CN113750290A - Polyether-ether-ketone composite implant and preparation method and application thereof - Google Patents
Polyether-ether-ketone composite implant and preparation method and application thereof Download PDFInfo
- Publication number
- CN113750290A CN113750290A CN202010495733.2A CN202010495733A CN113750290A CN 113750290 A CN113750290 A CN 113750290A CN 202010495733 A CN202010495733 A CN 202010495733A CN 113750290 A CN113750290 A CN 113750290A
- Authority
- CN
- China
- Prior art keywords
- function
- regulating
- substance
- osteogenesis
- immunity
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000004696 Poly ether ether ketone Substances 0.000 title claims abstract description 120
- 229920002530 polyetherether ketone Polymers 0.000 title claims abstract description 120
- 239000007943 implant Substances 0.000 title claims abstract description 36
- 239000002131 composite material Substances 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 238000002513 implantation Methods 0.000 title claims description 13
- 239000000126 substance Substances 0.000 claims abstract description 108
- 230000011164 ossification Effects 0.000 claims abstract description 100
- 238000000576 coating method Methods 0.000 claims abstract description 79
- 239000011248 coating agent Substances 0.000 claims abstract description 77
- 239000003814 drug Substances 0.000 claims abstract description 57
- 229920006237 degradable polymer Polymers 0.000 claims abstract description 47
- 210000000988 bone and bone Anatomy 0.000 claims abstract description 37
- 239000000463 material Substances 0.000 claims abstract description 32
- 239000000758 substrate Substances 0.000 claims abstract description 26
- 230000007547 defect Effects 0.000 claims abstract description 8
- 230000003213 activating effect Effects 0.000 claims abstract description 7
- 230000008975 immunomodulatory function Effects 0.000 claims abstract description 5
- 230000001105 regulatory effect Effects 0.000 claims description 131
- 230000036039 immunity Effects 0.000 claims description 46
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 claims description 35
- 229960003957 dexamethasone Drugs 0.000 claims description 32
- 229940079593 drug Drugs 0.000 claims description 32
- 238000000034 method Methods 0.000 claims description 27
- 238000007654 immersion Methods 0.000 claims description 26
- 239000007789 gas Substances 0.000 claims description 24
- 238000005468 ion implantation Methods 0.000 claims description 21
- 108090000174 Interleukin-10 Proteins 0.000 claims description 19
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 18
- 230000036737 immune function Effects 0.000 claims description 16
- 239000007924 injection Substances 0.000 claims description 14
- 238000002347 injection Methods 0.000 claims description 14
- 206010061218 Inflammation Diseases 0.000 claims description 13
- 230000004054 inflammatory process Effects 0.000 claims description 13
- 229920000642 polymer Polymers 0.000 claims description 13
- 239000000243 solution Substances 0.000 claims description 11
- 229920000166 polytrimethylene carbonate Polymers 0.000 claims description 10
- 230000035755 proliferation Effects 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- -1 PDGF Proteins 0.000 claims description 7
- 230000001737 promoting effect Effects 0.000 claims description 7
- 230000004663 cell proliferation Effects 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 150000002500 ions Chemical class 0.000 claims description 5
- 210000000963 osteoblast Anatomy 0.000 claims description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 4
- 108010049931 Bone Morphogenetic Protein 2 Proteins 0.000 claims description 4
- 102100024506 Bone morphogenetic protein 2 Human genes 0.000 claims description 4
- 230000003110 anti-inflammatory effect Effects 0.000 claims description 3
- 230000004069 differentiation Effects 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 239000004632 polycaprolactone Substances 0.000 claims description 3
- 229920001610 polycaprolactone Polymers 0.000 claims description 3
- 239000002243 precursor Substances 0.000 claims description 3
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 claims description 2
- OGSPWJRAVKPPFI-UHFFFAOYSA-N Alendronic Acid Chemical compound NCCCC(O)(P(O)(O)=O)P(O)(O)=O OGSPWJRAVKPPFI-UHFFFAOYSA-N 0.000 claims description 2
- 229920001634 Copolyester Polymers 0.000 claims description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 claims description 2
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 claims description 2
- 101000599951 Homo sapiens Insulin-like growth factor I Proteins 0.000 claims description 2
- 101000798130 Homo sapiens Tumor necrosis factor receptor superfamily member 11B Proteins 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 102100037852 Insulin-like growth factor I Human genes 0.000 claims description 2
- 108090000978 Interleukin-4 Proteins 0.000 claims description 2
- 108090001005 Interleukin-6 Proteins 0.000 claims description 2
- 229920000954 Polyglycolide Polymers 0.000 claims description 2
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 claims description 2
- 108010049264 Teriparatide Proteins 0.000 claims description 2
- PUJWFVBVNFXCHZ-SQEQANQOSA-N Tripdiolide Chemical compound O=C1OCC([C@@H]2C3)=C1[C@@H](O)C[C@]2(C)[C@]12O[C@H]1[C@@H]1O[C@]1(C(C)C)[C@@H](O)[C@]21[C@H]3O1 PUJWFVBVNFXCHZ-SQEQANQOSA-N 0.000 claims description 2
- 102100032236 Tumor necrosis factor receptor superfamily member 11B Human genes 0.000 claims description 2
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 claims description 2
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 claims description 2
- 229960002964 adalimumab Drugs 0.000 claims description 2
- 229920003232 aliphatic polyester Polymers 0.000 claims description 2
- 229910021529 ammonia Inorganic materials 0.000 claims description 2
- 230000033115 angiogenesis Effects 0.000 claims description 2
- 229910052786 argon Inorganic materials 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 230000004900 autophagic degradation Effects 0.000 claims description 2
- 238000011049 filling Methods 0.000 claims description 2
- 229940091249 fluoride supplement Drugs 0.000 claims description 2
- 239000003862 glucocorticoid Substances 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 claims description 2
- 229960003444 immunosuppressant agent Drugs 0.000 claims description 2
- 230000001861 immunosuppressant effect Effects 0.000 claims description 2
- 239000003018 immunosuppressive agent Substances 0.000 claims description 2
- 210000004969 inflammatory cell Anatomy 0.000 claims description 2
- 229960000598 infliximab Drugs 0.000 claims description 2
- 230000002401 inhibitory effect Effects 0.000 claims description 2
- RTGDFNSFWBGLEC-SYZQJQIISA-N mycophenolate mofetil Chemical compound COC1=C(C)C=2COC(=O)C=2C(O)=C1C\C=C(/C)CCC(=O)OCCN1CCOCC1 RTGDFNSFWBGLEC-SYZQJQIISA-N 0.000 claims description 2
- 229960004866 mycophenolate mofetil Drugs 0.000 claims description 2
- 239000004633 polyglycolic acid Substances 0.000 claims description 2
- 239000004626 polylactic acid Substances 0.000 claims description 2
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 claims description 2
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 claims description 2
- 229960002930 sirolimus Drugs 0.000 claims description 2
- 238000000935 solvent evaporation Methods 0.000 claims description 2
- 210000000130 stem cell Anatomy 0.000 claims description 2
- 229960001967 tacrolimus Drugs 0.000 claims description 2
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 claims description 2
- OGBMKVWORPGQRR-UMXFMPSGSA-N teriparatide Chemical compound C([C@H](NC(=O)[C@H](CCSC)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@@H](N)CO)C(C)C)[C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CNC=N1 OGBMKVWORPGQRR-UMXFMPSGSA-N 0.000 claims description 2
- 229960005460 teriparatide Drugs 0.000 claims description 2
- 229960003433 thalidomide Drugs 0.000 claims description 2
- 239000011247 coating layer Substances 0.000 claims 3
- 229940062527 alendronate Drugs 0.000 claims 1
- 238000003618 dip coating Methods 0.000 claims 1
- 210000002997 osteoclast Anatomy 0.000 claims 1
- 229920000747 poly(lactic acid) Polymers 0.000 claims 1
- 239000007921 spray Substances 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 18
- 230000006870 function Effects 0.000 description 64
- 210000002540 macrophage Anatomy 0.000 description 29
- 210000002381 plasma Anatomy 0.000 description 23
- 230000014509 gene expression Effects 0.000 description 20
- 241000700159 Rattus Species 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 239000001963 growth medium Substances 0.000 description 9
- 108090000623 proteins and genes Proteins 0.000 description 9
- 238000001727 in vivo Methods 0.000 description 8
- 238000001514 detection method Methods 0.000 description 7
- 238000003753 real-time PCR Methods 0.000 description 7
- 210000000689 upper leg Anatomy 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 230000033558 biomineral tissue development Effects 0.000 description 6
- 238000002156 mixing Methods 0.000 description 6
- 230000002188 osteogenic effect Effects 0.000 description 6
- 230000001954 sterilising effect Effects 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 239000003636 conditioned culture medium Substances 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- 230000004048 modification Effects 0.000 description 5
- 238000012986 modification Methods 0.000 description 5
- 238000008157 ELISA kit Methods 0.000 description 4
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 4
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 4
- 102100040247 Tumor necrosis factor Human genes 0.000 description 4
- 230000010478 bone regeneration Effects 0.000 description 4
- 230000015556 catabolic process Effects 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 238000006731 degradation reaction Methods 0.000 description 4
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 4
- 230000007365 immunoregulation Effects 0.000 description 4
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 4
- 238000010186 staining Methods 0.000 description 4
- 229930040373 Paraformaldehyde Natural products 0.000 description 3
