implantable or
 deployable in a vascular or endoluminal location within the body of a
 patient to maintain the lumen open at that location, and more particularly
 to improvements in stent coatings for biocompatibility and in methods for
 applying such coatings.
 Stents are expandable prostheses employed to maintain narrow vascular and
 endoluminal ducts or tracts of the human body open and unoccluded, such as
 a portion of the lumen of a coronary artery after dilatation of the artery
 by balloon angioplasty. While vascular usage is frequently discussed in
 this application, it will be understood by those skilled in the art that
 stents having the characteristics and features of the present invention
 may be implanted in other ducts or tracts of the human body to keep the
 lumen open, such as in the tracheo-bronchial system, the binary hepatic
 system, the esophageal bowel system, and the urinary tract system.
 In the case of an occluded coronary artery, for example, the original
 blockage is typically attributable to fatty deposits or plaque on the
 inner lining of the vessel. A different mechanism, however, produces a new
 blockage after an angioplasty procedure is performed to compress the
 deposits against the inner lining of the vessel, as by use of balloon
 angioplasty, or to virtual entirely remove the deposits, as by use of
 laser angioplasty or rotational cutting. The blood vessel wall is
 subjected to trauma by any of these procedures, which results in
 hyperplasia of the neointima, i.e., a rapid proliferation of muscle cells
 in the affected region of the wall, to cause restenosis and re-occlusion
 of the vessel lumen in a significant percentage of angioplasty patients
 within a period of from three to six months following the initial
 procedure.
 To avoid this re-occlusion and to maintain the lumen of the vessel open, it
 is customary procedure to install a stent at the site in the vessel where
 the angioplasty was performed. The stent is deployed by radial expansion
 under pressure exerted by the inflating balloon of a balloon catheter on
 which the stent is mounted, to engage the inner lining or surface of the
 vessel wall with sufficient resilience to allow some contraction but also
 to provide a degree of stiffness to resist the natural recoil of the
 vessel wall following expansion.
 The presence of the stent itself in the bloodstream, however, promotes
 thrombus formation and clotting as blood flows through the vessel. This,
 too, can result in sufficient blockage of the coronary artery to produce
 an infarction. Thrombus formation and clotting at the inner lumen of the
 stent, and fibrosis and restenosis at the site of the vessel wall where
 the angioplasty was performed and the outer surface of the stent is now
 engaged, can be significantly reduced by application of appropriate
 acutely acting drugs in the locality of the stent. In the past, some
 difficulty has been encountered in providing a stent surface which is
 suitable for retention of the necessary drug(s) to achieve those purposes.
 Additionally, the composition of the stent, or at least its surface
 material which is exposed to blood, other body fluid, or tissue, is a
 factor in the patient's tolerance of the stent in the vascular or
 endoluminal duct. Of course, the stent must have a composition which is
 biocompatible with the blood, fluids and tissue of the patient's body. But
 fully five percent of the human population exhibit allergies to chrome,
 nickel, and even medical grade 316L stainless steel (about 20%
 nickel)--materials of which stents are commonly composed. Special
 biomaterial coatings can provide surfaces which are non-allergenic.
 Another important consideration in stent selection and usage is its
 mechanical strength, particularly in applications where the small size of
 the duct severely limits the physical dimensions of the stent, such as in
 a coronary artery. The diameter of the stent and the thickness of its wall
 or wire must be maintained at a minimum, and yet still offer sufficient
 mechanical strength to resist the natural recoil of the vessel wall
 following implantation and to keep the lumen of the vessel open. A steel
 stent having a wall thickness of from 40 to 50 microns (micrometers,
 .mu.m) is feasible for use in the coronary artery and with proper design
 can be highly flexible when crimped on a balloon while providing
 significant mechanical strength when deployed. But the small diameter and
 thin wall of such a stent may not provide enough retention force for film
 attachment when the stent is crimped onto the balloon, particularly if the
 stent surface is polished as is frequently the case.
 Also, a stent of such small dimensions is virtually not visible on X-ray
 fluoroscopy as it is being implanted in the patient's body, or afterward
 when the implant site is examined during patient follow-up, because of its
 low X-ray absorption.
 Therefore, the principal aim of the present invention is to provide a
 method for manufacturing a small diameter stent which has excellent
 visibility on X-ray fluoroscopy, as well as high retention force when
 mounted onto a balloon, and excellent biocompatibility with low
 thrombogenicity when implanted in a vessel.
 A related aim is to provide a method of fabricating a stent in which a
 ceramic-like structure is applied as an outer layer to a base metal, where
 the two differ in tensile strength and physical characteristics.
