EP4271429A1

EP4271429A1 - Polydopamine-coated intracorporeal implants through electropolymerization method

Info

Publication number: EP4271429A1
Application number: EP21769827.3A
Authority: EP
Inventors: Afife Binnaz HAZAR; Oguler SAZCI; Gulcin GENC
Original assignee: Yildiz Teknik Universitesi
Current assignee: Yildiz Teknik Universitesi
Priority date: 2020-12-29
Filing date: 2021-06-14
Publication date: 2023-11-08
Also published as: TR202022312A2; WO2022146301A1

Abstract

The present invention provides a method for increasing the hydrophilicity of a surface of an intracorporeal implant of conductive material. The method comprises the step of coating said implant with a polymer layer by electropolymerization.

Description

POLYDOPAMINE-COATED INTRACORPOREAL IMPLANTS THROUGH ELECTROPOLYMERIZATION METHOD

Field of the Invention

The present invention relates to medical implant technologies. In particular, the present invention relates to a method and product for dental implants.

Background Art

A dental implant is an artificial tooth root placed in the jawbone in order to restore the function and impaired aesthetics of the missing tooth. Although the dental implant treatment is highly successful today, there are still serious losses due to some complications such as peri-mucositis and peri-implantitis.

Osseointegration is defined as the microscopic structural and functional connection between the intraosseous load-bearing implant and living bone tissue. An inadequate osseointegration of the implant with the bone, deterioration of the bacterial balance after unsuccessful osseointegration, infection of the soft tissues around the implant caused by the bone loss are the most important causes for dental implants loss. The occurrence of these complications are highly dependent on the patient's awareness of oral hygiene and the experience of the physician, as well as the material type and surface properties of the implant.

Microstructural changes on the dental implant surface are effective in the response of the tissues and cells to the implant. In order to establish a healthy osseointegration between the implant and the bone tissue, physical, chemical, physicochemical processes and/or combinations thereof are applied to the surface. With the healthy osseointegration, the possibility of inflammation in the tissues around the implant is reduced. However, existing surface treatments are not sufficient to prevent the occurrence of diseases such as peri-mucositis and peri-implantitis. In general, in line with the information obtained from the case studies and clinical studies, it is found that all of said methods may cause problems in implant-tissue compatibility.

Despite the existing surface studies, the fact that implant-induced intraoral inflammations are still experienced today is the main factor underlying the invention. Peri-implant diseases that occur because of three main factors, namely the patient, the physician and the implant material, are caused by the implant material if it is considered that the patient applies a regular oral care and the physician performs the correct treatment.

In the treatment of peri-implantitis, non-surgical periodontal treatments such as curette and mechanical treatment with ultrasonic devices, laser surface cleaning, and antimicrobial treatments as well as chemical decontamination and regenerative and resective surgical treatments can be used.

On the surfaces of the dental implants, in order to ensure the primary stability, increase the biological response and improve the osseointegration process in a positive way, a number of modifications are made on dental implant surfaces so as to improve tissue response, with the development of the technology and the increase in the number of researches. Whether the implant is conical or cylindrical, differences in length and diameter, number of threads, depth or shape, surface roughness value, morphology of the oxide layer on the surface, different surface topographies, and increasing the energy of the implant by binding different active groups or ions (Ca⁺², PO₄ ³' etc.) on the surface, etc. configure the behavior of the implant in the tissue. In some of these methods, there are situations that weaken the biocompatibility, while in some of them, biocompatibility may increase.

Objects of the Invention

The principal object of the present invention is to eliminate the prior art deficiencies.

Another object of the present invention is to increase the hydrophilicity of the surfaces of the medical and dental implants by means of a method that is fast and low-cost, and easy to monitor and control. Summary of the Invention

At present, since there is not a wide range of choice for the implant base material, the prior art tries to solve the aforementioned problem by means of an improvement in the implant surface.

In the present invention, a polydopamine (PDA) biopolymer is deposited on the surface by electropolymerization method in order to increase the surface energy and improve the bone-implant compatibility due to the increase in surface wettability. In addition to the hydrophilic feature imparted on the surface by PDA, the main purpose of its use is to ensure that different groups are simultaneously attached to the surface, given that it has the ability to adhere to almost any substance by virtue of its active ends. With the adhesive property of PDA and the superior properties of other groups, it is possible to increase the hydrophilicity and bioactivity of the implant surfaces. The coating times of less than 24 hours yield hydrophilicity below 50°.

