WO2002091956A1

WO2002091956A1 - Stent comprising a drug release coating thereon and delivering system thereof

Info

Publication number: WO2002091956A1
Application number: PCT/BR2001/000105
Authority: WO
Original assignee: Dias Maues, Christiane
Priority date: 2001-05-16
Filing date: 2001-08-22
Publication date: 2002-11-21
Also published as: BR0103255A

Abstract

A tubular cylindrical prosthetic device (50), in other words an implantable metallic stent for grafting into the human body, presenting an intraluminal delivering system and being expandable into a second shape by a balloon catheter (25), associated to a drug releasing biological outer coating (32), providing the function of slow and controlled liberation of antiproliferative and antithrombotic drugs, which are stores in various microcapsules (36), said microcapsules (36) being dispersed inside a slow releasing matrix (35). The device (50) presents a limited number of rings (45), formed by transversal rods (29). The transversal rods (29) are connected by longitudinal ligaments (12), disposed along the longitudinal axis of the prosthesis, in an intercepted way. The ligaments (12) are interconnected to the wire mesh tube with spheres of radioactive components (10). The intraluminal delivering system comprises a conventional floppy guidewire (17) for delivering the outer coating (32) in the body passageway, and a balloon catheter (25) attached to the prosthesis in a collapsed state thereon.

Description

STENT COMPRISING A DRUG RELEASE COATING THEREON AND DELIVERING^" SYSTEM THEREOF

FIELD OF THE INVENTION

This invention is related to MEDICAL DEVICES FOR GRAFTING INTO THE HUMAN BODY, and, more precisely, INTRAVASCULAR PROSTHETIC GRAFTS, expandable, of usual format, of metallic constitution, with favorable anatomical, physiological and mechanical properties, used for correction of stenoses or narrowings of the vascular wall or body passageways, aiming to maintain the dilated lumen for a more extended length of time; and a peculiar delivering system for coupling the prosthesis at any organic locus.

BACKGROUND ART

During the last ten years, several coronary prosthetic grafts have been produced and applied in large scale, in order to promote a reasonable expansion or dilation of a localized narrowing within the vascular system, or maintaining the complete expanded form of a vascular passageway, representing also a possible alternative to conventional revascularization surgery. In certain pathological circumstances such as coronary atherosclerosis, with the growth of a tumor of smooth muscular cells, associated with the impregnation of fats, collagen, fibrin and blood cells, affecting several layers of the artery wall and producing a restriction to the local blood flow, the use of percutaneous interventional therapeutic techniques, represented by the coronary angioplasty, associated or not with other methods, has been favorably and receptively assimilated in various medical-scientific institutions around the world. In these situations, the use of expandable metallic prosthesis is very important for the complementation of the initial therapeutic technique in order to obtain a best post-procedure result, for control of the growth of the atherosclerosis plaque and definitive restoration of the vascular blood flow; as well as preventing the restenosis of the treated blood vessel or removing the danger of acute occlusion phenomena, due to dissections of the arterial wall during the procedure.

Among the currently applicable prosthesis, some are differentiated according to the spatial geometric pattern, since they may present themselves with configuration in spiral, in latticework, in scales of interconnected cells, groups of circumferential rings connected by articulations, among others; as well as in relation to the several forms of medical application, that is: to reinforce collapsing structures in the urinary, respiratory and bile tract, support tonus of organs of the digestive apparatus, use in filters of the lower cava vein as prevention of pulmonary embolism episodes, etc. Prodromes of the implant technique of these prosthetic grafts report to 1969, when Dr. Charles Dotter and collaborators investigated the benefits of the experimental use of the spiral prosthetic graft, consisting of stainless steel, applied to popliteal arteries of canine animal experimental model; which at first presented temporarily consistent structural angiographic result, but with an inevitable narrowing of the vascular lumen later on. In this same research front, he obtained the subsequent development of a spiral bioprosthesis, molded in nitinol, a metallic alloy presenting properties of thermal memory. Such device required cooling before its insertion, and subsequent administration of local heat (electric heating) until its full expansion, with recovery of its initial configuration, different from the current balloon catheters widely used for inflation; such process reflected in a large disadvantage, causing serious damages to the surrounding vascular tissues and increasing the thrombogenic potential of blood.

The acquisition of the state of art began with the disclosure of the precursor endoprosthesis of Cesare Gianturco, referred in the U. S. Patent No. 4.580.568 of 1986, improved three years later, detailed in the U.S. Patent No. 4.800.882, where the initial zig-zag configuration, consisting of stainless steel and monofilament, was substituted for another one with spiral configuration, in coil, also monofilament, consisting of stainless steel, of low profile and low radio-opacity. The first one was delivered from a retraction sheath and presented consistent dimensions for use in large vessels of dogs, to the point of the latter required deformation of plastic material for its expansion (balloon catheter), and admitted available extensions in twelve and twenty millimeters, with variable diameters of 2.5 (two point five) to 4 (four) millimeters.