 Another important aim of the invention is to provide a stent and method of
 manufacture thereof in which a suitable coating is provided on the exposed
 surfaces of the stent to measurably reduce tissue irritation. The
 reduction in tissue irritation also reduces the traumatic response that
 produces rapid proliferation of the tissue, and hence, impedes the
 restenosis attributable to that mechanism. The coating improves
 thrombogenicity and provides a surface region which may be used to carry
 an additional biodegradable layer impregnated with anti-fibrotic and
 anti-thrombotic drugs, for example, which are released to avoid responses
 tending to initiate a reblockage of the vessel in which the stent is
 implanted, especially the coronary artery.
 Still another objective of the present invention is to provide a stent with
 a special coating that resists occlusion of a blood vessel at the implant
 site attributable to mechanical stress-induced hyperplasia of the intimal
 and neointimal region of the vessel wall, and stent-induced clotting and
 thrombus formation.
 Yet another aim of the invention is to provide a stent which has improved
 radiopacity for X-ray fluoroscopy viewing without increasing the physical
 dimensions of the stent.
 SUMMARY OF THE INVENTION
 In co-pending U.S. patent applications Ser. No. 09/059,053 and U.S. Ser.
 No. 09/175,919 of one of the applicants herein, both of which are assigned
 to the assignee of the present invention and incorporated by reference
 herein, stents and methods of manufacture thereof are described in which
 the basic stent is provided with multi-layer coatings, the outer layer of
 which is a ceraic-like material of relatively rough surface. Preferably,
 this outer layer is very thin and is composed of a compound or derivative
 of certain metals (including some of the noble metals) suitable as
 biocompatible coverage, such as either iridium oxide or titanium nitrate,
 most preferably iridium oxide (sometimes referred to herein as "IROX")
 This layer overlies the entire exposed surface of the stent, and is
 advantageous to reduce adverse tissue reaction that occurs in response to
 contact between the stent and the inner lining of the vessel wall at the
 implant site.
 The ceinic-like, metal derivative layer also provides an improved surface
 for retention of beneficial drugs or other agents having an
 anti-thrombotic, anti-platelet, anti-inflammatory, or anti-proliferative
 function, which are conveniently incorporated in a biodegradable carrier
 that adheres to the outer surface of the stent and disintegrates or
 decomposes in the presence of blood or other body fluid to release the
 drugs or agents therefrom. The IROX-mated outward facing surface of the
 stent preferably is utilized to retain drugs or agents (collectively
 referred to herein as substances) that suppress inflammation and
 proliferation of tissue, whereas the IROX-coated inward facing surface of
 the stent preferably is utilized to retain substances that suppress
 thrombus formation and clotting. Layering of the drugs themselves may be
 used to selectively inhibit acute and longer-term reactions. Details of
 such biodegradable carriers and impregnated substances are more fully
 described in U.S. Pat. No. 5,788,979 of one of the applicants herein,
 assigned to the assignee of the present invention. The disclosure of the
 '979 patent is incorporated by reference herein.
 A vascular stent is typically constructed from an elongate biocompatible
 metal member composed, for example, of 316L stainless steel (medical
 grade), titanium, Nitinol (nickel-titanium alloy with shape memory
 characteristics), idium, or other metal, which is configured in an
 open-ended cylinrical shape (e.g., coil, mesh, undulating single wire
 filament or perforated tube). For convenience, the portion of the stent
 between the open ends thereof is referred to herein as its sidewall,
 regardless of the particular cylindrical shape of the structure, and the
 sidewall is referred to herein as having openings therethrough even though
 a coil stent has only one continuous spiral opening in its sidewall and a
 continuous filament wire may have very large openings in its "sidewall."
 When mounted on a balloon or other catheter for implantation, the stent is
 of sufficiently small diameter to be inserted into and to traverse the
 vascular system or other duct of the patient's body to a preselected site
 at which the stent is to be deployed, such as within a coronary artery
 following or coincident with an angioplasty procedure. Deployment is
 achieved by application of a uniform radial outwardly directed force on
 the sidewall of the stent to increase its diameter, and thereby expand or
 open the stent until it is in firm contact or engagement with the inner
 lining of the vessel wall. Typically the stent is expanded by inflating a
 balloon on which it is mounted.
 The stent should possess sufficient mechanical strength to resist collapse
 under the natural recoil force exerted by the vessel wall, when the stent
 is fully deployed. Iridium oxide, titanium nitrate and related metal
 derivative coatings have structural characteristics of a ceramic material,
 with different tensile modulus, brittleness and ductility. Such coatings
 exhibit little flexibility unless deposited or formed in a sufficiently
 thin layer to resist flaking or peeling from the underlying metal member
 during expansion of the stent. Even a very thin IROX layer may undergo
 some fissuring or cracking during deployment of the stent, owing to the
 very substantial configurational change and related mechanical stress
 imposed when the stent goes from its initial or crimped diameter in an
 unexpanded state to a considerably larger diameter in its expanded state.
