Stent

Abstract

The invention provides a method of manufacturing a stent (12) using a three dimensional (3D) printer. The invention also extends to 3D printed stents and second medical uses of such stents. The invention also extends to electric signals carrying computer-executable instructions adapted to cause a 3D printer to print a stent, computer-readable programs and computer-readable mediums.

Claims

1. A method of manufacturing a stent using a three dimensional (3D) printer, the method comprising: (i) installing a computer-readable design of a stent on a computer, which is operably connected to a 3D printer comprising a nozzle and a stage; and (ii) instructing the 3D printer to print the design of the stent, such that a) non-metallic ink comprising a thermoplastic polymer is heated to a temperature at least 1 C. above the melting point/glass transition temperature of the ink, and is then expelled from the nozzle onto the stage to form a first layer of printed material, and consequently depositing layer upon layer of printed ink to thereby form the stent, or (b) a support material is expelled from the nozzle onto the stage to form a first layer, and then non-metallic ink comprising a thermoplastic polymer is heated to a temperature at least 1 C. above the melting point/glass transition temperature of the ink, and is then expelled from the nozzle onto the first layer to form a second layer, and the support material and the non-metallic ink are then expelled alternately to form alternate layers, and thereby form the stent.

2. A method according to claim 1, wherein the diameter of the printer nozzle outlet aperture is at least 10 m, 25 m, 50 m, 75 m, 85 m or 100 m, or wherein the diameter of the printer nozzle outlet aperture is less than 600 m, 500 m, 450 m, 400 m, 350 m or 300 m.

3. A method according to claim 1, wherein the printing resolution of the 3D printer is at least 6 m, 8 m, 10 m, 12 m, 14 m or 16 m.

4. A method according to claim 1, wherein the method comprises heating the ink to a temperature that is 10 C., 5 C., or 2 C. above the melting point/glass transition temperature of the ink before it is dispensed by the printer nozzle.

5. A method according to claim 1, wherein the ink is dispensed in a semi-liquid state or in the form of droplets.

6. A method according to claim 1, wherein the method comprises depositing the ink in or on the surface of a stent support structure.

7. A method according to claim 5, wherein the method comprises passing a milling head over the printed layer of the stent to ensure that it is of uniform thickness.

8. A method according to claim 1, wherein the computer-readable design is a computer-aided design (CAD).

9. A method according to claim 1, wherein the method comprises applying a therapeutic agent to the surface of the stent by spraying or by printing.

10. A method according to claim 1, wherein the method comprises contacting the ink with a therapeutic agent or drug to form a mixture which is then expelled through the nozzle to print the stent.

11. A method according to claim 10, wherein the method comprises heating the mixture of the ink and the therapeutic agent, such that hot melt is extruded from the printer nozzle and used to create the stent.

12. A stent obtained or obtainable by the method according to claim 1, wherein the ink has a tensile strength above 10 MPa.

13. A stent according to claim 12, wherein the stent is a bioabsorbable stent or a drug-eluting stent comprising a therapeutically effective amount of a therapeutic agent.

14. A stent according to claim 13, wherein the therapeutic agent is hydrophobic or hydrophilic or wherein the therapeutic agent is distributed in solidified ink of the stent.

15. A stent according to claim 12, wherein the ink has a tensile strength above 15 megapascal (MPa) or 20 MPa, or a tensile strength below 500 MPa, 375 MPa or 250 MPa.

16. A stent according to claim 12, wherein the thickness of struts of the stent is at least 80 m, 100 m or 150 m, or at most 650 m, 600 m or 550 m.

17. A stent according to claim 12, wherein the vascular coverage of the stent is 5 to 60%, 10 to 50% or 10 to 40%.

18. A method of treating a vascular disease in a subject in need of such treatment, the method comprising fitting the stent according to claim 12 into a blood vessel of the subject.

19. A method according to claim 18 wherein the vascular disease is stenosis, restenosis, thrombosis, hypertension, hemophilia, angioedema, hyperlipidemia, vasculitis, peripheral vascular disease, an aneurysm or an intracranial aneurysm.