In a preferred embodiment of the method, the step of coating the implant with the polymer layer comprises the following: i. immersing the implant as a working electrode in an electrolyte designed to provide a source of monomer; ii. electropolymerization coating of the implant by applying a voltage to said working electrode in the presence of a reference electrode and a counter electrode immersed in the electrolyte.

A preferred embodiment of the method comprises applying cyclic voltammetry in electropolymerization according to the following parameters: • a voltage ranging from -2 V to +2 V;

• a scanning rate ranging from 0.02 V/s to 0.5 V/s;

• a cycle number ranging from 5 to 100.

The method preferably comprises applying a voltage in the range of -1 V to +1 V and selecting an electropolymerization time in the range of 30 min to 24 hours.

The scanning rate can be 0.1 V/s.

The method preferably comprises using a dopamine-containing monomer as a monomer for coating with said polymer layer. Thus, a PDA layer is obtained on the implant surface. The dopamine-containing monomer may be dopamine HCI.

A preferred embodiment of the method may include adjusting the concentration of the monomer in the electrolyte at the start of electropolymerization to be in the range of 1 mg/mL to 4 mg/mL, and preparing the electrolyte to be a buffered conductive solution. The electrolyte may be buffered to a pH of 7.4. The electrolyte may be a tris buffered saline. The tris buffer may be present in the electrolyte at a concentration of 20 mM.

In an exemplary embodiment of the method, Ag-AgCI can be used as the material of the electrode and Pt can be used as the material of the counter electrode.

An exemplary embodiment of the method may include subjecting the implant surface to a pre-treatment prior to electropolymerization. Said pre-treatment may be selected from washing, oxide layer removal, or sandblasting.

Said conductive material may contain Co-Cr, Co-Ni-Cr, Co-Cr-Mo, Fe-Cr-Ni-Mo, a titanium alloy, a shape memory alloy, stainless steel, or a conductive polymer. For example, the conductive material may contain a titanium alloy selected from Ti-6AI-4V, Ti-6AI-4V-ELI, Ti-6AI-7Nb, Ti-5AI-2.5Fe. Or, for example, the conductive material may contain a shape memory alloy selected from Ni-Ti, Cu-Zn-AI, Cu-AI-Ni. Alternatively, the conductive material may contain a conductive polymer selected from PA, PPy, PT, PEDOT, PANI. Brief Description of the Drawings

The present invention is exemplified below with reference to the accompanying figures for better understanding thereof, which examples are only illustrative of the embodiments of the present invention and are not limiting other embodiments and general functions providing the solution of the technical problem.

Figure 1 is an image for the contact angle interpreted in Example 4, for a sample of a substrate (a disc sample of Ti-6AI-4V-ELI) without electropolymerization coating.

Figure 2 is an image for the contact angle interpreted in Example 4, for the PDA-coated surface (surface of the PDA-coated Ti-6AI-4V-ELI disc sample) by applying electropolymerization in the context of example 2, in order to observe the effect of the inventive improvement.

Figure 3 is the side-by-side and simultaneous photographic images of the (a) PDA- uncoated reference dental implant and (b) the PDA-coated implant, after water was dropped thereon in example 5.

Detailed Description of the Invention

Hereinafter, the present invention is described in detail, based on the drawings, whose brief description given above.

Within the scope of the present invention, it is possible to obtain polymer-coated implants in a controlled and fast manner by applying polydopamine coating on the conductive surfaces by electropolymerization method.

The electropolymerization method may be applied to any conductive surface. Examples of materials with conductive surfaces suitable for PDA coating by electropolymerization may include titanium alloys (e.g., Ti-6AI-4V, Ti-6AI-4V-ELI, Ti-6AI-7Nb, Ti-5AI-2.5Fe), Co- Cr, Co-Ni-Cr, Co-Cr-Mo, Fe-Cr-Ni-Mo, shape memory alloys (e.g., Ni-Ti, Cu-Zn-AI, Cu-AI- Ni), stainless steel and conductive polymers (e.g., PA, PPy, PT, PEDOT, PANI). Prior to the electropolymerization coating process, the surface of the substrate may be subjected to one or more of the pre-treatments known in the art, as needed.