- 102000046299 Transforming Growth Factor beta1 Human genes 0.000 description 3
- 101800002279 Transforming growth factor beta-1 Proteins 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 230000033228 biological regulation Effects 0.000 description 3
- 230000001276 controlling effect Effects 0.000 description 3
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 3
- 238000005553 drilling Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 230000001900 immune effect Effects 0.000 description 3
- 210000000987 immune system Anatomy 0.000 description 3
- 230000028709 inflammatory response Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 238000011835 investigation Methods 0.000 description 3
- 210000000629 knee joint Anatomy 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 238000010603 microCT Methods 0.000 description 3
- 229920002866 paraformaldehyde Polymers 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 239000002953 phosphate buffered saline Substances 0.000 description 3
- 230000010287 polarization Effects 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 230000000770 proinflammatory effect Effects 0.000 description 3
- 238000001878 scanning electron micrograph Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000004659 sterilization and disinfection Methods 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 2
- 101710149858 C-C chemokine receptor type 7 Proteins 0.000 description 2
- 101500025613 Mus musculus Transforming growth factor beta-1 Proteins 0.000 description 2
- 108010087230 Sincalide Proteins 0.000 description 2
- 238000004833 X-ray photoelectron spectroscopy Methods 0.000 description 2
- PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 description 2
- 238000005299 abrasion Methods 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 230000000975 bioactive effect Effects 0.000 description 2
- 238000010609 cell counting kit-8 assay Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000005520 cutting process Methods 0.000 description 2
- 230000035876 healing Effects 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 230000003832 immune regulation Effects 0.000 description 2
- 230000028993 immune response Effects 0.000 description 2
- 238000010166 immunofluorescence Methods 0.000 description 2
- 230000001976 improved effect Effects 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 238000010883 osseointegration Methods 0.000 description 2
- 229960001412 pentobarbital Drugs 0.000 description 2
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000004381 surface treatment Methods 0.000 description 2
- 239000004408 titanium dioxide Substances 0.000 description 2
- JKYKXTRKURYNGW-UHFFFAOYSA-N 3,4-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-sulfonic acid Chemical compound O=C1C2=CC=CC=C2C(=O)C2=C1C(O)=C(O)C(S(O)(=O)=O)=C2 JKYKXTRKURYNGW-UHFFFAOYSA-N 0.000 description 1
- FWBHETKCLVMNFS-UHFFFAOYSA-N 4',6-Diamino-2-phenylindol Chemical compound C1=CC(C(=N)N)=CC=C1C1=CC2=CC=C(C(N)=N)C=C2N1 FWBHETKCLVMNFS-UHFFFAOYSA-N 0.000 description 1
- GOZMBJCYMQQACI-UHFFFAOYSA-N 6,7-dimethyl-3-[[methyl-[2-[methyl-[[1-[3-(trifluoromethyl)phenyl]indol-3-yl]methyl]amino]ethyl]amino]methyl]chromen-4-one;dihydrochloride Chemical compound Cl.Cl.C=1OC2=CC(C)=C(C)C=C2C(=O)C=1CN(C)CCN(C)CC(C1=CC=CC=C11)=CN1C1=CC=CC(C(F)(F)F)=C1 GOZMBJCYMQQACI-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 208000006386 Bone Resorption Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 241001391944 Commicarpus scandens Species 0.000 description 1
- 102000015775 Core Binding Factor Alpha 1 Subunit Human genes 0.000 description 1
- 108010024682 Core Binding Factor Alpha 1 Subunit Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 101000998969 Homo sapiens Inositol-3-phosphate synthase 1 Proteins 0.000 description 1
- 102100036881 Inositol-3-phosphate synthase 1 Human genes 0.000 description 1
- 102100029438 Nitric oxide synthase, inducible Human genes 0.000 description 1
- 101710089543 Nitric oxide synthase, inducible Proteins 0.000 description 1
- 102100031475 Osteocalcin Human genes 0.000 description 1
- 206010031264 Osteonecrosis Diseases 0.000 description 1
- 102100040557 Osteopontin Human genes 0.000 description 1
- 102100029177 PDZ and LIM domain protein 3 Human genes 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 229960004343 alendronic acid Drugs 0.000 description 1
- RGCKGOZRHPZPFP-UHFFFAOYSA-N alizarin Chemical compound C1=CC=C2C(=O)C3=C(O)C(O)=CC=C3C(=O)C2=C1 RGCKGOZRHPZPFP-UHFFFAOYSA-N 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 238000000889 atomisation Methods 0.000 description 1
- 238000005452 bending Methods 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000002146 bilateral effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000024279 bone resorption Effects 0.000 description 1
- DEGAKNSWVGKMLS-UHFFFAOYSA-N calcein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC(CN(CC(O)=O)CC(O)=O)=C(O)C=C1OC1=C2C=C(CN(CC(O)=O)CC(=O)O)C(O)=C1 DEGAKNSWVGKMLS-UHFFFAOYSA-N 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 210000003855 cell nucleus Anatomy 0.000 description 1
- XMEVHPAGJVLHIG-FMZCEJRJSA-N chembl454950 Chemical compound [Cl-].C1=CC=C2[C@](O)(C)[C@H]3C[C@H]4[C@H]([NH+](C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O XMEVHPAGJVLHIG-FMZCEJRJSA-N 0.000 description 1
- 238000010382 chemical cross-linking Methods 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 230000001054 cortical effect Effects 0.000 description 1
- 239000003431 cross linking reagent Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 238000001215 fluorescent labelling Methods 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 230000005661 hydrophobic surface Effects 0.000 description 1
- 230000005965 immune activity Effects 0.000 description 1
- 230000008105 immune reaction Effects 0.000 description 1
- 238000003125 immunofluorescent labeling Methods 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000007769 metal material Substances 0.000 description 1
- 238000001000 micrograph Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 239000002103 nanocoating Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 229960002378 oftasceine Drugs 0.000 description 1
- 230000001599 osteoclastic effect Effects 0.000 description 1
- 230000009818 osteogenic differentiation Effects 0.000 description 1
- 150000002926 oxygen Chemical class 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 238000001420 photoelectron spectroscopy Methods 0.000 description 1
- 238000009832 plasma treatment Methods 0.000 description 1
- 238000005498 polishing Methods 0.000 description 1
- 229920001643 poly(ether ketone) Polymers 0.000 description 1
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 1
- 229920003229 poly(methyl methacrylate) Polymers 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 239000004926 polymethyl methacrylate Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 102000037983 regulatory factors Human genes 0.000 description 1
- 108091008025 regulatory factors Proteins 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 238000010839 reverse transcription Methods 0.000 description 1
- 239000004576 sand Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229960004989 tetracycline hydrochloride Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229920001169 thermoplastic Polymers 0.000 description 1
- 239000004416 thermosoftening plastic Substances 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000017423 tissue regeneration Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/28—Materials for coating prostheses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/28—Materials for coating prostheses
- A61L27/34—Macromolecular materials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/54—Biologically active materials, e.g. therapeutic substances
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/58—Materials at least partially resorbable by the body
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
- A61L2300/22—Lipids, fatty acids, e.g. prostaglandins, oils, fats, waxes
- A61L2300/222—Steroids, e.g. corticosteroids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/41—Anti-inflammatory agents, e.g. NSAIDs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/412—Tissue-regenerating or healing or proliferative agents
- A61L2300/414—Growth factors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/426—Immunomodulating agents, i.e. cytokines, interleukins, interferons
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/43—Hormones, e.g. dexamethasone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
- A61L2300/606—Coatings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants
Abstract
The invention discloses a polyetheretherketone composite implant and a preparation method and application thereof, wherein the composite implant comprises: the functional material comprises a polyether-ether-ketone substrate, a degradable polymer coating wrapped on the surface of the polyether-ether-ketone substrate, and a functional material loaded and/or grafted by the degradable polymer coating; the functional substance comprises a substance having an immune modulating function, and/or a substance having an osteogenesis modulating function. The preparation method comprises the following steps: constructing a degradable polymer coating loaded with functional substances on the surface of a polyether-ether-ketone substrate; modifying and activating the surface of the degradable polymer coating loaded with the functional substance, and introducing active groups on the surface of the degradable polymer coating loaded with the functional substance; the functional material is grafted by the active group. The application of the polyether-ether-ketone composite implant in preparing a medicine for treating bone defect. The polyether-ether-ketone composite implant prepared by the invention not only maintains the excellent mechanical property of the substrate polyether-ether-ketone, but also increases the immunocompetence and osteogenesis activity on the surface.
Description
Technical Field
The invention belongs to the technical field of biomedical high polymer materials, and relates to a polyether-ether-ketone composite implant with a bone immune regulation function, and a preparation method and application thereof.
