CN111381018A - Simulation liquid and method for in-vitro detection of zinc-containing medical instrument - Google Patents
Simulation liquid and method for in-vitro detection of zinc-containing medical instrument Download PDFInfo
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- CN111381018A CN111381018A CN201811641085.6A CN201811641085A CN111381018A CN 111381018 A CN111381018 A CN 111381018A CN 201811641085 A CN201811641085 A CN 201811641085A CN 111381018 A CN111381018 A CN 111381018A
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- Prior art keywords
- zinc
- containing medical
- medical device
- solution
- simulation
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- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 title claims abstract description 368
- 239000011701 zinc Substances 0.000 title claims abstract description 368
- 229910052725 zinc Inorganic materials 0.000 title claims abstract description 368
- 239000007788 liquid Substances 0.000 title claims abstract description 73
- 238000004088 simulation Methods 0.000 title claims abstract description 66
- 238000000338 in vitro Methods 0.000 title claims abstract description 57
- 238000000034 method Methods 0.000 title claims abstract description 40
- 238000001514 detection method Methods 0.000 title claims abstract description 21
- 230000007797 corrosion Effects 0.000 claims abstract description 154
- 238000005260 corrosion Methods 0.000 claims abstract description 154
- 238000004140 cleaning Methods 0.000 claims abstract description 54
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 claims abstract description 28
- 210000004369 blood Anatomy 0.000 claims abstract description 28
- 239000008280 blood Substances 0.000 claims abstract description 28
- 210000002966 serum Anatomy 0.000 claims abstract description 25
- 239000002609 medium Substances 0.000 claims abstract description 24
- 239000006174 pH buffer Substances 0.000 claims abstract description 4
- 239000000126 substance Substances 0.000 claims abstract description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 20
- 238000012360 testing method Methods 0.000 claims description 16
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 14
- 239000008139 complexing agent Substances 0.000 claims description 13
- 239000000022 bacteriostatic agent Substances 0.000 claims description 9
- 239000006172 buffering agent Substances 0.000 claims description 9
- 239000012530 fluid Substances 0.000 claims description 9
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 claims description 8
- 239000004471 Glycine Substances 0.000 claims description 7
- BELBBZDIHDAJOR-UHFFFAOYSA-N Phenolsulfonephthalein Chemical compound C1=CC(O)=CC=C1C1(C=2C=CC(O)=CC=2)C2=CC=CC=C2S(=O)(=O)O1 BELBBZDIHDAJOR-UHFFFAOYSA-N 0.000 claims description 7
- 238000001479 atomic absorption spectroscopy Methods 0.000 claims description 7
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 7
- 229960003531 phenolsulfonphthalein Drugs 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 6
- 150000001413 amino acids Chemical class 0.000 claims description 5
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims description 4
- 229930182555 Penicillin Natural products 0.000 claims description 4
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 claims description 4
- AYBSICMEDZIQTK-UHFFFAOYSA-K dipotassium sodium phosphoric acid phosphate Chemical compound [Na+].[K+].[K+].OP(O)(O)=O.[O-]P([O-])([O-])=O AYBSICMEDZIQTK-UHFFFAOYSA-K 0.000 claims description 4
- 229940049954 penicillin Drugs 0.000 claims description 4
- BUCIWTBCUUHRHZ-UHFFFAOYSA-K potassium;disodium;dihydrogen phosphate;hydrogen phosphate Chemical compound [Na+].[Na+].[K+].OP(O)([O-])=O.OP([O-])([O-])=O BUCIWTBCUUHRHZ-UHFFFAOYSA-K 0.000 claims description 4
- 229960005322 streptomycin Drugs 0.000 claims description 4
- SPOMEWBVWWDQBC-UHFFFAOYSA-K tripotassium;dihydrogen phosphate;hydrogen phosphate Chemical compound [K+].[K+].[K+].OP(O)([O-])=O.OP([O-])([O-])=O SPOMEWBVWWDQBC-UHFFFAOYSA-K 0.000 claims description 4
- LEAHFJQFYSDGGP-UHFFFAOYSA-K trisodium;dihydrogen phosphate;hydrogen phosphate Chemical compound [Na+].[Na+].[Na+].OP(O)([O-])=O.OP([O-])([O-])=O LEAHFJQFYSDGGP-UHFFFAOYSA-K 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 claims description 3
- 229910021538 borax Inorganic materials 0.000 claims description 3
- 238000004737 colorimetric analysis Methods 0.000 claims description 3
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 3
- KFGJICJPSZZEEP-UHFFFAOYSA-L dipotassium;hydrogen phosphate;hydrate Chemical compound O.[K+].[K+].OP([O-])([O-])=O KFGJICJPSZZEEP-UHFFFAOYSA-L 0.000 claims description 3
- CBMPTFJVXNIWHP-UHFFFAOYSA-L disodium;hydrogen phosphate;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [Na+].[Na+].OP([O-])([O-])=O.OC(=O)CC(O)(C(O)=O)CC(O)=O CBMPTFJVXNIWHP-UHFFFAOYSA-L 0.000 claims description 3
- LVXHNCUCBXIIPE-UHFFFAOYSA-L disodium;hydrogen phosphate;hydrate Chemical compound O.[Na+].[Na+].OP([O-])([O-])=O LVXHNCUCBXIIPE-UHFFFAOYSA-L 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N hydrochloric acid Substances Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 3
- 238000009616 inductively coupled plasma Methods 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 239000006179 pH buffering agent Substances 0.000 claims description 3
- LJSOLTRJEQZSHV-UHFFFAOYSA-L potassium;sodium;hydron;hydroxide;phosphate Chemical compound [OH-].[Na+].[K+].OP(O)([O-])=O LJSOLTRJEQZSHV-UHFFFAOYSA-L 0.000 claims description 3
- BHZOKUMUHVTPBX-UHFFFAOYSA-M sodium acetic acid acetate Chemical compound [Na+].CC(O)=O.CC([O-])=O BHZOKUMUHVTPBX-UHFFFAOYSA-M 0.000 claims description 3
- 239000004328 sodium tetraborate Substances 0.000 claims description 3
- HXMWJLVXIHYART-UHFFFAOYSA-M sodium;2-hydroxypropane-1,2,3-tricarboxylic acid;hydroxide;hydrochloride Chemical compound [OH-].[Na+].Cl.OC(=O)CC(O)(C(O)=O)CC(O)=O HXMWJLVXIHYART-UHFFFAOYSA-M 0.000 claims description 3
- 238000004611 spectroscopical analysis Methods 0.000 claims description 3
- 238000004448 titration Methods 0.000 claims description 3
- XPFJYKARVSSRHE-UHFFFAOYSA-K trisodium;2-hydroxypropane-1,2,3-tricarboxylate;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [Na+].[Na+].[Na+].OC(=O)CC(O)(C(O)=O)CC(O)=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O XPFJYKARVSSRHE-UHFFFAOYSA-K 0.000 claims description 3
- 239000001963 growth medium Substances 0.000 claims description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 claims 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- VWSFKUZDFAQMNX-UHFFFAOYSA-K trisodium 2-hydroxypropane-1,2,3-tricarboxylic acid phosphate Chemical compound P(=O)([O-])([O-])[O-].[Na+].C(CC(O)(C(=O)O)CC(=O)O)(=O)O.C(CC(O)(C(=O)O)CC(=O)O)(=O)O.[Na+].[Na+] VWSFKUZDFAQMNX-UHFFFAOYSA-K 0.000 claims 1
- 238000001727 in vivo Methods 0.000 abstract description 32
- 210000002381 plasma Anatomy 0.000 abstract description 20
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 238000012827 research and development Methods 0.000 abstract description 2
- 238000010998 test method Methods 0.000 abstract description 2
- 238000013461 design Methods 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 133
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- 238000000576 coating method Methods 0.000 description 23
- 210000001519 tissue Anatomy 0.000 description 21
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 20
- 150000002332 glycine derivatives Chemical class 0.000 description 19
- 239000011248 coating agent Substances 0.000 description 17
- 239000011159 matrix material Substances 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 241000283973 Oryctolagus cuniculus Species 0.000 description 14
- 210000000702 aorta abdominal Anatomy 0.000 description 13
- 210000004204 blood vessel Anatomy 0.000 description 13
