CN108434518B - Preparation method of traditional Chinese medicine monomer sequence slow-release osteogenic blood vessel calcium-phosphorus stent material - Google Patents
Preparation method of traditional Chinese medicine monomer sequence slow-release osteogenic blood vessel calcium-phosphorus stent material Download PDFInfo
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- CN108434518B CN108434518B CN201810513292.7A CN201810513292A CN108434518B CN 108434518 B CN108434518 B CN 108434518B CN 201810513292 A CN201810513292 A CN 201810513292A CN 108434518 B CN108434518 B CN 108434518B
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- 239000000463 material Substances 0.000 title claims abstract description 62
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- 239000000178 monomer Substances 0.000 title claims abstract description 28
- 230000002188 osteogenic effect Effects 0.000 title claims abstract description 22
- 239000003814 drug Substances 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
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- 230000033115 angiogenesis Effects 0.000 claims abstract description 11
- 239000000243 solution Substances 0.000 claims description 49
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical group [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims description 31
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- 239000001506 calcium phosphate Substances 0.000 claims description 23
- 229910000389 calcium phosphate Inorganic materials 0.000 claims description 23
- 235000011010 calcium phosphates Nutrition 0.000 claims description 17
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 14
- 239000002244 precipitate Substances 0.000 claims description 13
- 238000001035 drying Methods 0.000 claims description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 11
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- 238000003756 stirring Methods 0.000 claims description 10
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- 239000001110 calcium chloride Substances 0.000 claims description 8
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- 238000001816 cooling Methods 0.000 claims description 8
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- 238000000034 method Methods 0.000 claims description 8
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- 101100516503 Danio rerio neurog1 gene Proteins 0.000 claims description 7
- 101100364400 Mus musculus Rtn4r gene Proteins 0.000 claims description 7
- 101100516512 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) NGR1 gene Proteins 0.000 claims description 7
- 229910000397 disodium phosphate Inorganic materials 0.000 claims description 6
- 239000011574 phosphorus Substances 0.000 claims description 6
- 229910052698 phosphorus Inorganic materials 0.000 claims description 6
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- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 4
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- 239000008187 granular material Substances 0.000 claims description 2
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- SNKFFCBZYFGCQN-UHFFFAOYSA-N 2-[3-[3-[1-carboxy-2-(3,4-dihydroxyphenyl)ethoxy]carbonyl-2-(3,4-dihydroxyphenyl)-7-hydroxy-2,3-dihydro-1-benzofuran-4-yl]prop-2-enoyloxy]-3-(3,4-dihydroxyphenyl)propanoic acid Chemical compound C=1C=C(O)C=2OC(C=3C=C(O)C(O)=CC=3)C(C(=O)OC(CC=3C=C(O)C(O)=CC=3)C(O)=O)C=2C=1C=CC(=O)OC(C(=O)O)CC1=CC=C(O)C(O)=C1 SNKFFCBZYFGCQN-UHFFFAOYSA-N 0.000 abstract description 12
- SNKFFCBZYFGCQN-VWUOOIFGSA-N Lithospermic acid B Natural products C([C@H](C(=O)O)OC(=O)\C=C\C=1C=2[C@H](C(=O)O[C@H](CC=3C=C(O)C(O)=CC=3)C(O)=O)[C@H](OC=2C(O)=CC=1)C=1C=C(O)C(O)=CC=1)C1=CC=C(O)C(O)=C1 SNKFFCBZYFGCQN-VWUOOIFGSA-N 0.000 abstract description 12
- STCJJTBMWHMRCD-UHFFFAOYSA-N salvianolic acid B Natural products OC(=O)C(Cc1ccc(O)c(O)c1)OC(=O)C=Cc2cc(O)c(O)c3OC(C(C(=O)OC(Cc4ccc(O)c(O)c4)C(=O)O)c23)c5ccc(O)c(O)c5 STCJJTBMWHMRCD-UHFFFAOYSA-N 0.000 abstract description 12
- LLPWNQMSUYAGQI-QBQUQATFSA-N Ginsenoside R1 Natural products O([C@](CC/C=C(\C)/C)(C)[C@@H]1[C@H]2[C@@H](O)C[C@H]3[C@](C)([C@]2(C)CC1)C[C@H](O[C@@H]1[C@H](O[C@@H]2[C@@H](O)[C@@H](O)[C@@H](O)CO2)[C@@H](O)[C@H](O)[C@@H](CO)O1)[C@H]1C(C)(C)[C@@H](O)CC[C@]31C)[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 LLPWNQMSUYAGQI-QBQUQATFSA-N 0.000 abstract description 9
- LLPWNQMSUYAGQI-OOSPGMBYSA-N notoginsenoside R1 Chemical compound O([C@@](C)(CCC=C(C)C)[C@@H]1[C@@H]2[C@@]([C@@]3(C[C@@H]([C@H]4C(C)(C)[C@@H](O)CC[C@]4(C)[C@H]3C[C@H]2O)O[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O[C@H]2[C@@H]([C@@H](O)[C@H](O)CO2)O)C)(C)CC1)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O LLPWNQMSUYAGQI-OOSPGMBYSA-N 0.000 abstract description 9
