Patent Application
20170056552
This invention applies to the Chemistry, Pharmacy, Medicine, and Material Engineering field of activity and, more specifically, to the area of implants, since it refers to the development of a discontinuous coating composed of a biomaterial (which can be a bioceramic, a biopolymer or a bioactive composite), bioabsorbable and bioactive, applied to solid (smooth, rough or porous) substrates, so that after the implant there is interface between the newly formed tissue and the surface of the solid substrate (implant) in the end of the tissue recovery process and/or local initial stimulation for development of said tissue.
This coating may be applied to dental, hip, and knee implants, bone reconstruction plates, intervertebral spacers, pedicular screws of spinal implant systems, repair of anophthalmic socket, and any implantable solid component.
Since the average useful life of a full hip prosthesis hardly exceeds 15-20 years, and the number of people with implants increased and their average useful life decreased, the number of surgical procedures for implant replacement, or so-called revision surgeries, is increasingly higher. Because these surgeries are traumatic and risky to patients, it would be desirable for the average useful life of implants, both dental and orthopedic, to be approximately 40 years.
In order to address this need, a structural implant should have as its main feature not only the similarity with bone tissue of its elastic module, but also the ability to effectively interface with bone tissue, in other words, to be bioactive. Currently, there is no material that has all these characteristics, and the most used alternative is the “biofunctioning” of the surfaces of metallic implants, changing them physically and/or chemically, in order to grant the typical functional properties of biological systems.
Background
One of the options is to coat metallic implants with layers of bioactive ceramics. Nevertheless, these layers—specifically regarding interface, still an issue not completely solved, due to incompatibility of thermal expansion coefficients and elasticity modules of these two materials. This incompatibility is the main reason for flaws in coated implants and subsequent decrease of average useful life.
In this context, this invention proposes the coating of solid (smooth, rough or porous) substrates with “islands” of a bioactive and bioabsorbable biomaterial, preferably bioglass, so that they are consumed within a few days after implantation. In case of using bioglass, for example, the silica dissolution rate is directly related to bone growth rates. Thus, the process of full dissolution of this bioglass, as well as accelerating bone integration, would also eliminate eventual interface issues, which would lead to (1) an increase in the average useful life of said coated implants, (2) subsequent reduction of the number of revision surgeries due to the decrease in the number of flaws and, lastly, (3) increase in the quality of life of the patients with implants.
State of the Art
The patent application PI 0200698-7 relates to a process for obtaining a continuous bioactive calcium phosphate coating on solid substrates through chemical treatment of said coatings. The coating mentioned in the referred application is continuous.
The patent application PI 0306528-6 describes a coating process through biomimetic growth with replacement of the use of bioactive glass for a sodium silicate solution during the phosphate nucleation step on the surface of the substrate, with which a bioactive coating layer is produced, which coats polymeric, metallic and ceramic materials. There is no mention regarding the characteristics of the layer (continuous or discontinuous) but the biomaterial deposited is the hydroxyapatite, which is not bioabsorbable in the same way as bioglasses, as it is approximately 4 times less bioactive than a bioglass. This means that, even if the coating is discontinuous, it is not expected that hydroxyapatite is dissolved or eliminated from the surface before the end of the tissue scarring process and, thus, the metal-ceramic interface is present and shall potentially present flaws. On the other hand, in the present invention the metal-ceramic interface is consumed by the organism in the initial scarring stages, but not before stimulating tissue formation.
The patent application U.S. Pat. No. 5,578,086 describes a prosthesis that uses biocompatible composite material. The prosthesis may be crafted in two distinct ways: (1) dispersion of powdered hydroxyapatite throughout the surface of a continuous silicone or polyurethane rubber layer applied over the surface of the implant. After curing of the elastomeric material coating, it shall remain adhered to the implant, and the hydroxyapatite particles adhered to the coating (2). Powdered biomaterial, preferably hydroxyapatite, is mixed to the silicone or polyurethane. This mix (composite material) is applied to the surface of the implant that, after curing, shall remain adhered to it. The patent also includes bioglass as an alternative material. The adhesive elastomeric material coating, additionally to being continuous, is not bioabsorbable and, therefore, the implant shall not be in direct contact with the tissue to be formed.
The patent application U.S. Pat. No. 5,990,380 describes percutaneous implants and bioactive coatings, including a substrate and bioactive glass fibers and/or particles distributed over the substrate at a pre-determined distance between fibers of at least 20 um. Although the distribution of bioglass is discontinuous, the coating over the implant is not, as the adhesion of bioglass to the implant is done by the use of silicone as an adhesive, in other words, there is a continuous and non-bioabsorbable silicone coating over the implant which will not be eliminated and the newly formed tissue shall not interface with the implant.
