WO2022173405A1

WO2022173405A1 - Production method of titanium based biocomposite tissue scaffold

Info

Publication number: WO2022173405A1
Application number: PCT/TR2022/050116
Authority: WO
Inventors: Burak DİKİCİ; Mehmet GAVGALI; Mehmet TOPUZ
Original assignee: Atatürk Üni̇versi̇tesi̇ Rektörlüğü Bi̇li̇msel Araştirma Projeleri̇ ( Bap ) Koordi̇nasyon Bi̇ri̇mi̇
Priority date: 2021-02-12
Filing date: 2022-02-11
Publication date: 2022-08-18
Also published as: TR202102040A2

Abstract

The invention relates to a biocompatible new generation titanium-based biocomposite tissue scaffold that exhibits low elastic modulus (E) and sufficient mechanical properties, as an alternative to the biomaterials used in the body, and to the production method of said tissue scaffold.

Description

PRODUCTION METHOD OF TITANIUM BASED BIOCOMPOSITE TISSUE

SCAFFOLD

FIELD OF THE INVENTION

The invention relates to a biocompatible new generation titanium-based biocomposite tissue scaffold that exhibits low elastic modulus (E) and sufficient mechanical properties, as an alternative to the biomaterials used in the body, and to the production method of related tissue scaffold.

STATE OF THE ART

Many studies are carried out for the production of titanium (Ti)-based bone tissue scaffolds in the state of the art. The major problem encountered in these studies is that the elastic modulus (Young modulus (E)) of the developed materials is considerably higher than the E value (~ 5-30 GPa) of bone tissue. Therefore, load transfer between implant and bone is limited and bone density, known as the stress-shielding effect, decreases. In addition, since the biomaterials currently used for this purpose are composed of pure metal alloys, chemical integrity cannot be achieved between them and living tissue.

Another disadvantage of the alloy and/or composite biomaterials used in the state of the art is their inadequacy, especially in applications that require abrasion resistance.

Biocompatible composite nanofiber tissue scaffold is discussed as a supporting material in wound and burn treatments in the patent application numbered TR 2019/04572 which is one of the documents encountered in the patent and literature research on the state of the art. In related application, a composite tissue scaffold based on polyvinyl alcohol and bovine gelatin has been disclosed, but there is no description for a metal matrix biocompatible ceramic reinforced composite tissue scaffold.

Patent application numbered TR 2018/11205 relates to osteogenic osteoconductive biocompatible composite nanofiber tissue scaffold for bone and cartilage tissue damage repair. Related invention has a polycaprolactone-based structure comprising both bovine gelatin and bovine hydroxyapatite structures. In the invention, which defines a structurally different tissue scaffold, electro spinning is used as a method, and powder metallurgy and uniaxial pressing methods are not included.

A tissue scaffold for the repair of osteochondral defects is disclosed in the patent application numbered TR 2010/11221. Biodegradable and biocompatible tissue scaffolds are disclosed in related application. This scaffold consists of layers in a vertical position.

The document with publication number KR20090116202 A only relates to the preparation of titanium-hydroxyapatite tissue scaffolds, it does not contain a description about zirconia (ZrCh) reinforcement. On the other hand, hydrothermal synthesis method was used in the production method in said document.

The European patent application with publication number EP2517738 A1 discloses the production of collagen/hydroxyapatite tissue scaffolds. Moreover, the compressive strength of the tissue scaffolds is quite low (0.3 KPa), and its use in areas requiring strength is limited as mentioned in the invention.

In the Chinese patent application with publication number CN106563168 A, collagen/hydroxyapatite-based tissue scaffolds containing titanium dioxide (Ti02) at nanoscale have been disclosed. The use of T1O2 as a reinforcement made the structure completely ceramic-based brittle. It is not possible to make reference to a metal titanium (Ti) matrix in said application.

