GB2503949A

GB2503949A - An agent for promoting osseointegration of implants

Info

Publication number: GB2503949A
Application number: GB1212568.8A
Authority: GB
Inventors: Gunter Uhr
Original assignee: Nobel Biocare Services AG
Current assignee: Nobel Biocare Services AG
Priority date: 2012-07-14
Filing date: 2012-07-14
Publication date: 2014-01-15
Also published as: GB201212568D0; WO2014012630A1

Abstract

An agent for use in improving or promoting osseointegration or soft tissue sealing of a ceramic or metallic implant, wherein the agent comprises trisodium citrate, citric acid, monobasic sodium phosphate, dextrose and adenine. Preferably the agent is dissolved in water to form an aqueous solution and provides at least one coating on the implant, obtainable by immersing the implant in the agent. The surface of the ceramic or metallic implant is preferably hyperhydrophilic. Also claimed is the use of said agent for coating a ceramic or metallic implant, the implant itself having at least one coating of said agent, and a kit for use in a method of installing a ceramic or metallic implant and said agent. The invention preferably relates to dental implant technology for dental supports carrying tooth-like crowns.

Description

BIOACTIVATED IMPLANT

Field of the Invention

The invention generally relates to implant technology and, preferably to dental implant technology. More specifically, the present invention relates to a particular agent for use in improving or promoting osseointegration or soft tissue sealing of a ceramic or metallic implant, to the use of the particular agent for producing a coating on a metallic or ceramic implant, to a metallic or ceramic implant provided with a coating of said particular agent, and to a kit for use in a method of installing a ceramic or metallic implant.

Background of the Invention

Medical implants are manufactured to replace missing biological structures, to support a damaged biological structure or to enhance an existing one. In the human skeletal system, metallic or ceramic implants are used, for example, in the orthopedic, spine, maxillofacial and dental area.

In the early stages of implant technology a stable and long lasting fixation of an implant in bone was tried to be achieved by cementation. The cement forms an interface between bone and metal, and there was no direct bone contact to the metal surface. However, cement fixation has several disadvantages, such as an insufficient life time and stability.

A cementless fixation of implants was done at first for dental application. Machined titanium implants were placed in the jaw bone for carrying tooth-like crowns. Such osseointegrated implants have been greatly improved in the past. In most cases the dental implant process is carried out in two stages. At first the implant is inserted into the jaw bone. The gums are then olosed up to allow healing to take place. Usually, it takes about 3 to 6 months for the implant to firmly integrate in the bone. After this healing period the artificial tooth crown can be attached to the implant thereby finalizing the implant procedure.

It would, of course, be desirable to reduce the overall time of the dental implant procedure, in particular, to reduce the healing period by improving the osseointegration of the implant. It is also desirable to reduce the number of interactions during restorative treatment.

In the prior art there are basically two approaches for promoting the osseointegration, namely the physical modification of an implant's surface on the one hand and the chemical modification on the other hand.

For example, it has been suggested to roughen an implant's surface by acid-etching, grit-blasting, machining or spark anodization. However, it is of interest to further improve osseointegration of such surfaces and improve prospects of healing in around restorative components Furthermore, WO 00/44305 describes an osteophilic implant provided with a roughened, hydroxylated and hydrophilic surface which is at least sealed in a gas-tight and liquid-tight covering. The interior of said covering is provided with an inert atmosphere, preferably consisting of nitrogen, oxygen and/or inert gas and/or at least partially filled with purified water which optionally contains additives. However, such storing conditions are complicated and cost-intensive.

Another approach for improving osseointegration is described in Wa 2008/022478 Al. According to this approach an implant is treated in a weakly alkaline solution by which the surface exposed to bone and/or soft tissue is chemically modified.

While such prior art dental implants have been proven successful, there is a continuing desire to accelerate the osseointegration of an implant, such as a dental implant.

The object to be solved by the present invention is the provision of an agent having the ability of improving or promoting osseointegration of an implant, such as a dental implant, as well as the provision of an implant having excellent osseointegration properties.

