Method of manufacturing an implant for use in a surgical procedure

Abstract

A method of manufacturing an implant for use in a surgical procedure, a corresponding implant and the use thereof during the incorporation of a substance is presented. Specifically anodized and blasted titanium implant substrates are provided with a hydroxyapatite (HA) coating for incorporating for example a therapeutic agent. In particular, an anodizing procedure by an electrolytic process in an alkaline liquid is carried out. Moreover, blasting of the anodized titanium implant substrate is carried out by the presented method. The HA coating can be in the range of 1 to 5 m, particularly in the range of 1 to 3 m. A local delivery of the active pharmaceutical ingredient is achieved by the implant of the present invention. Moreover, the implant allows for the removal of the implant without damaging surrounding tissue or a bone. Moreover, the HA coating is provided to the substrate such that enhanced fixation as measured by pull-out force is achieved whilst having a relatively low removal torque. The HA coating and drug incorporation may be carried out sequentially but also co-precipitation approach can be used.

Claims

1. A method of manufacturing an implant for use in a surgical procedure, the method comprising: providing a titanium implant substrate, anodizing the titanium implant substrate by an electrolytic process in an alkaline liquid, blasting the anodized titanium implant substrate, soaking the blasted and anodized titanium implant substrate in a NaOH solution for a time period t.sub.p between 1 and 20 minutes without substantially changing the surface microstructure, and after the soaking step, coating the blasted and anodized substrate with hydroxyapatite (HA) by depositing a HA coating from a solution between 37 C. and 85 C. to produce the HA coating having a thickness between 0.5 m and 5 m.

2. The method according to claim 1, wherein the titanium implant substrate is formed of titanium alloy Ti6A1-4V.

3. The method according to claim 1, wherein the steps of anodizing and blasting are carried out according to AMS 2488-D resulting in a type II anodized titanium implant substrate.

4. The method according to claim 1, wherein the step of coating the substrate with HA is based on crystal growth of HA on a surface of the implant.

5. The method according to claim 1, wherein the solution is an aqueous solution containing ions.

6. The method according to claim 1, wherein the titanium implant substrate is inserted into the solution for a time period t.sub.c, and wherein the time period t.sub.c is between 20 h and 80 h.

7. The method according to claim 1, wherein the HA coating has a crystalline structure, and wherein the HA coating has a thickness which is between 1 m and 3 m.

8. The method according to claim 1, wherein the time period t.sub.p is between 5 and 15 minutes.

9. The method according to claim 1, the method further comprising: incorporating a substance into the HA coating, and wherein the substance is a therapeutic agent.

10. The method according to claim 2, wherein the steps of anodizing and blasting are carried out according to AMS 2488-D resulting in a type II anodized titanium implant substrate.

11. The method according to claim 1, wherein the solution has a temperature between 50 C. and 80 C.

12. The method according to claim 11, wherein the solution has a temperature between 65 C. and 75 C.

13. The method according to claim 6, wherein the time period t.sub.c is between 40 h and 80 h.

14. The method according to claim 13, wherein the time period t.sub.c is between 60 h and 80 h.

15. The method according to claim 14, wherein the time period t.sub.c is between 65 h and 75 h.

16. The method according to claim 15, wherein the time period t.sub.c is between 70 h and 75 h.

17. The method according to claim 8, wherein the time period t.sub.p is between 8 and 12 minutes.

18. The method according to claim 17, wherein the time period t.sub.p is between 9 and 11 minutes.

19. The method according to claim 9, wherein the therapeutic agent is selected from the group consisting of an osteoporotic drug, bisphosphonates, strontium, PTH, antibiotics, gentamycin, tobramycin, vancomycin, doxycycline, a chemotherapy drug, analgetics, antiphlogistics, metal ions, copper ions, silver ions, organic molecules, and any combination thereof.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 schematically shows a flow diagram of a manufacturing method according to an exemplary embodiment of the present invention.

(2) FIG. 2 schematically shows a flow diagram of a manufacturing method according to another exemplary embodiment of the present invention.

(3) FIG. 3 shows a type II anodized titanium implant substrate with a bioactive surface according to an exemplary embodiment of the present invention.

(4) FIG. 4 shows the implant of FIG. 3 after depositing a crystalline, HA coating on the implant.

(5) FIG. 5 schematically shows an SEM image of an HA coating according to exemplary embodiment of the present invention.

(6) FIG. 6 schematically shows SEM images of implant surfaces resulting from different NaOH pre-treatments.

(7) FIG. 7 schematically shows SEM images of implant surfaces resulting from different NaOH pre-treatments.

(8) The figures are schematic and not on scale.

