WO2022061430A1

WO2022061430A1 - Non-polymeric cylindrical tubular prosthetic device

Info

Publication number: WO2022061430A1
Application number: PCT/BR2021/050361
Authority: WO
Inventors: Christiane Dias MAUÉS
Original assignee: Maues Christiane Dias
Priority date: 2020-09-27
Filing date: 2021-08-25
Publication date: 2022-03-31
Also published as: BR102020019674A2

Abstract

The invention relates to a non-polymeric, biocompatible, expandable intravascular or organic prosthetic device (50, 51) for releasing multiple drugs (33), by extrinsic factors, such as precursor drugs (36), released via organic implants, namely intradermal microchips (43) (for the controlled, gradual release, pre-programmed via a remote central unit, by software, a device or a mobile device, of these precursor drugs, which reach the prosthesis and act on the release mechanism of the specific medications at the target site of the stent). The structure of these microchips can contain nanochips and biosensors (46) in order to optimize the control and release rate of the in-stent drugs, and can provide measurements of hemodynamic, chemical and homeostatic variables, to provide information about biases and clinical complications. The device is coupled to its internal release matrix, represented by an artificial biological membrane, the geometric spatial arrangement of which originates from the cells that form the stent itself, said cells being open on the entire internal surface.

Description

NON-POLYMERIC CYLINDRICAL TUBULAR PROSTHETIC DEVICE

FIELD OF THE INVENTION

[001] The present invention refers to medical devices implantable in the human body, and, more precisely, to intravascular prosthetic devices, called "stents", expandable, of usual shape, of metallic constitution, or biocompatible organic resin, with anatomical properties , physiological (pharmacological) and favorable mechanics, used in the correction of stenosis or narrowing of the vascular wall or body ducts, aiming to maintain their support for a longer period of time, in addition to promoting an ideal remodeling process due to balanced healing activity of the affected vascular wall. At first, the mechanical properties conferred by these prostheses, by obtaining the simple dilation of the segment of the affected vessel and the function of supporting the vascular wall (remodeling), were shown to be a static characteristic, that is, they were not capable of modifying the state of the vessel. biochemical and hemostatic of the affected vascular wall, where the inflammatory reactions typical of the vascular atherosclerosis process are present, either the immediate or late reaction to the therapeutic manipulation given by the interventional process itself with the balloon catheter and the consecutive implantation of the intravascular stent, called vascular restenosis. The complexity of this type of process could only be addressed by the local action of drugs, which occurred with the innovation of drug-eluting stents, since 2001. However, after several clinical meta-analyses around the world, it was found that such stents had a property deleterious to the vascular wall itself, since the way in which the drug, together with the polymer, was adhered and fixed to the stent structure was important in potentiating the side effects of these durable polymer coatings, leading to the perpetuation of the sources of inflammation, with low healing potential of the vascular wall and increased risk of local thrombosis. From this notion, it is stated that drug-eluting stents encompassed the sought after mechanical and pharmacological properties, however, they were statistically identified as a target of complications and clinical failure, such as late acute thrombosis.

[002] In this sense, aiming to solve this bias, some centers of research, in partnership with industry, developed bioabsorbable stents, which also did not bring the results that doctors imagined, and the effectiveness of the technique has been increasingly questioned, in view of the difficulties related to the preparation of the procedure, and the need for prior evaluation of the vessel wall using increasingly sophisticated imaging techniques, such as optical coherence tomography, according to some respected Brazilian and international researchers. Likewise, data from

2-year follow-up of the ABSORB III Study, showing target lesion failure rates of 11% with this bioabsorbable stent and 7.9% with the primary drug-eluting stent, with p = 0.03. This made the FDA ("Food and Drug Administration"), an American body for the inspection and certification of medical treatments, issue, on 03/18/17, a statement to all physicians, warning of the increased risk of adverse events. cardiovascular diseases with this bioabsorbable stent, reinforcing its use only for cases approved in the studies (simpler lesions) and not to implant in small-caliber vessels (< 2.5 mm).

[003] So, once again, this long-established therapeutic technique is adrift, in readiness for new emerging innovations for more reliable, more effective vascular stents that achieve optimal statistical results.

BACKGROUND OF THE INVENTION

[004] In the last twenty-five years, several coronary prosthetic devices have been produced and applied on a large scale, with the aim of promoting a reasonable expansion or dilation of a localized narrowing in the vascular system, or to maintain the neat patency in a duct. vascular system, also representing a possible alternative to conventional revascularization surgery. In certain pathological circumstances such as coronary atherosclerosis, where there is the growth of a tumor of smooth muscle cells, associated with the impregnation of fats, collagen, fibrin and cells of the hematopoietic system, affecting several layers of the arterial wall and producing a flow restriction. local blood flow, the use of percutaneous interventional therapeutic techniques, represented by coronary angioplasty, associated with other methods, has been receptively and favorably assimilated. in the most diverse medical-scientific institutions around the world.

[005] In these situations, the use of expandable metallic coronary prostheses is of great importance in complementing the initial therapeutic technique to obtain a better post-procedure result, in controlling the growth of atherosclerotic plaque and definitive restoration of vascular blood flow; as well as preventing re-obstruction of the treated vessel or ruling out the danger of acute or late occlusion phenomena, caused by arterial wall dissections during the procedure or complications inherent to the fatty plaque itself.

[006] Of the various prostheses currently applicable, some undergo differentiation as far as the spatial geometric pattern is concerned, since they can be presented with a spiral configuration, in a lattice, in interconnected cell scales, in groups of circumferential rings joined by joints, among others, regarding the constitution of drugs and polymers on its surface, such as drug-eluting stents; as well as in relation to the different forms of medical applicability, namely: maintaining openings in the urinary, respiratory and biliary tracts, sustaining digestive system organ tone, using filters in the inferior vena cava to prevent episodes of pulmonary embolism, etc.

[007] The prodromes of the technique of implantation of these prosthetic devices go back to 1969, when Dr. Charles Dotter et al. investigated the benefit of the experimental use of a spiral-shaped vascular prosthetic device, made of stainless steel, applied to popliteal arteries in an experimental canine animal model; which presented temporally compatible structural patency, but with inevitable narrowing of the vascular lumen. Keeping on this same research front, he managed to develop a spiral bioprosthesis, molded in nitinol, a metallic alloy that has thermal memory properties. Such a device required a cooling technique prior to its insertion, and the subsequent administration of local heat (electrical heating) until its complete expansion, with recovery of its initial configuration, unlike the current balloon catheters that are widely used for its insufflation; this process was reflected in a great disadvantage, causing serious injury to the surrounding vascular tissues and increasing blood thrombogenic potential.

[008] The acquisition of the state of the art had its beginnings with the disclosure of Cesare Gianturco's precursor endoprosthesis, referenced in US Patent No.

4,580,568, of 1986, whose improvement took place three years later, detailed in Patent 4,800,882, where the initial zigzag configuration, made of stainless steel and monofilament, was replaced by another with a spiral configuration, in serpentine, also monofilament, made of stainless steel, of low profile and low radiopacity. The former was implanted by a retraction sheath and had dimensions compatible with use in large dog vessels, since the latter required deformation of plastic material for its expansion (balloon-catheter), and allowed extensions available in twelve and twenty millimeters. , with variable diameters from 2.5 (two and a half) to 4 (four) millimeters.

[009] In this new generation, there was a mandatory need for the use of 8F guide catheters, with a large internal lumen (greater than 0.86 inches), and the use of a 0.018 inch or 0.014 metallic guide rope with reinforced internal support, while the endoprosthesis later available, it underwent, in 1995, new increments with regard to its configuration, with the addition of a stainless steel longitudinal bar along its entire length, in order to prevent deformation of the prosthesis, displacement or alignment of the rods and the occurrence of elastic retraction after its release. Even in this more modern standard, the release balloon catheters have a smaller profile, which allows the use of smaller guide catheters, being able to reach higher pressures, in addition to the conventional guide ropes for coronary angioplasty, with 0.014 inches. Radiopaque gold markings have been added to the ends of this latest generation of Gianturco prostheses for safer and more accurate positioning.

[0010] Among a wide variety of prosthetic devices widely used, the primarily used Palmaz-Schatz endoprosthesis is reported. Expandable through plastic mechanical deformation, US Patents No.

4,776,337 and US No. 24,733,665, from Palmaz, dating from 1988, demonstrate a tubular intraluminal prosthesis consisting of stainless steel monofilaments, or tissue, on its surface, configuring a plurality of elongated constituents, intersecting with each other, until reaching the boundary edges of the beginning and end of the tubular endoprosthesis. They are observed in two different ways regarding the geometric distribution pattern of the mesh, both in the pre- and post-expansion phases. It is coming to present a non-expandable initial shape, which allows its passage through radiopaque support and position tubes, called guide catheters, and an expanded final shape, which is acquired through the application of a centrifugal and radially directed pressure, whose intensity will directly determine the expandability potential of the endoprosthesis, located through the body duct. Another noteworthy reference is US Patent No. 5,102,417, by Palmaz and Schatz, complemented by US Patent No. 5,195,984, which differentiates from previous models, as the expandable tubular joints are connected by a bridge (articulation) of 1 mm, flexible, usually helical. The joints present slight rigidity, however, with the flexible joint, the prosthesis may present folds, especially when attached to curved blood vessels. Such a joint is somewhat limited in terms of range of motion, but the prosthesis had great radial strength, exhibiting high resistance to elastic retraction and providing good support to the vascular structure. Its global flexibility and radiopacity were somewhat reduced, characterizing a disadvantage, as well as its similarity to other stainless steel prostheses, since only through fluoroscopic techniques, visualization was allowed, the certainty of a precise deliberation of the prosthesis through the duct. or vessel, which is vital for obtaining a successful therapeutic result.

