Medical devices with coatings for enhanced echogenicity

Abstract

The disclosure provides medical devices comprising improved coatings for ultrasound detection, which provide optimal ultrasound images. Methods for preparing such devices are also provided.

Claims

1. A medical device comprising a coating for ultrasound detection, said coating comprising microparticles that are visible with ultrasound, wherein the microparticles are solid microspheres comprising glass or silicate, and wherein the diameter of at least 60% of said microparticles on said medical device is between 22 and 45 m and wherein the density of said microspheres on the surface of said medical device is between 45 and 450 microspheres/mm.sup.2, and wherein at least one of the following conditions a) -e) is met; a) the diameter of at least 60% of the microspheres on the medical device is between 22 and 27 m and the density of the microspheres on the surface of the medical device is between 150 and 450 microspheres/mm.sup.2; b) the diameter of at least 60% of the microspheres on the medical device is between 27 and 32 m and the density of the microspheres on the surface of the medical device is between 70 and 450 microspheres/mm.sup.2; c) the diameter of at least 60% microspheres on the medical device is between 32 and 38 m and the density of the microspheres on the surface of the medical device is between 45 and 225 microspheres/mm.sup.2; d) the diameter of at least 60% of the microspheres on the medical device is between 38 and 45 m and the density of the microspheres on the surface of the medical device is between 45 and 150 microspheres/mm.sup.2; and e) the diameter of at least 60% of the microspheres on the medical device is between 22 and 32 m and the density of the microspheres on the surface of the medical device is between 150 and 450 microspheres/mm.sup.2.

2. The medical device of claim 1, wherein said microparticles further comprise a material selected from the group consisting of polymers, ceramics, glasses, silicates, organic materials, metals and any combination thereof.

3. The medical device of claim 1, wherein said coating further comprises a matrix material selected from the group of polymers consisting of a poly(ether sulfone); a polyisocyanate; a polyurethane; a polytetrafluoroethylene; a polymer of N-vinyl-pyrrolidone, a copolymer of N-vinyl-pyrrolidone, a copolymer with butylacrylate; a poly(4-vinyl pyridine); a polyacrylamide, poly(N-isopropylacrylamide); a poly(amido-amine); a poly(ethylene imine); a polymer of ethylene oxide and propylene oxide, a block copolymer of ethylene oxide and propylene oxide, a poly(ethylene oxide-block-propylene oxide), a poly(ethylene oxide-block-propylene oxide-block-ethylene oxide); a block copolymer, a block styrene, poly(styrene-block-isobutylene-block-styrene), a poly(hydroxystyrene-block-isobutylene-block-hydroxystyrene); a polydialkylsiloxane; a polysaccharide; a polystyrene, a polyacrylate; a polyalkane, polyethylene, polypropylene, polybutadiene; a poly(ether ketone), a poly(ether ether ketone); a polyester, poly(ethylene terephthalate), polyglycolide, poly(trimethylene terephthalate), poly(ethylene naphthalate), poly(lactic acid), polycapralactone, poly(butylene terephthalate); polyamides, nylon-6,6, nylon-6, polyphthalamides, polyaramides; a polymethylmethacrylate, a poly(2-hydroxyethylinethacrylate); poly(ether sulfones), polyurethanes, polyacrylates, polymethacrylates, polyamides, polyisocyanates and combinations of any thereof.

4. The medical device of claim 1, wherein said medical device is selected from the group consisting of a catheter, a needle, a stent, a cannula, a tracheotome, an endoscope, a dilator, a tube, an introducer, a marker, a stylet, a snare, an angioplasty device a fiducial, a trocar and a forceps.

