Antibiotic silver-carrying modified artificial coral bone and preparation method thereofTechnical field
The present invention relates to antibiotic silver-carrying modified artificial coral bone and preparation method thereof, is a kind of ideal anti-infection property artificial bone packing material.Be adapted at the application in bone wound surgery and the shaping reconstructive surgery.Belong to biomedical materials field,
Background technology
At present, few for the damaged Therapeutic Method of infectivity or contaminative bone clinically, take first debridement, drain usually, treat to carry out autologous bone transplanting once more after the infected wound healing.Treatment cycle is long, weak effect.Some scholars are also arranged, compound certain antibiotic of artificial bone is used for the treatment of infectivity or the contaminative bone is damaged, but it is limited because of antibiotic antimicrobial spectrum eventually, use and to make antibacterial produce antibody in about 3 days, cause albuminous degeneration, thereby the drug resistance phenomenon occurs, and infection is increased the weight of, be difficult to control more.This way has been proved to be one of important channel of clinical drug-resistant bacterial strain increase, is the method for running counter to rational Application antibiotics principle.
People find that very early silver ion has good bactericidal action.In ancient times, people use silverware storage water and food, can be effectively anticorrosion.Modern study shows that silver ion has stronger cell wall penetration power function, can enter in the nucleus of antibacterial, suppresses the synthetic of cell protein, plays the effect of killing bacteria.
But scientific research shows, excessive heavy metal element can cause body to be poisoned, even dead.Therefore, how grasping rational consumption is the content that is related to a key of personal safety.And the existence of silver ion also is the key factor that influences the material antibacterial action, experimental results show that.
Summary of the invention
First purpose of the present invention is for a kind of antibiotic silver-carrying modified artificial coral bone is provided, and this artificial bone had both kept good bone guided, the osteoinductive energy of common modified artificial bone of coral, can treat infection again simultaneously, avoids repeatedly performing the operation.
Second purpose of the present invention is for a kind of preparation method of antibiotic silver-carrying modified artificial coral bone is provided.
First purpose of the present invention can reach by taking following measure:
Antibiotic silver-carrying modified artificial coral bone, its construction features is: the modified artificial bone of coral by the controlled speed degraded is a carrier, silver ion microgranule in the micropore of described modified artificial bone of coral and in the outer surface absorption; The main component of the modified artificial bone of coral of described controlled speed degraded is calcium carbonate and hydroxyapatite, and the weight percentage of calcium carbonate is 30%～70%; The described modified artificial bone of coral that is adsorbed with the silver ion microgranule keeps original microcellular structure.
First purpose of the present invention can also reach by taking following measure:
One embodiment of the present invention are: described silver ion microgranule is made of cotton-shaped silver nitride precipitation.
One embodiment of the present invention are: described modified artificial bone of coral is the granule that surface adsorption has the silver ion microgranule.
One embodiment of the present invention are: described silver ion microgranule is formed the silver chloride flocculent deposit of band silver ion through chemical reaction by silver nitrate solution and sodium chloride solution.
One embodiment of the present invention are: described modified artificial bone of coral derives from natural coral, keep its, three-dimensional porous structure, its porosity is 10～90%, the aperture is 100～500um; Main component is carbon, oxygen, calcium, phosphorus, silver, wherein the content of the content of the content of the content of carbon≤40%, oxygen≤30%, calcium≤50%, phosphorus be≤50%, content≤5% of silver.
Second purpose of the present invention can reach by taking following measure:
The preparation method of foregoing antibiotic silver-carrying modified artificial coral bone is characterized in:
1) modified artificial bone of coral of preparation controlled speed degraded, the main component of the modified artificial bone of coral of described controlled speed degraded is calcium carbonate and hydroxyapatite, the weight percentage of calcium carbonate is 30%～70%;
2) the 1st) dry after the modified artificial bone of coral cleaning that the step makes, aforementioned modified artificial bone of coral is fully immersed in fills in the silver nitrate solution container vacuum and low temperature lyophilizing under the lucifuge condition then; Add sodium chloride solution after the lyophilizing, silver nitrate and sodium chloride chemically reactive form silver chloride flocculent deposit, cryogenic vacuum lyophilizing under the lucifuge condition again on the surface of modified artificial bone of coral and the surface of micropore;
3) with the 2nd) step make the product distill water dialysis, make the modified artificial bone of coral finished product of carrying silver ion.
