Device for in vivo delivery of bioactive agents and method of manufacture thereof

ES 2 368 554 T3

DESCRIPTION

Device for the in vivo administration of bioactive agents and their manufacturing method

Background of the invention

The present invention relates generally to an implantable device for the in vivo administration of bioactive compounds. The present invention provides an implantable structural material having a three-dimensional conformation suitable for loading a bioactive agent into the structural material, implanting the structural material in vivo, and releasing the bioactive agent from the structural agent to deliver a pharmacologically acceptable level of the bioactive agent to an internal region of an organism. More particularly, the present invention relates to an endoluminal stent, which has regions with cavities incorporated within the material of the device with micropores that communicate a bioactive agent from the cavity to an external area of ​​the device.

The present invention can be used for any indication where it is desirable to deliver a bioactive agent to a localized site within an organism over a period of time. For example, the present invention can be used to treat occlusive vasculopathy, vascular injury or disorders, as an implantable contraceptive for the administration of a contraceptive agent delivered intrauterine or subcutaneously, to carry an antineoplastic agent or radioactive agent and implant within or adjacent to a tumor, such as for treating prostate cancer, for time-mediated administration of immunosuppressive agents, antiviral agents or antibiotics to treat autoimmune disorders such as transplant rejection or acquired immune disorders such as HIV, or to treat implant-related or non-implant-related inflammation or infections such as endocarditis.

Occlusive diseases, disorders, or trauma cause the body's open lumens to narrow and limit the flow or passage of fluid or materials through the body's lumen. An example of an occlusive disease is arteriosclerosis in which parts of blood vessels are occluded by the gradual formation of arteriosclerotic plaque, this process being known as stenosis. When vascular stenosis results in functional occlusion of a blood vessel, the blood vessel must be returned to its open state. Conventional therapies for the treatment of occluded lumen of the body include dilation of the lumen of the body using bioactive agents, such as tissue plasminogen activator (TPA) or vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF). , gene transfers that have improved blood flow and collateral development in the ischemic limb and myocardium (S. Yla-Herttuala, Cardiovascular Gene Therapy, Lancet, January 15, 2000), surgical intervention to remove the blockage, replacement of the blocked segment with a new segment of endogenous or exogenous graft tissue, or the use of such a catheter-mounted device such as a balloon catheter to dilate the lumen of the body or an arteriectomy catheter to remove occlusive material. Dilation of a blood vessel with a balloon catheter is called percutaneous transluminal angioplasty. During angioplasty, a deflated balloon catheter is inserted into an occluded segment of a blood vessel and inflated and deflated several times to expand the vessel. Due to inflation of the balloon catheter, the plaque formed on the vessel walls cracks and the vessel expands allowing more blood flow through the vessel.

In about sixty percent of angioplasty cases, the blood vessel remains open. However, the restenosis rate of approximately forty percent is unacceptably high. Endoluminal endoprostheses of a wide variety of materials, properties, and configurations have been used post-angioplasty in order to prevent restenosis and loss of patency in the vessel.

Although the use of endoluminal stents has successfully reduced the rate of restenosis in angioplasty patients, it has been found that a significant restenosis rate continues to exist even with the use of endoluminal stents. It is generally believed that the rate of restenosis after stenting is due, in large part, to the endothelial layer not regrowing over the stent and the incidence of smooth muscle cell-related neointimal growth on the luminal surfaces of the stent. the endoprosthesis. A lesion in the endothelium, the natural non-thrombogenic lining of the arterial lumen, is a significant factor contributing to restenosis at the site of a stent. An endothelial loss exposes the thrombogenic arterial wall proteins, which, along with the generally thrombogenic nature of many prosthetic materials, such as stainless steel, titanium, tantalum, nitinol, etc. that are custom used in stent fabrication, initiates platelet deposition and activation of the coagulation cascade, resulting in thrombus formation, ranging from partial coverage of the luminal surface of the stent to an occlusive thrombus . Additionally, endothelial loss at the stent site has been implicated in the development of neointimal hyperplasia at the stent site. Consequently, rapid re-endothelialization of the arterial wall with concomitant endothelialization of the blood or body fluid contact surfaces of the implanted device is considered critical to maintain the patency of the vasculature and prevent low flow thrombosis. To prevent restenosis and thrombosis in the angioplasty area, antithrombotic agents and other biologically active agents can be employed.