The electropolymerization method generates a coating layer (PDA coating layer) on the surface of a substrate placed in the environment (sample, in the case of the present invention: medical implant, especially dental implant) by causing oxidation and reduction reactions in the solution by means of a potential applied between a working electrode and a counter electrode in an electrolytic cell. In electropolymerization coating, the electrolytic cell is preferably connected to a potentiostat device. The potentiostat device is used to keep the potential between the working electrode and the reference electrode, i.e., the voltage value, constant. The substrate (sample) to be coated is coupled to the electrolytic cell as a "working electrode". Ag/AgCI can be used as the reference electrode and platinum as the counter electrode. Changing the reference electrode causes a change in the numerical values of the results, but does not cause a change in their interpretation. Therefore, different materials can be selected as the reference electrode and the counter electrode.

In the present invention, it is possible and preferred to apply cyclic voltammetry (CV) in carrying out the electropolymerization. In cyclic voltammetry, a negative or positive potential is applied to the working electrode over a predetermined range of values. Thus, current values are obtained depending on the changing potential value. Monitoring the current values throughout the coating process allows commenting on the progress of the coating process. A decrease observed in the current value indicates that the conductivity of the surface has decreased and the non-conductive polydopamine has been successfully coated on the surface. Therefore, it is possible to precisely monitor the performance of the inventive method.

The controllability of the parameters in the electropolymerization method is higher than that of the traditional method of immersion coating. In addition, the time required for the electropolymerization coating to take place is shorter than that in the prior art methods. Therefore, the method of the invention is attractive both in terms of accuracy and precision, and in terms of speed-based economic advantage, and it has high industrial applicability. The commercial end products expected to be obtained once the invention is used in the industry may include the following:

- polydopamine-coated conductive biomaterials,

- polydopamine-coated conductive intracorporeal implants, and

- polydopamine-coated dental implants.

The following examples are provided just for better understanding of the invention and are not intended to limit the scope of protection.

EXAMPLES

Hereinafter, in order to prove the concept set out by the invention, the steps of performing a coating process on an exemplary disc-shaped substrate made of Ti-6AI-4V- ELI are exemplified.

EXAMPLE 1:

An exemplary substrate with a conductive surface is selected in preparation for a proper coating process. The surface of the substrate may be subjected a pre-treatment, for example pre-cleaning by washing.

EXAMPLE 2:

The substrate used in this exemplary experiment is a sample made of Ti-6AI-4V-ELI, which is suitable for use in medical and especially dental implants as a sample of conductive surface material. The sample was chosen to be in the form of a disk, due to its flat surface, in order to facilitate the measurement of the contact angle after the coating process.

The cleaned substrate in Example 1 was coated by electropolymerization method. The coating process comprises the following: i. immersing the substrate as a working electrode in an electrolyte (coating solution) designed to provide a source of dopamine (monomer); ii. electropolymerization coating of the substrate by applying a voltage to said working electrode in the presence of a reference electrode and a counter electrode immersed in the electrolyte.

By electropolymerization, the source of dopamine (here, dopamine HCI) was chosen as a monomer, thereby obtaining a PDA layer as the polymer layer covering the surface of the substrate.

EXAMPLE 3: Exemplary elements and parameters used in electropolymerization

In the electropolymerization process in Example 2, the following were preferred as the appropriate elements and parameter values:

Dopamine HCI is selected as the dopamine source. Accordingly, the electrolyte is designed to:

- have a monomer (here: dopamine HCI) concentration (initial concentration) at the beginning of the electropolymerization, preferably in the range of 1 mg/mL to 4 mg/mL,

- to be a conductive solution preferably buffered to have a pH of 7.4; preferably tris buffered saline (TBS), in this example, the concentration of the tris buffer is 20 mM (20 millimoles per liter).