[0011] Likewise, we note the U.S. Patent Wiktor No. 4,886,062 demonstrating a balloon-expandable prosthetic device made of stainless steel, copper alloy, titanium or gold. In this remote era, several other examples of intravascular prosthetic device patents can be referenced as follows: U.S. No. 5,019,090 to Pinchuk; U.S. Patent No. 5,161,547, to Tower; U.S. Patent No. 4,969,458, to Wiktor, U.S. Patent No. 4,655,771, to Wallstent; Patent No. 5,195,984 to Schatz; Israel Patent PI 9508353-7 A; among others.

[0012] Until the beginning of the current century, despite the superb effort to create and industrial development of all these types of coronary prostheses mentioned above, restenosis (narrowing by atheromatous plaque "again") of the treated vessel, with this type of advent, still showed up at reasonable and, why not say, unacceptable rates. , ranging from 14% to 60%, in the first six months after implantation of the prosthesis, depending on the population studied, configuration and constitution of the material, number of implanted prostheses, treated vessel, lesion location, lesion length, luminal diameter vessel after the procedure and its minimum luminal gain, etc. This fact is relevantly supported by the occurrence of hyperplasia or intimal hyperproliferation of the treated vessel wall, as there is trivially an endothelial proliferation that incorporates the prosthesis into the vascular wall from one week after the procedure to three months following the procedure; fact that many claim to reduce the thrombogenicity of the prosthesis.

[0013] In fact, with the primary development of coronary endoprostheses, from 1986, relevant objectives were sought to improve the short and long-term results of coronary balloon angioplasty, reduce the incidence of acute occlusion and late restenosis. Several randomized studies, the main ones being STRESS and BENESTENT, when comparing the use of this type of coronary prosthesis ("stent") with conventional angioplasty, demonstrated the effectiveness of the first alternative, in this case the PALMAZ-SCHATZ prosthesis, in reducing the rates of restenosis after coronary angioplasty. From these works, among others, a field was opened for the investigation of different types of coronary prostheses, or "stents".

[0014] Immediate post-procedure success was shown to be satisfactory (98%), and subacute intraprosthesis thrombosis, occurring in the first three weeks, was revealed in 3% of cases. Despite the recognition of this fact, there are no formal reports on the type of injury that responds to the various therapeutic alternatives. Until that time, balloon angioplasty had been considered the therapy of choice for the treatment of vascular restenosis in this situation, with a high rate of primary success, but also of vessel re-obstruction, despite the fact that the world literature had already advocated technological innovations at the time, such as radiation brachytherapy, laser and viral replication techniques (genetic adjuvant therapy), see the study multicenter ITALICS; still needing more scientific evidence.

[0015] As previously stated, restenosis after stent placement was still present at considerable levels from 1999 to 2000, as they were metallic devices with mechanical properties that could provide TIMI III flow (complete revascularization), with immediate post-procedure angiographic success, but in the long term, there was a decrease in clinical success, due to vascular restenosis, at rates of 15%-20% in that period.

[0016] Such devices were only limited as a static characteristic, as they did not interact, modifying the properties of the affected vascular wall, which would only be possible with the local action of drugs, so far, tested in the control of the atherosclerotic evolutionary process. Since the beginning of their use, in 1987, common coronary stents have been increasingly used to treat increasingly complex pathological conditions, however frustrating expectations that they would be able to curb neointimal proliferation of the vascular wall. From their applicability, stents, by themselves, can prevent the phenomenon of post-intervention vascular elastic recoil and seem to also act in adverse remodeling, but in preventing in-stent restenosis, the additional use of an agent release strategy antiproliferative drugs of the stent itself, acting to synergistically reduce the restenotic lesion, was necessary.

[0017] From 1992, the approval of two of the most important stents used to date, Gianturco-Roubin (Cook) and Palmaz-Schatz, made universally feasible, with great credibility, the use of this type of endoprosthesis, since only the Palmaz-Schatz model, until 1996, reached 1,000,000 treated patients worldwide.

[0018] Regarding the clinical context, endoprostheses have current applicability both in acute ischemic syndromes (unstable angina and myocardial infarction) and in stable chronic coronary artery disease. With regard to acute myocardial infarction, its use has ranged from the primary interventional condition, such as rescue circumstances after failure of fibrinolytic treatment, and still the elective indication, when the presence of severe residual stenosis is verified.

[0019] Therefore, the first stents were developed with the aim of increasing short and long-term results in coronary angioplasty procedures, but with the introduction of the first drug-eluting stents, the immediate results showed a significant reduction in restenosis rates, but these concomitantly caused a chemical sweep of the subendothelial and neointimal layers of the vascular wall, rather than preventing a balanced tissue neoformation. Later effects related to polymeric biodegradation, involving the phenomenon of late thrombosis, inevitably emerged.

[0020] At the academic-scientific level, the ideal stent is the one that offers a biocompatible platform of polymeric material or, when absent, provides effective and safe rates and concentrations of drug release at the affected site, in addition to electrochemical properties and biomolecular, and high absorption capacity of the vascular wall. As a reference for records on drug-eluting stents, PI 0317150-7 A (Publication Date: 11/01/2005) is cited; PI0213279-6 A (Publication Date: 10/26/2004); PI 0503201-6 A (Publication Date: 03/13/2007); US 20100191323 A1 (Publication Date: 07/29/2010); US 20090182404 Al (Publication Date: 07/16/2009). Reference is also made to document PI 0103255-0, of 05/16/2001, supplemented by document W002/091956 Al (PCT/BR01/00105), of 08/22/2001, in which microcapsules/liposomes are also present, involved in a polymeric support matrix, contained in an external, biocompatible, artificial biological layer, together with an internal metallic stent support, in a spatial geometric pattern of mirror bricks ("mirror bricks"), peculiar to this intellectual property registration, also aiming at the long-term release of in-stent medications, in a gradual and controlled manner.

[0021] Therefore, the primary objective of the invention is the development of a biocompatible, non-polymeric intracoronary device for the release of multiple drugs, in a gradual and controlled manner, through extrinsic factors, such as precursor drugs released via implants organic - intradermal microchips (which would have the function of releasing in a controlled, gradual and pre- programmed, via remote central, by a software, device or cell phone, the precursor drugs, responsible for, through the bloodstream, reaching the prosthesis and acting in the mechanism of release of specific medications in the target site of the stent), or via matrices slow drug release organics, of polymeric constitution, or biological films, or even subdermal resins (release systems); and when that is the case, these microchips still contain nanochips and biosensors in their own structure, in order to optimize the control and the in-stent drug release pulse, in addition to providing real-time measurements of hemodynamic, chemical and homeostatic variables, aiming at this type of prosthesis to fill the gap of biases and clinical complications, through the analysis of its scientific feasibility and industrial production, and that has the following peculiarities:

[0022] Mechanical and physiological properties:

• expandability;

• flexibility;

• radial force;

• radiopacity;

• complacency;

• high profile;

• adaptability to vascular anatomy;

• low percentage of metallic coverage.

[0023] Electrochemical and biomolecular properties:

• antithrombogenicity;

• antichemotaxis;

• high absorption by the vascular wall (good diffusion coefficient of the envelope system);

• antiproliferative and antimitogenic activity;

• high biocompatibility.

[0024] In fact, the objective, through the control of vascular proliferative response or intimal hyperplasia, is to significantly reduce the rates of late restenosis and complications emerging from the post-drug stent era, whether thromboses intra- or peri-stent acute episodes. As a pioneering project, this privilege has a non-polymeric biological matrix constituting a release coating on its inner part, and which has the function of elution of biomolecules of chemical substances, with anti-atherogenic, antiproliferative, antithrombotic, antichemotactic and vascular wall restructuring agents, providing the storage and multi-release function of drugs, stored and grouped in microcapsules or microspheres (liposomes), involved in a network (matrix) of macromolecular protein composition, or a biological film that has chemical compatibility reaction with the various types of medication to be delivered extrinsically (such as a subdermal implanted precursor medication delivery biochip). Such a mechanism would be responsible for minimizing the late effects resulting from the degradation of polymers, since the first stents were introduced in 2001, with monotherapy-type delivery platforms (a single drug), eventually generating the fearsome long-term complications related to the necessary and massive oral antithrombotic prophylaxis (anticoagulation), as well as acute late in-stent thrombosis.

SUMMARY OF THE INVENTION

[0025] The skeleton of the prosthetic drug delivery system with a non-polymeric matrix, say cylindrical tubular prosthetic device or stenter-type prosthetic device itself, consists of a fenestrated tubular diagram, with a regular cylindrical shape, multifilament, without presenting, however, median joint; characterized by having an initial diameter, which allows its release intravascular or in any organic duct containing a lumen, and a final diameter, expanded, through the application of radial and centrifugal force, via balloon catheter, or simply being self-expanding. This force is achieved by the inflation of the aforementioned balloon, the dilated portion of the catheter that surrounds the guide, and its intensity will determine the support of the final diameter of the prosthesis, and this expanded, then, will determine the permanent dilation of the vascular lumen or organic duct. It can be molded in stainless steel alloys, nitinol, coated or not with inorganic chemical elements (polishing), as well as biocompatible organic resins, such as artificial cartilage, silicone organic or soapy. Nitinol is composed of a nickel-titanium metal alloy, with thermal memory properties, often used in medical prostheses and orthotics; shows good biocompatibility: minimal inflammatory response in adjacent tissues, without corrosion of the material. The first intravascular stents described by Dotter and subsequent authors were nitinol stents.

[0026] However, despite all these advantages, the possibility of using inorganic material as a cover that increases the biocompatibility of the prosthesis, as well as its antithrombogenicity, will have to be observed, which will be discussed later.