ES 2 368 554 T3

It has been found desirable to administer bioactive agents to the site where a stent is placed simultaneously with the implant of the stent. Many stents have been designed for the delivery of bioactive agents to the anatomical region of the stent implant. Some of these stents are biodegradable stents that are impregnated with bioactive agents. Examples of biodegradable impregnated stents are those found in US Patent Nos.^you 5,500,013, 5,429,634, and 5,443,458. Other bioactive agent delivery stents include a stent disclosed in US Patent No. 5,342,348 in which filaments are impregnated with a bioactive agent that are woven into or laminated to a stent. US Patent No. 5,234,456 discloses a hydrophilic stent that may include an adsorbed bioactive agent that may include a biologically active agent disposed within the hydrophilic material of the stent. Other bioactive agent delivery stents are disclosed in US Patent Nos.^you 5,201,778, 5,282,823, 5,383,927; 5,383,928, 5,423,885, 5,441,515, 5,443,496, 5,449,3 82, 4,464,450, and European Patent Application No. 0 528 039. Other devices for endoluminal administration of bioactive agents are given to know in US patents n.^you 3,797,485, 4,203,442, 4,309,776, 4,479,796, 5,002,661, 5,062,829, 5,180,366, 5,295,962, 5,304,121, 5,421,826, and in International Application No. WO 94 / 18906. A directional release bioactive agent stent is disclosed in US Patent No. 6,071,305 in which a stent is formed of a helical element having a groove in the abluminal surface of the helical element. A bioactive agent is loaded into the groove prior to endoluminal placement and thus, the bioactive agent is in direct apposition to the tissue treating the bioactive agent. Finally, International Application No. WO 00/18327 discloses a drug delivery stent in which a tubular conduit is wound into a helical stent. The tubular conduit has either a single continuous lumen or double continuous lumens that extend the entire length of the duct. The tubular conduit has regions or segments thereof that have pores to allow drug to "leak" from the conduit. One end of the tubular conduit is then in fluid communication with a delivery catheter, which introduces a fluid, such as a drug into the continuous lumen and through the pores. When biodegradable or non-biodegradable polymer-based or polymer-coated stents have been used, the polymers elicit an inflammatory immune response once the drug is eluted from the polymer. When using a polymer as a carrier for the bioactive agent, it is therefore desirable to isolate the polymer from body tissues in order to limit the inflammatory immune response after the bioactive agent has been eluted as can be achieved with the present invention.

Summary of the invention

As used herein, the term "bioactive agent" is intended to include one or more pharmacologically active compounds that may be in combination with pharmaceutically acceptable carriers and, optionally, additional components such as antioxidants, stabilizing agents, permeation enhancers, and the like. Examples of bioactive agents that can be used in the present invention include but are not limited to hydrophilic agents, hydrophilic agents, antiviral drugs, antibiotic drugs, steroids, fibronectin, anticoagulant drugs, drugs of antiplatelet function, drugs that prevent the growth of cells of smooth muscle in the inner surface wall of vessels, heparin, heparin fragments, aspirin, coumadin, tissue plasminogen activator (TPA), urokinase, hirudin, streptokinase, antiproliferative agents (methotrexate, cisplatin, fluorouracil, adriamycin), antioxidants (ascorbic acid, beta carotene, vitamin E), antimetabolites, thromboxane inhibitors, steroidal and nonsteroidal anti-inflammatory drugs, immunosuppressive agents, such as beta-rapamycin calcium channel blockers and blockers, genetic material including DNA and RNA fragments, fully expressed genes, antibodies, lymphokines, growth factors (vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF)), prostaglandins, leukotrienes, laminin, elastin, collagen, nitric oxide (NO), and integrins.