- 229960000448 lactic acid Drugs 0.000 description 12
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 12
- 229910052742 iron Inorganic materials 0.000 description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 239000008055 phosphate buffer solution Substances 0.000 description 8
- 239000007943 implant Substances 0.000 description 7
- 239000000758 substrate Substances 0.000 description 7
- 230000002792 vascular Effects 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 6
- 229910052751 metal Inorganic materials 0.000 description 6
- 239000002184 metal Substances 0.000 description 6
- 239000000463 material Substances 0.000 description 5
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 description 4
- 229910001297 Zn alloy Inorganic materials 0.000 description 4
- 235000001014 amino acid Nutrition 0.000 description 4
- 229940024606 amino acid Drugs 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 230000029087 digestion Effects 0.000 description 4
- DBLXOVFQHHSKRC-UHFFFAOYSA-N ethanesulfonic acid;2-piperazin-1-ylethanol Chemical compound CCS(O)(=O)=O.OCCN1CCNCC1 DBLXOVFQHHSKRC-UHFFFAOYSA-N 0.000 description 4
- 239000008103 glucose Substances 0.000 description 4
- 229910017604 nitric acid Inorganic materials 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 3
- 229930182816 L-glutamine Natural products 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 2
- 102000009123 Fibrin Human genes 0.000 description 2
- 108010073385 Fibrin Proteins 0.000 description 2
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 2
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 208000007536 Thrombosis Diseases 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 239000000956 alloy Substances 0.000 description 2
- 229960001230 asparagine Drugs 0.000 description 2
- 235000009582 asparagine Nutrition 0.000 description 2
- 229940125717 barbiturate Drugs 0.000 description 2
- HNYOPLTXPVRDBG-UHFFFAOYSA-N barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
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- 230000000694 effects Effects 0.000 description 2
- 229950003499 fibrin Drugs 0.000 description 2
- 238000000705 flame atomic absorption spectrometry Methods 0.000 description 2
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 2
- -1 for example Substances 0.000 description 2
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- VCJMYUPGQJHHFU-UHFFFAOYSA-N iron(3+);trinitrate Chemical compound [Fe+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O VCJMYUPGQJHHFU-UHFFFAOYSA-N 0.000 description 2
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Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
Abstract
A simulation solution for in-vitro detection of a zinc-containing medical device comprises 1-50 g/L of DMEM medium, 0-80% of serum or whole blood or blood plasma and a pH buffer substance in volume ratio. In vitro, the zinc-containing medical apparatus is placed in the simulation liquid, the zinc content in the simulation liquid and the cleaning liquid is tested, the biological risk can be evaluated, the zinc corrosion speed can be obtained, and the results can correspond to the zinc in vivo and in vitro. The test method can be used for detecting whether the zinc corrosion speed of a product in production is stable or not, and can also be used for preliminarily judging whether the design of the bracket meets the requirements or not in the research and development process.
Description
Technical Field
The invention relates to the field of medical instruments, in particular to a simulation liquid for in-vitro detection of a zinc-containing medical instrument and a method for in-vitro detection of the zinc-containing medical instrument.
Background
Zinc is a metal which has proper strength and hardness and can greatly improve the strength and hardness after being mixed with alloy elements such as aluminum, copper and the like. Zinc is one of the essential trace elements for human body, and zinc exists in human body. In the field of implantable degradable medical devices, zinc/zinc alloy is used as a device material, so that a proper mechanical supporting force can be provided, the device can effectively support tissues/blood vessels within a certain time, and the full degradation and full absorption can be safely realized in vivo. Meanwhile, zinc is used as a relatively active and safe metal element, a layer of zinc is plated on the metal surface (the metal activity is lower than that of zinc, such as iron) of the medical instrument, the corrosion of a metal matrix can be prolonged, and the zinc sacrificial anode protects the cathode, so that the instrument can maintain longer supporting force in the body. The implanted medical apparatus has a human body for a long time, is in direct contact with the human body, and has higher safety risk than common medical apparatuses, so the quality requirement on the implanted medical apparatus is strict, the whole production process control is an important means for ensuring the safety and effectiveness of products, and the potential risk of the implanted medical apparatus can be controlled to the maximum extent only by comprehensively detecting and controlling the product quality of the implanted medical apparatus, thereby ensuring the use safety.
In zinc-containing implantable medical devices, zinc naturally corrodes in the body at a rate and releases zinc ions that, above a certain concentration, exhibit toxic effects, such as Zn2+(mM) above 0.12mM, has a significant cytotoxic effect on L929 cells. The zinc corrosion is too fast to meet the requirements of early structural integrity and mechanical property, biological risks such as thrombus and inflammation are easy to occur at the implanted part, and the zinc corrosion is too slow, so that the medical instrument is affected by foreign matters in the growth period of a human body and possibly protrudes into the vascular lumen to induce thrombus formation. The corrosion speed and the release speed of zinc ions of the zinc-containing implanted medical device greatly influence the quality of the device, so that the corrosion speed and the release speed of the zinc ions are necessarily monitored in the quality control process of products, so as to ensure the safety and the effectiveness of the device and ensure the high-quality output of production investment.
For the monitoring mode of the zinc corrosion speed of the zinc-containing implantable medical device, a result close to that of a human can be obtained through animal experiments, but because the cost of the animal experiments in vivo is high, the period is long, a certain long time is needed for obtaining the test result, and the individual difference is large, in the research and development process of the medical device, the quality monitoring in the production of the device needs to be capable of quickly collecting the test result, simulating the corrosion condition of zinc in the body, and the relevance in vitro and in vivo is good.
Disclosure of Invention
Based on this, the invention needs to provide a simulation liquid for in vitro detection of zinc-containing medical instruments.
A simulation solution for in-vitro detection of a zinc-containing medical device comprises a DMEM medium of 1-50 g/L, 0-80% by volume of serum or whole blood or blood plasma and a pH value buffering substance.
Further, the simulation liquid for in vitro detection of the zinc-containing medical device further comprises a zinc complexing agent, wherein the zinc complexing agent is selected from at least one of ethylene diamine tetraacetic acid disodium salt and amino acid.
Furthermore, the content of the zinc complexing agent is 0.01-3 mol/L.
Further, the DMEM medium further includes phenol red.