The parameter values used and preferred in the application of a voltage are as follows:

- cyclic voltammetry (CV) was applied;

- applied voltage (potential value) ranging from: preferably -2 V to +2 V, more preferably -1 V to +1 V; in this example, a range of -1 V to +1 V is applied;

- voltage change rate (scanning rate): preferably in the range of 0.02 V/s to 0.5 V/s, for example/preferably 0.1 V/s; in this example, 0.1 V/s was applied;

- number of cycles: for example, 5 to 100 cycles, for example/preferably 100 cycles; in this example, 100 cycles are applied; - electropolymerization time: preferably in the range of 30 minutes to 24 hours.

40 mL as an exemplary value for the volume of the electrolyte (coating solution) used in this exemplary laboratory- scale experiment.

Ag-AgCI was used as the material of the reference electrode and Pt was used as the material of the counter electrode.

In the laboratory-scale exemplary experiment, the electropolymerization coating process was carried out in a triple-mouthed container (balloon) as an electrolytic cell (in terms of having suitable inlets for the reference electrode, counter electrode and anode).

The electropolymerization was optionally carried out in/under nitrogen or oxygen (or in/under air being a mixture thereof).

After the electropolymerization process is completed, the substrate (sample) was removed from the electrolyte (coating solution), rinsed and then dried. The rinsing was optionally carried out in an ultrasonic bath using ultra-pure water for 15 minutes. The drying was optionally carried out in nitrogen environment.

EXAMPLE 4:

An image of the contact angle was captured for a substrate surface (a PDA-uncoated Ti- 6AI-4V-ELI disc sample) on which the electropolymerization coating was not applied in Example 2, which is presented in Fig. 1. The contact angle on the uncoated surface was measured as 68.26° (an average of 68.24° and 68.27°), and the hydrophilicity level of said surface was taken as a reference.

In order to observe the effect of the improvement of the invention, in the context of example 2 (potential value ranging from -1 to +1 V, scanning rate of 0.1 V/s, 100 cycles), an image of the contact angle of the electropolymerized PDA-coated substrate (i.e. PDA-coated Ti-6AI-4V-ELI disc sample) was captured, which is presented in Fig. 2. With the method of the invention, the contact angle on the PDA-coated surface was measured as 15.81° (an average of 15.49° and 16.13°). Therefore, compared to the reference level, it was determined that the hydrophilicity of the surface is increased with the PDA coating.

In summary, according to the contact angle measurements presented in Figure 1 and Figure 2, the contact angle is reduced from 68.26° to 15.81°, and hydrophilicity is increased with the PDA coating.

EXAMPLE 5:

In order to test and prove the performance of the concept of the invention on the surfaces of the threaded dental implants (i.e. as a substrate, the substrates with relatively complex geometry), a qualitative comparative experiment was conducted.

Accordingly, of the two dental implants identical to each other in terms of material and geometry, one was maintained without coating (reference implant), and the other was coated with PDA by electropolymerization as described in Example 2 (PDA-coated implant). On the surfaces of the reference implant and the PDA-coated implant placed side by side, water was dropped in an identical manner, and then the photograph presented in Figure 3(a) and Figure 3(b) was captured. As seen in Figure 3:

- The water droplet on the surface of the reference implant adhered thereon without spreading, which is also evident from the fact that the threads aligned with the droplet appear larger than they actually are, due to the convex lens effect of the droplet. In addition, the bulged contour of the droplet is visible, the light reflection from its outer surface is evident so that it can be deduced that the droplet is not dispersed, and also an illuminated region created by the light projected through the droplet on a light-colored background is visible. Except for the part where the droplet hits, the remaining surfaces of the reference implant are dry and therefore optically opaque. Therefore, it is clear that the PDA-uncoated surface exhibits hydrophobic properties. - The droplet of water dropped on the PDA-coated implant spread rapidly on the surface and was sucked into the threads, thereby wetting the surface of the PDA- coated implant much more (extensively) and faster than the reference implant, and flowing from the PDA-coated implant surface. This is also evident from the fact that the bright reflections based on wetness on the PDA-uncoated implant surface, and the successive threads appear in similar alignments in Fig. 3. As the droplet spread on the surface of the PDA-coated implant, the droplet bulging quickly disappeared.

