Method for producing implants with a personalised surface

Abstract

The invention relates to a method for producing implants with a personalised surface, which aims to produce an implant with a surface that is bioactivated and treated in a personalised manner for each need. Said method essentially consists of cleaning / activation using plasma technology to ensure that the implant surface is clean and chemically receptive, and the application of a fluid solution with regenerative effects having a composition comprising a biofactor that is vitamin D3 and a linker that is polyvinylpyrrolidone (PVP), essentially in order to enhance the regeneration of hard and soft tissue around the implants to accelerate osseointegration in implantology, preferably in dental implantology, and increase the BIC (bone-implant contact) values between the bone and the implant.

Description

[0001] PROCEDURE FOR OBTAINING IMPLANTS WITH CUSTOMIZED SURFACE

[0002] OBJECT OF THE INVENTION

[0003] The invention relates to a procedure for obtaining implants with a customized surface that allows for increased biocompatibility and osseointegration of the implants in a safe and easy-to-use manner.

[0004] More specifically, the object of the invention focuses on a procedure whose purpose is to obtain an implant whose surface is bioactivated and treated in a customized manner for each need, consisting essentially of cleaning / activation using DBD plasma technology (dielectric barrier discharge) to ensure that the implant surface is clean and chemically receptive, and the application of a fluid solution with regenerative effects with a composition comprising a biofactor which is vitamin D3 (1 a,25-(OH)2D3) and a linker which is polyvinylpyrrolidone (PVP), essentially with the aim of enhancing the regeneration of hard and soft tissues around the implants to accelerate osseointegration in implantology, preferably in dental implantology.and increase the BIC (bone implant contact) values ​​between the bone and the implant.

[0005] BACKGROUND OF THE INVENTION

[0006] As is well known, treating missing or deficient teeth or bones with implants is a reliable solution with high success rates. However, there are situations in which deficiencies, medical treatments, or the patient's own pathologies mean that implant treatment must be ruled out or has little expectation of success.

[0007] The search for mechanisms to increase biocompatibility, osseointegration, and consequently, the success of implants, has been relentless over the past 50 years, and numerous patent applications have been filed in this area. For example, the publication "Titanium implants coated with UV-irradiated vitamin D precursor and vitamin E: in vivo performance and coating stability," by Satue et al. (2017), already demonstrated the increased biocompatibility of implants through the use of vitamin D precursors. However, several issues remain unaddressed. First, they used 7-dehydrocholesterol (7-DHC), a precursor of vitamin D3 that requires activation in several steps. The first step involves ultraviolet (UV) light—which is hazardous to humans, with increased risk in dental clinics—before it is subsequently processed in the liver and kidneys.These last two steps not only cause a crucial delay in activation time, but also mean that the molecules must travel throughout the body to return to the site of action and be used. Secondly, they do not specify how vitamin D binds to the implant surface.

[0008] Surface activation of titanium using dielectric barrier discharge (DBD) plasma has also been investigated, and specific devices for this purpose have even been patented, as it increases the wettability of titanium and is related to an increase in osseointegration rates.

[0009] However, these procedures described above have biological / physiological deficiencies that lead to implant rejection and decrease the success rate of these treatments in the short, medium and long term, and may cause diseases in the tissues around the prosthesis.

[0010] It is also known that by applying DBD plasma (dielectric barrier discharge) of oxygen, argon or helium, impurities and contaminants can be removed, as well as activating the surfaces of certain materials, obtaining surfaces called ultraclean that facilitate the adhesion of products.

[0011] Document US2014 / 004481 A1 discloses a procedure for obtaining dental implants with a customized surface in which the surface of the dental implants is cleaned / activated by using DBD plasma (dielectric barrier discharge) of nitrogen, helium or argon to remove organic debris and contaminants, including an implant ion layer, creating sites with radicals and generating a reactive surface.

[0012] The present invention proposes a procedure for obtaining implants with a customized surface that solves all the previous drawbacks.

[0013] DESCRIPTION OF THE INVENTION

[0014] The present invention relates to a procedure for obtaining implants with a customized surface that allows for a specific selection of the molecule and protocol necessary to increase the biocompatibility and osseointegration of the implants through a safe and easy-to-use procedure.