Summary of the Invention

The present inventor has surprisingly found that the presence of citrate, citric acid, phosphate, dextrose and adenine on an implant's surface induces blood protein coating on an implant's surface, platelet activation and a tight fibrin fiber connection to the implant surface. Ihese effects, i.e. an improved blood protein coating, an improved platelet activation and a tight fibrin fiber connection, are basic reguirements for an excellent csseointegration and soft tissue sealing of an implant.

In view of the above finding, in a first aspect, the present invention relates to an agent for use in improving or promoting osseointegration or soft tissue sealing of a ceramic or metallic implant, wherein the agent comprises trisodium citrate, citric acid, monobasic sodium phosphate, dextrose, and adenine.

In a second aspect, the present invention relates to the use of an agent for producing a coating on a ceramic or metallic implant, wherein the agent comprises trisodium citrate, citric acid, monobasic sodium phosphate, dextrose, and adenine.

In a third aspect, the present invention relates to a ceramic or metallic implant characterized in that the ceramic or metallic implant is provided with at least one coating, wherein the coating is obtainable by immersing the ceramic or metallic implant in an aqueous solution comprising trisodium citrate, citric acid, monobasic sodium phosphate, dextrose, and adenine.

In a fourth aspect, the present invention relates to a kit for use in a method of installing a ceramic or metallic implant wherein the kit comprises a ceramic or metallic implant, trisodium citrate, citric acid, monobasic sodium phosphate, dextrose and adenine.

It is surprising to see that an agent according to the invention promotes osseointegration since its primary use is as an anticoagulant when mixed with blood.

Brief Description of the Drawings

Fig. la shows a SEN photograph (magnification = 14,000-fold) of a dental implant after exposure to uncoagulated blood, wherein the dental implant has not been provided with a coating as described in the present application. The dental implant is a bone level implant by the company "Institut Straumann PG" and has a sand-blasted and acid etched surface.

Fig. lb shows a SEN photograph (magnification = 14,000-fold) of a dental implant according to the present invention after exposure to uncoagulated blood. The dental implant is a bone level implant by the company "Institut Straumann ZG" and has a sand-blasted and acid etched surface.

Fig. 2a shows a SEN photograph (magnification = 14,000-fold) of an abutment after exposure to uncoagulated blood, wherein the abutment has not been provided with a coating as described in the present application. The abutment is a zirconium oxide-type abutment and has a rather polished, machined surface.

Fig. 2b shows a SEN photograph (magnifioation = 14,000-fold of an abutment according to the present invention after exposure to uncoagulated blood. The abutment is a zirconium oxide-type abutment and has a rather polished, machined surface.

Fig. 3a shows a SEN photograph (magnification = 14,000-fold) of a zirconium oxide dental implant after exposure to uncoagulated blood, wherein the dental implant has not been provided with a coating as described in the present application. The dental implant has a porous and, thus, rather rough surface texture as compared with the machined surface of the abutment shown in Figs. 2a and 2b.

Fig. 3b shows a SEN photograph (magnification = 14,000-fold) of a zirconium oxide dental implant according to the present invention after exposure to uncoagulated blood. The dental implant has a porous and, thus, rather rough surface texture.

Fig. 4a shows a SEN photograph (magnification = 14,000-fold) of a dental implant having TiUnite surface after exposure to unccagulated blood, wherein the dental implant has not been provided with a coating as described in the present application. The dental implant has a porous and smooth surface texture as compared with the machined surface of the abutment shown in Figs. 2a and 2b.

Fig. 4b shows a SEN photograph (magnification = 14,000-fold) of a dental implant having TiUnite surface according to the present invention after exposure to uncoagulated blood. The dental implant has a porous and, thus, rather rough surface texture.

Fig. 5 shows a dental implant in a side view.

Fig. 6 shows an abutment in a side view.

Detailed Description

According to the first aspect, the present inventicn provides an agent for use in a method of improving or promoting osseointegration or soft tissue sealing of a ceramic or metallic implant 1, wherein the agent comprises trisodlum citrate, citric acid, monobasic sodium phosphate, dextrose and adenine.