 In practice, this change may be from an initial diameter of one mm to an
 expanded state diameter of 10 mm or more. The advantages of natural
 resistance to tissue irritation and improved surface characteristics for
 retention of beneficial substances may be of little or no value unless
 suitably tight adherence of the outer layer to the underlying material is
 achieved.
 Various coatings have been employed on stents in the past, such as
 zirconium oxide and zirconium nitride as disclosed in U.S. Pat. No.
 5,649,951 to Davidson, and metals from Group VA of the periodic table as
 disclosed in U.S. Pat. No. 5,607,463 to Schwartz. In general, these
 coatings have been used to provide tissue compatibility and/or
 thrombogenicity, but fail to offer the many additional advantages of
 iridium oxide.
 In the aforementioned '919 application, a muti-layer stent is composed of
 three different layers consisting of a core material, an intermediate
 corrosion-resistant layer overlying the core material, and a thin
 ceramic-like metal or derivative thereof outer layer overlying the
 intermediate layer. In an exemplary embodiment, the core material is
 medical grade stainless steel, the intermediate layer is gold, and the
 outer layer is IROX. A tight adherence of each of the intermediate and
 outer layers to its respective directly underlying material is essential.
 Such a tightly adherent coating of gold on steel is achieved by techniques
 described in U.S. Pat. No. 5,824,045 of one of the applicants herein,
 assigned to the assignee of the present invention. While in principle,
 gold is a very soft and ductile metal which is readily adjusted to
 different configurations, the ceramic-like noble metal derivative outer
 coating offers a significantly greater challenge to achieving tight
 adherence and film attachment to its underlying metal, and maintaining
 that firm attachment despite the mechanical stress that occurs with
 substantial configurational change during deployment of the stent to its
 expanded state.
 The present invention provides a method of depositing a ceramic-like
 coating of suitable biocompatible metal or metal derivative such as
 iridium oxide for example, onto the base or core metal of a stent, and
 preferably atop an intermediate noble metal (such as gold) layer to
 achieve a sufficiently firm attachment of a thin biocompatible layer of
 the iridium oxide as an outer exposed layer, film or coating of relatively
 roughened surface characteristics on the stent such that the iridium oxide
 resists being dislodged therefrom upon expansion of the stent in a vessel
 (whether it be a blood vessel, a duct or tract) of the human body during
 implantation of the stent. The method includes the steps of submerging the
 stent at a stage where the intermediate layer has been applied, or even
 where only the base metal is exposed, in a solution having an adequate
 concentration of an iridium compound in a suitable liquid vehicle, and
 subecting the solution with the stet sub merged therein to combined
 heating and application of ultrasonic energy at a temperature and energy
 level and for a time interval sufficient to form on the intermediate layer
 or directly on the base metal a layer of iridium oxide of desired
 thickness. The iridium oxide layer is formed with a relatively rough outer
 surface.
 Preferably, combined heating to a specific suitable temperature and
 application of ultrasonic energy is achieved by the mere application of
 the ultrasonic energy. In any event, that step is ceased when the layer is
 of the desired thickness, preferably in a range from about 500 nanometers
 (mm) to about 1 micron (.mu.m).
 Thereafter, the coated stent is removed from the solion, rinsed with water,
 and dried at room temperature. The dried coated stent is then heated at a
 temperature and for a time sufficient to convert residual iridium chloride
 compounds in the formed layer to oxidized iridium to complete the iridium
 oxide layer.
 The thickness and surface roughness of the layer formed in the solution are
 controlled by variation of each of the ultrasonic energy source, duration
 of the coating process, iridium compound, liquid vehicle, and
 concentration of the selected iridium compound in the liquid vehicle A
 relatively rough outer surface is well-adapted for retention of selected
 drugs or agents such as the types mentioned above, in indentations,
 reservoirs or repositories thereof for time release therefrom after the
 stent is implanted, as a suitable biodegradable carrier in which the drugs
 are incorporated undergoes disintegration, to assist the stent in
 maintaining the lumen of the vessel open. A rough outer surface also
 serves to increase the friction or retention force of the stent when
 mounted on a balloon for implantation in the vessel of the human body.
 Preferably, the iridium compound is iridium chloride, and the liquid
 vehicle is formed by dissolving the iridium chloride in a suitable volume
 of a reduced percentage of hydrochloric acid, boiling the result solution
 to reduce its volume to approximately one-fifth of its original volume,
 and then restoring the original volume by adding to that reduced volume of
 the resulting solution a suitable quantity of 100% isopropanol to
 constitute the prepared solution in which the stent is to be submerged.
