CN117462692A - 一种基于肖特基异质结的增强型压电纳米颗粒在制备骨组织再生治疗制剂中的应用 - Google Patents
一种基于肖特基异质结的增强型压电纳米颗粒在制备骨组织再生治疗制剂中的应用 Download PDFInfo
- Publication number
- CN117462692A CN117462692A CN202311405204.9A CN202311405204A CN117462692A CN 117462692 A CN117462692 A CN 117462692A CN 202311405204 A CN202311405204 A CN 202311405204A CN 117462692 A CN117462692 A CN 117462692A
- Authority
- CN
- China
- Prior art keywords
- batio
- bone tissue
- piezoelectric
- tissue regeneration
- preparation
- 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
- 210000000988 bone and bone Anatomy 0.000 title claims abstract description 56
- 239000002105 nanoparticle Substances 0.000 title claims abstract description 24
- 230000017423 tissue regeneration Effects 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 239000010936 titanium Substances 0.000 claims abstract description 76
- 230000000694 effects Effects 0.000 claims abstract description 27
- 210000002901 mesenchymal stem cell Anatomy 0.000 claims abstract description 26
- 229910002113 barium titanate Inorganic materials 0.000 claims abstract description 18
- 239000000463 material Substances 0.000 claims abstract description 11
- 239000002131 composite material Substances 0.000 claims abstract description 10
- 230000009818 osteogenic differentiation Effects 0.000 claims abstract description 10
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 claims abstract description 9
- 229910052719 titanium Inorganic materials 0.000 claims abstract description 9
- MTPVUVINMAGMJL-UHFFFAOYSA-N trimethyl(1,1,2,2,2-pentafluoroethyl)silane Chemical compound C[Si](C)(C)C(F)(F)C(F)(F)F MTPVUVINMAGMJL-UHFFFAOYSA-N 0.000 claims abstract description 9
- JRPBQTZRNDNNOP-UHFFFAOYSA-N barium titanate Chemical compound [Ba+2].[Ba+2].[O-][Ti]([O-])([O-])[O-] JRPBQTZRNDNNOP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000004065 semiconductor Substances 0.000 claims abstract description 6
- 230000002708 enhancing effect Effects 0.000 claims abstract description 4
- 238000000707 layer-by-layer assembly Methods 0.000 claims abstract 2
- 239000002135 nanosheet Substances 0.000 claims abstract 2
- 229920001661 Chitosan Polymers 0.000 claims description 20
- 238000003756 stirring Methods 0.000 claims description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 9
- 239000002356 single layer Substances 0.000 claims description 9
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 5
- 238000001291 vacuum drying Methods 0.000 claims description 5
- 230000009471 action Effects 0.000 claims description 4
- 239000008367 deionised water Substances 0.000 claims description 3
- 229910021641 deionized water Inorganic materials 0.000 claims description 3