In this new generation, there was an obligatory need to use 8F guide catheters, with large internal lumen (over 0.86 inches), and use of metallic guide cord of 0.018 inches or 0.014 with reinforced internal support, while the available endoprosthesis today received, during 1995, new increments relative to its configuration, with the addiction of a longitudinal bar in stainless steel along all its extension, in order to avoid the deformation of the prosthesis, displacement or cording of the shafts and the occurrence of elastic retraction after its delivery. Still in this modern pattern, the delivery balloon catheters have smaller profile, allowing the use of smaller guiding catheters, able to reach higher pressures, and availability of conventional coronary angioplasty guide cords, with 0.014 inches. Golden radio-opaque markings where added to the ends of this last generation of Gianturco prosthesis, for a safer and more precise positioning. Among a large variety of widely used prosthetic grafts, is the endoprosthesis of Palmaz-Schatz. Expandable through mechanic plastic deformation, the U.S. Patents No. 4.776.337 and U.S. No. 4J33.665, of Palmaz, dated of 1988, demonstrate a tubular intraluminar prosthesis consisting of monofilaments of stainless steel, or cloth, on the surface, configuring a plurality of elongated constituents, intersected among themselves, until reaching the limit borders of the beginning and end of the tubular endoprosthesis. Two distinct forms are observed as to the distribution pattern of the mesh, in the pre and post-expansion phase. This one presenting a non-expandable initial format, allowing it to pass through radio-opaque delivery tubes called guiding catheters, and a final expanded format, obtained with the application of centrifugal force in radial direction, whose intensity will determine directly the expansibility potential of the endoprosthesis, located in the body passageway. Other reference worth mentioning is the U.S. Patent No. 5.102.417, of Palmaz and Schatz, complemented by the U.S. Patent No. 5.195.984, that determines a differentiation of the former models, since the expandable tubular unions are connected by a flexible, generally helicoid bridge (articulation) of 1 mm,. The unions present a discreet rigidity, but with the flexible articulation, the prosthesis may fold, specially when coupled to curved blood vessels. This articulation is somewhat limited relative to movement amplitude, but the prosthesis has a high radial strength, presenting high strength to elastic recoil and allowing good support to the vascular structure. Its global flexibihty and radio-opacity are also remarkable, characterizing a disadvantage, as well as its similarity to other stainless steel prosthesis, since only the fluoroscopic techniques allow the visualization, for assurance of a precise dilation of the prosthesis within the duct or vessel, which is vital for obtaining a successful therapeutic result, hi the same way, we have observed the U.S. Patent No 4.886.062, of Wiktor, demonstrating a balloon expandable prosthetic graft, consisting of stainless steel, copper, titanium or gold alloy. Other various examples of intravascular prosthetic grafts may be referred as follows: U.S. Patent No 5.019.090, of Pinchuk, U.S. Patent No 5.161.547, of Tower; U.S. Patent No 4.969.458, of Wiktor, U.S. Patent No 4.655.771, of Wallsten, U.S. Patent No 5.195.984, of Schatz, Patent PI 9508353-7 A, of Israel; among others. Until today, in spite of the superb effort for industrial creation and development of all these types of the above mentioned coronary prosthesis, the restenosis ("de novo" narrowing of atheroma plaque) of the treated vessel, with this type of advent, is still demonstrated at reasonable rates, and even non-acceptable, varying from the range of 14% to 60%, during the first six months after the implant of the prosthesis, depending on the studied population, configuration and constitution of the material, number of implanted prosthesis, treated vessel, location of the injury, length of the injury, minimal luminal diameter of the vessel after the procedure and minimal luminal gain, etc. This fact is relevantly supported on the occurrence of hyperplasy or intimal hyperproliferation of the wall belonging to the treated vessel, since there is trivially an endothelial proliferation incorporating the prosthesis to the vascular wall up to one week after the procedure to three months from it; a fact that is affirmed by many investigators as reducing the thrombogenicity of the prosthesis.

In fact, with the primary development of the coronary endoprosthesis, since 1986, it was sought as relevant objectives, to improve the short and long tenn results of coronary angioplasty with balloon, to reduce the incidence of acute occlusion and late restenosis. Several random studies, among the main ones, STRESS and BENESTENT, when comparing the use of this type of coronary prosthesis ("stent") with the conventional angioplasty, demonstrated the efficacy of the first alternative, in this case the PALMAZ-SCHATZ prosthesis, for reducing the rates of coronary angioplasty restenosis. Colombo et al made a revolution in the graft technique a posteriori, proving that the high pressure balloon used in the end of the procedure for placing the prosthesis, through the technique of coronaiy angioplasty, allows the appropriate expansion of same, significantly lowering the rates of thrombosis without the use of anticoagulation measures, previously adopted. From these works, among others, a field was open for the investigation of several types of coronary prosthesis, or "stents".

The immediate post-procedure success has shown satisfactory levels (98%), and the subacute intraprosthesis thrombosis, occurring during the first three weeks, has appeared in 3% of the cases. In spite of the acceptance of this fact, there are no formal reports on the type of injury corresponding to the various therapeutic alternatives. The balloon angioplasty has been considered the choice therapy for treatment of vascular restenosis in this situation, with high rate of primary success, but also of restenosis, in spite of the world literature already preconizing technological innovations, such as radiation brachytherapy, laser and viral replication techniques (genetic co-adjuvant therapeutic), see the ITALICS multi center study; still needing more scientific evidence.

As mentioned before, the restenosis after the placement of the stent is still present in considerable levels, since they are metallic devices with mechanical properties allowing TIMI III flow (complete revascularization), with total immediate post-procedure angiographic success, but at long term, there was a reduction of the clinical success, due to vascular restenosis, in ranges of 15% - 20% nowadays.

Such devices present a static characteristic, since they do not act by changing the properties of the affected vascular wall, which would only be possible with local action of drugs, until the moment, tested for the control of the atherosclerotic evolution process. The paramount objective of the invention is, thus, the development of an intra-coronary SRP ("Slow Releasing Pattern") device and an intravascular coupling system, with the analysis of its scientific feasibility and industrial production, and presenting the following characteristics: Mechanical and physiological properties:

Expansibility;

Flexibility;

Radial strength;

Radio-opacity; • Complacence;

High profile;

Adaptability to vascular anatomy;

Low percentage of metallic coating.