Patent P10605628-8 relates to a product and acquisition process of a low-cost and mechanically resistant bioactive porous ceramic matrix, applicable to bone implants and grafts, in the following areas: Oral and maxillofacial, orthopedics and dentistry, composed of alumina (Al2O3), hydroxyapatite ([Ca10(PO4)6(OH)2] and bioglass (SiO2, Na2O, CaO, CaO/P2O5). This patent relates to the production of a porous alumina composite with addition of bioglass and hydroxyapatite infiltrated in the alumina pores. This product is applied to bone grafts and is not related to the present invention except for use of bioglass as a bioactive material.
No proposals were found for coating of solid substrates using discontinuous bioactive and bioabsorbable coatings in the form presented and, for this reason, the present invention features an innovative proposal. Note that in the proposals presented in this section, and which describe layers, interface between the implant and the newly formed tissue does not take place in any of the situations and at no point in the process after implantation, in other words, in all cases implants are coated with a continuous and non-bioabsorbable layer, which intends only to fix the biomaterial particles. It should also be noted that, despite the presence of biomaterial that stimulates tissue formation, permanent layers shall remain in place, whose interfaces may potentially lead to flaws in the implant.
The objective of the present invention is to grant typical bioactivity of biomaterials, such as bioglasses, to any non-bioactive solid substrate without the disadvantages of continuous coatings.
The deposition of the proposed discontinuous coating solves two critical problems: (1) metal surfaces such as titanium, for example, become bioactive, and (2) eliminates the inherent possibility of flaws of continuous bioceramic coatings over metallic implants due to the fact of being a layer to be fully consumed in the initial scarring stages. This ensures the newly formed tissue directly interfaces the implant and stimulates its formation in the initial scarring stages.
In addition to eliminate any eventual issue with the interface, bioglass dissolution process also stimulates the formation of the tissue, since bioglasses feature bone producing, bone inducing and angiogenic properties which accelerate bone integration, as well as anti-inflammatory and bacteriostatic characteristics which may reduce the occurrence of post-operative infections. All these properties of bioglass shall be present on the surface of the implant while the bioglass is not fully dissolved.
The invention relates to the development of a discontinuous coating of a biomaterial (which can be a bioceramic, a biopolymer or a bioactive composite), bioabsorbable and bioactive, applied on solid (smooth, rough or porous) substrates, in order to have interface of the newly formed tissue with the implant and local stimulation for growth of said tissue in the initial scarring stages. The coating has islands of biomaterial with equivalent diameter ranges between 1 and 1200 μm. For substrates with higher melting point than that of the biomaterial, particles shall adhere directly to the solid substrate due to the softening effect during the temperature increase in higher levels than the vitreous transition of the biomaterial. With substrates with lower melting point than the biomaterial particles, said particles shall adhere to its surface through use of a bioabsorbable polymer-based gel coating, preferably cellulose or collagen-based. In both cases, said coating shall be fully consumed in up to 10 days after implantation, in order to stimulate interface between the newly formed tissue and the implant, and acceleration of its initial formation.
The proposed discontinuous coating may be obtained through any method, which allows deposition of a continuous layer, once process parameters are duly adjusted, such as thermal spray, airbrushing or air atomizing, dip coating, drip coating and brush coating. The preferred method for applying this discontinuous layer is air atomizing. The reasons for this choice were: (1) low operational costs; (2) low complexity for use; (3) low residue generation; (4) minimal use of materials, which are not part of the production chain of dental or orthopedic implants, (5) safety, regarding use of non-hazardous materials or processes only, and (6) accuracy and reproducibility regarding the amount of deposited material. The thermal spray technique is an alternative for fixing biomaterial particles with lower melting point than the solid substrate. This technique generates cast biomaterial particles over the substrate, where they remain adhered.
The layer material can be any bioactive and bioabsorbable biomaterial, preferably bioglasses or bioabsorbable composites containing bioglasses, island-shaped, with size distribution in its final use form between 1 and 1200 μm and partially coating fractions of the surface of the solid substrate ranging from 2 to 80%.
The layer may be applied over any smooth, rough or porous solid substrate where, after the end of the initial tissue regeneration process, interface between the newly formed tissue and the substrate surface without a continuous layer of another material between these parts. Examples of use: dental, hip and knee implants, bone reconstruction plates, intervertebral spacers, pedicular screws of spinal implant systems, repair of anophthalmic sockets and any implantable solid substrate.