- 239000002244 precipitate Substances 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- 230000001225 therapeutic effect Effects 0.000 claims 1
- 230000007547 defect Effects 0.000 abstract description 26
- 210000001185 bone marrow Anatomy 0.000 abstract description 17
- 210000003625 skull Anatomy 0.000 abstract description 11
- 230000000638 stimulation Effects 0.000 abstract description 7
- 239000011159 matrix material Substances 0.000 abstract 1
- 230000001737 promoting effect Effects 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- 238000011069 regeneration method Methods 0.000 description 9
- 238000000034 method Methods 0.000 description 7
- 108090000623 proteins and genes Proteins 0.000 description 7
- 230000008929 regeneration Effects 0.000 description 7
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 6
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 5
- 230000010478 bone regeneration Effects 0.000 description 5
- 230000035876 healing Effects 0.000 description 5
- 230000006698 induction Effects 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 230000008439 repair process Effects 0.000 description 4
- 238000012546 transfer Methods 0.000 description 4
- 208000010392 Bone Fractures Diseases 0.000 description 3
- 206010017076 Fracture Diseases 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000010186 staining Methods 0.000 description 3
- 210000000130 stem cell Anatomy 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 230000008021 deposition Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 150000002739 metals Chemical class 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000011164 ossification Effects 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000027756 respiratory electron transport chain Effects 0.000 description 2
- 210000004872 soft tissue Anatomy 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000002604 ultrasonography Methods 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 102400000888 Cholecystokinin-8 Human genes 0.000 description 1
- 101800005151 Cholecystokinin-8 Proteins 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- 206010031252 Osteomyelitis Diseases 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 206010039203 Road traffic accident Diseases 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 230000032683 aging Effects 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
- 239000000956 alloy Substances 0.000 description 1
- 229910045601 alloy Inorganic materials 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 230000010072 bone remodeling Effects 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 229910010293 ceramic material Inorganic materials 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000003436 cytoskeletal effect Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 210000001951 dura mater Anatomy 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 238000010603 microCT Methods 0.000 description 1