Electrochemical and biomolecular properties: • Antithrombogenicity and Antichemitaxy;

High absorption by the vascular wall (good diffusion coefficient of the coating system);

Anti-proliferation and anti-mitogenic activity;

High biocompatibility. In fact, the aim is, through the control of vascular proliferative response or intimal hyperplasy, the significant reduction of the angiographic restenosis rates. The SRP coating (biological drug releasing coating) presents the function of releasing biomolecules of chemicals, with anti-proliferative properties, stored and grouped into microcapsules or microspheres involved in an oily vehicle of slow release, with random spatial arrangement.

DISCLOSURE OF THE INVENTION

The skeleton of the "Coated Stent SRP" system, that is, the tubular cylindrical prosthetic graft or stentor type prosthetic graft, consists of a fenestrated tubular diagram, of regular cylindrical format, multifilament, however without presenting median articulation; characterized for having an initial diameter, allowing its intravascular delivery or in any organic passageway containing a lumen, and a final diameter, expanded by the application of radial and centrifuge force. This force is obtained by the inflation of a dilated part of the catheter covering the guidewire, called balloon catheter, and its intensity will determine the support of the final diameter of the prosthesis, and this continuous expansion will then determine the permanent dilation of the vascular lumen or organic passageway. It is an expandable balloon device, molded in tantalum or nitinol. Nitinol is a nickel titanium metallic alloy, with properties of thermal memory, frequently used in medical prosthesis and orfhesis, presenting good biocompatibiUty, minimum inflammatory response in adjacent tissues, with no material corrosion. The first intravascular stents described by Dotter and subsequent authors were moulded in nitinol. Tantalum is universally recognized by its radio-opacity potential.

However, in spite of all these advantages, we should observe the possibility of using organic material as coating which will increase the biocompatibility of the prosthesis, as well as its anti-thrombogenicity what will be discussed later. The association of spheres of radioactive chemical components is possible in the internal surface of the stent. Its spatial structure is arranged in transversal rods performing the shape of a narrow and elongated "S", connected up by intercepted ligaments, arranged in the longitudinal direction of the prosthesis. Observing it globally, it seems to be a structure with spatial distribution of one single pavement, arranged in "mirror-bricks", growing in the axial direction of the prosthesis.

Initially, at the level of experimental production, the objective is the manufacture of the prosthesis in diameters of 4.0 mm and 5.0 mm, with lengths varying from 12 mm, 18 mm, and 24 mm. The thickness of its transversal rods may vary between 0.08 up to 0.12 mm, so that the metal coated area reaches a rate less than 20%; an important feet to reduce the tendency to thrombosis and traumatism of the vascular wall, which also is a consequence of the finish process of the prosthesis, including chemical polishing of the rods and laser cut for configuration of the material and its spatial structure. The outer coating, that is, the biological coating of the prosthesis, is represented by an artificial biological membrane, biocompatible, which may consist of aminoacids and lipids, or similar substrate, microporous, allowing good capacity for diffusion and drug release. The spatial geometric design is arranged in longitudinal rectangular purses, fully closed, in all the external surface of the stent, in a proportional number to each differentiated dimension of the prosthesis, thus the 4.0 mm prosthesis having the equivalent often (10) rectangular purses, and the 5.0 mm prosthesis having the equivalent of twelve (12) rectangular purses around it. The microcapsules, included inside the rectangular longitudinal purses, are immersed in a slow release vehicle and include several drug types, in liquid or crystal format, such slow release substances being associated with polymer type composites, that regulate the release coefficient thereof; emphasizing that during all stages of the process of manufacture, evaluation, production, in vitro and in vivo scientific feasibility tests, it is possible to modify, eliminate, add or melt whatever types of drugs, according to the necessary formalities, as well as obliterate or rebuild pertinent elements, as long as there are no deep changes in the global set formerly idealized.

The intravascular coupling system, obeying the requirements of low hemodynamic profile, will consist, peculiarly, of a conventional guidewire (guide cord), supporting the deflated biological coating around it, this guide cord being later wrapped up, crossing a balloon catheter consistent with the metallic prosthesis (skeleton of the coated stent), already pre-mounted over it, that will then be coupled inside the biological coating, by sliding the catheters, one under the other.

This invention has been objectively established to attenuate or eliminate the occurrence of restenosis (recurrent growth of the atherosclerotic plaque), even after the dilation by balloon and/or placement of stent type prosthesis on the vascular wall, which appears due to several facts as follows:

1. Miointimal hyperplasy, or proliferation of neointimal tissue is one of the main responsible mechanisms for intra-stent restenosis.*

2. Certain chronic diseases such as diabetes, unstable angina, among others. 3. Relative to aspects of the vascular anatomy itself: restenotic chronic injuries, smaller reference diameters of the treated vessel**, that is, vascular basal calibre to optimize a post-procedure result, extension of the treated plaque (plaques over

15 mm long have a higher risk of post-stent restenosis).

4. Measurement of the minimal diameter of the lumen at the end of the intervention and calculation of the immediate gain of the diameter of the treated site (minimum diameter of the post-procedure lumen minus minimum diameter of pre-procedure lumen).

* It is believed that the presence of the prosthesis inside the vessel under tension may cause an inflammatory reaction due to the enclosure of plaque thrombus. The inflammation inherent to the process stimulates the migration of smooth muscular cells to the sub-intimal region, proliferating with variable intensity concomitantly the secretion of cells from the extracellular matrix, which may result in the formation of a new obstructive intimal layer. Thus, this in situ prosthesis stimulates hyperplasy and formation of a new intimal layer due to the injury of the vessel, since there is an attack to its internal elastic layer.

** Some works define the reference diameter of the vessel as an independent predictor of the late evolution for restenosis, after the graft of intracoronary stents.

