Implant and method for manufacturing same

Abstract

A method for manufacturing an implant and an implant, in particular an intraluminal endoprosthesis, including a body having a coating on at least a portion of the surface thereof, and the degradation of which can be influenced from the outside in a targeted manner, the method having the following steps: a) providing an implant body, and b) applying a coating to the surface of the implant body, wherein the coating comprises unfilled cavities, preferably in the form of microbubbles (2).

Claims

1. A method for manufacturing a biodegradable implant comprising the following steps: a) providing an implant body; b) applying a pharmaceutical layer to the implant body, wherein the pharmaceutical layer comprises a pharmaceutically active substance; and c) applying a coating comprising rupturable, unfilled microbubbles over the pharmaceutical layer, wherein the microbubbles are configured to rupture by way of ultrasonic excitation.

2. The method according to claim 1, wherein the microbubbles are formed of polylactic acid (PLA) and the pharmaceutically active substance is hyaluronic acid.

3. A biodegradable implant comprising a body at least partially coated with a pharmaceutical layer and over the pharmaceutical layer is a coating of microbubbles filled with inert gas and configured to rupture by way of ultrasonic excitation.

4. The implant according to claim 3, characterized in that the implant body comprises struts, wherein a luminal side of the struts comprises recesses coated with the microbubbles.

5. A biodegradable implant comprising a body at least partially coated with a pharmaceutical layer coated with microbubbles filled with inert gas and configured to rupture by way of ultrasonic excitation, characterized in that the microbubbles are attached to a surface of the implant body using an embedding matrix, wherein the matrix comprises at least one material selected from the group consisting of a polymer, a lipid, a citrate-based softening agent, a protein and a peptide.

6. The implant according to claim 3, wherein the gas comprises molecules sized to prevent diffusion of the molecules through shells of the microbubbles.

7. The implant according to claim 3, wherein the gas comprises perfluorocarbons or sulphur tetrafluoride.

Description

DESCRIPTION OF THE DRAWINGS

(1) Shown schematically, in a cross section in each case, are:

(2) FIG. 1 a first example embodiment of an implant according to the invention,

(3) FIG. 2 a second example embodiment of an implant according to the invention,

(4) FIG. 3 a third example embodiment of an implant according to the invention,

(5) FIG. 4 a fourth example embodiment of an implant according to the invention and

(6) FIG. 5 a fifth example embodiment of an implant according to the invention.

DETAILED DESCRIPTION

(7) FIG. 1 shows a section of a stent, namely the section of a stent strut 1 made of a magnesium alloy comprising at least 50% magnesium by weight. A coating including microbubbles 2 made of PLA is disposed on the outer surface of the stent strut 1. The inner space of the microbubbles 2 is filled with an inert, poorly soluble gas, such as nitrogen or sulphur tetrachloride (SF.sub.6). The mean diameter of the microbubbles 2 is approximately 5 μm. The microbubbles 2 are attached by way of the surface tension thereof to the outer surface of the stent strut 1 and, additionally, chemical anchor chains can be applied onto/into the wall of the microbubbles 2 to improve the adhesion of the microbubbles 2 to the surface of the stent strut 1.

(8) The second example embodiment, which is presented in FIG. 2, corresponds to the example shown in FIG. 1, with the difference that the microbubbles 2 are embedded in a matrix 3 made of PLLA or hyaluronic acid.

(9) Example embodiments of an implant according to the invention are presented in FIGS. 3 and 4, which correspond to the second example embodiment and additionally include a layer 4 having a pharmaceutically active substance, wherein the layer 4 contains BTHC and paclitaxel, for example, in the case of FIG. 3, and PLLA and sirolimus, for example, in the case of FIG. 4. In the third example embodiment, which is shown in FIG. 3, the layer 4 is disposed underneath the layer comprising the microbubbles 2, while, in the example embodiment depicted in FIG. 4, the layer 4 having the pharmaceutically active substance lies above the layer having the microbubbles 2. Analogous to the second example embodiment, all the microbubbles 2 are embedded in the matrix 3. Alternatively, and analogous to the first example embodiment depicted in FIG. 1, the microbubbles can also be attached to the surface of the stent strut 1 or the layer 4 without matrix material.

