WO2021025655A1

WO2021025655A1 - Magnesium and/or strontium doped coatings for the acceleration of osteosynthesis/osseointegration

Info

Publication number: WO2021025655A1
Application number: PCT/TR2020/050692
Authority: WO
Inventors: Mustafa Kamil URGEN; Muhammet Kursat KAZMANLI; Fatma Nese KOK; Yetkin OZTURK; Erkan KACAR; Gamze Torun Kose; Kenda SABOUNI; Seyhun SOLAKOGLU; Hasan Serdar MUTLU; Sakip ONDER
Original assignee: Istanbul Teknik Universitesi; Yeditepe Universitesi; Istanbul Universitesi Rektorlugu; Yildiz Teknik Universitesi
Priority date: 2019-08-06
Filing date: 2020-08-05
Publication date: 2021-02-11
Also published as: EP4010039A1; EP4010039A4; TR201911986A2

Abstract

Mg- and/or Sr-doped biocompatible coatings (e.g. TiN), that are the subject of this invention, behave as Mg and/or Sr sources producing regional Mg and/or Sr ions from the surface to the fracture line and accelerate osteosynthesis/osseointegration.

Description

MAGNESIUM AND/OR STRONTIUM DOPED COATINGS FOR THE ACCELERATION OF OSTEOSYNTHESIS/OSSEOINTEGRATION

Technical Field

The invention is related to a method for rendering the surface of biomaterials capable of releasing Mg (magnesium) or Sr (strontium) by means of coating and/or surface alloying to promote osteosynthesis/osseointegration.

Material surfaces that are the subject of this invention are used to accelerate osteosynthesis and/or osseointegration in a bone that is fractured or under treatment.

Prior Art

The state of the art comprises applications based on improving the corrosion- and abrasion-resistance of bone fixation systems (implants and prostheses) by means of applying corrosion-resistant hard coatings such as TiN on the said fixation systems used in the treatment of bone fractures. In addition, applications such as various hydroxyapatite (HAp) coatings are performed to improve the osseointegration of dental implants and orthopedic prostheses. Apart from coatings, these applications include oxidizing (e.g. forming titanium oxide on the surfaces of Ti alloys) the surfaces of biomaterials (e.g. plate and screw systems) in order to increase their biocompatibility. One commonly preferred application among these is to increase osseointegration by means of coating surfaces of biomaterials with in-vitro synthesized HAp. Due to its low mechanical strength, HAp is not used individually but as coating on surfaces of biomaterials, especially in load-bearing areas. However, these applications may fail to function effectively due to HAp peeling off from the surface especially in screw applications.

As the biocompatibility and mechanical properties of magnesium and its alloys allow them to be used inside the human body, there is a lot of research into their use in bone fixation systems. Moreover, magnesium is essential in various metabolic reactions, so it can actively contribute to recovery process. In addition, magnesium replaces Ca in HAp, which is a constituent of bones and teeth and increases the biocompatibility of HAp. However, magnesium and its alloys have their disadvantages, such as low corrosion resistance inside the body and the release of gas as a result of corrosion. This limits the use of magnesium alloys as a biomaterial. In practice, HAp is generally used as a coating on the surface of intraosseous prostheses and dental screws for the purpose of improving osseointegration. As stated above, these applications may involve issues such as HAp losing its efficacy by peeling off from the surface due to mechanical impacts.

The bone fixation systems used in the present system have the function of putting the fracture edges together. In these fixation systems, oxide coatings are applied in order to improve the anti -corrosive properties. These bone fixation systems function as mechanical support to ensure the broken bone remains immobile in the course of its recovery by keeping the fracture edges together; however, they have no positive effect on the acceleration of the recovery of the fracture line through the acceleration of osteosynthesis. The mentioned bone fixation systems, therefore, lack the feature which the 3rd generation biomaterials are supposed to have; namely, the function of triggering/accelerating tissue repair. This created the need to develop Mg- or Sr-doped coatings for the acceleration of osteosynthesis, which is the subject of this invention.