 The prepared solution is best used in the practice of the method within
 about seven days after preparation thereof, to form the layer of iridium
 oxide on the intermediate layer (preferred), or the base metal if no
 intermediate layer is used After the coated stent is removed from the
 prepared solution, any residual iridium chloride in the formed layer is
 converted to iridium oxide by heating the coated stent at a temperature
 and for a period of time sufficient to produce the conversion, preferably
 at a temperature in excess of 300.degree. C., for a period of about 12
 hours.
 The method of combined heating and application of ultrasonic energy is
 preferably carried out by applying the ultrasonic energy to heat a water
 bath in which is immersed the containment vessel with stent submerged in
 the prepared solution therein. For example, the ultrasonic energy is
 applied at an energy level of 320 watts (2.times.160 watts, as will be
 explained below) to vibrate the containment vessel at a frequency of about
 35 kHz and to heat the water bath of about 3 liters to its boiling point
 of 100.degree. C. The heat and vibration are maintained with the
 ultrasonic energy application for a period of about 5 to 6 hours to
 produce an iridium oxide layer thickness in the preferred range from about
 500 nm to about 1 .mu.m.
 Accordingly, it is an additional primal aim of the present invention to
 provide a method of fabricating a stent (or other implantable medical
 device) which achieves reliably tight adherence and firm attachment of the
 metal or metal derivative coating to its underlying intermediate layer or
 base layer despite configurational changes of the type experienced by the
 stent (or other implantable medical device) during implantation thereof,
 and which achieves this in a cost-effective way.
 Another aspect of the present invention resides in certain surprising
 characteristics of the ultrasonically-applied iridium oxide coating which
 to the applicants' knowledge have not previously been observed in coatings
 applied by other methods. Applicants' research has shown that the iridium
 oxide in the outer layer of the stent fabricated according to the method
 of the invention has catalytic properties. In particular, the research and
 tests conducted by the applicants herein demonstrates that the iridium
 oxide coating surface acts as a catalyst in a reaction in the body in
 which hydrogen peroxide is converted into water and oxygen or an oxide.
 The effect is that a biologically active surface is created by the
 primarily passive structure of the iridium oxide coating surface, which
 measurably assists in preventing inflammatory reactions to the
 implantation of the structure in the body.

DETAILED DESCRIPTION OF PREFERRED METHOD AND EMBODIMENT
 Stents to be coated with a final outer layer of iridium oxide are
 preferably fabricated initially in the manner disclosed in the co-pending
 '053 application, but the fabrication of the final layer is instead
 performed as described herein. Briefly, as described in the '053
 application, which is incorporated in its entirety by reference herein,
 the base metal of the stent which may be medical grade stainless steel,
 iridium, titanium, Nitinol, or other conventional material used for this
 purpose, is coated initially with a thin, tightly adherent intermediate
 layer of noble metal. Preferably the noble metal is gold, or
 alternatively, an alloy which is primarily composed of gold or other noble
 metal. This is achieved by a method described in the '045 patent, which is
 incorporated in its entirety herein by reference. The noble metal layer is
 applied to cover the entire exposed surface of the base metal stent. For
 example, this intermediate layer has a thickness in the range from
 approximately 1.mu.m to approximately 20 .mu.m, preferably about five
 .mu.m.
 In the preferred process of the '045 patent, gold is deposited onto the
 surface of the core or base metal of the stent by ion beam deposition to
 provide a firm, tightly bonded, extremely thin foundation layer, which
 allows the bond between base metal and noble metal to flex without
 suffering fracture or peeling of the overlying layer. Gold ions from
 vaporized gold are accelerated in a vacuum environment to deposit on the
 exposed surfaces of the metal core of the stent. This initial foundation
 layer is built upon by then employing a conventional galvanic process to
 apply one or more additional thin, tightly adherent uniform layers of gold
 onto the foundation layer to form an over composite layer of gold having a
 thickness of from about 3 .mu.m to about 6 .mu.m on each side of the
 sidewall of the stent. Two layers may be applied to the base thickness of
 the stent wall. The overall effect provides adherence that will inhibit
 cracking, peeling or flaking of any portion of the overall gold layer from
 the underlying surface of the steel core, which could otherwise occur
 during times when the stent is undergoing mechanical stress and
 distortion, in going from an unexpanded state to and expanded state during
 deployment.
 The thus-far coated stent is then cleaned by heating under vacuum to a
 temperature that depends on the coating and the underlying material. For
 gold on steel, for example, the cleaning step may be carried out at a
 temperature of about 250.degree. C. and a pressure of about 0.10
 atmosphere. A final outermost layer of iridium oxide or the like (e.g.,
 titanium nitrate) is then to be formed as a biocompatible layer that
 serves a primary purpose of avoiding tissue irritation and thrombus
 formation, with surface roughness for purposes which will be further
 described below.
