WO2022166408A1 - 一种生物活性骨用复合材料及其制备方法和应用 - Google Patents
一种生物活性骨用复合材料及其制备方法和应用 Download PDFInfo
- Publication number
- WO2022166408A1 WO2022166408A1 PCT/CN2021/137603 CN2021137603W WO2022166408A1 WO 2022166408 A1 WO2022166408 A1 WO 2022166408A1 CN 2021137603 W CN2021137603 W CN 2021137603W WO 2022166408 A1 WO2022166408 A1 WO 2022166408A1
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- WO
- WIPO (PCT)
- Prior art keywords
- bone
- composite material
- magnesium silicide
- biodegradable polymer
- composite
- Prior art date
Links
- 239000002131 composite material Substances 0.000 title claims abstract description 118
- 210000000988 bone and bone Anatomy 0.000 title claims abstract description 93
- 238000002360 preparation method Methods 0.000 title claims abstract description 43
- 230000000975 bioactive effect Effects 0.000 title abstract 2
- YTHCQFKNFVSQBC-UHFFFAOYSA-N magnesium silicide Chemical compound [Mg]=[Si]=[Mg] YTHCQFKNFVSQBC-UHFFFAOYSA-N 0.000 claims abstract description 85
- 229910021338 magnesium silicide Inorganic materials 0.000 claims abstract description 83
- 229920002988 biodegradable polymer Polymers 0.000 claims abstract description 50
- 239000004621 biodegradable polymer Substances 0.000 claims abstract description 50
- 230000001737 promoting effect Effects 0.000 claims abstract description 25
- 230000011164 ossification Effects 0.000 claims abstract description 21
- 230000008439 repair process Effects 0.000 claims abstract description 19
- -1 small molecule organic acid Chemical class 0.000 claims abstract description 17
- 206010061363 Skeletal injury Diseases 0.000 claims abstract description 11
- 239000007864 aqueous solution Substances 0.000 claims abstract description 11
- 239000000463 material Substances 0.000 claims description 46
- 239000002245 particle Substances 0.000 claims description 31
- 239000011575 calcium Substances 0.000 claims description 30
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 29
- 229910052791 calcium Inorganic materials 0.000 claims description 29
- 239000000243 solution Substances 0.000 claims description 28
- 238000000034 method Methods 0.000 claims description 26
- 238000010146 3D printing Methods 0.000 claims description 25
- 229910017053 inorganic salt Inorganic materials 0.000 claims description 25
- 238000005516 engineering process Methods 0.000 claims description 19
- 230000008021 deposition Effects 0.000 claims description 18
- 230000014509 gene expression Effects 0.000 claims description 17
- 239000002904 solvent Substances 0.000 claims description 17
- 238000000465 moulding Methods 0.000 claims description 14
- 229920001610 polycaprolactone Polymers 0.000 claims description 13
- 239000004632 polycaprolactone Substances 0.000 claims description 13
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 12
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 claims description 11
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 claims description 10
- 239000004626 polylactic acid Substances 0.000 claims description 10
- 230000002792 vascular Effects 0.000 claims description 9
- 229920000954 Polyglycolide Polymers 0.000 claims description 8
- 239000001506 calcium phosphate Substances 0.000 claims description 8
- 230000008472 epithelial growth Effects 0.000 claims description 8
- 239000003102 growth factor Substances 0.000 claims description 8
- 238000002386 leaching Methods 0.000 claims description 8
- 150000007524 organic acids Chemical class 0.000 claims description 8
- 239000004633 polyglycolic acid Substances 0.000 claims description 8
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical group [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims description 8
- 206010029113 Neovascularisation Diseases 0.000 claims description 6
- 229920001577 copolymer Polymers 0.000 claims description 6
- 239000004310 lactic acid Substances 0.000 claims description 6
- 235000014655 lactic acid Nutrition 0.000 claims description 6
- 229920000747 poly(lactic acid) Polymers 0.000 claims description 6
- 235000011010 calcium phosphates Nutrition 0.000 claims description 5
- 238000005266 casting Methods 0.000 claims description 5
- 238000001704 evaporation Methods 0.000 claims description 5
- 229910052588 hydroxylapatite Inorganic materials 0.000 claims description 5
- 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 claims description 5
- IWHLYPDWHHPVAA-UHFFFAOYSA-N 6-hydroxyhexanoic acid Chemical compound OCCCCCC(O)=O IWHLYPDWHHPVAA-UHFFFAOYSA-N 0.000 claims description 4
- 229910000389 calcium phosphate Inorganic materials 0.000 claims description 4
- 238000005187 foaming Methods 0.000 claims description 4
- 239000007789 gas Substances 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 238000001746 injection moulding Methods 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 235000005985 organic acids Nutrition 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 229910052918 calcium silicate Inorganic materials 0.000 claims description 3
- 239000000378 calcium silicate Substances 0.000 claims description 3
- 235000012241 calcium silicate Nutrition 0.000 claims description 3
- 235000011132 calcium sulphate Nutrition 0.000 claims description 3
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 229910000391 tricalcium phosphate Inorganic materials 0.000 claims description 3
- 235000019731 tricalcium phosphate Nutrition 0.000 claims description 3
- 229940078499 tricalcium phosphate Drugs 0.000 claims description 3
- 238000002347 injection Methods 0.000 claims 1
- 239000007924 injection Substances 0.000 claims 1
- 229920000642 polymer Polymers 0.000 claims 1
- 238000006731 degradation reaction Methods 0.000 abstract description 16
- 230000000694 effects Effects 0.000 abstract description 15
- 230000015556 catabolic process Effects 0.000 abstract description 14
- 230000033115 angiogenesis Effects 0.000 abstract description 12
- 230000007547 defect Effects 0.000 abstract description 9
- 239000010703 silicon Substances 0.000 abstract description 8
- 229910052710 silicon Inorganic materials 0.000 abstract description 8
- 239000000758 substrate Substances 0.000 abstract description 7
- JLVVSXFLKOJNIY-UHFFFAOYSA-N Magnesium ion Chemical compound [Mg+2] JLVVSXFLKOJNIY-UHFFFAOYSA-N 0.000 abstract description 6
- 230000004071 biological effect Effects 0.000 abstract description 6
- 229910001425 magnesium ion Inorganic materials 0.000 abstract description 6
- 238000002513 implantation Methods 0.000 abstract description 5
- 230000002378 acidificating effect Effects 0.000 abstract description 4
- 206010021143 Hypoxia Diseases 0.000 abstract 1
- 230000007954 hypoxia Effects 0.000 abstract 1
- 230000001105 regulatory effect Effects 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 13
- 238000000338 in vitro Methods 0.000 description 12
- 239000011148 porous material Substances 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 11
- 238000012360 testing method Methods 0.000 description 10
- 239000007943 implant Substances 0.000 description 9
- 230000002188 osteogenic effect Effects 0.000 description 9
- 101001046870 Homo sapiens Hypoxia-inducible factor 1-alpha Proteins 0.000 description 8
- 102100022875 Hypoxia-inducible factor 1-alpha Human genes 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 239000002994 raw material Substances 0.000 description 7
- 210000003606 umbilical vein Anatomy 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 230000033558 biomineral tissue development Effects 0.000 description 6
- 230000007910 cell fusion Effects 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000003960 organic solvent Substances 0.000 description 6
- 210000000963 osteoblast Anatomy 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 5
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
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- 238000001356 surgical procedure Methods 0.000 description 5
- 229910019018 Mg 2 Si Inorganic materials 0.000 description 4
- 208000003251 Pruritus Diseases 0.000 description 4
- 229910004298 SiO 2 Inorganic materials 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 230000007803 itching Effects 0.000 description 4
- 239000011777 magnesium Substances 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 description 3
- 229910001069 Ti alloy Inorganic materials 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 238000012925 biological evaluation Methods 0.000 description 3
- 230000001186 cumulative effect Effects 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 230000001939 inductive effect Effects 0.000 description 3
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- 238000010603 microCT Methods 0.000 description 3
- 230000000399 orthopedic effect Effects 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 229920001432 poly(L-lactide) Polymers 0.000 description 3
- 239000003361 porogen Substances 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 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 2
- 229920000249 biocompatible polymer Polymers 0.000 description 2
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- 239000012153 distilled water Substances 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
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- 238000001727 in vivo Methods 0.000 description 2
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- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 239000002861 polymer material Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- GUVRBAGPIYLISA-UHFFFAOYSA-N tantalum atom Chemical compound [Ta] GUVRBAGPIYLISA-UHFFFAOYSA-N 0.000 description 2
- 208000018084 Bone neoplasm Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- MKYBYDHXWVHEJW-UHFFFAOYSA-N N-[1-oxo-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propan-2-yl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(C(C)NC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 MKYBYDHXWVHEJW-UHFFFAOYSA-N 0.000 description 1
- 206010031264 Osteonecrosis Diseases 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 238000011529 RT qPCR Methods 0.000 description 1
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 1
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 1
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 208000010029 ameloblastoma Diseases 0.000 description 1
- 230000002491 angiogenic effect Effects 0.000 description 1