Further, the pH buffering substance is selected from at least one of 4-hydroxyethylpiperazine ethanesulfonic acid, piperazine-1, 4-diethylsulfonic acid, glycine, disodium hydrogen phosphate-citric acid, citric acid-sodium hydroxide-hydrochloric acid, citric acid-sodium citrate, acetic acid-sodium acetate, disodium hydrogen phosphate-potassium dihydrogen phosphate, dipotassium hydrogen phosphate-potassium dihydrogen phosphate, disodium hydrogen phosphate-sodium dihydrogen phosphate, dipotassium hydrogen phosphate-sodium dihydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate-sodium hydroxide, potassium dihydrogen phosphate-potassium hydroxide, sodium dihydrogen phosphate-sodium hydroxide, barbiturate sodium-hydrochloric acid, Tris-hydrochloric acid, and boric acid-borax.
Further, the concentration range of the pH value buffering substance is 0.1-50 mmol/L.
Furthermore, the simulation liquid also comprises a bacteriostatic agent with the concentration range of 0.1-20 g/L.
Further, the bacteriostatic agent is mixed solution of penicillin and streptomycin or sodium azide.
A method for in vitro detection of a zinc containing medical device comprising the steps of: and (2) placing the zinc-containing medical device in the simulated liquid, reacting at 20-60 ℃, and detecting the zinc content in the simulated liquid to obtain the zinc release amount of the zinc-containing medical device.
Further, the method for in vitro detection of a zinc-containing medical device further comprises:
washing the reacted zinc-containing medical instrument with a cleaning solution, detecting the zinc content of the cleaning solution, and calculating the sum of the zinc contents of the simulation solution and the cleaning solution to obtain the zinc corrosion amount of the zinc-containing medical instrument; and the number of the first and second groups,
and calculating the percentage of the ratio of the zinc corrosion amount of the zinc-containing medical apparatus to the total mass of zinc in the zinc-containing medical apparatus, namely the percentage of the zinc corrosion amount.
Further, the method for detecting the zinc content in the simulation solution and the method for detecting the zinc content in the cleaning solution are all a titration method, a colorimetric method, an atomic absorption spectrometry method or an inductively coupled plasma spectrometry method.
The simulation liquid for in-vitro detection of the zinc-containing medical instrument can simulate the corrosion condition of zinc in vivo through the DMEM medium containing 1-50 g/L, 0-80% of serum or whole blood or plasma and pH buffer substances, has good in-vivo and in-vitro correlation, and can quickly collect test results.
Detailed Description
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein, but rather should be construed as broadly as the present invention is capable of modification in various respects, all without departing from the spirit and scope of the present invention.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
The embodiment provides a simulation solution for in-vitro detection of a zinc-containing medical instrument, which comprises 1-50 g/L of DMEM culture medium, 0-80% of serum or whole blood or plasma in volume ratio and a pH value buffering substance.
Wherein, 1-50 g/L refers to that each liter of simulation solution contains 1-50 g of DMEM medium, 0-80% volume ratio refers to that the volume of serum or whole blood or plasma accounts for 0-80% of the total volume of the simulation solution, and the amount of pH value buffering substances is enough to maintain the pH value of the simulation solution in a required range in the experimental process.
Wherein the DMEM medium is called dulbecco's modified eagle medium, is a solution very close to the in vivo environment, and comprises various amino acids such as glycine, alanine, arginine hydrochloride, asparagine, aspartic acid, valine and the like; calcium pantothenate, folic acid, nicotinamide, riboflavin, inositol, and other vitamins; various inorganic salts such as sodium chloride, calcium chloride, ferric nitrate, magnesium nitrate, potassium chloride, and the like; transferrin, recombinant insulin full-chain protein and other proteins; ammonium metavanadate, copper sulfate, manganese chloride, sodium selenite and other trace elements; and other components such as glucose, ethanolamine, glutathione, phenol, and sodium pyruvate.
The DMEM medium is selected from one of a high-sugar DMEM medium, a low-sugar DMEM medium and a sugar-free DMEM medium. Generally, the high-sugar type contains 4500mg/L of glucose, and the low-sugar type contains 1000mg/L of glucose.
In one embodiment, the simulant further comprises a zinc complexing agent selected from at least one of disodium ethylenediaminetetraacetate and an amino acid. The amino acid is selected from GlutaMAXTMAt least one of L-glutamine, glycine, asparagine, and threonine. The zinc complexing agent is used for complexing the corrosion product of zinc, so that the zinc corrosion product can be quickly diffused into the simulation liquid, and the process can simulate the process that the zinc corrosion product is metabolized by tissues after being released in vivo.
In one embodiment, the concentration of the zinc complexing agent is 0.01-3 mol/L, so that, on one hand, the amount of the zinc complexing agent is enough to complex the corrosion products of zinc; on the other hand, the concentration of the zinc complexing agent is ensured not to influence the property of the simulation liquid. The zinc complexing agent enables the simulation liquid to better simulate the process that in vivo zinc corrosion products leave a zinc-containing medical instrument and enter tissue metabolism, so as to ensure that the correlation between in vitro test results and in vivo test results is better.
Note that there is commercially available DMEM medium containing GlutaMAXTMOr L-glutamine, optionally containing GlutaMAXTMOr DMEM medium containing L-glutamine without adding zinc complexAnd (3) adding an agent or ensuring that the total concentration of the zinc complexing agent is controlled within 0.01-3 mol/L after adding an additional zinc complexing agent.
In one embodiment, the DMEM medium further comprises phenol red, which acts as an indicator and shows a range of pH change from the appearance of the simulant.
The blood environment can be better simulated by adding serum or whole blood or plasma into the simulation solution. Whole blood contains red blood cells and plasma, which contains fibrin and platelets, is an amorphous, fibrous, elastic solid that can form a gel, constituting a fibrin clot, a process that mimics the formation of endothelium in vitro. In order to ensure the effect of using the effective components in the serum or the whole blood or the plasma, a simulant containing the serum or the whole blood or the plasma is used at a pH of 7.4 and 37 ℃.
The volume percentage of the plasma, serum or whole blood is 0-80%. In one embodiment, no serum or whole blood or plasma may be added, and the higher the concentration of serum or whole blood or plasma, the slower the corrosion rate, the more capable of simulating the in vivo environment. Further, when it is desired to better simulate the in vivo environment, the volume percentage of the plasma or serum or whole blood is in the range of 10-80%. Further, when in-vitro accelerated corrosion is needed, the volume percentage of the blood plasma or the blood serum or the whole blood is 10-50%, and a proper proportion of 10-50% is selected, so that the accelerated corrosion can be realized, and the over-quick corrosion can be prevented. Still further, the volume of plasma or serum or whole blood in the simulant is 10% of the total volume of the simulant.
The pH value of the simulated liquid is 1-9, and the pH value is adjusted by acid and alkali solutions, for example, the acid is hydrochloric acid, and the alkali is sodium hydroxide solution. Zinc is an amphoteric metal, and zinc corrodes the slowest when neutral, and the corrosion speed of zinc is accelerated when the zinc is acidic or alkaline. In the experiment, the pH value of the simulated liquid can be adjusted according to the use position of the device. For example, the pH value of normal blood is 7.4, the pH value of normal bile is 7.4, the pH value of pancreatic juice is 7.8-8.4, the pH value of saliva is 6.5-7.8, the pH value of interstitial fluid is 7.0-7.5, the pH value of cell sap is 7.20-7.45, the pH value of seminal fluid is 7.8-9.2, and the pH value of cervix is 7.5-8.8. In simulating an in vivo blood environment, the pH of the simulated fluid was adjusted to 7.4 to match the pH of normal blood.
