CN111388761B - Application of gastrodin in medical titanium metal use in diabetes environment - Google Patents
Application of gastrodin in medical titanium metal use in diabetes environment Download PDFInfo
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- CN111388761B CN111388761B CN202010229501.2A CN202010229501A CN111388761B CN 111388761 B CN111388761 B CN 111388761B CN 202010229501 A CN202010229501 A CN 202010229501A CN 111388761 B CN111388761 B CN 111388761B
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- gastrodin
- titanium
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- bone
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Abstract
The application of gastrodin in the medical titanium metal implant in the diabetes environment. After the medical material is implanted into a human body, the tissue repair of a 'material-bone' interface mainly relates to the integration of new bone tissues and materials, wherein the biological activity and the function of osteoblasts responsible for osteogenic differentiation on the materials determine the osseointegration effect of the materials. The invention establishes an in vitro 'titanium-bone' interface model by carrying out osteoblast adhesion culture on the surface of medical titanium metal, and uses gastrodin with therapeutic dose for addition culture, thereby proving the improvement effect of the gastrodin on the biological function of the 'titanium-bone' interface osteoblasts in a diabetic environment. The invention solves the clinical problems that the diabetes environment causes oxidative stress damage to the osteoblasts at the titanium-bone interface, influences the biological function of cells and aggravates apoptosis damage, and finally leads to poor osseointegration and long-term loosening of the titanium metal implant in the prior art, so as to improve the stability of the medical titanium metal implant.
Description
Technical Field
The invention belongs to the field of medical biomaterials, and particularly relates to application of gastrodin in improving medical titanium metal osseointegration effect and long-term stability in a diabetic environment.
Background
Titanium is the bone implant material with the widest application range so far, however, the long-term instability rate of the titanium implant is obviously increased in some general metabolic disease people such as diabetics. Research shows that the loosening rate of the spinal screws of the diabetic patients is as high as 30 percent and 10 times of that of normal people. The long-term instability of titanium metal implants imposes a great burden on the family and society of patients. With the increasing number of diabetic patients, the need for internal fixation of such patients with titanium metal implants is increasing in clinical practice. Therefore, it is an urgent clinical problem to elucidate the mechanism of occurrence of instability of titanium metal implants and to take effective improvement measures accordingly.
Early studies have shown that the structural and functional damage of osteoblasts caused by excessive accumulation of Reactive Oxygen Species (ROS) at the interface between titanium metal and bone in diabetic environment is an important reason for the damage of interfacial osseointegration and the occurrence of instability of titanium metal implants. Currently, an effective solution is not available clinically for the core problem of the titanium metal implant loosening and instability caused by oxidative stress outbreak caused by diabetes. At present, oral hypoglycemic drugs or a method for controlling blood sugar by using insulin subcutaneous injection are mostly adopted to reduce the occurrence of looseness of the titanium metal implant. However, it is difficult to improve the interface local bone condition and the bonding strength in a short time for regulating blood sugar so as to meet the urgent need of the internal implant surgery.
The individual basic medical research improves the osseointegration effect of the material to a certain extent by compounding degradable or non-degradable biological coating materials such as silk fibroin, hydroxyapatite and the like on the surface of a titanium metal material, but the surface coating material has complex preparation process, higher cost and easy abrasion, and the safety of degradation products in vivo needs to be deeply researched. The antioxidant NAC is proved to have the function of improving osteoblast function in vitro cell experiments, however, the side effect of NAC on human cells for a long time is not clear and is expensive; some researchers try to improve the osseointegration effect of the titanium metal implant in the diabetic environment by using high molecular compounds such as resveratrol (patent CN 106176695A), however, the extraction cost of the compounds is extremely high, the purity and safety of artificial synthesis are still to be proved, and the current clinical application is limited. Therefore, a medicament or a compound which is easier to extract and prepare, can be massively produced and used for clinic needs to be found so as to solve the clinical problems of poor osseointegration and long-term loosening of the medical titanium metal implant in the diabetic environment.
Disclosure of Invention
The purpose of the invention is as follows: the invention provides application of gastrodin in a medical titanium metal implant in a diabetes environment, and aims to solve the clinical problems that the diabetes environment causes oxidative stress damage to osteoblasts at a titanium-bone interface, influences the biological function of cells and aggravates apoptosis damage, and finally leads to poor bone integration and long-term loosening of the titanium metal implant in the prior art so as to improve the stability of the medical titanium metal implant.