In the application with the publication number US 2014/0236299 Al, porous composite biomaterials and related methods are described. Said application contains Ti and HA, but does not contain any information on ZrC>2 addition. It is stated in this invention that which form the composite structure can contain reinforcement and how they are arranged. It focused on the production and usage areas of biocomposite porous materials from this aspect.

The US patent numbered US 10092676 B2 relates to the biohybrid composite scaffold. Said composite structure fully consists of biodegradable and biocompatible elastomeric polymers. What is meant by reinforcement is that it consists of a three-dimensional structure containing macromolecules such as collagen, enzyme or protein, known as the ECM (extracellular matrix). The composite scaffold mentioned here contains highly sensitive molecules and is disadvantageous in terms of mechanical strength. Soft tissue scaffolds that can allow the use of hydroxyapatite (HA) as reinforcement are disclosed in the US patent numbered US 9427495 B2. However, the matrix structure fully consists of polymer instead of Ti and does not contain any ZrCh content.

The patent with publication number CN102910605 B relates to a method of preparing titanium-containing HA-ZrC>2 biological composite nano powder. The invention described in said patent is entirely related to powder production, but the main subject of our application is the production of bulk and porous biocomposite tissue scaffolds from prepared powders. In said invention, the Ti ratios vary between 0.2% and 1.6% by weight, while the ZrC ratios remain constant at 20%, the remaining 78.4 - 79.8% consists of HA. In other words, this structure has a ceramic-based composition. It is known that high ceramic content makes sintering difficult and HA cannot maintain its thermodynamic stability at high temperature. On the other hand, cold pressing and salt leaching processes are not mentioned in said patent document, many technical features that depend on these processes cannot be provided.

Korean patent numbered KR101186370 B1 relates to a porous biomaterial with multi-layer structure. It is stated in this document that the elements specified in the structure are not used in pure form, but completely in the form of oxides. For example, Ti is used as T1O2, not pure. It is emphasized in the document that it is ceramic-based at many points. Also, the cold pressing process is not mentioned in the production method.

As a result, due to the abovementioned disadvantages and the insufficiency of the current solutions regarding the subject matter, a development is required to be made in the relevant technical field.

BRIEF DESCRIPTION OF THE INVENTION

The present invention relates to a titanium based biocomposite tissue scaffold and production method of said tissue scaffold which fulfills the abovementioned requirements, eliminate all disadvantages and bring some additional advantages.

The main object of the present invention is to provide a biocompatible new generation titanium-based biocomposite tissue scaffold that exhibits low elastic modulus (E) and sufficient mechanical properties, as an alternative to the biomaterials used in the body, and to the production method of said tissue scaffold. The tissue scaffold, which is produced specific to the invention and designed in a porous structure, is functionalized with hydroxyapatite (HA) and zirconia (Zr02), giving it a bioactive structure. This function structure on one hand, directs the tissue development to the porosities, on the other hand, can contribute to the sufficient load bearing of the bone structure and to reduce the problem known as the stress-shielding effect (decrease in bone density).

Another object of the invention is to obtain a titanium-based biocomposite tissue scaffold that contributes to the shortening of the osseointegration time between living tissue/implant. Its HA additive contributes to the shortening of the osseointegration time between the living tissue/implant after implantation by inducing new Ca- and P-based components on the tissue scaffold. Zr02 which is another reinforcing phase in the biocomposite structure can be easily used in long-term load-bearing implants needs by increasing the abrasion and strength resistance of the implant.

Compared to the conventional alloy and/or composite materials used as implant material, the inventive titanium-based biocomposite tissue scaffold stands out with its low E value, high biocompatibility and improved mechanical properties and/or abrasion resistance. It is possible to obtain a low E value with the pore structure of the material provided according to the invention with the invention; on the other hand the major technical problem mentioned in the methods in the state of the art is the high E value of the biomaterials produced in bulk.

Depending on the difference in the chemical structure of the bone structure compared to the biomaterials used as a pure alloy, its HA structure is used to avoid low biocompatibility problems. The problems such as low abrasion resistance and mechanical strength, which are frequently seen, are eliminated with the addition of ZrC>2 in implant applications with porous structure produced with the prior art methods.

