Magnesium alloy and resorbable stents containing the same

Abstract

The present invention is directed to a magnesium alloy containing 5.0% by wt.-25.5% by wt. dysprosium, 0.01% by wt.-5.0% by wt. neodymium and/or europium, 0.1% by wt. 3.0% by wt. zinc, 0.1% by wt.-2.0% by wt. Zirconium, and balance to 100.0% by wt. magnesium, being degradable under physiological conditions and which is particularly suitable for the production of absorbable stents and to stents made thereof.

Claims

1. Absorbable stent consisting of a magnesium alloy which consists of the following components based on the total weight of the alloy: TABLE-US-00037 5.0% by wt.-25.5% by wt. dysprosium 0.01% by wt.-5.0% by wt. neodymium and/or europium 0.1% by wt.-3.0% by wt. zinc 0.1% by wt.-2.0% by wt. zirconium 1 ppm-0.4% by wt. impurities balance to 100.0% by wt. magnesium, wherein the alloy contains in total not more than 0.1% per wt. of the elements terbium, holmium, erbium, thulium, ytterbium and lutetium, and wherein the alloy contains no yttrium and no gadolinium.

2. Absorbable stent of a magnesium alloy according to claim 1 comprising: TABLE-US-00038 0.1% by wt.-2.0% by wt. zinc.

3. Absorbable stent of a magnesium alloy according to claim 1 comprising: TABLE-US-00039 0.1% by wt.-0.3% by wt. zirconium.

4. Absorbable stent of a magnesium alloy according to claim 1 consisting of: TABLE-US-00040 80.7% by wt.-94.7% by wt. magnesium 5.0% by wt.-15.0% by wt. dysprosium 0.1% by wt.-2.0% by wt. neodymium 0.1% by wt.-2.0% by wt. zinc 0.1% by wt.-0.3% by wt. impurities wherein the alloy contains no yttrium and no gadolinium.

5. Absorbable stent of a magnesium alloy according to claim 1 consisting of: TABLE-US-00041 80.4% by wt.-94.6% by wt. magnesium 5.0% by wt.-15.0% by wt. dysprosium 0.1% by wt.-2.0% by wt. neodymium and/or europium 0.1% by wt.-2.0% by wt. zinc 0.1% by wt.-0.3% by wt. zirconium 0.1% by wt.-0.3% by wt. impurities wherein the alloy contains no yttrium and no gadolinium.

6. Absorbable stent according to claim 1, wherein the absorbable stent is a stent for blood vessels, urinary tracts, respiratory tracts, biliary tracts or the digestive tract.

Description

DESCRIPTION OF THE FIGURES

(1) FIG. 1: shows an image for determining the grain size of a magnesium alloy with 10% by wt. Dy and 1% by wt. Nd.

(2) FIG. 2: shows an image for determining the grain size of a magnesium alloy with 10% by wt. Dy, 1% by wt. Nd and 0.6% by wt. Zr.

(3) FIG. 3: shows an image for determining the grain size of a magnesium alloy with 10% by wt. Dy, 1% by wt. Nd and 0.2% by wt. Zr. The grain size is 102 m.

(4) FIG. 4: shows an image for determining the grain size of a magnesium alloy with 10% by wt. Dy, 1% by wt. Nd and 0.4% by wt. Zr. The grain size is 68 m.

(5) FIG. 5: shows an image for determining the grain size of a magnesium alloy with 10% by wt. Dy, 1% by wt. Nd and 0.6% by wt. Zr. The grain size is 64 m.

(6) FIG. 6: shows 4 snapshots during the balloon angioplasty for implantation of an uncoated stent of the invention in a pig (see Example 8). FIG. 6A has been taken without an X-ray contrast agent, after the catheter has been advanced up to the appropriate coronary artery. The two arrows point to the radio-opaque markers distal and proximal of the still folded catheter balloon on which the stent is mounted. FIG. 6B has been taken with X-ray contrast agent during the dilatation of the catheter balloon to expand and place the stent. The two arrows mark the ends of the catheter balloon. The catheter balloon occludes the vessel, so that the X-ray contrast agent cannot penetrate into the underlying part of the vessel. The stent balloon to artery ratio was 1.2 to 1. FIG. 6C has been taken without X-ray contrast agent after the catheter with the balloon has been withdrawn from the vessel. Thereby the stent remains in the vessel, but is not visible on the image, because the magnesium alloy of the invention is not radio-opaque.