EXAMPLE 6:

Before starting electropolymerization coating process (i.e. as a pre-treatment), an oxide layer on the surface of the sample that is intended to be coated can be removed. In this example, a constant potential was applied for 30 seconds at a voltage of -3V as a pretreatment for the removal of the oxide layer on the surface of the sample (titanium- based disc). Thus, a substrate with a high conductive surface was obtained which is suitable for a highly efficient electropolymerization.

After the pre-treatment, electropolymerization was performed using CV in the context of Example 3. The parameters used are given below:

• applied potential ranging from: -1 V to +1 V

• Number of scans: 50 cycles

• Scanning rate: 0.1 V/s

• Monomer (dopamine HCI) concentration: 1 mg/mL.

At the end of the process, a coating having a similar performance to the results in Example 4 and Example 5 was successfully obtained.

EXAMPLE 7:

In this example, as a pre-treatment, the surface of the sample (titanium-based disc) was roughened with a sandblasting material (CaP sand). In another experiment of the invention, the titanium disc sample was roughened with the sandblasting material (CaP sand). Thus, a substrate is obtained having a high surface area (or surface energy) per unit projected area, suitable for a highly efficient el ectropolymerization . After the pre-treatment, electropolymerization was performed using CV in the context of Example 3. The parameters used are given below:

• applied potential ranging from: -1 V to +1 V

• Number of scans: 50 cycles

• Scanning rate: 0.1 V/s • Monomer (dopamine HCI) concentration: 1 mg/mL.

Claims

1. A method for increasing the hydrophilicity of a surface of an intracorporeal implant of conductive material, comprising the step of coating said implant with a polymer layer by el ectropolymerization .

2. The method according to claim 1, wherein the step of covering the implant with a polymer layer comprises the following: iii. immersing the implant as a working electrode in an electrolyte designed to provide a source of monomer; iv. electropolymerization coating of the implant by applying a voltage to said working electrode in the presence of a reference electrode and a counter electrode immersed in the electrolyte.

3. The method according to claim 2, comprising applying cyclic voltammetry in electropolymerization according to the following parameters:

- a voltage ranging from -2 V to +2 V;

- a scanning rate ranging from 0.02 V/s to 0.5 V/s;

- a cycle number ranging from 5 to 100.

4. The method according to claim 3, comprising applying a voltage in the range of -1 V to +1 V and selecting an electropolymerization time in the range of 30 min to 24 hours.

5. The method according to any one of claims 3 or 4, wherein the scanning rate is 0.1 V/s.

6. The method according to any one of claims 1 to 5, comprising using a dopamine- containing monomer as a monomer for coating with said polymer layer.

7. The method according to claim 6, wherein dopamine HCI is used as a monomer.

8. The method according to any one of claims 2 to 7, comprising adjusting the monomer concentration in the electrolyte at the start of electropolymerization to be in the range of 1 mg/mL to 4 mg/mL, and preparing the electrolyte to be a buffered conductive solution.

9. The method according to claim 8, wherein the electrolyte is buffered to a pH of 7.4.

10. The method according to any one of claims 8 or 9, wherein the electrolyte is a tris buffered salt solution.

11. The method according to claim 10, wherein the tris buffer is present in the electrolyte at a concentration of 20 mM.

12. The method according to any one of claims 2 to 11, wherein Ag-AgCI is used as the material of the electrode and Pt is used as the material of the counter electrode.

13. The method according to any one of claims 1 to 12, comprising subjecting the implant surface to a pre-treatment selected from washing, oxide layer removal or sandblasting, prior to electropolymerization.

14. The method according to any one of claims 1 to 13, wherein said conductive material contains Co-Cr, Co-Ni-Cr, Co-Cr-Mo, Fe-Cr-Ni-Mo, a titanium alloy, a shape memory alloy, stainless steel, or a conductive polymer.

15. The method according to claim 14, wherein said conductive material contains a titanium alloy selected from TI-6AI-4V, T-6AI-4V-ELI, Ti-6AI-7Nb, Ti-5AI-2.5Fe.

16. The method according to claim 14, wherein said conductive material contain a shape memory alloy selected from Ni-Ti, Cu-Zn-AI, Cu-AI-Ni.

17. The method according to claim 14, wherein said conductive material contains a conductive polymer selected from PA, PPy, PT, PEDOT, PANE