The technical scheme is as follows:
the application of gastrodin in the medical titanium metal implant in the diabetes environment.
The gastrodin is applied to the medicine of medical titanium metal implants in the diabetes environment and the materials of the implants.
The implant medicine is a medicine for promoting the osseointegration of the implant, a surface medicine coating of titanium metal, a medicine for promoting the adhesion state of the osteoblasts at the interface of the titanium-bone in the surface of the material, a medicine for improving the proliferation level of the osteoblasts at the interface of the titanium-bone in the diabetic environment, a medicine for promoting the osteogenic differentiation of the osteoblasts at the interface of the titanium-bone in the diabetic environment, a medicine for inhibiting the pathological apoptosis of the osteoblasts at the interface of the titanium-bone in the diabetic environment, a medicine for enhancing the oxidation stress resistance of the osteoblasts at the interface of the titanium-bone in the diabetic environment and a medicine for improving the osseointegration effect and long-term stability.
The implant can be made into tablet, capsule, powder, pill, granule, emulsion or injection.
The implant material is a functional composite material for loading gastrodin on the medical titanium metal implant in the environment of preparing diabetes.
The advantages and effects are as follows:
(1) after the medical material is implanted into a human body, the tissue repair of a 'material-bone' interface mainly relates to the integration of new bone tissues and materials, wherein the biological activity and the function of osteoblasts responsible for osteogenic differentiation on the materials determine the osseointegration effect of the materials. The invention establishes an in vitro 'titanium-bone' interface model by carrying out osteoblast adhesion culture on the surface of medical titanium metal, and uses gastrodin with therapeutic dose for addition culture, thereby proving the improvement effect of the gastrodin on the biological function of the 'titanium-bone' interface osteoblasts in a diabetic environment.
(2) The adhesion state of osteoblasts at a titanium-bone interface is improved; the proliferation level of osteoblasts at the interface of titanium and bone in the environment of diabetes is improved; the osteogenic differentiation capacity of osteoblasts is enhanced; inhibit the apoptosis damage of osteoblasts. The damage of oxidative stress caused by the diabetes environment to osteoblasts on the interface is reduced, and the oxidative stress resistance of the osteoblasts is enhanced; these directly demonstrate the therapeutic role played by gastrodin at the "titanium-bone" interface in the diabetic environment.
(3) The titanium-bone interface model in vivo is established by implanting a titanium metal material in the body of a large diabetic animal, and local tissues of the implanted material are administered in an injection mode, so that the effect of gastrodin on improving the osseointegration effect of the titanium metal implant in a diabetic environment is further proved.
(4) The gastrodin can be used as a medicine for systemically improving the physiological environment of diabetes mellitus by oral administration, intravenous infusion and the like, can also be used as a composite material component for functionally improving a titanium metal material to construct a medicine coating or a functional composite material, and enters local tissues around the material through slow release, so that a therapeutic effect is exerted, the osseointegration effect of the titanium metal implant in the diabetic environment is improved, and the occurrence of loosening and instability of a long-term implant is reduced.
(5) The current method for obtaining gastrodin by extraction is mature, has low price, is not limited by sources, can ensure sufficient medicine supply, and has lower production cost.
Drawings
FIG. 1 shows the effect of gastrodin on the adhesion morphology of osteoblasts on titanium metal surfaces in a diabetic environment (phalloidin staining);
FIG. 2 is a data analysis of the cell area of titanium metal surface osteoblasts in an environment with gastrodin affecting diabetes;
FIG. 3 is a data analysis of the cell density of titanium metal surface osteoblasts in an environment with gastrodin affecting diabetes;
FIG. 4 is a graph of the effect of gastrodin on the level of osteoblast proliferation on the surface of titanium in a diabetic environment;
FIG. 5 is a graph of the effect of gastrodin on osteogenic differentiation of osteoblasts on the surface of titanium in a diabetic environment;
FIG. 6 is a graph of the effect of gastrodin on apoptotic damage to osteoblasts on the titanium metal surface in a diabetic environment;
FIG. 7 is a data analysis of the effect of gastrodin on the apoptosis rate of osteoblasts on the surface of titanium metal in a diabetic environment;
FIG. 8 is a data analysis of the effect of gastrodin on the activity of osteoblast apoptosis pathway proteins on the surface of titanium metal in a diabetic environment;
FIG. 9 is a representative micro CT tomographic scan and partial three-dimensional reconstruction of the effect of gastrodin on osseointegration of titanium metal material implanted in diabetic animals;
FIG. 10 is a result of quantitative analysis of the effect of gastrodin on the formation of new bone in the titanium metal material implanted in diabetic animals;
FIG. 11 shows the biomechanical strength results of gastrodin affecting osseointegration of titanium metal materials implanted in diabetic animals;
FIG. 12 is a graph showing data analysis of the effect of gastrodin on the fluorescence level of 2',7' -dichloro-fluorescent yellow diacetate (DCF-DA) in osteoblasts on the surface of titanium in a diabetic environment;
FIG. 13 shows that gastrodin affects H in osteoblasts on titanium surface in diabetic environment2O2Data analysis of expression levels;
FIG. 14 is a data analysis of the effect of gastrodin on lipid peroxide (TBARS) expression levels in titanium metal surface osteoblasts in a diabetic environment;
FIG. 15 is a data analysis of gastrodin effect on superoxide dismutase (SOD) activity in osteoblasts on titanium metal surface in diabetic environment;
the data in the figures are all means ± standard deviation; represents the statistical difference compared with the normal group (P <0.05), # represents the statistical difference compared with the diabetes group (P <0.05), + represents the statistical difference compared with the diabetes group and +1 μ M gastrodin.