DETAILED DESCRIPTION OF EMBODIMENTS

(9) FIG. 1 schematically shows a method of manufacturing an implant for use in a surgical procedure according to an exemplary embodiment of the present invention. The titanium implant substrate, for example a Ti6A1-4V substrate, is provided. This provision of the substrate is shown with step S1 whereas step S2 depicts the anodization of this substrate by an electrolytic process in an alkaline liquid. Preferably, this anodization step may be carried out in accordance with the standard defined by AMS 2488-D. Moreover, the method of FIG. 1 comprises the blasting of the anodized titanium implant substrate in step S3. Also this step can preferably be embodied as the blasting step defined in AMS 2488-D. Moreover, the blasted and anodized substrate is subsequently coated with a hydroxyapatite (HA) layer/coating in step S4. The implant manufactured by the method of FIG. 1 provides the advantage that the coating remains within the body of the patient when the implant is removed from the body. In particular, either the coating has been dissolved within the body or the coating is separated from the titanium implant substrate during the removal of the implant. In particular, the HA coating of the implant of the present invention demonstrates enhanced fixation as measured by pull-out force whilst having a relatively low removal torque. The HA coating of the present invention can be embodied as very thin porous coating and can be deposited during the usage of a chemical biomimetic method. In different embodiments which can be derived from the embodiment of FIG. 1, a cleaning process may used in addition. Moreover, if desired, a NaOH pre-treatment, as has been described before, can be comprised, but is not mandatory. Furthermore, the use of a type II anodized titanium implant during the incorporation of a medical or pharmaceutical product into the HA coating of the implant can be combined with the method of FIG. 1. The method of FIG. 1 may also be seen as a method for providing an implant interface, or providing an implant with a HA coating.

(10) According to a further specified embodiment, FIG. 2 shows a flow diagram of a manufacturing method. In particular, for steps S1 and S4 it is referred to the descriptions of FIG. 1. After step S1, a specific anodization S2b of the titanium implant substrate by an electrolytic process in an alkaline liquid as defined by AMS 2488-D is carried out. Moreover, blasting step S3b is carried out according to AMS 2488-D standard. In the embodiment of FIG. 2 also a NaOH pre-treatment is carried out in step S5. The titanium implant substrate is inserted into a NaOH solution before the step of coating, which is carried out in step S4. Thereby, the titanium implant substrate is kept in the NaOH solution for 10 minutes. However, in other exemplary embodiments other time periods as described herein for the NaOH pre-treatment may be used by the skilled person.

(11) FIG. 3 shows an implant 300 according to the present invention. The implant 300 is manufactured by the presented method and provides the advantage that the coating remains within the body of the patient when the implant is removed from the body. FIG. 3 shows a titanium implant substrate 301 which comprises a bioactive surface 302. The substrate 301 is a type II anodized substrate, as has been described before in detail. The bioactive surface 302 may be provided via a NaOH pre-treatment as has been described with different parameters before. For example, a 10 minutes soaking step in 5 M NaOH solution at 70 C. may be used. No significant change in the morphology or roughness of the substrate 301 is caused.

(12) FIG. 4 schematically shows the implant 300 as described with respect to FIG. 3. In addition to the substrate 301 and the bioactive surface 302, a HA coating 400 is shown. This coating is ultrathin and in the range of 1 to 3 m. Moreover, the HA coating is provided in a crystalline form. Such a thin and porous coating 400 allows for a local delivery of active pharmaceutical ingredients and allows removing subsequently the implant without damaging surrounding bone. The used NaOH pre-treatment of the substrate can be very short and does not alter the surface microstructure of the substrate. Furthermore, the ultrathin thicknesses can be achieved without self cracking. An unexpected feature is also that the growth of the coatings tends to even out the underlying roughness, which leads to a smoothening effect. Moreover, a special drug loading with pressure under evaluated temperature can be applied subsequently.

(13) FIG. 5 shows a scanning electron microscope image (SEM) of an implant having an HA coating according to the present invention. FIG. 5 shows an untreated surface of the titanium implant substrate which can be observed in the underlying surface. In other words, in the example of FIG. 5, no NaOH pre-treatment was carried out.

(14) Furthermore, the HA coating is depicted in FIG. 5 showing a coating thickness of approx 1.5 m and a nanoporous microstructure.

(15) FIG. 6 shows the impact of NaOH treatment on an type II anodized titanium surface after storage in NaOH solution for different time points, namely 9 h, 3 h, and 1 h, by SEM imaging. For each time period two different magnifications are presented. NaOH pre-treatment for all durations resulted in changes of the surface structure. The longer the treatment duration the greater is the impact on the surface. Additionally several cracks can be observed for all time points tested.

(16) FIG. 7 schematically shows SEM images of implant surfaces resulting from different time durations of NaOH pre-treatments, namely 40 and 10 minutes. After 40 minutes minor changes in surfaces morphology and minor self-cracking can be observed. After 10 minutes of NaOH pre-treatment nearly no morphological change was demonstrated by SEM analyses.

EXAMPLE

(17) In the following an exemplary process of depositing hydroxyapatite on an anodized type II titanium implant will be described, as well as an exemplary incorporation process for incorporating an antibiotic substance into such a HA coating.