Background
Bone defects are a common clinical condition and the implantation of filler materials is a common current method of treating bone defects. Performance requirements for conventional bone implant materials include: the material has excellent physical and chemical properties, such as good corrosion resistance, difficult surface abrasion and no toxic action of abrasive dust on a machine body; the mechanical properties are matched with bone tissues and good biological properties such as histocompatibility are required. With the development of implant materials and the further understanding of the interaction between implant materials and human body, especially the study of the interaction between implant and immune system, it is shown that the early immune environment after the material is implanted into the body has important influence on the later osseointegration, and it is found that the implant material existing as a foreign body, if it is continuously caused to cause local or systemic inflammation, will impair the healing of the bone[1]. Modern clinical medicine puts higher performance requirements on implanted materials, such as low immunogenicity, and even better induction of bone tissue regeneration can be realized by actively regulating immune response, namely, the material is used for regulating and controlling early bone immune environment, so that better bone regeneration is facilitated.
Poly-ether-ether-ketone (PEEK) is a semi-crystalline, thermoplastic, linear aromatic polymer, lightweight, biologically stable, non-toxic, mechanically close to human bone, approved by FDA and used clinically. Compared with traditional metal materials, the elastic modulus of PEEK is lower and is close to that of human cortical bone. This similarity may reduce the stress shielding effect caused by elastic mismatch, avoiding possible bone damage. In addition, PEEK has natural radiopacity, excellent mechanical properties and chemical resistance, however, PEEK materials are inherently bio-inert, lack immunological and osteogenic activity, and osteointegrative properties limit its clinical use.
PEEK is very limited in its ability to be chemically modified on its surface due to its exceptionally stable chemical inertness, often by physical means such as blending, surface physical coating functional coatingsLayer and physically mediated grafting. Common methods for modifying PEEK include blending with active substance (hydroxyapatite) or constructing a hydroxyapatite coating on the surface of the active substance[2](ii) a Injecting zinc ions into the plasmas after the surface of the PEEK is sulfonated[3](ii) a Grafting BMP-2 on the surface of PEEK by wet chemical grafting to improve osteogenesis performance[4](ii) a The plasma immersion ion implantation is carried out to construct a titanium dioxide or diamond-like carbon coating on the surface of the PEEK, increase the roughness of the surface, chemically modify and combine other bioactive particles[5,6]. The bone forming agent is modified by blending with active substances, and the mechanical property of the bone forming agent is changed to cause mismatching with adjacent bone tissues and influence the bone forming effect; the PEEK surface is constructed with a calcium phosphate or hydroxyapatite coating which can improve the surface bioactivity, but the prepared coating has limited bonding strength with the PEEK surface, can be peeled off, the hydroxyapatite layer on the substrate is easy to break, and can generate particle abrasion fragments which can change immune response, secrete inflammatory factors and cause pathological bone resorption. BMP-2 is chemically grafted by a wet method to improve osteogenesis performance, but a series of oxygen-containing groups are generated on the surface in the reaction, so that the uncertainty of subsequent experiments is increased, the protein is not favorably fixed in a directional manner, the reaction is not accurate enough, the reaction repeatability is poor, and the randomness of experimental results is high. The plasma immersion ion implantation is carried out to construct a titanium dioxide or diamond-like coating on the surface of the PEEK, so that the roughness of the surface of the PEEK can be increased, chemical modification can be carried out, and other bioactive particles can be combined; zinc ions are injected into plasmas after the surface of the PEEK is sulfonated, so that the roughness and the osteoconductivity of the surface are increased, but the performance of the coating or factors connected with the surface is single, the influence of inflammation on osteogenesis after the material is implanted is not considered, the inconsistent in-vivo and in-vitro results can be caused, and the implantation failure can be caused.
In summary, aiming at the problems of lack of immunological activity and osteogenesis activity, poor osseointegration property and the like on the surface of the PEEK material, the invention provides the PEEK composite implant with the bone immunological regulation function on the basis of the prior art, and has important application value.
Reference to the literature
[1]Wei F,Xiao Y.Modulation of the Osteoimmune Environment in the Development of Biomaterials for Osteogenesis[M]//Novel Biomaterials for Regenerative Medicine.Springer,Singapore,2018:69-86.
[2]S.-W.Ha,J.Mayer,B.Koch,and E.Wintermantel,“Plasma-sprayed hydroxylapatite coating on carbon fibre reinforced thermoplastic composite materials,”Journal of Materials Science:Materials in Medicine,vol.5,no.6-7,pp.481–484,1994.
[3]Liu,Wei,et al."Zinc-modified sulfonated polyetheretherketone surface with immunomodulatory function for guiding cell fate and bone regeneration."Advanced Science 5.10(2018):1800749.
[4]Liu L,Zheng Y,Zhang Q,et al.Surface phosphonation treatment shows dose-dependent enhancement of the bioactivity of polyetheretherketone[J].RSC Advances,2019,9.
[5]T.Lu,X.Liu,S.Qian et al.,“Multilevel surface engineering of nanostructured TiO2 on carbon-fiber-reinforced polyetheretherketone,”Biomaterials,vol.35,no.22,pp.5731–5740,2014.
[6]Dufils J,Faverjon F,Heau C,et al.Combination of laser surface texturing and DLC coating on PEEK for enhanced tribological properties[J].Surface&Coatings Technology,2017:29-41.
Disclosure of Invention
In order to solve the technical problems in the background art, the invention aims to provide a polyetheretherketone composite implant, a preparation method and an application thereof. The polyether-ether-ketone composite implant not only maintains the excellent mechanical property of PEEK, but also increases the osteogenic activity on the surface, can actively regulate and control the bone immunity in the early stage of implantation to realize better bone regeneration, and has simple and convenient preparation method operation.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows: in a first aspect, the present invention provides a polyetheretherketone composite implant comprising: the functional material comprises a polyether-ether-ketone substrate, a degradable polymer coating wrapped on the surface of the polyether-ether-ketone substrate, and a functional material loaded and/or grafted by the degradable polymer coating;
the functional substance comprises a substance with the function of regulating immunity and/or a substance with the function of regulating osteogenesis; preferably, the functional substance includes a substance having an immune modulating function and a substance having an osteogenesis modulating function;
the substance with the function of regulating the immunity comprises a biological molecule with the function of regulating the immunity and/or a medicament with the function of regulating the immunity; the substance having an osteogenesis regulating function includes a biomolecule having an osteogenesis regulating function, and/or a drug having an osteogenesis regulating function.
Further, comprising: the functional material comprises a polyether-ether-ketone substrate, a degradable polymer coating wrapped on the surface of the polyether-ether-ketone substrate, and a functional material loaded and grafted by the degradable polymer coating;
preferably, the functional substance grafted on the degradable polymer coating comprises a substance with an immune function, the substance with the immune function comprises a biomolecule with an immune function, and/or a drug with an immune function; the functional substance loaded on the degradable polymer coating comprises a substance with the function of regulating bone formation, and the substance with the function of regulating bone formation comprises a biological molecule with the function of regulating bone formation and/or a medicament with the function of regulating bone formation.
Further, the biomolecule having a regulatory immune function includes one or a combination of at least two of biomolecules having an effect of regulating inflammation, preferably, the biomolecule having a regulatory immune function includes one or a combination of at least two of IL-4, IL-6, IL-10, a precursor of NO, IL-12, TGF; more preferably, the biomolecule having a regulatory immune function is the cytokine IL-10;
the medicine with the function of regulating the immunity comprises one or the combination of at least two of immunosuppressant which can inhibit inflammatory reaction, inhibit inflammatory cell proliferation and activate autophagy reaction, and preferably, the medicine with the function of regulating the immunity comprises one or the combination of at least two of glucocorticoid, tacrolimus, rapamycin, thalidomide, triptodiolide, infliximab, adalimumab and mycophenolate mofetil.
Further, the medicine for regulating osteogenesis comprises one or a combination of at least two of medicines with anti-inflammatory, bone-promoting or osteoclastic inhibition effects, preferably, the medicine for regulating osteogenesis comprises one or a combination of at least two of dexamethasone, alendronate sodium, fluoride, statins, teriparatide and terlidine; more preferably, the osteogenesis modulating drug is Dexamethasone (DEX);
the biomolecule having the function of regulating the bone formation comprises one or a combination of at least two of the biomolecules capable of promoting angiogenesis, or promoting differentiation of stem cells into osteoblasts, or having the function of promoting proliferation of osteoblasts, and preferably, the biomolecule having the function of regulating the bone formation comprises one or a combination of at least two of BMP-2, VEGF, OPG, PDGF, TGF, and insulin-like growth factor-1.
Further, the degradable polymer coating comprises a coating formed by wrapping one or a combination of at least two of the following polymers on the surface of a polyether-ether-ketone substrate, wherein the polymers comprise polytrimethylene carbonate (PTMC), polylactic acid (PLA), Polycaprolactone (PCL), polylactic-polyglycolic acid (PLGA), aliphatic polyester polymers and aromatic-aliphatic copolyester;
preferably, the molecular weight of the polymer is 5000-50 ten thousand daltons.