- 239000002064 nanoplatelet Substances 0.000 description 1
- 230000037311 normal skin Effects 0.000 description 1
- 210000000963 osteoblast Anatomy 0.000 description 1
- 230000002188 osteogenic effect Effects 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000001172 regenerating effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- 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 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/02—Prostheses implantable into the body
- A61F2/28—Bones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
-
- 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
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/02—Prostheses implantable into the body
- A61F2/28—Bones
- A61F2002/2835—Bone graft implants for filling a bony defect or an endoprosthesis cavity, e.g. by synthetic material or biological material
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/02—Prostheses implantable into the body
- A61F2/30—Joints
- A61F2002/30001—Additional features of subject-matter classified in A61F2/28, A61F2/30 and subgroups thereof
- A61F2002/30003—Material related properties of the prosthesis or of a coating on the prosthesis
- A61F2002/3006—Properties of materials and coating materials
- A61F2002/30087—Properties of materials and coating materials piezoelectric
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/02—Prostheses implantable into the body
- A61F2/30—Joints
- A61F2/30767—Special external or bone-contacting surface, e.g. coating for improving bone ingrowth
- A61F2002/3093—Special external or bone-contacting surface, e.g. coating for improving bone ingrowth for promoting ingrowth of bone tissue
Abstract
本发明提供一种基于肖特基异质结的增强型压电纳米颗粒在制备骨组织再生治疗制剂中的应用，所述基于肖特基异质结的增强型压电纳米颗粒为Ti3C2‑BaTiO3。本发明以电负性的二维MXene纳米片碳化钛为基体，通过静电自组装效应，将天然带正电的壳聚糖修饰的压电半导体材料钛酸钡组装于Ti3C2表面，形成含有增强压电效应的肖特基异质结的碳化钛‑钛酸钡复合纳米颗粒。所制备的Ti3C2‑BaTiO3具有良好的生物相容性，在无外界因素刺激下能够促进骨髓间充质干细胞成骨分化；同时，将Ti3C2‑BaTiO3埋植于颅骨缺损模型处可明显促进骨组织再生。本发明首次发现Ti3C2‑BaTiO3这种基于肖特基异质结的增强型压电纳米颗粒，能够用于骨组织再生的治疗。
Description
技术领域：
本发明属于医药技术领域，具体涉及一种基于肖特基异质结的增强型压电纳米颗粒在制备骨组织再生治疗制剂中的应用。
背景技术：
骨质疏松、骨肉瘤、骨感染、衰老以及交通事故引起的骨折等多种因素会导致骨组织缺损，促进骨缺损的修复是临床工作中极具挑战的医疗难题。对于严重的骨缺损患者，通常需要手术治疗，给予一定的移植物填充，才能营造骨组织再生的微环境。然而，鉴于自体移植物获取困难，而异体移植物会带来难以避免的免疫反应和毒副作用，开发适当的骨组织工程替代方案具有极大的临床应用价值。
骨组织是一种天然的压电材料，在运动过程中，机体对骨组织产生的压力负荷会使骨组织产生生物压电，这一压电信号可有效促进骨骼重塑与再生。研究显示，电荷刺激是一种促进骨缺损愈合的有效方法，可显著提高骨折愈合率，提高骨缺损再生填充的速度与质量。然而，目前采用的植入式电刺激器需要插入额外的导线和电池，而电容耦合作为骨折愈合的非侵入性电刺激方法需要连续的外部设备，这种需要借助外界刺激的骨组织再生方法的应用前景受到了极大的限制。因此，积极开发无需借助外接设备的微电流刺激方式，将为多种原因引起的骨组织缺损再生修复提供潜在的解决方案。