5. A method for preparing the medical device of claim 1, the method comprising: providing a medical device, and coating said medical device with microparticles that are solid microspheres comprising glass or silicate and that are visible with ultrasound, such that the diameter of at least 60% of said microparticles on said medical device is between 22 and 45 m and the density of said microspheres on the surface of said medical device is between 45and 450 microspheres/mm.sup.2, and wherein at least one of the following conditions a)-e) is met; a) the diameter of at least 60% of the microspheres on the medical device is between 22 and 27 m and the density of the microspheres on the surface of the medical device is between 150 and 450 microspheres/mm.sup.2; b) the diameter of at least 60% of the microspheres on the medical device is between 27 and 32 m and the density of the microspheres on the surface of the medical device is between 70 and 450 microspheres/mm.sup.2; c) the diameter of at least 60% of the microspheres on the medical device is between 32 and 38 m and the density of the microspheres on the surface of the medical device is between 45 and 225 microspheres/mm.sup.2; d) the diameter of at least 60% of the microspheres on the medical device is between 38 and 45 m and the density of the microspheres on the surface of the medical device is between 45 and 150 microspheres/mm.sup.2; and e) the diameter of at least 60% of the microspheres on the medical device is between 22 and 32 m and the density of the microspheres on the surface of the medical device is between 150 and 450 microspheres/mm.sup.2.

6. The method of claim 5, wherein the microparticles further comprise a material selected from the group consisting of polymer(s), ceramic(s), glass(es), silicate(s), organic material(s), metal(s), and any combination thereof.

7. The method of claim 5, wherein the coating further comprises a matrix material selected from the group consisting of a poly(ether sulfone), a polyisocyanate, a polyurethane, a polytetrafluoroethylene, a polymer of N-vinyl-pyrrolidone, a copolymer of N-vinyl-pyrrolidone, a copolymer with butylacrylate, a poly(4-vinyl pyridine), a polyacrylamide, poly(N-isopropylacrylamide), a poly(amido-amine), a poly(ethylene imine), a polymer of ethylene oxide and propylene oxide, a block copolymer of ethylene oxide and propylene oxide, a poly(ethylene oxide-block-propylene oxide), a poly(ethylene oxide-block-propylene oxide-block-ethylene oxide), a block copolymer, a block styrene, poly(styrene-block-isobutylene-block-styrene), a poly(hydroxystyrene-block-isobutylene-block-hydroxystyrene), a polydialkylsiloxane, a polysaccharide, a polystyrene, a polyacrylate, a polyalkane, polyethylene, polypropylene, polybutadiene, a poly(ether ketone), a poly(ether ketone), a polyester, a poly(ethylene terephthalate), a polyglycolide, a poly(trimethylene terephthalate), a poly(ethylene naphthalate), a poly(lactic acid), a polycapralactone, a poly(butylene terephthalate), polyamides, nylon-6,6, nylon-6, polyphthalamides, polyaramides, a polymethylmethacrylate, a poly(2-hydroxyethylmethaerylate), poly(ether sulfones), polyurethanes, polyacrylates, polymethacrylates, polyamides, polyisocyanates and combinations of any thereof.

8. The method of claim 5, wherein the medical device is selected from the group consisting of a catheter, a needle, a stent, a cannula, a tracheotome, an endoscope, a dilator, a tube, an introducer, a marker, a stylet, a snare, an angioplasty device, a fiducial, a trocar and a forceps.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

(2) FIG. 1: Plot of the CNR against the microsphere density on the surface for different microsphere sizes.

(3) FIG. 2: For microspheres with a diameter between 22 and 27 m, the CNR is plotted against the microsphere density, along with the US estimation error on the secondary y-axis.

(4) FIG. 3: For microspheres with a diameter between 27 and 32 m, the CNR is plotted against the microsphere density, along with the US estimation error on the secondary y-axis.

(5) FIG. 4: For microspheres with a diameter between 32 and 38 m, the CNR is plotted against the microsphere density, along with the US estimation error on the secondary y-axis.

(6) FIG. 5: For microspheres with a diameter between 38 and 45 m, the CNR is plotted against the microsphere density, along with the US estimation error on the secondary y-axis.