Detailed Description
The present invention will be explained in further detail with reference to examples.
Gastrodine, also known as gastrodine, is the most important active ingredient in the extract of Gastrodia elata Blume, has low cost and wide application, and has various classical pharmacological actions beneficial to human body, such as tranquilizing, treating diabetic peripheral neuropathy, improving blood supply, etc. Research shows that gastrodin can reduce the concentration of blood sugar, triglyceride and total cholesterol of diabetic mice, improve the activity of superoxide dismutase in cells, and show good clinical application prospect of antioxidant stress.
Diabetes causes excessive production of endogenous ROS in 'titanium-bone' interface cells, which leads to adhesion, proliferation and differentiation dysfunction of osteoblasts and aggravation of apoptosis injury, and is a key mechanism of titanium metal instability caused by diabetes.
The following embodiments of the present invention are provided, and it should be noted that the present invention is not limited to the following embodiments, and all equivalent changes based on the technical solutions of the present invention are within the protection scope of the present invention.
It should be noted that: the "diabetic environment" in the present invention refers to the use of diabetic serum extracted from diabetic animals for cell culture in examples 1 to 5, and refers to the use in diabetic sheep in example 6. The extraction process of the blood serum of the diabetes comprises the following steps: tetraoxypyrimidine (STZ) was injected into SD male rats weighing 200-250 g at a dose of 40mg/kg through the tail vein 1 time a day for 5 consecutive days. The fasting blood glucose of SD rats is measured 2 weeks after the last injection, and the fasting blood glucose of more than 300mg/dl is determined as the success of the model building of the diabetic animals. Blood of diabetic rats is collected by ventricles, diabetic serum is extracted by a standard serum separation method, and the diabetic serum is filtered and sterilized for later use.
The "diabetic environment" in the present invention is different from the "high sugar condition" in the general sense: the former refers to the real environment for the survival of cells in the body of a diabetic animal, the diabetes is a metabolic disease with complex pathological mechanism, and the serum of the diabetes has the abnormality of various components, such as the increase of blood sugar, the increase of oxidative stress level, the excessive accumulation of advanced glycation end products (AGEs), the content abnormality of various endocrine hormones such as insulin and the like, and the content abnormality of various blood fat components; in the in vitro experiment of the invention, the diabetic serum is directly extracted from the body of a diabetic animal to culture cells, so that the living environment of the cells in the in vivo environment of the diabetic animal can be simulated to the maximum extent; the term "high-sugar conditions" refers to simply increasing the glucose concentration in a liquid in which cells are cultured using normal serum, which is two concepts of the diabetic serum environment proposed in the present invention. The results of the studies obtained under these two different conditions are not equivalent. In-vivo experiments, a diabetic sheep is used as a diabetic big animal model, gastrodin intervention is carried out through local injection administration, the method is different from the method that a titanium metal material is implanted into a common diabetic rat or a diabetic rabbit, and the big animal can simulate the real local environment of a diabetic patient to the maximum extent.
Example 1:
the embodiment provides the application of gastrodin in preparing a medicine for improving the osteoblast adhesion function of a titanium-bone interface in a diabetes environment, namely the effect of gastrodin on improving the osteoblast adhesion state on the surface of titanium metal in the diabetes environment.