钛酸钡(BaTiO3)是一种极具临床应用前景的压电陶瓷材料，因其可通过触发引起压电效应，可用于促进骨组织再生与修复。因此，有研究尝试在钛合金假体表面涂覆BaTiO3，从而提升植入假体与宿主骨组织的整合度，有助于假体稳定固定。值得一提的是，以BaTiO3为基础涂层假体，需要体外使用低强度脉冲超声刺激，才能促进BaTiO3内部的电子转移，诱发压电效应，从而维持骨组织中的电生理微环境稳态，促进骨组织再生。因此，能否开发一种，自发产生压电效应的纳米粒子，使其能够在无外接设备的触发下，产生压电效应，促进骨组织再生，仍不清楚。
综上，本发明针对上述临床困境，巧妙利用金属半导体碳化钛(Ti3C2)与压电材料(BaTiO3)之间形成肖特基异质结，合成具有放大压电效应的碳化钛-钛酸钡复合纳米颗粒(Ti3C2-BaTiO3)，促进载流子从半导体(Ti3C2)定向高效转移到金属(BaTiO3)，起到放大压电效应的作用，进而促进骨髓间充质干细胞成骨分化，并有效促进骨缺损修复。
发明内容：
本发明的目的是针对现有骨组织缺损有效治疗方案缺乏的问题，利用骨组织本身是一种天然的压电材料，受到适当电信号刺激后可促进骨再生的特性，提供一种基于肖特基异质结的增强型压电纳米颗粒在制备骨组织再生治疗制剂中的应用。本发明首次提出以肖特基异质结为基础的增强型压电纳米颗粒用于促进骨再生，在无任何外接因素刺激下，可以有效促进骨髓间充质干细胞成骨分化，并促进骨缺损模型中骨组织原位再生，实现对骨缺损的有效治疗。
为了实现上述目的，本发明采用以下技术方案：
本发明提供一种基于肖特基异质结的增强型压电纳米颗粒在制备骨组织再生治疗制剂中的应用。
进一步的，所述基于肖特基异质结的增强型压电纳米颗粒为Ti3C2-BaTiO3。
进一步的，所述Ti3C2-BaTiO3是通过物理合成手段，将钛酸钡(BaTiO3)合成于薄层片状的碳化钛(Ti3C2)表面，二者形成一个完整的整体。
进一步的，所述Ti3C2-BaTiO3的制备方法为：以电负性的二维MXene纳米片碳化钛(Ti3C2)为基，通过静电自组装效应，将天然带正电的壳聚糖修饰的压电半导体材料钛酸钡(BaTiO3)组装于碳化钛(Ti3C2)表面，形成含有增强压电效应的肖特基异质结的碳化钛-钛酸钡复合纳米颗粒(Ti3C2-BaTiO3)。
进一步的，所述Ti3C2-BaTiO3的制备方法为：使用DMSO剥离溶解在氢氟酸中的Ti3AlC2，去离子水冲洗后真空干燥过夜，得到单层Ti3C2；将BaTiO3加入壳聚糖溶液中搅拌，形成均质壳聚糖修饰BaTiO3溶液；将单层Ti3C2加入壳聚糖修饰BaTiO3溶液中搅拌，离心取沉淀物，真空干燥后，得到碳化钛-钛酸钡复合纳米颗粒(Ti3C2-BaTiO3)。
进一步的，所述BaTiO3与壳聚糖溶液的质量体积比为2.0％w/v；BaTiO3加入壳聚糖溶液中搅拌时间为24h；单层Ti3C2加入壳聚糖修饰BaTiO3溶液中搅拌时间为2h。
进一步的，在无外界刺激因素作用下，所述Ti3C2-BaTiO3通过增强的压电效应促进骨髓间充质干细胞成骨分化，促进骨缺损的愈合，实现骨组织的再生。
进一步的，所述增强的压电效应是指，在钛酸钡(BaTiO3)本身具有压电效应的基础上，将其与具有金属性质的碳化钛(Ti3C2)合成，在肖特基异质结的作用下，促进电子从BaTiO3转移到Ti3C2，从而增强电子流动的速度，增强压电效应。
进一步的，所述无外界刺激因素是指本发明克服了现有技术中压电材料需要外界超声等触发方式刺激才能发挥压电效应的缺点，本发明在肖特基异质结介导的电子转移下，能够增强钛酸钡(BaTiO3)和碳化钛(Ti3C2)之间的自发电子传递，无需额外施加刺激因素。
进一步的，所述骨髓间充质干细胞是指在小鼠骨髓中提取的原代干细胞，具有多向分化的潜能，可用于检验Ti3C2-BaTiO3促成骨作用的强弱。所述骨髓间充质干细胞成骨分化是指在Ti3C2-BaTiO3的诱导下，骨髓间充质干细胞高表达成骨相关的基因和蛋白，由原来的干细胞状态分化为成骨细胞状态，具有促进骨再生的潜能。
进一步的，所述Ti3C2-BaTiO3促进骨再生的方法为：将Ti3C2-BaTiO3埋植于骨缺损处，能够促进缺损处新生骨形成，即促进骨缺损愈合。
本发明的有益效果：
与现有技术相比，本发明具有如下优点：
(1)本发明利用骨组织本身受到电信号刺激后会触发再生反应的特点，结合钛酸钡(BaTiO3)是一种优良的压电材料的特性，开发了一种碳化钛-钛酸钡复合纳米颗粒(Ti3C2-BaTiO3)，在无任何外接刺激的情况下，可促进载流子从半导体(BaTiO3)定向高效转移到金属(Ti3C2)，起到放大压电效应的作用，进而促进骨髓间充质干细胞成骨分化，并有效促进骨缺损修复；
(2)本发明克服了现有压电材料应用时需要额外施加超声等物理刺激的缺点，增强对成骨过程的刺激作用，有效促进骨缺损修复，实现骨组织的再生。
附图说明
图1为BaTiO3-Ti3C2在PBS、FBS和DMEM中的粒径分布示意图；
图2为使用第一性原理模拟Ti3C2-BaTiO3中BaTiO3的能带位置变化示意图；
图3为使用不同浓度的Ti3C2-BaTiO3诱导培养骨髓间充质干细胞24小时细胞活力图；
图4为Ti3C2-BaTiO3(TC@BTO)诱导培养骨髓间充质干细胞后细胞面积变化示意图；
图5为Ti3C2-BaTiO3(TC@BTO)诱导培养骨髓间充质干细胞后成骨相关基因和蛋白的表达水平示意图；
图6为Ti3C2-BaTiO3(TC@BTO)诱导培养骨髓间充质干细胞后碱性磷酸酶(ALP)的活性图；
图7为Ti3C2-BaTiO3(TC@BTO)处理颅骨缺损模型后颅骨骨组织再生效果图。
具体实施方式：
为使本发明的目的、技术方案和优点更加清楚，下面将结合相关附图，对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例是本发明的一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动的前提下所获得的所有其他实施例，都属于本发明保护的范围。实施例中未注明的实施条件通常为常规实验中的条件。
实施例1：碳化钛-钛酸钡复合纳米颗粒(Ti3C2-BaTiO3)的制备
(1)以Ti3AlC2为原料，采用化学剥落法制备单层Ti3C2，简单来说，使用DMSO剥离溶解在氢氟酸中的Ti3AlC2，去离子水冲洗后真空下干燥过夜即可得到单层Ti3C2。