With respect to any existing patents in the literature, patent from China numbered CN105349858A refers to the use of alloys containing Mg and Ag, with no reference to the effects of the mentioned alloys on osteosynthesis. Another Chinese patent in the field numbered CN105597160A also used Mg alloy and aimed at improving the mechanical properties of the material and osteosynthesis. The patent numbered CN106999284A refers to a base unit made from magnesium or magnesium alloy in order to increase the hydrophilicity of implant materials and a porous anodic oxide coating film formed on the surface of the base unit. In the mentioned patent, the purpose of the porous anodic oxide film coating on the magnesium alloy is to increase biocompatibility and there is no reference to its effect on osteosynthesis. The Chinese patent numbered CN107119260A in the existing literature refers to the method of magnesium-copper coating and preparation that could be used in bone prostheses in order to resolve the issues of osseointegration and infection in implant materials. The French patent document numbered FR2751201A1 refers to an osteosynthesis implant designed to attach the two sides of the skeleton together.

The Turkish patent document numbered TR 2015/13719 refers to an Mg alloy whose biodegradation rate can easily be controlled and which can be used in the bone treatment or as a bone substitute due to its perfect stability and interface stability for bone tissue.

The methods and materials in the literature summary above are generally designed for bone fixation and the improvement of osseointegration. The main function of the materials suggested for bone fixation systems is to increase mechanical strength and corrosion resistance whereas they do not have the function of triggering/accelerating tissue repair, which the 3rd generation biomaterials are supposed to have.

Purposes and Brief Description of the Invention

The purpose of this invention is to form coatings or surfaces that accelerate osteosynthesis/osseointegration by means of Mg or Sr doping. To that end, the invention aims at accelerating osteosynthesis by doping a coating system approved by FDA for use in the body (e.g. TiN) with Mg and/or Sr on biomaterials that are currently in use. The mentioned coatings or surfaces also make it possible to accelerate osseointegration.

Corrosion problems encountered in existing Mg alloy applications and the inflammation problems caused by the release of gas due to corrosion restrict the direct use of Mg and its alloys inside the body. Another purpose of the invention in connection therewith is to develop coatings/surfaces with high corrosion resistance that overcome the inflammation problem by means of replacing Mg (magnesium) alloy coatings with Mg(magnesium)-doped coatings or surface alloying with low Mg content.

By doping the biocompatible and highly corrosion resistant coatings such as TiN, CrN, DLC with Mg and/or Sr, which is the subject of this invention, it is made possible for these coatings to behave like Mg and/or Sr sources allowing regional Mg and/or Sr release to hard tissues. It is aimed that osteosynthesis will be accelerated on the fracture line as a result of this release, which in turn will shorten the treatment period. In addition, it is possible that osseointegration will increase due to the fact that the released Mg and/or Sr ions could trigger the in-vivo Mg- HAp and/or Sr-HAp formation on the surface of the biomaterial. Therefore, the coatings described in the invention are capable of performing the function of triggering/accelerating tissue repair as required in 3rd generation biomaterials. Single or hybrid coating methods can be used in the production of Sr- and magnesium-doped films and alloyed surfaces. Examples to these methods include cathodic arc deposition, sputtering in a magnetic field, e-beam evaporation, ion injection, laser/e-beam surface alloying and systems where all these methods are combined in the same chamber (hybrid).

Another important feature of these coatings with respect to their application is that their hardness rate is high. High surface hardness will make it easier to screw the implants to be integrated into the bone (e.g. dental implants).

Detailed Description of the Invention

Two practical examples of the said invention are given below.

Example 1: Ti6A14V-based plate and screw systems are used in fixing bone fracture lines. In order to determine the contribution of the developed coating on bone repair (osteosynthesis), the plate and screw systems were tested on New Zealand rabbits. For this purpose and through the method whose steps and details are given below, the plate and screw system was coated to produce thin films in the forms of TiN without Mg and TiN containing max 15% Mg. Then fracture lines were formed on the femoral bones of the rabbits and the plate and screw systems were used to fix the fracture lines. Mg-free TiN coatings were used as control tests.