[0027] Its spatial structure is arranged in hexagonal cells, coapted together, arranged in the longitudinal direction of the prosthesis. Overall, visually observing, we obtain a structure with spatial distribution of a honeycomb wall, with cells that grow in the axial direction of the prosthesis. A second model may present this "design" of hexagonal cells, coapted at their lower and upper ends by diamond cells, or thinner and narrower hexagonal cells, intersecting the trivial (primary) hexagonal cells. The alternative production of this organic or vascular prosthetic device should be considered in derivation of this second model, of hexagonal cells, coapted at their lower and upper ends by diamond cells, and these, in turn, fenestrated, not internally coated in their area. by the "coating" of drug release, consisting of an advantage and property of indication for the introduction of vascular prosthesis in situations of lesions in bifurcations/trifurcations, collateral vessels emerging from the lesion site, among other indications.

[0028] Initially, at the level of experimental production, the objective is the elaboration of prostheses in diameters of 4.0 mm and 5.0 mm, with lengths ranging from 12 mm, 18 mm and 24 mm, not discarding a posteriori a smaller diameter and/or longer length molding. The thickness of the stem cells can range from 0.08 to 0.12 mm, an important fact to reduce the tendency to thrombosis and trauma to the vascular wall, which is also a consequence of the prosthesis finishing process, which includes the chemical polishing of the rods and laser cutting for the configuration of the material and its spatial structure.

[0029] The internal matrix of release, "internal coating", is represented by an artificial biological membrane, biocompatible, and may consist of phospholipids and/or macroproteins, or similar substrate, and may or may not be microporous, as long as it allows good capacity for diffusion and release of drugs. The spatial geometric design is arranged in hexagonal cells that come from the extension of the supporting prosthesis, that is, from the cells that compose the spatial conformation of the "stent" itself, open, on the entire internal surface of the stent, that is, in towards the vascular lumen. This inner layer will also follow the format compatible with the "design" of the mesh of the stent to be chosen, whether with pure hexagonal cells, hexagonal cells coapted at the lower and upper ends by diamond cells, or intercepted by hexagonal cells in a more cylindrical shape, largest longitudinal diameter, interposed between standard hexagonal cells.

[0030] The microcapsules or groups of liposomes, contained within the hexagonal cells that form the supporting biological membrane, are arranged in aggregate and sustained, immersed in a matrix that forms chains or networks of protein macromolecules, or these conjugated to other molecules organic compounds such as phospholipids, in the form of a biological film or gel, so that they provide sufficient sustainability and an ideal fixation rate.

[0031] In this sense, the microcapsules/liposomes (which in this space would be grouped into morulae) will be gradually and selectively released through a combination action and pharmacological reaction (from precursor drugs released in a controlled and programmed way by an implanted intradermal microchip, subject to the control of any modality of external central, or even from electrical stimuli or release of the same types of pharmacological precursors from nanochips on the internal surface of the stent, arranged in the proper intervals, corridors separating the hexagonal cells of the "coating" internal), responsible for the rupture of connection bridges and stabilization of macromolecular protein chains, a process that occurs via enzymatic degradation. Process also known for attaching proteins to a biologically compatible resin, contained in porous or non-porous surface, such as the use of albumin, with the objective of increasing the matrix porosity coefficient.

[0032] The expressive efficiency presented in biocompatible macromolecules in the selection of reagents and mechanisms of interaction of high specificity in the chemical reaction sites has been promoting a growing interest in the field of research that involves films of macromolecules of thinner in association with optimized materials and purified, as well as biological protein macromolecules.

[0033] In liquid form, fast-dissolving solid, gel or crystals, the drugs released from the encapsulated structure or from the liposomal group will be gradually and protocolarily submitted to an investigation process in an experimental model, computational analysis, pre-clinical and clinical studies, in order to evaluate with effectiveness and certainty the compatible pharmacological type to be used, the ideal concentration to be reached in the vessel lumen, the best diffusion coefficient, the speed and intervals of release, half-life at the vascular locus, metabolism and toxicity, among other aspects; emphasizing that, during all phases of the elaboration, evaluation, production, "in vitro" and "in vivo" scientific feasibility tests, it will be possible to modify, eliminate, add or merge whatever types of drugs, according to the necessary formalities, as well as obliterating or reconstructing pertinent elements, provided that there are no profound changes in the previously idealized global set.

[0034] The present invention is objectively established to attenuate or eliminate the occurrence of restenosis (recurrent atheromatous plaque growth), later on, and still prevent late acute thrombosis, even after balloon angioplasty and/or prosthesis placement stenting type of the vascular wall, which arise from a variety of factors, namely:

1 . Myointimal hyperplasia, or proliferation of neointimal tissue, is one of the main mechanisms responsible for in-stent restenosis.(*)

two . Certain chronic diseases such as diabetes, unstable angina, among others.

3 . Regarding aspects of the vascular anatomy itself: chronic restenotic lesions, smaller reference diameters of the treated vessel, that is, the basal caliber from which a post-procedure result is optimized, extension of the plaque addressed (plaques greater than 15 mm in length are associated with a higher risk of post-stent restenosis and late acute thrombosis).

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

(*) It is believed that the presence of the pharmacological prosthesis inside the vessel under tension triggers an inflammatory reaction as a result of the confinement of a platelet thrombus. The inflammation inherent to the process stimulates the migration of smooth muscle cells towards the subintimal region, proliferating with variable intensity alongside the secretion of cells from the extracellular matrix, which can result in the formation of a new obstructive intima. This "in situ" prosthesis, therefore, stimulates hyperplasia and the formation of a new intima through vessel injury, as its internal elastic lamina is affected. In summary, the first generation of these bioabsorbable stents had higher rates of cardiovascular events and long-term thrombosis, being withdrawn from the market by the manufacturer in September 2017. Others are being developed with other materials and other drugs, and the results are awaited. results of clinical studies with a greater number of patients and with a longer follow-up, aiming to obtain safety and efficacy in the treatment of coronary disease.

[0035] The use of micro or nanochips in conjunction with intravascular or organic devices: much has been reported about the innovative possibility of incorporating drugs into medical implants, thus using multiple reservoirs containing small doses of these drugs. In this line, microchips represent a new type of technology capable of releasing different drugs for long periods of time.

[0036] In this sense, the development of controlled delivery systems has emerged as a promise in the solution of old dilemmas regarding the achievement of optimal dose efficacy and the increasing complexity of optimized drug treatment routes, in the demand to reach specific sites. [0037] Initially, the development of drug delivery systems was directed to present a sustained release of a given drug during a certain period of time, with the priority use of polymeric components, which remained in the system until its late degradation; however, combined with the controlled release function, some clinical situations required pulses of pharmacological release at variable time intervals.

[0038] Technological advancement led to the emergence of prolonged drug delivery systems, acronym IDDS ("Implantable Drug Delivery Systems"), initially classified into three groups: biodegradable and non-biodegradable, physiological pump systems of microfluids, and the newest class, the micromanufacturing of controlled release systems, endowed with an intelligent and programmable microelectronic capacity, which microchips consist of. These are viable to be produced in different patterns and formats, with a simultaneously pulsatile function, providing higher rates of accuracy, and isolation of the drug from the external environment.

[0039] Several literary descriptions state that implantable microchips solved the need for a controlled release system, being mostly made of silicone, containing multiple drug reservoirs, in a possibility of different forms and presentations, usually hermetically sealed, and covered by a metallic membrane, to be dissolved by electrical stimulation, allowing the release of its constituents (drugs) to the environment.

[0040] Microchips are manufactured using the same technology developed in microelectronic integrated circuits and systems of microelectromechanical origin, a process used for the manufacture of microdevices, such as flow and pressure sensors, ink printer heads, etc. Still, it is noteworthy that the manufacture of this technology involves the use of surface substrate, ceramic, and more often silicone, combining photolithography techniques, aiming at the creation of desired geometric shapes to be applied to the reservoirs. Then, anode-cationic dipoles are created, and, after that, complementation with the drugs of choice.

[0041] The drug release from the interior of these reservoirs would take place with an electrical stimulus between the thin anodic metal layer comprising the membrane covering the reservoir and the cathode, resulting in an electromechanical release by dissolving this membrane. Such an electrical stimulus can be activated by a remote central, with the control circuit inside the microchip, which can contain a "timer"-timer, microprocessor or energy sources, such as biosensors, for example, with a pharmacological release function. controlled and pre-adjusted according to the indication and need demonstrated, for months to years.

[0042] The growing development of this innovative type of technology and its indications in clinical practice are encouraging factors for the continuity of several studies, whose prodrome was detailed in the Santini Jr patent. et al, in 1998, US Patent "Microchip Drug Delivery Devices", with progression towards optimization of the technique aiming at acquiring information via remote central in real time and energy transfer units.

[0043] In addition, some preclinical and clinical studies showed that drug delivery via microchips reached therapeutic ranges and serum levels similar to those provided by other standard intraorganic drug delivery systems (polymer matrices, for example).

[0044] The case to which the microchip is attached also demonstrated a high rate of biocompatibility, with absence of immune response and of serum levels of inflammatory markers, parameters verified in the overwhelming majority of cases, since there is an enveloping of the implant (tissue capsule) by the organism itself, which also did not affect the kinetics of drug release.

[0045] In this way, the widespread application of this type of technology demonstrates disruptive potential in the current clinical approach and treatment of various diseases, with the possibility of enormous expansion to a diversity of areas of medicine, and before numerous therapeutic modalities considered difficult dosage fractionation and poor patient adherence, become viable when administered by this technology, in the sense of showing as a new automated way of drug treatment to induce the release of drugs at a distance, increasing the expected safety and efficacy. BRIEF DESCRIPTION OF THE DRAWINGS

[0046] According to the respective figures presented in this report, this privilege of invention will be object of appreciation and understanding, in a general way in this topic, and in a more detailed way with the information described below.