(2)利用壳聚糖修饰BaTiO3，将BaTiO3加入壳聚糖溶液中(壳聚糖溶液体积为1.0ml，浓度为1.0mg/ml)搅拌24小时，其中，BaTiO3在壳聚糖溶液的质量体积百分比为2.0％；
(3)将0.2g单层Ti3C2加入至步骤(2)得到的1.0ml壳聚糖修饰BaTiO3溶液中，搅拌2小时后离心得到沉淀物，使其在真空下干燥即得到碳化钛-钛酸钡复合纳米颗粒(Ti3C2-BaTiO3)。
由图1可知，所制备的Ti3C2-BaTiO3在PBS、FBS和DMEM中均表现出良好的分散性与粒径均一性。使用第一性原理模拟Ti3C2-BaTiO3中BaTiO3的能带位置变化情况，参照图2，表明其具有优良的压电效应。
实施例2：Ti3C2-BaTiO3促进骨髓间充质干细胞成骨分化效果试验
提取小鼠原代骨髓间充质干细胞，传至P1代后，加入50μg/ml的Ti3C2-BaTiO3，通过CCK8检测骨髓间充质干细胞活力以评估其生物相容性，细胞骨架染色观察细胞面积变化情况。分别在Ti3C2-BaTiO3处理骨髓间充质干细胞24小时和48小时后，提取细胞RNA和蛋白质，检测Ti3C2-BaTiO3对骨髓间充质干细胞成骨分化的影响。分别在Ti3C2-BaTiO3处理骨髓间充质干细胞7天和14天时，进行碱性磷酸酶染色和茜素红染色，评估对骨髓间充质干细胞成骨分化过程中碱性磷酸酶活性和钙结节沉积的影响。
参照图3，使用不同浓度的Ti3C2-BaTiO3诱导培养骨髓间充质干细胞24小时，表明Ti3C2-BaTiO3对细胞没有明显的毒性。
参照图4，Ti3C2-BaTiO3(TC@BTO)诱导培养骨髓间充质干细胞后促进细胞面积增大，新生成丝状伪足，且比单纯的Ti3C2(TC)和BaTiO3(BTO)表现出更强的促进细胞面积增大的能力。
参照图5，Ti3C2-BaTiO3(TC@BTO)诱导培养骨髓间充质干细胞后可促进成骨相关基因和蛋白的表达，且促进效果明显优于单纯的Ti3C2(TC)和BaTiO3(BTO)。
参照图6，Ti3C2-BaTiO3(TC@BTO)诱导培养骨髓间充质干细胞后可促进碱性磷酸酶(ALP)的活性并促进钙结节的沉积，且促进效果明显优于单纯的Ti3C2(TC)和BaTiO3(BTO)。
实施例3：Ti3C2-BaTiO3促进骨组织再生试验
颅骨缺损模型的构建：选取8周龄的C57BL/6雄性小鼠用于实验，异氟烷吸入麻醉后常规备皮，于头颅正中部位小心切开皮肤，逐层剥离软组织后暴露颅骨，使用直径为3mm的牙科磨钻于颅骨人字缝正中部位磨取一直径3mm的全层骨缺损，小心注意不损伤硬脑膜。
以生理盐水为对照组，Ti3C2-BaTiO3为试验组，进行给药。分组及给药方式见表1。
表1
| 分组 | 给药频次 | 药物 | 药物剂型 | 给药方式 |
| 1 | 一次 | 生理盐水 | 注射液 | 局部注射 |
| 2 | 一次 | Ti3C2-BaTiO3 | 粉末制剂 | 患处固定 |
将Ti3C2-BaTiO3均匀置于颅骨缺损处(剂量：每千克小鼠体重给予2mg Ti3C2-BaTiO3)后，小心逐层缝合软组织。术后不做任何固定措施，每日腹腔注射青霉素，连续3天。3天后观察小鼠头部皮肤是否发生感染，未感染小鼠继续进行下一步实验。
处死实验动物后，获取颅骨标本，进行microCT分析，分析颅骨缺损处骨组织再生情况与骨质情况。如图7所示，在颅骨缺损模型中，与对照组相比，Ti3C2-BaTiO3(TC@BTO)可明显促进局部骨组织再生。
因此，本实施例明确了本发明提出的基于肖特基异质结的增强型碳化钛-钛酸钡复合纳米颗粒(Ti3C2-BaTiO3)用于骨组织缺损的治疗，可有效促进骨组织再生。
以上仅是本发明的优选实施方式，本发明的保护范围并不仅局限于上述实施例，凡属于本发明思路下的技术方案均属于本发明的保护范围，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理前提下的若干改进和润饰，应视为本发明的保护范围。
Claims (6)
1.一种基于肖特基异质结的增强型压电纳米颗粒在制备骨组织再生治疗制剂中的应用。
2.根据权利要求1所述的应用，其特征在于，所述基于肖特基异质结的增强型压电纳米颗粒为Ti3C2-BaTiO3。
3.根据权利要求2所述的应用，其特征在于，
所述Ti3C2-BaTiO3的制备方法为：以电负性的二维MXene纳米片碳化钛为基，通过静电自组装效应，将带正电的壳聚糖修饰的压电半导体材料钛酸钡组装于碳化钛表面，形成含有增强压电效应的肖特基异质结的碳化钛-钛酸钡复合纳米颗粒。
4.根据权利要求3所述的应用，其特征在于，
所述Ti3C2-BaTiO3的制备方法为：
使用DMSO剥离溶解在氢氟酸中的Ti3AlC2，去离子水冲洗后真空干燥过夜，得到单层Ti3C2；
将BaTiO3加入壳聚糖溶液中搅拌，形成均质壳聚糖修饰BaTiO3溶液；
将单层Ti3C2加入壳聚糖修饰BaTiO3溶液中搅拌，离心取沉淀物，真空干燥后，得到碳化钛-钛酸钡复合纳米颗粒。
5.根据权利要求4所述的应用，其特征在于，
所述BaTiO3与壳聚糖溶液的质量体积比为2.0％w/v；
BaTiO3加入壳聚糖溶液中搅拌时间为24h；单层Ti3C2加入壳聚糖修饰BaTiO3溶液中搅拌时间为2h。
6.根据权利要求2所述的应用，其特征在于，
在无外界刺激因素作用下，所述Ti3C2-BaTiO3通过增强的压电效应促进骨髓间充质干细胞成骨分化，促进骨组织的再生。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311405204.9A CN117462692A (zh) | 2023-10-27 | 2023-10-27 | 一种基于肖特基异质结的增强型压电纳米颗粒在制备骨组织再生治疗制剂中的应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311405204.9A CN117462692A (zh) | 2023-10-27 | 2023-10-27 | 一种基于肖特基异质结的增强型压电纳米颗粒在制备骨组织再生治疗制剂中的应用 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN117462692A true CN117462692A (zh) | 2024-01-30 |
Family
ID=89624953