Coating Method and Steps:

- After the samples were placed in the vacuum chamber, the pressure of the vacuum chamber was decreased to 5 _* 10³ Pa level using a diffusion pump.

- After introducing argon gas into the vacuum chamber, the surfaces of the samples were cleaned through biasing at -600, -800, -1000 V respectively for 60 seconds at each voltage level.

- In the argon atmosphere, only the titanium cathodes were activated to perform the coating on the titanium substrate through biasing at -150 V for 4 minutes,

- Argon was replaced with nitrogen and the pressure in the vacuum chamber was adjusted to 1 Pa,

- Two Ti (with 90 amperes of cathode current) and one Mg/Sr (with 15 A cathode current) targets were activated and the coating was performed for 60 seconds,

- In the coating stage, biasing was applied at -150 V.

- To ensure compositional homogeneity of the coatings, the samples were rotated around their own axes and around another axis that passes through the center of the vacuum chamber along with the coating,

At the end of the sixth week after implantation, the plate and screw systems were removed from the rabbits and analytical studies were carried out on the bone regeneration (osteosynthesis) that took place on the bone fracture lines. For this purpose, X-ray analyses (Figure 1), microtomography analyses (pCT) (Figure 2) and histological analyses (Figure 3) were carried out. X-ray imaging, pCT and SEM analyses on 6-week bone samples showed that bone repair and compact bone mass were better in fracture lines with Mg-containing TiN coatings (i.e. Mg release) whereas the bone-cartilage mass was greater in samples with Mg-free TiN coatings (i.e. no Mg release).

Example 2:

Ti6A14V-based plate and screw systems were used in fixing bone fracture lines and when applying the plate and screw system, the screws were fixed on the strong parts of the bone. In order to determine the effect of the Mg-containing TiN coating on how new bonds were formed (osseointegration), the plate and screw systems were coated as detailed in example 1 above and tested on New Zealand rabbits. Screw holes were drilled on the femoral bones of the rabbits and the plates were fixed onto these holes. Bone cell density and mineralization provides information on how osseointegration progresses and higher amount on implant surface indicates better osseointegration. For this purpose, scanning electron microscope (SEM) analyses (Figure 4), energy-dispersive X-ray spectroscopy (EDS) (Figure 5) and von Kossa analyses were performed on areas where the plates/screws come into contact with bone surfaces. Mg-free TiN coatings were again used as control tests.

SEM, EDS and von Kossa analyses performed on six-week implanted plate/screw samples showed that the surfaces coated with Mg-containing TiN had more bone cells and better mineralization.

Description of Figures

Figure 1 -X-ray image of the plate and screw system and the fracture line after six weeks of recovery

Figure 2 -pCT image of the fracture line from different angles after six weeks of recovery

Figure 3 - Histological analyses of the fracture line after six weeks of recovery Figure 4 - SEM image of the surface of the screw coated with Mg-containing TiN removed from the femoral bone at the end of six weeks

Figure 5 - EDS results of the surface of the plate coated with Mg-containing TiN removed from the femoral bone at the end of six weeks

Claims

1- A coating material containing Mg and/or Sr for the acceleration of osteosynthesis/osseointegration. 2- In the coating material as the one defined in claim 1 the ratio of the total moles of the Mg and/or Sr dopant(s) to the total mole of the coating material is 15% or less.

3- The coating material that corresponds to claim 1 or 2 consist of titanium and/or other biocompatible metal(s) and alloys, and/or biocompatible metal/alloys nitride, carbide, carbonitride and oxide forms, and/or diamond-like carbon (DLC) coating as a matrix.

4- A coating material according to claim 3, consists of the said biocompatible metal and/or alloys that are selected from the list of Titanium, Zirconium, Tantalum and Niobium.