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 24
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 24
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- 230000007547 defect Effects 0.000 description 18
- 230000000694 effects Effects 0.000 description 14
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- 239000008280 blood Substances 0.000 description 8
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- 239000011734 sodium Substances 0.000 description 7
- WMFHUUKYIUOHRA-UHFFFAOYSA-N (3-phenoxyphenyl)methanamine;hydrochloride Chemical compound Cl.NCC1=CC=CC(OC=2C=CC=CC=2)=C1 WMFHUUKYIUOHRA-UHFFFAOYSA-N 0.000 description 6
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- DHRRIBDTHFBPNG-UHFFFAOYSA-L magnesium dichloride hexahydrate Chemical compound O.O.O.O.O.O.[Mg+2].[Cl-].[Cl-] DHRRIBDTHFBPNG-UHFFFAOYSA-L 0.000 description 5
- 235000015097 nutrients Nutrition 0.000 description 5
- 230000008439 repair process Effects 0.000 description 5
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 4
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 4
- 239000011575 calcium Substances 0.000 description 4
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- 238000003501 co-culture Methods 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
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- LVXHNCUCBXIIPE-UHFFFAOYSA-L disodium;hydrogen phosphate;hydrate Chemical compound O.[Na+].[Na+].OP([O-])([O-])=O LVXHNCUCBXIIPE-UHFFFAOYSA-L 0.000 description 3
- 239000003102 growth factor Substances 0.000 description 3
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- 210000000963 osteoblast Anatomy 0.000 description 3
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- MWKXCSMICWVRGW-UHFFFAOYSA-N calcium;phosphane Chemical compound P.[Ca] MWKXCSMICWVRGW-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention relates to a preparation method of a traditional Chinese medicine monomer sequence slow-release osteogenic angiogenesis calcium-phosphorus stent material, which comprises the following steps: 1) preparing a calcium-phosphorus crystal bracket; 2) a slow-release osteogenic coating; 3) a slow-release angiogenic coating; 4) repeating the functional particles for 2-5 cycles, crystallizing, freeze-drying, and performing all operations in sterile environment; according to different clinical requirements, the calcium-phosphorus stent with the required size and shape is prepared. The invention has the beneficial effects that: carrying Chinese medicinal monomer components of salvianolic acid B and notoginsenoside R1 in order and circularly by using a low-temperature micro-nano microdeposition technology to construct a composite bionic calcium-phosphorus scaffold material capable of promoting osteogenesis and vascularization simultaneously; the low-temperature micro-nano micro-deposition technology is characterized in that a bionic coating prepared by the low-temperature micro-nano micro-deposition technology is utilized to form calcium-phosphorus micro-nano crystals in a buffer system, and the crystals can be condensed into a stent with certain strength at normal temperature.
Description
Technical Field
The invention relates to a preparation method of a traditional Chinese medicine monomer sequence slow-release osteogenic angiogenesis calcium-phosphorus stent material, which can be prepared into the calcium-phosphorus stent material widely applied to plastic surgery, trauma orthopedics and oral implantation repair and reconstruction operations, and belongs to the technical field of medical instruments.
Background
Repair of long-segment bone defects caused by trauma, tumors, inflammation, etc. is one of the most difficult problems facing clinicians. The difficulty of repairing long-section bone defect is mainly due to poor blood supply at the bone defect part, difficulty in growing new blood vessels and incapability of supplying nutrition in time, thereby influencing the osteogenesis effect. At present, the vascularization promotion of engineered bone is mainly achieved by a combined microsurgical technique, but the method provides blood transportation for the graft mainly through an exogenous way, and the effect of the method cannot meet the clinical requirement. The combination of growth factors (such as VEGF and BMP) can induce the formation of new blood vessels, but the high price and the high dosage of the growth factors cause side effects which limit the clinical application of the growth factors.