The structural material of the invention has a three-dimensional conformation having a geometry and construction in which there is an internal cavity or a plurality of internal cavities within the structural material and a conduit or opening or plurality of conduits or openings communicating between the internal cavity. and external of the structural material. The three-dimensional shape of the structural material may take a cylindrical, tubular, flat, spherical, curvilinear, or other general shape that is desired and suitable for a particular implant application. In accordance with the present invention, there is provided an endoluminal stent that is comprised of a plurality of structural elements that define a generally tubular shape for the endoluminal stent as defined in claim 1. At least some of the plurality of structural elements are composed of the structural material of the invention and have at least one internal cavity and at least one conduit or opening that communicates between the internal and external cavity of the endoprosthesis.

The endoprosthesis of the invention for the administration of bioactive agents generally consists of a plurality of structural elements, of which at least some of which have internal cavities that retain the bioactive agents, and openings that pass between the internal cavities and the surface. of the structural elements to communicate the bioactive agent from the internal and external cavity of the endoprosthesis. Other than as described herein, the present invention is not dependent on the particular geometry, material, material properties, or configuration of the stent.

Due to its use as structural support and the requirement that stents be placed using

ES 2 368 554 T3 transcatheter, stents are necessarily placed in a reduced diameter state and are expanded or allowed to expand in vivo to an enlarged diameter state. Thus, all stents have certain framework regions that are subjected to conditions of greater stress and strain than other framework regions of the stent. Thus, it is advantageous to locate the internal cavities that retain bioactive agents in structural regions of the stent that are subjected to relatively low stress and tension during endoluminal placement and deployment.

Diffusion forces then elute the remaining bioactive agent present in the regions of least stress and stress.

Brief description of the drawings

Figure 1 is a perspective view of an implantable element.

Figure 2 is a perspective view of an endoluminal stent having a plurality of structural elements.

Figure 3 is a cross-sectional view taken along line 3-3 of Figure 2.

Figure 4 is a cross-sectional view taken along line 4-4 of Figure 2.

Figure 5 is a fragmentary perspective view.

Figure 6 is a cross-sectional view taken along line 6-6 of Figure 5.

Figure 7 is a cross-sectional view taken along line 7-7 of Figure 5.

Figure 8 is a perspective view of a planar structural element for the administration of a bioactive agent.

Figure 9 is a cross-sectional view taken along line 9-9 of Figure 8.

Figure 10 is a cross-sectional view taken along line 10-10 of Figure 8.

Figure 11 is a plan view of an alternative embodiment.

Figure 12 is a photomicrographic cross-sectional view taken along line 12-12 of Figure

11.

Figures 13A-13F are sequence diagrams illustrating the method of fabricating the endoluminal stent.

Figure 14 are joint photomicrographs illustrating the selective formation of an internal cavity within the endoluminal stent.

Detailed description of the preferred embodiments

As indicated above, the term "bioactive agent" is intended to encompass one or more pharmacologically active compounds that may be in combination with pharmaceutically acceptable carriers and, optionally, additional components such as antioxidants, stabilizing agents, permeation enhancers, and the like. Examples of bioactive agents that can be used in the present invention include but are not limited to antibiotic drugs, antiviral drugs, antineoplastic agents, steroids, fibronectin, anticoagulant drugs, drugs of antiplatelet function, drugs that prevent the growth of smooth muscle cells in the inner surface wall of the vessels, heparin, heparin fragments, aspirin, coumadin, tissue plasminogen activator (TPA), urokinase, hirudin, streptokinase, antiproliferative agents (methotrexate, cisplatin, fluorouracil, adriamycin), antioxidants (ascorbic acid, beta carotene, vitamin E), antimetabolites, thromboxane inhibitors, steroidal and non-steroidal anti-inflammatory drugs, immunosuppressive agents, such as rapamycin, beta-blocking agents calcium channel blockers, genetic materials including DNA and RNA fragments, fully expressed genes, antibodies, lymphokines, growth factors (vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF)), prostaglandins, leukotrienes, laminin, elastin, collagen, nitric oxide (NO), and integrins.