Besides allowing a better response of the vascular tonus post-therapeutic procedure, this stent type prosthesis with biological coating presents several characteristics of prevention of coronary restenosis, thus improving the conditions of blood flow and irrigation wholly.

BRIEF DESCRIPTION OF DRAWINGS

According to the respective figures presented in this report, this privilege of invention will be object of appreciation and understanding, in general in this topic, and with more details with the information described below.

FIGURE 1 is a perspective illustration of a tubular cylindrical prosthetic graft, standard stent type, infraluminally expandable, associated with a biological outer coating for drug release, including a cross section in the front area for demonstration of the arrangement and contents of its internal material; consisting of a single object, presenting a pre-dilation initial diameter, allowing its delivery in an intravascular lumen or organic passageway.

FIGURE 2 is a perspective illustration of the same prosthetic graft of FIGURE 1, together with its coating described above, presenting a post-dilation diameter, in its expanded configuration, after its delivery in an intravascular lumen or organic passageway.

FIGURE 3 is a perspective illustration of the mentioned tubular cylindrical prosthetic graft, standard stent type, intraluminally expandable, not associated with its biological outer coating for drug release, in its pre-dilation diameter. FIGURE 4 is a perspective illustration of the same prosthetic graft of FIGURE 3, presenting a post-dilation diameter, in its expanded configuration, after its delivery in an intravascular lumen or organic passageway.

FIGURE 5 is a perspective illustration of the biological outer coating for drug release, separately from the standard stent type prosthetic graft, with a cross section of the front area to demonstrate the arrangement of its internal contents: microcapsules where the antimioproliferation, antiatherosclerotic, and antithrombogenic drugs are immersed in a substrate of controlled slow release, and time controlled release vehicle, dispersed among the same microcapsules. FIGURE 6 shows a perspective view of an intraluminal delivering system, peculiar to this prosthesis type. In an initial stage, with introduction of the biological outer coating inside the internal vascular lumen or organic passageway.

FIGURE 7 shows a perspective view the same intraliuninal delivering system of FIGURE 6, in a stage after the introduction of the system including balloon catheter + standard stent type prosthetic graft, this latter being pre-assembled over the deflated balloon.

FIGURE 8 shows in the same way said intraluminal delivering system of FIGURE 7, in the stage of conclusion of the coupling of the system including balloon catheter + stent type prosthetic graft, inside the biological outer coating, obtained through the introduction and sliding of the balloon catheter over the guidewire.

FIGURE 9 shows the final perspective view of the system including balloon catheter + stent type prosthetic graft, already coupled to the biological outer coating, at initial pre-dilation diameter, as shown in FIGURE 1, at the stage of expectation for the inflation process and expansion of the prosthesis as a whole, for dilation and support of the intravascular lumen or the organic passageway.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENT

More specifically, certain references are presented below related to FIGURES 1 and 2, which show a first embodiment of a tubular cylindrical prosthetic graft 50, intraluminal expandable, or stent type prosthetic graft, or simply prosthesis, associated with its respective biological outer coating for drug release 32, built according to the standards of this invention. It should be understood that the mentioned terms "intraluminal expandable tubular cylindrical prosthetic graft", "stent type prosthetic graft", or simply "prosthesis" are applied in simultaneous forms to name the internal part of this invention, since this is done integrally with the presence of the biological outer coating for drug release 32, as well as the latter may have its use attributed to vascular segments in general, as well as to organic ducts, in order to correct stenoses or narrowings and support their tonus.

FIGURE 1 shows the stent type prosthetic graft 50, detailed in FIGURE 3, associated with its biological outer coating 32, at an initial pre-dilation or pre-inflation diameter, allowing its delivery in an intravascular lumen or organic duct, and FIGURE 2 shows the mentioned object in the post-inflation stage (post-dilation diameter), in its expanded configuration. For effects of perspective illustration, in this document there will he a standard use as model the prosthesis of 5.0 mm diameter and 12 mm long. In reference to FIGURES 1, 2, 3 and 4, the stent type prosthetic graft 50 has a surface consisting of a fenestrated tubular diagram, with no median articulation, in cylindrical rectangular format, multi filament, associated with a biological outer coating for drug release 32. It is an expandable balloon device, molded in tantalum or nitinol.

Now observing with more details, in reference to FIGURES 3 and 4, which show the stent type prosthetic graft 50, not provided with its biological outer coating for drug release 32, in non-expanded configuration and post-inflation stage, respectively. Its spatial structure is arranged in transversal rods 29, in the shape of a narrow elongated "S", connected up by longitudinal ligaments 12, arranged and intercepted in the longitudinal direction of the stent type prosthetic graft 50. So that the union of all the transversal rods 29, forming the geometric figure of a circumference, forming a ring 45, and between each ring 45 arranged in the axial direction of the prosthesis, there will be an intraring space 55, where the longitudinal ligaments 12 will be arranged. The longitudinal ligaments 12 present a geometric arrangement such that at each interval of two transversal rods 29, in relation to the same intraring space 55, they will be present, arranged inside the mentioned intraring space 55, making the connection between two rings 45, but intercalated in relation to the adjoining intraring space 55. Globally observing, there will be a structure with spatial distribution of a single pavement, arranged in "mirror-bricks", growing in the axial direction of the prosthesis. This characteristic may reflect in large radial strength and enough resistance to elastic retraction, due to a smaller flexibihty level of the material. The geometric arrangement of the metal mesh and permanent association of a biological outer coating for drug release 32 do not exclude the impairment, although slight, of blood vessels branches adjoining to the primary injury, as the case may be, and may cause relative imprisonment of these branches and obstruct their access, if necessary, after the graft implant, so that, during the process of scientific evaluation and industrial production of this invention, the possibihty to create some apparatus to minimize or eliminate this difficulty should be considered, such as for example, make opening windows on the surface of the biological outer coating for drug release 32.