The degradability of the ideal bone repair scaffold material is consistent with the formation speed of new bones, and meanwhile, the new blood vessels can provide nutrients, stem cells and the like required in the osteogenesis process in time, so that the integration of the osteogenesis and the vascularization is further the key for repairing large-section bone defects. The traditional Chinese medicine monomer salvianolic acid B (SALB) has good angiogenesis activity, the notoginsenoside R1(NGR1) has good osteogenesis activity, the traditional Chinese medicine monomer has definite components and low price, so that the clinical use can obviously reduce the clinical treatment cost and relieve the economic burden of patients, and the bone filling material used clinically at present mainly comes from abroad, has high price and unsatisfactory osteogenesis effect, is slowly absorbed and is not easy to heal clinically, and the clinical action time is prolonged.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provides a preparation method of a traditional Chinese medicine monomer sequence sustained-release osteogenic blood vessel calcium phosphate scaffold material.
The preparation method of the traditional Chinese medicine monomer sequence slow-release osteogenic angiogenesis calcium-phosphorus stent material comprises the following steps:
1) preparing a calcium-phosphorus crystal scaffold:
1.1) taking 40.1-42.5g NaCL, 0.8-1.2g KCL and 1.2-1.5g CaCL22H2O，0.8-1.2gMgCL26H2O, dissolving the 4 parts of materials in ultrapure water simultaneously, stirring, adding 15-20 ml of 1mM HCl with the concentration of 1mM, and reducing the pH to 1.8-2 to obtain a solution I;
1.2) taking 0.3-0.4g of Na2HPO42H2Dissolving O in ultrapure water, namely solution II, and pouring the solution II into the solution I;
1.3) slowly pouring 4.5-5.5g of sodium bicarbonate into the solution I, and simultaneously dropwise adding 1mM of 1mM HCl to monitor the pH value of the solution to keep the pH value between 5.8 and 6.2 all the time;
1.4) finally adding ultrapure water, controlling the temperature at 36.5-37.5 ℃, and simultaneously monitoring the pH value for 12-14 hours;
1.5) generating a precipitate, removing supernatant, resuspending the precipitate with ultrapure water, centrifuging on a centrifuge, and repeating the cleaning steps for 4-5 times;
1.6) carrying out vacuum filtration by using a sterile filter, collecting the calcium phosphate obtained in the filter in a former, putting the former in an oven, and drying the support material to obtain an opalescent calcium phosphate support material;
2) slow-release osteogenic coating:
2.1) putting the calcium-phosphorus crystal bracket into a supersaturated calcium-phosphorus solution containing sterile NGR1, wherein the mixture ratio is as follows: 7-9g HCl; 0.33-0.4g Na2HPO4·2H2O；0.5-0.7g CaCl2·2H2O; 5-7 g; adding 35-45 ml of 1M HCL into the TRIS base to adjust the pH value to 7.35-7.45;
2.2) filtering the supersaturated solution by using a sterile filter, stirring for 36-48 hours, cooling to room temperature, collecting the stent material, ultrasonically treating for 5-10 seconds, washing by using ultrapure water, and drying in vacuum to form the NGR 1-calcium-phosphorus stent;
3) slow-release vascularization coating:
3.1) putting the NGR 1-calcium phosphate scaffold into a supersaturated calcium phosphate solution containing sterile SalB, wherein the mixture ratio is as follows: 7-9g HCl; 0.33-0.4g Na2HPO4·2H2O；0.5-0.7g CaCl2·2H2O; adding 5-7g of TRIS (hydroxymethyl) aminomethane (TRIS) base into 35-45 ml of 1M HCL to adjust the pH value to 7.35-7.45;
3.2) filtering the supersaturated solution by using a sterile filter, stirring for 36-48 hours, cooling to room temperature, collecting the stent material, ultrasonically treating for 5-10 seconds, washing by using ultrapure water, and drying in vacuum to form a SalB-NGR 1-calcium phosphate stent;
4) repeating the above functional granules for 2-5 cycles, crystallizing, lyophilizing, and performing all operations in sterile environment; according to different clinical requirements, the calcium-phosphorus stent with the required size and shape is prepared.