According to a preferred embodiment of the present invention the agent is dissolved in water forming an aqueous solution.

It is particularly preferred that this aqueous solution for use in improving or promoting osseointegration or soft tissue sealing of a ceramic or metallic implant comprises: -1.32 to 105.20 g/l, preferably 2.63 to 26.3 gIl of trisodium citrate, -0.16 to 13.08 g/l, preferably 0.33 to 3.27 gIl of citric acid, -0.11 to 8.88 g/l, preferably 0.22 to 2.22 g/1 of monobasic sodium phosphate, -1.60 to 127.60 g/l, preferably 3.19 to 31.90 g/l of dextrose, and -0.01 to 1.1 gIl, preferably 0.03 to 0.28 of adenine.

Such an aqueous solution (in the following also referred to as "the coating solution") as defined above is preferred because an aqueous solution containing 26.3 g/l of trisodium citrate, 3.27 g/l of citric acid, 2.22 g/l monobasic sodium phosphate, 31.9 gIl dextrose and 0.275 g/l adenine is a solution already approved by the FDA and the European authorities. Such a solution, so-called CPDA-l solution, is established as an anticoagulant-preservative and adjuvant for blood bags to enable storage for 35 days without substantial loss of blood cell vitality.

According to a particularly preferred embodiment, the solution for use according to the present invention is a 5 to vol.-% solution of the above-mentioned CPDA-i solution.

According to the most preferred embodiment it is used a 10 to vol.-% solution of the above-mentioned CPDA-1 solution.

In other words, acoording to a particularly preferred embodiment of the present invention it is used an aqueous solution consisting of 2.63 to 5.26 g/l of trisodium citrate, 0.327 to 0.654 g/l of citric acid, 0.222 to 0.444 gIl of monobasic sodium phosphate, 3.19 to 6.38 g/l of dextrose, and 0.0275 to 0.055 g/l of adenine, and the rest is water.

The "implant" according to the present invention can be any ceramic or metallic implant known in the art which wouid benefit from improved osseointegration or heal-in to body tissue. According to a preferred aspect of the present invention, the term "implant" specifically includes or is adapted to carry any dental support component, such as a dental implant, e.g. a load-bearing dental implant, dental bridges, PTBs (implant support bridges), overdenture bars, abutments, and cover screws.

Ceramic or metallic implants are usually made of titanium, titanium alloys, zirconium alloys, titanium ceramic bodies or zirconium ceramic bodies. Furthermore, the preferably used dental support component is usually made of titanium, cobalt chromium although other materials may be used, such as zirconium oxide, aluminium oxide etc. In addition to a coating prepared by using the above-defined agent, the outer surface of the implant, including the dental support component, may be provided with additional means of promoting osseointegration. For example, the surface area of the outer surface of the dental support component may be increased by roughening the implant body in several different manners, such as, e.g. by acid-etching, grit blasting, spark-anodization and/or machining. Alternative, the outer surface can comprise macroscopic struotures, such as, for example, threads, micro-threads, indentations, and/or grooves that are configured to promote osseointegration and can be used alone or combined with the roughening. In one embodiment of the present application, the outer surface may comprise a microstructure surface, such as, a highly crystalline and phosphate euriohed titanium oxide microstructures surface with open pores in the low miorometer range. An example of such a surface is sold under the trademark iiuniteTM by Nobel BiocareTM. In another embodiment, the implant, in particular the dental support component, may be made of a zirconium ceramic body that is coated with porous zirconium to provide a microstructure surface. It is also possible to use a dental support component having a surface that is provided with growth factors, preferably transforming growth facors Beta, e.g. bone morphogenetic protein (BMP-2, -4, -7), or in combination with platelet rich plasma (PRP) . Growth factors may further include any one selected from the group consisting of platelet-derived growth factor (PDGF) , vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF), fibroblast growth factors (FGF), differentiation factor 5 (GDF-5) Osseointegration is the direct structural and functional connection between living bone and the surface of an implant.