In one embodiment, the pH buffering substance is selected from the group consisting of 4-hydroxyethylpiperazine ethanesulfonic acid (HEPES), piperazine-1, 4-diethylsulfonic acid (PIPES), glycine, disodium hydrogen phosphate-citric acid, citric acid-sodium hydroxide-hydrochloric acid, citric acid-sodium citrate, acetic acid-sodium acetate, disodium hydrogen phosphate-potassium dihydrogen phosphate, dipotassium hydrogen phosphate-potassium dihydrogen phosphate, disodium hydrogen phosphate-sodium dihydrogen phosphate, at least one group of dipotassium hydrogen phosphate-sodium dihydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate-sodium hydroxide, potassium dihydrogen phosphate-potassium hydroxide, sodium dihydrogen phosphate-sodium hydroxide, barbiturate sodium-hydrochloric acid, Tris-hydrochloric acid, boric acid-borax. The pH value buffering substance can enable the solution to maintain a stable pH value for a long time and can not fluctuate under the influence of corrosion of instruments. In the specific use process, different pH value buffering substances have a certain pH value application range, namely, a proper pH value buffering substance is selected for the pH value of the simulation liquid with specific requirements. The concentration range of the pH value buffering substance is 0.1-50 mmol/L. Further, when the pH of the simulant is 7.4, the pH buffer substance is selected from the group consisting of 4-hydroxyethylpiperazine ethanesulfonic acid (HEPES), disodium hydrogen phosphate-potassium dihydrogen phosphate, dipotassium hydrogen phosphate-potassium dihydrogen phosphate, disodium hydrogen phosphate-sodium dihydrogen phosphate, dipotassium hydrogen phosphate-sodium dihydrogen phosphate, disodium hydrogen phosphate, and disodium hydrogen phosphate.
The simulated liquid can also contain bacteriostatic agent to prevent bacteria from growing too fast. In one embodiment, the bacteriostatic agent is sodium azide or diabody (mixed solution of penicillin and streptomycin), and when the simulated solution contains serum or plasma or whole blood and the instruments and experimental environment do not reach a sterile/aseptic state, the bacteriostatic agent is added into the simulated solution to prevent the corruption of the serum or plasma or whole blood in the simulated solution from causing the change of the pH value of the solution. The concentration range of the bacteriostatic agent is 0.1-20 g/L, and the proper type and the proper proportion of the bacteriostatic agent can be selected according to the experiment environment and the time for which the test time simulation liquid needs to be stored in the experiment.
Wherein, when the pH value of the simulation solution is 7.4, the bacteriostatic effect of the sodium azide is better under the non-aseptic condition.
In this embodiment, the preparation method of the simulation solution includes: weighing DMEM powder and an antibacterial agent, adding water to a constant volume, adding serum or whole blood or plasma to a constant volume, and adjusting the pH value to obtain the simulated solution.
The present embodiments also provide a method for in vitro testing of a zinc containing medical device, comprising the steps of: and (3) placing the zinc-containing medical appliance in the simulated liquid, reacting at 20-60 ℃, and detecting the zinc content in the simulated liquid to obtain the zinc release amount of the zinc-containing medical appliance.
The zinc release amount of the zinc-containing medical device in the simulated liquid is used for representing the quality of zinc corroded and released into surrounding tissues in vivo, the biological safety of the zinc-containing implant device can be preliminarily analyzed, and the higher the quality of released zinc in the same time is, the higher the biological risk is.
In one embodiment, the reaction time is 6 hours to 28 days.
The volume of the simulation liquid is 5-100 times of the minimum volume of the submersible apparatus. The material of the container can be any container which does not react with the simulation liquid, such as plastic, glass, polytetrafluoroethylene and the like. The oxygen content of the solution can be controlled by capping and sealing or ventilating, or the solution can be communicated with the atmosphere by capping but not completely sealing so as to keep the concentration of the dissolved oxygen in the solution unchanged. The more the oxygen content in the simulation liquid is, the corrosion speed of the zinc-containing medical appliance can be accelerated, and the oxygen content in the simulation liquid can be controlled, so that the corrosion speed of the zinc-containing medical appliance can be controlled.
In one embodiment, the reaction temperature is 20-60 ℃, and the temperature can be controlled by temperature-controllable equipment such as a water bath, an air bath, an oven and the like. The reaction temperature depends on the desired corrosion rate, the higher the temperature, the faster the corrosion rate, and the corrosion temperature of the zinciferous devices can be set according to experimental requirements. In simulating an in vivo environment, the simulated fluid may be used at a temperature of 37 ℃, which is suitable for a simulated fluid containing serum/plasma/whole blood.
In one embodiment, the method for in vitro testing of a zinc containing medical device further comprises the steps of:
washing the reacted zinc-containing medical instrument with a cleaning solution, detecting the zinc content of the cleaning solution, and calculating the sum of the zinc contents in the simulation solution and the cleaning solution to obtain the zinc corrosion amount of the zinc-containing medical instrument; and the number of the first and second groups,
and calculating the percentage of the ratio of the zinc corrosion amount of the zinc-containing medical apparatus to the total mass of zinc in the zinc-containing medical apparatus, namely the percentage of the zinc corrosion amount.
The method comprises the steps of reacting zinc-containing medical equipment, removing corrosion products on the surface of the zinc-containing medical equipment by using a cleaning solution, dissolving the corrosion products in the cleaning solution, detecting the zinc content of the cleaning solution, calculating the sum of the zinc contents of the simulation solution and the cleaning solution, and obtaining the zinc corrosion amount of the zinc-containing medical equipment.
And finally, calculating the percentage of the ratio of the zinc corrosion amount of the zinc-containing medical apparatus to the total mass of zinc in the zinc-containing medical apparatus, namely the percentage of the zinc corrosion amount. The percentage of zinc corrosion in the same time period can be used to characterize the corrosion rate of zinc.
In this embodiment, the method for detecting the zinc content in the simulated liquid and the zinc content in the cleaning liquid is a titration method, a colorimetric method, an atomic absorption spectrometry or an inductively coupled plasma spectrometry.
In this embodiment, the matrix of the zinc-containing medical device may be a pure zinc material, a zinc alloy material, or a zinc-plated material. The galvanized material may be iron surface galvanized. At least a portion of the surface of the zinc-containing medical device substrate may also have a coating.
In this embodiment, the zinc-containing medical device is a vascular stent, an orthopedic implant, a gynecological implant, a male implant, a respiratory implant, or an orthopedic implant.
It should be noted that, in order to obtain more intuitive data results for analyzing the in vitro zinc corrosion speed, six types of the same 30015 specifications (diameter 3.0mm, length 15mm) and the same surface area (66 mm) are adopted in each example2) The in-vivo and in-vitro zinc corrosion speed sequence of the zinc-containing stent shows the in-vivo and in-vitro correlation. When the in-vitro and in-vivo zinc corrosion speed trends are consistent, the in-vitro test method can be used for a watchCharacterization of in vivo outcome of zinc-containing implant devices.