 A three layer stent structure can be produced with an overall thickness
 less than or equal to 60 .mu.m. The stainless steel wall may be fabricated
 in a thickness of approximately 45 .mu.m, which offers sufficient
 mechanical strength to resist the natural recoil of the blood vessel wall
 following deployment of the stent. The gold intermediate layer is applied
 in a 5 .mu.m thickness, for example, to all exposed surfaces of the base
 layer, giving a total additional thickness of 10 .mu.m to the structure,
 and serving to avoid a galvanic potential. The outermost layer of iridium
 oxide is applied by the method of the invention to a thickness preferably
 in a range from 500 .mu.m to about 1.0 .mu.m.
 According to the invention, the method of producing the outermost stent
 coating of iridium oxide employs a combination of a chemical bath process
 together with application of heat and mechanical forces. With reference to
 FIG. 1 of the drawing (not to scale, and for the sake of clarity the bath
 is shown as being transparent), the preferred environment for performing
 the coating method includes an ultrasonic bath 10 which has an ultrasonic
 generator 12 at one end and a container 13 for the water constituting the
 bath occupying the space between the generator end 25 and the opposite end
 26. A thermostat 14 includes an extended thermometer portion which is
 partly immersed in the water to measure the temperature of the water bath,
 and a gauge 15 to provide a visual indication of the bath temperature if
 desired. A damped feedback circuit (not shown) or other conventional means
 may be coupled to the thermostat and to the ultrasonic generator to
 maintain the water temperature at the preset level of the thermostat when
 the ultrasonic bath 10 is in operation.
 One or more trays or holders such as 16 are situated for retention at the
 sides 27 and 28 of container 13, and provided with spaced-apart holes to
 snugly accept a plurality of substantially identical glass vials 17
 therein for partial submergence in the water bath. In the presently
 preferred embodiment, each of the vials 17 had a liquid content capacity
 of one milliliter (ml). In practice, the vials or other containers
 suitable for use in the process of the invention should be sufficiently
 sized to accept a stent 20 together with sufficient coating solution 21 to
 cover the stent. In the present example, 500 microliters (.mu.l) of
 coating solution is sufficient for that purpose. Each vial 17 is then
 closed with a stopper or cap 18 to seal the vial except for a tiny hole 19
 through the cap to relieve pressure within the vial during operation of
 the bath in the coating process of the invention.
 Using this apparatus (or a similar apparatus as will occur to those skilled
 in the art from the nature of the preferred coating process), the stent 20
 is processed as follows. Before inset the stent into a vial 17, the sure
 of the stent to be coated with iridium oxide is activated to prepare it
 for the coating process. For a gold-coated stent, which is preferred, with
 a base or core metal of medical grade stainless steel, iridium, titanium
 or Nitinol, for example, adequate surface activation was achieved at this
 stage of the process by immersing the stent in a 10% solution of oxalic
 acid at a temperature of about 100.degree. C., for a period of
 approximately 30 minutes. After "cooling" the stent in this manner, it is
 rinsed thoroughly with distilled water to remove all traces of the acid.
 After rinsing, adhesion of water to the activated surface of the stent is
 prevented by drying the stent in air at a laminar flow at room
 temperature. At this stage, when fully dried, the stent 20 is inserted
 into a glass vial 17 for the coating process.
 To provide an iridium oxide coating on the stent, a coating solution 21 is
 first prepared by dissolving 200 milligrams (mg) of iridium chloride in 5
 ml of 20% hydrochloric acid, in a separate reaction vial. The resulting
 solution is then boiled slowly at approximately 100.degree. C. until the
 solution is evaporated to approximately 20% of its original volume, e.g.,
 from 5 ml to one ml. At that point, the original volume is restored by
 adding a sufficient quantity of 100% isopropanol. For example, if the
 original volume of the solution was 5 ml, and it is reduced to one ml by
 the boiling process, restoration to original volume requires addition of 4
 ml of the isopropanol This coating solution may then be stored, but is
 preferably used within a period of seven days after its preparation.
 The coating solution 21 is then added to each glass vial 17 containing a
 stent 20 so as to fully cover the stent- Am amount of the coating solution
 required to be added to a vial for a particular stent will depend on and
 be adjusted according to the size and surface dimensions of the stent to
 be coated. A stopper 18 is then press-fit into the opening in each vial
 17, to prevent evaporation of the liquid contents during operation of the
 ultrasonic bath 10, and the vials are inserted into separate holes in
 holder or retention frame 16, which is supported at the sides 27, 28 of
 container 13 in preparation for further processing of the stents. With
 this arrangement, the vials 17 are held in an upright position and
 partially immersed in the bath 10 so that the contents including the stent
 and coating solution are below or no higher than the surface of the bath
 liquid. The small opening 19 through the stopper is designed to relieve
 pressure within the vial during the ultrasonic heating portion of the
 process.