[0015] The procedure for obtaining implants with a customized surface comprises the following stages:

[0016] - cleaning / activation of the implant surface by using DBD (dielectric barrier discharge) plasma of oxygen, argon or helium to remove organic debris and contaminants, including an oxide layer from the implant, creating sites with radicals and generating a reactive surface; and;

[0017] - application of a fluid solution to the reactive surface of the implant, wherein the fluid solution comprises a biofactor such as vitamin D3 (1 a,25-(OH)2D3) and a linker such as polyvinylpyrrolidone (PVP), wherein the fluid solution thus constituted is configured to enhance tissue regeneration to the reactive surface of the implant.

[0018] In this way, in addition to increasing the biocompatibility and osseointegration of the implants through a safe and easy-to-use procedure, the use of vitamin D3 (1 a,25-(OH)2D3) as a biofactor together with polyvinylpyrrolidone (PVP) as a linker, allows for increased cell proliferation and differentiation, as well as ensuring its safety with respect to the immune system of the individual where the implant will be placed, its ability to bind to titanium through the linker and the progressive release of the fluid solution, all this together with the appropriate selection of the reactive surface of the implant and the activation treatment with DBD plasma (dielectric barrier discharge).

[0019] Optionally, the cleaning / activation stage of the implant surface is carried out with the implant arranged inside a vial and the application of the fluid solution to the reactive surface is carried out inside the vial containing the implant.

[0020] The procedure includes a stage following the application of the fluid solution where the reactive surface of the implant is dried along with the applied fluid solution, preferably by air drying.

[0021] As previously mentioned, the fluid solution is applied to the implant after cleaning and surface activation using DBD plasma technology (dielectric barrier discharge). Once this cleaning / activation process is complete, the fluid solution is applied to the implant, preferably via an ampoule, while the implant is still in its vial. Within a short time, the implant surface will be bioactivated for that patient.

[0022] Specifically, the procedure essentially comprises cleaning / activating the implant surface using DBD plasma technology (dielectric barrier discharge) to make it chemically receptive and, consequently, suitable for the application of a specific fluid solution comprising vitamin D3 (1 a,25-(OH)2D3) as a biofactor and polyvinylidene (PVP) as a linker.

[0023] The objective of the invention is the cleaning / activation of the implant surface by using DBD plasma (dielectric barrier discharge), preferably argon, to remove all organic debris and contaminants, including the oxide layer present on the implant due to its contact with atmospheric oxygen, and to activate said surface by creating sites with radicals so that it is highly reactive and the fluid solution comprising vitamin D3 (1 a,25-(OH)2D3) as a biofactor and polyvinylpyrrolidone (PVP) as a linker can be applied, and which, due to the reactivity of the surface, will fully impregnate the implant, making its personalized behavior effective.

[0024] This method avoids the activation of vitamin D3 precursors (1α,25-(OH)₂D₃) by ultraviolet light, which is harmful to humans and consequently increases costs. Furthermore, the use of polyvinylpyrrolidone (PVP) as a binder and release aid also reduces coating treatment costs and ensures biocompatibility.

[0025] By biofunctionalizing the surface of the implants with the fluid solution described above, based on the biological characteristics of each patient, it has been proven that the success rate increases substantially in the short, medium and long term, since it accelerates osseointegration in implantology and increases the BIC values ​​(Bone Implant Contact) between the bone and the implant.

[0026] PREFERRED EMBODIMENT OF THE INVENTION

[0027] A preferred method for carrying out the invention of a procedure for obtaining implants with a customized surface will be described in detail below. Once the specific case has been planned—that is, after studying the patient's anatomical needs, the biology of the maxillary bone, their habits, medical history, and analyzing any potential surgical traumas—and based on the data obtained, a fluid solution will be applied to the reactive surface of the implant with the aim of increasing the BIC (Bone Implant Contact) values. This fluid solution comprises a biofactor such as vitamin D3 (1α,25-(OH)2D3) and a linker such as polyvinylpyrrolidone (PVP), and the resulting fluid solution is configured to enhance tissue regeneration on the reactive surface of the implant.

[0028] To ensure that the fluid solution penetrates all the micropores of the implant surface, prior to the application of the fluid solution, the implant surface is cleaned / activated using DBD plasma (dielectric barrier discharge) of oxygen, argon or helium to remove organic debris and contaminants, including an oxide layer from the implant, creating areas with radicals and generating a reactive surface.