The experimental method comprises the following steps: cutting medical titanium metal into titanium sheets, polishing the surfaces of the titanium sheets, and cleaning and disinfecting the titanium sheets for later use. Primary osteoblasts of the skull of SD rat suckling mice were isolated and cultured with trypsin and passaged at 1X 104The cell density of each ml is inoculated on the surface of titanium metal in the same quantity, and an in vitro 'titanium-bone' interface model is established.
The method is divided into 5 groups:
1) normal serogroup (normal group);
2) diabetic serogroup (diabetic group);
3) diabetes + gastrodin 1 μ M;
4) diabetes mellitus + gastrodin 5 μ M;
5) diabetes mellitus + gastrodin 10 μ M.
On day 3 of culture, rhodamine-labeled phalloidin and DAPI were subjected to fluorescent staining on the osteoblast skeletons and nuclei, respectively, and observed and photographed using a laser confocal microscope. Pictures on three titanium sheets are collected in each group (the experiment is repeated for 3 times), 6 fields selected randomly on each titanium sheet are photographed, and two indexes of cell density and cell area of each group are subjected to statistical analysis by using Image J software. Comparing the difference between groups, and evaluating the influence of gastrodin on the adhesion morphology, the spreading area and the cell density of osteoblasts on the surface of titanium metal in a diabetes environment.
As a result: as shown in fig. 1, red is rhodamine-labeled cytoskeleton and blue is DAPI-labeled nuclei. The osteoblast skeletons cultured in the diabetic serum were disorganized and distorted compared to the normal control group, and as shown in fig. 1, the adhesion of osteoblasts to titanium metal was poor, and the osteoblast area in fig. 2 and the osteoblast density in fig. 3 were both significantly decreased. As shown in fig. 1-3, after gastrodin was added to the diabetic environment, the arrangement and adhesion state of osteoblast cytoskeleton were significantly improved. After 1 mu M gastrodin is added, the cell area and the cell density are both increased, and after 5 mu M gastrodin and 10 mu M gastrodin are added, the cell area and the cell density are obviously increased compared with 1 mu M gastrodin, but the two have no statistical difference.
And (4) analyzing results: the results show that the osteoblasts at the interface of titanium-bone are not well adhered to the surface of titanium metal due to the internal environment of diabetes, and the cell extension area and the cell density are reduced; the gastrodin with the concentration of 5 mu M or more can effectively improve the adhesion state of osteoblasts on the surface of titanium metal in the diabetic environment.
Example 2:
the embodiment provides the application of gastrodin in preparing a medicament for improving the proliferation and differentiation of 'titanium-bone' interface osteoblasts on the surface of a material in a diabetes environment, namely, the improvement effect of gastrodin on the proliferation capacity and osteogenic differentiation level of osteoblasts on the surface of titanium in the diabetes environment is provided.
The experimental method comprises the following steps: osteoblasts were seeded on the surface of the titanium plate and cultured, and the grouping was the same as in example 1. MTT detection was performed on the cells on the surface of the titanium plate on days 4 and 7 of culture, and ALP detection was performed on the cells on the surface of the titanium plate on day 7 of culture.
As a result: as shown in fig. 4 and 5, the proliferation and differentiation levels of osteoblasts in the diabetic group were significantly inhibited compared to the normal control group, while the proliferation and differentiation abilities of osteoblasts at different culture time points were significantly improved after adding gastrodin to the diabetic serum, and the proliferation and differentiation levels of osteoblasts were the highest and were not statistically different after adding 5 μ M gastrodin and 10 μ M gastrodin.
And (4) analyzing results: the results show that the gastrodin with the concentration of 5 mu M or more has obvious improvement effect on the proliferation and differentiation level of the 'titanium-bone' interface osteoblasts in the diabetic environment.
Example 3:
the embodiment provides the application of gastrodin in preparing the medicine for inhibiting pathological apoptosis of the osteoblasts on the titanium-bone interface in the diabetic environment, namely the protective effect of gastrodin on reducing the apoptosis damage of the osteoblasts on the surface of titanium metal in the diabetic environment.
The experimental method comprises the following steps: osteoblasts were seeded on a titanium metal surface and cultured, and the grouping was the same as in example 1. On day 7 of culture, double-label staining was performed using TUNEL and DAPI, and observation was performed using a confocal microscope; the activity of an apoptosis pathway protein Caspase-3 is detected by using a Caspase-3 kit, and the influence of gastrodin on the apoptosis level of osteoblasts in a diabetes environment is evaluated.