Second purpose of the present invention can also reach by taking following measure:
One embodiment of the present invention are: the aforementioned the 2nd) Bu low temperature is meant-30 ℃～-70 ℃.
One embodiment of the present invention are: the aforementioned the 2nd) Bu vacuum is meant air molecule number≤107/ L.
One embodiment of the present invention are: the dense of aforementioned silver nitrate solution is 0.0001M～0.1M; The dense of sodium chloride solution is 0.0001M～0.1M.
One embodiment of the present invention are: aforementioned silver nitrate solution and sodium chloride solution
The present invention has following outstanding beneficial effect:
1, The present invention be directed to present infectivity and the damaged case of contaminative bone, overcome the shortcoming of common artificial bone, what find out can antimicrobial artificial bone packing material.Because silver ion is the surface that is adsorbed on modified artificial bone of coral with cotton-shaped silver nitride precipitation, therefore, can guarantee that degrade (in 7 days to 30 days) in silver ion is during reasonably, like this, can play effectively antibiotic, sterilization functions on the one hand, the infection once again of protecting from infection property and contaminative bone defect, on the other hand, can the sense of acceleration metachromia and the healing of contaminative bone defect.
2, the present invention is a carrier for utilizing modification Corallium Japonicum Kishinouye (calcium carbonate/hydroxyapatite complex) artificial bone with natural three-dimensional porous structure, contain the solution of silver ion and in addition under the situation of reactant solution concentration in control, adopt the way of cryogenic vacuum and chemical reaction, make the flocculent deposit that contains silver ion be deposited on the inside and outside micropore surface of modified artificial bone of coral, and don't influence the structure of micropore, obtain this kind material.In live body body fluid, the silver ion of antibiotic silver-carrying modified artificial coral bone slowly releases, the microenvironment metabolic activity around participating in, reach the effect of kill bacteria, and in the regular hour, discharge and finish, thereby do not influence normal cell growth, tissue repair, bone healing.
The specific embodiment
Embodiment 1:
To make modified artificial bone of coral by oneself and be prepared into 20 of 5mm * 5mm * 5mm cubic granules, the oven dry back is standby after the ultrasonic waves for cleaning, above-mentioned granule is fully immersed in fills in the 0.01M silver nitrate solution 10ml small beaker, vacuum and low temperature lyophilizing under the lucifuge condition, in beaker, add 0.01M sodium chloride 10ml, vacuum and low temperature lyophilizing under the lucifuge condition after the lyophilizing.The temperature of this low-temperature freeze drying is-30 ℃ ,-50 ℃ or-70 ℃.Obtain product and use distill water dialysis 24 hours, obtain being loaded with the modified artificial bone of coral of silver nitride precipitation.The weight percentage of calcium carbonate is 30%～70% in the described modified artificial bone of coral, and it derives from natural coral, keep its, three-dimensional porous structure, its porosity is 10～90%, the aperture is 100～500um.
Embodiment 2:
To make modified artificial bone of coral by oneself and be prepared into 20 of 5mm * 5mm * 5mm cubic granules, the oven dry back is standby after the ultrasonic waves for cleaning, above-mentioned granule is fully immersed in fills in the 0.005M silver nitrate solution 10ml small beaker, vacuum and low temperature lyophilizing under the lucifuge condition, in beaker, add 0.005M sodium chloride 10ml, vacuum and low temperature lyophilizing under the lucifuge condition after the lyophilizing.The temperature of this low-temperature freeze drying is-30 ℃ ,-50 ℃ or-70 ℃.Obtain product and use distill water dialysis 24 hours, obtain planting the modified artificial bone of coral of silver chloride.The main component of described modified artificial bone of coral is carbon, oxygen, calcium, phosphorus, silver, wherein the content of the content of the content of the content of carbon≤40%, oxygen≤30%, calcium≤50%, phosphorus be≤50%, content≤5% of silver.All the other are with embodiment 1.