With particular reference to Figure 1, the device generally consists of a body element 10 having a three-dimensional conformation defining the X, Y and Z axes of the body element 10 and at least one of a plurality of defined interior cavities 12 within the body element 10, and at least one of a plurality of passages or pores 14 communicating between the at least one of a plurality of interior and exterior cavities 12

ES 2 368 554 T3 with respect to the body element 10. Although the body element 10 depicted in Figure 1 is of a generally cylindrical three-dimensional conformation, alternative three-dimensional conformations are contemplated, such as flat, spherical, ovular, tetrahedral, curvilinear, or virtually any other three-dimensional conformation suitable for implantation in a living organism. . The plurality of passages 14 have sufficient dimensions to allow the bioactive agent to elute by diffusion, osmotic pressure or under the influence of a positive pressure applied by cell growth into the plurality of interior cavities 12.

The location of the plurality of passages 14 depends on the particular application for which the body element 10 is intended. For example, with particular reference to Figures 2-5, in which the body element 10 is a tubular body 20 composed of a plurality of interconnected structural elements 21, such as a stent, stent graft, or graft, defining a central lumen 22 and has openings 24 at opposite proximal and distal ends of tubular body 20, the plurality of passages 14 are formed in at least some of the plurality of interconnected structural elements 21 and may be disposed only on the luminal surface 26 or only on the abluminal surface 28 of the tubular body 20, or both. The pores 14 on the luminal surface 26 will only communicate the bioactive agent within the lumen and any bodily fluids, such as blood, flowing through the central lumen of the tubular body, while the pores 14 only on the surface 26 abluminal will communicate the bioactive agent with the abluminal surface of the tubular body. At least a portion of some of the plurality of interior cavities 12 may communicate with either proximal or distal ends of at least some of the plurality of interconnected structural elements 21. In this case, the proximal and / or distal ends of at least some of the plurality of interconnected structural elements may be tapered so as to self-channel body tissue during placement and deployment. The bioactive agent retained with the internal cavity 12 that communicates with the proximal and / or distal ends of at least some of the plurality of interconnected structural elements will then pass out of the proximal and / or distal ends in a similar manner as it does. a fluid that flows through an injection needle.

In addition to the above location of the pores 14, both the plurality of internal cavities 12 and the plurality of pores 14 can be positioned to be discontinuous and in regions of different circumference and different length of the tubular body 20. Within a single one of the plurality of interconnected structural elements 21, the internal cavities 12 may be separated by a separating element 25, which completely subtends the internal cavity 12, divides it into discrete discontinuous internal cavities 12. The advantages of forming a plurality of discontinuous internal cavities 12 is that it allows different bioactive agents to be loaded into different regions of the body member 10 or tubular member 20 to isolate different regions for delivery of different bioactive agents to different sites within a body. For example, a first group of a plurality of internal cavities 12 and associated plurality of pores 14 can be located at a proximal end of the tubular body 20, and a second group of a plurality of internal cavities 12 and associated plurality of pores 14 can be located at an intermediate region of the tubular body 20, and a third group of a plurality of internal cavities 12 and associated plurality of pores 14 may be located at a distal end of the tubular body 20. A first bioactive agent can be loaded in the first and third groups of a plurality of internal cavities 12, while a second bioactive agent can be loaded in the second group of a plurality of internal cavities 12. When, for example, the tubular body 20 is an endoluminal stent, stent graft, or graft that is implanted after angioplasty, the proximal and distal ends of the tubular body 20 are attached adjacent to healthy tissue while the intermediate region of the body 20 tubular is located adjacent to injured or diseased tissue. In this configuration, a first bioactive agent, such as an endothelial growth factor and / or contrast medium to confer greater radiopacity to the tubular body 20 can be carried in the first and third groups of a plurality of internal cavities 12 and associated pores 14, whereas an anticoagulant, such as heparin, can be carried in the second group of a plurality of internal cavities 12 and associated pores 14. In this way, the tubular body has increased radiopacity to aid in placement and deployment and endothelial growth factors to enhance endothelialization of the tubular body, while delivering an anticoagulant directly to the site of tissue injury.