The invention relates to a discontinuous coating composed of a biomaterial (which can be a bioceramic, biopolymer or bioactive composite), bioabsorbable and bioactive applied over a solid substrate. It refers, therefore, to a discontinuous layer which will be absorbed by the body during the tissue scarring process which ensures a lack of interfaces (potential cause of flaws), and direct contact of the solid substrate (implant) with the newly formed tissue as shown schematically on
Material used: biomaterial in particle form, preferably bioglass.
Fixation method: temperature increase for situations in which the substrates have higher melting point than the biomaterial to be deposited and use of bioabsorbable polymeric gel as an adhesive substance for situations in which the substrates have lower melting point than the biomaterial to be deposited.
The definition of the amount of powder to be fixed to the surface is based on the answer to the following question: what is the minimum fraction of particles that produce, after a bioactivity test, a hydroxyapatite layer that coats 100% of the surface.
The results of these tests have shown that the range of precipitation of hydroxyapatite from the edge of the particles depends on the particle size distribution of the bioglass powder and its composition. For the bioglass used, the F18 bioglass, with a particle distribution between 10 and 100 um, this distance was approximately equal to the particle diameter, as seen in
Usage of other types of bioglass with various powder grain sizes changes the coated fraction, which leads to maximum formation of hydroxyapatite in the bioactivity test due to differences in particle speed dissolution. Thus, it was possible to determine that, if regions of bioactivity test with average diameter between 1 and 1200 μm coat surface fractions between 2 and 80%, the aforementioned condition (surface 100% coated by hydroxyapatite after bioactivity test) will be met.
Based on previously established criteria, five methods of transferring biomaterial to the solid substrate may be used:
1. Brush painting.
2. Drip coating
3. Dip Coating
4. Airbrushing or air atomizing.
5. Thermal spray.
Titanium discs with 10 mm diameter and 3 mm thickness were used in this example. The transfer of biomaterial to the surface of the solid substrate, or coating, used biomaterial particles with particle size distribution between 5 and 500 μm.
There is no information in the literature of the invention regarding the airbrushing method in the field of embodiment of this invention. For this reason, some parameters were necessary for this process in order to make it repeatable. Initially, the term “stroke” was established. In the graphic and art fields, in which the airbrush is extensively used, “stroke” refers to the pattern of the deposited paint—more or less dense, more or less wide, left by the airbrush in the work surface. In the current situation, the stroke shall be the particle deposition pattern over the titanium surface, characterized by the particle distribution and fraction delivered to the surface by the airbrush. This deposition pattern shall be determined by the following parameters:
1. Stroke density—average fraction of the surface area covered by the particles delivered to the surface during the first coating.
2. Final Stroke Density or work density—final average fraction of the surface area covered by the particles delivered to the surface. As many coatings as needed may be used to reach the final density.
3. Stroke Width—region in which the area fraction range covered by the particles delivered to the surface has the same values as the final stroke density.
The characteristics of the stroke used in this example are graphically presented in
Stroke Width: 1 to 40 mm
Stroke density: 1 to 5%
Work density for 4 coatings: 25 to 30%
Work density for 5 coatings: 45 to 50%
Work density for 6 coatings: 50 to 60%
Through
The other parameters used in airbrushing were:
Air pressure between 0.5 and 3 Pascal, preferably 1 Pascal,
Distance from the nozzle to the surface between 10 and 40 mm, preferably 20 mm,
Nozzle needle between 60 and 120 μm,
Applying speed between 5 and 100 mm/s,
For situations of dental implant coating, said implants must be positioned at a 0 to 45° horizontal angle and under rotation from 0.5 to 4 rpm,
Relative air humidity between 44 and 49%,
Temperature between 19 and 28° C.
The study of this example shows that it is possible to adjust a continuous layer production technique, such as airbrushing, in order to generate a discontinuous layer. Furthermore, it also shows that it is possible to project discontinuous layers with any biomaterial fraction. In this example, if generating discontinuous layers with 25% of the surface coated with bioglass is needed, 4 coatings should be applied.
The ability of bone-integrated dental implants to withstand loads depends on the quality and quantity of bone tissue connected to the implant that, in turn, is strongly influenced by the implant surface characteristics. Hydrophilic surfaces improve bone apposition and provide a quicker bone-implant contact.
Countless in vitro, in vivo and clinical results have shown the importance of this wetting or contact angle test for the dental implant field.
Table 1 shows the results of contact angle measurements for various conditions of the titanium surface.
From the samples coated with the F18 bioglass, the rough surface obtained through double acid etching featured the lowest contact angle. The angle value obtained was 5±2°.
Most implant surfaces available at the market have contact angles higher than 10°. A few examples, including one national version, have contact angles around 5°. Nevertheless, it is possible to find in the market an implant with zero contact angle, in other words, with full wetting and that leads to better bone integration results than surfaces with higher wetting angles. These implants are manufactured by a worldwide leading company in the manufacture of dental implants.