(7) FIG. 6: For microspheres with a diameter between 45 and 53 m, the CNR is plotted against the microsphere density, along with the US estimation error on the secondary y-axis.

(8) FIG. 7: CNR values for glass and plastic surfaces coated with solid glass microspheres with a diameter ranging from 38 to 45 m.

(9) FIG. 8: CNR values for glass slides coated with solid glass microparticles and hollow glass microparticles.

(10) FIG. 9: Influence of the microsphere density on the surface. A microparticle density of lower than 250 particles/mm.sup.2 on the surface of a medical device provides better ultrasound images than higher densities. (Panel A) Left image: hollow glass microspheres, surface density=about 130 particles/mm.sup.2; (Panel B) Left image: hollow glass microspheres, surface density=about 180 particles/mm.sup.2; (Panel C) Left image: hollow glass microspheres, surface density=about 250 particles/mm.sup.2. Of note, the left part of each image shows a blank consisting of a chicken breast without tube; the right part of each image shows the results with a chicken breast with a coated tube.

(11) FIG. 10: Ultrasound images taken in a phantom gel of glass slides on which marker bands (width 1 cm) were applied of Sono-Coat comprising different concentrations of microspheres (size range 38-45 m).

(12) FIG. 11: US estimation error plotted against the microsphere density on glass and plastic surfaces coated with microspheres with a diameter between 27-32 m.

DETAILED DESCRIPTION

Examples

Example 1

(13) Commercially available solid glass microspheres (from Cospheric) with diameters ranging from 10 to 22 m, 22 to 27 m, 27 to 32 m, 32 to 38 m, 38 to 45 m and 45 to 53 m, all with a density of 2.5 g/mL, were mixed through a polyurethane coating matrix. The microspheres were added in different amounts in order to prepare mixtures containing 0.5 to 75.0 vol. % microspheres in the coating matrix. Subsequently, either 30- or 60-m thick coating films were drawn on both glass and PEBAX 6233 slides as substrates using a film applicator. The density of microspheres was determined to vary from 2 to 1831 particles/mm.sup.2.

(14) The coated substrates were measured by ultrasound using a 33 mm linear array probe operating in brightness-mode (B-mode) at 6 MHz. The substrates were placed under an approximate angle of 45 degrees inside a commercially available ultrasound phantom, which acted as the medium.

(15) From the recorded images, the contrast-to-noise ratio (CNR) was determined by comparing the average pixel intensity and standard deviation of the coated objects to the values obtained for the surrounding medium, according to:

(16) $\mathrm{CNR}=\frac{P_{\mathrm{ROI}}-P_{\mathrm{medium}}}{\sqrt{\frac{{}_{\mathrm{ROI}}^2-{}_{\mathrm{medium}}^2}{2}}}$ where P.sub.ROI=average pixel intensity of region of interest P.sub.medium=average pixel intensity of medium .sub.ROI=standard deviation in region of interest .sub.medium=standard deviation in medium

(17) The determined CNRs were plotted against the microsphere density in particles/mm.sup.2 (FIG. 1).

(18) As can be seen in FIG. 1, the CNR approaches a value of approximately 3.5 with an increasing amount of microspheres on the surface. For the microspheres ranging from 10 to 22 m, the maximum attainable CNR was approximately 2.5. Higher CNR values could not be obtained due to the fact that the complete surface is covered with glass microspheres. Adding a second layer of microspheres on top did not result in an increase of the CNR. Therefore, particles with a diameter between 22 and 45 m are more preferred.

Example 2

(19) Commercially available solid glass microspheres with diameters ranging from 10 to 22 m, 22 to 27 m, 27 to 32 m, 32 to 38 m, 38 to 45 m and 45 to 53 m, all with a density of 2.5 g/mL, were mixed through a polyurethane coating matrix. The microspheres were added in different amounts in order to prepare mixtures containing 1.0 to 75.0 vol. % microspheres in the coating matrix. Subsequently, either 30- or 60-m thick marker bands of coating were drawn on glass slides using a film applicator. These marker bands were applied by masking the area that was required to be uncoated. The width of the marker bands was measured.