Reporting again to the FIGURES 3 and 4, and in lesser scope to FIGURES 1 and 2, there are also, in the illustration of the stent type prosthetic graft 50, spheres of radioactive chemicals components 10 in the internal surface of the same, with spatial distribution connected to the longitudinal ligaments 12, at their intersection with the rings 45 of the prosthesis 50. Each transversal rod 29 in the pre-expansion and post-expansion format, has an acute angle 13, formed by the ascending curve of each transversal rod 29, and an obtuse angle 14, formed by the descending curve of the same structure formerly mentioned.

Observing that each arterial caliber determines the variation of the diameters of the prosthesis, in each prosthesis model there has been observed genuinely different characteristics. The prosthesis of 4.0 mm diameter may present, when expanded, a total number of 7 (seven) transversal rods 29, in order to fill its circumference, originating a ring 45, repeated at each 1.5 mm, which interval will have the longitudinal ligaments 12 in intercalated distribution (brick structure), understanding clearly that each of them will measure 1.5 mm. In this prosthesis model, 12 mm long, there will be a group of 8 (eight) rings 45, with 7 (seven) transversal rods 29 each; observing that, whatever the length of the prosthesis in this same diameter (4 mm), there will always be 7 (seven) transversal rods 29 in each ring 45 and the intraring coaxial spaces 55 - initial and final - will contain 7 (seven) longitudinal ligaments 12, obligatorily; in the other parts of the prosthesis, the distribution will be intercalated. Still considering the prosthesis of 4.0 mm, there may be obtained as circumferential length of each transversal rod 29 the approximate value of 1J9 mm, at the expanded configuration, and 0J6 mm. for each transversal rod 29, when the prosthesis is not yet inflated. In this last case, there will be a circumferential perimeter of 5.33 mm, and in the post-expansion diameter, a circumferential perimeter around 12.56 mm. Considering the prosthesis of 4.0 mm diameter and 18 mm long, there will be a group of 12 (twelve) rings 45, with 7 (seven) transversal rods 29 each; thus the 4.0 mm / 26 mm prosthesis will have 16 (sixteen) rings 45, with 7 (seven) transversal rods 29 each.

On the other side, the characterization of the geometric measurements in relation to the 5.0 mm prosthesis, standard model chosen to illustrate the figures of this document, will be completely changed. The circumferential length of the transversal rods 29 with the prosthesis in the expanded configuration will be around 1J4 mm each, these will grow to a total number of 9 (nine) around the circumference of the prosthesis; consecutively there will be 9 (nine) longitudinal ligaments 12 in the intraring coaxial spaces 55, that is, on the ends, also measuring 1.5 mm each, that will be arranged intercalatedly to the remaining surface of the prosthesis, interconnecting the rings 45. Following the former example, it is observed that the number of transversal rods 29, in each ring 45. that constitutes the prosthesis, will not be changed, since what changes is the length of the prosthesis in relation to its diameter. Thus, in the prosthesis of 5.0 mm/12 mm, 5.0 mm/18 mm and 5.0 mm/24 mm, there will be 8 (eight), 12 (twelve) and 16 (sixteen) rings 45 respectively grouped. The relevant fact is that in the example above, each transversal rod 29 will have a circumferential length of 0.87 mm in a non-expanded configuration; so, there will be a difference of 0.87 mm in the expanded form in relation to the non-expanded form, in relation to each transversal rod 29. Thus, the metal filament, be it tantalum or nitinol, may present a real extension of 1.94 mm per transversal rod 29, since even in the post- expansion format, the transversal rod 29 still has a slight central bend, "S" type, obeying the original format, since it does not obtain a straight line format by itself, since this fact would affect the efficacy of the mechanical properties of the stent type prosthetic graft 50. This geometry has the purpose of creating small area spaces with the metal mesh consisting the stent type prosthetic graft 50, reducing the phenomena of local turbulence due to the internal smooth surface, providing good support to the arterial wall to contain dissections and rotations, and reducing the size of the in-stent window to avoid the inflow of atherosclerotic plaque during the graft implant.

FIGURE 5 shows a perspective illustration of the biological outer coating for drag release 32, already shown consisting the prosthesis as a whole, in the FIGURES 1 and 2, whose structure is represented by an artificial biological membrane, biocompatible, consisting of primary oligoelements, normally present in the biologic cellular membranes in general, such as phospholipids, triglycerides, proteins, among others; since it is microporous, it presents good capacity for diffusion and drug releasing. The spatial geometric design is arranged in longitudinal rectangular purses 11, fully closed, distributed in all the external surface of the stent type prosthetic graft 50, shown in FIGURES 3 and 4, along its axial direction, having an organized amount of micro capsules 36 inside it, also consisting of the same type of substrate used in the production of the clothing membrane of the biological outer coating for drug release 32. Drugs with antimioproliferation, antiatherosclerotic, and antithrombogemc effects will be present inside these microcapsules 36, and will be immersed in substrates with controlled slow release, such as the polymer type composites, the microcapsules 36 will be dispersed in a liquid-gelatin vehicle of time controlled release 35. Still in relation to FIGURES 1 and 2, and especially FIGURE 5, the contents of the artificial biological membrane 34, constituting the biological outer coating for drug release 32, are presented in double layer, with an external surface of membrane 15 and an internal surface of membrane 16, possibly of hy rophilic polarity, since all the experimental models for production of artificial biological cellular membranes obey the rule of the general organic pattern. The longitudinal rectangular purses 11 are connected among themselves by a connection seal 37, in order to avoid the unorganized dispersion of their internal material, that is, the microcapsules 36 and the liquid-gelatin vehicle of time controlled release 35, as well as a coaxial closing seal 38 also is present in the ends of the longitudinal rectangular purses 11, with the same function as described above.

