KR101178939B1 - Dental Bone Graft Comprising 4-Hexylresorcinol and Implant Coating with the Same - Google Patents

Abstract

The present invention relates to a dental bone graft comprising 4-hexylresorcinol and an implant surface-treated with the bone graft. By using 4-hexylresorcinol as an additive in the present invention, compared to conventional dental implants, the antimicrobial activity and the activity of alkaline phosphatase in osteoblasts increased, and the adhesion of osteoblasts to the implant and implant surface And increased adhesion rate, and adhesion with bone significantly.

Hexyl resorcinol, bone graft, implant, hydroxyapatite

Description

Dental Bone Graft Comprising with Hexyl Resorcinol and Implant Coating with the Same

The present invention relates to a dental bone graft comprising 4-hexylresorcinol and an implant surface treated with a dental bone graft.

The first treatment considered as a remedy for the loss of teeth is the use of an implant. Factors affecting the success of the implant are similar to factors affecting the success of other bone grafts, which are affected by the patient's condition, the nature of the material used, and the skill of the operator. Patient conditions affecting the success rate include the age of the patient, the presence of systemic disease, the habit of the patient or the height or bone quality of the remaining alveolar bone. ^{As for 1,2,3} material factors, factors such as the diameter, length, shape and surface treatment of the material will influence the success rate. ⁴ operator technology is also an important factor affecting the success of the procedure. ⁵ Therefore, various techniques have been developed to increase the success rate of dental implants. Although the physical condition of the patient does not provide the ideal condition for the implant procedure, the success rate of the implant can be dramatically improved through the development of technology based on materials.

The implant surface is the main area in contact with the bone. The tight junction between the bone and the implant is a prerequisite for a successful implant. Therefore, by innovatively improving the surface of the implant to aid in the attachment and proliferation of osteoblasts, a close bond between the implant and the surrounding bone can occur quickly. Hydroxyapatite (HA) is the main component of bone and is used alone as a implant, and is also used for the surface treatment of implants. ^{9 There} are many reports on the success rate of implants coated with hydroxyapatite. ^10,11 Although papers with a good success rate account for the majority, there are similar concerns about hydroxyapatite as a coating material for dental implants, as well as concerns about the use of hydroxyapatite as a implant. The first problem is the concern about hydroxyapatite as a coating material. When hydroxyapatite is dissolved at a high temperature and then coated on the metal surface, the part where the interface is opened due to the difference in thermal expansion coefficient between the metal material and the hydroxyapatite material is cooled. Will happen. ¹² These cracks will act as physical weaknesses and cause frictional dropping during the placement of dental implants in the bone. This problem was overcome by the method of coating hydroxyapatite at room temperature. ^13,14

The second problem is that hydroxyapatite is a highly hydrophilic material, and this characteristic and the rough surface will synergize, providing ideal conditions for the attachment of microorganisms. Experimentally, various kinds of bacteria easily adhere to the surface of hydroxyapatite. ^According to the results of ^15,16 ophthalmic distribution, many cases of porous hydroxyapatite graft failure were reported to be caused by bacterial infection. ^17-19 The same is true in the case of an implant coated by hydroxyapatite, as well as hydroxyapatite implant materials. ²⁰

Since hydroxyapatite has many advantages such as inducing bone formation, inventing functional additives that can be mixed with hydroxyapatite may be used as an ideal graft or coating material with the advantages of conventional hydroxyapatite. Such attempts have been made in the past, a typical attempt being to make hydroxyapatite implants or coatings containing antibiotics. In many cases, however, implant coatings, including antibiotics, inhibited the action of osteoblasts or caused toxicity to osteoblasts, which interfered with adhesion between implants and bone. Therefore, it would be useful as an implant surface coating material if it can increase osteoblast adhesion and induce fast platelet formation when added to the implant surface material, while having antibacterial activity and using hydroxyapatite alone.

Throughout this specification many patent documents are referenced and their citations are indicated. The disclosures of the cited patent documents are hereby incorporated by reference herein in their entirety to better illustrate the state of the art to which the invention pertains and the teachings of the present invention.