[0029] Thus, with this preliminary stage of cleaning / activation of the implant surface using DBD plasma (dielectric barrier discharge) of oxygen, argon or helium, a highly reactive surface is obtained without the oxide layer present on titanium when in contact with air, thus ensuring that the fluid solution is perfectly impregnated throughout the implant surface.

[0030] Preferably, the implant is a dental implant.

[0031] Preferably, the plasma used in cleaning / activating the implant surface is an argon DBD (dielectric barrier discharge) plasma.

[0032] Dental implants are typically supplied sterile. The packaging consists of the implant itself placed in a vial, which is then placed in a blister pack and hermetically sealed to maintain sterility.

[0033] To ensure the effectiveness (regenerative effect) of the biofactor (Vitamin D3, 1α, 25-(OH)2D3), the linker polyvinylpyrrolidone (PVP) is used. This slowly degradable compound retains the biofactor (Vitamin D3, 1α, 25-(OH)2D3) within its structure. As the linker degrades over time, it releases the biofactor (Vitamin D3, 1α, 25-(OH)2D3) into the surrounding medium after a few hours. This ensures, on the one hand, the correct adhesion of the biofactor (Vitamin D3, 1α, 25-(OH)2D3) to the surface via the polyvinylpyrrolidone (PVP) linker; And on the other hand, since the biofactor (vitamin D3, 1 a,25-(OH)2D3) is linked to the linker and this is attached to the surface of the implant, the immune system will be prevented from eliminating the biofactor (Vitamin D3, 1 a,25-(OH)2D3) by reducing its availability on the surface of the implant for bone regenerating cells (osteoblasts).

[0034] Thus, once the patient's data regarding their bone type, biology, history and habits that may influence proper osseointegration have been obtained, a fluid solution comprising the biofactor vitamin D3 (1 a,25-(OH)2D3) and the linker polyvinylpyrrolidone (PVP) will be applied, after the aforementioned cleaning / activation stage.

[0035] Preferably, the fluid solution comprises between 0.25 and 1.75 pl of vitamin D3 (1α,25-(OH)2D3) in ethanol (C2H6O) at a concentration of between 5 and 15 pM and between 20 and 40 pl of polyvinylpyrrolidone (PVP) in ethanol (C2H6O) at a concentration of between 25 and 35 mg-ml. 1 .

[0036] More preferably, the fluid solution comprises 1 pl of vitamin D3 (1a,25-(OH)2D3) in ethanol (C2H6O) at a concentration of 10 pM and 30 pl of polyvinylpyrrolidone (PVP) in ethanol (C2H6O) at a concentration of 30 mg-ml 1 .

[0037] Preferably, prior to surgery, which is not the subject of this invention, the implants to be placed in the patient undergo a DBD (dielectric barrier discharge) plasma cleaning / activation process, preferably for a period of less than 15 minutes, and preferably between 10 and 15 minutes. To carry out this step, the sealed blister pack is opened, the vial containing the implant is removed, and it is placed in a DBD plasma machine.

[0038] This DBD (dielectric barrier discharge) plasma cleaning process consists of several phases. First, activated species and short-wave ultraviolet light photons generated in the plasma break down and remove most organic adhesives and any surface contaminants present on the implant. The particles removed from the surface react chemically with oxygen ions in the plasma (if oxygen is used), producing other molecules such as water and carbon dioxide, which are extracted from the chamber using a vacuum system. In plasmas generated for cleaning oxidizable metals, where oxygen is absent, the particles removed from the surface are directly extracted from the chamber to prevent material redeposition, leaving the surface ultra-clean and ready for bonding.Once the programmed cycle is complete, the vial containing the implant is removed, and the vial cap is taken out. Without removing the implants from the vial, the fluid solution containing biofactor (vitamin D3, 1α,25-(OH)2D3) and polyvinylpyrrolidone (PVP) is poured into the vial to reduce any deficiencies and / or enhance the patient's biological properties, thereby increasing BIC (Bone Implant Contact) values ​​and improving the osseointegration of the implant with the bone of that specific patient.

[0039] The implant is then removed from the vial, once immersed in the fluid solution, and left to air dry, preferably for at least 10 minutes.

[0040] Next, the implants are ready to be placed in the patient in the conventional manner.

[0041] EXAMPLE

[0042] Trials were conducted to provide a polylactic acid (PLA) coating for the surface of a titanium implant. Since these results were unsuccessful, polyvinylpyrrolidone (PVP) was then tested as a linker for the vitamin D3 biofactor (1α,25-(OH)₂D₃).