- 230000001174 ascending effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000005312 bioglass Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000005137 deposition process Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000002059 diagnostic imaging Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000002481 ethanol extraction Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 210000004394 hip joint Anatomy 0.000 description 1
- GPRLSGONYQIRFK-UHFFFAOYSA-N hydron Chemical compound [H+] GPRLSGONYQIRFK-UHFFFAOYSA-N 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 238000001095 inductively coupled plasma mass spectrometry Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229910052909 inorganic silicate Inorganic materials 0.000 description 1
- 210000000629 knee joint Anatomy 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 210000004373 mandible Anatomy 0.000 description 1
- 238000007734 materials engineering Methods 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 239000007769 metal material Substances 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000004820 osteoconduction Effects 0.000 description 1
- 230000004819 osteoinduction Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000011505 plaster Substances 0.000 description 1
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 1
- 239000004810 polytetrafluoroethylene Substances 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 238000007639 printing Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 238000003762 quantitative reverse transcription PCR Methods 0.000 description 1
- 238000012113 quantitative test Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 239000011833 salt mixture Substances 0.000 description 1
- 229910000077 silane Inorganic materials 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 238000002791 soaking Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- 229910052715 tantalum Inorganic materials 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
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- 230000008733 trauma Effects 0.000 description 1
- 238000009777 vacuum freeze-drying Methods 0.000 description 1
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
- A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
- A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
- A61L27/46—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with phosphorus-containing inorganic fillers
-
- 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
- A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
- A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
- A61L27/446—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with other specific inorganic fillers other than those covered by A61L27/443 or A61L27/46
-
- 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
- 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
- A61L2300/10—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
- A61L2300/102—Metals or metal compounds, e.g. salts such as bicarbonates, carbonates, oxides, zeolites, silicates
-
- 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
- A61L2300/602—Type of release, e.g. controlled, sustained, slow
- A61L2300/604—Biodegradation
-
- 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
Definitions
- the invention belongs to the field of biomaterials, and in particular relates to a bone composite material with osteopromoting and angiogenesis activities and a preparation method and application thereof.
- Bone defect is the destruction of the structural integrity of bone tissue, the loss of part of the bone, the formation of large gaps between the bone tissue.
- Various traumas, diseases (such as osteoporosis, bone tumor, osteonecrosis, etc.) or surgery are common factors that cause bone defects. Due to the existence of bone defects, bone non-union, delayed or even non-union, and local dysfunction are often caused.
- the repair and functional reconstruction of large segmental bone defects that cannot heal on their own has always been a major clinical challenge for orthopaedics. If it cannot be effectively repaired, the resulting disability and deformity rate is very high, which seriously affects the postoperative quality of life of patients [1- 3]. According to statistics, there are about 3 million cases of bone defects in my country every year.
- non-animal derived artificial bone repair materials are roughly divided into four categories in terms of components: bioglass, calcium phosphate, calcium sulfate and hydroxyapatite.
- the main component of the product is silicon dioxide, which exists in the body as a foreign body after implantation, but only degrades and does not absorb.
- the representative manufacturers of calcium phosphates are Olympus Osfanlang, Wuhan Huawei and Shanghai Beioru, which are sintered at high temperature, brittle after implantation, and have poor plasticity.
- the representative manufacturer of calcium sulfate is Wright in the United States. The plaster is improved, but the degradation is too fast to cause nonunion, and it is fragile after implantation.
- hydroxyapatite Naaikang from Sichuan Guona and Tianbo from Beijing Yihuajian, which do not degrade or degrade too slowly after implantation.
- traditional artificial bone materials also have shortcomings such as low osteoconduction and osteoinduction biological activities, mismatched mechanical properties and immune rejection.
- Medical 3D printing technology carries out precise computer-aided design (CAD) according to the specific shape of the patient's bone defect obtained by the medical imaging system and the mechanical properties of the corresponding parts of the human body, and uses the computer numerical control molding system to carry out the precise molding of biomaterials to manufacture personalized bone. Repair with implanted stents [4, 5].
- CAD computer-aided design
- the application of metal materials for structural reconstruction and fixation in the direction of orthopedics has achieved great achievements, so it is also the first material to be combined with 3D printing technology for the manufacture of personalized orthopedic implant stents.
- Belgium cooperated with a research institution in the Netherlands to customize and implant a personalized 3D printed titanium alloy mandibular prosthesis for an 83-year-old female patient.
- 3D printed bone implant scaffolds are all porous metal scaffolds, mainly composed of titanium and tantalum [6,7].
- the number of 3D printed bone implant stents on the market is very limited.
- the U.S. Food and Drug Administration (FDA) has only approved less than 10 3D printing-based standardized vertebral fusion cages, acetabular cups and other products for the market. Only 4 imported products have been approved by the State Food and Drug Administration (CFDA), and all the approved products belong to the field of metal 3D printing technology.
- FDA Food and Drug Administration
- CFDA State Food and Drug Administration
- my country's first 3D printed human implant - artificial hip joint product belongs to The three types of orthopedic implants are jointly developed by Zhang Ke, Liu Zhongjun, Dr. Cai Hong and Beijing Aikang Yicheng Medical Equipment Co., Ltd.
- one aspect of the present invention provides a composite material for bone having pro-osteogenic and angiogenic activities.
- one aspect of the present invention provides a composite material for bone, the composite material comprising a base of a biodegradable polymer, and the base further comprises magnesium silicide; wherein the base of the biodegradable polymer can be used in an aqueous solution environment Provides hydrogen ions.
- the substrate further comprises calcium-containing inorganic salt; preferably, the calcium-containing inorganic salt is selected from calcium phosphate, tricalcium phosphate, calcium sulfate, calcium silicate or hydroxyapatite .
- the biodegradable polymer is selected from the group of organic acids that can be degraded in an aqueous solution to generate small molecules, preferably, the organic acid is selected from lactic acid, glycolic acid, 6-hydroxycaproic acid .
- the biodegradable polymer is selected from polylactic acid-glycolic acid copolymer (PLGA), polylactic acid-glycolic acid copolymer modified material, polycaprolactone (PCL), polycaprolactone At least one of lactone (PCL) modified material, polylactic acid (PLA), polylactic acid (PLA) modified material, polyglycolic acid (PGA) and polyglycolic acid modified material;
- the bone composite material comprises the following components by mass percentage: 20%-95% biodegradable polymer, 1%-50% magnesium silicide, 0-50% calcium-containing inorganic salt . It is preferably 20% ⁇ 95% biodegradable polymer, 5% ⁇ 25% magnesium silicide, 0 ⁇ 50% calcium-containing inorganic salt. More preferably, it is 30% ⁇ 90% biodegradable polymer, 10% ⁇ 20% magnesium silicide, 0 ⁇ 50% calcium-containing inorganic salt.
- the composite material for bone is prepared by the following methods: mixing the biodegradable polymer with a solvent, adding magnesium silicide particles to mix evenly, and removing the solvent after molding to obtain the composite material for bone; Optionally, further comprising the step of dispersing the calcium-containing inorganic salt in a solvent comprising the biodegradable; or
- the biodegradable polymer is heated and melted, the magnesium silicide particles are added to mix uniformly, and the composite material for bone is obtained by cooling after molding; optionally, the step of dispersing calcium-containing inorganic salt in the molten biodegradable material is also included.
- a second aspect of the present invention provides a composite scaffold for bone, which is prepared from the above-mentioned composite material for bone of the present invention.
- the composite scaffold for bone is prepared from the above-mentioned composite material for bone of the present invention.
- the composite scaffold for bone will include: Biocompatible polymers of magnesium silicide particles to prepare composite scaffolds for osteogenesis.
- the third aspect of the present invention provides the use of magnesium silicide as a bone repair material.
- a biodegradable polymer is used as a base in the bone repair material, wherein the base of the biodegradable polymer can provide hydrogen ions in an aqueous solution environment.
- the fourth aspect of the present invention provides the use of the composite material for bone in the preparation of a bone injury repair material.