The present inventors have tried to develop a functional additive that can be mixed and used in a conventional dental bone graft. As a result, the inventors of the present invention have prepared a 4-hexyl resorcinol-added bone graft or an implant surface-treated with the bone graft, thereby reducing the antibacterial and alkaline phosphatase activity in osteoblasts as compared to conventional dental grafts and implants. The present invention was completed by identifying significant increases in activity, an increase in the adhesion and rate of adhesion of osteoblasts to the surface of implants and implants, and adhesion to bone.

Accordingly, an object of the present invention is to provide a dental bone graft.

Another object of the present invention to provide an implant surface treatment of the dental bone graft.

Other objects and advantages of the present invention will become more apparent from the following detailed description of the invention, claims and drawings.

According to one aspect of the present invention, the present invention provides a dental bone graft comprising 4-hexylresorcinol.

The present inventors have tried to develop a functional additive that can be mixed and used in a conventional dental bone graft. As a result, the inventors of the present invention have prepared a 4-hexyl resorcinol-added bone graft or an implant surface-treated with the bone graft, thereby reducing the antibacterial and alkaline phosphatase activity in osteoblasts as compared to conventional dental grafts and implants. It has been found to significantly improve the activity, increase the adhesion and rate of adhesion of osteoblasts to the surface of implants and implants, and significantly improve adhesion to bone.

As used herein, the term “dental bone graft” refers to a graft material used to replace a bone tissue defect caused by various dental diseases, thereby filling the space in the bone tissue and promoting the formation of new bone.

In addition, the term “implant” refers to the replacement of the missing natural tooth itself, or a screw-shaped implant fixation to the alveolar bone, allowing it to fuse with the bone for a period of time and then abutment thereon. And it means a dental procedure that restores the original function of the teeth by fixing the prosthesis (crown), such as artificial teeth, in the present specification means the replacement of the natural tooth itself lost.

The IUPAC name of 4-hexylresorcinol included as an additive in the dental bone graft of the present invention is 4-hexylbenzene-1,3-diol and the formula As a compound, it is conventionally used in olive oil for the purpose of treating enteritis or recently added for the purpose of preventing discoloration of sea shrimp, but it has not been used as an additive for dental bone graft or dental implant coating material implanted in the human body. .

Formula 1

According to a preferred embodiment of the present invention, 4-hexyl resorcinol is included in the present invention at 0.01-10% by weight based on the total weight of the dental bone graft, more preferably 0.1-5% by weight, most preferably Preferably 0.1-2% by weight. When the weight of 4-hexyl resorcinol is less than 0.01% by weight, antimicrobial effect is difficult to expect, and when it exceeds 10% by weight, the effect of increasing the content is very small, but the stability of the formulation is secured. There is a problem that the coating is not well on the implant surface.

According to another preferred embodiment of the present invention, the bone graft of the present invention is selected from the group consisting of hydroxyapatite, monocalcium phosphate, tricalcium phosphate and silica, more preferably hydroxyapatite or tricalcium Phosphoric acid, most preferably hydroxyapatite.

In particular, hydroxyapatite is the same ingredient as the enamel of human bones and teeth, and has a great effect on the repair of enamel defects of teeth, and this restoration effect restores the original color of teeth. Is also in the limelight.

Dental bone graft material of the present invention can be used in the form of putty, paste, moldable strip, block, chip, etc., using methods such as compression, compression, pressure contact, packing, pressing, hardening, chemical additives It can be used in the form of gels, powders, pastes, tablets, pellets and the like, it is also possible to use as it is in powder form.

When the bone graft is formulated and used as described above, it is preferable to use a biologically active substance, and the growth factor for promoting bone growth as the biologically active substance, peptides and proteins for inducing bone tissue formation, fibrin, bone Morphogenic factors, bone growth agents, chemotherapeutic agents, antibiotics, analgesics, bisphosphonates, strontum salts, fluoride salts, magnesium salts, sodium salts and the like can be used.

The growth factors include bone morphogenic protein (BMP), platelet-derived growth factor (PDGF), transgenic growth factor (TGF-beta), insulin-like growth factor (IGF-I), IGF-II, and fibroblast growth factor (FGF). ) And BGDF-II (beta-2-microglobulin) can be used.

As the bone tissue formation enhancing peptides and proteins, various peptides including RGD sequences and various proteins such as collagen and fibronogen may be used.

As the bone morphogenesis factor, osteocalcin, headquarter alloprotein, bonesialo protein, osteogenin, BMP and the like can be used.