The use method of the traditional Chinese medicine monomer sequence slow-release osteogenic angiogenesis calcium-phosphorus stent material comprises the following steps:
1) when the support material is filled into the bone defect part, macrophages in blood phagocytose the coating on the surface of the material, and release salvianolic acid B and calcium and phosphorus slowly, the salvianolic acid B activates stem cells in the blood, so that angiogenesis is quickly induced, a vascular system is formed at the bone defect part, and blood circulation supplies nutrient components and raw materials to the bone defect part;
2) the coating continues to degrade while the notoginsenoside R1 is slowly released, stem cells brought by blood circulation are efficiently induced to differentiate into osteoblasts, and degraded calcium and phosphorus components are utilized to mineralize new bones at defect positions, so that structures such as new bone trabecula and the like can be compared with physiological bone structures.
The invention has the beneficial effects that the low-temperature micro-nano micro-deposition technology is used for orderly and circularly carrying the Chinese medicinal monomer components of salvianolic acid B and notoginsenoside R1 to construct the composite bionic calcium-phosphorus stent material capable of simultaneously promoting osteogenesis and vascularization. The low-temperature micro-nano micro-deposition technology is characterized in that a bionic coating prepared by the low-temperature micro-nano micro-deposition technology is utilized to form calcium-phosphorus micro-nano crystals in a buffer system, and the crystals can be condensed into a stent with certain strength at normal temperature. The bracket can realize the orderly carrying of the components of the Chinese medicinal monomers, is different from the traditional bracket sintering forming technology, and can better keep the activity of the Chinese medicinal monomers by the low-temperature micro-deposition technology. The notoginsenoside R1 and the salvianolic acid B are circularly loaded while the slow-release coating is formed, a petal-shaped circularly-interactive traditional Chinese medicine monomer structure is formed, the salvianolic acid B is slowly released while the calcium-phosphorus coating is dissolved, the formation of new blood vessels is promoted, and factors and nutrients necessary for stem cells and an osteogenesis process are brought by blood circulation. The calcium-phosphorus coating further dissolves and slowly releases notoginsenoside R1, which can better utilize stem cells from blood supply, efficiently induce the conversion of the stem cells to osteoblasts, and promote osteogenic mineralization and the formation of new bones. Bone morphogenetic protein BMP has been used clinically in recent years, but it is expensive, and its clinical use is affected by side effects such as excessive osteogenesis osteophytes (lack of angiogenisis), excessive activation of osteoclasts to cause bone lysis, and the like. The problem can be well solved by the slow release of the monomer sequence of the traditional Chinese medicine, the salvianolic acid B has good hemangiogenic activity to provide new bone energy and a stem cell source, and the notoginsenoside R1 has been used for treating bone defects for thousands of years in the traditional Chinese medicine, has almost no side effect, can not only continuously form bone, but also can prevent side effects such as bone dissolution and the like. The local slow release of the scaffold material can enable the osteogenesis and angiogenesis to be completed, the optimal osteogenesis induction effect is obtained, the formed new bone can be similar to the normal bone structure, in addition, the traditional Chinese medicine monomer compounded by the scaffold material is sourced from China, the source is wide, the price is low, and the clinical bone repair scaffold material with low cost and high bone inductivity is the urgent need of repairing large bone defects in China.
Drawings
FIG. 1 is a schematic diagram of a synthesis process;
FIG. 2 is a Scanning Electron Micrograph (SEM) showing a coral-shaped single layer of Chinese medicinal material;
FIG. 3 is a angiogram (left: control group, right: material group);
fig. 4 is an osteogenic mineralization map (left: control group, right: material group);
FIG. 5 is a MicroCT image of in vivo osteogenesis experiment showing the morphology of new bone;
FIG. 6 is a Scanning Electron Microscope (SEM) view showing a relatively uniform coral-shaped single layer of Chinese medicinal material;
FIG. 7 is a angiogram (left: control group, right: material group);
fig. 8 is an osteogenic mineralization map (left: control group, right: material group);
fig. 9 is a MicroCT image of in vivo osteogenesis experiment, showing the morphology of new bone.
Detailed Description
The present invention will be further described with reference to the following examples. The following examples are set forth merely to aid in the understanding of the invention. It should be noted that, for those skilled in the art, it is possible to make various improvements and modifications to the present invention without departing from the principle of the present invention, and those improvements and modifications also fall within the scope of the claims of the present invention.