FIGURES 6 to 9 show a perspective illustration of an intraluminal delivering system, characteristic to an expandable intraluminal tubular cylindrical prosthetic graft 50, shown in FIGURES 3 and 4, associated with a biological outer coating for drug release 32, as characterized in this invention embodiment. FIGURE 6 shows the schematic representation of a peripheral blood vessel 22, presenting a lumen 19, as would be applicable to any organic duct presenting a lumen, this blood vessel corresponds to a standardized access for percutaneous transluminal angioplasty, preferably performed in obstructed coronary arteries, normally executed with the puncture of external femoral arteries. Thus, establishing a peripheral access site at the femoral arterial level, a guiding catheter 20 is introduced, 8 French, or with larger caliber if possible, where, through its proximal connector 24, the support system will be guided and coupled, and the prosthesis will be dehvered. In this characteristic situation, a conventional guidewire 17 will be molded, with moderate flexibihty (the ones most used vary from 0.012 to 0.016 inches), presenting a localized thickening in its course, where the biological outer coating for drug release 32 will already be coupled, which thickening will be limited at its ends by spheres consisting of material with high radio-opacity level 23, with the function of facilitating the fluoroscopic view of the biological outer coating 32 and the subsequent coupling of the stent type prosthetic graft 50, during the procedure. Introducing this conventional guidewire 17, through the guiding catheter 20, and viewing the biological outer coating 32, the next stage wul be the coupling of the metallic structure inside the latter mentioned. FIGURE 7 shows a perspective view of the introduction of a balloon catheter 25, consistent with the stent type prosthetic graft 50, already pre-assembled on the deflated balloon 26, where we can observe the transversal rods 29; through the same guiding catheter 20, this balloon catheter 25 will be guided until the level of location of the biological outer coating 32, inside a lumen 18 of the guiding catheter 20, with the deflated balloon 26, and the stent type prosthetic graft 50 coupled to it, also limited at its ends with spheres of high radio-opacity level 23a, that in a similar way will facilitate the unequivocal location and coupling of the stent type prosthetic graft 50 to the biological outer coating for drag release 32. In relation to FIGURE 8, the illustration represents a stent type prosthetic graft 50, detailed in FIGURES 3 and 4, already attached inside its biological outer coating for drug release 32, through the introduction of a balloon catheter 25, inside the lumen 18 of a guiding catheter 20, introduced by puncturing, in a lumen 19 of a peripheral blood vessel 22, where the conventional guidewire 17, initially designed to support and direct the biological outer coating 32, may optionally be withdrawned, and changed by another guide cord with better performance related to the procedure, concluding then the final stage of coupling the structures including balloon catheter 25 + stent type prosthetic graft 50 + biological outer coating 32, in its pre-inflation initial diameter, as shown in FIGURE 1 of this document, with the complete system to be directed to the target lesion, that is, stenoses or occlusions within blood vessels, specially coronary arteries, and within organic ducts in general, through the guiding catheter 20. A special configuration may be assigned to this guiding catheter 20, with transparent material, since it would allow the view of all the structures to be directed and coupled inside it, since the conventional guiding catheters are manufactured with radio-opaque material and dark color, with the exceptional need of configuration with radio-opaque material at the last five centimeters of its length, during the guidance of the same through the blood vessel or organic duct and in relation to the complex of the stent type prosthetic graft 50 and its biological outer coating 32, in the pre-inflation stage. In order to facilitate the coupling and sliding between the structures of the system, a slightly adhesive resin will be applied inside the biological outer coating for drug release 32, not offering risk to the orgamc structures relative to the adherence potential, to provide enough safety to avoid intraluminal loss or migration of the biological outer coating 32, and also to facilitate the fixation of the deflated balloon system 26 + stent type prosthetic graft 50 to the biological outer coating 32, during the process of inflation and dilation of the components, that is, the transluminal angioplasty process itself.

FIGURE 9 ends the perspective illustrations of this document, showing the same components of the balloon catheter system 25 + stent type prosthetic graft 50 + biological outer coating for drug release 32, shown in FIGURE 8, emphasizing them without the presence of a peripheral blood vessel 22, in a expectation stage for the process of inflation and expansion of the prosthesis as a whole, for the dilation and support of the stenosed vascular segment or organic duct. The inflation potential of the system shall be ideal to produce optimum expansion of the stent type prosthetic graft 50 associated with a biological outer coating for drug release 32, with acquisition of a good luminal minimum diameter immediately after the procedure; the indication of the prosthesis is not recommended for ostial injuries, with bending or calcification, when applied to blood vessels, associated, in these cases, with the use of complementary devices for a better angiographic result.

BEST MODE FOR CARRYING OUT THE INVENTION The best mode for carrying out this invention is the production of the tubular cylindrical prosthetic graft 50, as shown in FIGURES 3 and 4, through the obtainment of treated raw material, that is, tantalum or nitinol, and molding it in industrial oven according to the required diameters and lengths, which means obtaining several molds, namely: preparation for the 4.0 mm diameter prosthesis, in three lengths of 12 mm, 18 mm and 24 mm; preparation for the 5.0 mm diameter prosthesis, in three lengths also of 12 mm, 18 mm and 24 mm. The molds will be based on a non-expanded configuration of the prosthesis, thus, for the 4.0 mm model, there will be an approximate profile of 1J0 mm, and for the 5.0 mm model, an approximate profile of 2.5 mm.