An intense blood protein coating and an intense fibrin network integration of the implant surface will influence the cascade of cell-interrogation, recruitment, proliferation, differentiation and maturation of matrix. Fibrin fibers which form the preliminary matrix are "highways" on which soft tissue and hard tissue forming cells move along to the implant surface. Proteins and growth factors released from activated platelets support and organize cellular communication. The platelet-released factors also induce and amplify the migration, proliferation and differentiation of endothelial cells and thereby initiating angiogenesis. The invasion and sprouding of blood vessels is a prerequisite for a sufficient nutrition and oxygen supply, demanded by highly active regenerative cells. By optimizing the wound healing processes on the surfaces of an implant, such as a dental support component, the contact-osteogenesis will occur earlier and finally ossecintegration will be accelerated.

Soft tissue sealing around an implant and, in particular a dental support element such as an abutment, is a prereguisite for a long lasting fixation of an inserted implant. For example, especially in case of tooth replacement, the dental support element, i.e. implant, abutment, crown, is exposed to the oral microflora, such as bacteria, fungi, viruses.

Leakage of the soft tissue sealing can induce pen-implantitis which, in the worst case, leads to a loss of the implant.

According to the second aspect of the present invention, the above-defined agent is used for producing a coating on a dental support component. As explained above, according to a preferred embodiment of the present invention, the agent is dissolved in water forming an agueous solution. Preferably, the aqueous solution for producing a coating on the surface of the ceramic or metallic implant is as defined above.

The method of coating the ceramic or metallic implant with the above-defined agent is not particularly limited and any known method may be employed.

In case of using the agent in form of an aqueous solution as defined above, the ceramic or metallic implant, e.g. the dental support component, may be immersed in the aqueous solution, i.e. the above-defined aqueous solution, at ambient temperature (25 °C) for e.g. 10 mm. In case of a porous dental support component it is recommendable to apply a low vacuum (e.g. 600 unbar) for e.g. about 10 mm to ensure that the coating solution penetrates into the pores. Subsequently, the implant is removed from the solution and air-dried by e.g. 37°C for 30 mm. A drying of the coated implant is not essential though. Alternatively, it is also possible to directly use the as-ooated implant, i.e. without drying, for implantation into hard or soft tissue of a patient.

The above exemplified method can be suitably modified, if desired. For example, it is possible to apply a vacuum to the implant first, thereby removing water adsorbed on the surface. Such a pre-treatment is preferred in case of a porous implant because it is beneficial to remove adsorbed water inside the pores before carrying out the coating procedure. Afterwards the so-treated implant is coated with the coating solution by e.g. immersing the implant, e.g. the dental support component, in the coating solution.

Especially in case of a non-porous implant where a penetration of the coating solution into pores is not an issue it is possible to pour the coating solution directly into the wound of a patient, e.g. into an extraction socket or drill hole, immediately before the implant, e.g. a dental implant, is inserted in the hard or soft tissue. Thereby, it is possible to obtain a covering of the implant with the coating solution.

It is also possible to apply the coating of the surface of the implant step by step using single-component solutions.

For example, it is possible to first immerse the implant in a solution containing trisodium citrate, thereafter in a solution containing citric acid, afterwards the implant is immersed in a solution containing monobasic sodium phosphate, after this the so-treated implant is immersed in a solution containing dextrose and finally the implant is immersed in a solution containing adenine. The single-component solutions can be applied to the implant's surface in any order.

Alternatively, it is also possible to prepare solutions of two, three or four of the above-mentioned agents prior to the coating step.

In case the agent is not dissolved in water, as alternative methods for applying the coating to the implant chemical vapor deposition and exposure to the dry crystalline agents can be mentioned.

According to the third aspect, the present invention provides a ceramic or metallic implant that is provided with at least one coating, wherein said coating is obtainable by immersing the ceramic or metallic implant in an aqueous solution comprising trisodium citrate, citric acid, monobasic sodium phosphate, dextrose and adenine. The aqueous solution is the same as specified above.

The thickness of the coating is not specifically limited and may be between a few micrometers to some millimeters. The thickness of the coating depends on the concentration of the coating solution and the coating conditions. In generalL it can be said that a higher concentrated coating solution increases the thickness of the coating on the implant.