- the fifth aspect of the present invention provides the use of a composite material for bone or magnesium silicide in the preparation of a material for promoting the expression of vascular epithelial growth factor.
- the sixth aspect of the present invention provides the use of a composite material for bone in the preparation of a material for promoting osteogenesis-related neovascularization and promoting osteogenesis.
- the seventh aspect of the present invention provides the use of the above-mentioned composite scaffold for bone in the preparation of bone injury repair materials; or in the preparation of a medical device for promoting the expression of vascular epithelial growth factor; or in the preparation of promoting osteogenesis-related neovascularization. and/or use in a medical device for promoting osteogenesis.
- the present invention discovers for the first time the special effect of magnesium silicide acting on the bone injury site.
- the present invention utilizes the biodegradable polymer substrate to degrade under physiological environment to generate small molecular organic acid, which makes the surrounding environment of the stent slightly acidic, thus triggering Mg 2 Si
- the degradation of SiO 2 achieves controllable long-acting Mg 2+ ion release along with the scaffold degradation process, and exerts osteogenic activity; the generated SiO 2 gradually degrades to release silicate ions, which also has osteogenic biological activity.
- the consumption of oxygen during the degradation of Mg 2 Si creates a local microenvironment of itching, which can stimulate the production of itching-inducing factor (HIF-1 ⁇ ), thereby up-regulating the expression of vascular epithelial growth factor (VEGF), promoting angiogenesis and further promoting osteogenesis .
- HIF-1 ⁇ itching-inducing factor
- VEGF vascular epithelial growth factor
- the present invention finds that adding magnesium silicide can not only achieve stable release of magnesium ions and silicon ions, but also achieve higher compressive strength and compressive modulus. Parts work better.
- the material and preparation process of the invention are simple, the effect is remarkable, and more effective bone defect repair can be realized.
- Figure 1 is a schematic diagram of the preparation of the magnesium silicide composite porous scaffold.
- Figure 2 shows the in vitro degradation characteristics of PLGA/ ⁇ MS composite porous scaffolds: A. Magnesium ion accumulation and release (mmol/L); B. Silicon ion accumulation and release (mmol/L); C. pH value test of the 7-week degradation solution .
- Figure 3 shows the angiogenesis activity and mechanism of PLGA/ ⁇ MS composite porous scaffold on human umbilical vein cell fusion cells (Eahy-926) in vitro: A. HIF-1 ⁇ gene expression level; B. VEGF gene expression level.
- Figure 4 is an in vitro test of the angiogenesis activity of PLGA/ ⁇ MS composite porous scaffolds on human umbilical vein cell fusion cells (Eahy-926): A. Optical observation of lumen formation; B. Fluorescence observation of lumen formation; C. Lumen formation Combined observation of white light and fluorescence.
- Figure 5 shows the study on the osteogenic activity of the PLGA/ ⁇ MS composite porous scaffold leaching liquid in vitro: A. 21-day mineralization experiment in vitro; B. Proliferation test results of osteoblasts; C. 21-day mineralization in vitro Quantitative test results.
- Figure 6 shows the morphology of the PLGA/ ⁇ MS composite porous scaffold: A. Photograph of the scaffold; B. 35 ⁇ magnification; C. 1000 ⁇ magnification.
- Figure 7 shows the mechanical properties test of the PLGA/ ⁇ MS composite porous scaffold: A. compressive strength; B. compressive elastic modulus.
- a composite material for bone includes a base of a biodegradable polymer, and the base further includes magnesium silicide; wherein the base of the biodegradable polymer can be provided in an aqueous solution environment Hydrogen ion.
- the water environment is an environment in which water is contained in the liquid, such as an aqueous solution in vitro, or a physiological environment in vivo.
- the water environment is an environment with water as a solvent or a liquid containing water as a solvent, wherein the environment is not limited to an aqueous solution, an aqueous solution containing buffered salts, body fluids, blood or tissue fluids and other in vivo physiological environments.
- the substrate further comprises a calcium-containing inorganic salt; preferably, the calcium-containing inorganic salt is selected from calcium phosphate, tricalcium phosphate, calcium sulfate, calcium silicate or hydroxyl apatite.
- the biodegradable polymer is selected from the group consisting of organic acids that can be degraded in an aqueous solution environment to generate small molecules, preferably, the organic acid is selected from lactic acid, glycolic acid, 6- Hydroxyhexanoic acid.
- the biodegradable polymer is selected from polylactic acid-glycolic acid copolymer (PLGA), polylactic acid-glycolic acid copolymer modified material, polycaprolactone (PCL) , at least one of polycaprolactone (PCL) modified material, polylactic acid (PLA), polylactic acid (PLA) modified material, polyglycolic acid (PGA) and polyglycolic acid modified material;
- PLGA polylactic acid-glycolic acid copolymer
- PCL polycaprolactone
- PCL polycaprolactone
- the bone composite material comprises the following components by mass percentage: 20% ⁇ 95% biodegradable polymer, 1% ⁇ 50% magnesium silicide, 0 ⁇ 50% containing Calcium inorganic salt. It is preferably 20% ⁇ 95% biodegradable polymer, 5% ⁇ 25% magnesium silicide, 0 ⁇ 50% calcium-containing inorganic salt. More preferably, it is 30% ⁇ 90% biodegradable polymer, 10% ⁇ 20% magnesium silicide, 0 ⁇ 50% calcium-containing inorganic salt.
- the composite material for bone is prepared by mixing the biodegradable polymer with a solvent, adding magnesium silicide particles to mix evenly, and removing the solvent after molding to obtain the composite material for bone material; optionally, further comprising the step of dispersing a calcium-containing inorganic salt in a solvent comprising a biodegradable; or
- the biodegradable polymer is heated and melted, the magnesium silicide particles are added to mix uniformly, and the composite material for bone is obtained by cooling after molding; optionally, the step of dispersing calcium-containing inorganic salt in the molten biodegradable material is also included.
- a composite scaffold for bone is provided, and the composite scaffold for bone is prepared from the above-mentioned composite material for bone of the present invention.
- the method for removing the solvent in the preparation process of the above-mentioned composite material for bone, includes a method for removing the solvent under normal pressure or reduced pressure, and the process for removing the solvent adopts heating or room temperature conditions.
- a method for removing the solvent under normal pressure or reduced pressure and the process for removing the solvent adopts heating or room temperature conditions.
- natural volatilization, evaporation under reduced pressure, freeze-drying and the like are used.
- the composite scaffold for bone uses low-temperature deposition rapid prototyping 3D printing technology, fused deposition 3D printing technology, melt injection molding method, solution evaporation method, solution casting particle leaching method, and gas foaming method.
- Methods A biocompatible polymer comprising magnesium silicide particles was prepared to produce a composite scaffold for osteogenesis.
- the composite scaffold for bone can be set in different sizes or shapes according to different application sites and needs, for example: block (rectangular, square), cylindrical, elliptical, spherical, non- Regular shape.
- different porosity can be set in the composite scaffold for bone, for example, 3D printing technology is used to set the porosity to 50% ⁇ 90%.
- the pore diameters of the pores provided on the composite scaffold for bone are: the macroscopic pore diameter ranges from 100 to 600 ⁇ m, and the microscopic pore diameters are distributed in the material and range from 0.1 to 100 ⁇ m.
- the pore structures of the pores provided on the composite scaffold for bone are circular, square, triangular, parallelogram, and rhombus evenly and regularly distributed;
- the pore connectivity rate of the pores provided on the composite scaffold for bone 50% to 100%.
- Some embodiments of the present invention provide the use of magnesium silicide as a bone repair material.
- a biodegradable polymer is used as a base in the bone repair material, wherein the base of the biodegradable polymer can provide hydrogen ions in an aqueous solution environment.
- Some embodiments of the present invention provide the use of the composite material for bone of the present invention in the preparation of a bone injury repair material.
- Some embodiments of the present invention provide the use of the composite material for bone or magnesium silicide of the present invention in the preparation of a material for promoting the expression of vascular epithelial growth factor.
- Some embodiments of the present invention provide the use of the composite material for bone of the present invention in the preparation of a material for promoting osteogenesis-related neovascularization and promoting osteogenesis.
- Some embodiments of the present invention provide the use of the above-mentioned composite scaffold for bone in the preparation of bone injury repair materials; or in the preparation of a medical device for promoting the expression of vascular epithelial growth factor; or in the preparation of promoting osteogenesis-related neovascularization. and or use in medical devices for promoting osteogenesis.