The bone growth agent may be used without limitation as long as it is harmless to the human body and promotes bone growth, and may use nucleic acids that promote bone formation, antagonists of substances that inhibit bone formation, and the like.

According to another aspect of the present invention, the present invention provides an implant surface-treated with the above-described dental bone graft.

When the dental bone graft of the present invention is treated on the implant surface, the dental graft can be used in various formulations, such as gels, powders, pastes, tablets, pellets, etc., preferably in powder form. Use as.

As used herein, the term “surface treatment” refers to various coating treatments known in the art to improve the surface of the implant.

Coating the dental bone graft of the present invention in the form of a thin film on the surface of the implant, it is coated by a known physical and chemical thin film deposition method, preferably pulsed laser deposition (PLD), sputtering (sputtering), chemical vapor deposition method (CVD), dip coating, plating, or 3D plasma gun deposition. When the pulsed laser deposition (PLD), sputtering, sputtering, chemical vapor deposition (CVD), plating (plating) and 3D plasma gun deposition method (3D plasma gun deposition) by rotating the implant or laser, spa While rotating the turing gun, crucible or plasma gun to be evenly coated on the outer circumferential surface, the dip coating method is to be coated by immersing the implant in a predetermined solution.

According to a preferred embodiment of the present invention, the implant of the present invention comprises implants of various materials known in the art, and more preferably uses titanium or a titanium alloy. Titanium alloys are Ti-6Al-4V, Ti-6Al-7Nb or Ti-13Nb-13Zr.

The features and advantages of the present invention are summarized as follows:

(a) The present invention provides a dental bone graft comprising 4-hexylresorcinol and an implant surface-treated with the dental bone graft.

(b) By using 4-hexylresorcinol as an additive, the antimicrobial activity and the activity of alkaline phosphatase in osteoblasts were increased as compared to conventional dental implants.

(c) It also significantly improved the adhesion and rate of adhesion of osteoblasts to the implant and implant surface, and adhesion to bone.

Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not to be construed as limiting the scope of the present invention. It will be self-evident.

Example

Throughout this specification, unless otherwise indicated, “%” used to indicate the concentration of a particular substance is solid / solid (weight / weight)%, solid / liquid (weight / volume)%, and Liquid / liquid is (volume / volume)%.

Materials and Methods

Cell culture and alkaline phosphatase ( alkaline phosphatase ) Activity Assay

MG63 cells; using (ATCC, Manassas, VA, USA osteoblasts (osteoblast like cell)) In In vitro tests were performed. 80% Cone in Dulbecco Modified Eagle's Medium (DMEM) -PAG (PAA Laboratories, Pasching, Austria), supplemented with 10% fetal bovine serum (PAA, Canada) and containing 1% penicillin / streptomycin (100X) The cells were propagated until fluence and stored at 37 ° C. under 5% CO ₂ and 99% humidity. The medium was changed three times a day. Protein concentrations of lysates determined by commercially available colorimetric assays (Anaspec, Fremont, CA, USA) were measured. The activity of alkaline phosphatase was measured using an alkaline phosphatase assay kit (Sigma, St. Louis, MO, USA), p-nitriphenyl depending on the activity of the enzyme at 37 ° C. and pH 10.2. The degree of conversion of phosphate to p-nitrophenol was evaluated by measuring absorbance.

Antimicrobial Test Method

A. Titanium Plate Coating

CP (commercially pure) titanium disks are coated with 0.3% 4-hexyl resorcinol (Sigma, USA) mixed with hydroxyapatite at room temperature, or 0.3% with hydroxyapatite Gentamicin (Kookje Inc., Seoul, South Korea) of the mixed material was coated or coated with hydroxyapatite alone. The coating process used a method of spraying fine powder on the surface of the metal to be coated in a vacuum at room temperature to adsorb to the surface. ²¹

B. Bacteria

Two periodontal pathogens ( Porphyromonas porphyromonas gingivalis , ATCC 49417 And Prevotella Intermedia intermedia , ATCC 25611) was purchased from KCTC (Korean Collection for Type Cultures, Daejeon, South Korea). And Staphylococcus aureus , ATCC 25923) was purchased from the American Type Culture Collection (Manassas, VA, USA). The porphyromonas ginjivalis And Prebotella intermedia was incubated with anaerobic Brain Heart Infusion broth containing 1.0 μg / ml Vit K1 and 5 μg / ml Hemin. Staphylococcus longus was then incubated on nutrient agar under aerobic conditions.