[0047] FIGURE 1 is a perspective illustration of a cylindrical tubular prosthetic device, standardized stent type, intraluminally expandable, balloon-catheter or self-expanding, in metallic support or in biocompatible resin, isolated from its internal matrix of release, "coating" as described (FIGURE IA and FIGURE 1B), where the conformational pattern of its mesh, support or support of the internal biological coating can be observed, and in the complete presentation showing its internal "coating" (FIGURE 1C), and also a peripheral intradermal microchip, working together with the stent; the one with its spatial structure arranged in hexagonal cells, coapted together, in a regular polyhedral geometric conformation (FIGURE 1B), or in the pattern of hexagonal cells coapted by lozenge cells, arranged in the longitudinal direction of the prosthesis (FIGURE IA), emphasizing the direction of arrangement of the hexagonal mesh can be alternative, if in a transverse arrangement (sides of the hexagon make up the edges of the prosthesis), FIGURE 2A and 2B, and FIGURE 3A, or arrangement in a direction parallel to the axial (vertices of acute angles form the edges of the prosthesis), FIGURE IA. Overall, visually observing, we obtain a structure with a spatial distribution of a wall in a flat and contiguous structure of hexagonal cells, which grow in the axial direction of the prosthesis, presenting an initial predilation diameter, which allows its positioning in the intravascular lumen or organic duet. Such a prosthetic device will be responsible for the gradual, regulated and continuous release of different drugs, in order to prevent coronary restenosis and induce early regeneration of the previously affected vascular wall, from the release of precursor drugs, coming from this peripheral intradermal biochip, which at released into the bloodstream, after a certain period of time, reach the vascular prosthetic device, drug-eluting stent, in its inner layer, and through a conjugation with the internal matrix of the hexagonal cells (combination and pharmacological reaction, mainly by enzymatic hydrolysis, or other alternative types of chemical reaction compatible with the medium), are responsible for carrying out the release of in-stent medications, whether microcapsules, or unified groups of liposomes, contained and housed in specific superimposed layers in which constitute the hexagonal cells of the internal coating of the stent. These precursor drugs, released in a controlled and programmed manner by this intradermal microchip, present their pulse of release into the bloodstream, as well as intervals, concentration, and other potentially measurable pharmacological variables, subject to control over this microchip implant from any external central modality. , software or mobile communication device. Presence of supporting nanosensors in the structure of the releasing biochip is possible to introduce, with the function of measuring the volume of release pulses, hemodynamic and serum biochemical variables, control of intervals, concentrations, etc.

[0048] FIGURE 2 indicates a perspective illustration of the same standardized stent-type cylindrical tubular prosthetic device, intraluminally expandable, by balloon-catheter or self-expanding, in metallic support or in biocompatible resin (FIGURE 2A), stripped of its internal matrix of release, internal coating as described, revealing that the incorporation of nanosensors/nanochips is feasible not only in this implantable biochip in the skin, but can even be represented and located on the internal surface of the stent (FIGURE 2B), or arranged in the proper intervals between cells, separating corridors of the hexagonal cells of the internal coating of the prosthesis, able to regulate and compulsorily measure the concentration rates of intra-stent drugs, serum medication half-life, sequential metabolism rate, and drug elimination time , among several other pharmacological and metabolic variables, as well as biochemical markers.

[0049] FIGURE 3 is a different perspective illustration of a cylindrical tubular prosthetic device, standardized stent type, intraluminally expandable, balloon-catheter or self-expanding, in metallic support or in biocompatible resin, isolated from its internal matrix of release ( FIGURE 3A), internal coating as described, where the conformational pattern of its mesh can be observed, different from the the former, as a support or support of the internal biological coating, and the global prototype with the aforementioned "coating" (FIGURE 3B), and a peripheral intradermal microchip, in joint action; the one with its spatial structure arranged in hexagonal cells, coapted laterally to each other, in a regular polyhedral geometric conformation, and intercepted at their upper and lower ends, that is, sides that make up the acute internal angle of the hexagonal cells, by cells in the shape of a diamond, in complete contiguity, arranged in the longitudinal direction of the prosthesis. Overall, visually observing, we obtain a perspective with spatial distribution of a wall in a flat and contiguous structure of hexagonal cells, coapted on their sides, at obtuse angles, one to the other, and intercepted by lozenge cells, superior and inferior, that grow in the axial direction of the prosthesis, presenting an initial pre-dilation diameter, which allows its positioning in the intravascular lumen or organic duct (FIGURE 3C). Such a prosthetic device will also be responsible for the gradual, regulated and continuous release of several drugs, in order to prevent coronary restenosis and induce early regeneration of the previously affected vascular wall, from the release by precursor drugs, coming from this peripheral intradermal biochip, which when released into the bloodstream, after a certain period of time, they reach the vascular prosthetic device, drug-eluting stent, in its inner layer, and through a conjugation with the internal matrix contained in both hexagonal and diamond cells (combination and pharmacological reaction, primarily by enzymatic hydrolysis, or other alternative types of chemical reaction compatible with the medium), are responsible for executing the release of in-stent medications, whether microcapsules, or unified groups of liposomes, contained and housed in specific layers superimposed on that make up the hexagonal and rhombus cells es of the internal stent coating. These precursor drugs released in a controlled and programmed manner by this intradermal microchip, present their pulse of release into the bloodstream, as well as intervals, concentration, and other potentially measurable pharmacological variables, subject to control over this microchip implant of any external central modality, software or device mobile communication, through the use of radio frequency waves, or any other compatible energy transmission/transformation system. Nanosensors/nanochips can also be present in this implantable biochip in association, which constitutes the delivery system in its complexity, or even be represented by nanochips or nanosensors, located on the inner surface of the stent, or arranged in the very intervals between cells, corridors for separating hexagonal and diamond cells from the internal coating of the prosthesis, capable of regulating and compulsorily measuring the concentration rates of in-stent drugs, drug serum half-life, sequential metabolism rate, and drug elimination time , among several other pharmacological, metabolic, and biochemical markers.

[0050] FIGURE 4 and FIGURE 5 represent a perspective illustration of the same prosthetic device of FIGURES 1 and 2, now together with its internal release matrix, described internal "coating", which is represented by artificial biological membrane, biocompatible, It can be produced by tissue engineering techniques and consist of phospholipids and proteins, or similar substrate of organic constitution or synthesized in tissue engineering, and can be microporous or not, as long as it allows good diffusion and drug release capacity. The spatial geometric design of the internal coating is arranged in hexagonal cells, as shown in FIGURE 1B and FIGURE 1C, which come from the extension of the support prosthesis, that is, from the cells that make up the spatial conformation of the stent itself, open , on the entire internal surface of the stentor, that is, towards the vascular lumen (FIGURE 4A, 4B and 4C), or it is arranged in alternating hexagonal cells with lozenge cells intercepted to the last ones, according to the "design" shown of the metallic mesh in FIGURE IA, which also come from the extension of the supporting prosthesis, that is, from the cells that make up the spatial conformation of the stent itself, open, on the entire internal surface of the stent, that is, towards the vascular lumen (FIGURE 5A and 5B ).

[0051] FIGURE 6 shows, from an approximate focus, the microcapsules or group of liposomes, contained within the hexagonal cells, since referenced specifically, the first type of stent, with a conformational pattern of its "design" of mesh continued between hexagonal cells, as already highlighted in the epigraph, these then form the biological support membrane, and which are arranged in aggregates and sustained, in specific layers , immersed in a matrix that forms chains or networks of protein macromolecules, or these conjugated to other organic molecules such as phospholipids, in the form of a biological film or gel, in a way that provides sufficient sustainability and an ideal fixation rate.

[0052] FIGURES 6 and 7 are perspective illustrations of said cylindrical tubular prosthetic device, standardized stent type, intraluminally expandable, with its internal drug delivery matrix, in an approximate section that shows how this matrix is arranged, whether in cells also hexagonal, in a universal conformational pattern (FIGURE 6), or according to the diverse model with hexagonal cells coapted laterally, intercepted superiorly and inferiorly by lozenge cells, thus forming a conformational pattern of its mesh "design" alternating between hexagonal cells and lozenge, as already mentioned in the title (FIGURE 7); that come from the extension of the supporting prosthesis, that is, from the cells that compose the spatial conformation of the prosthesis, according to its reference "design-model", properly speaking, open, on the entire internal surface of the stent, that is, towards the to vascular light. It can be seen that the microcapsules or groups of liposomes, contained within the hexagonal cells, or hexagonal cells + diamond cells, which form the biological support membrane, are arranged in aggregates and supported, in homogeneous layers, one on top of the other (in the figures , represented by different colors, that is, each layer shown in a certain color, representing a modality of liposome/microcapsule group, containing a different type of drug), immersed in a matrix that forms chains or networks of protein macromolecules, or others types of biomolecules, in a way that provides sufficient sustainability and an ideal fixation rate. Each layer will be formed by a support matrix of different chemical composition, one from the other, aiming to provide the specificity and selectivity of release of a certain in-stent drug, contained in liposomes/microcapsules, according to the type of medication. released by the intradermal microchip implant, this release being fully optimized by a remote control center, regarding the release pulse interval, concentration, doses, pharmacological specificity, etc. This precursor drug, released via intradermal microchip implantation, when falling into the bloodstream, reaching the internal surface of the stent, will be responsible for interacting with the specific support matrix of a certain layer, for which it is programmed, dissolving and releasing it, selectively and specifically, a particular type of drug, aiming not only to control vascular restenosis, but also to modulate the inflammatory and proliferative response of the myointimal wall, adversity that frequently occurred in the implantation of polymeric drug-eluting stents, in general.