In a second aspect, the present invention provides a method for preparing a peek composite implant, including the following steps:
constructing a degradable polymer coating loaded with functional substances on the surface of a polyether-ether-ketone substrate;
the functional substance comprises a substance with the function of regulating immunity and/or a substance with the function of regulating osteogenesis;
the substance with the function of regulating the immunity comprises a biological molecule with the function of regulating the immunity and/or a medicament with the function of regulating the immunity; the substance having an osteogenesis regulating function includes a biomolecule having an osteogenesis regulating function, and/or a drug having an osteogenesis regulating function.
Or 1) constructing a degradable polymer coating on the surface of the polyether-ether-ketone substrate;
2) modifying and activating the surface of the degradable polymer coating, and introducing active groups on the surface of the degradable polymer coating;
3) grafting a functional substance through an active group;
the functional substance comprises a substance with the function of regulating immunity and/or a substance with the function of regulating osteogenesis;
the substance with the function of regulating the immunity comprises a biological molecule with the function of regulating the immunity and/or a medicament with the function of regulating the immunity; the substance having an osteogenesis regulating function includes a biomolecule having an osteogenesis regulating function, and/or a drug having an osteogenesis regulating function.
Or 1) constructing a degradable polymer coating loaded with functional substances on the surface of a polyether-ether-ketone substrate;
2) modifying and activating the surface of the degradable polymer coating loaded with the functional substance, and introducing active groups on the surface of the degradable polymer coating loaded with the functional substance;
3) grafting a functional substance through an active group;
the functional substance comprises a substance with the function of regulating immunity and/or a substance with the function of regulating osteogenesis;
the substance with the function of regulating the immunity comprises a biological molecule with the function of regulating the immunity and/or a medicament with the function of regulating the immunity; the substance having an osteogenesis regulating function includes a biomolecule having an osteogenesis regulating function, and/or a drug having an osteogenesis regulating function.
Preferably, the method comprises the following steps:
1) constructing a degradable polymer coating loaded with a substance with an osteogenesis adjusting function on the surface of a polyether-ether-ketone substrate;
2) modifying and activating the surface of the degradable polymer coating loaded with the substance with the function of regulating osteogenesis, and introducing active groups into the surface of the degradable polymer coating loaded with the substance with the function of regulating osteogenesis;
3) grafting a substance with an immune function through an active group;
the substance with the function of regulating the immunity comprises a biological molecule with the function of regulating the immunity and/or a medicament with the function of regulating the immunity; the substance having an osteogenesis regulating function includes a biomolecule having an osteogenesis regulating function, and/or a drug having an osteogenesis regulating function.
Further, the method for constructing the degradable polymer coating loaded with the substance having the function of regulating osteogenesis comprises a solvent evaporation method, a pulling and leaching method or an atomization spraying method;
preferably, the mass ratio of the substance with the function of regulating bone formation to the polymer in the degradable polymer coating loaded with the substance with the function of regulating bone formation constructed on the surface of the polyetheretherketone substrate is 1: 1-30. When the content is outside the range, the content is too small to have a therapeutic effect, and the content is too high to have toxicity.
Further, the method for introducing active groups on the surface of the degradable polymer coating loaded with the substance with the function of regulating osteogenesis is gas plasma immersion ion implantation;
preferably, the gas used for the gas plasma immersion ion implantation comprises one or a combination of at least two of argon, nitrogen, ammonia, oxygen, hydrogen and the like;
preferably, the background vacuum degree used by the gas plasma immersion ion implantation is 1 × 10-3～9×10-3Pa；
Preferably, the gas introduction flow rate used for the gas plasma immersion ion implantation is 20-100 SCCM;
preferably, the negative bias voltage applied to the sample disc used for gas plasma immersion ion implantation is 0-10 kV;
preferably, the injection pulse width used for the gas plasma immersion ion injection is 20-200 microseconds;
preferably, the injection pulse frequency used for the gas plasma immersion ion injection is 50-500 Hz;
preferably, the radio frequency power used for the gas plasma immersion ion implantation is 100-1000W;
preferably, the implantation time for the gas plasma immersion ion implantation is 10-120 minutes.
Further, the method for grafting the substance with the immunoregulation function through the active group is to immerse the surface of the degradable polymer coating which is modified and activated to load the substance with the osteogenesis regulating function into a solution containing the substance with the immunoregulation function and incubate for a certain time to covalently graft the substance with the immunoregulation function. (ii) a
Preferably, the concentration of the solution containing the substance with the function of regulating the immunity is 10ng/mL-10 mu g/mL;
preferably, the grafting time is 6 to 72 hours.
In a third aspect, the invention provides the use of any one of the polyetheretherketone composite implants described above in the preparation of an implant for a bone defect filling site.
Compared with the prior art, the medicine-carrying modified coating constructed on the PEEK surface has the following advantages:
1) has bone immunity regulating function;
2) the drug-loaded modified coating constructed on the surface of the PEEK has time-sequence property on the controlled release of drugs, simulates the self-repairing process after the occurrence of human fracture or bone defect, regulates and controls inflammatory reaction and then osteogenesis, and improves the immunocompetence and osteogenesis activity of the PEEK material by superposing the double-layer effects of regulating and controlling inflammation and osteogenesis;
3) the PEEK composite implant has the characteristic of releasing regulatory factors in a time sequence in vivo, namely in the early inflammatory reaction stage, along with the degradation of a coating, immunoregulation molecules grafted on the surface are preferentially released to regulate and control the immune reaction in an osseous immune environment, along with the gradual degradation of a degradable high-molecular coating in the middle and later period of osteogenesis, and regulating osteogenesis medicines loaded inside, such as dexamethasone and the like, are released continuously to regulate and control osteogenesis, so that the material has both the immune activity and the osteogenesis activity, and is better applied clinically;
4) the drug-loaded coating constructed on the surface of the PEEK can control the long-term stable release of the drug, the cytotoxicity caused by overhigh local drug concentration can be avoided, the concentration of the released drug can be regulated and controlled by controlling the ratio of the drug to the high molecules, and the degradation period of the coating can be controlled by regulating the thickness of the coating and the molecular weight of the high molecules (for example, the higher the molecular weight of the polytrimethylene carbonate, the faster the degradation speed); the grafted biomolecule content can be controlled by adjusting the concentration of the grafted biomolecule solution;
5) compared with the construction of inorganic and metal non-degradable coatings on the surface of the PEEK, the drug-loaded coating does not change the properties of the PEEK material, keeps the excellent mechanical properties of the substrate PEEK, and has tight combination of the surface coating and a matrix;
6) according to the invention, the biological molecules can be directly grafted after the surface of the drug-loaded polymer is treated by plasma immersion ion injection, and a chemical cross-linking agent is not required, so that the method is safe, simple and convenient.
7) The drug-loaded coating constructed on the surface of the PEEK can greatly improve the surface physicochemical properties such as hydrophilic and hydrophobic properties, surface energy and surface chemical components and improve the surface bioactivity of the PEEK on the premise of not influencing the performance of a PEEK material matrix.
8) The method for constructing the drug-loaded coating on the PEEK surface is simple and convenient, and the operation is simple.
Drawings
FIG. 1a is a scanning electron micrograph of poly (ether ketone) (PEEK) without modification according to example 1 of the present invention; FIG. 1b is a scanning electron micrograph of a surface of a 5% DEX coating on a PEEK surface prepared by a solution evaporation method in example 1 according to the present invention;
FIG. 2 is a scanning electron micrograph of a 5% DEX surface treated by nitrogen plasma immersion ion implantation in example 2 of the present invention;
FIG. 3 is a scanning electron microscope image of the surface of 2KV-IL-10 with IL-10 concentration of 40ng/ml after nitrogen plasma immersion ion implantation in example 3 of the present invention;
FIG. 4a shows the results of the static water contact angles of the front and back surfaces of the modified PEEK material in example 4 of the present invention; FIG. 4b is a graph showing the results of measuring the water contact angle of the sample after the plasma surface treatment of example 2 in example 4 of the present invention after being left for one month;
FIG. 5 is a full spectrum of surface elements of the modified PEEK material of example 5 of the present invention measured by an X-ray electron spectrometer;
FIG. 6a is a graph showing the results of proliferation of macrophage RAW264.7 on the surface of each sample in example 6 of the present invention; FIG. 6b is a graph showing the results of detecting the expression of inflammation-associated factors TNF- α and TGF- β 1 by use of the Mouse TGF-beta1 value ELISA kit (R & D system) and the Mouse TNF-A value ELISA kit (R & D) in example 6 of the present invention; FIG. 6c is a graph showing the results of detecting the expression of M1 and M2 related genes by real-time fluorescent quantitative PCR in example 6 of the present invention;
FIG. 7 shows the results of real-time fluorescent quantitative PCR detection of the expression of bone-formation-related genes in conditioned medium in example 7 of the present invention; wherein RAW264.7(+) represents conditioned medium and RAW264.7(-) represents unconditioned medium;
FIG. 8a is a graph showing the proliferation of MC3T3-E1 cells on the surface of each sample in example 8 of the present invention; FIG. 8b is a graph showing the results of real-time quantitative fluorescence PCR detection of the expression of the osteogenesis related gene of MC3T3-E1 cells on the surface of the sample and their mineralization on the surface of the sample in example 8 of the present invention;
FIG. 9 is a graph showing immunofluorescence results for macrophage phenotype after implantation of each sample subcutaneously into rats in example 9 of the present invention;
FIG. 10a is a 3D model and 2D image obtained by Micro-CT after implantation of each sample into rat femur in example 10 of the present invention FIG. 10b is the VG staining result of the section of the rat femur after implantation of each sample into the new bone tissue in example 10 of the present invention.