A, appliance A: the absorbable iron matrix galvanized coronary stent has the specification of 30015, and the surface area of the iron matrix is 66mm2. The surface of an iron substrate is galvanized, zinc completely covers the surface of the iron substrate, the mass of the zinc is 0.5mg, the surface of a zinc layer is coated with a poly-dl-lactic acid coating, the poly-dl-lactic acid coating completely covers the surface of the zinc layer, the thickness of the poly-dl-lactic acid coating is 10 mu m, and the molecular weight of the poly-dl-lactic acid is 20W.
B, appliance: the absorbable iron matrix galvanized coronary stent has the specification of 30015, and the surface area of the iron matrix is 66mm2. And (3) galvanizing the surface of the iron matrix, wherein zinc completely covers the surface of the iron matrix, and the mass of the zinc is 0.5 mg.
C, appliance: the pure zinc matrix coronary stent has the specification of 30015, and the surface area of the matrix is 66mm2The zinc mass is 7.5mg, the surface of the substrate is coated with a poly-dl-lactic acid coating, the poly-dl-lactic acid coating completely covers the surface of the substrate, the thickness of the poly-dl-lactic acid coating is 10 mu m, and the molecular weight of the poly-dl-lactic acid is 20W.
D, apparatus: the pure zinc matrix coronary stent has the specification of 30015, and the surface area of the matrix is 66mm2And the mass of the zinc is 7.5 mg.
E, apparatus: the zinc alloy matrix coronary stent has the specification of 30015, and the surface area of the matrix is 66mm2The zinc mass is 4.5mg, the surface of the substrate is coated with a poly-dl-lactic acid coating, the poly-dl-lactic acid coating completely covers the surface of the substrate, the thickness of the poly-dl-lactic acid coating is 10 mu m, and the molecular weight of the poly-dl-lactic acid is 20W.
F, appliance: the zinc alloy matrix coronary stent has the specification of 30015, and the surface area of the matrix is 66mm2And the mass of zinc is 4.5 mg.
In vivo test:
in vivo corrosion test: respectively implanting the 6 groups of stents into abdominal aorta of rabbit, taking out the stent one month later, peeling the vascular tissue from the stent, and testing the zinc release amount, zinc corrosion amount and zinc corrosion amount percentage of the stent released to the vascular tissue after zinc corrosion.
And (3) detecting the release amount of zinc: after vascular tissues are weighed, 1mL of nitric acid is added for microwave digestion, the digestion tank is taken out after cooling, acid is removed on an electric hot plate at 135 ℃, the digestion tank is cooled, digestion liquid is transferred to a 10mL volumetric flask, the digestion tank is washed for 2 to 3 times by a small amount of water, washing liquid is merged into the volumetric flask, the volume is fixed to a scale by pure water, the mixture is uniformly mixed, and the zinc release amount is detected by flame Atomic Absorption Spectrometry (AAS).
Detecting the percentage of zinc corrosion amount to zinc corrosion amount: immersing the stent corroded by zinc in organic solvents such as ethyl acetate or chloroform and the like, and ultrasonically cleaning for 30min to remove polymers on the surface of the stent (if the stent has no polymer coating, the step is omitted); and (3) fishing out the stent from organic solvents such as ethyl acetate or chloroform and the like, airing, placing in a saturated glycine solution, and ultrasonically cleaning for 1min to remove zinc corrosion products on the surface of the stent, so that the zinc corrosion products on the surface are dissolved in the saturated glycine solution. The scaffolds were then removed from the saturated glycine solution and the saturated glycine solution (wash) was collected. Detecting the zinc content in the cleaning solution by adopting an Atomic Absorption Spectrometer (AAS), adding the zinc release amount in the vascular tissue and the zinc mass in the cleaning solution to obtain the zinc corrosion amount (unit microgram), and calculating the percentage of the ratio of the zinc corrosion amount of the zinc-containing medical equipment to the total zinc mass in the zinc-containing medical equipment as the percentage of the zinc corrosion amount.
The zinc corrosion amount of the stent in the rabbit body at one month is 160 mug, 350 mug, 140 mug, 320 mug, 100 mug and 260 mug. The percentage of zinc corrosion was 32% for a, 70% for B, 1.9% for C, 4.3% for D, 2.2% for E, and 5.8% for F, respectively, giving the order of the zinc corrosion rates in vivo, B > a, D > C, and F > E. The zinc release amount of the vascular tissue where the in-vivo stent is located is A & lt 10 mu g, B & lt 15 mu g, C & lt 9 mu g, D & lt 13 mu g, E & lt 7 mu g, F & lt 11 mu g, namely, the biological risk B & gt A, D & gt C and F & gt E.
In vitro testing:
expanding the 6 groups of stents to 3.0mm in diameter, and then putting the expanded stents into a blood collection tube filled with 5mL of simulation solution, wherein the blood collection tube does not contain anticoagulant, coagulant or heparin sodium; and tightly covering, placing the blood collection tube in a reaction temperature device at 20-60 ℃, and taking out the bracket from the simulation solution at a corresponding time point.
And (3) detecting the release amount of zinc: firstly, adding 10mL of concentrated nitric acid into a simulated solution after reaction, then digesting by microwave to release zinc in the form of ions, and then heating to evaporate redundant nitric acid in the solution; after the solution was cooled, diluted nitric acid was added to a constant volume, and then the zinc content in the solution was measured in μ g by flame Atomic Absorption Spectrometry (AAS). If the test concentration is higher than the range of the detection line of the instrument, the mother liquor can be diluted and then tested.
Detecting the percentage of zinc corrosion amount to zinc corrosion amount: taking out the stent from the simulation solution, immersing the stent in organic solvents such as ethyl acetate or chloroform and the like, and ultrasonically cleaning for 30min to remove polymers on the surface of the stent; and (3) fishing out the stent from organic solvents such as ethyl acetate or chloroform and the like, airing, placing in a saturated glycine solution, and ultrasonically cleaning for 1min to remove zinc corrosion products on the surface of the stent, so that the zinc corrosion products on the surface are dissolved in the saturated glycine solution. The scaffold was then removed from the saturated glycine solution and the wash collected. Detecting the zinc content of the cleaning solution by adopting an Atomic Absorption Spectrometer (AAS), calculating the sum of the zinc content in the simulation solution and the cleaning solution to obtain the zinc corrosion amount (unit microgram) of the zinc-containing medical instrument, and calculating the percentage of the ratio of the zinc corrosion amount of the zinc-containing medical instrument to the total mass of zinc in the zinc-containing medical instrument, namely the percentage of the zinc corrosion amount.
It should be noted that, in this embodiment, the corrosion environment of the stent in the coronary vessel is simulated, and the instrument takes the coronary stent as an example, the pH value of the corresponding simulation liquid is selected to be 7.4. The temperature can be varied to adjust the etch rate during the experiment.
Example 1:
simulation liquid: 10g/L of low-sugar DMEM medium, 20mmol/L of 4-hydroxyethyl piperazine ethanesulfonic acid (HEPES), 10% by volume of serum and 1g/L of sodium azide.
Respectively placing the A and B supports in 10mL of simulation solution, enabling the solution to completely submerge the supports, taking out the supports after the supports are corroded in water bath at 37 ℃ for 2 days, wherein the surface coatings of the A supports are firstly removed by ethyl acetate, then the A and B supports are respectively cleaned for 1min by saturated glycine solution in an ultrasonic mode, respectively collecting cleaning solutions of the A and B supports, and the percentages of zinc release amount, zinc corrosion amount and zinc corrosion amount are obtained by respectively detecting and calculating through the method.