[0053] FIGURES 8 and 9 are perspective illustrations of said cylindrical tubular prosthetic device, standardized stent type, intraluminally expandable, with its internal drug delivery matrix, and the schematic representation of the substance released via intradermal implant of any constitution (precursor drugs ), represented by polymeric matrices for remote release, microfluids, but mainly by a biochip for releasing pharmacological substances, remotely programmed and controlled, among others. Biochip that may have an inorganic or organic constitution, polymer or silicone, or any other compatible resin. These precursor drugs, released via an intradermal microchip, will gradually reach the surface of the stent, where they will be responsible for interacting in the specific sites for which they are programmed, dissolving the support matrix of the particular intra-stent drug to be released, a process that occurs from the highest (outer) to the lowest (deep) layers.

[0054] FIGURES 10 and 11 are a new perspective illustration of the same prosthetic device as FIGURES 1, 2, 3 and 4 in which they portray the arrival of substances/medications released by subdermal implants, those with a different biochemical constitution from the previous one, mainly in the with regard to the application of a subdermal implanted biochip, whose release of these precursor drugs must be controlled, quantified and monitored by a remote external central, reaching the light of the vessel in which the prosthetic device is located, and interact with the support matrix of the layers that form and fill the internal cavity of each hexagonal cell, or hexagonal and diamond-shaped, of the delivery platform. Obviously, these substances will interact with the first layers of the support matrix located towards the vessel light, that is, only and specifically with those layers whose chemical constituents are reactive to the action of these substances, thus providing the release of microcapsules/groups of liposomes stored and supported by this matrix. Thus, it is clear the possibility of effecting a selectivity and diversity in the release mechanism of drugs applied intra-stent or intra-prosthetic device. In schematic color presentations, the different representations of each type of medication administered are differentiated by each color, and this is also applied to the microcapsules/groups of liposomes programmed to be released, from the specific layer (hexagonal or lozenge cell support matrix) .

[0055] FIGURES 12 to 16 sequentially represent the perspective illustration of the mechanism of interaction of the precursor substance/medication, released by the intradermal biochip, which reaches the stent, with its internal surface where it combines the support layers of the liposomes/microcapsules, and these are progressively released to act on the vascular wall. Microcapsules/groups of liposomes in which antimyoproliferative, antiatherogenic and antithrombogenic drugs may be imbibed alone or conjugated to a biological substrate of spatial support, dispersed among the same microcapsules, in any presentation, whether solid, liquid, gel, etc.

[0056] FIGURES 17 to 24 also represent, in perspective view through the vascular prosthetic device, a new process of arrival of a different administered substance released by any other route, whether it is an intradermal implant of chemical or electronic constitution (biochip with reservoir drug release, controlled by an external central), that is, an intradermal biochip, reaching the inner surface of the stent, culminating, in the same way as described in the last paragraph, with the release of other types of in-stent drugs, compatible and programmed for release according to the action of the substance released by the intradermal implant.

[0057] Finally, FIGURE 25 demonstrates, in essence or scope, the novelty and pioneering spirit on which this privilege is based, with the introduction of a new modality of drug release in vascular stent, through the remote action of a biochip implantable, containing one or more activation-reception boards, operated by any modality of central/external command, be it automated control, telephony devices, PC unit, etc. support of the precursor drugs, these will then be released via the bloodstream, reaching the vascular stent, and acting locally in the specific pharmacological release, arranged in its internal cover, under temporal control pulses, concentration and specific type of in-stent medication. FIGURE 26 emphasizes that it is feasible and opportune to consider the alternative production of this organic or vascular prosthetic device in a variant of this second model, with hexagonal cells, coapted at their lower and upper ends by diamond cells, and these, in turn, are fenestrated. , not coated internally in their area by the drug release coating, which is an advantage and an indication property for the introduction of vascular prosthesis in situations of lesions in collateral branches.

[0058] FIGURES 27 to 30 demonstrate in perspective view the same intraluminal drug delivery system of the previous figures, in which, in a next step of new administration of another type of substance, it already reaches, interacts and releases another type of intraluminal medication - stent, contained in aggregated microcapsules/liposomes and supported in a different layer, consisting of a compatible support matrix. DETAILED DESCRIPTION OF THE PREFERRED MODALITY

[0059] More specifically, certain references are presented below, in relation to FIGURES 1, 2, 3 and 4, which illustrate a first and second embodiment of an expandable intraluminal cylindrical tubular prosthetic device, or stent type prosthetic device, or simply a prosthesis, or even a stent, built in accordance with the standards of the present invention. It should be understood that the aforementioned terms "expandable intraluminal cylindrical tubular prosthetic device", "stent type prosthetic device", "stent" or simply "prosthesis" are applied simultaneously to name the present invention, as the latter may have its use attributed to vascular segments in a general, as well as to organic ducts, with the aim of correcting stenosis or narrowing and sustaining their tonus.

[0060] FIGURE 1 presents the prosthetic device type stenter 41 (FIGURE IA), in metallic support or in biocompatible resin, with its spatial structure arranged in hexagonal cells, coapted laterally to each other, in regular polyhedral geometric conformation, and intercepted in its upper and lower ends, that is, sides that make up the internal acute angle of the hexagonal cells, by diamond-shaped cells, in complete contiguity, arranged in the longitudinal direction of the prosthesis. FIGURE 1B shows the same stent type prosthetic device 31, in metallic support or biocompatible resin, whose spatial structure configures the conformational alternative modality of hexagonal cells, coapted together, arranged in the longitudinal direction of the prosthesis, isolated from its internal matrix of release , internal "coating" as described above 32, where the conformational pattern of its mesh, support or support of the internal biological coating can be observed, this increased to FIGURE 1C, which defines the global structure of the stent (intravascular prosthetic device) 50 , already associated or together with its internal release matrix, described internal "coating", which is represented by an artificial biological membrane, biocompatible, which may consist of phospholipids and proteins, or similar substrate, and may or may not be microporous, as long as allow good diffusion capacity and drug release 32. In addition, it is also observed in FIGURE 1, a microc peripheral intradermal implanted hip 43, acting together with the stent, causing the release of precursor drugs 36, contained in plate(s) 44 that are located inside, arranged in groups of micro-reservoirs, surrounded by peculiar circuits 45, each which contains a specific type of precursor drug 36, which will be released into the bloodstream, which, after a certain time interval, reaches the vascular prosthetic device 50, drug-eluting stent, in its inner layer, and through a conjugation with the matrix of the cells that constitute their "coating" (internal coating) 32, stratified in layers with specific intra-stent medications 33, will be responsible for carrying out the release of these, either the microcapsules 33 or unified groups of liposomes, contained and housed in specific superimposed layers that constitute the hexagonal or diamond-shaped cells of the stent's internal coating 32. As already mentioned, these precursor drugs 36, released in a controlled and programmed manner by this intradermal microchip 43, present their release pulse in the bloodstream, as well as ranges, concentration, and other potentially measurable pharmacological variables, subject to control over this microchip implant from any form of external switch, software, or mobile communication device. As already alluded to, the presence of nanosensor(s) 46 adjunct(s) in the structure of the releasing biochip is subject to introduction, as also shown in FIGURE 1, with the function of measuring the volume of release pulses, hemodynamic and serum biochemical variables , control of intervals, concentrations, etc.

[0061] FIGURE 2 is a different perspective illustration of a cylindrical tubular prosthetic device, standardized stenter type 41, intraluminally expandable, by balloon-catheter or self-expanding, in metallic support or in biocompatible resin (FIGURE 2A), proving to be feasible the incorporation of nanosensors/nanochips 49 not only in this skin implantable biochip 43, but they can even be represented and located on the inner surface of the "stent" (FIGURE 2A and FIGURE 2B), whose functions are described above. In FIGURE 3, the cylindrical tubular prosthetic device, standardized stenter type 41, is accompanied by its internal release matrix, internal "coating" as described 42, see FIGURE 3A and FIGURE 3C, whose spatial conformation ("design") follows the geometric spatial pattern of the metallic support stent 41, detailed in this one, where the conformational pattern of its mesh, different from the previous one, as support or support of the internal biological coating 42, and a peripheral intradermal implanted microchip 43, in joint action; the one with its spatial structure arranged in hexagonal cells 47, coapted laterally to each other, in polyhedral regular geometric conformation, and intercepted at their upper and lower ends, that is, sides that make up the internal acute angle of the hexagonal cells, by rhombus-shaped cells 48, in complete contiguity, arranged in the longitudinal direction of the prosthesis. Overall, visually observing, we obtain a structure with spatial distribution of a wall in a flat and contiguous structure of hexagonal cells 47, coaptation on their sides, at obtuse angles, one to the other, and intercepted by lozenge cells 48, superior and inferiorly, which grow in the axial direction of the prosthesis, presenting an initial pre-dilation diameter, which allows its positioning in the intravascular lumen 60 or organic duct. Such a prosthetic device will also be responsible for the gradual, regulated and continuous release of different drugs via microcapsules or a group of liposomes 33, in the sense of preventing coronary restenosis and inducing early regeneration of the previously affected vascular wall, from the release by precursor drugs, coming from this peripheral intradermal biochip 43, which, when released into the bloodstream, after a certain time interval, reach the vascular prosthetic device, drug-eluting stent 51, in this example of a different modality from the precursor 50, in its inner layer, and through a conjugation with the internal matrix 35 contained in both hexagonal and lozenge cells (combination and pharmacological reaction, mainly by enzymatic hydrolysis, or other alternative types of chemical reaction compatible with the medium), are responsible for executing the in-stent medication release, either namely, microcapsules, or unified groups of liposomes 33 , contained and housed in specific superimposed layers that make up the hexagonal 47 and lozenge 48 cells of the stent's internal coating 42. These precursor drugs 36 released in a controlled and programmed manner by this intradermal microchip 43, present their release pulse in the current blood, as well as ranges, concentration, and other potentially measurable pharmacological variables, subject to control over this microchip implant from any form of external central, software or mobile communication device, through the use of radiofrequency waves or any other transmission/ compatible energy transformation. Nanosensors/nanochips 46 can also be present in this implantable biochip in association, which constitutes the delivery system in its complexity, or even be represented by nanochips or nanosensors 49, located on the inner surface of the stent 51, see letters (B) and (C), in any of their modalities, or arranged in the intervals between cells, separating corridors of hexagonal 47 and lozenge 48 cells of the internal coating of the prosthesis 42, as explicit in FIGURE 2, capable of regulating and compulsorily measuring the concentration rates of in-stent drugs , serum medication half-life, sequential metabolism rate, and drug elimination time, among several other pharmacological, metabolic, and biochemical markers.