Alternatively, if it is intended to increase the amount of coating on the implant, it is possible to repeat the coating step as often as desired.

Furthermore, the surface of the implant coated with the above-defined agent, in particular with the above-defined coating solution, comprising trisodium citrate, citric acid, monobasic sodium phosphate, dextrose and adenine, is preferably hyperhydrophilic. The wettability of the coated implants has been determined by measuring the contact angle according to the Sessile-Drop-Method. The coated implant according to the present invention shows a contact angie of below 300, in particular of about 20°, at the time t=Os (time of the first contact of the water droplet with the surface) However, the water droplet completely spreads on the surface within some seconds, such as below 50 ms, more particuiar about 5 to iO ms. Such a wetting behavior is typical for hyperhydrcphilic surfaces.

In a fourth aspect, the present invention relates to a kit for use in a method of installing a ceramic or metallic implant, wherein the kit comprises a ceramic or metallic implant, such as a dental support element, trisodium citrate, citric acid, mcncbasic sodium phosphate, dextrose and adenine.

It is possible that the kit according to the fourth aspect contains trisodium citrate, citric acid, monobasic sodium phosphate, dextrose and adenine as dry agents packaged in the form of dry powders. Such dry powders may be packaged separately or as a mixture of two or more or all of the dry agents. Before coating of the dental support component, these dry powders can be dissolved in an appropriate amount of water to prepare the above-defined coating solution.

According to a further preferred embodiment of the fourth aspect of the present invention, the kit contains an aqueous solution containing trisodium citrate, citric acid, monobasic sodium phosphate, dextrose and adenine. It is preferred that the kit contains the aqueous solution according to the above described preferred embodiments. For examples, the aqueous solution to be contained in the kit of the present invention consists of 2.63 to 5.26 g/l of trisodium citrate, 0.327 to 0.654 g/l of citric acid, 0.222 to 0.444 g/l of monobasic sodium phosphate, 3.i9 to 6.38 g/l of dextrose, and 0.0275 to 0.055 g/l of adenine, and the rest is water.

Examples

Example 1

It has been used a standard dental implant, a bone level implant, produced by the company "Institut Straumann AG".

This implant has a sand-blasted and acid etched surface. It has been coated with an aguecus coating sclution having the fcllcwing compcsition: -2.63 g/l of trisodium citrate, -0.327 g/l of citric acid, -0.222 q/l monobasic sodium phosphate, -3.19 g/l dextrose and -0.0275 g/l adenine.

The implant has been immersed in the coating solution for 10 mm. Then, low vacuum of 600 mbar has been applied. After 10 mm, the implant has been removed from the coating solution and dried at 37°C for 20 mm.

For determining the coagulation of blood in direct contact with the implant surface the coated implant has been exposed to fresh (i.e. uncoagulated) human blood. The coagulation property serves as an indication of beneficial conditions for enabling osseointegration. Therefore, the coated implant was placed in an Eppendorf vial and the blood was added. After 10 mm the implant was removed and fixed in a formaldehyde solution. The so-fixed implant was stored over night at 4 00.

For comparative reasons, the same standard dental implant produced by the company "Institut Straumann AG" but which has not been provided with the above-described coating has been treated with blood in the same way as described above.

Fig. la shows a SEN photograph (magnification = 14,000-fold) of the dental implant after exposure to uncoagulated blood, wherein the dental implant has not been provided with a coating according to the present invention.

Fig. lb shows a SEN photograph (magnification = 14,000-fold) of the dental implant according to the present invention after exposure to uncoagulated blood.

It is apparent from the comparison of Fig. la with Fig. lb that the blood protein coating, the platelet activation and fibrin fiber connection is greatly improved on the surface of the implant according to the present invention compared to an untreated implant.

Example 2

7\ zirconium oxide-type abutment having a rather polished, machined surface has been coated in the same way as described

in Example 1.

The coated abutment has been treated with blood in the same way as described in Example 1.

Furthermore, for comparative reasons, the non-coated abutment has been treated with blood in the same way.