- the medical device is a filler for bone repair, or a medical appliance for bone injury.
- the molecular weight of the biodegradable polymer is 50,000-300,000 Daltons, and the distribution coefficient D (Mw/Mn) does not exceed 2.0.
- the viscosity of the biodegradable polymer 1.0 ⁇ 2.5 dl/L;
- magnesium silicide and calcium-containing inorganic salt are both powder materials, and the particle size of the powder is 0.1-150 ⁇ m;
- the magnesium silicide compound used in the present invention has unique chemical properties, it will not degrade in a neutral solution environment, but can react in a slightly acidic (pH ⁇ 7.0) environment to generate magnesium ions and silane, which in turn Further react with oxygen molecules in the environment to generate silica and water, see the following reaction formula:
- the biodegradable polymer substrate used in the present invention is degraded under physiological environment to generate small molecular organic acids (such as lactic acid, glycolic acid, 6-hydroxycaproic acid), which makes the surrounding environment of the stent slightly acidic, which can trigger Mg 2 Si
- small molecular organic acids such as lactic acid, glycolic acid, 6-hydroxycaproic acid
- the degradation of SiO 2 achieves controllable long-acting Mg 2+ ion release along with the scaffold degradation process, and exerts osteogenic activity; the generated SiO 2 gradually degrades to release silicate ions, which also has osteogenic biological activity.
- the consumption of oxygen during the degradation of Mg 2 Si creates a local microenvironment of itching, which can stimulate the production of itching-inducing factor (HIF-1 ⁇ ), thereby up-regulating the expression of vascular epithelial growth factor (VEGF), promoting angiogenesis and further promoting osteogenesis .
- HIF-1 ⁇ itching-inducing factor
- VEGF vascular epithelial growth factor
- bone repair scaffolds were prepared by low-temperature deposition rapid prototyping 3D printing technology, fused deposition 3D printing technology, melt injection molding method, solution evaporation method, solution casting particle leaching method, gas foaming method and other methods.
- Example 1 Preparation of porous scaffolds using low temperature deposition rapid prototyping 3D printing technology.
- controllable preparation is carried out through the control of the manufacturing process parameters of the low-temperature deposition rapid prototyping 3D printing technology to meet the special needs of various osteogenic material structures.
- Forming raw material preparation Dissolve the biodegradable polymer PLGA in the organic solvent 1,4-dioxane, stir to fully dissolve, and then pour the mixed solution into a low-temperature rapid deposition system for 3D printing to prepare magnesium silicide composite porous bracket.
- Forming and preparation of porous stents According to the selected ingredients, the raw materials are mixed and placed in the material tank of the low-temperature deposition rapid prototyping system. The raw materials are transported from the material tank to the low-temperature deposition chamber through the feeding pipe, and the forming temperature is -200 °C ⁇ 0 °C , extruded through the nozzle parts of different specifications, sprayed to the forming platform, deposited layer by layer, and freeze-dried by vacuum freeze-drying equipment for 24-48 hours after forming, and finally obtained the porous structure of magnesium silicide composite porous scaffold.
- Example 1 the mass fraction of magnesium silicide in the porous scaffold was 0%.
- Example 2 PLGA/ ⁇ MS magnesium silicide composite porous scaffold: the mass fraction of magnesium silicide is 10%.
- the composite porous scaffold was prepared by the same preparation method as in Example 1.
- the difference from the preparation method in Example 1 is that in the preparation process of the molding raw materials, the biodegradable polymer PLGA is dissolved in the organic solvent 1,4-dioxane, and after stirring to fully dissolve it, magnesium silicide is added. The particles are uniformly dispersed in it, and then the mixed solution is poured into a low-temperature rapid deposition system for 3D printing to prepare a magnesium silicide composite porous scaffold.
- the amount of magnesium silicide particles added was 10% of the mass of the composite porous scaffold.
- Example 3 PLGA/ ⁇ MS magnesium silicide composite porous scaffold: the mass fraction of magnesium silicide is 20%.
- the composite porous scaffold was prepared by the same preparation method as in Example 1.
- the difference from the preparation method in Example 1 is that in the preparation process of the molding raw materials, the biodegradable polymer PLGA is dissolved in the organic solvent 1,4-dioxane, and after stirring to fully dissolve it, magnesium silicide is added. The particles are uniformly dispersed in it, and then the mixed solution is poured into a low-temperature rapid deposition system for 3D printing to prepare a magnesium silicide composite porous scaffold.
- the amount of magnesium silicide particles added was 20% of the mass of the composite porous scaffold.
- Example 4 PLGA/ ⁇ MS magnesium silicide composite porous scaffold: the mass fraction of magnesium silicide is 30%.
- the composite porous scaffold was prepared by the same preparation method as in Example 1.
- the difference from the preparation method in Example 1 is that in the preparation process of the molding raw materials, the biodegradable polymer PLGA is dissolved in the organic solvent 1,4-dioxane, and after stirring to fully dissolve it, magnesium silicide is added. The particles are uniformly dispersed in it, and then the mixed solution is poured into a low-temperature rapid deposition system for 3D printing to prepare a magnesium silicide composite porous scaffold.
- the amount of magnesium silicide particles added was 30% of the mass of the composite porous scaffold.
- the in vitro degradation characteristics of the porous scaffold were investigated.
- the porous scaffolds were immersed in physiological saline on the 1st, 3rd, 7th days, the 2nd week, the 3rd week and the 7th week after the immersion.
- the pH value of the soaking solution was detected, the volume and mass of the scaffold were measured, the pore size and porosity were measured by SEM, Micro-CT, and ethanol method, and the change in mechanical strength was measured by compression method.
- the concentrations of Mg 2+ , Ca 2+ and SiO4 4- in the degradation solution were measured by ICP-MS and lactic acid content detection kit.
- the experimental results show that the composite scaffold containing magnesium silicide (the composite scaffolds of Examples 2-4) achieves a substantially uniform cumulative release of magnesium ions and silicon ions within 7 weeks, and the cumulative release of silicon ions increases with the increase of magnesium silicide content.
- the amount showed a dose-dependent increase, and there was a significant difference in cumulative release over 7 weeks between Examples 4 and 3, and between Examples 3 and 2.
- the release amount of silicon ions it can be seen that with the increase of magnesium silicide content in Examples 3 and 4, the release amount of silicon ions also increases compared with Example 2 (10% content).
- the observation of pH value shows that the addition of magnesium silicide will affect the pH value of the composite scaffold, and the pH value decreases slightly and stabilizes around 7.5 with the extension of time. Although the pH values of different contents of magnesium silicide were different in 1-5 weeks, the pH values of different proportions of magnesium silicide composite scaffolds tended to be the same at 7 weeks.
- Example 6 Study on osteopromoting and angiogenesis activities of magnesium silicide composite porous scaffolds in vitro.
- RT-qPCR technology was used to detect the effect of PLGA/ ⁇ MS composite porous scaffold on the expression of hypoitchy-inducing factor (HIF-1 ⁇ ) and vascular endothelial growth factor (VEGF) in human umbilical vein cell fusion cells (Eahy-926).
- HEF-1 ⁇ hypoitchy-inducing factor
- VEGF vascular endothelial growth factor
- the fusion cells of human umbilical vein cells were inoculated into porous materials and then routinely cultured.
- the culture medium was collected on the 3rd day, and the cells were collected to extract RNA and protein.
- the expression levels of HIF-1 ⁇ and VEGF gene and protein in the culture medium were detected. .
- the collected culture medium was used as the conditioned medium to continue to culture human umbilical vein cell fusion cells (Eahy-926), and the formation of the lumen was observed by microscope after 24 hours.
- the test results are shown in Figure 3 and Figure 4.
- Figure 3 shows the angiogenesis activity and mechanism of PLGA/ ⁇ MS composite porous scaffold on human umbilical vein cell fusion cells (Eahy-926) in vitro: A. HIF-1 ⁇ gene expression level; B. VEGF gene expression level.
- Figure 3 shows that with the increase of magnesium silicide content, the expression of HIF-1 ⁇ protein is increased in a dose-dependent manner, and the expression level of VEGF is further induced, and VEGF plays an important role in the angiogenesis of bone tissue. Can promote the formation of blood vessels, ossification and new bone maturation.
- Figure 4 is an in vitro test of the angiogenesis activity of PLGA/ ⁇ MS composite porous scaffolds on human umbilical vein cell fusion cells (Eahy-926): A. Optical observation of lumen formation; B. Fluorescence observation of lumen formation; C. Lumen formation Combined observation of white light and fluorescence.