After the acquisition of the pre-molded format of each prosthesis, the units will be submitted to laser cutting, controlled by computer, obtaining thus the final configuration and design of the mentioned tubular cylindrical prosthetic graft 50, as shown in FIGURES 3 and 4, then the same may also receive a final polishing with a coat of sihcon carbonate, or similar antithrombogenic material, after this the spheres of radioactive chemical components 10 will be fixed by thermal welding in the internal surface of the prosthesis.

The preparation of the biological outer coating for drug release 32, shown in FIGURES 1, 2 and 5, is done with the in vitro production of the contents of the artificial biological cellular membrane 34, with a protein lipid matrix, easily prepared in specialized laboratories. After the manufacture of several strips, with width related to each prosthesis length, that is, 12 mm, 18 mm and 24 mm, the artificial biological cellular membranes are placed one over the other and, with specific industrial apparatus, the longitudinal rectangular purses 11 are molded continuously, separated among themselves by a connection seal 37, FIGURES 1, 2 and 5. The ends of each biological coating for drug release 32 are connected again with a secondary connection seal 37, obviously respecting the dimensions of each prosthesis and its exclusive expansion potential. The contents of the longitudinal rectangular purses 11, that is, the liquid-gelatin vehicle of time controlled release 35, according to FIGURES 1, 2 and 5, more accurately, may be applied inside them, after the introduction of the microcapsules 36, containing specific drags inside them, and the application of the coaxial closing seal 38 at one of the ends, FIGURE 5. After this process, the following procedure is the total closure of the longitudinal rectangular purses 11, FIGURES 1, 2 and 5, with the application of the coaxial closing seal 38, at the other end of the same.

It is important to observe that for assembling the delivery system of the prosthesis, the tubular cylindrical prosthetic graft 50, FIGURES 3 and 4, remains separated from the biological outer coating for drag release 32, FIGURES 1, 2 and 5, during the stages of production and assembling of the kit, this tubular cylindrical prosthetic graft 50 may be manually pre-assembled by the expert physician who will perform the procedure, or it can be pre-assembled on the deflated balloon 26, in the original kit.

The biological outer coating for drug release 32, FIGURES 6 and 7, will be already pre-attached to the conventional guidewire 17, but without the application of the slightly adhesive resin inside the biological outer coating for drug release 32, subsequently performed by the expert physician responsible for the procedure.

INDUSTRIAL APPLICABILITY

The industrial use and commercial designation of this object of invention has a reasonable number of advantages, since this type of prosthesis may be used for the treatment of multivascular atherosclerotic disease, correcting stenoses or obstructions of blood vessels, while providing the maintenance of the patency thereof during a long time period, that is, optimizing the initial therapeutic results, and may also be used for the dilation or expansion of body passageways, collapsed due to different etiology diseases, present in the urogenital system and the respiratory and bile tracts, besides supporting the tonus of organs of the digestive system, such as the esophagus and duodenum, intestines, among others.

Isolatedly, the tubular cylindrical prosthetic graft 50, FIGURES 3 and 4, may offer more general applications such as the ones described in the precursor patents formerly mentioned in this document, working as a simple prosthesis, without the function of local drug releasing, since the pathological situations are not always homogenously presented as a whole. Diseases such as coarctation of the aorta, congenital stenoses of renal, subclavian, iliac arteries and veins, without a degenerative condition of the arterial wall, are relevantly indicated for the use of these peculiar type of metallic prosthesis, the stents, by themselves, since the anomaly is of anatomic origin, not acquired.

The biological outer coating for drug release 32, FIGURES 1, 2 and 5, presents several applicable characteristics such as: use as coating in other stent types, intravascular or not; attachment to natural and artificial cardiac valves, in order to lengthen the durability of the first one, and reduce the rate of complications of the second one, exemplified by thrombosis, embolism, valve endocarditis and hemolysis, among others; application associated with intravascular filters, such as the ones used in the lower cava vein to prevent embolism phenomena; association to intraorganic birth control devices such as IUD (intra-uterine device), for example, for local drag releasing, such as hormones, antibiotics, anti-inflammatory drags, etc.; use as coating for several types of intraorganic devices used for cancer treatment, for releasing drugs inherent to the pathology or to increase the desired effect; use as bioactive protection coating in implantable defibrillators or cardiac pacemakers; among other applications. Its geometrical design may be changed as a function of the application of the device with which this coating will be associated.

The concept that the investigative science of therapy is still crawling is true and, also, more precisely, of the prophylaxis of local release of intraorganic substances through implantable grafts, but in view of the seriousness and reliability imposed by this subject, soon we will conquer another relevant challenge and move forward to a new age of human development.

Claims

1. A tubular cylindrical prosthetic device (50), in fact a metallic stent, characterized for being deliberated in blood vessels and body passageways, comprising: a collapsible tube member having a first end and a second end, said collapsible tube being a wire formed into a brick-work configuration, straightened along the longitudinal direction of the prosthesis; a limited number of transversal rods (29), according to the presentation model, in which said structures are represented as a series of bends, having the geometric shape of a letter "s", in a narrow and lengthened direction, said transversal rods (29) connected up by longitudinal hgaments (12), disposed in and intercepted along the longitudinal direction of the prosthesis, to form the stent (50); wherein said tubular cylindrical prosthetic device (50) is resihently depressible into a smaller first shape wherein said transversal rods (29) are compressed in a shorter disposition, more contractile; wherein said tubular cylindrical prosthetic device (50) is resihently expandable, by the release of stress applied to its metallic components and provided from a balloon (26) inflation, into a second shape wherein said transversal rods (29) elongate from the former shape to support the wall of the passageway, in order to maintain it open; an outer coating (32) formed into an artificial biological compatible membrane, said outer coating (32) having a geometrical design of longitudinal rectangular purses (11) joined to one another, extending along the outer surface of the prosthesis.