 Since the water level in the bath 10 is at least as high as the level of
 coating solution 21 in the vials, and the coating solution covers the full
 height of the stent 20, the entire stent itself will lie completely below
 the bath water level. Upon commencement of the operation of the bath 10,
 the ultrasonic generator 12 is activated. In an exemplary laboratory
 set-up by the applicants herein, a mean energy of 320 watts was delivered
 by two power heads of 160 watts each, at a frequency of 35 kiloHertz
 (kHz). This caused the vials 17 and the stents 20 therein to undergo
 vibration at that same frequency, as well as a heating of the water in
 bath 10. When the water reaches the boiling point of 100.degree. C., the
 preset thermostat 14 and associated feedback circuit can maintain the
 water temperature at that set point value by applying limited flow of
 coolant water to the exterior of the bath, but in any event the ultrasonic
 vibrational energy is needed continuously for the adherence of the
 coating.
 Additional water (which may serve a dual purpose of maintaining a set water
 temperature) may be added to the bath 10 from time to time to compensate
 for evaporation, or the bath may be held within a separate container to
 prevent or reduce loss of water by evaporation, or the stent and
 surrounding coating solution in the vial may be maintained sufficiently
 below the bath water level to allow for water loss through evaporation
 without exposing coating solution or stent above the water level during
 the period of ultrasonic bath operation.
 During the overall period of ultrasonic bath operation, by virtue of the
 ultrasonic vibration and heating the iridium chloride in the coating
 solution 21 substantially uniformly coats the stent submerged therein with
 a layer of idium chloride, which is ultimately converted to iridium oxide.
 Conversion of the iridium chloride to iridium oxide coating takes place
 during retention of the vials in the bath in the presence of heat and
 particularly of ultrasonic energy, according to the following reaction:
 ##STR1##
 In the above reaction, iridium tetrachloride (IrCl.sub.4) and isopropanol
 (C.sub.3 H.sub.7 0H) are converted to iridium oxide (IrO.sub.2) plus
 carbon dioxide (CO) plus water .sub.2 (H O) plus some residual unconverted
 iridium tetrachloride. But, as will be described immediately below,
 continued heating at about 320.degree. C. in the presence of air (which
 includes H.sub.2 O +O.sub.2) serves to convert the residual IrCl.sub.4
 into IrO.sub.2 and hydrochloric gas (HCl) which evaporates into the
 ambient atmosphere. Additionally, any molecular bound water in the crystal
 structure of the iridium oxide leaves the crystal structure following the
 heating.
 After at least 6 hours in the ultrasonically heated water bath 10 at the
 vapor point temperature, the vials 17 are removed from the bath by
 withdrawing them from the retention frame 16. The stents 20 are then
 removed from the vials for post-bath processing. These coated stents are
 rinsed with de-ionized pure water, and are then dried in a laminar flow of
 air for approximately one hour at room temperature. Thereafter, the coated
 stents are placed in an oven and heated for approximately 12 hours at a
 temperature of 320.degree. C. As noted above, this heating converts any
 residual iridium chloride which remains in the coating to iridium oxide,
 so as to create the final complete iridium oxide coating.
 Following the latter heating step, the stents are cleaned ultrasonically
 and with alcohol for about ten minutes, as is customary with biomedical
 implants.
 We found that stents which were on average 16 mm long, with a diameter of
 2.0 mm and a strut thickness of 65 .+-.5 .mu.m underwent an increase in
 weight in a range from about 0.1 to 0.6 mg, which depended on the desired
 coating thickness. Thus far, a coating thickness ranging from about 500 nm
 to about 1 micron has appeared to be optimum.
 Tests conducted on stents coated by this method--including vibrational,
 ultrasonic, bench and maximum expansion/repeated crimping tests--have
 demonstrated that the iridium oxide is firmly attached to the underlying
 base or core metal of the stent. Thus, this final outer coating or layer
 will neither flake off nor disintegrate from the stent even with maximum
 expansion during subsequent implantation and deployment. The details of
 these significantly improved performance characteristics of the coating
 are to be explained by molecular physics. In essence, by the continuous
 application of ultrasonic energy in the coating method, only those iridium
 oxide molecules that attach to the underlying base metal enter into a very
 firm bond, while the other molecules are removed from the stent and, with
 the ultrasonic induced vibration, are dissolved in the prepared solution.