- Figure 4 shows that the conditioned medium obtained by culturing Eahy-926 cells with PLGA/ ⁇ MS composite porous scaffolds is rich in HIF-1 ⁇ and VEGF, which can effectively promote the formation of vascular lumen in Eahy-926 cells, showing a good biological activity for promoting angiogenesis.
- the composite scaffolds of Examples 1-4 were sterilized and then immersed in the cell culture medium. After 24 hours, the scaffolds were taken out to obtain the leaching solution.
- the normal osteoblasts (MC 3T3-E1) were seeded on the cell culture plate, and after 3 days of normal culture, the leaching solution of the composite scaffolds of Example 1-4 was added for continuous induction for 21 days, and the culture solution was replaced every two days. After 21 days of osteogenic induction, cells were fixed with 10% neutral formalin, stained with 1% alizarin red for 30 minutes, and then photographed with a microscope to observe mineralized calcium nodules; alkaline phosphatase color development kit was used according to the instructions. Methods The cells were stained and photographed under microscope to observe the activity of alkaline phosphatase.
- the results of the alizarin red experiment showed that the composite scaffold leachate added with magnesium silicide compounds could significantly improve the mineralization of osteoblasts.
- the experimental results of bone-derived alkaline phosphatase also support the above results.
- the composite scaffold leachate added with magnesium silicide compounds can significantly increase the expression level of alkaline phosphatase in osteoblasts.
- the deposition process of the stone and the elimination of pyrophosphates inhibit the formation of bone mineral and promote the mineralization of osteoblasts. Therefore, the experimental results confirmed the effect of magnesium silicide compounds on osteoblast activity and mineralization.
- an organic solvent one or several mixed solvents such as chloroform, dichloromethane, tetrahydrofuran, acetone, 1,4-dioxane, etc.
- an organic solvent one or several mixed solvents such as chloroform, dichloromethane, tetrahydrofuran, acetone, 1,4-dioxane, etc.
- magnesium silicide The particles or magnesium silicide and calcium-containing inorganic salt particles are uniformly dispersed therein, and then the mixed solution is poured into a mold of a specific shape and size, and the magnesium silicide composite stent is formed after the organic solvent is completely volatilized.
- the present invention can use various known methods to uniformly mix the biodegradable polymer and magnesium silicide, and prepare a stent with characteristic shape.
- the density and pore size of the stent were determined by Micro-CT scanning and SEM using the method established in the inventor's previous research. . SEM was used to characterize the physical morphology of the surface and cross-section of the scaffold, and Micro-CT and ethanol extraction were used to measure the porosity and pore connection rate of the scaffold. The test results are shown in Figure 6.
- the composite material with magnesium silicide can increase the compressive strength and compressive elastic modulus of the material, making it closer to human cancellous bone.
- the density is more useful for the application.
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Abstract
本发明涉及一种生物活性骨用复合材料及其制备方法和应用。具体公开了一种骨用复合材料,其特征在于,所述骨用复合材料包括生物可降解聚合物的基底,且基底中还包含硅化镁;所述的生物可降解聚合物选自能够水溶液环境下发生降解生成小分子有机酸。本发明首次发现硅化镁作用于骨损伤部位的特殊效果,本发明利用生物可降解聚合物基底在生理环境下发生降解生成小分子有机酸,使支架周围环境呈微酸性,因而能触发硅化镁的降解,实现随支架降解过程可控的长效镁离子和硅离子释放,发挥促成骨活性;同时调节植入部位形成乏氧微环境,促进血管新生。本发明的含硅化镁骨用复合材料显示出促成骨和成血管生物活性,可实现有效的骨缺损修复。
Description