20. A method according to claim 1, wherein the thermoplastic polymer is selected from the group consisting of: poly-lactic acid (PLA), poly-caprolcatone (PCL), poly-glycolic acid (PGA), poly(D,L-lactide-co-glycolide) (PLGA), poly (D,L-lactide) (PLLA), polymethyl methacrylate (PMMA), chitosan, polyurethane, hydroxypropylmethylcellulose (HPMC), gelatine, and combinations thereof.

21. A method according to claim 1, wherein the stage comprises a substantially flat surface.

Description

(1) For a better understanding of the invention, and to show how embodiments of the same may be carried into effect, reference will now be made, by way of example, to the accompanying Figures, in which:

(2) FIG. 1 is a hollow tube/cylinder from which a prior art stent is created;

(3) FIG. 2 is a computer-aided design of a first embodiment of a prior art stent;

(4) FIG. 3 is a computer-aided design of a second embodiment of a prior art stent;

(5) FIG. 4 is a computer-aided design of a third embodiment of a prior art stent;

(6) FIG. 5 is a computer-aided design of a first embodiment of a stent created by the method and apparatus according to the invention;

(7) FIG. 6 is a computer-aided design of a second embodiment of a stent created by the method and apparatus according to the invention;

(8) FIGS. 7 to 8 are pictures of a drug-eluting stent created by the method according to the invention, which are based on the embodiment of FIG. 6;

(9) FIG. 9 is a picture of a drug-eluting stent created by the method according to the invention, which is based upon the embodiment of FIGS. 5 and 6;

(10) FIG. 10 is a computer-aided design of a cross-section of a drug-eluting stent according to the invention;

(11) FIG. 11 is a schematic of an embodiment of an apparatus used to print stents according to the invention;

(12) FIG. 12 is a computer-aided design of a third embodiment of a stent created by the method and apparatus according to the invention; and

(13) FIG. 13 is a computer-aided design of a fourth embodiment of a stent created by the method and apparatus according to the invention.

EXAMPLES

(14) FIG. 1 shows a hollow metallic cylinder, which may be converted into a prior art stent using known laser cutting technology. A laser cutter is used to cut and remove material from the wall of the cylinder, such that the cylinder is converted into a mesh tube or stent. The diameter of the cylinder must be small enough so that once it has been converted into a stent, it can be introduced into the lumen of the relevant blood vessel of a subject needing therapy. Referring to FIG. 2, there is shown a computer-aided design (CAD) of a prior art stent, which has been created from a metallic cylinder such as the one shown in FIG. 1. FIGS. 3 and 4 are CADs of alternative embodiments of prior art stents. Each stent comprises interconnected struts of varying lengths, shapes and thickness.

Example 1

CADs of Stents According to the Invention

(15) FIGS. 5, 6, 12 and 13 are CADs of stents 12 that have been printed from a polymer such as polylactic acid (PLA) using the method according to the invention and apparatus 2 shown in FIG. 11, as described below.

Example 2

Apparatus for Creating the Stent

(16) Referring to Figure ii, there is shown an apparatus 2 for producing the stent 12 using 3D printing. Each stent 12 was designed using the CAD software, SolidWorks, and then uploaded in the form of an .stl file on to a control computer 4. The control computer 4 is connected to a Fortus 900 3D printer 6 which includes two dispensing heads 14, each having a nozzle 8 responsible for dispensing the ink 10 used to create the stent 12. Each nozzle has an aperture of 100 to 300 m in diameter through which the polymeric ink 10 is ejected.

(17) After the .stl file had been uploaded onto the control computer 4, the computer 4 slices the schematic representation of the stent 12 into a plurality of layers and simultaneously directs the x-y movement of the nozzles 8 and the z-movement of a stage 26 on which the resultant stent 12 is supported in accordance with the CAD representation in order to selectively dispense the ink material 10 at the appropriate areas to form the 3D stent 12. PCL is supplied as the polymeric ink 10 to the dispensing heads 14 of the printer 6 in the form of a flexible strand of heated material. Once melted at a temperature of 150 C., the PCL is dispensed by the printer nozzles 8, and it cools down and creates a first layer of printed PCL, which is supported on the stage 26. As more heated PCL is ejected from the heads 14, the next layer binds to the previous layer of printed PCL. The thickness of the layers of PCL is about 300 m.