[0062] Referring to FIGURES 1, 2, 3 and 4, the stenter-type prosthetic devices 50 and 51 are constituted on their surface by a fenestrated tubular diagram 31 and 41, without presenting median articulation, with a regular cylindrical shape, multifilament, associated with internal coating for drug delivery, which can be a self-expanding or balloon-expandable device. Looking now in more detail, with reference to FIGURE 4, which illustrates the stent-type prosthetic device 50, showing, from an approximate focus, the microcapsules or liposomes 33, contained within the hexagonal cells 34 that form the biological support membrane , and which are arranged in aggregate and sustained, immersed in a matrix that forms chains or networks of protein macromolecules 35, or these conjugated to other organic molecules such as phospholipids, in the form of a biological film or gel, in a way that provides sufficient sustainability and a ideal fixation rate.

[0063] FIGURE 3 refers to a different perspective illustration of a cylindrical tubular prosthetic device, standardized stenter type 41, as shown in FIGURE 3A, intraluminally expandable, by balloon-catheter or self-expandable, in metallic support or in resin biocompatible, unaccompanied by its internal release matrix, and in FIGURE 3B, this matrix in question is already accompanied, internal "coating" as described 42, whose spatial conformation ("design") follows the geometric spatial pattern of the metallic support stent 41, where the conformational pattern of its mesh can be observed, different from the previous one, as support or support of this internal biological coating 42, and a microchip implanted peripheral intradermal 43, working together; the one with its spatial structure arranged in hexagonal cells 47, coapted laterally to each other, in regular polyhedral geometric conformation, and intercepted at their upper and lower ends, that is, sides that make up the acute internal angle of the hexagonal cells, by cells in the form of of diamond 48, in complete contiguity, arranged in the longitudinal direction of the prosthesis. Such a prosthetic device will also be responsible for the gradual, regulated and continuous release of different drugs via microcapsules or a group of liposomes 33, in the sense of preventing coronary restenosis and inducing early regeneration of the previously affected vascular wall, from the release by precursor drugs 36 , arising from this peripheral intradermal biochip 43, which reach the vascular prosthetic device, drug-eluting stent 51, in its inner layer, and through a conjugation with the internal matrix 35 contained in both hexagonal and lozenge cells, these being precursor drugs 36 responsible for perform the release of in-stent medications, whether microcapsules or unified groups of liposomes 33, contained and housed in specific superimposed layers in which the hexagonal 47 and lozenge 48 cells of the stent's internal coating 42 are constituted. 36 precursors released in a controlled and programmed manner by this microchip in 43, present their pulse of release into the bloodstream, as well as intervals, concentration, and other potentially measurable pharmacological variables, subject to control, exercised on this microchip implant, of any external central modality, software or mobile communication device 55, through the use of radio frequency waves, or any other compatible energy transmission/transformation system. Nanosensors/nanochips 46 can also be present in this implantable biochip in association, which constitutes the delivery system in its complexity, or even be represented by nanochips or nanosensors 49, located on the inner surface of the stent 51, in any of its modalities , or arranged in the intervals between cells, separating corridors of the hexagonal 47 and lozenge 48 cells of the internal coating of the prosthesis 42, as explicit in FIGURE 2, capable of regulating and compulsorily measuring the concentration rates of in-stent drugs, drug serum half-life, sequential metabolism rate, and drug elimination time, among several other pharmacological, metabolic, and biochemical markers.

[0064] FIGURES 5 and 6 are perspective illustrations of said cylindrical tubular prosthetic device, standardized stent type, intraluminally expandable 51, as seen in FIGURE 5A, in an alternative geometric pattern, with its internal drug delivery matrix 42, in a section approximation that shows how this matrix is arranged, either in hexagonal cells 47 and lozenge 48, which come from the extension of the supporting prosthesis 41, that is, from the cells that make up the spatial conformation of the prosthesis, properly speaking, open, on the entire internal surface of the stentor 51, that is, towards the vascular lumen. It can be seen that the microcapsules or liposomes 33, contained within the hexagonal cells 47 and adjacent and coapted rhombus cells 48, which form the biological support membrane 42, are arranged aggregated and supported, in homogeneous layers, one on top of the other (in the figures, represented by different colors, that is, each layer shown in a certain color, representing a modality of liposome/microcapsule 33, containing a different type of drug), immersed in a matrix that forms chains or networks of protein macromolecules 35 (matrix support), or other types of biomolecules, in a way that provides sufficient sustainability and an ideal rate of fixation. Each layer will be formed by a support matrix of different chemical composition, one from the other, aiming to provide the specificity and selectivity of release of a given drug, contained in the groups of liposomes/microcapsules 33, according to the type of medication remotely selected and released 36 by the implanted biochip 43, which, when it falls into the bloodstream, reaching the surface of the stent, will be responsible for interacting with the specific support matrix of a certain layer 35, for which it is programmed, dissolving and releasing it, selectively and specific type of drug 33, aiming not only to control vascular restenosis, but also to modulate the inflammatory and proliferative response of the myointimal wall, an adversity that frequently occurred in the implantation of first and second-generation drug-eluting stents, polymers in general. That is, according to the type of medication released by the intradermal microchip implant 43, there will be a specific medication to be released also on the inner surface of the vascular stent 51, according to this alternative design pattern, being that release of the precursor drug 36 with fully optimized control by remote control 55, regarding the release pulses interval, concentration, doses, pharmacological specificity, etc.; this precursor drug 33, released via intradermal microchip implant 43, when falling into the bloodstream, and reaching the inner surface of the stent 51, thus defining the peculiar process of drug delivery characterized by this innovative system. From an approximate focus, FIGURE 5B shows the microcapsules or group of liposomes 33, contained within the hexagonal 47 and lozenge 48 cells (specifically in the second conformational modality of the stent) that form the biological support membrane 42, and which are arranged aggregated and sustained, in specific layers, immersed in a matrix that forms chains or networks of protein macromolecules, or these conjugated to other organic molecules such as phospholipids, in the form of a biological film or gel, in a way that provides sufficient sustainability and an ideal rate. of fixation.

[0065] FIGURE 6 shows a perspective illustration in section/section of a certain area of the internal intra-stent drug delivery matrix 32 of said cylindrical tubular prosthetic device, standardized stent type, intraluminally expandable 50, showing how this matrix is arranged , that is, in hexagonal cells 34, which come from the extension of the support prosthesis 31, that is, from the cells that make up the spatial conformation of the prosthesis, itself, open, on the entire internal surface of the stent 50, that is, towards the vascular lumen. It can be seen that the microcapsules or liposomes 33, contained within the hexagonal cells 34, which form the biological support membrane 32, are arranged in aggregate and supported, in homogeneous layers, one on top of the other, ditto immersed in a matrix that forms chains or networks of protein macromolecules 35, or other types of biomolecules, in such a way that they provide sufficient sustainability and an ideal fixation rate. Each layer will be formed by a matrix of support of different chemical composition, one from the other, aiming to provide the specificity and selectivity of release of a certain drug, contained in liposomes/microcapsules 33, according to the type of medication released 36 by the intradermal implant - biochip 43, which, when falling in the bloodstream, gradually reaching the surface of the stent 50, will be responsible for interacting at specific sites with the given support matrix 35 of a given layer, for which it is programmed, dissolving it and releasing, selectively and specifically, a given type of drug, a process that occurs from the highest (external) to the lowest (deep) layers, encompassing the same therapeutic efficacy objectives of the aforementioned alternative standard.