C. Screening of Antimicrobial Activity

Each bacteria was incubated and diluted with sterile medium at 0.5 absorbance at 450 nm. Porphyromonas Zinvivalis And 200 μl of bacterial solution was dispersed on agar agar plates supplemented with 5% sheep blood, 1.0 μg / ml Vit K1 and 5 μg / ml hemin for Prebotella intermedia. Staphylococcus longus was distributed on Mller hinton agar medium in the same manner. The antimicrobial activity was investigated in two ways. One was the disk diffusion method, after which the paper disc for antimicrobial test was soaked in a solution containing 4-hexyl resorcinol from 0.1 μg / ml to 10 mg / ml. As a positive control, a paper disc containing 30 μg of vancomycin (Ilyang Pharm, Yongin, Korea) was used as a method of applying the bacteria to the culture medium after drying. The second method uses nano-silver coated disks, HA-coated disks, Ti-disks, and 0.05, 0.1, and 0.3% 4-hexyl to determine whether the antimicrobial agent is released in the coated disks to help suppress bacterial growth. Three titanium discs coated with resorcinol were placed on each plate surface. The plates were reacted under anaerobic conditions at 37 ° C. for 2 days. In the case of Staphylococcus longus, the plates were reacted under 37 ° C. aerobic conditions for 1 day. The maximum inhibition zone diameter was measured in both experiments.

Electron microscopy

Animal testing

Animals and Experimental Materials

Ten four-month-old New Zealand rabbits with an average body weight of 2.7 kg (2.5-3.0 kg) were used in the experiments of the present invention. The experiment of the present invention was approved by the Animal Experimental Ethics Committee of the Bioventure Culture Center (National Hanbat University, Daejeon, Korea) (No. 2009-NCT-006).

Surgical Method

0.4 ml of ketamine (100 mg / ml) (Ketara; Yuhan, Seoul, South Korea) and 0.3 ml of xylazine (10 mg / kg body weight; Rompun; Bayer Korea, Seoul, General anesthesia was induced by intramuscular injection of a combination of Tibia area was shaved and disinfected with povidine-iodine. An incision was then made in the periosteum. A sharp subperiosteal dissection was performed to expose the tibial area. Two implants (diameter: 3.0 mm, length: 10.0 mm: MSP30103R, Osstem, Seoul, South Korea) were placed in one rat, one implanted with hydroxyapatite and the other with 0.3% 4-hexyl resorcinol. It was an implant coated with hydroxyapatite. Before placement of the implant on the tibial part 10 ⁴ pfu of implant concentration peri organisms own, Ill Martino Bacillus evil Martino Mai settem Cormier Tansu ^22: was a 10 minute exposure to (Actinobacillus Actinomycetemcomitans ATCC, USA). Two implants were then placed at 5 mm intervals. The periosteum and skin then filled the layer with 3-0 silk. Intramuscular injection of 1 mg / kg of gentamicin (Kookje Inc., Seoul, South Korea) was applied to rabbits three times a day for 3 days after surgery. Each rabbit was individually trapped and fed with feed and water. At 8 parking lots 10 rabbits were sacrificed. Ten implants from five rabbits were used for removal torque measurement. The maximum torque required to remove the implant was measured using a digital torque meter (D-1700, Emobile Tech, Seoul South Korea). Ten implants were fixed in 10 rabbits with 10% formalin and histomorphologic evaluation was performed.

Histomorphologic Evaluation

Sample preparation was carried out by the procedure described in the prior art. ²³ The samples were stained in villanueva bone staining solution (# 16280, Polysciences Inc., Warrington, PA, USA) for 7 days. After the dehydration process, samples were embedded in methylmethacylate resin (Polysciences Inc., Warrington, PA, USA). The sections were then cut along the long axis of the implant using a low speed diamond wheel saw. Finally, the sections were ground to a thickness of 30 μm. And digital images of the sections were taken using a digital camera (DP-20; Olympus, Tokyo, Japan).

Statistical analysis

Paired t-tests were used to compare the animal samples. Statistically significant levels were set to P <0.05.