Embodiment 3:
To make modified artificial bone of coral by oneself and be prepared into 20 of 5mm * 5mm * 5mm cubic granules, the oven dry back is standby after the ultrasonic waves for cleaning, above-mentioned granule is fully immersed in fills in the 0.001M silver nitrate solution 10ml small beaker, vacuum and low temperature lyophilizing under the lucifuge condition, in beaker, add 0.001M sodium chloride 10ml, vacuum and low temperature lyophilizing under the lucifuge condition after the lyophilizing.The temperature of this low-temperature freeze drying is-30 ℃ ,-50 ℃ or-70 ℃.Obtain product and use distill water dialysis 24 hours, obtain planting the modified artificial bone of coral of silver chloride.
The resulting silver-carrying modified artificial coral bone sample of above-mentioned 3 embodiment, carry out following detection:
Confirm through Guangzhou Geochemistry Inst., Chinese Academy of Sciences's scanning electron microscope: silver-carrying modified artificial coral bone, keep good three-dimensional porous structure, have good porosity and aperture; Surface adsorption an amount of silver chloride granules.
Confirm through Guangzhou Geochemistry Inst., Chinese Academy of Sciences's energy spectrum analysis: silver-carrying modified artificial coral bone, contain calcium, phosphorus and an amount of silver element.
Confirm through the X-ray diffraction analysis of test center of Zhongshan University: silver-carrying modified artificial coral bone is aragonite and hydroxyapatite complex.
Confirm through clinical laboratory of Guangzhou General Hospital Guangzhou Military Command Bacteriology Room: silver-carrying modified artificial coral bone all has good bactericidal action to escherichia coli clinical strain, staphylococcus aureus clinical strain, bacillus pyocyaneus clinical strain.
Confirm through the Medicine Experimental Section, Guangzhou General Hospital, Guangzhou Military Region Cytology Lab: its cytotoxicity is the 0-1 level, meets state food drug administration related standards.
Confirm through Guangzhou General Hospital Guangzhou Military Command clinical medicine pharmacology base: in the foregoing description vitro degradation properties, silver ion kept respectively 30 days, 16 days, 7 days.
Among other embodiment of the present invention: the dense of aforementioned silver nitrate solution is 0.0001M, 0.0008M, 0.003M, 0.008M, 0.05M, 0.08M or 0.1M; The dense of sodium chloride solution is 0.0001M, 0.0008M, 0.003M, 0.008M, 0.05M, 0.08M or 0.1M.Perhaps control silver nitrate in silver nitrate solution and the sodium chloride solution: sodium chloride=1: 2.All the other are with specific embodiment 1.
The present invention reaches the regulation and control of degradation rate by the ratio of control control calcium carbonate and hydroxyapatite.Concentration by control silver nitrate and sodium chloride solution, adopt the method for reacting under the vacuum, control the different silver ion contents in the resultant artificial bone, reach in desired time, slowly to discharge and finish, and guarantee to reach both kill bacteria, do not influence the clinical effectiveness of normal bone healing and tissue repair again.
Application example 1:
Silver-carrying modified artificial coral bone is applied in the femur infection model of experimental dog, experimental group bone defective region infects and disappears, and skeleton well heals; Matched group (common modified artificial bone of coral group) infects not control, and skeleton does not heal.
Application example 2:
Silver-carrying modified artificial coral bone is applied to the damaged case of the infectious bone of clinical tibia, and (male, 34 years old, firearm injury caused right fracture of tibia and fibula companion and infects) patient fractured in 3 months and well heals, and followed up a case by regular visits to 2 years, and it is good to suffer from the limb function, can operate as normal and life.
Application example 3:
Silver-carrying modified artificial coral bone is applied to the damaged case of the nearly infectious bone of section of clinical humerus, (male, 8 years old, the infectious bone of the nearly section of left humerus is damaged), patient fractured in 3 months and well heals, and followed up a case by regular visits to 3 years, it is good to suffer from the limb function, and artificial bone is well degraded, and the patient can normally learn and live.