Furthermore, when the internal cavities 12 are discontinuous, the plurality of pores 14 can be configured to include degradable plugs that degrade at different rates to expose different bioactive agents in the internal cavities 12 to the body at different times. Alternatively or additionally, the degradable plugs can degrade at different rates to expose the same bioactive agent in different internal cavities 12 for different periods of time to effectively extend the period of time during which the bioactive agent is administered. Alternatively, the plurality of pores 14 may be sized to allow different elution rates of the bioactive agent and to provide over time or longer release of the bioactive agent from the internal cavities 12. Furthermore, by adjusting the bioactive agent carriers, eg, to provide more or less ability to elute in vivo, in combination with alternative dimensions and orientations of the plurality of pores 14, eg, luminally or abluminally oriented, can be adjusted both the elution time as the elution duration.

The body element 10 is preferably formed of a metal such as titanium, vanadium, aluminum, nickel, tantalum, zirconium, chromium, silver, gold, silicon, magnesium, niobium, scandium, platinum, cobalt, palladium, manganese, molybdenum and alloys. thereof, such as zirconium-titanium-tantalum alloys, nitinol, or stainless steel.

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Returning to Figures 5-7 an endoluminal stent fabricated from a plurality of tubular structural elements 31 shaped into a tubular stent and having a desired geometry is illustrated. It will be appreciated that the generally hexagonal cell geometric pattern illustrated in Figure 5 is merely exemplary and the invention contemplates thousands of different geometric complexities. Each of the tubular structural elements 31 has a central lumen 37 that forms the internal cavity within each structural element 31. A plurality of spacing elements 38 may be provided to subdivide the internal cavity 37 into a plurality of discontinuous internal cavities 37. Each of the tubular structural elements 31 has a plurality of openings 36 communicating between the internal cavity 37 and one or both of a luminal surface 33 or an abluminal surface 35 of each of the plurality of tubular structural elements 31. The tubular structural elements 31 can adopt any cross-sectional configuration having a central span.

Those skilled in the stent-forming arts will understand that in order to form an endoluminal tubular stent from tubular elements 31, it is necessary to join at least some of the plurality of tubular elements 31. Conventionally, a plurality of spot welds 34 serve to interconnect sections of individual tubular elements 31 in juxtaposed relationship to one another. The plurality of spot welds 34 may also be used to seal the inner cavity 37 at the spot weld position, thereby creating a spacer element 38 within the inner cavity 37 of each individual tubular element 31 and forming a cavity. 37 internal discontinuous.

As noted above, the plurality of apertures 36 are dimensioned to allow the bioactive agent to elute from the at least one of a plurality of internal cavities 37 and through the associated plurality of apertures 36 by diffusion, osmotic pressure or under the influence of a positive pressure applied by cell growth inside the plurality of internal cavities 37 or under a positive pressure applied by tension and / or stress exerted on the plurality of internal cavities 37 due to deformation of the individual tubular structural elements 31. Additionally, the location of the plurality of openings 36 with respect to the individual tubular structural elements 31 and the endoluminal stent as a whole can be adapted to deliver varying amounts of or different bioactive agents from different regions of the different or tubular structural elements 31. regions of the endoluminal stent 30. In addition, the proximal and / or distal ends of the individual tubular framework elements 31 may be tapered so as to form self-channeling ends of the individual tubular framework elements 31 that penetrate the body tissue and allow the bioactive agent to be communicated from the internal cavity 37 outward from the proximal or distal end of the tubular structural member 31 in a manner similar to a hypodermic needle.

An implantable device 40 consisting of a structural body 42 having a three-dimensional conformation that extends dimensionally in the X-axis, Y-axis, and Z-axis is illustrated and disclosed in Figures 8-10. Although the embodiment of the structural body 42 is flat, those skilled in the art of medical device fabrication will understand that it is within the skill of the skilled person how to fabricate the structural body 42 of any desired three-dimensional conformation depending on the desired use and indication of the implantable device 40. The three-dimensional conformation of the structural body 42 can be cylindrical, tubular, quadrilateral, flat, spherical, ovular, tetrahedral, curvilinear, or virtually any other three-dimensional conformation suitable for implantation in a living organism.