(7) FIG. 6D has been taken with X-ray contrast medium after the catheter with the balloon has been withdrawn from the vessel. Thereby the stent remains in the vessel. The arrows point to the ends of the stent. In the region of the stent slightly more contrast agent accumulates. But the stent itself is not recognizable.

(8) FIG. 7: shows a graphic representation of the results of the corrosion tests with binary magnesium alloys containing between 5 and 20% dysprosium and magnesium as balance. The corrosion was measured in 0.9% saline solution in a eudiometer. The data in % refer to the content of dysprosium in % by weight.

(9) FIG. 8: shows a graphic representation of the dependence of the tendency for hot crack formation in connection with the amount of zinc in the alloy. Magnesium alloys according to the invention containing 10% dysprosium, 1.0% by weight neodymium, increasing % by weight zinc, 0.2% by weight zirconium and the balance of magnesium were tested. The data in % refer to the content of zinc in % by weight.

EXAMPLES

Example 1

Production of the Alloys

(10) The alloys were produced in the so-called permanent mold direct chill casting (Ttenguverfahren). This method is used to produce precursors for the subsequent extrusion and is characterized in that material with a homogeneous microstructure and a homogeneous distribution of alloying elements in the ingot can be produced. Therefore it is exceptionally suitable to produce smaller quantities of high quality pins for the metal forming.

(11) With this method, the magnesium alloys (L1, L2, . . . , L34) are melted in a smoothed steel crucible. As a crucible material virtually any nickel-free steel may be used. Graphite would be another possibility. All melting operations are carried out under inert gas. The temperatures of the molten bath are in the range of 660-740 C. Upon reaching the temperature of the molten bath, the alloying elements in the form of pure elements or as master alloys were added. After addition of the alloying elements the melt was stirred mechanically. The stirring time is dependent on how long it takes for the elements or master alloys to completely dissolve in the melt. After this preparation, the melt was transferred to a thin-walled coquille which was preheated to a temperature of 600 C. After a period of about 60 minutes, the coquille was immersed in a water bath having a temperature of 15-20 C. Upon immersing the coquille completely solidified.

(12) Prior to extrusion the surface of the cast part was adjusted to the diameter of the recipient of the extrusion press. In addition, prior to extrusion the casting pin has been heated to a temperature of 250-500 C. and kept for 3-6 hours at this temperature to dissolve intermetallic phases or to homogenize segregations. Subsequent to this extrusion followed and the billet produced in this manner was cooled in air to room temperature. Wires were obtained which were then transformed into tubes.

(13) The following alloys were prepared:

(14) TABLE-US-00029 Alloy L1: 87.8% by wt. magnesium 10.0% by wt. dysprosium 1.0% by wt. neodymium 1.0% by wt. zinc 0.2% by wt. Impurities comprising Si, Ni, Fe, Cu and other metals and non-metals. Alloy L2: 88.6% by wt. magnesium 10.0% by wt. dysprosium 1.0% by wt. neodymium 0.2% by wt. zirconium 0.2% by wt. Impurities comprising Si, Ni, Fe, Cu and other metals and non-metals. Alloy L3: 87.6% by wt. magnesium 10.0% by wt. dysprosium 1.0% by wt. neodymium 1.0% by wt. zinc 0.2% by wt. zirconium 0.2% by wt. Impurities comprising Si, Ni, Fe, Cu and other metals and non-metals. Alloy L4: 89.7% by wt. magnesium 6.0% by wt. dysprosium 2.0% by wt. neodymium 2.0% by wt. zinc 0.3% by wt. Impurities comprising Si, Ni, Fe, Cu and other metals and non-metals. Alloy L5: 90.7% by wt. magnesium 5.5% by wt. dysprosium 3.0% by wt. neodymium 0.5% by wt. zirconium 0.3% by wt. Impurities comprising Si, Ni, Fe, Cu and other metals and non-metals. Alloy L6: 87.4% by wt. magnesium 8.0% by wt. dysprosium 2.2% by wt. neodymium 1.8% by wt. zinc 0.3% by wt. zirconium 0.3% by wt. Impurities comprising Si, Ni, Fe, Cu and other metals and non-metals. Alloy L7: 82.7% by wt. magnesium 12.0% by wt. dysprosium 2.5% by wt. neodymium 2.5% by wt. zinc 0.3% by wt. Impurities comprising Si, Ni, Fe, Cu and other metals and non-metals. Alloy L8: 74.2% by wt. magnesium 22.5% by wt. dysprosium 2.6% by wt. neodymium 0.4% by wt. zirconium 0.3% by wt. Impurities comprising Si, Ni, Fe, Cu and other metals and non-metals. Alloy L9: 83.1% by wt. magnesium 15.2% by wt. dysprosium 1.2% by wt. neodymium 0.2% by wt. zirconium 0.3% by wt. Impurities comprising Si, Ni, Fe, Cu and other metals and non-metals. Alloy L10: 88.9% by wt. magnesium 8.0% by wt. dysprosium 1.4% by wt. neodymium 1.2% by wt. zinc 0.2% by wt. zirconium 0.3% by wt. Impurities comprising Si, Ni, Fe, Cu and other metals and non-metals. Alloy L11: 90.6% by wt. magnesium 8.0% by wt. dysprosium 1.0% by wt. neodymium 0.2% by wt. zinc 0.2% by wt. zirconium Alloy L12: 89.3% by wt. magnesium 8.0% by wt. dysprosium 1.0% by wt. neodymium 1.0% by wt. europium 0.5% by wt. zinc 0.2% by wt. zirconium Alloy L13: 86.0% by wt. magnesium 12.0% by wt. dysprosium 1.0% by wt. neodymium 0.8% by wt. zinc 0.2% by wt. zirconium Alloy L14: 90.1% by wt. magnesium 6.0% by wt. dysprosium 1.0% by wt. neodymium 1.0% by wt. europium 1.5% by wt. zinc 0.4% by wt. zirconium Alloy L15: 86.8% by wt. magnesium 10.0% by wt. dysprosium 1.0% by wt. neodymium 1.0% by wt. europium 1.0% by wt. zinc 0.2% by wt. zirconium Alloy L16: 82.8% by wt. magnesium 14.0% by wt. dysprosium 0.5% by wt. neodymium 0.5% by wt. europium 2.0% by wt. zinc 0.2% by wt. zirconium Alloy L17: 87.3% by wt. magnesium 10.0% by wt. dysprosium 1.5% by wt. neodymium 1.0% by wt. zinc 0.2% by wt. zirconium Alloy L18: 87.45% by wt. magnesium 10.0% by wt. dysprosium 1.5% by wt. neodymium 1.0% by wt. zinc 0.05% by wt. iron Alloy L19: 83.1% by wt. magnesium 15.0% by wt. dysprosium 0.9% by wt. neodymium 1.0% by wt. zirconium Alloy L20: 95.0% by wt. magnesium 4.5% by wt. dysprosium 0.5% by wt. neodymium Alloy L21: 73.7% by wt. magnesium 20.0% by wt. dysprosium 5.0% by wt. neodymium 1.0% by wt. zinc 0.3% by wt. zirconium Alloy L22: 87.25% by wt. magnesium 10.0% by wt. dysprosium 1.5% by wt. neodymium 1.0% by wt. zinc 0.05% by wt. iron 0.2% by wt. zirconium Alloy L23: 85.8% by wt. magnesium 12.0% by wt. dysprosium 1.0% by wt. neodymium 1.0% by wt. zinc 0.2% by wt. zirconium Alloy L24: 82.1% by wt. magnesium 15.0% by wt. dysprosium 0.9% by wt. neodymium 1.0% by wt. zinc 1.0% by wt. zirconium Alloy L25: 79.1% by wt. magnesium 20.0% by wt. yttrium 0.9% by wt. europium Alloy L26: 92.5% by wt. magnesium 5.0% by wt. dysprosium 2.5% by wt. europium Alloy L27: 82.1% by wt. magnesium 15.5% by wt. dysprosium 1.2% by wt. neodymium 1.0% by wt. zinc 0.2% by wt. zirconium 0.001% by wt. Impurities comprising Si, Ni, Fe, Cu and other metals and non-metals. Alloy L28: 72.0% by wt. magnesium 20.0% by wt. gadolinium 5.0% by wt. neodymium 1.0% by wt. zinc 2.0% by wt. zirconium Alloy L29: 88.8% by wt. magnesium 6.0% by wt. dysprosium 4.0% by wt. europium 1.0% by wt. zinc 0.2% by wt. zirconium Alloy L30: 89.8% by wt. magnesium 8.0% by wt. dysprosium 1.0% by wt. europium 1.0% by wt. zinc 0.2% by wt. zirconium Alloy L31: 73.2% by wt. magnesium 25.0% by wt. dysprosium 0.4% by wt. neodymium 1.4% by wt. europium Alloy L32: 87.4% by wt. magnesium 10.0% by wt. dysprosium 1.0% by wt. europium 0.5% by wt. neodymium 1.0% by wt. zinc 0.1% by wt. zirconium Alloy L33: 87.0% by wt. magnesium 10.0% by wt. dysprosium 0.3% by wt. europium 1.5% by wt. neodymium 1.0% by wt. zinc 0.2% by wt. zirconium Alloy L34: 86.0% by wt. magnesium 12.0% by wt. dysprosium 1.0% by wt. europium 0.8% by wt. zinc 0.2% by wt. zirconium