The invention is divided into calcium phosphate crystal and slow release coating, under the action of osteoclast in organism, the calcium phosphate in the slow release coating releases traditional Chinese medicine monomer salvianolic acid B while degrading, acts on the bone defect part to promote angiogenesis, and brings stem cells and nutrient components in blood to the bone defect part after neovascularization. And the calcium-phosphorus coating is continuously degraded to slowly release notoginsenoside R1, stem cells in blood can be efficiently induced to differentiate towards an osteogenic direction, the degraded calcium and phosphorus are used as raw materials, trace components and factors in the blood provide nutrition, and finally bionic physical repair of the whole bone defect is efficiently completed.
The technical scheme adopted by the invention is as follows: the preparation method of the traditional Chinese medicine monomer sequence slow-release osteogenic blood vessel calcium phosphate stent material is characterized by comprising the following steps:
preparing a calcium-phosphorus crystal scaffold: the operation is carried out in a sterile clean bench. Collecting 40.1-42.5g sodium chloride (NaCL), 0.8-1.2g potassium chloride (KCL), and 1.2-1.5g calcium chloride hydrate (CaCL)22H2O), 0.8-1.2g magnesium chloride hydrate (MgCL)26H2O), the 4 parts of the above material are simultaneously dissolved in ultrapure water (MillQ water) and stirred, 15-20 ml of 1mM HCl (1mM HCl) are added, the pH is reduced to 1.8-2, this is solution one. Collecting 0.3-0.4g disodium hydrogen phosphate hydrate (Na)2HPO42H2O) was dissolved in 5 ml of ultrapure water (MillQ water), which was solution two, which was poured into solution one. 4.5-5.5g of sodium bicarbonate was slowly poured into the first solution while monitoring the pH of the solution by adding 1mM HCl (1mM HCl) dropwise to maintain the pH between 5.8-6.2. Finally, ultrapure water was added so that the total amount of the liquid became 1000ml, and the pH was monitored for 12 to 14 hours while controlling the temperature at 36.5 to 37.5 ℃ on a magnetic stirrer at a rotational speed (260 r/min). And (3) generating a precipitate, removing a supernatant, re-suspending the precipitate with ultrapure water for 5 minutes, centrifuging the precipitate for 5 minutes at 5000r/min by a centrifuge, repeating the cleaning steps for 4-5 times, performing vacuum filtration by using a 0.22-micron sterile filter, collecting the calcium phosphate obtained in the filter in a former (taking a self-made circular former with the diameter of 5mm as an example), putting the former in a 37-degree oven for 12 hours, and drying the support material to obtain a milky white calcium phosphate support material.
Slow-release osteogenic coating: the calcium phosphate crystal scaffolds were placed in 1000ml of supersaturated calcium phosphate solution (7-9g HCl; 0.33-0.4g Na; containing sterile 1mg,10mg,100mg,1g NGR1 (monomer component is clear and available)2HPO4·2H2O；0.5-0.7g CaCl2·2H2O; 5-7g Tris base [ Sigma ]]And adding 35-45 ml of 1M HCL to adjust the pH value to 7.35-7.45. Filtering the supersaturated solution by a 0.2-micron sterile filter), keeping the temperature at 37 ℃ and the rotating speed at 50 rpm, stirring for 36-48 hours, cooling to room temperature, collecting the stent material, performing ultrasonic treatment for 5-10 seconds, rinsing with ultrapure water, and performing vacuum drying to form the NGR 1-calcium phosphate stent.
Slow-release vascularization coating: placing NGR 1-calcium phosphate scaffold into sterile container0.1mg,1mg,10mg,100mg of SalB (monomer component is clear and available) in 1000ml of supersaturated calcium phosphorus solution (7-9g HCl; 0.33-0.4g Na)2HPO4·2H2O；0.5-0.7g CaCl2·2H2O; 5-7g Tris base [ Sigma ]]And adding 35-45 ml of 1MHCL to adjust the pH value to 7.35-7.45. Filtering the supersaturated solution by a 0.2-micron sterile filter), keeping the temperature at 37 ℃ and the rotating speed at 50 rpm, stirring for 36-48 hours, cooling to room temperature, collecting the stent material, ultrasonically treating for 5-10 seconds, washing with ultrapure water, and drying in vacuum to form the SalB-NGR 1-calcium phosphate stent.
The functional particles are repeated for 2-5 cycles, and the crystals are lyophilized for use, all operations being performed in a sterile environment (schematic synthesis 1). The calcium phosphate scaffold with the required size and shape can be prepared according to different clinical requirements.