The release amount of zinc in the simulated solution of the stent A and the stent B is 40 mug and 150 mug respectively, namely the content of zinc released into the simulated solution of the stent B after corrosion is higher than that of the zinc released into the simulated solution, and the biological risk B is more than A; the zinc content in the cleaning solution is respectively 80 mug and 200 mug, the sum of the zinc content (zinc corrosion amount) of the two solutions is respectively 120 mug and 350 mug, the percentage of the zinc corrosion amount is respectively 24 percent and 70 percent, and the in vitro zinc corrosion speed B is more than A.
Respectively implanting the A and B stents into the abdominal aorta of a rabbit, taking out the stents after one month, measuring the zinc release amount of the tissues of the blood vessel where the stents are positioned, and calculating the percentage relation of the zinc corrosion amount, wherein the percentage relation is B larger than A, and the biological risk and the zinc corrosion speed result can correspond to the internal and external of a body.
Example 2:
simulation liquid: 10g/L high-sugar DMEM medium without phenol red, 20 mmol/L4-hydroxyethyl piperazine ethanesulfonic acid (HEPES) and 10% by volume of serum.
Respectively placing the C support and the D support in 10mL of simulation solution, enabling the solution to completely submerge the supports respectively, taking out the supports after the C support is corroded in water bath at 37 ℃ for 2 days, wherein the surface coating of the C support needs to be removed by ethyl acetate firstly, then ultrasonically cleaning the C support and the D support for 1min by saturated glycine solutions respectively, collecting cleaning solutions of the C support and the D support respectively, and detecting and calculating by the method respectively to obtain the percentages of zinc release amount, zinc corrosion amount and zinc corrosion amount.
The release amount of zinc in the simulated liquid of the stent C and the stent D is 60 mug and 200 mug respectively, namely the content of zinc released into the simulated liquid of the stent D after being corroded is higher than that of the zinc released into the simulated liquid of the stent D, and the biological risk D is more than C; the zinc content in the cleaning solution is respectively 70 mug and 230 mug, the sum of the zinc content (zinc corrosion amount) of the two solutions is respectively 130 mug and 430 mug, the percentage of the zinc corrosion amount is respectively 1.7 percent and 5.7 percent, and the in vitro zinc corrosion speed D is more than C.
Respectively implanting the C and D stents into the abdominal aorta of a rabbit, taking out the stents after one month, measuring the zinc release amount D > C in the tissues of the blood vessel where the stents are positioned, calculating the percentage relation of the zinc corrosion amount D > C, and corresponding the biological risk and the zinc corrosion speed results in vivo and in vitro.
Example 3:
simulation liquid: 50g/L of high-sugar DMEM medium, 10mmol/L of HEPES, 80% by volume of serum and 20g/L of sodium azide.
Respectively placing the E and F stents into 10mL of simulation solution, enabling the solution to completely submerge the stents, carrying out oven corrosion at 37 ℃ for 28 days, taking out the stents, wherein the E stents need to be firstly removed with ethyl acetate to remove the surface coatings of the E stents, then respectively carrying out ultrasonic cleaning on the E and F stents with saturated glycine solution for 1min, respectively collecting cleaning solutions of the E and F stents, and respectively detecting and calculating by using the method to obtain the percentages of zinc release amount, zinc corrosion amount and zinc corrosion amount.
The release amount of zinc in the simulated liquid of the E bracket and the F bracket is respectively 110 mug and 300 mug, namely the content of zinc released into the simulated liquid of the F bracket after being corroded is higher than that of the zinc released into the simulated liquid of the F bracket, and the biological risk F is more than E; the zinc content in the cleaning solution is 130 mug and 320 mug respectively, the sum of the zinc content (zinc corrosion amount) of the two solutions is 240 mug and 620 mug respectively, namely the percentage of the zinc corrosion amount is 5.3 percent and 13.8 percent respectively, namely the in vitro zinc corrosion speed F is more than E.
Respectively implanting the E and F stents into the abdominal aorta of a rabbit, taking out the stents after one month, measuring the zinc release amount of the tissues of the blood vessel where the stents are positioned, wherein the zinc release amount is F larger than E, calculating the relation of the percentage of zinc corrosion amount, wherein the biological risk and the zinc corrosion speed result can correspond to each other in vivo and in vitro.
Example 4:
simulation liquid: 1g/L of sugar-free DMEM medium and 50mmol/L of HEPES.
Respectively placing the A and B supports in 10mL of simulation solution, enabling the solution to completely submerge the supports, taking out the supports after the supports are corroded in water bath at 45 ℃ for 1 day, wherein the surface coatings of the A supports are firstly removed by ethyl acetate, then the A and B supports are respectively cleaned by saturated glycine solution for 1min, respectively collecting cleaning solutions of the A and B supports, and respectively detecting and calculating by the method to obtain the percentages of zinc release amount, zinc corrosion amount and zinc corrosion amount.
The release amount of zinc in the simulated liquid of the stent A and the stent B is respectively 30 mug and 190 mug, namely the content of zinc released into the simulated liquid of the stent B after being corroded is higher than that of the zinc released into the simulated liquid of the stent B, and the biological risk B is more than A; the zinc content in the cleaning solution is 60 mug and 210 mug respectively, the sum of the zinc content (zinc corrosion amount) of the two solutions is 90 mug and 400 mug respectively, namely the percentage of the zinc corrosion amount is 18 percent and 80 percent respectively, and the in vitro zinc corrosion speed B is more than A.
Respectively implanting the A and B stents into the abdominal aorta of a rabbit, taking out the stents after one month, measuring the zinc release amount of the tissues of the blood vessel where the stents are positioned, and calculating the percentage relation of the zinc corrosion amount, wherein the percentage relation is B larger than A, and the biological risk and the zinc corrosion speed result can correspond to the internal and external of a body.
Example 5:
simulation liquid: 40g/L of high-sugar DMEM medium containing phenol red, 20mmol/L of disodium hydrogen phosphate and 3g/L of sodium azide.
Respectively placing the C support and the D support in 10mL of simulation solution, enabling the solution to completely submerge the supports, taking out the supports after the supports are corroded in water bath at 60 ℃ for 1 day, wherein the surface coating of the C support needs to be removed by ethyl acetate, then ultrasonically cleaning the C support and the D support for 1min by saturated glycine solution respectively, collecting cleaning solutions of the C support and the D support respectively, and detecting and calculating by the method respectively to obtain the percentage of zinc release amount, zinc corrosion amount and zinc corrosion amount.
The release amount of zinc in the simulated liquid of the stent C and the stent D is respectively 140 mug and 400 mug, namely the content of zinc released into the simulated liquid of the stent D after being corroded is higher than that of the zinc released into the simulated liquid of the stent D, and the biological risk D is more than C; the zinc content in the cleaning solution is 240 mug and 600 mug respectively, the sum of the zinc content (zinc corrosion amount) of the two solutions is 380 mug and 1000 mug respectively, the percentage of the zinc corrosion amount is 5.1 percent and 13.3 percent respectively, and the in vitro zinc corrosion speed D is more than C.
Respectively implanting the C and D stents into the abdominal aorta of a rabbit, taking out the stents after one month, measuring the zinc release amount D > C in the tissues of the blood vessel where the stents are positioned, calculating the percentage relation of the zinc corrosion amount D > C, and corresponding the biological risk and the zinc corrosion speed results in vivo and in vitro.