As a result: FIG. 6 shows the staining results for each set of apoptotic cells, with green images of TUNEL-labeled apoptotic nuclei. FIG. 7 is a statistical analysis of TUNEL staining, in which the osteoblast apoptosis ratio in the diabetic group was significantly increased, while the addition of gastrodin in the diabetic environment significantly decreased the apoptotic cell ratio, and the anti-apoptotic effects of 5. mu.M gastrodin and 10. mu.M gastrodin were strongest and there was no significant difference therebetween, compared with the normal control group. Caspase-3 activity assays in FIG. 8 show the same trend as TUNEL assays.
And (4) analyzing results: the results show that gastrodin can obviously reduce apoptosis damage of osteoblasts at a titanium-bone interface in a diabetic environment. Gastrodin with concentration of 5 μ M or above has obvious effect of relieving apoptosis injury of osteoblasts at titanium-bone interface in diabetic environment.
Example 4:
the embodiment provides the application of gastrodin in preparing the medicine for promoting the osseointegration of the medical titanium metal implant in the diabetic environment, namely the effect of the gastrodin in improving the osseointegration of the titanium metal implant implanted in the body of a diabetic animal.
The experimental method comprises the following steps: tetraoxypyrimidine (STZ) is intravenously injected into small-tailed Han sheep with weight of 50-60kg at the concentration of 60mg/kg (drug amount/weight), 1 time per day, and continuously for 5-7 days. And detecting the blood glucose concentration 3 weeks after the last injection, and determining that the model of the diabetic large animal is successfully made if the blood glucose concentration continuously exceeds 180mg/dL for subsequent experiments. Under the condition of surgical operation, porous titanium metal material with the diameter of 12mm, the height of 5mm, the porosity of about 70 percent and the pore diameter of about 350-400nm is implanted into the sheep iliac defect so as to establish an in-vivo titanium-bone interface model. After the diabetic sheep are anesthetized and skin prepared, the sheep are disinfected and paved by a conventional method. After the skin is cut and the sheep ilium platform is exposed, a cylindrical bone defect with the diameter of 12mm and the height of 5mm is drilled by using an electric drill, and the material is completely placed into the ilium bone. 4 pieces of material are placed into each side of the ilium, and the wound is sutured layer by layer. Dissolving gastrodine in physiological saline at different concentrations to prepare topical application to animals. Animals were randomized into 3 groups of 3 animals each:
1) a normal control group;
2) diabetes group: once every 2 days, 50ml of normal saline is locally injected into the ilium part of the sheep with diabetes;
3) diabetes + gastrodin 5 mg/kg: the gastrodin is prepared into 50ml of normal saline with the concentration of 5mg/kg and is locally injected to the ilium part of the sheep with diabetes after being taken for 2 days;
the materials are taken when the materials are implanted for 12 weeks, iliac samples containing the implanted materials are taken, the left iliac of each sheep is used for micro-CT scanning (GE company) detection, and the right iliac is used for biomechanical detection of material osseointegration. The bone ingrowth fraction (the new bone volume/the scaffold pore volume) of the titanium-bone interface is calculated by using micro CT scanning data, the vertical compression rigidity of the material combined with bone is measured by using a biomechanics tester, and the osseointegration effect of each group of titanium metal materials is comprehensively evaluated.
As a result: compared with normal animals, the titanium metal material in the diabetic animal body has poor bone ingrowth, the newborn bone number is remarkably reduced in fig. 10, and the vertical rigidity is remarkably reduced in biomechanical detection in fig. 11, which indicates that the material osseointegration effect is poor. After the gastrodin is administrated to the diabetic animals, the bone ingrowth fraction is obviously increased, the biomechanical strength is improved, and the difference has statistical significance.
And (4) analyzing results: the results show that the gastrodin can effectively improve the osseointegration effect of the titanium metal implant in the body of the diabetic animal and enhance the stability of the implant.
Example 5
In this example, different doses of gastrodin, positive control group NAC, and literature-reported optimal therapeutic dose of resveratrol and curcumin are added in the diabetic environment, and the fluorescence intensity and H of DCF in osteoblasts of the diabetic group2O2The influence of the level, the TBARS level and the SOD activity is compared and evaluated to evaluate the influence of gastrodin on the ROS level and the oxidation resistance in osteoblasts on the surface of titanium metal in a diabetic environment, and the application of the gastrodin in preparing a medicament for improving the oxidation stress damage resistance of the osteoblasts on a titanium-bone interface in the diabetic environment.