As in the previously described embodiments, the structural body 42 has at least one of a plurality of internal cavities 47, each carrying a bioactive agent 47, and a plurality of openings 44 passing from at least one upper surface 46, lower 48 or lateral 45 of the structural body 42, through the thickness of the Z axis of the body and communicating with the at least one of a plurality of internal cavities 47 in the structural body 42. When a plurality of internal cavities 47 are provided within the structural body 42, a plurality of bioactive agents 49 may be loaded into the structural body 42 with one or more bioactive agents 49 being loaded into each of the plurality of internal cavities 47.

Each of the embodiments described above can be manufactured by various methods. It is contemplated that either the formation of formed metal pieces, such as capillaries, in the implantable device or the formation of implantable devices by vacuum deposition techniques are the preferred methods of fabrication of the implantable structural elements. When an implantable device is to be manufactured from a plurality of individual tubular elements, as depicted in Figures 5-7, previously existing microtubular elements having an outer diameter of, for example, between 60 and 400 m and a 10-350 m wall thickness, to manufacture extremely small device dimensions suitable for intracranial or coronary artery applications. The microtubule elements can be formed into a cylindrical endoluminal device, such as by braiding or bending and joining the microtubule elements together by spot welding. When the ends of the microtubule elements are formed for self-channeling, the self-channeling ends can be exposed on the abluminal surface of an endoluminal device at any point along the longitudinal axis of the device. The plurality of openings through the wall of each of the individual tubular elements can be formed by microperforating the openings through the wall and into the internal cavity or lumen of the elements.

ES 2 368 554 T3 individual tubular. The plurality of apertures can be laser cut, etched or formed by EDM methods, and can be formed either before or after the formation of the tubular elements in the three-dimensional shaping of the implantable device. When an implantable device is to be formed from previously non-existent structural elements, vacuum deposition techniques may be employed to form the implantable structural body, such as spraying, reactive ion etching, chemical vapor deposition, phase deposition. plasma activated vapor, or the like, as is known in the microelectronic component manufacturing arts and is more fully described in co-pending U.S. Patent Application Serial No. 09 / 443,929, filed November 19, 1999. Since internal cavities and openings must be formed during deposition, vacuum deposition techniques must be modified to deposit necessary patterns of sacrificial material to form the regions of internal cavities and openings, on a base layer of structural material, then depositing a second layer of structural material over the sacrificial material and the base layer. The sacrificial material can then be removed, such as by etching, to form the internal cavities and the plurality of openings within the deposited bulk material.

An embodiment depicting an endoluminal stent configuration is illustrated in Figures 11 and 12. According to the embodiment, an endoluminal stent 50 is illustrated composed of a plurality of structural elements 52 interconnected to a plurality of articulated regions 54 and defining a plurality of interstices 56 joined by the plurality of structural elements and the plurality of articulated regions 54. As described above, the material used to make the inventive device has a Z-axis wall thickness in the material of the device. The device of the invention incorporates at least one of a plurality of internal cavities 56 within the wall thickness of the material used to form the implantable device or endoluminal stent 50. A plurality of micropores 58 are provided and communicated between an external surface of the device 50 and one of the plurality of internal cavities 56. As noted above, the plurality of micropores 58 are dimensioned to allow the bioactive agent to elute from the at least one of a plurality of internal cavities 56 and through the associated plurality of micropores 58 by diffusion, osmotic pressure or under the influence of a positive pressure applied by cell growth to the interior of the plurality of internal cavities 56 or under a positive pressure applied by the stress and / or stress exerted on the plurality of internal cavities 56 due to deformation of the individual structural elements 52. The plurality of micropores 58 may further be provided to communicate between an internal cavity 56 and either a luminal or abluminal surface of the inventive stent, such as to expose the bioactive agent retained within the plurality of internal cavities 56 or to the bloodstream in the case of the luminal micropores 58, and / or the adjacent tissue, in the case of the abluminal micropores 58.