Example 6:
simulation liquid: 10g/L of high-sugar phenol red-free DMEM medium, 50% by volume of whole blood, 10mmol/L of HEPES and 10g/L of sodium azide.
Respectively placing the E and F stents into 10mL of simulation solution, respectively completely immersing the stents in the solution, carrying out water bath corrosion at 37 ℃ for 14 days, then taking out the stents, wherein the E stents need to remove the surface coatings by ethyl acetate, then carrying out ultrasonic cleaning on the E and F stents by saturated glycine solution for 1min, respectively collecting cleaning solutions of the E and F stents, and respectively detecting and calculating by the method to obtain the percentages of zinc release amount, zinc corrosion amount and zinc corrosion amount.
The release contents of zinc in the simulated liquid of the E bracket and the F bracket are respectively 90 mug and 275 mug, namely the content released into the simulated liquid after the zinc of the F bracket is corroded is higher than that of the E bracket, and the biological risk F is more than E; the zinc content in the cleaning solution is respectively 30 mug and 90 mug, the sum of the zinc content (zinc corrosion amount) of the two solutions is respectively 120 mug and 365 mug, namely the percentage of the zinc corrosion amount is respectively 2.7 percent and 8.1 percent, and the in vitro zinc corrosion speed F is more than E.
Respectively implanting the E and F stents into the abdominal aorta of a rabbit, taking out the stents after one month, measuring the zinc release amount of the tissues of the blood vessel where the stents are positioned, wherein the zinc release amount is F larger than E, calculating the relation of the percentage of zinc corrosion amount, wherein the biological risk and the zinc corrosion speed result can correspond to each other in vivo and in vitro.
Example 7:
simulation liquid: 10g/L high-glucose DMEM medium, 1% serum by volume, 0.1mmol/L HEPES and 0.1g/L sodium azide.
Respectively placing the A and B supports in 10mL of simulation solution, enabling the solution to completely submerge the supports, taking out the supports after the supports are corroded in water bath at 37 ℃ for 6 hours, wherein the surface coatings of the A supports are firstly removed by ethyl acetate, then the A and B supports are respectively cleaned for 1min by saturated glycine solution in an ultrasonic mode, respectively collecting cleaning solutions of the A and B supports, and the percentages of zinc release amount, zinc corrosion amount and zinc corrosion amount are obtained by respectively detecting and calculating through the method.
The release amount of zinc in the simulated liquid of the stent A and the stent B is 20 mug and 70 mug respectively, namely the content of zinc released into the simulated liquid of the stent B after being corroded is higher than that of the zinc released into the simulated liquid of the stent B, and the biological risk B is more than A; the zinc content in the cleaning solution is respectively 35 mug and 90 mug, the sum of the zinc content (zinc corrosion amount) of the two solutions is respectively 55 mug and 160 mug, namely the percentage of the zinc corrosion amount is respectively 11 percent and 32 percent, and the in vitro zinc corrosion speed B is more than A.
Respectively implanting the A and B stents into the abdominal aorta of a rabbit, taking out the stents after one month, measuring the zinc release amount in the tissue of the blood vessel where the stent is positioned, and calculating the relation of the zinc corrosion percentage, wherein the relation is B is more than A, and the biological risk and the zinc corrosion speed result can correspond to the internal and external of a body.
Example 8:
simulation liquid: 30g/L sugar-free DMEM medium containing phenol red, 15mmol/L disodium hydrogen phosphate, 30% by volume of plasma and 1g/L of a mixture of penicillin and streptomycin.
Respectively placing the E and F stents in 10mL of simulation solution, respectively completely immersing the stents in the solution, taking out the stents after the stents are corroded in water bath at 37 ℃ for 4 days, wherein the surface coating of the E stent is firstly removed by ethyl acetate, then the E and F stents are respectively cleaned by saturated glycine solution for 1min, respectively collecting the cleaning solutions of the E and F stents, and respectively detecting and calculating by the method to obtain the percentages of zinc release amount, zinc corrosion amount and zinc corrosion amount.
The release amount of zinc in the simulated liquid of the E bracket and the F bracket is respectively 50 mug and 160 mug, namely the content of zinc released into the simulated liquid of the F bracket after being corroded is higher than that of the zinc released into the simulated liquid of the F bracket, and the biological risk F is more than E; the zinc content in the cleaning solution is 65 mug and 170 mug respectively, the sum of the zinc content (zinc corrosion amount) of the two solutions is 115 mug and 330 mug respectively, namely the percentage of the zinc corrosion amount is 2.6 percent and 7.3 percent respectively, and the in vitro zinc corrosion speed F is more than E.
Respectively implanting the E and F stents into the abdominal aorta of a rabbit, taking out the stents after one month, measuring the zinc release amount of the tissues of the blood vessel where the stents are positioned, wherein the zinc release amount is F larger than E, calculating the relation of the zinc corrosion percentage, wherein the relation is F larger than E, and the biological risk and the zinc corrosion speed result can correspond to the internal and external of a body.
Example 9:
simulation liquid: 10g/L of low-sugar DMEM medium, 20mmol/L of HEPES, 10% by volume of serum, 0.01mol/L of disodium ethylenediamine tetraacetic acid and 1g/L of sodium azide.
Respectively placing the A and B supports in 10mL of simulation solution, enabling the solution to completely submerge the supports, taking out the supports after the supports are corroded in water bath at 37 ℃ for 2 days, wherein the surface coatings of the A supports are firstly removed by ethyl acetate, then the A and B supports are respectively cleaned for 1min by saturated glycine solution in an ultrasonic mode, respectively collecting cleaning solutions of the A and B supports, and the percentages of zinc release amount, zinc corrosion amount and zinc corrosion amount are obtained by respectively detecting and calculating through the method.
The release amount of zinc in the bracket A and the bracket B simulated liquid is 60 mug and 180 mug, namely the content of zinc released into the simulated liquid after the bracket B is corroded is higher than that of the zinc released into the simulated liquid, and the biological risk B is more than A; the zinc content in the cleaning solution is 50 mug and 160 mug, the sum of the zinc content (zinc corrosion amount) of the two solutions is 110 mug and 340 mug, the percentage of the zinc corrosion amount is 22 percent and 68 percent, and the in vitro zinc corrosion speed B is more than A.
Respectively implanting the A and B stents into the abdominal aorta of a rabbit, taking out the stents after one month, measuring the zinc release amount of the tissues of the blood vessel where the stents are positioned, and calculating the percentage relation of the zinc corrosion amount, wherein the percentage relation is B larger than A, and the biological risk and the zinc corrosion speed result can correspond to the internal and external of a body.
Example 10:
simulation liquid: 10g/L high-sugar DMEM medium without phenol red, 20mmol/L HEPES, 10% by volume serum and 3mol/L glycine.
Respectively placing the C support and the D support in 10mL of simulation solution, enabling the solution to completely submerge the supports respectively, taking out the supports after the C support is corroded in water bath at 37 ℃ for 2 days, wherein the surface coating of the C support needs to be removed by ethyl acetate firstly, then ultrasonically cleaning the C support and the D support for 1min by saturated glycine solutions respectively, collecting cleaning solutions of the C support and the D support respectively, and detecting and calculating by the method respectively to obtain the percentages of zinc release amount, zinc corrosion amount and zinc corrosion amount.