 In further explanation, we have observed that the initial steps of the
 foregoing process results in a very first layer being formed after surface
 activation in the presence of oxalic acid (H.sub.2 C.sub.2 O.sub.4). The
 iridium (Ir.sup.4+) binds in the presence of the oxalic acid according to
 the formula:
EQU Ir.sup.4+ +4Cl +H.sub.2 C.sub.2 O.sub.4 Ir (C.sub.2 O.sub.4) on the surface
 to Ir (C.sub.2 O.sub.4).sub.3.sup.2-, H.sub.2 O and HCl
 This initial binding is very important to the final firm adherence of the
 outer layer. The additional application of ultrasonic energy in the bath
 assures that only those molecules which are firmly bound to the surface
 will attach and form a somewhat rough surface structure. A coating process
 performed with the same chemical agents but without application of
 ultrasonic energy forms layers on the surface of iridium oxide that later
 flake off and break apart when changes are made to the physical dimensions
 of the stent (or other biomedical implant coated by the same process).
 Therefore, it is most important that the coating process is done in the
 presence of ultrasonic energy delivery, which prevents any appositions of
 the iridium oxide that would subsequently have a tendency to disintegrate
 or flake off in use. In the ultrasonic bath heating process, an
 equivalence is reached between apposition and dissolution of the iridium
 oxide molecules on the surface of the stent.
 The thickness of the iridium oxide layer which is formed on the base metal
 of the stent by virtue of the method of the present invention, as well as
 the roughness of its exposed surface, are controlled by appropriate
 variation of the iridium compound, which is iridium chloride in the
 preferred method, and its amount and concentration in the prepared
 solution, as well as by the characteristics of the ultrasonic bath. A
 relatively rough outer surface on the firmly bonded iridium oxide layer,
 and thus of the overall stent itself provides numerous indentations,
 reservoirs or repositories for retention of selected beneficial drugs.
 Desired anti-inflammatory and/or anti-proliferation drugs may be applied
 to enter these repositories at the rough outward facing surface and
 adjacent edges of the stent, whereas desired anti-thrombotic and/or
 anti-platelet agents may be applied to enter the repositories at the rough
 inward facing surface and adjacent edges of the stent. As a consequence of
 being stored in this manner, the drugs or agents are, to an extent, time
 released from the stent to provide a primarily acute response to tissue
 trauma and clotting mechanisms, and thereby assist in maintaining the
 lumen of the vessel open.
 Additionally, or alternatively, the timed release of the beneficial drugs
 from these reservoirs in the outer layer surface may be controlled by
 incorporating the drugs in a biodegradable carrier, preferably of a type
 disclosed in one of the applicant's U.S. Pat. No. 5,788,979 which is
 assigned to the assignee of the present invention and incorporated herein
 in its entirety by reference. Noncontrolled release in this instance is
 attributable to the speed (including slowness) at which degradation or
 disintegration of the biodegradable carrier itself occurs, so that the
 drug or other agent remains captive within the carrier until it is
 dispensed or released, i-e., freed from its host, by progressive
 dissolution upon continuing diffusion of the carrier from the reservoir
 The drug tends to act locally rather than systemically by such an
 arrangement.
 As an alternative to the infusion or incorporation of anti-proliferative or
 anti-inflammatory drugs into the reservoir along the outward facing porous
 structure of the outer layer, gene transfer may be used to inhibit the
 smooth muscle cell growth that leads to neointima and restenosis. In
 principle, a viral vector is used to transfer the desired information into
 the genome of the target cells. Viruses capable of such gene transfer are,
 for example, adenovirus and herpervirus, or fractions of the virus. By
 viral transfer, which is believed to occur by virtue of absorption and
 diffusion, part of the genetic information of interest is provided to the
 target cell. Such information can relate to several mechanisms of cellular
 proliferation, with the aim of inhibiting restenosis which, if unchecked,
 could result in at least partial and perhaps complete blockage of the
 vessel's lumen, despite the presence of the deployed stent at the site.
 One important technique involves blocking the proliferation stimulating
 factors such as cytoKines, nF-kappa B, platelet derived growth factors or
 other growth factors that originate from platelet deposition, thrombus
 formation, mechanical stress, or injury and inflammation.
 The virus transfer is performed by incorporating the gene transfer agent--a
 viral vector or virus of the above-mentioned type that contains the viral
 genetic information desired to be transferred to the target cell(s)--into
 a biodegradable carrier for release from the reservoir into which it has
 been infused and dispensed by the process of biodegradation.
 Alternatively, the release to effect the gene transfer may be accomplished
 by release from a solution in the reservoir which contains liposomes as
 the viral vector.