When the support material is filled into the bone defect part, macrophages in blood phagocytose the coating on the surface of the material, and release salvianolic acid B and calcium phosphorus slowly, the salvianolic acid B activates stem cells in the blood, so that angiogenesis is quickly induced, a vascular system is formed at the bone defect part, and blood circulation supplies nutrient components and raw materials to the bone defect part. The coating continues to degrade while the notoginsenoside R1 is slowly released, stem cells brought by blood circulation are efficiently induced to differentiate into osteoblasts, and degraded calcium and phosphorus components are utilized to mineralize new bones at defect positions, so that structures such as new bone trabecula and the like can be compared with physiological bone structures.
The first embodiment is as follows:
preparing a calcium-phosphorus crystal scaffold: the operation is carried out in a sterile clean bench. Collecting 42g sodium chloride (NaCL), 1g potassium chloride (KCL), and 1.4g calcium chloride hydrate (CaCL)22H2O), 1g of magnesium chloride hydrate (MgCL)26H2O), the 4 parts of material described above are simultaneously dissolved in ultrapure water (MillQ water) and stirred, 18 ml of 1mM hydrogen chloride (1mM HCL) are added and the PH is reduced to 2, this being solution one. 0.35g of disodium hydrogenphosphate hydrate (Na) was taken2HPO42H2O) was dissolved in 5 ml of ultrapure water (MillQ water), which was solution two, which was poured into solution one. 5g of sodium bicarbonate was slowly poured into solution one, while 1mM HCl (1mM HCl) was added dropwise to monitor the dissolutionThe pH of the solution was kept at 6. The final addition of ultrapure water was carried out so that the total amount of liquid was 1000ml, the pH was monitored for 14 hours while controlling the temperature at 37 ℃ on a magnetic stirrer at a rotating speed (260 r/min). And (3) generating a precipitate, removing a supernatant, resuspending the precipitate with ultrapure water for 5 minutes, centrifuging the precipitate for 5 minutes at 5000r/min by a centrifuge, repeating the cleaning steps for 5 times, performing vacuum filtration by using a 0.22-micron sterile filter, collecting the calcium phosphate obtained in the filter in a former (taking a self-made circular former with the diameter of 5mm as an example), putting the former in a 37-DEG oven for 12 hours, and drying the support material to obtain an opalescent calcium phosphate support material.
Slow-release osteogenic coating: the calcium phosphate crystal scaffolds were placed in 1000ml of supersaturated calcium phosphate solution (8g HCl; 0.38g Na) containing sterile 100mg of NGR1 (monomer component explicitly available)2HPO4·2H2O；0.6g CaCl2·2H2O; 6g Tris base [ Sigma ]]40 ml of 1M HCl was added to adjust the pH to 7.4. Filtering the supersaturated solution by a 0.2-micron sterile filter), keeping the temperature constant and the rotating speed at 37 ℃ at 50 rpm, stirring for 48 hours, cooling to room temperature, collecting the stent material, ultrasonically treating for 5 seconds, rinsing with ultrapure water, and drying in vacuum to form the NGR 1-calcium phosphate stent.
Slow-release vascularization coating: NGR 1-calcium phosphate scaffolds were placed in 1000ml of supersaturated calcium phosphate solution (8g HCl; 0.38g Na) containing 10mg of sterile SalB (monomer component is clearly available)2HPO4·2H2O；0.6g CaCl2·2H2O; 6g Tris base [ Sigma ]]40 ml of 1M HCl was added to adjust the pH to 7.4. Filtering the supersaturated solution by a 0.2-micron sterile filter), keeping the temperature constant and the rotating speed at 37 ℃ at 50 rpm, stirring for 48 hours, cooling to room temperature, collecting the stent material, ultrasonically treating for 5 seconds, washing by ultrapure water, and drying in vacuum to form the SalB-NGR 1-calcium phosphate stent.
The functional particles are repeated for four cycles, crystallized and freeze-dried for later use, and all operations are carried out in a sterile environment.
In the example, a coral-shaped coating of the Chinese medicinal monomers is uniformly distributed on the surface of the stent under a scanning electron microscope (fig. 2). The slow-release calcium phosphate scaffold material is used in a system of umbilical vein endothelial cell-material co-culture and mesenchymal stem cell-material co-culture, and the material is found to have better and obviously different osteogenic and angiogenetic effects compared with a single calcium phosphate scaffold material (figures 3 and 4). The induced osteogenesis experiment in animal bodies shows that the osteogenesis amount is obviously better than that of the clinically used osteogenesis material, the osteogenesis effect is more obvious after six weeks, and MicroCT shows that the trabecular bone distance of the new bone is closer and the structure of the new bone is closer to that of the normal bone (figure 5).