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202311405204.9A Pending CN117462692A (zh) | 2023-10-27 | 2023-10-27 | 一种基于肖特基异质结的增强型压电纳米颗粒在制备骨组织再生治疗制剂中的应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN117462692A (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116173210A (zh) * | 2023-03-31 | 2023-05-30 | 南通南京大学材料工程技术研究院 | 一种用于骨肿瘤治疗的光-声响应的宽禁带肖特基异质结、制备方法及应用 |
-
2023
- 2023-10-27 CN CN202311405204.9A patent/CN117462692A/zh active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116173210A (zh) * | 2023-03-31 | 2023-05-30 | 南通南京大学材料工程技术研究院 | 一种用于骨肿瘤治疗的光-声响应的宽禁带肖特基异质结、制备方法及应用 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| OHLIN et al. | The Pathogenesis of Loosening of Total Hip Arthroplasties: The Production of Factors by Periprosthetic Tissues That Stimulate In Vitro Bone Resorption. | |
| CA2792081C (en) | Layered compositions comprising 3d nanofibre webbing for tissue repair | |
| CN117462692A (zh) | 一种基于肖特基异质结的增强型压电纳米颗粒在制备骨组织再生治疗制剂中的应用 | |
| CN108715830B (zh) | 尿源干细胞外泌体的提取方法及其应用 | |
| EP2273997B1 (de) | Verfahren und zusammensetzung zur regeneration von gewebe mit hilfe von stamm- oder knochenmarkzellen | |
| CN103025335A (zh) | 产生腐蚀电流的金属颗粒及其用途 | |
| Xiong et al. | Novel reduced graphene oxide/zinc silicate/calcium silicate electroconductive biocomposite for stimulating osteoporotic bone regeneration | |
| WO2008082323A1 (fr) | Composition de stimulation de croissance et de régénération de cellules et procédé de fabrication correspondant | |
| CN109125292A (zh) | 一种具有高亲和性的新型骨靶向纳米粒及其制备方法 | |
| CN104689374B (zh) | 一种有机/无机双相杂化靶磁性载中药复合微球 | |
| Zhou et al. | Biomimetic mineralization: From microscopic to macroscopic materials and their biomedical applications | |
| CN105412986A (zh) | 小肠黏膜下层载药补片及其制备方法和应用 | |
| CN110787322B (zh) | 一种矿化角蛋白仿生材料及其制备方法 | |
| Askari et al. | Investigation the molecular structure of novel graphene hybrid scaffold in nerve regeneration | |
| US9446031B2 (en) | Compositions and methods for neovascularization | |
| CN115429898A (zh) | 一种用于治疗肺纤维化的干细胞制剂及其制备方法 | |
| CN114672456A (zh) | 利用超声刺激提高脂肪干细胞分泌胞外囊泡效率的方法及应用 | |
| CN115350322A (zh) | 一种神经酸钙纳米颗粒的制备方法及其在制备骨缺损修复材料中的应用 | |
| Meng et al. | Effect of Hypoxia-Inducible Factor-1α on Osteogenesis of Titanium Dioxide Nanotube Bone Marrow Mesenchymal Stem Cells with Different Diameters Under Periodic Tensile Stress | |
| CN109320600B (zh) | 一种基于蛋白结构域重建的新型pth模拟肽及其应用 | |
| CN108057031B (zh) | 预防手术后异位骨化的缓释吲哚美辛纳米颗粒及其注射剂 | |
| JP2004315454A (ja) | 骨粗鬆症治療剤及び破骨細胞形成抑制剤 | |
| CN104922698B (zh) | 人干细胞生长因子注射液及其制备方法 | |
| Gu et al. | Probiotic Biofilm Modified 3D‐Printing Scaffolds for Improving Chemo‐Immunotherapy of Bone Tumor and Promoting Osteogenesis | |
| CN104623197A (zh) | 一种左归丸纳米微球缓释系统及其制备方法 |
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 |