 A rough outer surface also serves to increase the friction or retention
 force of the stent when mounted on a balloon for implantation in the
 vessel of the human body. A certain risk is present that a balloon
 catheter-mounted stent might be dislodged from the uninflated or partially
 inflated balloon as a result of navigation through the tortuous path of
 the cardiovascular system or other vessels of the body to the preselected
 site for deployment, particularly if the stent surface is smooth and/or
 the stent thickness and diameter are small. The rough surface of the outer
 layer provided by the method of the invention provides the stent with high
 retention force, exceeding 2.5 Newton, even where less mechanical grip is
 present because of thin stent strut thickness, and even when the stent is
 mounted on a small diameter (e.g.,&lt;1 mm) balloon.
 According to a farther aspect of the present invention, the stent which has
 an iridium oxide coating on its base metal is, in essence, an inorganic
 biomaterial but displays a propensity to reduce the degree of inflammation
 which otherwise occurs when such a biomaterial is brought into contact
 with the human body, as by implantation in the body. Normally, an
 inorganic biomaterial is a passive structure with only passive mechanical
 properties. But research conducted by the applicants herein has shown that
 the iridium oxide produced by the method of the invention has catalytic
 properties, capable of promoting a reaction in which hydrogen peroxide
 (H.sub.2 O.sub.2) is converted into water (H.sub.2 O) and oxygen
 (O.sub.2). This reaction normally occurs only in the presence of a
 catalyst, since hydrogen peroxide is normally kinetically stable and will
 not decompose spontaneously. To become unstable, a certain kinetic energy
 is required to overcome the activation energy for hydrogen peroxide
 decomposition.
 It is known that one of the very first responses of the human body to the
 implantation of a foreign body, such as a stent surface, into the blood
 vessels is the activation of leukocytes, white blood cells which are one
 of the formed elements of the circulating blood system. This activation
 causes oxidative stress with a burst of reactive oxygen compounds (100
 times higher than the baseline production). One of the key molecules in
 this process is hydrogen peroxide, released by neutrophilic graniocytes
 which constitute one of the five types of leukocytes. While O.sub.2 is
 always present and generated in a normal cell cycle, in the mitochondria
 the reaction of O.sub.2 to superoxide anion O.sub.2 (i.e., reactive form
 of oxygen when molecular oxygen gains a single electron) is reduced to
 H.sub.2 O.sub.2 by the enzyme superoxide dismutase. The enzyme calase
 serves as a converter of H.sub.2 O.sub.2. The presence of H.sub.2 O.sub.2
 is a very strong trigger for inflammation. And in a situation where
 inflammation is occurring, when the granuloytes produce 100 times more
 O.sub.2 than normal, the normal catalytic activity of the body is
 insufficient to convert the increased amount of H.sub.2 O.sub.2 to water
 and oxygen in its metabolic process. But we have discovered that hisi
 iridium oxide surface of the stent, though a primarily passive structure,
 is a biologically active surface which is highly effective in preventing
 inflammatory reactions. This is a surprising discovery of an otherwise
 biologically inactive surface and of catalytic properties of this
 biomaterial, which appears to be partly attributable to the nature of the
 iridium structure owing to molecular adherence as discussed above and
 partly attributable to the porous sur structure of the iridium oxide
 layer, to enable the stent to be implanted without significant
 inflammation even without the use of anti-inflammatory drugs.
 It is important to observe that these properties of the iridium oxide
 coating surface produced by the method of the invention are applicable not
 only in the specific case of coated stents, but also to other biomedical
 implants.
 With reference to FIG. 2, a metal device, instrument or prosthesis 40 is
 shown in an exaggerated crossectional view in which it is implanted in a
 human body at an adjacent layer of tissue 42. For example, the device 40
 may be a stent which is implanted in an artery whose wall is illustrated
 as 42. It will be understood that only a fragmentary portion of the stent
 is shown in the Figure. The sidewall 44 is composed in part of base metal
 layer 41, and intermediate gold layer 43 which enhances visibility of the
 stent and provides a complete coverage of the base metal as an hermetic
 seal. The outer layer 45 is composed of iridium oxide with a rough outer
 surface 46. Layer 45 is formed on the intermediate gold layer 43 by the
 method which has been described with reference to FIG. 1. The repositories
 or reservoirs 48 formed in the porous surface may be impregnated with a
 biodegradable carrier 50 into which the appropriate beneficial substances
 are incorporated.
 Although certain preferred and alternative methods and embodiment of the
 present invention have been disclosed herein, it will be appreciated by
 those skilled in the art to which the invention pertains, from a
 consideration of the foregoing description, that variations and
 modifications may be made without departing from the spirit and scope of
 the invention. Accordingly, it is intended that the invention shall be
 limited only by the appended claims and the rules and principles of
 applicable law.