本发明属于生物材料领域,具体涉及具有促成骨及成血管活性的骨用复合材料及其制备方法和应用。
骨缺损是骨组织的结构完整性被破坏,丧失了部分骨质,使骨组织之间形成较大的空隙。各种创伤、疾病(如骨质疏松、骨肿瘤、骨坏死等)或手术等是造成骨缺损的常见因素。由于骨缺损的存在,常造成骨不连接,延迟愈合甚至不愈合,及局部的功能障碍。无法自行愈合的大段骨缺损的修复和功能重建一直是骨科临床面临的重大挑战,若无法得到有效修复,导致的致残致畸率非常高,严重影响病患的术后生活质量[1-3]。据统计,我国每年骨缺损病例约为300万例。我国骨科植入类医用耗材市场由2010年的72亿元增长至2017年的212亿元,预计至2020年达到300亿元左右。随着社会的高速发展,人口老龄化进程加快,骨损伤患者数量呈日益增多的趋势,骨损伤已成为威胁人民健康、导致伤残病废的主要疾病之一。
目前市场上,非动物源性人工骨修复材料从组分上大致分为生物玻璃、磷酸钙、硫酸钙和羟基磷灰石等四大类,其中生物玻璃类的代表制造商有美国诺邦,产品主要成分为二氧化硅,植入人体后以异物存在体内,但只降解不吸收。磷酸钙类的代表制造商有奥林巴斯奥斯泛浪、武汉华威和上海贝奥路,高温烧结成型,植入后易碎,可塑性差。硫酸钙类的代表制造商有美国瑞特Wright,石膏改良,但降解太快易造成骨不连,且植入后易碎。羟基磷灰石类的代表制造商有四川国纳的纳艾康和北京意华健的天博,植入后不降解或降解过慢。目前传统的人工骨材料也存在着骨传导和骨诱导生物活性较低、力学性能不匹配和免疫排斥等缺点。
医学3D打印技术根据医学影像系统获得的患者骨缺损部位的特定形态和人体相应部位的力学特性进行精准的计算机辅助设计(CAD),并通过计算机数控成型系统进行生物材料的精确成型制造个性化骨修复植入支架[4, 5]。在过去的几十年研究和发展中,在骨科方向应用金属材料进行结构的重建及固定已有很大造诣,因而也是最早与3D打印技术结合进行个性化骨科植入支架制造的材料。2012年,比利时与荷兰的研究机构合作,为一位83岁的女性病人定制并植入了个性化3D打印钛合金下颌骨假体。这是世界上首次完全使用3D打印定制植入物代替整个下颌骨。2014年,上海市解放军第四医院口腔专科中心刘国勤教授,术中采用3D打印钛合金下颌骨植入体对1例单侧下颌骨体部与升支造釉细胞瘤患者进行修复。同年,北京大学第三医院完成世界首例应用3D打印技术制备钛合金枢椎椎体置换手术。2017年,陆军军医大学西南医院关节外科完成全球首例个体化3D打印钽金属垫块修复巨大骨缺损膝关节翻修手术。截至目前,临床使用的3D打印骨植入支架均为多孔金属支架,主要由钛和钽组成[6,7]。全球上市的3D打印骨植入支架产品数量非常有限,美国食品药品管理局(FDA)仅批准不到10个基于3D打印标准化的椎体融合器、髋臼杯等产品上市,而我国3D打印植入物产品仅有4个获得国家食品药品监督管理总局(CFDA)的批准,并且获批产品均属于金属3D打印技术领域,如我国首个3D打印人体植入物——人工髋关节产品,属于三类骨科植入物,是由北京大学第三医院骨科张克、刘忠军、蔡宏医生和北京爱康宜诚医疗器材股份有限公司合作研制。
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为了解决上述问题,本发明一个方面提供了一种具有促成骨和成血管活性的骨用复合材料。
具体地,本发明一个方面提供了一种骨用复合材料,所述复合材料包括生物可降解聚合物的基底,且基底中还包含硅化镁;其中生物可降解聚合物的基底能够在水溶液环境下提供氢离子。
在本发明的技术方案中,所述的基底中还包含含钙无机盐;优选地,所述的含钙无机盐选自磷酸钙、磷酸三钙、硫酸钙、硅酸钙或羟基磷灰石。
在本发明的技术方案中,所述的生物可降解聚合物选自能够水溶液环境下发生降解生成小分子有机酸,优选地,所述的有机酸选自乳酸、羟基乙酸、6-羟基己酸。
在本发明的技术方案中,所述的生物可降解聚合物选自聚乳酸-羟基乙酸共聚物(PLGA)、聚乳酸-羟基乙酸共聚物改性材料、聚己内酯(PCL)、聚己内酯(PCL)改性材料、聚乳酸(PLA)、聚乳酸(PLA)改性材料、聚羟基乙酸(PGA)和聚羟基乙酸改性材料中的至少一种;
在本发明的技术方案中,所述的骨用复合材料包含质量百分比如下的组分:20%~95%生物可降解聚合物、1%~50%硅化镁、0~50%含钙无机盐。优选为20%~95%生物可降解聚合物、5%~25%硅化镁、0~50%含钙无机盐。更优选为30%~90%生物可降解聚合物、10%~20%硅化镁、0~50%含钙无机盐。
在本发明的技术方案中,所述的骨用复合材料通过以下方式制备获得,将生物可降解聚合物以溶剂混合,并加入硅化镁颗粒混合均匀,成型后去除溶剂获得骨用复合材料;任选地,还包括将含钙无机盐分散在包含生物可降解物的溶剂中的步骤;或者
将生物可降解聚合物加热熔融,并加入硅化镁颗粒混合均匀,成型后冷却获得骨用复合材料;任选地,还包括将含钙无机盐分散在熔融的生物可降解物中的步骤。
本发明第二个方面提供了一种骨用复合支架,所述骨用复合支架由本发明上述骨用复合材料制备而成。
在本发明的技术方案中,所述骨用复合支架由本发明上述骨用复合材料制备而成。
在本发明的技术方案中,所述骨用复合支架通过低温沉积快速成型3D打印技术、熔融沉积3D打印技术、熔融注塑法、溶液挥发法、溶液浇铸粒子浸出法、气体发泡法方法将包含硅化镁颗粒的生物相容性聚合物制备成骨用复合支架。
本发明第三个方面提供了硅化镁作为骨修复材料的用途。
优选地,所述骨修复材料中以生物可降解聚合物作为基底,其中生物可降解聚合物的基底能够在水溶液环境下提供氢离子。
本发明第四个方面提供了骨用复合材料在制备骨损伤修复材料中的用途。
本发明第五个方面提供了骨用复合材料或硅化镁在制备促进血管上皮生长因子表达的材料中的用途。
本发明第六个方面提供了骨用复合材料在制备促进成骨相关新生血管生成和促进骨生成的材料中的用途。
本发明第七个方面提供了上述的骨用复合支架在制备骨损伤修复材料中的用途;或者在制备促进血管上皮生长因子表达的医用装置中的用途;或者在制备促进成骨相关新生血管生成和/或促进骨生成的医用装置中的用途。
本发明首次发现硅化镁作用于骨损伤部位的特殊效果,本发明利用生物可降解聚合物基底在生理环境下发生降解生成小分子有机酸,使支架周围环境呈微酸性,因而能触发Mg
2Si的降解,实现随支架降解过程可控的长效Mg
2+离子释放,发挥促成骨活性;生成的SiO
2逐渐降解释放出硅酸根离子,也具有促成骨生物活性。同时,Mg
2Si降解过程中消耗氧气造成局部乏痒微环境,能够刺激乏痒诱导因子(HIF-1α)产生,进而上调血管上皮生长因子(VEGF)表达,促进新生血管生成从而进一步促进骨生成。
本发明发现通过添加硅化镁除了能够实现稳定的镁离子和硅离子释放,还能够实现更高的压缩强度和压缩模量,其具有与人体松质骨类似的密度和强度,能够实现在骨损伤部位更好的作用。
本发明材料和制备工艺简单,效果显著,能够实现更有效的骨缺损修复。
图1为硅化镁复合多孔支架制备示意图。
图2为PLGA/χMS复合多孔支架体外降解特性测试:A. 镁离子积累释放量(mmol/L);B. 硅离子积累释放量(mmol/L);C. 7周降解液的pH值测试。
图3为PLGA/χMS复合多孔支架体外对人脐静脉细胞融合细胞(Eahy-926)成血管活性及机制研究:A. HIF-1α基因表达水平;B. VEGF基因表达水平。
图4为 PLGA/χMS复合多孔支架体外对人脐静脉细胞融合细胞(Eahy-926)成血管活性测试:A. 管腔形成光学观察图;B. 管腔形成荧光观察图;C. 管腔形成白光和荧光合并观察图。
图5为PLGA/χMS复合多孔支架浸提液体外促成骨活性研究:A. 体外成骨诱导21天矿化实验;B. 成骨细胞的增殖测试结果;C. 体外成骨诱导21天矿化定量测试结果。
图6为PLGA/χMS复合多孔支架形貌:A. 支架照片;B. 35×倍镜; C. 1000×倍镜。
图7为PLGA/χMS复合多孔支架力学性能测试:A. 压缩强度;B. 压缩弹性模量。
为了使本发明的上述目的、特征和优点能够更加明显易懂,下面对本发明的具体实施方式做详细的说明,但不能理解为对本发明的可实施范围的限定。
本发明一些实施例中提供了一种骨用复合材料,所述复合材料包括生物可降解聚合物的基底,且基底中还包含硅化镁;其中生物可降解聚合物的基底能够在水溶液环境下提供氢离子。
在本发明中,所述的水环境为液体中包含水的环境,例如体外的水溶液,或者体内生理环境。所述的水环境为以水作为溶剂,或者以包含水的液体作为溶剂的环境,其中该环境中不限于水溶液、含缓冲盐的水溶液,体液、血液或组织液等体内的生理环境。