Example 2

Tube Production

(15) From the alloys L1 to L10 extruded wires were prepared according to Example 1. In these extruded wires, a precision drill-hole is introduced in the longitudinal direction, which already co-determines the wall thickness of the later stents. Through several forming steps, a tube of predetermined diameter and certain wall thickness is made. Between the individual forming steps repeating heat treatment take place.

Example 3

Stent Production

(16) A tube manufactured according to Example 2 is fixed into an adapter in the laser machine. A pulsed solid-state laser (FKL) cuts the contours of the stent design out of the tube. The laser cutting is performed under an inert gas atmosphere.

(17) The stent design is stored in a NC program (numerical control). This provides the laser the traverse path (cutting pattern), after which the tube is structured. By the laser beam cutting burr formation occurs, especially on the inside of the tube, along the entire cutting contour. This can cause that remain in the contour after the end of the cutting process. The off-cuts and cut-outs will be mechanically removed and the stent is cleaned from manufacturing residues. In a first optical visual control an inspection of the cutting contour is performed.

(18) In the following, the stent is electrochemically polished. The stent is anodically connected and immersed in an acid bath. Via a cathode fixed in the bath, an electric circuit is closed. The electric circuit is maintained for several minutes. The electropolishing is an inverted galvanic process where material is removed in a controlled manner from the surface of the anodically connected component. Due to the method removal takes preferably place at sharp corners and edges. The stent obtains a smooth surface and rounded edges along the contours. After polishing, the stent is cleaned and freed from acid residues. During the final cleaning all still remaining manufacturing residues are removed from the stent surface. In a last optical visual control the stent geometry is measured and the surface is tested on cleanliness.

Example 4

Determination of Grain Size

(19) The counting of the grain size was made using linear intercept method. Grains which are only half cut at the end of the line were here counted as half grains. The magnification was selected such that at least 50 grains were cut by the grid. At least 5 sites with a total of at least 250 points of intersection were evaluated on the sample.