(18) The printing apparatus 2 also comprises a temperature controller 18, which is responsive to temperature sensors 20 disposed on the dispensing head 14 of the printing apparatus 2. The temperature controller 18 finely adjusts the temperature of the PCL such that it is approximately 1 C. above the temperature at which PCL 10 solidifies so that it solidifies just after it has been deposited on the previous layer of ink. This improves the precision with which the nozzle 8 can dispense the PCL used to create the stent 12. A supplemental heater 22 disposed on the nozzle tip 8 responsive to the temperature controller 18 provides accurate control of the temperature of the ink material 10 as it is discharged, to ensure that it is in a fluid state slightly above its solidification temperature 150 C.

(19) Alternatively, the apparatus may be used to perform DoD 3D printing. A partially complete wax mould of the stent 12, which acts as a support structure, is filled or coated in microdroplets of PCL. The wax may, for example, be 3Z Support, from Solidscape. The PCL is dispensed in the form of microdroplets at a temperature ranging from 50 C. to 70 C. As the PCL cools, it solidifies on the wax mould to form the stent 12. A milling head is then passed over the printed stent in order to ensure that it is of uniform thickness. After the stent has been completed the wax mould is then removed by melting it.

Example 3

Stents

(20) FIGS. 7 to 8 show a stent 12 that has been made, based on the CAD of FIG. 6, using the 3D printer 6 connected to computer 4 with the SolidWorks program. The struts 24 of the stent 12 are 300 m thick and have a width of 340 m. The stent 12 covers approximately 10 to 25% of the internal surface area of the section vasculature in which it is located.

(21) Similarly, FIG. 9 shows two stents 12 that have been made, based on the CADs of FIGS. 5 and 6, using the method according to the invention. These stents 12 have been created by building successive layers of PLA ink material on top of each other (i.e. additive manufacturing). They have been made from PLA, which is bioabsorbable polymer. PLA is a biocompatible material that is less likely to cause any of the problems associated with prior art stents.

Example 4

Drug-eluting Stents

(22) The apparatus and method described above has also been used to create a drug-eluting stent 28, as shown in FIG. 10. This embodiment of the stent 28 is rendered drug-eluting by two different methods.

(23) In the first approach, the drug or therapeutic agent and the PLA polymer are simultaneously extruded (i.e. hot melt extrusion) to produce an ink strand 10 (1.7 mm) which is ejected from the nozzles 8. The drug is homogeneously distributed within the structure of the polymeric stent 12 itself, and this approach applies to heat-resistant drugs (e.g. Paclitaxel). Hence, the drug surrounds the polymeric ink, which has been used to create the struts 24 of the stent 12. This embodiment is capable of temporarily storing a drug/composition that can slowly be eluted through the walls of the struts 12 into the blood vessel in which the stent 12 is inserted.

(24) In a second approach to make the drug-eluting embodiment of the stent 12, the PLA polymer ink 10 is extruded without the drug, and the stent 12 is printed following the same process as described in Examples 2 and 3. The drug is then coated on the stent's outer surface by spraying it onto the surface of the stent using any device which can generate microdroplets and can be used for fine spray applications. These devices can based on inkjet printing technology (piezoelectric, thermal, electrostatic), ultrasonic spray technology, air brush technology. Hydrophobic drugs such as, sirolimus and paclitaxel, may need to be dissolved in ethanol prior to spraying, ink jetting from an organic solution such as dissolved in ethanol. This approach applies to heat sensitive drugs (e.g. Biolimus or Zotarolimus). In this embodiment, the drug is located primarily on the outer layers of the stent 12 where it is expected to have a faster release rate.

SUMMARY

(25) Advantages of the Method and Apparatus 2 of the Invention Reside in: the diameter of the aperture of the printer nozzle 8 through which the ink 10 is ejected. Each nozzle has an aperture of 100 to 300 m in diameter; the thickness of each printed layer. The thickness is 6 to 32 m; the thickness of the struts 24 of the stent 12 is about 300 to 400 m; the width of the struts of the stent 12 is about 300 to 400 m; the length of the stent 12 is about 2 to 50 mm; the vascular coverage of the stent 12 is about 10 to 25%; the ink 10 used to create the stent 12 and its mechanical properties, e.g. PLA; the temperature at which the ink 10 is dispensed or printed, i.e. 1 C. above the melting point/glass transition temperature of the ink; and the 3D printer software used (i.e. SolidWorks) because they provide variable printer resolution.