2. The tubular cylindrical prosthetic device (50) of claim 1, wherein said longitudinal rectangular purses (11) along the outer coating further comprising a variety of microcapsules (36) therein, said microcapsules (36) being scattered in a slow releasing vehicle containing polymerics substances (35); and, wherein said microcapsules (36) additionally containing antimioproliferative and antithrombotic drugs, associated to polymerics compounds therein, which confers a controlled releasing coefficient on the prosthesis itself.

3. The tubular cylindrical prosthetic device (50) of claim 1 is made of antithrombotic and thermal shape memory metal, like tantalum and nitinol, said prosthesis being expandable by a balloon-inflated catheter (25); and, wherein said tubular cylindrical prosthetic device (50) has a wire mesh tube varying from 0.08mm to 0.12mm in prosthetic thickness, according to the presentation model, to make possible to have a small percentage of covered metal, providing a smaller rate of complications; and, wherein said outer coating's membrane (15,16) is porous, providing good releasing capacity and drugs diffusion, and could present multiple layers comprising various orifices of interconnection between the intraluminal space and the organic surface (wall of blood vessels or body passageway ) adjoining the prosthesis.

4. The tubular cylindrical prosthetic device (50) of claim 1 wherein said prosthesis in its second shape is 12 mm, 18 mm and 24 mm long, and 4.0 mm in diameter - relative final dimensions after dilation.

5. The tubular cylindrical prosthetic device (50) of claim 1 wherein said prosthesis in its second shape is 12 mm, 18 mm and 24 mm long, and 5.0 mm in diameter - relative final dimensions after dilation.

6. The tubular cylindrical prosthetic device (50) of claims 4 and 5 wherein said prosthesis has 7 (seven) transversal rods (29), performing its circumference, repeatedly each 1.5 mm interval, in which the longitudinal hgaments (12) stand on, interleaved with said transversal rods (29), similarly to bricks wall; and, wherein said longitudinal hgaments (12) are 1.5 mm long, in both 4.0 mm and 5.0 mm diameter prosthesis.

7. The tubular cylindrical prosthetic device (50) of claim 4 wherein said prosthesis containing 8 (eight) rings (45) formed into 7 (seven) transversal rods (29) each. Finally, concerning the 24 mm long presentation model, there are 16 (sixteen) rings (45), containing the same 7 (seven) transversal rods (29) each; and, wherein said each transversal rod (29) nearly measures 1J9 mm in length, when the prosthesis is expanded, and 0.76 mm in length, when the one is still not inflated. A circumferencial perimeter of 5.33 mm is nearly acquired in its first shape, which means before dilation, and 12.56 mm in perimeter after being expanded into its second shape.

8. The tubular cylindrical prosthetic device (50) of claim 4 wherein said the 4 mm prosthesis, whatever length is present (12mm, 18mm or 24mm), the first and last rings (45) will compulsorily comprise 7 (seven) longitudinal hgaments (12), and the remainder disposition will be interleaved with each other through the prosthesis.

9. The tubular cylindrical prosthetic device (50) of claim 5 wherein said the 5 mm prosthesis presents 9 (nine) transversal rods (29) making up the circumference of the rings (45) along the prosthesis, and said transversal rods (29) nearly measuring, in circumferencial length, 1.74 mm each, when in an expanded status, and 0.87 mm in a not inflated one; wherein said prosthesis similarly presents variable lengths just like the former: 12 mm, 18 mm and 24 mm long; and thus there will be respectively groups of 8 (eight), 12 (twelve) and 16 (sixteen) rings (45) in each specific presentation model of the prosthesis; and, wherein said first and last rings (45) of the prosthesis will compulsorily comprise 9 (nine) longitudinal hgaments (12), also measuring 1.5 mm long, and the remainder disposition will be interleaved with each other through the prosthesis.

10. The tubular cylindrical prosthetic device (50) of claim 1 additionally comprising spheres of radioactive components joined to the wire mesh tube, in order to provide beta radiation emission mainly, and even other kinds of radiation sources.

11. A peculiar delivering system for inserting a tubular cylindrical prosthetic device into a blood vessel or body passageway which comprises: a set containing a floppy steerable guidewire (17) and a premounted biological outer coating (32) on, but in a not inflated status, and said outer coating (32) is luminally filled with a slightly adhesive resin and then coupled with the floppy guidewire (17). a tubular cylindrical prosthetic device (50) being premounted and coupled onto a deflated balloon catheter, and this system later being driven and attached into the outer coating (32). As well as in routine conventional angioplasty procedures, both floppy guidewire (17) and balloon catheter are manipulated so that the floppy guidewire (17) is withdrawned, and the complete balloon-prosthesis-outer coating set stands ready to be driven towards the target lesion. A quick-exchange system catheter is considered to be extremely useful, in this specific subject.

12. A peculiar delivering system of claim 11 wherein said system is wholly premounted, in other words, the coupling of the metallic prosthesis into the biological outer coating (32), either infraluminally or out of the punctured blood vessel (22) and body passageway, but never at the site of the target lesion, must obviously be performed inside a conventional guiding catheter (20), which is frequently used in vessel peripheric access and presents a large caliber. This maneuver may provide more safety during the handling of catheters exchange and the attachment of structures. In a variable way, this guiding catheter (20) for peripheric access, which can be an 8 French or a larger one, should be produced in transparent material, so that it allows better visualization in handling and attachment of structures during the medical procedure, with the exception of its last 5 (five) cm, whose material demands permanent radio-opacity during the handling of intravascular procedure.