在本发明的一些具体的实施例中,所述的基底中还包含含钙无机盐;优选地,所述的含钙无机盐选自磷酸钙、磷酸三钙、硫酸钙、硅酸钙或羟基磷灰石。
在本发明的一些具体的实施例中,所述的生物可降解聚合物选自能够水溶液环境下发生降解生成小分子有机酸,优选地,所述的有机酸选自乳酸、羟基乙酸、6-羟基己酸。
在本发明的一些具体的实施例中,所述的生物可降解聚合物选自聚乳酸-羟基乙酸共聚物(PLGA)、聚乳酸-羟基乙酸共聚物改性材料、聚己内酯(PCL)、聚己内酯(PCL)改性材料、聚乳酸(PLA)、聚乳酸(PLA)改性材料、聚羟基乙酸(PGA)和聚羟基乙酸改性材料中的至少一种;
在本发明的一些具体的实施例中,所述的骨用复合材料包含质量百分比如下的组分:20%~95%生物可降解聚合物、1%~50%硅化镁、0~50%含钙无机盐。优选为20%~95%生物可降解聚合物、5%~25%硅化镁、0~50%含钙无机盐。更优选为30%~90%生物可降解聚合物、10%~20%硅化镁、0~50%含钙无机盐。
在本发明的一些具体的实施例中,所述的骨用复合材料通过以下方式制备获得,将生物可降解聚合物以溶剂混合,并加入硅化镁颗粒混合均匀,成型后去除溶剂获得骨用复合材料;任选地,还包括将含钙无机盐分散在包含生物可降解物的溶剂中的步骤;或者
将生物可降解聚合物加热熔融,并加入硅化镁颗粒混合均匀,成型后冷却获得骨用复合材料;任选地,还包括将含钙无机盐分散在熔融的生物可降解物中的步骤。
本发明一些实施例中提供了一种骨用复合支架,所述骨用复合支架由本发明上述骨用复合材料制备而成。
在本发明的一些具体的实施例中,在上述骨用复合材料制备过程中,去除溶剂的方法包括常压或减压条件下去除溶剂的方法,去除溶剂的过程中采用加热或室温的条件。例如采用自然挥发、减压蒸发、冷冻干燥等。
在本发明的一些具体的实施例中,所述骨用复合支架通过低温沉积快速成型3D打印技术、熔融沉积3D打印技术、熔融注塑法、溶液挥发法、溶液浇铸粒子浸出法、气体发泡法方法将包含硅化镁颗粒的生物相容性聚合物制备成骨用复合支架。
在本发明的一些具体的实施例中,骨用复合支架根据不同的应用部位和需求可以设置成不同的大小或形状,例如:块状(长方形、正方形)、圆柱状、椭圆球形、球形、不规则形。
在本发明的一些具体的实施例中,为了增加或降低骨用复合支架中硅化镁的释放,可以在骨用复合支架中设置不同的孔隙率,例如采用3D打印技术设置孔隙率为50%~90%。
在本发明的一些具体的实施例中,骨用复合支架上设置的孔隙的孔径为:宏观孔径范围为100~600um,微观孔径分布于材料中,范围为0.1~100 μm。
在本发明的一些具体的实施例中,骨用复合支架上设置的孔隙的孔结构为圆形、正方形、三角形、平行四边形、菱形均匀有规律分布;
在本发明的一些具体的实施例中,骨用复合支架上设置的孔隙的孔连通率:50%~100%。
本发明一些实施例中提供了硅化镁作为骨修复材料的用途。优选地,所述骨修复材料中以生物可降解聚合物作为基底,其中生物可降解聚合物的基底能够在水溶液环境下提供氢离子。
本发明一些实施例中提供了本发明骨用复合材料在制备骨损伤修复材料中的用途。
本发明一些实施例中提供了本发明骨用复合材料或硅化镁在制备促进血管上皮生长因子表达的材料中的用途。
本发明一些实施例中提供了本发明骨用复合材料在制备促进成骨相关新生血管生成和促进骨生成的材料中的用途。
本发明一些实施例中提供了上述的骨用复合支架在制备骨损伤修复材料中的用途;或者在制备促进血管上皮生长因子表达的医用装置中的用途;或者在制备促进成骨相关新生血管生成和或促进骨生成的医用装置中的用途。
在本发明的一些具体实施例中,所述的医用装置为骨修复用填充物、或者用于骨损伤的医用器具。
在本发明的一些具体实施例中,所述的生物可降解聚合物的分子量为5万~30万道尔顿,分布系数D(Mw/Mn)不超过2.0。
在本发明的一些具体的实施例中,生物可降解聚合物的粘度:1.0~2.5 dl/L;
在本发明的一些具体的实施例中,硅化镁和含钙无机盐均为粉体材料,其粉体粒径在0.1~150 μm;
本发明所使用的硅化镁化合物具有独特的化学性质,其在中性溶液环境下不会发生降解,而在微酸性(pH≤7.0)环境下即可发生反应,生成镁离子和硅烷,硅烷又进一步与环境中的氧分子反应生成二氧化硅和水,见如下反应式:
本发明所使用的生物可降解聚合物基底在生理环境下发生降解生成小分子有机酸(例如乳酸、羟基乙酸、6-羟基己酸),使支架周围环境呈微酸性,因而能触发Mg
2Si的降解,实现随支架降解过程可控的长效Mg
2+离子释放,发挥促成骨活性;生成的SiO
2逐渐降解释放出硅酸根离子,也具有促成骨生物活性。同时,Mg
2Si降解过程中消耗氧气造成局部乏痒微环境,能够刺激乏痒诱导因子(HIF-1α)产生,进而上调血管上皮生长因子(VEGF)表达,促进新生血管生成从而进一步促进骨生成。
然后,基于以上复合成分利用低温沉积快速成型3D打印技术、熔融沉积3D打印技术、熔融注塑法、溶液挥发法、溶液浇铸粒子浸出法、气体发泡法等方法制备骨修复支架。
实施例1利用低温沉积快速成型3D打印技术制备多孔支架。
利用已建立并优化结构及组成的计算机模型,通过低温沉积快速成型3D打印技术的制造工艺参数控制进行可控制备,以满足各种成骨材料结构的特殊需求。
成型原料配制:将生物可降解聚合物PLGA溶解于有机溶剂1,4-二氧六环中,搅拌使其充分溶解,然后将混合溶液倒入低温快速沉积系统进行3D打印,制备硅化镁复合多孔支架。
多孔支架的成型制备:根据选定的成分,将制备原料混合置于低温沉积快速成型系统物料罐中,原料由物料罐通过输料管输送至低温沉积室,成形温度为-200℃~0℃,通过不同规格的喷头部位挤出,喷射至成型平台,逐层沉积,成型后经真空冷冻干燥设备冻干24~48小时,最后得到多孔结构的硅化镁复合多孔支架。
实施例1中多孔支架中硅化镁质量分数为0%。
实施例2:PLGA/χMS硅化镁复合多孔支架:硅化镁质量分数为10%。
采用与实施例1相同的制备方法制备复合多孔支架。与实施例1制备方法不同之处在于,在成型原料配制过程中,在将生物可降解聚合物PLGA溶解于有机溶剂1,4-二氧六环中,搅拌使其充分溶解后,加入硅化镁颗粒均匀分散于其中,然后将混合溶液倒入低温快速沉积系统进行3D打印,制备硅化镁复合多孔支架。其中硅化镁颗粒的加入量为复合多孔支架质量的10%。
实施例3:PLGA/χMS硅化镁复合多孔支架:硅化镁质量分数为20%。
采用与实施例1相同的制备方法制备复合多孔支架。与实施例1制备方法不同之处在于,在成型原料配制过程中,在将生物可降解聚合物PLGA溶解于有机溶剂1,4-二氧六环中,搅拌使其充分溶解后,加入硅化镁颗粒均匀分散于其中,然后将混合溶液倒入低温快速沉积系统进行3D打印,制备硅化镁复合多孔支架。其中硅化镁颗粒的加入量为复合多孔支架质量的20%。
实施例4:PLGA/χMS硅化镁复合多孔支架:硅化镁质量分数为30%。
采用与实施例1相同的制备方法制备复合多孔支架。与实施例1制备方法不同之处在于,在成型原料配制过程中,在将生物可降解聚合物PLGA溶解于有机溶剂1,4-二氧六环中,搅拌使其充分溶解后,加入硅化镁颗粒均匀分散于其中,然后将混合溶液倒入低温快速沉积系统进行3D打印,制备硅化镁复合多孔支架。其中硅化镁颗粒的加入量为复合多孔支架质量的30%。
实施例5 硅化镁复合多孔支架体外降解特性
根据医疗器械生物学评价的国家标准(GB/T16886.13-2001)的要求,考察该多孔支架的体外降解特性。将多孔支架浸泡于生理盐水中,于浸泡后第1,3,7天,第2周,第3周直至第7周。检测浸泡液的pH值变化,测量支架的体积、质量,利用SEM、Micro-CT、乙醇法测量孔径和孔隙率,及用压缩法测量力学强度的变化。同时用ICP-MS及乳酸含量检测试剂盒测降解液中Mg
2+、Ca
2+、SiO4
4-的浓度。掌握其降解动力学,评估多孔支架降解性能与组成比例之间的关系及对时间的依赖性。测试结果见图2。
实验结果显示,包含硅化镁的复合支架(实施例2-4的复合支架),在7周时间内实现镁离子和硅离子的基本均匀的累计释放且随着硅化镁含量的提高硅离子累计释放量呈现剂量依赖性提高,实施例4与3之间,实施例3与2之间在7周累计释放量上存在显著性差异。而对于硅离子的释放量可知,随着硅化镁含量的提高实施例3和4和显示出比实施例2(10%含量),硅离子的释放量也有所提高。对于pH值的观察可知添加硅化镁后会影响到复合支架的pH值,且随着时间的延长pH值小幅下降并稳定在7.5附近。虽然不同含量的硅化镁在1-5周时间内pH值有所差异,但是在7周时不同比例硅化镁复合支架pH值趋于一致。
实验结果表明在生物可降解聚合物PLGA释放乳酸和羟基乙酸,使硅化镁能够稳定释放硅离子和镁离子。