Detailed Description
For a better understanding of the present invention, reference is made to the following detailed description taken in conjunction with the accompanying drawings, and the scope of the invention is not limited to the following examples.
Example 1 preparation of PEEK and 5% DEX samples
And sequentially polishing the PEEK wafer with the diameter of 15mm and the thickness of 1mm by using sand with the mesh number of 600, 800, 1000, 1200 and 2000, and ultrasonically cleaning the polished PEEK by using acetone, alcohol and deionized water. The pretreated sample was labeled PEEK.
A drug-loaded coating is constructed on the surface of the PEEK by a solvent volatilization method. The selected polymer coating is polytrimethylene carbonate (PTMC), the solvent is dichloromethane, the medicament is dexamethasone, and the mass ratio of the medicament to the polymer is 1: 5. the pretreated sample was labeled 5% DEX. The preparation method comprises the following steps: firstly, mixing PTMC and dexamethasone according to a mass ratio of 5: 1 adding the mixture into a dichloromethane solution to be dissolved and uniformly mixed to form a uniform solution, pouring the uniform solution containing the PTMC and the dexamethasone on the surface of a PEEK sample, and forming a uniform coating on the surface of the PEEK after the dichloromethane serving as a solvent is completely volatilized.
And observing the surface of the polyetheretherketone before and after treatment by a scanning electron microscope to obtain the surface micro-morphology shown in figure 1. Fig. 1a shows that the trace of sanding is visible on the PEEK surface without the coating, and fig. 1b shows that the entire surface is smooth and flat after the drug-loaded coating is formed on the PEEK surface, and no drug is enriched on the PEEK surface.
EXAMPLE 22 preparation of KV samples
The 5% DEX in example 1 was treated using a gas plasma immersion ion implantation technique. The specific treatment process comprises the following steps: background vacuum degree of 2X 10-3Pa, the gas introduction flow rate is 60SCCM, the negative bias voltage applied to the sample plate is 2kV, the injection pulse width is 50 microseconds, the injection pulse frequency is 50Hz, and the radio frequency power is 1000W. The nitrogen injection time was 60 minutes, and the treated sample was referred to as 2 KV. The surface of 5% DEX after the nitrogen plasma immersion ion implantation treatment was observed by a scanning electron microscope to obtain a surface microtopography photograph shown in fig. 2. As can be seen from FIG. 2, there was no significant difference between the surface of the 5% DEX and the surface of the 2KV sample, indicating that the nitrogen plasma immersion ion implantation treatment pairThe surface morphology of the 5% DEX did not change significantly.
EXAMPLE 32 KV-IL-10 sample preparation
The 2KV sample after the modification treatment in example 2 was immersed in a Phosphate Buffered Saline (PBS) containing IL-10 at a concentration of 40ng/ml for 24 hours at 4 ℃. The coupon was then removed from the IL-10 solution and rinsed with IL-10 free PBS to remove ungrafted IL-10, which was labeled 2 KV-IL-10. The microstructure of the sample after grafting IL-10 was observed by a scanning electron microscope, and the result is shown in FIG. 3. From FIG. 3 it can be seen that there is no significant change in the surface of the coating after grafting of IL-10.
Example 4 test of hydrophilicity and hydrophobicity of samples obtained in example 1, example 2, and example 3
The samples obtained in example 1, example 2 and example 3 were dried in a vacuum oven for 24 hours, and then the surface hydrophilicity and hydrophobicity thereof was measured using a water contact angle meter, and the results are shown in fig. 4 a. From fig. 4a, it can be seen that the water contact angle of PEEK is 95 degrees, the PEEK is a hydrophobic surface, after a 5% dexamethasone-loaded coating is constructed on the surface of the PEEK, the contact angle of the 5% DEX surface is 85 degrees, the hydrophilicity is obviously improved, after nitrogen plasma treatment, the surface hydrophilic groups are increased, the surface contact angle of 2KV is reduced to 56 degrees, the water contact angle of the 2KV-IL-10 surface after IL-10 grafting is 38 degrees, and it can be seen that the hydrophilicity is significantly improved after the PEEK surface is modified. The sample after the plasma surface treatment in example 2 was left for one month and then subjected to the water contact angle detection again, and the detection result is shown in fig. 4b, which indicates that the hydrophilic and hydrophobic properties of the sample surface were not changed after one month, and the improvement effect on the hydrophilicity was long-lasting.
Example 5X-ray photoelectron spectroscopy measurements of samples obtained in example 1, example 2 and example 3
The samples obtained in example 1, example 2 and example 3 were analyzed for changes in surface elements by X-ray photoelectron spectroscopy (XPS), and the total spectrum is shown in fig. 5. As can be seen from FIG. 5, only characteristic peaks of C1s (285.14eV) and O1s (532.03eV) and N1s (400.00eV) are appeared in the pattern of polytrimethylene carbonate (PTMC) and 5% DEX, after the treatment of nitrogen plasma, a characteristic peak of Sp2(164.02eV) is newly appeared in the sample of 2KV, and after the grafting of IL-10, the N signal is remarkably enhanced in the sample, because the IL-10 protein is grafted, and the IL-10 protein contains a large amount of N elements.
Example 6 the samples obtained in example 1, example 2, example 3 were tested in vitro for the experimental modulation of inflammatory responses
4 ten thousand macrophages RAW264.7 are inoculated on the surface of each sample after ultraviolet sterilization, the increment of the macrophages RAW264.7 is measured by CCK-8 after the samples are cultured for 1, 3 and 5 days, the result is shown in figure 6a, figure 6a is a result of the increment of the macrophages RAW264.7 on the surface of the sample, the result in the figure shows that the PEEK surface has an inhibition effect on the proliferation of the macrophages after being loaded with dexamethasone, the inhibition effect on the macrophages after the surface is grafted with IL-10 after being treated by plasma is more obvious, and the coating prepared on the PEEK surface can inhibit the proliferation of the macrophages.
4 ten thousand macrophages RAW264.7 are inoculated on the surface of each sample after ultraviolet sterilization, after inoculation for 6 hours, cell culture medium supernatant of each sample is collected and centrifuged at 2000rpm for 5 minutes, then a Mouse TGF-beta1 value ELISA kit (R & D system) and a Mouse TNF-A value ELISA kit (R & D) are used for detecting the expression of inflammation related factors TNF-alpha and TGF-beta1 according to the specification of the kit, the detection result is shown in figure 6b, compared with a PEEK group, other three groups have the functions of inhibiting the release of a macrophage proinflammatory inflammatory factor TNF-alpha and promoting the release of a macrophage proinflammatory factor TGF-beta1, wherein the effect of a 2KV-IL-10 group is the most obvious.
After the samples are subjected to ultraviolet sterilization, 4 ten thousand macrophages RAW264.7 are inoculated on the surfaces of the samples, after the cells are cultured on the surfaces of the samples for 1 day and 3 days, macrophage RNA is extracted by Trizol, after reverse transcription, the relative expression of M1 phenotype genes CCR-7, TNF-a and IL 1-beta and the relative expression of M2 phenotype genes CD206, IL-10 and TGF-beta1 are further detected by real-time fluorescence quantitative PCR after the macrophages are cultured on the surfaces of the samples for 1 day and 3 days, and the results are shown in figure 6 c. The relative expressions of M1 type genes CCR-7, TNF-a and IL-1b are lower than that of a PEEK group after other three groups of macrophages are cultured for 1 day and 3 days, and the relative expressions of M2 type genes CD206, IL-10 and TGF-b are higher than that of the PEEK group, so that the relative expressions of the M1 type genes can be inhibited and the expression of the M2 type genes can be promoted after a drug-loaded coating is constructed on the PEEK.
In conclusion, the results in fig. 6b and fig. 6c show that the modified coating 2KV-IL-10 on the PEEK surface can better inhibit the macrophage polarization to M1 type and promote the macrophage polarization to M2 type compared with other groups.
Example 7 investigation of the effects of the PEEK surface modification layer on the regulation of macrophage on osteogenesis
Culturing macrophages on the samples in example 1, example 2 and example 3 for 1 to 3 days, collecting culture medium to obtain culture medium supernatant, and mixing the macrophage culture medium supernatant and DMEM high-sugar medium in a volume ratio of 2: 1 mixing and preparing a conditioned medium; the treatment mode of each sample is consistent with the treatment mode of inoculating macrophages, the samples are placed in a 24-well plate, an equal volume of serum-free and cell-free high-sugar culture medium is added into each well, the culture medium with 1 day to three days is collected to be used as an unconditional culture medium, 3 thousands of mouse embryonic osteoblast precursor cells (MC3T3-E1) are inoculated into the 24-well plate, the culture medium is removed after 12 hours, the conditioned medium and the unconditional culture medium with corresponding days are replaced every day, the expression of osteogenic genes ALP, OCN, OPN and RUNX2 is detected by real-time fluorescence quantitative PCR after three days of culture, the influence of a PEEK surface modification layer on osteogenesis after regulating the macrophages is researched, and the result is shown in figure 7. As can be seen from the expression of the real-time fluorescence quantitative PCR osteogenesis related genes in FIG. 7, the macrophage conditioned medium group has higher expression than the unconditioned medium group, and compared with the PEEK group, the expression of each gene in the other three groups is higher, wherein the difference between the 2KV-IL-10 group and the PEEK group is the largest, which indicates that the PEEK can regulate and control macrophages to promote osteogenesis after being modified.