[0066] FIGURES 7, 8, 9, 10, 11 are a perspective illustration of the same prosthetic device as FIGURES 1, 2, 3, 4 and 5 with its internal drug delivery matrix 32 (of the stent in hexagon geometry only ) and 42 (of the stent in geometry of intercepted hexagons and diamonds), in an approximate section that shows how this matrix is arranged, either in hexagonal cells 34 or hexagonal/lozenge 47 and 48, which come from the extension of the prosthesis of support 31 (model with hexagonal geometric pattern only) and 41 (model with hexagonal and diamond geometric pattern), that is, of the metallic base cells or biological resin material as previously described, which make up the spatial conformation of the prosthesis itself , open, on the entire internal surface of the stentor, that is, towards the vascular lumen, with microcapsules or groups of liposomes 33, contained within the hexagonal cells that form the biological support membrane 32 and 42, and are arranged aggregated and supported, in homogeneous layers, one on top of the other; so that FIGURE 7A shows a perspective view of the second model vascular prosthesis 41, and an internal view along its entire axis from where the hexagonal 47 and lozenge 48 cells are observed. approximated the interior of the prosthesis 51, with identification in section of the hexagonal cells 47 and lozenge 48, and their internal constituents of microcapsules/groups of liposomes 33, in view of the geometric spatial conformation of the second model of prosthesis 41, correlated to the stentor 51, implanted inside a blood vessel 60. Such figures, especially with regard to 8 to 11, depict the arrival of substances/medications released 36 via an intradermal biochip 43 of remote location, so that, reaching the vessel lumen in which the prosthetic device is located, interact with the support matrix of the layers 35 that form and fill the internal cavity of each hexagonal or diamond cell of the delivery platform. Obviously, these substances will interact with the first layers of the support matrix 35 located towards the light of the vessel, that is, only and specifically with those layers whose chemical constituents are reactive to the action of these substances, thus providing the release of microcapsules/ liposomes stored and supported by this matrix. Thus, it is clear the possibility of effecting a selectivity and diversity in the release mechanism of drugs applied intra-stent or intra-prosthetic device. In schematic color presentations, the different representations of each type of medication administered are differentiated by each color used, and this is also applied to the microcapsules/liposomes programmed to be released, from the specific layer (support matrix of each hexagonal or lozenge cell) 35. Similarly, it is noted that FIGURE 8A defines a standard initial stent 50, obeying a metallic geometric conformation 41, in a blood vessel 60, and the arrival of a precursor medication 36, eliminated from a subdermal intra-chip plate 44 43, as well as FIGURE 8B defines this stent in close-up focus, with the sectional view of the drug delivery system 32, the parent drug 36, and the in-stent medication 33 (microcapsules/liposomes). FIGURE 8C shows an approximate 3D section of the biological coverage of medication release 32, constituting the in-stent cells 34, and the effect produced by the precursor drug 36 when it reaches the interior of the prosthesis, precipitating the release of in-stent medications 33 , represented by microcapsules. FIGURE 9A demonstrates, in approximate focus, the process of releasing the precursor medication from the microcapsule/liposomal groups 36, coming from the plate 44, from the implanted microchip 43, through its microreservoirs. FIGURE 9B shows a sequential moment of release of in-stent medications, contained in the microcapsules/liposomes 33, in a sense that can occur both for the vessel lumen and for the face of the vascular wall, if it is delimited or indicated that the immersion of the microcapsules 33 is carried out in a single type or pharmacological species, in all layers, and with only one type of support matrix, of a single biochemical nature. Finally, FIGURE 9C indicates a later moment of release of these intra-capsulated medications 33 in the vessel lumen, in a standard stentor 50.

[0067] FIGURES 12 to 16 represent in perspective view the same drug delivery system 33, intraluminal, of the previous figures, as a new process of arrival of a different substance released by the organic implant (precursor drug) 36, said implantable biochip intradermally 43, to the inner surface of the stent, which reaches, interacts and releases another type of in-stent medication 33, compatible and programmed for release according to the action of the substance released 36 by the implanted biochip, culminating, in the same way as described in last paragraph, with the release of other types of in-stent drugs, contained in aggregated microcapsules/liposomes 33 and supported in different layers, consisting of a compatible support matrix 35. These precursor drugs 36, released in a controlled and programmed manner by this microchip 43, present their pulse of release into the bloodstream, as well as intervals, concentration, and other variables. potentially measurable pharmacological variables subject to control by any modality of external switch, software or mobile communication device 55, as noted in FIGURE 13. FIGURE 12A relates to a new 3D view perspective of a standard stent 50, and its internal drug delivery system 32, with the arrival of a new precursor drug 36, in the vessel lumen 60, and its moment of release of its drug content responsible for releasing the in-stent medications 33, either represented by microcapsules. Sequentially, in approximate focus, in FIGURE 12B, this precursor drug 36, coming from the microreservoirs of the plate 44, contained in the microchip 43, dissolving and acting on the intracellular matrix of support 35 of the microcapsules 33, releasing them to the vessel lumen and , according to the single-drug method, to the affected vascular wall. Finally, FIGURE 12C shows a further moment of release of the in-stent medications, represented and encapsulated in structure 33. FIGURE 13A shows a schematic 3D section of the hexagonal cells 34, delimiting the various superimposed layers in which the microcapsules 33 are constituted, housing the in-stent medications, and the arrival of precursor drugs 36, coming from plate 44, attached to the microchip implanted in the organism 43, in a continuous process of controlled, pulsatile, and intelligent release. An external switch, which can be represented by a cell phone, an application or any other type of software 55 sends the signal to the microchip, aiming to trigger this process. FIGURE 13B depicts a later moment of release of these microcapsules 33, with the in situ action of the precursor drug 36. Subsequently, FIGURE 13C confirms the dissolution of the internal matrix 35, intracellular of the stent, through these precursor drugs 36, releasing in-stent medications 33, in microcapsule content.

[0068] FIGURES 17 to 24 represent in perspective view the same drug delivery system 33, intraluminal, of the previous figures, as a new process of arrival of a different substance released by the organic implant (precursor drug) 36, said implantable biochip intradermally 43, up to the internal surface of the stent, which reaches, interacts and releases another type of in-stent medication 33, compatible and programmed for release according to the action of the substance released 36 by the implanted biochip, culminating, in the same way as described in last paragraph, with the release of other types of in-stent drugs 33.

[0069] FIGURE 25 refers to the perspective demonstration of the structure of the plate 44, inside the implanted biochip 43, containing reservoirs that differ according to the type of medication remotely selected and released 36 by it, which when falling into the current blood, reaching the inner surface of the stent 50 or 51, will be responsible for interacting with the certain support matrix of a certain layer 35, for which it is programmed, dissolving it and releasing, in a selective and specific way, the certain type of drug 33, aiming not only to control vascular restenosis, but also to modulate the inflammatory and proliferative response of the myointimal wall, an adversity that frequently occurred in the implantation of first and second-generation, drug-eluting, polymeric stents of a generally. It therefore acts on the same prosthetic device as in FIGURES 1, 2 and 3, in perspective illustration shown together with its internal release matrix, internal coating described 32 and 42, according to the prosthesis modality, which is represented by an artificial, biocompatible biological membrane, arranged in hexagonal cells or hexagonal + lozenge cells, which come from the extension of the supporting prosthesis, that is, from the cells that make up the spatial conformation of the stent itself, containing the microcapsules or liposomes 33, and these aggregates are sustained, immersed in a matrix that forms chains or networks of protein macromolecules 35, in such a way that they provide sufficient sustainability and an ideal fixation rate.

[0070] FIGURE 26, in an exceptional way, shows the possibility of the mesh design of the intravascular prosthetic device 51 to be fenestrated, since the alternative production of this organic or vascular prosthetic device in derivation of the second model, of cells hexagonal 47, coapted at their lower and upper ends by diamond cells 48, and these, in turn, remain fenestrated, not coated internally in their area by the drug release coating 42, consisting of an advantage and indication property for the introduction of vascular prosthesis in situations of lesions in bifurcations/trifurcations, collateral vessels emerging from the lesion site, among other indications. FIGURE 26A composes the metallic geometric pattern 41 of the stent 51, in axial spatial arrangement along the cut of a patterned organic vessel 60, in a "design" of hexagonal cells 47 alternating with diamond cells 48. The fenestrated mesh, as already described, is a favorable factor in certain types of coronary angioplasty procedure indication. FIGURE 26B shows, in close focus, the fenestrated mesh of the stent 51, with emphasis on the release system - biocompatible coating 42, and the in-stent cells 47 and 48.

[0071] Tens of millions of patients around the world undergo coronary interventional procedures annually, and vascular "stents" represent, in this case, the greatest advance in the area, being routinely used in more than 90% of cases. A reasonable number of advantages and applicability can be found as:

1 . Treatment of multivascular atherosclerotic disease;

two . Dilation of organic ducts, such as in the urogenital, respiratory and biliary tract, as well as congenital strictures of vascular origin;

3 . Biological coating has its acceptable application as a coating for artificial and natural aac valves, intravascular filters, and intraorganic devices;

4 . Able to offer an ideal support platform for the deposit and release of stem cells, aiming to promote the remodeling process and balanced physiological resolution of the affected vascular wall.

[0072] The field of Interventional Cardiology has developed greatly, and the application of percutaneous transluminal coronary angioplasty has become increasingly routine. The first drug-eluting, drug-eluting stents were primarily designed to reduce in-stent neointimal proliferation, thereby preventing the early or late occurrence of vascular restenosis. Although the first generation of these drug-eluting stents were relatively effective in reducing restenosis across virtually all groups and types of lesions, their safety was limited due to the low biocompatibility of the polymeric matrices used, the process of late reendothelization of the prosthesis in the layer of the vessel, causing an increase in the chances of clinical occurrence of late intravascular thrombosis, in addition to the local toxicity of in-stent medications in the vascular segment addressed.

[0073] Therefore, as the polymers of long duration and considerable thickness, used in the previous generation of drug-eluting stents, were identified as responsible for the perpetuation of the local vascular inflammatory response, and for potentially inducing the complication of acute and sub-acute thrombosis. , the development of non-polymeric drug-eluting stents became essential, and consequently, the concept of creating a device that would encompass the function of carrying, releasing and controlling the process of elution of in-stent drugs, during a predetermined period of time. , emerges as a promising alternative. [0074] In this segment, the use of implantable devices consisting of controlled drug delivery systems has been representing the greatest advances obtained in the area of biotechnological research, with the emergence of new classes of controlled drug delivery systems, endowed with programmable microelectronic function and intelligent, called implantable microchips.

[0075] Finally, the scope of this invention privilege resides in the application of these intelligent microelectronic implantable devices, able to be programmed by any command source or remote central, and may contain hundreds of micro-reservoirs that bring together different modalities of drugs (in this case , called precursor drugs), which, when released in the body, will reach the inner surface of the vascular stent and, acting directly on the constituents of its organic matrix, which make up the internal biological cover of the stent, will be responsible for the dissolution and release of a certain in-stent drug. In fact, these implantable microchips are capable of exhibiting highly complex release patterns, simultaneously at constant intervals and controlled pulses, demonstrating greater accuracy, as well as maintaining drug isolation from the external environment.