The at least one of a plurality of internal cavities 56 may be continuous or discontinuous through the inventive device 50. Specifically, in accordance with a preferred embodiment of the invention, the plurality of internal cavities 56 are discontinuous and each of the plurality of discontinuous internal cavities 56 resides within regions of device 50 that are substantially non-load bearing regions of the device. In the particular embodiment illustrated in Figure 11, the plurality of articulated regions 54 lack internal cavities 56 because they are load bearing regions of the stent. But nevertheless, It is contemplated that regions of the device 50 of the invention that are deformed or load bearing may include either continuous internal cavities 56 or discontinuous internal cavities within their wall thickness and provide elution of a bioactive agent retained within the internal cavity located in the load-bearing region under the influence of a positive motive pressure exerted on the bioactive agent by deformation or transferred load stress by the geometry of the device to the internal cavity and the bioactive agent. By providing continuous and discontinuous internal well regions 56, a plurality of bioactive agents can be loaded into different internal wells 56 to achieve different elution rates and pharmacological effects. Figure 12 is a photomicrograph illustrating a cross-sectional view through a single structural member 52 illustrating internal cavity 56.

Turning now to Figures 13A-F and 14 a method for manufacturing the devices of the invention for the delivery of bioactive agents is depicted. In Figure 13A, a first layer 64 is formed of a device-forming metal, such as titanium, vanadium, aluminum, nickel, tantalum, zirconium, chromium, silver, gold, silicon, magnesium, niobium, scandium, platinum, cobalt. , palladium, manganese, molybdenum, and alloys thereof, such as zirconium-titanium-tantalum alloys, nitinol, or stainless steel, on a sacrificial substrate material 62. A sacrificial layer 66 is formed of a sacrificial material that can be selectively removed without removing the underlying first layer 64. The next stage involves the selective removal of portions of the sacrificial layer 66 to leave void-forming portions 68 of the first sacrificial layer 66. A second layer 70 of a device-forming metal, such as those listed above, is then formed over the first layer 62 of the device-forming metal and covers the cavity-forming portions 68. In the next stage, shown in FIG. 13D, the plurality of micropores 72 are formed and traverse the second layer 70 and communicate with the cavity-forming portions 68. The plurality of micropores 72 can be formed by selective removal of the second layer 70 such as by laser or etching. Alternatively, the second layer 70 of the device-forming metal may be selectively formed such as to form the plurality of micropores 70 during the formation of the second layer 70. In the next step, depicted in FIG. 13E, sacrificial material is selectively removed from the cavity-forming portions 68, such as by etching

ES 2 368 554 T3 chemistry of the cavity-forming parts 68, without removing or affecting the material properties of either the first layer 64 or the second layer 70 of the device material, thereby leaving a plurality of cavities 74 internally defined within the second layer 70 and joined by the first layer 64 of device material, the plurality of micropores 70 communicating between the plurality of internal cavities 74 and an external surface of device material 70. Finally, in step 13F, the sacrificial substrate material 62 is selectively removed thereby obtaining the implantable device of the invention. Figure 14 is a photomicrograph illustrating a device formed at step 13E in the left panel and at step 13F in the right panel.

According to a preferred embodiment of the present invention, the above method is performed by vacuum deposition techniques to form the implantable device of the invention. Suitable processing includes, for example, spraying, reactive ion etching, chemical vapor deposition, plasma activated vapor deposition, or the like, as is known in the microelectronic component manufacturing arts and is described more fully in co-pending U.S. Patent Application Serial No. 09 / 443,929, filed November 19, 1999.

Regardless of which manufacturing method is employed, the bioactive agent must be loaded into the internal cavities of the implantable device. Loading of the bioactive agent can be accomplished by flowing a liquid or semi-liquid state of the bioactive agent through the plurality of openings and into the internal cavities, either throughout the device or in regions of the implantable device. Flow loading can be facilitated by applying positive pressure, temperature change, or both, as used in hot isostatic pressing (HIP). In HIP, the pressurizing medium is typically a gas, and the process is carried out at elevated temperatures for specific periods of time. Although HIP is commonly used to densify materials, repair casting defects and voids, or to bond similar or dissimilar materials, it can be used to drive a fluid or semi-fluid from outside the implantable device into the internal cavities of the implantable device. Diffusion-mediated loading, osmotic loading, or alternative vacuum loading can be employed to load the bioactive agent into the internal cavities.