The release amount of zinc in the simulated liquid of the C stent and the D stent is 100 mug and 350 mug, namely the content of zinc released into the simulated liquid after the D stent is corroded is higher than that of the C, and the biological risk D is more than C; the zinc content in the cleaning solution is 40 mug and 100 mug, the sum of the zinc content (zinc corrosion amount) of the two solutions is 140 mug and 450 mug, the percentage of the zinc corrosion amount is 1.9 percent and 6.0 percent, and the in vitro zinc corrosion speed D is more than C.
Respectively implanting the C and D stents into the abdominal aorta of a rabbit, taking out the stents after one month, measuring the zinc release amount D > C in the tissues of the blood vessel where the stents are positioned, calculating the percentage relation of the zinc corrosion amount D > C, and corresponding the biological risk and the zinc corrosion speed results in vivo and in vitro.
Comparative example 1:
simulation liquid: PBS solution.
Respectively placing the A stent and the B stent in 10mL PBS (phosphate buffer solution) with the pH value of 7.4, enabling the solutions to completely submerge the stents, corroding the stents in water bath at 37 ℃ for 2 days, then taking out the stents, wherein the surface coating of the A stent needs to be removed by ethyl acetate, then ultrasonically cleaning the A stent and the B stent for 1min by saturated glycine solutions respectively, collecting cleaning solutions of the A stent and the B stent respectively, and detecting and calculating by the method respectively to obtain the percentages of zinc release amount, zinc corrosion amount and zinc corrosion amount.
The release amount of zinc in the PBS solution of the A bracket and the B bracket is respectively 8 mug and 6 mug, namely the content of zinc released into the simulation solution after the A bracket is corroded is higher than that of the zinc released into the simulation solution, and the biological risk A is more than B; the zinc content in the cleaning solution is respectively 100 mug and 46 mug, the sum of the zinc content quality (zinc corrosion amount) of the two solutions is respectively 108 mug and 52 mug, namely the percentage of the zinc corrosion amount is respectively 21.6 percent and 10.4 percent, and the in vitro zinc corrosion speed A is more than B.
Respectively implanting the A and B stents into the abdominal aorta of a rabbit, taking out the stents after one month, measuring the zinc release amount B in the tissues of the blood vessel where the stents are positioned, calculating the relation of the percentage of zinc corrosion amount in vivo as B > A, and the biological risk and zinc corrosion speed results can not correspond in vitro and in vivo.
Comparative example 2:
simulation liquid: PBS solution.
Respectively placing the C stent and the D stent in 10mL PBS (phosphate buffer solution) with the pH value of 7.4, completely immersing the stent in the solution, corroding the stent in water bath at 37 ℃ for 2 days, then taking out the stent, wherein the surface coating of the C stent needs to be removed by ethyl acetate, then ultrasonically cleaning the C stent and the D stent for 1min by saturated glycine solution respectively, collecting cleaning liquids of the C stent and the D stent respectively, and detecting and calculating by the method respectively to obtain the percentages of the zinc release amount, the zinc corrosion amount and the zinc corrosion amount.
The release amount of zinc in PBS solution of C and D support is 9 mug and 5 mug respectively, namely the content released into the simulation solution after the zinc of C support is corroded is higher than that of D, and the biological risk C is more than D; the zinc content in the cleaning solution is respectively 90 mug and 45 mug, the sum of the zinc content (zinc corrosion amount) of the two solutions is respectively 99 mug and 50 mug, namely the percentage of the zinc corrosion amount is respectively 1.3 percent and 0.7 percent, and the in vitro zinc corrosion speed C is more than D.
Respectively implanting the C and D stents into the abdominal aorta of the rabbit, taking out the stents after one month, measuring the zinc release amount D in the tissues of the blood vessel where the stents are positioned, and calculating the relation of the percentage of zinc corrosion amount in vivo, wherein the relation is D larger than C, and the biological risk and zinc corrosion speed results can not correspond in vitro and in vivo.
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (11)
1. The simulation liquid for in-vitro detection of the zinc-containing medical instrument is characterized by comprising 1-50 g/L of DMEM culture medium, 0-80% of serum or whole blood or plasma in volume ratio and a pH value buffering substance.
2. The simulant fluid for in vitro testing of a zinc-containing medical device according to claim 1, further comprising a zinc complexing agent selected from at least one of ethylenediaminetetraacetic acid disodium salt and amino acids.
3. The simulant for in vitro detection of medical devices containing zinc according to claim 2, wherein the content of the zinc complexing agent is 0.01-3 mol/L.
4. The simulant for in vitro detection of a zinc containing medical device according to claim 1, wherein said DMEM medium further comprises phenol red.
5. The simulant for in vitro detection of a zinc-containing medical device according to claim 1, wherein the pH buffering substance is selected from the group consisting of 4-hydroxyethylpiperazineethanesulfonic acid, piperazine-1, 4-diethylsulfonic acid, glycine, disodium hydrogenphosphate-citric acid, citric acid-sodium hydroxide-hydrochloric acid, citric acid-sodium citrate, acetic acid-sodium acetate, disodium hydrogenphosphate-potassium dihydrogenphosphate, dipotassium hydrogenphosphate-potassium dihydrogenphosphate, disodium hydrogenphosphate-sodium dihydrogenphosphate, dipotassium hydrogenphosphate-sodium dihydrogenphosphate, disodium hydrogenphosphate, dipotassium hydrogenphosphate, potassium dihydrogenphosphate-sodium hydroxide, potassium dihydrogenphosphate-potassium hydroxide, sodium dihydrogenphosphate-sodium hydroxide, barbiturate-hydrochloric acid, glycine, disodium hydrogenphosphate-citric acid-sodium citrate, sodium, At least one of Tris-hydrochloric acid and boric acid-borax.
6. The simulant fluid for in vitro detection of a zinc-containing medical device according to claim 1, wherein the concentration of the pH buffer substance is in the range of 0.1 to 50 mmol/L.
7. The simulation fluid for in-vitro detection of the zinc-containing medical device according to claim 1, further comprising a bacteriostatic agent with a concentration range of 0.1-20 g/L.
8. The simulant fluid for in vitro testing of a zinc-containing medical device of claim 7, wherein the bacteriostatic agent is a mixture of penicillin and streptomycin or sodium azide.
9. A method for in vitro detection of a zinc containing medical device comprising the steps of: placing a zinc-containing medical device in the simulation liquid of any one of claims 1-8, reacting at 20-60 ℃, and detecting the zinc content in the simulation liquid to obtain the zinc release amount of the zinc-containing medical device.
10. The method for in vitro testing of a zinc containing medical device of claim 9, further comprising:
washing the reacted zinc-containing medical instrument with a cleaning solution, detecting the zinc content of the cleaning solution, and calculating the sum of the zinc contents of the simulation solution and the cleaning solution to obtain the zinc corrosion amount of the zinc-containing medical instrument; and the number of the first and second groups,
and calculating the percentage of the ratio of the zinc corrosion amount of the zinc-containing medical apparatus to the total mass of zinc in the zinc-containing medical apparatus, namely the percentage of the zinc corrosion amount.
11. The method for in vitro detection of a zinc-containing medical device according to claim 10, wherein the method of detecting the zinc content in the simulant fluid and the method of detecting the zinc content in the cleaning fluid are each a titration method, a colorimetric method, an atomic absorption spectroscopy method or an inductively coupled plasma spectroscopy method.
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