Example 5

Determination of Corrosion

(20) At room temperature, the corrosion rates of various alloys were determined for a period of 3 days in a physiological saline solution (see Table 1). An alloy was tested containing 90.8% by wt. Mg, 8% by wt. Dy, 1% by wt. Nd and 0.2% by wt. Zr, an alloy containing 89.8% by wt. Mg, 8% by wt. Dy, 1% by wt. Nd, 1% by wt. Eu and 0.2% by wt. Zr, an alloy containing 86.8% by wt. Mg, 12% by wt. Dy, 1% by wt. Nd, and 0.2% by wt. Zr, and an alloy containing 87.8% by wt. Mg, 10% by wt. Dy, 1% by wt. Nd, 1% by wt. Eu and 0.2% by wt. Zr. In addition alloys containing 1.0% by wt. neodymium, 1.0% by wt. zinc, 0.2% by wt. zirconium, between 5 and 20% dysprosium and the balance magnesium (see FIG. 7) were tested. Corrosion products were removed by immersing the samples in chromic acid (180 g/L) for 20 min at room temperature. The average corrosion rate was calculated in mm per year by the following equation:

(21) $\mathrm{CR}=\frac{8.76{10}^{4}g}{A.Math.t.Math.}$

(22) TABLE-US-00030 TABLE 1 Corrosion rate of alloys of the invention, measured over 3 days at room temperature, and in 0.9% NaCl, the specification of the components of the alloy are in % by weight and Mg as major component adds always up to 100% of the alloy. The alloys were tested after casting, without heat treatment, the average values and standard deviations of the various alloys are listed. Corrosion rate No. Composition (mm/year) L11 Mg8Dy1Nd0.2Zn0.2Zr 9.25 0.38 L15 Mg10Dy1Nd1Eu1Zn0.2Zr 0.81 0.06 L23 Mg12Dy1Nd1Zn0.2Zr 2.94 1.88 L16 Mg8Dy1Nd1Eu1Zn0.1Zr 4.9 1.62 L14 Mg6Dy1Nd1Eu1.5Zn0.4Zr 9.56 0.29 L16 Mg14Dy0.5Nd0.5Eu2Zn0.2Zr 1.25 0.12 L18 Mg10Dy1.5Nd1Zn0.05Fe 12.41 2.16 L20 Mg4.5Dy0.5Nd 25.56 2.34 L24 Mg15Dy0.9Nd1Zr1Zn 2.98 1.78 L25 Mg20Y0.9Eu 44.71 3.22 L28 Mg20Gd5Nd1Zn2Zr 38.96 1.34 L30 Mg8Dy1Eu1Zn0.2Zr 3.88 1.87 L22 Mg10Dy1.5Nd1Zn0.2Zr0.05Fe 4.47 2.11 L34 Mg12Dy1Eu0.8Zn0.2Zr 5.46 1.22 L29 Mg6Dy4Eu1Zn0.2Zr 12.20 1.36 L33 Mg10Dy0.3Eu1.5Nd1Zn0.2Zr 1.25 0.67 L26 Mg5Dy2.5Eu 23.56 1.56 L31 Mg25Dy0.4Nd1.4Eu 48.71 1.87

Example 6

Mechanical Characteristics of the Alloys

(23) The alloys and cast parts were produced according to Example 1 and extruded. The heat treatment T4 was carried out at 510 C. over 8 hours and eventually afterwards the heat treatment T6 at 200 C. over a period of time of 72 hours. After T4 heat treatment the samples were immediately quenched in water. All samples were taken from the same position of the blocks.

(24) The tensile tests were performed at room temperature according to DIN EN 10002-1 (corresponds to ISO 6892 and ASTM E8) and compression tests were performed at room temperature according to DIN 50106 (corresponds to ISO 604 and ASTM D695). At least 3 samples were tested for each value. The tensile strength was calculated in terms of the maximum tensile force achieved in the tensile test in regard to the original cross-section of the sample.