(20) The coated substrates were measured by ultrasound using a 33 mm linear array probe operating in brightness-mode (B-mode) at 6 MHz. The substrates were placed under an approximate angle of 45 degrees inside a commercially available ultrasound phantom, which acted as the medium.

(21) From the recorded images, the width of the marker bands as visible under ultrasound was determined. The under or overestimation of the width of the marker band under ultrasound is expressed as:

(22) $\mathrm{US}\mathrm{estimation}\mathrm{error}=\frac{L_{\mathrm{US}}-L_{\mathrm{actual}}}{L_{\mathrm{actual}}}100\%$ where L.sub.US=the width of the ultrasound signal stemming from the marker band L.sub.actual=the actual width of the marker band

(23) In principle, an US estimation error of below 10% is considered acceptable. Preferably, the US estimation error is between 0 and about 5%.

(24) In FIG. 2, for microspheres with a diameter between 22 and 27 m, the CNR is plotted against the microsphere density, along with the US estimation error on the secondary y-axis. As can be seen in FIG. 2, the optimum range for these microspheres is lying between 150 and 450 particles/mm.sup.2. Less microspheres on the surface leads to an underestimation of the width of the marker band, whereas above the upper limit, overestimation of the width occurs. The most optimal range for these microspheres is lying between 150 and 300 particles/mm.sup.2.

(25) In this fashion, the optimum microsphere density for each size range was established.

(26) In FIG. 3, for microspheres with a diameter between 27 and 32 m, the CNR is plotted against the microsphere density, along with the US estimation error on the secondary y-axis. As can be seen in FIG. 3, the optimum range for these microspheres is lying between 70 and 450 particles/mm.sup.2. Less microspheres on the surface leads to an underestimation of the width of the marker band, whereas above the upper limit, overestimation of the width occurs. A particular optimal range for these microspheres is lying between 80 and 300 particles/mm.sup.2.

(27) In FIG. 4, for microspheres with a diameter between 32 and 38 m, the CNR is plotted against the microsphere density, along with the US estimation error on the secondary y-axis. As can be seen in FIG. 4, the optimum range for these microspheres is lying between 45 and 225 particles/mm.sup.2. Less microspheres on the surface leads to an underestimation of the width of the marker band, whereas above the upper limit, overestimation of the width occurs.

(28) In FIG. 5, for microspheres with a diameter between 38 and 45 m, the CNR is plotted against the microsphere density, along with the US estimation error on the secondary y-axis. As can be seen in FIG. 5, the optimum range for these microspheres is lying between 45 and 150 particles/mm.sup.2. Less microspheres on the surface leads to an underestimation of the width of the marker band, whereas above the upper limit, overestimation of the width occurs.

(29) For microspheres with diameters between 45 and 53 m, on the other hand, no optimum particle density was found because overestimation of the width of the marker band is manifested over the complete range of particle density (FIG. 6).

Example 3

(30) Solid glass microspheres with a diameter ranging from 38 to 45 m, as described above, with a density of 2.5 g/mL, were mixed through a polyurethane coating matrix. Subsequently, glass slides and plastic (PEBAX 6233) were coated with these particles in different densities. The coated substrates were measured by ultrasound using a 33-mm linear array probe operating in brightness-mode (B-mode) at 6 MHz. The substrates were placed under an approximate angle of 45 degrees inside a commercially available ultrasound phantom, which acted as the medium. From the recorded images, the contrast-to-noise ratio (CNR) was determined in the same way as described in Example 1, and the determined CNRs were plotted against the microsphere concentration (FIG. 7).

(31) As can be seen in FIG. 7, the CNR values for glass and plastic coated with the same amount of particles are comparable. This demonstrates that the material of the used surfaces does not significantly affect the CNRs.