实施例6 硅化镁复合多孔支架体外促成骨及成血管活性的研究。
采用RT-qPCR技术检测PLGA/χMS复合多孔支架对人脐静脉细胞融合细胞(Eahy-926)表达乏痒诱导因子(HIF-1α)、血管内皮生长因子(VEGF)等的影响。
将人脐静脉细胞融合细胞(Eahy-926)接种于多孔材料后常规培养,于第3天收集培养液,同时收集细胞提RNA和蛋白,检测培养液中HIF-1α,VEGF基因与蛋白表达水平。以收集的培养液为条件培养基继续培养人脐静脉细胞融合细胞(Eahy-926),24小时后通过显微镜观察管腔形成情况。测试结果见图3和图4。
其中,图3为PLGA/χMS复合多孔支架体外对人脐静脉细胞融合细胞(Eahy-926)成血管活性及机制研究:A. HIF-1α基因表达水平;B. VEGF基因表达水平。
图3显示随着硅化镁含量的提高了HIF-1α蛋白表达,且存在剂量依赖性,而且进一步诱导了VEGF的表达水平,而VEGF在骨组织血管生成中起到重要作用,在骨损伤后,能够促进血管的形成,骨化以及新骨成熟。
图4为PLGA/χMS复合多孔支架体外对人脐静脉细胞融合细胞(Eahy-926)成血管活性测试:A. 管腔形成光学观察图;B. 管腔形成荧光观察图;C. 管腔形成白光和荧光合并观察图。
图4显示PLGA/χMS复合多孔支架培养Eahy-926细胞所得的条件培养基富含HIF-1α和VEGF,能有效促进Eahy-926细胞形成血管管腔,显示出良好的促进血管新生的生物活性。
实施例7 成骨活性和矿化研究
将实施例1-4复合支架灭菌处理,然后浸入细胞培养基中,24小时后取出支架得到浸出液。将正常成骨细胞(MC 3T3-E1)接种在细胞培养板上,正常培养3天后加入实施例1-4复合支架的浸出液,连续诱导21天,每隔两天更换一次培养液。细胞成骨诱导21天后,用10%中性福尔马林固定细胞,用1%茜素红染色30分钟后显微镜拍照观察矿化钙结节;用碱性磷酸酯酶显色试剂盒按照说明书方法染色细胞,显微镜拍照观察碱性磷酸酯酶活性。
采用碱性磷酸酶活性染色。测试结果见图5。
实验结果中茜素红实验结果显示,加入硅化镁化合物的复合支架浸出液能够显著提高成骨细胞的矿化。而骨源性碱性磷酸酶实验结果也对上述结果进行来佐证,加入硅化镁化合物的复合支架浸出液能够显著提高成骨细胞表达碱性磷酸酶的水平,而碱性磷酸酶通过参与羟磷灰石的沉积过程和消除焦磷酸盐骨矿物质形成抑制作用促进成骨细胞的矿化。所以实验结果证实了硅化镁化合物对于成骨细胞活性以及矿化的影响。
实施例8 利用熔融沉积3D打印技术制备硅化镁复合支架
将PLGA、PLLA、PLA、PCL等生物可降解聚合物与一定比例的硅化镁颗粒或硅化镁与含钙无机盐混合物颗粒混合均匀,加入熔融沉积3D打印成型系统物料罐中,原料由物料罐通过输料管输送至打印喷头及成型室,物料颗粒在喷头中经加热熔融然后挤出,喷射至成型平台,按照建立的计算机模型逐层沉积,最后得到硅化镁复合支架。
实施例9熔融注塑法制备硅化镁复合支架
将PLGA、PLLA、PLA、PCL等生物可降解聚合物与一定比例的硅化镁颗粒或硅化镁与含钙无机盐颗粒混合物颗粒混合均匀,加热至熔融,倒入特定形状尺寸的模具中,冷却成型,最后得到硅化镁复合支架。
实施例10溶液挥发法制备硅化镁复合支架
将生物可降解聚合物溶解于有机溶剂(氯仿,二氯甲烷、四氢呋喃、丙酮、1,4-二氧六环等一种或几种混合溶剂)中,搅拌使其充分溶解,然后加入硅化镁颗粒或硅化镁与含钙无机盐颗粒均匀分散于其中,然后将混合溶液倒入特定形状大小的模具中,待有机溶剂完全挥发即成型得到硅化镁复合支架。
实施例11利用溶液浇铸粒子浸出法制备硅化镁复合多孔支架
将PLGA、PLLA、PLA、PCL等生物可降解聚合物其中成分至少一种溶于氯仿配成5~20%浓度的溶液,加入一定量的经过筛分的致孔剂(氯化钠)、硅化镁颗粒(组分范围为1%~50%)、含钙无机盐颗粒(组分范围为0~50%)。致孔剂与不同高分子材料溶液充分混匀后,浇铸到聚四氟乙烯模具里,待氯仿挥发后,把不同高分子材料溶液与致孔剂的复合物浸人到蒸馏水中,使氯化钠溶出,每隔6小时更换一次蒸馏水,直至氯化钠完全洗净,得到多孔的硅化镁复合多孔支架,室温下真空干燥48小时。
通过上述实施例可以看出,本发明可以采用各种已知的方法将生物可降解聚合物与硅化镁进行均匀混合,并制备成特性造型的支架。
实施例12 硅化镁复合多孔支架的结构特征和力学性能
根据医疗器械生物学评价的国家标准GB/T16886.18-2011及GB/T16886.19-2011,用本发明人前期研究中已经建立的方法,用 Micro-CT扫描及SEM测定支架的密度,孔径。利用SEM表征支架表面、断面的物理形貌,利用Micro-CT和乙醇抽提法测支架的孔隙率和孔连接率。测试结果见图6。
根据医疗器械生物学评价的国家标准GB/T8813-2008(ISO 844:2004)的要求和标准,利用压缩法测定复合多孔支架的压缩强度及压缩弹性模量。测试结果见图7。
通过对比添加硅化镁或不添加硅化镁的复合支架的压缩强度和压缩弹性模量可知,添加硅化镁的复合材料可以增加材料的压缩强度和压缩弹性模量,使其更接近于人体松质骨的密度,更有利用应用。
Claims (10)
- 一种骨用复合材料,其特征在于,所述骨用复合材料包括生物可降解聚合物的基底,且基底中还包含硅化镁;其中生物可降解聚合物的基底能够在水溶液环境下提供氢离子;优选地,所述的生物可降解聚合物选自能够水溶液环境下发生降解,生成小分子有机酸,更优选地,所述的有机酸选自乳酸、羟基乙酸、6-羟基己酸。
- 根据权利要求1所述的骨用复合材料,其特征在于,所述的生物可降解聚合物选自聚乳酸-羟基乙酸共聚物、聚己内酯、聚己内酯改性材料、聚乳酸-羟基乙酸共聚物改性材料、聚乳酸、聚乳酸改性材料、聚羟基乙酸和聚羟基乙酸改性材料中的至少一种。
- 根据权利要求1-2任一项所述的骨用复合材料,其特征在于,所述的骨用复合材料包含质量百分比如下的组分:20%~95%生物可降解聚合物、1%~50%硅化镁、0~50%含钙无机盐;优选为20%~95%生物可降解聚合物、5%~25%硅化镁、0~50%含钙无机盐;更优选为30%~90%生物可降解聚合物、10%~20%硅化镁、0~50%含钙无机盐。
- 根据权利要求1-3任一项所述的骨用复合材料,其特征在于,所述的基底中还包含含钙无机盐;优选地,所述的含钙无机盐选自磷酸钙、磷酸三钙、硫酸钙、硅酸钙或羟基磷灰石。
- 根据权利要求1-4任一项所述的骨用复合材料,其特征在于,所述的骨用复合材料通过以下方式制备获得,将所述生物可降解聚合物以溶剂混合,并加入硅化镁颗粒混合均匀,成型后去除溶剂获得骨用复合材料;任选地,还包括将含钙无机盐分散在包含生物可降解物的溶剂中的步骤;或者,将所述生物可降解聚合物加热熔融,并加入硅化镁颗粒混合均匀,成型后冷却获得骨用复合材料;任选地,还包括将含钙无机盐分散在熔融的生物可降解物中的步骤。
- 根据权利要求1-5任一项的骨用复合材料的制备方法,其特征在于,所述的骨用复合材料通过以下方式制备获得,将所述生物可降解聚合物以溶剂混合,并加入硅化镁颗粒混合均匀,成型后去除溶剂获得骨用复合材料;任选地,还包括将含钙无机盐分散在包含生物可降解物的溶剂中的步骤;或者,将所述生物可降解聚合物加热熔融,并加入硅化镁颗粒混合均匀,成型后冷却获得骨用复合材料;任选地,还包括将含钙无机盐分散在熔融的生物可降解物中的步骤。
- 一种骨用复合支架,所述骨用复合支架由权利要求1-5任一项所述的骨用复合材料制备而成;优选地,所述骨用复合支架通过低温沉积快速成型3D打印技术、熔融沉积3D打印技术、熔融注塑法、溶液挥发法、溶液浇铸粒子浸出法、气体发泡法方法将包含硅化镁颗粒的生物相容性聚合物制备成骨用复合支架。
- 根据权利要求7所述的骨用复合支架的制备方法,所述的骨用复合支架通过以下方法制备:通过低温沉积快速成型3D打印技术、熔融沉积3D打印技术、熔融注塑法、溶液挥发法、溶液浇铸粒子浸出法、气体发泡法方法将权利要求1-5任一项所述的骨用复合材料制备成骨用复合支架。
- 硅化镁或权利要求1-5任一项所述的骨用复合材料在制备骨损伤修复材料中的用途;或者在制备促进血管上皮生长因子表达的材料中的用途;或者在制备促进成骨相关新生血管生成和或促进骨生成的材料中的用途。
- 权利要求7所述的骨用复合支架在制备骨损伤修复材料中的用途;或者在制备促进血管上皮生长因子表达的医用装置中的用途;或者在制备促进成骨相关新生血管生成和/或促进骨生成的医用装置中的用途。
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