(25) TABLE-US-00031 TABLE 2 Mechanical characteristics of alloys according to the invention. Alloys were tested as a sample after the extrusion (ST, without heat treatment) and after different heat treatments, T4 (solution annealed), and T6 (a further heat treatment after T4, also known as ageing). The information on the components of the alloys are in % by wt. and Mg as the main component complements the quantitative data always up to 100% of the alloy. SD means standard deviation of the average values, which are indicated in the left column (n = 3). Yield Tensile Break at strength strength elongstion Composition (MPa) SD (MPa) SD (%) SD ST Mg8Dy1Nd0.2 Zn0.2Zr 107.33 1.8 208.5 0.85 28.12 3.41 T4 87.54 0.46 176.84 2.03 18.83 1.79 T6 97.95 1.67 194.11 1.1 19.33 0.68 ST Mg10Dy1Nd1Eu1Zn0.2Zr 169.30 0.74 283.89 0.68 16.96 1 T4 151.97 1.77 259.50 2.57 18.02 0.29 T6 159.23 2.23 275.55 1.78 18.15 2.77 ST Mg12Dy1Nd1Zn0.2Zr 126.07 1.8 226.04 0.35 28.55 0.08 T4 98.38 0.43 188.45 0.5 20.47 0.91 T6 114.6 1.69 205.2 1.25 17.99 0.79 ST Mg8Dy1Nd1Eu1Zn0.1Zr 132.24 1.1 227.21 0.59 19.75 1.11 T4 114.93 1.25 210.73 1.51 20.89 1.01 T6 136.77 1.77 223.28 0.67 23.64 2.01 ST Mg6Dy1Nd1Eu1.5Zn0.4Zr 128.14 8.02 202.74 2.91 24.62 2.09 T4 80.97 2.27 173.47 2.02 23.78 3.52 T6 84.26 2.57 178.26 1.35 26.32 2.5 ST Mg14Dy0.5Nd0.5Eu2Zn0.2Zr 165.64 4.95 218.17 3.07 18.9 1.14 T4 110.78 1.87 201.28 1.19 21.62 1.07 T6 153.15 3.55 264.09 0.71 17.66 1.33 ST Mg10Dy1.5Nd1Zn0.05Fe 145.46 3.55 237.21 0.75 28.9 1.73 T4 102.78 4.38 193.36 5.84 27.57 0.88 T6 108.84 1.68 200.16 2.97 25.56 1.66 ST Mg4.5Dy0.5Nd 68.39 7.9 208.48 2.03 28.4 0.72 T4 60.31 1.71 179.04 0.83 23.17 0.38 T6 75.13 1.32 250.34 1.42 13.34 0.74 ST Mg15Dy0.9Nd1Zr1Zn 136.93 1.6 227.07 0.42 22.9 3.03 T4 95.79 1.94 200.59 2.59 21.57 0.34 T6 112.09 0.41 206.11 0.19 19.56 0.66 ST Mg20Y0.9Eu 159.75 1.99 238.55 0.76 11.57 0.58 T4 123.19 4.83 214 1.42 19.62 2.74 T6 144.08 4.37 220.2 2.58 15.58 0.94 ST Mg20Gd5Nd1Zn2Zr 297.75 8.12 338.53 5.67 1.53 0.27 T4 195.82 15.65 276.89 0.91 6.58 0.95 T6 327.07 17.57 378.45 14.94 0.76 0.32 ST Mg8Dy1Eu1Zn0.2Zr 112.85 1.15 198.9 0.43 24.07 1.05 T4 93.5 1.01 182.38 0.91 24.02 0.81 T6 99 0.99 185.7 0.4 25.9 1.16 ST Mg10Dy1.5Nd1Zn0.2Zr0.05Fe 127.8 4.62 215.84 1 19.39 1.4 T4 96.72 4.02 192.99 2.87 25.92 0.98 T6 112.34 3.1 201.35 2.18 24.44 1.91 ST Mg12Dy1Eu0.8Zn0.2Zr 182.30 1.52 293.62 1.37 22.39 2.06 T4 164.48 1.44 268.66 0.45 23.70 1.63 T6 172.34 2.12 271.35 1.82 23.34 1.79 ST Mg6Dy4Eu1Zn0.2Zr 115.09 1.39 208.3 1.68 2.30 0.51 T4 97.55 0.74 189.39 0.84 4.78 1.71 T6 112.58 1.59 196.71 2.31 3.41 0.69 ST Mg10Dy0.3Eu1.5Nd1Zn0.2Zr 168.54 6.15 277.11 2.09 16.46 2.33 T4 136.36 5.11 244.89 2.37 20.67 3.15 T6 152.22 2.42 253.91 2.33 18.56 1.87 ST Mg5Dy2.5Eu 74.25 1.63 283.50 1.44 21.60 1.27 T4 60.19 1.69 264.46 0.91 23.16 1.43 T6 65.38 1.83 266.64 1.36 22.85 1.64 ST Mg25Dy0.4Nd1.4Eu 106.34 2.98 211.15 1.65 18.90 1.55 T4 88.74 1.69 178.56 2.03 20.03 2.31 T6 94.21 1.34 191.25 1.67 19.54 1.99