Example 8 the samples obtained in example 1, example 2, example 3 were tested in vitro for the experimental regulation of osteogenesis
Performing experiments for regulating osteogenesis on the samples in example 1, example 2 and example 3 in vitro, inoculating MC3T3-E1 cells on the surface of each sample, and measuring the proliferation effect of the cells on the surface by a CCK-8 reagent after 1, 3 and 7 days; after 80% of the surface-planted cells grow, the normal culture medium is changed into osteogenesis inducing liquid to be cultured again for 7,14 and 21 days, the expression of osteogenesis related genes ALP, OCN and OPN is detected through real-time fluorescence quantitative PCR, the degree of mineralization of the cells on the surface of the sample is detected through alizarin red staining, and the result is shown in figure 8. FIG. 8a is a result of proliferation of MC3T3-E1 cells on the surface of each sample; FIG. 8b shows the results of real-time fluorescent quantitative PCR detection of the expression of the osteogenesis related genes ALP, OCN and OPN in MC3T3-E1 cells on the surface of the sample and their mineralization on the surface of the sample. As can be seen from the results of proliferation of MC3T3-E1 cells in FIG. 8a, after 1 day, 3 days, and 7 days of culture, the 5% DEX group and the 2KV group have lower cell proliferation than PEEK due to the action of dexamethasone, and the 2KV-IL-10 group has higher cell proliferation than PEEK, which indicates that the modified coating 2KV-IL-10 prepared on the PEEK surface can promote the proliferation of MC3T3-E1 cells in vitro, and as can be seen from the relative expression of ALP, OCN and OPN of osteogenic genes in FIG. 8b, three groups of 5% DEX, 2KV and 2KV-IL-10 have higher expression than PEEK group, the expression of the 2KV-IL-10 group is the highest, and the mineralization of the surfaces of the three groups of 5% DEX, 2KV and 2KV-IL-10 is more obvious than that of the PEEK group as can be seen from the mineralization result of 21 days, wherein the effect of the 2KV-IL-10 group is the most obvious. The experiments related to cell proliferation and osteogenesis show that the modified coating 2KV-IL-10 prepared on the surface can promote the cell proliferation and osteogenesis differentiation of MC3T 3-E1.
Example 9 investigation of whether the sample PEEK, 5% DEX, 2KV-IL-10 of example 1, example 3 could modulate inflammatory responses in vivo
The samples PEEK, 5% DEX, 2KV-IL-10 obtained in example 1 and example 3 were implanted subcutaneously in SD rats in the following manner: 9 SD female rats of about 12 weeks old were randomly divided into three groups, anesthetized by preoperative injection of 2% sodium pentobarbital (2.3ml/kg), and after appropriate anesthesia, the rats were stood on an operating table. Preparing skin, sterilizing with conventional iodophor, cutting at symmetrical positions on mouse back, implanting each group of samples under skin, suturing, and sterilizing with iodophor. Rats were sacrificed 3 days after material implantation. The tissue with the implant was fixed in 4% paraformaldehyde, and after fixation, immunofluorescence staining was performed to investigate whether the PEEK modified could regulate the inflammatory response in vivo, and the immunofluorescence results of regulating macrophage phenotype are shown in fig. 9. In FIG. 9, DAPI stains cell nucleus, INOS stains macrophage expressing M1 type, CD163 stains M2 type, and it can be seen that 5% DEX and 2KV-IL-10 group iNOS are expressed less than PEEK, and CD163 is expressed more than PEEK, wherein 2KV-IL-10 group is more significant than 5% DEX group, and the results show that 5% DEX and 2KV-IL-10 of modified PEEK sample can also inhibit inflammatory reaction in vivo, and regulate macrophage polarization to M2 type.
Example 10 investigation of the osteogenic Effect of the sample PEEK, 5% DEX, 2KV-IL-10 of example 1, example 3 in vivo
The PEEK samples from example 1 and example 3, 5% DEX, 2KV IL-10, were implanted into the femurs of SD rats as follows: 9 SD female rats of about 12 weeks old were randomly divided into three groups, anesthetized by preoperative injection of 2% sodium pentobarbital (2.3ml/kg), and after appropriate anesthesia, the rats were fixed on an operating table in a supine position. Preparing skin, sterilizing with conventional iodophor and ethanol. Fixing the knee joint at the maximum bending position, cutting a longitudinal incision with the length of about 10mm along the outer side of the knee joint, separating muscles bluntly, displacing the knee joint to expose the far end of the femur, drilling a cylindrical hole with the diameter of 2mm (cooling with physiological saline while drilling to prevent bone necrosis caused by overhigh temperature) at the intercondylar notch of the far end of the femur, flushing the residual scraps with the physiological saline after drilling the hole, implanting the prepared sample, and making each rat as a bilateral far-end femur defect. The wound was carefully sutured closed. The iodine disinfects the wound after operation. To characterize the formation and mineralization of new bone, multicolor sequential fluorescent labeling was used, followed by sequential intraperitoneal injections of the fluorescent stains alizarin red S (purchased from sigma-Aldrich, usa), tetracycline hydrochloride 25mg/kg and calcein (sigma-Aldrich) 20mg/kg at 2, 4 and 6 weeks post-surgery. Rats were sacrificed 8 weeks after material implantation. Fixing the femur with the implant in 4% paraformaldehyde, and after fixing, carrying out Micro-CT detection and histomorphology observation to explore the osteogenesis effect in vivo; the removed bones containing the samples were fixed with 4% paraformaldehyde, gradient ethanol dehydrated (80%, 90%, 100%), PMMA embedded, sectioned and then characterized for new bone formation by VG staining, the results of which are shown in fig. 10. FIG. 10a is a 3D model and 2D image obtained by Micro-CT, the results show that after 8 weeks, new bone around the material is generated by 5% DEX and the 2KV-IL-10 group samples are significantly higher than the PEEK group samples, which indicates that the two groups of samples can stimulate more new bone to grow in the marrow cavity, and show better bone integration, especially the 2KV-IL-10 effect is significant; FIG. 10b is the VG staining of the new bone tissue after sectioning, showing that new bone was formed around both the 5% DEX and 2KV-IL-10 groups and the bone layer was intact and thicker than the PEEK group, indicating that the modified PEEK had good osteogenic activity and the 2KV-IL-10 group was more effective than the 5% DEX group.
In conclusion, the PEEK composite implant can simulate the human bone regeneration process, and promote the rapid regeneration of bones at bone defect positions by regulating a bone immune system and bone healing growth factors. In the early stage of implantation in vivo, the phenotype of macrophage can be regulated and controlled by cytokine, so that the macrophage is polarized from the pro-inflammatory phenotype M1 type to the anti-inflammatory M2 type, namely the immune system is regulated to be converted from inflammatory reaction to promotion of bone repair; and further promotes osteogenic differentiation through subsequent drug release, thereby endowing the prepared PEEK compound implant with active bone immune regulation and control capability and realizing better bone regeneration. The preparation method of the composite implant is simple to operate, safe and harmless.
The above description is only a specific embodiment of the present invention, and not all embodiments, and any equivalent modifications of the technical solutions of the present invention, which are made by those skilled in the art through reading the present specification, are covered by the claims of the present invention.
Claims (10)
1. A polyetheretherketone composite implant, comprising: the functional material comprises a polyether-ether-ketone substrate, a degradable polymer coating wrapped on the surface of the polyether-ether-ketone substrate, and a functional material loaded and/or grafted by the degradable polymer coating;
the functional substance comprises a substance with the function of regulating immunity and/or a substance with the function of regulating osteogenesis;
the substance with the function of regulating the immunity comprises a biological molecule with the function of regulating the immunity and/or a medicament with the function of regulating the immunity; the substance having an osteogenesis regulating function includes a biomolecule having an osteogenesis regulating function, and/or a drug having an osteogenesis regulating function.
2. The polyetheretherketone composite implant of claim 1, comprising: the functional material comprises a polyether-ether-ketone substrate, a degradable polymer coating wrapped on the surface of the polyether-ether-ketone substrate, and a functional material loaded and grafted by the degradable polymer coating;
preferably, the functional substance grafted on the degradable polymer coating comprises a substance with an immune function, the substance with the immune function comprises a biomolecule with an immune function, and/or a drug with an immune function; the functional substance loaded on the degradable polymer coating comprises a substance with the function of regulating bone formation, and the substance with the function of regulating bone formation comprises a biological molecule with the function of regulating bone formation and/or a medicament with the function of regulating bone formation.