0.8 ± 0.6
Micro-indentations with 200 gf loads were generated on the surfaces of the bioglass islands fixed to the solid substrates. The objective was to quantitatively evaluate interface adhesion, an important parameter for placement dental implants. On
The objective of in vitro tests is to evaluate the biocompatibility of the biomaterial in a biological environment. Biocompatibility is related to the acceptance of a biomaterial by the nearby tissue and by the body as a whole, in other words, it determines if the performance of the biomaterial is compatible with the expectations and does not harm the patient/user.
Smooth titanium discs were coated by airbrushing as described in the section “Example of coating process of titanium discs through airbrushing” to be tested in vitro. Smooth titanium discs with no coating were tested for control purposes.
For in vitro tests, a strain of tumor cells established from human osteosarcoma, named SaOS-2 was used (origin: Banco de Celulas do Rio de Janeiro—BCBRJ).
The cytotoxicity evaluation was carried out through the MTT method, or metabolic oxidization of 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT of Sigma company—Saint Louis—MO—EUA) for 1, 3 and 5 days. The experiment was performed in triplicate.
The cell adhesion test evaluated the viability of cells adhered to the surface after 4 hours of incubation. After this time, samples were taken from the incubator and the cells were enzymatically detached from the titanium surfaces.
According to the results produced by the MTT test (
No significant statistical differences were observed between the tested samples—coated or not coated. For this reason, the coated surfaces analyzed have no cytotoxic effect, since according to the ISO 10993-5 standard “Biological evaluation of medical devices Part 5: Tests for in vitro cytotoxicity”, the cytotoxic effect is verified where there is reduction of at least 30% in cell viability in relation to the known pattern—which is pure titanium in this case.
The option for testing airbrushing coating on dental implants was due to its higher geometric complexity and reduced sizes in comparison to orthopedic implants, for example.
The implant coatings used the same parameters used for coating the aforementioned titanium discs.
It should be highlighted that, aside from smooth surfaced implants, implants with double acid-etched surfaces—or rough—were coated. This surface is the best surface currently available commercially. Rough surfaces coated with bioglass, as already presented, have excellent wetting (low contact angle), which is very desirable for a bone integrating implant.
The homogeneity analysis was based in approximately 200 images. Coated dental implants featured an average coating area of 25%.
As the dental implant is a “bone screw”, the ASTM F-543:2007 standard—Attachment A2 (“Test Method for Driving Torque of Medical Bone Screws”) was used as test reference. Based on this standard, the implant insertion was simulated, but under more severe test conditions. These conditions were: (1) test performed in both ways, in other words, insertion and removal of the implant; (2) the process was carried out on a dry basis and (3) on a material that emulates the cortical bone—denser, and generally present in just part of the insertion depth of the implant. Thus, it is expected that, if the coating withstands these test conditions, it will certainly withstand the real insertion process.
The parameters of this test, based on the ASTM F-543:2007 standard—Attachment A2, basically relate to the standardization of the test block. Thus, the testing parameters were:
Test block material: 40 degree polyurethane with equivalent density and properties to a cortical bone.
Block dimensions: 100 mm height, 40 mm diameter. The standard indicates that the lowest dimension must be higher than 10× the nominal diameter of the screw to be tested, and minimum 4.8 mm height.
Screw insertion hole: conditions as provided by the manufacturer—for this test, 2 mm up to a 9 mm depth and 2.8 mm up to a 7 mm depth, for a 3.5 mm diameter implant.
As evidenced on
The airbrushing coating process is viable for obtaining discontinuous coatings with any desired final fractions, as it was possible to project and produce coatings in an accurate and reproducible manner.
By this example of suitability of a method for obtaining a continuous layer—airbrushing—it may be stated that it is possible to obtain a discontinuous layer through any continuous layer deposition method, upon correct adjustment of the respective process parameters.
The addition of the F18 bioglass layer has generated a surface with a contact angle on par with the best implants currently on the world market, in other words, 0<5°.
The results obtained on in vitro tests show that the discontinuous layer obtained may provide significant improvements to the general performance of implants (specially orthopedic and dental implants).
The bioglass layer applied over the titanium dental implant surface was found to be very homogenous. The adhesion of particles to the metallic substrate was suitable, as the dental implant, although tested under more severe conditions than the real use conditions—from the viewpoint of shearing forces, showed no flaws on its layer.
| Number | Date | Country | Kind |
|---|---|---|---|
| BR1020140038175 | Feb 2014 | BR | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/BR2015/000029 | 2/18/2015 | WO | 00 |