The present invention is the production of a metal matrix biocomposite tissue scaffold with varying porosity ratio (porosity), biocompatible and functionalized with titanium-based HA and ZrC>2, which are biocompatible and exhibit adequate mechanical properties.

The structural and characteristic features of the present invention will be understood clearly by the figures and the detailed description with reference to the figures. Therefore the evaluation shall be made by taking said figures and detailed description into consideration.

FIGURES CLARIFYING THE INVENTION

In Figure 1, a) biocomposite production process steps, b) produced biocomposite tissue scaffold, c) top view, d) cross-sectional view, e) abrasive cut shape, f) microstructure image, g) microstructure inside porosity, h) titanium (Ti) additive analysis, i) hydroxyapatite (HA) additive analysis, j) zirconia (Zr02) additive analysis graphs are given.

DETAILED DESCRIPTION OF THE INVENTION

In this detailed description, the inventive titanium based biocomposite tissue scaffold and production method of said tissue scaffold is described only for clarifying the subject matter in a manner such that no limiting effect is created.

The present invention relates to the production method of titanium based biocomposite tissue scaffold. In the said production process, first of all, weight calculations of titanium (Ti), hydroxyapatite (HA), zirconia (Zr02) and sodium chloride (NaCI) powders are made. Density values of the powders are used in this process step. The resulting Ti, HA and ZrCh powder mixtures are mixed first preferably for 2 hours, then with NaCI powders that will allow the formation of porosity, preferably 1 more hour with the help of a turbula mixer, preferably for a total of 3 hours. Thus, it is possible to obtain various chemical and mechanical properties.

Cold pressing is applied in the next process step. Said pressing process is preferably carried out in cylindrical form pressing molds with a diameter of 20 mm, preferably under 700 MPa pressure and for 15 minutes. The pressure value in this process was selected higher than the yield strength of Ti, high strength is achieved with the sintering process after production. Cold pressing is important for maintaining the bulk integrity of the structure during the salt leaching process.

Salt leaching process is applied after cold pressing process so as to create porosity in composite tissue scaffolds. Ultrapure water (purity: 99%) with a temperature of preferably 70 °C is used in the beaker so that the composite tissue scaffold is suspended in the liquid according to this aim and preferably NaCI powders in the structure are dissolved with the help of a magnetic stirrer at a speed of 100 revolution/sec.

Sintering must be applied to contribute to its bulking together with heat transfer so as to make the hybrid powder mixture to have sufficient structural strength. The sintering heat treatment is carried out for 1 hour, preferably under 1000 °C, so as to sinter the Ti on one hand and to preserve the structural integrity of the HA on the other hand. The sintering heat treatment is carried out under argon (Ar) gas (purity: >95) due to the high reactivity of Ti during the process. A continuous sweeping process is applied to the sample surface with Ar gas by using a vertically positioned tube furnace since argon gas is heavier than air. Again in this process step, The composite tissue scaffold is closed with titanium foam (Ti sponge) and pure Ti so as to avoid any reaction (oxidation) on the composite tissue scaffold surface. Tissue scaffolds are produced successful with the successful performance of the heat treatment. Said tissue scaffolds are advantageous in that they allow tissue orientation and have a low elastic modulus, with their porous structure.

As shown in Figure 1, the porous structure on the surface of the produced tissue scaffolds was determined. Porosity is important in terms of obtaining a high surface area during the use of the bulk structure and supporting the growth of tissues in these areas.

In case the cross-sections of the produced samples are taken and observed, it is clearly seen that these pores are combined with each other (connected pore structure). Such interconnected pore structures are presented as evidence that the biocomposite tissue scaffold will migrate towards and into the surface of the surrounding living tissue structures (tissue growth progresses along the cross-section in a bulk structure) during use. Moreover, it can be seen in Figure 1 that it is convenient to cut and use biocomposite tissue scaffolds from all directions. This phenomenon shows that it is possible to cut the biocomposite scaffold produced in various sizes according to the desired region and benefit and can be prepared in various forms.