3. The peek composite implant according to claim 1 or 2, wherein the biomolecule having a regulatory immune function comprises one or a combination of at least two of biomolecules having a role in regulating inflammation, preferably the biomolecule having a regulatory immune function comprises one or a combination of at least two of IL-4, IL-6, IL-10, precursors of NO, IL-12, TGF; more preferably, the biomolecule having a regulatory immune function is the cytokine IL-10;
the medicine with the function of regulating the immunity comprises one or the combination of at least two of immunosuppressant which can inhibit inflammatory reaction, inhibit inflammatory cell proliferation and activate autophagy reaction, and preferably, the medicine with the function of regulating the immunity comprises one or the combination of at least two of glucocorticoid, tacrolimus, rapamycin, thalidomide, triptodiolide, infliximab, adalimumab and mycophenolate mofetil.
4. The peek composite implant of claim 1 or 2, wherein the drug having an osteogenesis regulating function includes one or a combination of at least two of drugs having an anti-inflammatory, bone-promoting or osteoclast-inhibiting effect, preferably the drug having an osteogenesis regulating function includes one or a combination of at least two of dexamethasone, alendronate, fluoride, statins, teriparatide, and terlidine; more preferably, the osteogenesis modulating drug is dexamethasone;
the biomolecule having the function of regulating the bone formation comprises one or a combination of at least two of the biomolecules capable of promoting angiogenesis, or promoting differentiation of stem cells into osteoblasts, or having the function of promoting proliferation of osteoblasts, and preferably, the biomolecule having the function of regulating the bone formation comprises one or a combination of at least two of BMP-2, VEGF, OPG, PDGF, TGF, and insulin-like growth factor-1.
5. The peek composite implant of claim 1 or 2, wherein the degradable polymer coating layer comprises a coating layer formed by wrapping one or a combination of at least two of the following polymers on the surface of the peek substrate, wherein the polymers include polytrimethylene carbonate, polylactic acid, polycaprolactone, polylactic acid-polyglycolic acid, aliphatic polyester-based polymer, and aromatic-aliphatic copolyester.
6. The method of preparing a polyetheretherketone composite implant according to any of claims 1 to 5, comprising the steps of:
constructing a degradable polymer coating loaded with functional substances on the surface of a polyether-ether-ketone substrate;
the functional substance comprises a substance with the function of regulating immunity and/or a substance with the function of regulating osteogenesis;
the substance with the function of regulating the immunity comprises a biological molecule with the function of regulating the immunity and/or a medicament with the function of regulating the immunity; the substance with the function of regulating the bone formation comprises a biological molecule with the function of regulating the bone formation and/or a medicament with the function of regulating the bone formation;
or 1) constructing a degradable polymer coating on the surface of the polyether-ether-ketone substrate;
2) modifying and activating the surface of the degradable polymer coating, and introducing active groups on the surface of the degradable polymer coating;
3) grafting a functional substance through an active group;
the functional substance comprises a substance with the function of regulating immunity and/or a substance with the function of regulating osteogenesis;
the substance with the function of regulating the immunity comprises a biological molecule with the function of regulating the immunity and/or a medicament with the function of regulating the immunity; the substance with the function of regulating the bone formation comprises a biological molecule with the function of regulating the bone formation and/or a medicament with the function of regulating the bone formation;
or 1) constructing a degradable polymer coating loaded with functional substances on the surface of a polyether-ether-ketone substrate;
2) modifying and activating the surface of the degradable polymer coating loaded with the functional substance, and introducing active groups on the surface of the degradable polymer coating loaded with the functional substance;
3) grafting a functional substance through an active group;
the functional substance comprises a substance with the function of regulating immunity and/or a substance with the function of regulating osteogenesis;
the substance with the function of regulating the immunity comprises a biological molecule with the function of regulating the immunity and/or a medicament with the function of regulating the immunity; the substance with the function of regulating the bone formation comprises a biological molecule with the function of regulating the bone formation and/or a medicament with the function of regulating the bone formation;
preferably, the method comprises the following steps:
1) constructing a degradable polymer coating loaded with a substance with an osteogenesis adjusting function on the surface of a polyether-ether-ketone substrate;
2) modifying and activating the surface of the degradable polymer coating loaded with the substance with the function of regulating osteogenesis, and introducing active groups into the surface of the degradable polymer coating loaded with the substance with the function of regulating osteogenesis;
3) grafting a substance with an immune function through an active group;
the substance with the function of regulating the immunity comprises a biological molecule with the function of regulating the immunity and/or a medicament with the function of regulating the immunity; the substance having an osteogenesis regulating function includes a biomolecule having an osteogenesis regulating function, and/or a drug having an osteogenesis regulating function.
7. The method for preparing a polyetheretherketone composite implant according to claim 6, wherein the method for constructing the degradable polymer coating loaded with the substance having an osteogenesis-regulating function comprises a solvent evaporation method, a dip-coating method or an atomized spray method;
preferably, the mass ratio of the substance with the function of regulating bone formation to the polymer in the degradable polymer coating loaded with the substance with the function of regulating bone formation constructed on the surface of the polyetheretherketone substrate is 1: 1-30.
8. The method for preparing a polyetheretherketone composite implant according to claim 6, wherein the method for introducing active groups on the surface of the degradable polymer coating loaded with the substance having the function of regulating bone formation is gas plasma immersion ion implantation;
preferably, the gas used for the gas plasma immersion ion implantation comprises one or a combination of at least two of argon, nitrogen, ammonia, oxygen, hydrogen and the like;
preferably, the background vacuum degree used by the gas plasma immersion ion implantation is 1 × 10-3～9×10-3Pa；
Preferably, the gas introduction flow rate used for the gas plasma immersion ion implantation is 20-100 SCCM;
preferably, the negative bias voltage applied to the sample disc used for gas plasma immersion ion implantation is 0-10 kV;
preferably, the injection pulse width used for the gas plasma immersion ion injection is 20-200 microseconds;
preferably, the injection pulse frequency used for the gas plasma immersion ion injection is 50-500 Hz;
preferably, the radio frequency power used for the gas plasma immersion ion implantation is 100-1000W;
preferably, the implantation time for the gas plasma immersion ion implantation is 10-120 minutes.
9. The method for preparing a polyetheretherketone composite implant according to claim 6, wherein the method for grafting a substance having an immune modulating function by an active group comprises immersing the surface of the degradable polymer coating layer modified to activate and load the substance having an osteogenesis modulating function in a solution containing the substance having an immune modulating function and incubating for a certain time to covalently graft the substance having an immune modulating function;
preferably, the concentration of the solution containing the substance with the function of regulating the immunity is 10ng/mL-10 mu g/mL;
preferably, the grafting time is 6 to 72 hours.