(10) Finally, FIG. 5 shows an example embodiment, in the case of which a layer 4 including hyaluronic acid and an anti-inflammatory agent is disposed in a recess 5 in the stent strut 1. A further layer is disposed over the layer 4, likewise in the recess 5, the layer including microbubbles 2 made of PLA with a matrix 3 made of PLLA or hyaluronic acid, which is disposed on the surface of the layer 4 and within the recess 5. Alternatively, the microbubbles 2 can be disposed on the layer 4 in the recess 5 by way of the surface tension thereof, or by way of a form-fit connection in the recess 5, i.e. without a matrix.

(11) The production of an implant according to the invention is presented in the following using the example of a biodegradable vascular support in the form of a coronary stent.

(12) The support frame of the vascular support is a biodegradable, balloon-expandable metal stent, produced by way of laser cutting from a tube made of the biocompatible, biodegradable magnesium alloy WE43. The stent is provided with recesses at a plurality of defined points for accommodating microbubbles. The recesses can also be produced by way of laser cutting. The recesses are preferably disposed in strut regions that, during dilation, undergo less mechanical load or are hardly deformed at all compared to other regions.

(13) To facilitate a coating to be applied into the recesses in a targeted manner, the stent is mounted on a positioning device in a micropipetting system.

(14) Immediately before coating, a microbubble suspension of microbubbles having a size of 2 μm to 10 μm and comprising a phospholipid shell containing the filling gas SF.sub.6 is prepared. The suspension is preferably reconstituted from the granulate (e.g. SONOVUE from BRACCO Imaging S.p.A., Amsterdam), well sealed from the air, with addition of an aqueous solvent, for example a 0.9% saline solution (optionally with additives), and intensive shaking for a period of at least 20 s until a homogeneous, milky white suspension is obtained. The suspension produced in this manner is filled into the micropipetting system and is applied onto/into the above-mentioned recesses or other protected regions on the support frame. The deposited droplets of the suspension containing the microbubbles remain adhered in the recesses by way of the surface tension thereof. In a preferred example embodiment, the suspension is propelled in the micropipetting system by application of pressure with the filling gas SF.sub.6. This gas also serves to prevent other gasses from entering.

(15) Alternatively or in addition to phospholipids, the microbubble shells can contain at least one material from the group comprising galactose, albumin and Perflutren.

(16) In the next step, the matrix component, which in this case is hyaluronic acid in aqueous solution, is added to the layer comprising the microbubbles, which is disposed in the recesses, in the same manner using the micropipetting system. The matrix component serves to adhere the microbubbles onto the surface of the stent. Application in a subsequent manner permits the matrix component to come to rest primarily in the outer regions of the coating and to thereby better protect the more deeply embedded bubbles against damage.

(17) Alternatively, the matrix component of the layer, which in this case is hyaluronic acid in aqueous solution, can be applied into the recesses using the micropipetting system together (i.e. simultaneously) with the microbubble suspension. To this end, the two solutions are combined immediately before emerging from the outlet opening of the micropipetting system from separate reservoirs. The matrix component becomes evenly distributed in the coating, thereby resulting in uniform acoustic properties of the embedded microbubbles. By shutting off the driving pumps at different times, it is possible for the matrix component to be disposed primarily in the outer regions of the coating, thereby protecting the more deeply embedded microbubbles against damage.

(18) Finally, in both variants of the application, an (incomplete/partial) drying step is carried out, which serves the primary purpose of stabilizing the outer surface of the bubble depots disposed in the recesses for the subsequent processing steps. To this end, the coated stent support frame is stored in a dry environment, e.g. in a slow (laminar) stream of cold or moderately heated nitrogen or argon or another inert gas, e.g. at a temperature in the range of 10° C. to 50° C., for a specific time period of a few minutes.

(19) For drying, an alternative to the use of the slow stream is to use a closed drying room with removal of water by way of at least one cooling finger (cooled with liquid nitrogen, dry ice or Peltier cooling) or a constant-temperature oven with a stationary inert-gas atmosphere.

(20) Finally, a coating containing PLLA is applied to the stent, over the entire surface or only a portion thereof, by way of spray coating. The PLLA coating provides protection against corrosion for the corresponding regions of the stent, improves the mechanical adhesion of the microbubble layer and protects it against wear.

(21) It will be apparent to those skilled in the art that numerous modifications and variations of the described examples and embodiments are possible in light of the above teaching. The disclosed examples and embodiments are presented for purposes of illustration only. Other alternate embodiments may include some or all of the features disclosed herein. Therefore, it is the intent to cover all such modifications and alternate embodiments as may come within the true scope of this invention.

LIST OF REFERENCE SIGNS

(22) 1 Stent strut 2 Microbubble 3 Matrix 4 Layer comprising pharmaceutically active substance 5 Recess