Example 7

Animal Study

(26) 8 stents prepared according to Example 2 and 3 were implanted in the coronary arteries of 4 domestic pigs. The stents had a diameter of 3.0 mm and a length of 14 mm (length of the catheter balloon 15 mm), were not coated (BMS), and were made of an alloy of the following composition:

(27) TABLE-US-00032 87.8 Gew.-% magnesium 10.0 Gew.-% dysprosium 1.0 Gew.-% neodymium 1.0 Gew.-% zinc 0.2 Gew.-% zirconium

(28) The follow up period has been chosen for all 4 animals at 4 weeks after implantation. One day prior to stent implantation a single dose of Clopidogrel (300 mg) and Aspirin (250 mg) were administered orally. Under general anaesthesia, access to the femoral artery was obtained by surgical exposure and a bolus of heparin sodium (10 000 IU) was administered. A 6F coronary guiding catheter was inserted through the femoral artery into the Aorta descendens. Coronary angiography was performed using hand injection of nonionic contrast agent to obtain the anatomic conditions for performance of the procedure.

(29) The stents were implanted in the ramus interventricularis anterior (RIVA or LAD) and ramus circumflexus (RCX or LCx). Inflation pressure of the balloon for stent implantation was chosen to achieve a stent balloon to artery ratio of 1.2 to 1. The pigs were then allowed to recover. During the entire 4 weeks of follow up, the animals receive orally a daily dose of 100 mg aspirin and 75 mg clopidogrel per 30 g body weight.

(30) After 4 weeks follow up, control angiography and optical coherence tomography (OCT) were performed. In the OCT procedure a 0.014 inch guidewire was inserted into the LAD and the LCx and pushed through the implanted stent into the distal part of the vessel. An OCT intravascular catheter was subsequently advanced distal to the stent, over the guide wire. The injection pump was turned on to inject contrast agents at a speed of 3.0 ml/s to transiently displace the blood. The entire length of the lesion was imaged using an automatic pullback device at 10 mm/s. After imaging, the OCT catheter was withdrawn, and the images were saved. The animals were then euthanized, and the coronary arteries were explanted.

(31) The explanted arteries were fixed by perfusion with a pressure of 100 mmHg for 1 h using 7% formalin. The stents were processed for light microscopy. For light microscopy, the arteries were cut into 3 sections: proximal, mid and distal stent segments.

(32) The stented sections were embedded in methyl-metacrylate (Technovit 9100). The segments of the stented arteries were cut into 4-6 m slices using a rotary microtome, and stained with hematoxylin and eosin.

(33) As part of the analysis details of the study were listed such as the stent position, the dilation pressure and the inflation time, as well as any complications during the implantation.

(34) Quantitative Coronary Angiography (QCA)

(35) A QCA was performed to analyze the in-stent restenosis. The following parameters were thereby determined: vessel diameter pre and post stent implantation, minimal lumen diameter (MLD) after stent implantation and at follow up and the diameter of a reference segment (RD) at follow up. Here, the minimal lumen diameter is the smallest absolute internal vessel diameter in the region of the dilated segment, averaged from the two orthogonal projection planes. LLL (late lumen loss) is a measure of the narrowing of the lumen by neointimal hyperplasia. The lumen diameter is measured directly after the intervention and 4 weeks post interventional, the difference between the two is given as LLL. The length of the stenosed or dilated segment has been checked and the stenosis in percent was calculated.