10. Use of a polyetheretherketone composite implant according to any one of claims 1 to 5 for the preparation of an implant for the filling of a bone defect site.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010495733.2A CN113750290A (en) | 2020-06-03 | 2020-06-03 | Polyether-ether-ketone composite implant and preparation method and application thereof |
| PCT/CN2020/131209 WO2021243979A1 (en) | 2020-06-03 | 2020-11-24 | Polyether-ether-ketone composite implant, preparation method therefor and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010495733.2A CN113750290A (en) | 2020-06-03 | 2020-06-03 | Polyether-ether-ketone composite implant and preparation method and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN113750290A true CN113750290A (en) | 2021-12-07 |
Family
ID=78783337
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010495733.2A Pending CN113750290A (en) | 2020-06-03 | 2020-06-03 | Polyether-ether-ketone composite implant and preparation method and application thereof |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN113750290A (en) |
| WO (1) | WO2021243979A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114805888A (en) * | 2022-03-29 | 2022-07-29 | 陕西师范大学 | Method for improving surface bioactivity and osseointegration performance of polyether-ether-ketone substrate |
| CN115282335A (en) * | 2022-08-05 | 2022-11-04 | 河北医科大学口腔医院 | Preparation method of bone repair scaffold |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114712558B (en) * | 2022-03-18 | 2023-03-28 | 华中科技大学 | Polyether-ether-ketone biological composite powder and preparation method and application thereof |
| CN114668894B (en) * | 2022-04-07 | 2022-10-14 | 吉林大学 | Preparation method of MOF coating modified polyether-ether-ketone base material implantation material |
| CN115382017B (en) * | 2022-08-16 | 2023-06-20 | 兰州大学 | Novel 3D printing polyether-ether-ketone implant capable of carrying medicine and preparation method thereof |
Citations (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1453354A (en) * | 2003-05-19 | 2003-11-05 | 浙江大学 | Method of introducing cell growth factor to surface of biological polymer material |
| US20050031689A1 (en) * | 2003-05-21 | 2005-02-10 | Dexcom, Inc. | Biointerface membranes incorporating bioactive agents |
| CN102018996A (en) * | 2010-12-14 | 2011-04-20 | 中国医学科学院生物医学工程研究所 | Manufacturing method of drug vessel support with antibody immobilized on surface of support |
| US20120010599A1 (en) * | 2010-07-06 | 2012-01-12 | The Regents Of The University Of California | Inorganically surface-modified polymers and methods for making and using them |
| CN103865084A (en) * | 2014-04-09 | 2014-06-18 | 中国科学院上海硅酸盐研究所 | Polyether-ether-ketone material and surface modification method thereof |
| CN104107459A (en) * | 2014-04-22 | 2014-10-22 | 吉林大学 | Degradable polymer coating support with sequential response function, and making method thereof |
| CN106178104A (en) * | 2016-08-29 | 2016-12-07 | 上海交通大学 | A kind of medical medicine-carried porous polyether-ether-ketone and manufacture method thereof and application |
| CN106702341A (en) * | 2016-11-24 | 2017-05-24 | 中国科学院深圳先进技术研究院 | Polyether-ether-ketone material and modification method based on plasma immersion ion implantation and application |
| CN107189096A (en) * | 2017-04-28 | 2017-09-22 | 深圳先进技术研究院 | A kind of macromolecule material surface modification method and products thereof and purposes |
| CN108310457A (en) * | 2018-03-15 | 2018-07-24 | 四川大学 | Polyether-ether-ketone bone impairment renovation material and preparation method |
| WO2019034207A2 (en) * | 2017-08-14 | 2019-02-21 | Verein zur Förderung von Innovationen durch Forschung, Entwicklung und Technologietransfer e.V. (Verein INNOVENT e.V.) | Method for producing a biocompatible layer on an implant surface |
| CN109485896A (en) * | 2018-11-13 | 2019-03-19 | 山东凯旋美奥口腔门诊部有限公司 | A kind of preparation method and purposes of modified polyether ether ketone |
| CN110279890A (en) * | 2019-04-15 | 2019-09-27 | 首都医科大学附属北京世纪坛医院 | Method of modifying and application of the dexamethasone/minocycline based on liposome on the surface PEEK |
| US20200022814A1 (en) * | 2018-07-19 | 2020-01-23 | CryoHeart Laboratories, Inc. | System and method to fuse bone |
-
2020
- 2020-06-03 CN CN202010495733.2A patent/CN113750290A/en active Pending
- 2020-11-24 WO PCT/CN2020/131209 patent/WO2021243979A1/en active Application Filing
Patent Citations (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1453354A (en) * | 2003-05-19 | 2003-11-05 | 浙江大学 | Method of introducing cell growth factor to surface of biological polymer material |
| US20050031689A1 (en) * | 2003-05-21 | 2005-02-10 | Dexcom, Inc. | Biointerface membranes incorporating bioactive agents |
| US20120010599A1 (en) * | 2010-07-06 | 2012-01-12 | The Regents Of The University Of California | Inorganically surface-modified polymers and methods for making and using them |
| CN102018996A (en) * | 2010-12-14 | 2011-04-20 | 中国医学科学院生物医学工程研究所 | Manufacturing method of drug vessel support with antibody immobilized on surface of support |
| CN103865084A (en) * | 2014-04-09 | 2014-06-18 | 中国科学院上海硅酸盐研究所 | Polyether-ether-ketone material and surface modification method thereof |
| CN104107459A (en) * | 2014-04-22 | 2014-10-22 | 吉林大学 | Degradable polymer coating support with sequential response function, and making method thereof |
| CN106178104A (en) * | 2016-08-29 | 2016-12-07 | 上海交通大学 | A kind of medical medicine-carried porous polyether-ether-ketone and manufacture method thereof and application |
| CN106702341A (en) * | 2016-11-24 | 2017-05-24 | 中国科学院深圳先进技术研究院 | Polyether-ether-ketone material and modification method based on plasma immersion ion implantation and application |
| CN107189096A (en) * | 2017-04-28 | 2017-09-22 | 深圳先进技术研究院 | A kind of macromolecule material surface modification method and products thereof and purposes |
| WO2019034207A2 (en) * | 2017-08-14 | 2019-02-21 | Verein zur Förderung von Innovationen durch Forschung, Entwicklung und Technologietransfer e.V. (Verein INNOVENT e.V.) | Method for producing a biocompatible layer on an implant surface |
| CN108310457A (en) * | 2018-03-15 | 2018-07-24 | 四川大学 | Polyether-ether-ketone bone impairment renovation material and preparation method |
| US20200022814A1 (en) * | 2018-07-19 | 2020-01-23 | CryoHeart Laboratories, Inc. | System and method to fuse bone |
| CN109485896A (en) * | 2018-11-13 | 2019-03-19 | 山东凯旋美奥口腔门诊部有限公司 | A kind of preparation method and purposes of modified polyether ether ketone |
| CN110279890A (en) * | 2019-04-15 | 2019-09-27 | 首都医科大学附属北京世纪坛医院 | Method of modifying and application of the dexamethasone/minocycline based on liposome on the surface PEEK |
Non-Patent Citations (3)
| Title |
|---|
| XIE, LINGXIA等: "Programmed surface on poly(aryl-ether-ether-ketone) initiating immune mediation and fulfilling bone regeneration sequentially", 《INNOVATION (NEW YORK, N.Y.)》 * |
| 倪墡玲等: "提高聚醚醚酮生物活性材料的研究进展", 《中华老年口腔医学杂志》 * |
| 李中杰等: "聚醚醚酮材料表面改性后成骨效能的研究进展", 《广东医学》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114805888A (en) * | 2022-03-29 | 2022-07-29 | 陕西师范大学 | Method for improving surface bioactivity and osseointegration performance of polyether-ether-ketone substrate |
| CN114805888B (en) * | 2022-03-29 | 2023-08-08 | 陕西师范大学 | Method for improving surface bioactivity and osseointegration performance of polyether-ether-ketone base material |
| CN115282335A (en) * | 2022-08-05 | 2022-11-04 | 河北医科大学口腔医院 | Preparation method of bone repair scaffold |
| CN115282335B (en) * | 2022-08-05 | 2023-08-29 | 河北医科大学口腔医院 | Preparation method of bone repair stent |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2021243979A1 (en) | 2021-12-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Gao et al. | Biofunctional magnesium coated Ti6Al4V scaffold enhances osteogenesis and angiogenesis in vitro and in vivo for orthopedic application | |
| CN113750290A (en) | Polyether-ether-ketone composite implant and preparation method and application thereof | |
| Xu et al. | Triple-functional polyetheretherketone surface with enhanced bacteriostasis and anti-inflammatory and osseointegrative properties for implant application | |
| Xie et al. | Programmed surface on poly (aryl-ether-ether-ketone) initiating immune mediation and fulfilling bone regeneration sequentially | |
| Gan et al. | Bioactivity and antibacterial effect of nitrogen plasma immersion ion implantation on polyetheretherketone | |
| Meng et al. | KR-12 coating of polyetheretherketone (PEEK) surface via polydopamine improves osteointegration and antibacterial activity in vivo | |
| Dashnyam et al. | Angiogenesis-promoted bone repair with silicate-shelled hydrogel fiber scaffolds | |
| Liu et al. | Polydopamine-modified poly (l-lactic acid) nanofiber scaffolds immobilized with an osteogenic growth peptide for bone tissue regeneration | |
| Griffin et al. | Enhancing tissue integration and angiogenesis of a novel nanocomposite polymer using plasma surface polymerisation, an in vitro and in vivo study | |
| Wu et al. | Enhanced bacteriostatic activity, osteogenesis and osseointegration of silicon nitride/polyetherketoneketone composites with femtosecond laser induced micro/nano structural surface | |
| Wu et al. | Growth factors enhanced angiogenesis and osteogenesis on polydopamine coated titanium surface for bone regeneration | |
| KR101461159B1 (en) | Preparation method of implant comprising drug delivery layer and implant compostion for living donor transplantation comprising the same | |
| CN113368305B (en) | Bone induction and immunity double-effect coating, preparation method and application in osseointegration | |
| CN106702341B (en) | Polyetheretherketonematerials materials and based on plasma immersion injection method of modifying and application | |
| Wang et al. | Bioactive effects of low-temperature argon–oxygen plasma on a titanium implant surface | |
| Kim et al. | Enhancement of bone formation on LBL-coated Mg alloy depending on the different concentration of BMP-2 | |
| Zheng et al. | Surface Modification of Poly (ether ether ketone) by Simple Chemical Grafting of Strontium Chondroitin Sulfate to Improve its Anti‐Inflammation, Angiogenesis, Osteogenic Properties | |
| Guo et al. | Bioactive calcium phosphate silicate ceramic surface-modified PLGA for tendon-to-bone healing | |
| EP2793911B1 (en) | Methods for improving the bioactivity characteristics of a surface and objects with surfaces improved thereby | |
| Zhang et al. | Surface bisphosphonation of polyetheretherketone to manipulate immune response for advanced osseointegration | |
| JP5914464B2 (en) | Method for improving bioactive properties of surfaces and objects having improved surfaces thereby | |
| KR102422432B1 (en) | silicate-shell hydrogel fiber scaffold and preparation method thereof | |
| Amemiya et al. | Tissue response of surface-modified three-dimensional titanium fiber structure | |
| JP2014525817A (en) | Method for improving bioactive characteristics of an object surface and surface improved thereby | |
| US20140074159A1 (en) | Methods for improving the bioactivity characteristics of a surface and objects with surfaces improved thereby |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20211207 |