Example two:
preparing a calcium-phosphorus crystal scaffold: the operation is carried out in a sterile clean bench. 40g of sodium chloride (NaCL), 0.8g of potassium chloride (KCL) and 1.2g of calcium chloride hydrate (CaCL)22H2O), 0.8g of hydrated magnesium chloride (MgCL)26H2O), the 4 parts of material described above were simultaneously dissolved in ultrapure water (MillQ water) and stirred, 16 ml of 1mM hydrogen chloride (1mM HCL) were added, the PH was reduced to 1.8, this was solution one. 0.3g of disodium hydrogenphosphate hydrate (Na) was taken2HPO42H2O) was dissolved in 5 ml of ultrapure water (MillQ water), which was solution two, which was poured into solution one. 4.5g of sodium bicarbonate was slowly poured into the first solution while the pH of the solution was monitored by the addition of 1mM HCl (1mM HCl) to maintain the pH at 5.8. Finally, ultrapure water was added so that the total amount of the liquid became 1000ml, and the pH was monitored for 12 hours while controlling the temperature at 36.5 ℃ on a magnetic stirrer at a rotating speed (260 r/min). And (3) generating a precipitate, removing a supernatant, resuspending the precipitate with ultrapure water for 5 minutes, centrifuging the precipitate for 5 minutes at 5000r/min by a centrifuge, repeating the cleaning steps for 5 times, performing vacuum filtration by using a 0.22-micron sterile filter, collecting the calcium phosphate obtained in the filter in a former (taking a self-made circular former with the diameter of 5mm as an example), putting the former in a 37-DEG oven for 12 hours, and drying the support material to obtain an opalescent calcium phosphate support material.
Slow-release osteogenic coating: the calcium phosphate crystal scaffolds were placed in 1000ml of supersaturated calcium phosphate solution (7g HCl; 0.34g Na2HPO 4.2H 2O; 0.55g CaCl 2.2H 2O; 5g Tris TRIS base [ Sigma ] added to 38 ml 1M HCl to adjust the pH to 7.35.0.2 μ M sterile filter to filter the supersaturated solution) containing sterile 1mg NGR1 (the monomer component is clearly available), stirred at constant temperature of 50 rpm at 37 ℃ for 48 hours, cooled to room temperature, the scaffolds were subjected to ultrasound for 5 seconds, rinsed with ultra pure water, and vacuum dried to form NGR 1-calcium phosphate scaffolds.
Slow-release vascularization coating: NGR 1-Ca-P stent was put into 1000ml of a supersaturated Ca-P solution containing 0.1mg of sterile SalB (the monomer component was clearly available) (7g of HCl; 0.34g of Na2HPO 4.2H 2O; 0.55g of CaCl 2.2H 2O; 5g of Tris TRIS base [ Sigma ] was added to 38 ml of 1M HCl to adjust the pH value to 7.35.0.2 μ M, and the supersaturated solution was filtered), and the mixture was stirred at a constant temperature of 50 rpm at 37 ℃ for 48 hours, cooled to room temperature, and then the stent material was ultrasonically treated for 5 seconds, rinsed with ultrapure water, and vacuum-dried to form a SalB-NGR 1-Ca-P stent.
The above functional particles are repeated for two cycles, crystallized and lyophilized for use, and all operations are performed in a sterile environment.
In example two, it can be seen by scanning electron microscope that coral-like Chinese medicinal monomer coating is relatively uniformly distributed on the surface of the stent (fig. 6). The slow-release calcium-phosphorus stent material is used in a system of umbilical vein endothelial cell-material co-culture and mesenchymal stem cell-material co-culture, and the material is found to have a good osteogenic and angiogenizing effect (figures 7 and 8). The induced osteogenesis experiment in animal bodies shows that the osteogenesis amount is large, the osteogenesis effect is more obvious after six weeks, and the bone trabecular structure of the new bone is similar to the physiological bone structure through MicroCT (micro computed tomography) (figure 9).