Claims

1. Non-polymeric cylindrical tubular prosthetic device, characterized by being fenestrated, metallic, multifilament, molded in stainless steel alloys, or nitinol, coated or not with inorganic chemical elements (polishing), as well as with biological flexible organic resins, of high biocompatibility, "stent" type, able to be released in intravascular routes and organic ducts, and for having an initial diameter, which allows its release intravascular or in any organic duct containing a lumen, and a final diameter, expanded, through the application of radial and centrifugal force, via balloon catheter, or simply being self-expanding.

2. Non-polymeric cylindrical tubular prosthetic device according to claim 1, characterized in that it has, in its first mesh model or geometric design (31), a spatial structure arranged in hexagonal cells (34), coapted together, in conformation regular polyhedral geometry, arranged in the longitudinal direction of the prosthesis; and in a second mesh model or geometric design (41), present spatial arrangement in hexagonal cells (47), coapted at their lower and upper ends by diamond cells (48), that is, by the sides that make up the acute internal angle of the hexagonal cells (47), in complete contiguity, arranged in the longitudinal direction of the prosthesis, or even thinner and elongated hexagonal cells, intercepting the trivial (primary) hexagonal cells.

3. Non-polymeric cylindrical tubular prosthetic device according to claim 2, characterized by a structure that contains a non-polymeric drug release platform, that is, internal release matrix (32), internal coating, which is represented by artificial biological membrane, biocompatible, which may consist of phospholipids and/or proteins, or similar organic substrate, and may or may not be microporous, as long as it allows good diffusion and drug release capacity, and whose spatial geometric design is available in cells as well. hexagonal (34) that come from the extension of the supporting prosthesis, that is, from the cells that make up the spatial conformation of the metallic prosthetic device itself, open, on the entire internal surface of the stent (31), that is, towards the light vascular.

4. Non-polymeric cylindrical tubular prosthetic device according to claim 2, characterized by presenting, in its alternative geometric model, an internal cover (42) that will also follow the format compatible with the mesh design of the referred prosthetic device, coming as a extension of its base, either in hexagonal cells (47) coapted at the lower and upper ends by diamond cells (48), or intercepted by hexagonal cells in a more cylindrical shape, of greater longitudinal diameter, interposed between the standard hexagonal cells, open, on the entire internal surface of the stentor (41), that is, towards the vascular lumen.

5. Cylindrical tubular prosthetic device according to claims 3 and 4, characterized in that the inner lining, represented by the biological support membrane (32, 42), contains microcapsules or groups of liposomes (33), arranged in sequential layers one on top of the other, inside the hexagonal cells (34), according to the first model, and in the hexagonal (47) and lozenge cells (48), in the second model, which are arranged in aggregates and supported, immersed in a matrix (35) which forms chains or networks of protein macromolecules, or these conjugated to other organic molecules such as phospholipids, in the form of a biological film or gel, in a way that provides sufficient sustainability and an ideal fixation rate.

6. Non-polymeric cylindrical tubular prosthetic device according to claim 5, characterized in that the drugs located inside the microcapsules or groups of liposomes (33) have a controlled release coefficient, and can be prepared in liquid, solid form of fast dissolution, gel or crystals, allowing good diffusion and release capacity in the vascular lumen; and when released from the encapsulated structure or from the liposomal group (33) they will be gradually and protocolarily submitted to a process of investigation in an experimental model, computational analysis, pre-clinical and clinical studies, in order to evaluate with effectiveness and certainty the compatible pharmacological type to be employed, the ideal concentration to be reached in the vessel lumen, the best diffusion coefficient, the velocity and the intervals of release, half-life at the vascular locus, metabolism and toxicity, among other aspects.

7. Non-polymeric cylindrical tubular prosthetic device according to claim 5, characterized in that the microcapsules/liposomes (33) will be gradually and selectively released, through a combination action and pharmacological reaction, via enzymatic degradation (the from precursor drugs (36) released in a controlled and programmed manner by an implanted intradermal microchip (43), subject to the control of any external central modality (55), or even from electrical stimuli or release of the same types of pharmacological precursors (36) originating from nanochips on the internal surface of the stent (49), arranged inside the internal biological coating (32, 42), so that these precursor drugs (36), which will be released in a controlled and programmed manner by this intradermal microchip (43), present their pulse of release into the bloodstream, as well as intervals, concentration, and other potentially lower pharmacological variables. through the action of nanosensors (46) of this microchip implant (43), and it is subject to the control of any modality of external central, software or mobile communication device (55), known as remote or wireless monitoring process, by real-time data analysis, in such a way that the possibility of making a selectivity and diversity in the drug release mechanism (33) applied intra-stent or intra-prosthetic device becomes patent.

8. Non-polymeric cylindrical tubular prosthetic device according to claims 2, 3, 4, 5 and 7, characterized in that it represents the novelty, specificity and pioneering spirit in the use of this modality of gradual, programmed, long-term drug release distance, assuming to be the only and differentiated system in the field of international intellectual property designed to include the use of an implantable organic biochip (43), as an intelligent drug delivery system.

9. Non-polymeric cylindrical tubular prosthetic device according to claim 7, characterized in that it is part of a system connected to an implantable biochip (43), which combined with photolithography techniques, allow the creation of desired geometric shapes to be applied to its reservoirs present on its plate (44), and its subsequent complementation with the drugs (36) of choice.

10. Non-polymeric cylindrical tubular prosthetic device according to claims 7 and 9, characterized by operating together with an implantable biochip (43), whose drug release from the interior of its reservoirs would occur with an electrical stimulus between the thin layer of anodic metal consisting of the membrane covering the reservoir and the existing cathode, resulting in an electromechanical release by dissolving this membrane, so that the electrical stimulus can be activated by a remote control unit (55), with the control circuit inside the microchip, performing the function of controlled and pre-adjusted pharmacological release according to the indication and need demonstrated, for months to years, in addition to performing other intelligent functions through its biosensors (46), such as measuring serum metabolic parameters, concentration rate or half-life of released precursor drugs, interaction with nanosensors or nanochips (49) alternatively present ments on the inner surface of the prosthetic device (51), aiming to make it feasible to measure local metabolic indices, chemical mediators, hormones, neuromodulators, compulsorily measure the concentration rates of in-stent drugs (33), serum half-life of the medication released at the vascular locus addressed, sequential metabolism rate, and drug elimination time, among several other pharmacological, metabolic, and biochemical markers, etc., as well as measurement of physiological and electromechanical parameters of the vascular wall.

11. Non-polymeric cylindrical tubular prosthetic device according to claims 2, 3, 4, 5 and 7, characterized by the fact that it consists of an integrated system composed of in-stent drug delivery (33) through the action of a biochip (43), implantable under the skin, containing one or more activation-reception boards (44), operated by any modality of central/external command (55), whether automated control, telephone sets, PC unit , etc., and that multiple micro-reservoirs supporting and sustaining the precursor drugs are observed (36), these will then be released and via the bloodstream, will reach the vascular "stent" (50, 51), that is, acting on any vascular prosthetic device at a distance, through the programmed release of precursor drugs (36) contained in its structure, responsible for interacting with the inner surface of the vascular stent (35) , releasing the medications contained in the microcapsules and/or group of liposomes (33), with antimyoproliferative, antiatherogenic, antithrombogenic, antichemotactic, anti-inflammatory and vascular wall restructuring functions; thus, acting locally in the specific pharmacological release, arranged in the internal cover of the vascular or intraorganic prosthetic device (32, 42), under temporal control pulses, of concentration and specific type of in-stent medication (33).

12. Non-polymeric cylindrical tubular prosthetic device according to claims 5, 6 and 7, characterized by having an internal drug release matrix (32, 42), arranged in hexagonal (34), or hexagonal (47) and lozenge cells (48), containing microcapsules or groups of liposomes (33) that, in this sense, would be gradually and selectively released through a combination action and pharmacological reaction, in each support layer of the microcapsules or liposomes, by the substances (36) released by the electronic implant - biochip (43), presenting, among other biocompatible peculiarities, an internal drug release matrix (32, 42), which, in addition to having multiple layers, may contain interconnection holes or gaps between its cells, aiming to allow a greater diffusion and accessibility of released drugs (33) also in relation to the vascular wall "protected" by the prosthesis.

13. Non-polymeric cylindrical tubular prosthetic device according to claims 2, 3, 4 and 5, characterized in that each support layer of the microcapsules or liposome groups (33) will be formed by a matrix (35) of support of different chemical composition, one from the other, aiming to provide the specificity and selectivity of release of a given drug, contained in liposomes/microcapsules (33), according to the type of medication (precursor drug) (36) released by the implantable biochip (43) .

14. Non-polymeric cylindrical tubular prosthetic device according to claims 1, 2, 3 and 4, characterized in that initially, at the production level experimental, allow the elaboration of prostheses in diameters of 4.0 mm and 5.0 mm, with lengths that vary from 12 mm, 18 mm and 24 mm, not discarding a posteriori the molding in smaller diameter and/or greater length; the thickness of its stem cells can range from 0.08 to 0.12 mm, an important fact to reduce the tendency to thrombosis and trauma to the vascular wall, which is also a consequence of the prosthesis finishing process, which includes chemical polishing of the rods and laser cutting for the configuration of the material and its spatial structure.

15. Non-polymeric cylindrical tubular prosthetic device according to claims 2 and 4, characterized in that the alternative production of this organic or vascular prosthetic device (51) in a variant of this second model, of hexagonal cells (47) must be considered , coapted at their lower and upper ends by diamond cells (48), and these, in turn, are fenestrated, not coated internally in their area by the drug release coating (42), consisting of a indication property for the introduction of vascular prosthesis in situations of bifurcation/trifurcation lesions, collateral vessels emerging from the lesion site, among other indications.