Experiment result

Alkaline phosphatase ( alkaline phosphatase ) Active measurement result

As can be seen in Figure 1, MG-63 was placed on each disk and grown for 72 hours, after which the activity level of alkaline phosphatase was examined, and when the relative activity when grown without disk was set to 1, In the case of uncoated titanium discs, the activity was increased by about 3.5%, and when 0.3% of gentamicin was mixed with hydroxyapatite (HA + GM), the activity was decreased by about 2.7%. In comparison, when 0.3% of 4-hexyl resorcinol was mixed with hydroxyapatite (HA + HR), the activity was increased by 17.1%. This is statistically significant compared to HA + GM ( P <0.001).

In addition, as can be seen in Figure 2, MG-63 was added to the plate cultured without disk only 4-hexyl resorcinol and the activity of the alkaline phosphatase was examined, the continuous dose up to 20 μg / ml In proportion, the activity of alkaline phosphatase was increased.

Antibacterial test result

Figure 3 is a result of applying to the bacterial medium after wetting the antimicrobial to be tested on the antimicrobial test disk. The antimicrobial activity of 4-hexyl resorcinol against Actinobacillus actinomycettemcomitans showed that almost no inhibitory ring was observed at 0.1 and 1 μg, but distinct inhibitory ring was observed at 10 μg to 10 mg. From 100 μg, it showed stronger antimicrobial activity than 30 μg vancomycin. Meanwhile, the disc labeled C at the top left represents a disc containing 30 μg vancomycin used as a control. Almost the same results were obtained for the trials of Prebotella Intermedia. The position of the disk used for the test of Prebotella intermedia is the same as that of the disk used for the antibacterial test against Actinobacillus actinomycete thacomitans.

In general, in the case of hydroxyapatite containing an antimicrobial agent, the extent to which the antimicrobial agent is released from the surface will be an important factor in determining the antimicrobial activity. Therefore, the range of emission from the surface is limited when it contains a small amount of about 0.3%. Figure 4 is a photo of the titanium surface coated with hydroxide hepatite (HA) containing 4-hexyl resorcinol and analyzed the antimicrobial activity against porphyromonas jinjivalis, prebotella intermedia and Staphylococcus longus to be. HA coated disc containing 0.05% 4-hexyl resorcinol clockwise from top left, titanium disc without any coating, HA coated disc, HA coated disc with 0.3% silver nanoparticles, 0.3% 4- HA coated discs containing hexyl resorcinol, HA coated discs containing 0.1% 4-hexyl resorcinol. The only discs with transparent zones for all three strains were HA coated discs containing 0.3% 4-hexyl resorcinol.

Result of attachment of cells to disk

As can be seen in FIG. 5, MG-63 cells were placed in a disc coated with hydroxyapatite (HA) alone and in a disc containing 0.3% 4-hexyl resorcinol in hydroxyapatite (HA) and after 4 hours, a scanning electron microscope. As a result, the cell adhesion was hardly observed on the titanium metal surface coated with only hydroxyapatite (HA) alone, but a large number of cell adhesion could be observed on the titanium metal surface coated with HA containing 4-hexyl resorcinol. there was.

6 shows MG-63 cells in a disk coated with hydroxyapatite (HA) alone and a disk containing 0.3% 4-hexyl resorcinol in hydroxyapatite (HA) and photographed with a scanning electron microscope after 24 hours. As a photograph, the result showed that the cell density of 0.3% 4-hexyl resorcinol + HA was higher than that of hydroxyapatite (HA) alone.

When hexyl resorcinol exceeded 10%, the titanium metal surface was poorly coated when mixed with hydroxyapatite, and when it was less than 0.01%, antibacterial activity was hardly expected.

Removal torque ( removal torque Value measurement results

As can be seen in Figure 7, implants coated with 0.3% 4-hexyl resorcinol + HA and implants coated with hydroxyapatite (HA) alone side by side at 5 mm intervals in the condition of contaminated bacteria in the iliac bone of the same rabbit The torque value for implant removal after 8 weeks of implantation was measured, and 37.67 ± 8.23 N.cm was measured for hydroxyapatite and 65.67 ± for implant coated with 0.3% 4-hexyl resorcinol + HA. 1.99 Ncm was measured. Therefore, the removal torque value was increased statistically significant when 4-hexyl resorcinol contained in bacteria contaminated implants ( P <0.001). This means that when the bacteria are contaminated, implants coated with 0.3% 4-hexyl resorcinol + HA significantly increase bone adhesion compared to implants coated with hydroxyapatite (HA) alone.