[0043] It was found that the polyvinylpyrrolidone (PVP) coating disappeared completely after one week of degradation. Treatment of the implant surface with this solution, composed of vitamin D3 (1α,25-(OH)2D3) and polyvinylpyrrolidone (PVP) as a binder, modulates the abrupt release of vitamin D3 (1α,25-(OH)2D3) on the first day.

[0044] Argon plasma dielectric barrier discharge (DBD) is chosen because it is similar to oxygen plasma, for clinical safety reasons. This treatment with argon plasma DBD increases the adhesion capacity of mesenchymal stem cells to sandblasted titanium surfaces. Other treatments, such as melatonin (Mel) therapy, do not induce significant changes in the viability of osteoblasts derived from patients. Fibronectin (FN) therapy increases cell viability but not differentiation.

[0045] However, treatment with vitamin D3 (1 a,25-(OH)2D3) and argon plasma slightly decreases the viability of osteoblasts seeded on the surface of the titanium implant, and increases their mineralization capacity, in addition to the fact that polyvinylpyrrolidone (PVP) has been shown not to exert toxic effects on human osteoblasts nor to trigger a macrophage-mediated inflammatory response.

[0046] The viability and mineralization results of the biofactors bound to polyvinylpyrrolidone (PVP) are similar to those obtained without polyvinylpyrrolidone (PVP), since polyvinylpyrrolidone (PVP) is harmless although necessary for vitamin D3 (1 a,25-(OH)2D3) to be bound to the surface.

[0047] Titanium-argon plasma surfaces treated with polyvinylpyrrolidone (PVP) containing vitamin D3 (1 a,25-(OH)2D3) release the hormone into the culture medium and this release increases from 1 to 3 days, with the total release of the fluid solution into the medium observed in less than a week.

Claims

1. Procedure for obtaining implants with a customized surface comprising the following stages: - cleaning / activation of the implant surface by using DBD (dielectric barrier discharge) plasma of oxygen, argon or helium to remove organic debris and contaminants, including an oxide layer from the implant, creating sites with radicals and generating a reactive surface; and; - application of a fluid solution to the reactive surface of the implant, wherein the fluid solution comprises a biofactor such as vitamin D3 (1 a,25-(OH)2D3) and a linker such as polyvinylpyrrolidone (PVP), wherein the fluid solution thus constituted is configured to enhance tissue regeneration to the reactive surface of the implant.

2. Method according to claim 1, characterized in that the cleaning / activation step of the implant surface is carried out with the implant disposed within a vial and the application of the fluid solution to the reactive surface is carried out within the vial containing the implant.

3. A method according to any of the preceding claims, characterized in that it comprises a step subsequent to the step of applying the fluid solution where the drying of the reactive surface of the implant is carried out together with the applied fluid solution.

4. Process according to claim 3, characterized in that the drying step is an air drying step.

5. A method according to any of the preceding claims, characterized in that the plasma used in cleaning / activating the implant surface is an argon DBD (dielectric barrier discharge) plasma.

6. A method according to any of the preceding claims, characterized in that the fluid solution comprises between 0.25 and 1.75 ml of vitamin D3 (1α,25-(OH)2D3) in ethanol (C2H6O) at a concentration of between 5 and 15 pM and between 20 and 40 pM of polyvinylpyrrolidone (PVP), in ethanol (C2H6O) at a concentration of between 25 and 35 mg-ml' 1 .

7. Process according to claim 6, characterized in that the fluid solution comprises 1 pl of vitamin D3 (1a,25-(OH)2D3) in ethanol (C2H6O) at a concentration of 10 pM and 30 pl of polyvinylpyrrolidone (PVP) in ethanol (C2H6O) at a concentration of 30 mg-ml 1 .

8. A method according to any of the preceding claims, characterized in that the duration of the cleaning / activation stage of the implant surface with DBD plasma (dielectric barrier discharge) is less than 15 minutes.

9. A method according to any of the preceding claims, characterized in that during the application of a fluid solution to the reactive surface of the implant, Vitamin D3 (1 a,25-(OH)2D3) is released from the implant surface within a period of less than 1 week.

10. Method according to any of the preceding claims, characterized in that the implant is a dental implant.

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