(18) A biomimetic hydroxyapatite coating is deposited on anodized type II titanium implants by a biomimetic method. The implant, both untreated and NaOH treated as described herein, were soaked in phosphate buffered saline (PBS) (Dulbecco's PBS, Sigma, Steinheim, Germany) for a defined time period at a defined temperature. In this Example, a 72 h storage in the solution at 70 C. was used. The HA coating was biomimetically precipitated on the TiO.sub.2 coated pins using PBS containing CaCl.sub.2 and MgCl.sub.2 as ion source. Screws for example were often placed in a system with the tips hanging down. The beaker container for examples had a volume of 100 ml of PBS.

(19) The PBS was constantly stirred during the deposition process with a magnetic stir bar to ensure a more even HA coating. After removal from the PBS solution, the implants were rinsed in deionized water and dried with a flow of N.sub.2. In this example the PBS solution D 8662 as described below was used. Different other PBS solutions comprising CaCl.sub.2 and MgCl.sub.2 as summarized in the following can also be used. However, also other solutions may be used for the HA coating/deposition in accordance with the present invention:

(20) TABLE-US-00001 DULBECCO'S PHOSPHATE BUFFERED SALINE D 8662 D 5527 D 5780 D 8537 [1X] D 5773 D 5652 D 7030 [1X] COMPONENT g/L g/L g/L g/L g/L INORGANIC SALTS CaCl.sub.22H.sub.2O 0.133 MgCl.sub.26H.sub.2O 0.1 0.1 KCl 0.2 0.2 0.2 0.2 0.2 KH.sub.2PO.sub.4 (anhyd) 0.2 0.2 0.2 0.2 0.2 NaCl 8.0 8.0 8.0 8.0 8.0 Na.sub.2HPO.sub.4 (anhyd) 1.15 1.15 1.15 1.15 1.15 Grams of powder N/A 9.7 9.6 9.6 N/A required to prepare 1 L D 4031 D 1283 D 1408 D 6650 [1X] [10X] [10X] COMPONENT g/L g/L g/L g/L INORGANIC SALTS CaCl.sub.22H.sub.2O 0.133* 0.133 1.33 MgCl.sub.26H.sub.2O 0.1 0.1 1.0 KCl 0.2 0.2 2.0 2.0 KH.sub.2PO.sub.4 (anhydrous) 0.2 0.2 2.0 2.0 NaCl 8.0 8.0 80.0 80.0 Na.sub.2HPO.sub.4 (anhyd) 1.15 1.15 11.5 11.5 OTHER D-Glucose 1.0 1.0 Kanamycin Sulfate 0.1 Penicillin G (sulfate) 10.sup.6 units* Pyruvic AcidNa 0.036 0.036 Streptomycin Sulfate 0.05 0.05 *Supplied separately

(21) Moreover, such HA coated implant can be loaded with e.g. Tobramycin by the following loading procedure. As an example, Ti bone screws were loaded by adsorption in Tobramycin containing water of double distilled quality at a concentration of e.g. 4 mg/ml, 20 mg/ml or 40 mg/ml. Loading at room temperature was performed by filling a test tube with 2 ml of Tobramycin stock solution, transferring the sample into the test tube for a loading time of 5 minutes. Afterwards the screw was removed by the help of an artery clamp and dried in an oven for 24 hours at 37 C. in a vertical position. The loading under temperature and pressure were prepared by placing the HA-coated implants in 30 ml of stock solution containing e.g. 4 mg/ml, 20 mg/ml or 40 mg/ml Tobramycin in a stainless steel tube under an applied pressure. The elevated temperature prevailing during loading was ensured by preheating the steel tube and the stock solution prior to the loading procedure. The loaded implants were placed in an oven for drying. Thus, in a first alternative, the loading is carried after depositing the HA coating and can be carried out by inserting the HA coated implant into the antibiotic solution. Further, as a second alternative, also an simultaneous incorporation and HA coating process can be used. This has been described before as a co-precipitation approach, which approach combines the biomimetic growth of HA with incorporation of an active pharmaceutical ingredient or ions at the time of nucleation. In summary, the ingredients or ions to be incorporated are present during the biomimetic coating process. As an outcome of the process, the implant is coated with HA which simultaneously incorporates the therapeutic ingredient or ion by co-precipitation during manufacturing. Therefore, no additional drug or ion loading of the HA coating is necessary when using the co-precipitation approach.

(22) Other variations to the disclosed embodiments can be understood and effected by those skilled in the art in practicing the claimed invention, from the study of the drawings, the disclosure, and the appended claims. In the claims the word comprising does not exclude other elements or steps and the indefinite article a or an does not exclude a plurality. Any reference signs in the claims should not be construed as limiting the scope of the claims. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. Reference signs in the claims shall not be construed to be limiting in any way.