Histomorphologic Evaluation Results

As can be seen in FIG. 8, implants coated with 0.3% 4-hexyl resorcinol + HA and implants coated with hydroxyapatite (HA) alone are placed side by side at 5 mm intervals in a state contaminated with bacteria in the iliac bone of the same rabbit. When the histologic findings were observed after 8 weeks, platelet formation was observed more extensively in the 0.3% 4-hexyl resorcinol + HA than the HA-only coating.

Thus, the addition of 4-hexyl resorcinol increases the antibacterial properties of hydroxyapatite implants, increases the activity of alkaline phosphatase in osteoblasts, helps the osteoblasts adhere quickly to the surface of implants, and implants in infection situations. And significantly increased adhesion to the bone.

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the same is by way of illustration and example only and is not to be construed as limiting the scope of the present invention. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.

References

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Figure 1 is a graph showing the activity of alkaline phosphatase (alkaline phosphatase) after raising 72 hours on the disk MG-63 cells. HA stands for hydroxyapatite, HR stands for 4-hexylresorcinol and GM stands for gentamicin.

2 is a graph showing the activity level of alkaline phosphatase when 4-hexyl resorcinol alone is administered to MG-63 cells.

3 is a photograph showing the antimicrobial activity of 4-hexylesorcinol against actinobacillus actinomycettemcomitans and the right is a photograph showing the antimicrobial activity against prebotella intermedia. The figures on the disc in the figure on the left indicate the amount of 4-hexyl resorcinol contained in the disc and the disc labeled C is the disc containing vancomycin used as a control.

4 is a photograph of titanium surface coated with hydroxide hexite (HA) containing 4-hexyl resorcinol and analyzed for antimicrobial activity against Porphyromonas jinjivalis, Pribotella intermedia and Staphylococcus longus. . HA coated disc containing 0.05% 4-hexyl resorcinol clockwise from top left, titanium disc without any coating, HA coated disc, HA coated disc with 0.3% silver nanoparticles, 0.3% 4- HA coated discs containing hexyl resorcinol, HA coated discs containing 0.1% 4-hexyl resorcinol. The only discs with transparent zones for all three strains were HA coated discs containing 0.3% 4-hexyl resorcinol.

Figure 5 shows a photograph taken with a scanning electron microscope 4 hours after the MG-63 cells into the disk. The photo on the right shows the results of cell attachment to the titanium metal surface coated with only hydroxyapatite (HA) alone, and the photo on the left shows the results of cell adhesion on the titanium metal surface coated with HA containing 4-hexylesorcinol.

Figure 6 shows a photograph taken with a scanning electron microscope 24 hours after the MG-63 cells into the disk. The photo on the right shows the cell density of a titanium metal surface coated only with hydroxyapatite (HA) alone, and the photo on the left shows the cell density of a titanium metal surface coated with HA containing 4-hexyl resorcinol.

7 is a graph showing the removal torque value of the implant after implanting the implant coated with 0.3% 4-hexyl resorcinol + HA and the implant coated with hydroxyapatite (HA) alone in the soil of the iliac bone of the rabbit to be.

FIG. 8 is a photograph showing the results of implantation of an implant coated with 0.3% 4-hexyl resorcinol + HA and an implant coated with hydroxyapatite (HA) alone in a soil contaminated with bacteria in the iliac bone of rabbits. to be.

Claims (8)

delete delete delete delete A composition for coating a dental implant for use in improving adhesion between an implant and a bone containing 4-hexylresorcinol as an active ingredient. The composition of claim 5, wherein the 4-hexyl resorcinol is included in an amount of 0.01 to 10% by weight based on the total weight of the composition. 6. A composition according to claim 5, wherein the composition comprises a host selected from the group consisting of hydroxyapatite, monocalcium phosphate, tricalcium phosphate and silica as a host. The method of claim 5, wherein the 4-hexyl resorcinol (i) increases the activity of alkaline phosphatase (ALP) in osteoblasts; (Ii) improving the adhesion and rate of adhesion of osteoblasts to the implant surface; And (iii) an activity of improving adhesion between the implant and the bone.

Images