The surfaces of the blood-treated abutments are shown In Figs. 2a and 2b. It is apparent from the comparison of Fig. 2a with Fig. 2b that the blood protein coating, the platelet activation and fibrin fiber connection is greatly improved on the surface of the implant according to the present invention compared to an untreated implant.

Example 3

A zirconium oxide dental implant having a porous and, thus, rather rough surface texture has been coated in the same way as described in Example 1.

The coated dental implant has been treated with blood in the same way as described in Example 1.

Furthermore, for comparative reasons, the non-coated dental implant has been treated with blood in the same way.

The surfaces of the blood-treated dental implants are shown in Figs. 3a and 3b. It is apparent from the comparison of Fig. 3a with Fig. 3b that the blood protein coating, the platelet activation and fibrin fiber connection is greatly improved on the surface of the implant according to the present invention compared to an untreated implant.

Example 4

A titanium dental implant having an oxidized porous surface sold under the trademark TiUnitelM has been coated in the same way as described in Example 1.

The coated dental implant has been treated with blood in the same way as described in Example i.Furthermore, for comparative reasons, the non-coated dental implant has been treated with blood in the same way.

The surfaces of the blood-treated dental implants are shown in Figs. 4a and 4b. It is apparent from the comparison of Fig. 4a with Fig. 4b that the blood protein coating, the platelet activation and fibrin fiber connection is greatly improved on the surface of the implant according to the present invention compared to an untreated implant.

Claims

CLAIMS1. Agent for use in improving or promoting osseointegration or soft tissue sealing of a ceramic or metallic implant, wherein the agent comprises trisodium citrate, citric acid, monobasic sodium phosphate, dextrose, and adenine.
2. Agent according to claim 1 wherein the ceramic or metallic implant is a dental support element.
3. Agent according to claim 1 or 2 wherein the agent is dissolved in water forming an aqueous solution.
4. Agent according to claim 3 wherein the aqueous solution comprises -1.32 to 105.20 g/l of trisodium citrate, -0.16 to 13.08 g/l of citric acid, -0.11 to 8.88 g/l of monobasic sodium phosphate, -1.60 to 127.60 g/l of dextrose, and -0.01 to 1.10 g/l of adenine.
5. Use of an agent for producing a coating on a ceramic or metallic implant, wherein the agent comprises trisodium citrate, citric acid, monobasic sodium phosphate, dextrose, and adenine.
6. Use according to claim 5 wherein the ceramic or metallic implant in a dental support component.
7. Use according to claim 5 or 6 wherein the agent is dissolved in water forming an aqueous solution.
8. Use according to claim 7 wherein the aqueous solution comprises -1.32 to 105.20 g/l of trisodium citrate, -0.16 to 13.08 g/l of citric acid, -0.11 to 8.88 g/l of monobasic sodium phosphate, -1.60 to 127.60 g/l of dextrose, and -0.01 to 1.10 gIl of adenine.
9. A ceramic or metallic implant characterized in that it is provided with at least one coating, wherein the coating is obtainable by immersing the ceramic or metallic implant in an aqueous solution comprising trisodium citrate, citric acid, monobasic sodium phosphate, dextrose, and adenine.
10. The ceramic or metallic implant according to claim 9, wherein the ceramic or metallic implant is a dental support element.
11. The ceramic or metallic implant according to claim 9 or 10, wherein the aqueous solution comprises -1.32 to 105.20 g/l of trisodium citrate, -0.16 to 13.08 g/l of citric acid, -0.11 to 8.88 gIl of monobasic sodium phosphate, -1.60 to 127.60 g/l of dextrose, and -0.01 to 1.10 g/l of adenine.
12. The ceramic or metallic implant according to any one of claims 9-11, wherein the surface of the ceramic or metallic implant is hyperhydrophilic.
13. A kit for use in a method of installing a ceramic or metallic implant, wherein the kit comprises a ceramic or metallic implant, trisodium citrate, citric acid, monobasic sodium phosphate, dextrose and adenine.
14. Kit according to claim 13 wherein trisodium citrate, citric acid, monobasic sodium phosphate, dextrose and adenine are present in an aqueous solution.