(36) Optical Coherence Tomography (OCT)

(37) The images of the optical coherence tomography were analyzed in accordance with the relevant guideline (JACC, 2012). The following parameters were obtained: stent malapposition, stent strut coverage, tissue protrusion, the arterial dissection, thrombosis. The quantitative analysis of the OCT images includes the minimal and maximal stent diameter and the lumen area. The following parameters were calculated: maximal area stenosis and stent symmetry. For the quantitative analysis the worst cross-section per test group was determined.
% AS=Intimal area/Stent area=(Stent arealumen area)/Stent areaCalculation of area stenosis (% AS):
Stent symmetry=(Maximal Stent diameterMinimal stent diameter)/Maximal stent diameterCalculation of stent symmetry:

(38) Fibrin deposition, degree of inflammation (intima and adventitia), haemorrhages and necrosis were analyzed in accordance with the published guidelines.

(39) Histomorphometry

(40) Histomorphometry has been carried out using computer-assisted planimetry. The lumen, the area of the internal elastic lamina and external elastic lamina and the maximal neointimal thickness were measured. The extension of the neointima and the media as well as the stenosis in percent was calculated.

(41) Results

(42) The dilation pressure used was between 12 and 18 atm. The balloon inflation took 30 sec. In general, the handling of the stent and balloon were excellent; very good pushability and very short deflation time was recorded.

(43) TABLE-US-00033 TABLE 3 Results of quantitative coronary angiography (QCA), the average values and standard deviations (SD) are listed; MLD = minimal lumen diameter, RD = diameter of a reference segment, % DS = percent diameter stenosis, FUP = follow-up, LLL = late lumen loss Pre-MLD Post-MLD FUP-MLD FUP-RD FUP-% DS LLL (mm) (mm) (mm) (mm) (%) (mm) bare metal stents (BMS) 2.68 2.93 2.08 2.92 28.75 0.85 SD 0.11 0.07 0.53 0.20 16.79 0.47

(44) TABLE-US-00034 TABLE 4 Qualitative analysis of the optical coherence tomography (OCT) per implanted stent animal stent- tissue in-stent in-stent edge endotheliali- No. artery group malapposition protrusion thrombosis dissection dissection zation MEKO-1 LAD BMS 0 0 0 0 0 complete MEKO-1 LCx BMS 0 0 0 0 0 incomplete MEKO-2 LAD BMS 0 0 0 0 0 complete MEKO-2 LCx BMS 0 0 0 0 0 complete MEKO-3 LAD BMS 0 0 0 0 0 complete MEKO-3 LCx BMS 0 0 0 0 0 complete MEKO-4 LAD BMS 0 0 0 0 0 complete MEKO-4 LCx BMS 0 0 0 0 0 complete

(45) TABLE-US-00035 TABLE 5 Qualitative analysis of the optical coherence tomography (OCT) in regard to the number of implanted stents (n = 8, all values in percent) stent- tissue in-stent in-stent edge completed malapposition protrusion thrombosis dissection dissection endothelialization BMS n = 8 0 0 0 0 0 87.5

(46) From Tables 3, 4 and 5 can be gathered that firstly none of the tested complications occurred when using a stent according to the invention and, secondly, that an endothelialization was almost always completed after 4 weeks, which meant that the increased risk of in-stent thrombosis due to not completed endothelialization or inflammation reactions was no longer present. Comparable results were also obtained with stents made of a magnesium alloy containing europium instead of neodymium.

(47) TABLE-US-00036 TABLE 6 Further results of the qualitative analysis of the optical coherence tomography (OCT), listed are average values and standard deviations (SD). minimal maximal stent diameter stent diameter stent area lumen area Type (mm) (mm) (mm.sup.2) (mm.sup.2) % AS (%) stent symmetry BMS n = 8 2.54 2.72 7.58 5.08 34.0 0.07 SD 0.34 0.35 1.80 1.69 13.2 0.02