Different tissue scaffolds have been produced so as to show the characterizing features and effectiveness of the invention that differ from the state of the art. First, only Ti tissue scaffold was produced. In this way, it is possible to make comparisons with HA and HA-ZrC>2 tissue scaffolds. As a result of microstructural characterization processes, only Ti was detected in the produced Ti tissue scaffold. However, its interaction with the surrounding tissues remains weak depending on its chemical difference compared to pure Ti tissues. Therefore, the production of Ti-HA tissue scaffolds was performed. It is aimed to increase biocompatibility with the production of Ti-HA tissue scaffolds and to eliminate unexpected reactions after implantation with HA.

When the microstructural characterization of Ti-HA tissue scaffolds was examined, Ca and P elements were found similar to the bone tissue structure in their content. It is known that this will play a positive role in the first interaction of the relevant tissue scaffold with living tissue. However, as it is known, HA doped structures cannot provide sufficient mechanical and tribological properties when used individually or in combination with other alloys. Therefore, sufficient tribological and mechanical properties are obtained with the ZrC>2 additive in Ti/HA-ZrCh tissue scaffolds developed according to the invention. Since it contains three or more materials, it is important for increasing the bulk properties that decrease with HA addition. In this sense, the main aspect defining the invention is the production of Ti/HA- ZrC>2 tissue scaffold in porous structure by powder metallurgy method. Unlike many other tissue scaffolds, production in hybrid structure is provided with the combination of HA additive, which provides biocompatibility, and ZrC>2, which improves mechanical and tribological properties.

The sizes of Ti, HA, ZrC>2 and NaCI powders used in the production of biocomposite tissue scaffolds respectively range from -325 mesh (45 pm), 3-5 pm, 5-10 pm, and 150-550 pm.

Purity levels of the powders and for Ti, HA, Zr0₂ and NaCI, respectively; 99.5%, >97%, 99% and 99.998%. Both powder sizes and degrees of purity have an important effect on the final structure and change all its properties in the production of biocomposite tissue scaffolds.

Ti ratio is >90% by volume, and the HA-ZrCh ratio varies between 5% and 10% in total in the inventive method.

In order to solve the existing problems in the technical field and to fulfill the mentioned objectives, the present invention is the production method of biocomposite tissue scaffold, comprising the following process steps;

• Preparation of powder mixture containing Ti, HA, ZrC>2 and NaCI,

• Applying cold pressing to the obtained powder mixture,

• Applying salt leaching process after cold pressing so as to create porosity,

• Applying sintering heat treatment.

Claims

1. Production method of titanium based biocomposite tissue scaffold of the present invention, characterized in that; it comprises the following process steps;

• Preparation of powder mixture containing Ti, HA, ZrC>2 and NaCI,

• Applying cold pressing to the obtained powder mixture,

• Applying sintering heat treatment.

2. A production method according to claim 1, characterized in that; it comprises the process step of applying cold pressing in cylindrical form pressing molds with a diameter of 20 mm under 700 MPa pressure and for 15 minutes.

3. A production method according to claim 1, characterized in that; it comprises the process step of dissolving NaCI powders in the structure with pure water of 99% purity at 70 °C with the help of a magnetic stirrer at a speed of 100 revolution/sec in a beaker so as to suspend the composite tissue scaffold in the liquid in order to create porosity in composite tissue scaffolds.

4. A production method according to claim 1, characterized in that; it comprises the process step of applying sintering heat treatment under 1000 °C In order to contribute to the bulking of the hybrid powder mixture with heat transfer to gain sufficient structural strength.

5. A production method according to claim 4, characterized in that; it comprises the process step of applying sintering heat treatment under argon gas of 99% purity.

6. A production method according to claim 1, characterized in that; the purity degrees of the powders for Ti, HA, ZrC>2 and NaCI, are respectively; >99%, >97%, >99%, and