Claims (2)
1. A preparation method of a traditional Chinese medicine monomer sequence slow-release osteogenic angiogenesis calcium phosphate scaffold material is characterized by comprising the following steps: the method comprises the following steps:
1) preparing a calcium-phosphorus crystal scaffold:
1.1) taking 40.1-42.5g NaCL, 0.8-1.2g KCL and 1.2-1.5g CaCL22H2O，0.8-1.2g MgCL26H2O, dissolving the 4 parts of materials in ultrapure water simultaneously, stirring, adding 15-20 ml of 1mM HCL with the concentration of 1mM, and reducing the pH to 1.8-2 to obtain a solution I;
1.2) taking 0.3-0.4g of Na2HPO42H2Dissolving O in ultrapure water, namely solution II, and pouring the solution II into the solution I;
1.3) 4.5 to 5.5g of sodium bicarbonate is slowly poured into the solution I, and 1mM of 1mM HCl is dripped to monitor the pH value of the solution to be kept between 5.8 and 6.2 all the time;
1.4) finally adding ultrapure water, controlling the temperature at 36.5-37.5 ℃, and simultaneously monitoring the pH value for 12-14 hours;
1.5) generating a precipitate, removing supernatant, resuspending the precipitate with ultrapure water, centrifuging on a centrifuge, and repeating the cleaning steps for 4-5 times;
1.6) carrying out vacuum filtration by using a sterile filter, collecting the calcium phosphate obtained in the filter in a former, putting the former in an oven, and drying the support material to obtain an opalescent calcium phosphate support material;
2) slow-release osteogenic coating:
2.1) putting the calcium-phosphorus crystal bracket into a supersaturated calcium-phosphorus solution containing sterile NGR1, wherein the mixture ratio is as follows: 7-9g HCl; 0.33-0.4g Na2HPO4·2H2O；0.5-0.7g CaCl2·2H2O; 5-7 g; adding 35-45 ml of 1M HCL into the TRIS base to adjust the pH value to 7.35-7.45;
2.2) filtering the supersaturated solution by using a sterile filter, stirring for 36-48 hours, cooling to room temperature, collecting the stent material, ultrasonically treating for 5-10 seconds, washing by using ultrapure water, and drying in vacuum to form the NGR 1-calcium-phosphorus stent;
3) slow-release vascularization coating:
3.1) putting the NGR 1-calcium phosphate scaffold into a supersaturated calcium phosphate solution containing sterile SalB, wherein the mixture ratio is as follows: 7-9g HCl; 0.33-0.4g Na2HPO4·2H2O；0.5-0.7g CaCl2·2H2O; adding 5-7g of TRIS (hydroxymethyl) aminomethane (TRIS) base into 35-45 ml of 1M HCL to adjust the pH value to 7.35-7.45;
3.2) filtering the supersaturated solution by using a sterile filter, stirring for 36-48 hours, cooling to room temperature, collecting the stent material, ultrasonically treating for 5-10 seconds, washing by using ultrapure water, and drying in vacuum to form a SalB-NGR 1-calcium phosphate stent;
4) repeating the above functional granules for 2-5 cycles, crystallizing, lyophilizing, and performing all operations in sterile environment; according to different clinical requirements, the calcium-phosphorus stent with the required size and shape is prepared.
2. The preparation method of the traditional Chinese medicine monomer sequence slow-release osteogenic angiogenesis calcium phosphate scaffold material according to claim 1, which is characterized in that: respectively putting the calcium phosphate crystal bracket into 1000ml of supersaturated calcium phosphate solution containing 1mg,10mg,100mg and 1g of sterile NGR1 in the step 2.1); step 3.1) NGR 1-calcium phosphate scaffold was put into 1000ml of supersaturated calcium phosphate solution containing sterile SalB of 0.1mg,1mg,10mg,100mg, respectively.
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Effective date of registration: 20200103 Address after: 311217 Room 301, block B, Chuang Chuang, Xinzhong street, Xinjie street, Xiaoshan, Hangzhou, Zhejiang. Applicant after: HANGZHOU HUIBO TECHNOLOGY Co.,Ltd. Address before: 510632 Whampoa West Road, Guangdong, Guangzhou, No. 601, No. Applicant before: Lin Zhen |
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Inventor after: Lin Zhen Inventor after: Liu Yi Inventor after: Wang Jing Inventor after: Du Jiang Inventor before: Liu Yi Inventor before: Lin Zhen Inventor before: Wang Jing Inventor before: Du Jiang |
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Denomination of invention: Preparation method of calcium phosphate scaffold material for sustained release osteogenesis and vascularization of traditional Chinese medicine monomer sequence Effective date of registration: 20221030 Granted publication date: 20200207 Pledgee: Zhejiang Xiaoshan Rural Commercial Bank Co.,Ltd. Development Zone sub branch Pledgor: HANGZHOU HUIBO TECHNOLOGY Co.,Ltd. Registration number: Y2022330002852 |