The experimental method comprises the following steps: inoculating osteoblast on the surface of titanium metal for culturing. On day 7 of culture, staining with DCFH-DA, H2O2The kit detects the content of reactive oxygen species in cells, TBARS staining is used for evaluating the level of lipid peroxide in the cells, SOD activity detection is used for evaluating the anti-oxidative damage capability, three parallel samples are made in each group, and the average values are taken for comparison.
The method is divided into 6 groups:
1) normal serogroup (normal group);
2) diabetic serogroup (diabetic group);
3) diabetes + gastrodin 1 μ M;
4) diabetes mellitus + gastrodin 5 μ M;
5) diabetes mellitus + gastrodin 10 μ M;
6) diabetes + NAC 20 mM;
7) diabetes mellitus + 250 μ M resveratrol;
8) diabetes + curcumin 500 μ M;
as a result: according to FIGS. 12-15, diabetic groups compared to normal controlsGroup comparison, DCF fluorescence intensity in osteoblasts on Material, H2O2The level and TBARS level are obviously increased, and the SOD activity is obviously reduced, which indicates that the diabetes environment causes oxidative stress damage of the osteoblasts at the interface of titanium and bone. After adding gastrodin, DCF fluorescence intensity and H2O2The level and TBARS level are obviously reduced, the SOD activity is obviously improved, and 5 mu M gastrodin and 10 mu M gastrodin both obviously reduce the oxidative stress level of interfacial osteoblasts and improve the antioxidant capacity. Although the DCF fluorescence level of the 10 mu M gastrodin group is not obviously different from that of the resveratrol and curcumin group, H2O2The level is obviously lower than that of a curcumin group, the TBARS level of a 10 mu M gastrodin group is obviously lower than that of a resveratrol group, a curcumin group and a 5 mu M gastrodin group, and the antioxidant capacity is stronger than that of a resveratrol group. Therefore, the 10 mu M gastrodin group in the diabetic environment has the strongest antioxidant improvement effect, and has similar action with the positive control group NAC.
And (4) analyzing results: the results show that in the diabetic environment, the gastrodin can effectively enhance the oxidation resistance of the osteoblast at the interface of titanium-bone and relieve the oxidative stress injury of the cells, and the effect of the 10 mu M gastrodin is superior to that of resveratrol and curcumin under the optimal therapeutic dose.
The application example 4 proves that the gastrodin can effectively improve the osseointegration effect of the titanium metal implant in the body of a diabetic animal and enhance the stability of the implant by applying the gastrodin to the preparation of the medicine for promoting the osseointegration of the medical titanium metal implant in the diabetic environment. The gastrodin can be used as a composite coating of a medical titanium alloy material for tissue local drug slow release and promoting the osseointegration of plants in the titanium alloy of diabetic patients, namely the gastrodin can be applied to a functional composite material of the plants in the medical titanium alloy under the condition of preparing diabetes, and the gastrodin can also be used as a surface drug coating or a composite material of the titanium alloy for improving the biological properties of the plants in the medical titanium alloy, so that the gastrodin plays a therapeutic role in tissue local and improves the osseointegration effect of the plant materials in the titanium alloy under the condition of diabetes.
Claims (4)
1. The application of gastrodin in preparing medicines or materials for medical titanium metal implants in diabetes environments.
2. The use of gastrodine in medical titanium metal implants in diabetic environments as claimed in claim 1, characterized in that: the implant medicine is a medicine for promoting the osseointegration of the implant, a surface medicine coating of titanium metal, a medicine for promoting the adhesion state of the osteoblasts at the interface of the titanium-bone in the surface of the material, a medicine for improving the proliferation level of the osteoblasts at the interface of the titanium-bone in the diabetic environment, a medicine for promoting the osteogenic differentiation of the osteoblasts at the interface of the titanium-bone in the diabetic environment, a medicine for inhibiting the pathological apoptosis of the osteoblasts at the interface of the titanium-bone in the diabetic environment, a medicine for enhancing the oxidation stress resistance of the osteoblasts at the interface of the titanium-bone in the diabetic environment and a medicine for improving the osseointegration effect and long-term stability.
3. The use of gastrodine in medical titanium metal implants in diabetic environments as claimed in claim 2, characterized in that: the implant can be made into tablet, capsule, powder, pill, granule, emulsion or injection.
4. The use of gastrodine in medical titanium metal implants in diabetic environments as claimed in claim 1, characterized in that: the implant material is a functional composite material for loading gastrodin on the medical titanium metal implant in the environment of preparing diabetes.
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