Example 4

(32) Example 1 was repeated with the solid glass microspheres with a diameter ranging from 22 to 27 m, as described above, and with hollow glass microspheres with a diameter ranging from 25 to 27 m and densities of 0.14 g/mL and 0.46 g/mL. Glass slides were coated with these particles in different densities. The coated substrates were measured by ultrasound using a 33-mm linear array probe operating in brightness-mode (B-mode) at 6 MHz. The substrates were placed under an approximate angle of 45 degrees inside a commercially available ultrasound phantom, which acted as the medium. From the recorded images, the contrast-to-noise ratio (CNR) was determined in the same way as described in Example 1, and the determined CNRs were plotted against the microsphere concentration (FIG. 8).

(33) As can be seen in FIG. 8, the CNR values for the solid and hollow particles are comparable, meaning that both solid and hollow particles are suitable for improving the visibility of a medical device according to this disclosure.

Example 5

(34) Commercially available air-filled glass microspheres (from Cospheric) with diameters between 38 and 45 m and a density of 0.46 g/mL were mixed through a coating matrix, Labo coat, which is commercially available from Labo Groep (Tilburg, The Netherlands). The microspheres were added in different amounts in order to prepare mixtures containing 2.0, 3.0 and 4.0 wt. % microspheres in the coating matrix. The coating was applied by dip coating on polyurethane tubes, resulting in coated tubes with a microsphere density of about 130 particles/mm.sup.2 (image of Panel A of FIG. 9), about 180 particles/mm.sup.2 (image of Panel B of FIG. 9), and about 250 particles/mm.sup.2 (image of Panel C of FIG. 9), respectively.

(35) The coated tubes were tested by ultrasound with a chicken breast as medium to record the images in.

(36) Studying the different tubes with ultrasound showed that for higher amounts of microparticles on the surface, the surface of the tube starts to appear as rough, whereas at lower amounts, the surface appears to be smooth (see FIG. 9). At lower amounts, the visibility (sharpness of the image) improves.

Example 6

(37) Solid glass microspheres with a diameter ranging from 38 to 45 m, as described above in Example 1, were mixed through a polyurethane coating matrix. The microspheres were added in different amounts in order to prepare mixtures containing 1.0 to 75.0 vol. % microspheres in the coating matrix. Subsequently, either 30- or 60-m thick marker bands of coating were drawn on glass slides using a film applicator. These marker bands were applied by masking the area that was required to be uncoated. The width of the marker bands was measured.

(38) The coated substrates were measured by ultrasound using a 33-mm linear array probe operating in brightness-mode (B-mode) at 6 MHz. The substrates were placed under an approximate angle of 45 degrees inside a commercially available ultrasound phantom, which acted as the medium.

(39) FIG. 10 shows ultrasound images taken in a phantom gel of glass slides on which marker bands (width 1 cm) were applied of Sono-Coat comprising the microspheres (size range 38-45 m) in a concentration of 38 particles/mm.sup.2, 125 particles/mm.sup.2, and 346 particles/mm.sup.2. It is clear that the middle image, which is within the density range of 45-150 particles/mm.sup.2 according to the disclosure, provides the best visibility combined with an accurate measurement of the width of the marker band. The lower image (density of 346 particles/mm.sup.2) is more vague and overestimation of the marker band width occurs, whereas the upper image is also more vague, appears as a dotted line, and underestimates the width of the marker band.

Example 7

(40) The same kind of experiment as Example 2 was repeated. The same kind of 27-32 m microspheres were used. These microspheres were coated on glass slides as well as on plastic (PEBAX) surfaces. In FIG. 11, the US estimation error is plotted against the microsphere density. From FIG. 11, it is clear that the optimum microsphere density range is the same for both the coated glass and the coated plastic surfaces. Like in FIG. 3, the optimum range for these microspheres is between 70 and 450 particles/mm.sup.2. Hence, the visibility is dependent upon the scattering effect of the coating, not the surface itself.

REFERENCES

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