CN109276759B - Bionic antibacterial abdominal wall repair material - Google Patents

Bionic antibacterial abdominal wall repair material Download PDF

Info

Publication number
CN109276759B
CN109276759B CN201811426674.2A CN201811426674A CN109276759B CN 109276759 B CN109276759 B CN 109276759B CN 201811426674 A CN201811426674 A CN 201811426674A CN 109276759 B CN109276759 B CN 109276759B
Authority
CN
China
Prior art keywords
abdominal wall
chitosan
small intestine
intestine submucosa
elastin fiber
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.)
Active
Application number
CN201811426674.2A
Other languages
Chinese (zh)
Other versions
CN109276759A (en
Inventor
李晓明
曹广秀
牛旭锋
樊瑜波
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Beihang University
Original Assignee
Beihang University
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Beihang University filed Critical Beihang University
Priority to CN201811426674.2A priority Critical patent/CN109276759B/en
Publication of CN109276759A publication Critical patent/CN109276759A/en
Application granted granted Critical
Publication of CN109276759B publication Critical patent/CN109276759B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/3604Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the human or animal origin of the biological material, e.g. hair, fascia, fish scales, silk, shellac, pericardium, pleura, renal tissue, amniotic membrane, parenchymal tissue, fetal tissue, muscle tissue, fat tissue, enamel
    • A61L27/3629Intestinal tissue, e.g. small intestinal submucosa
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14Macromolecular materials
    • A61L27/20Polysaccharides
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14Macromolecular materials
    • A61L27/22Polypeptides or derivatives thereof, e.g. degradation products
    • A61L27/227Other specific proteins or polypeptides not covered by A61L27/222, A61L27/225 or A61L27/24
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54Biologically active materials, e.g. therapeutic substances
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/252Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404Biocides, antimicrobial agents, antiseptic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/606Coatings

Abstract

The invention discloses a bionic antibacterial abdominal wall repairing material, which comprises a porcine small intestine submucosa and a chitosan-elastin fiber net layer coated on the porcine small intestine submucosa; and the chitosan-elastin fiber net layer is an electrostatic spinning nano-scale chitosan-elastin fiber net. The antibacterial ability of the obtained abdominal wall repairing material is effectively improved by combining the chitosan-elastin fiber net layer with the porcine small intestine submucosa coating; meanwhile, the mechanical strength and the degradation performance of the abdominal wall repairing material meet the abdominal wall repairing requirement, can promote angiogenesis to facilitate tissue regeneration, is beneficial to solving the existing technical bottleneck of the abdominal wall repairing material, and effectively improves the treatment effect of abdominal wall defect repair.

Description

Bionic antibacterial abdominal wall repair material
Technical Field
The invention belongs to the technical field of medical consumables, and particularly relates to a bionic antibacterial abdominal wall repair material.
Background
The development and application of abdominal wall repair materials is an important direction in current hernia and abdominal wall surgical research. The existing abdominal wall repairing patch has a plurality of problems to be solved. Their main drawback is still the low biological activity, resulting in poor vascularization and uneven cellularity of the implant itself, eventually leading to lack of integration with the surrounding tissue and tissue regeneration. The recent use of acellular matrices in abdominal wall repair represents an effort to develop biomimetic implants characterized by higher biocompatibility and improved in vivo performance. After implantation, the graft undergoes one of the following fates: (i) neovascularization and new ECM deposition; (ii) fibrosis encapsulation; (iii) resorption/degradation. Thus, an ideal graft should facilitate early neovascularization, be fully biocompatible and biomimetic to promote regenerative immune responses, rather than inflammation that may lead to fibrotic encapsulation. Furthermore, it should allow the recruitment of stem cells and adult tissue-specific cells to eventually restore tissue function. Researchers have now studied biological heuristics for biomimetic patches for abdominal wall reconstruction.
This clinical need is addressed using the general principles of bionics to create materials that better resemble the composition, structure and mechanical properties of the target tissue. Collagen and elastin are the most abundant components of the extracellular matrix (ECM) in almost all tissues in the body, providing the necessary cues for cell attachment, migration and organization. Collagen and elastin are also two major components of the abdominal wall extracellular matrix, and changes in their proportion or metabolism are associated with abdominal wall hernia. The decellularized porcine small intestine submucosa is a natural biological material rich in active factors, mainly comprises collagen, a plurality of growth factors and signal molecules, has excellent biological activity, has more outstanding biological advantages when being applied to the repair of various tissue defects, and can obtain the reconstruction of tissue structures and functions. Elastin provides elasticity and deformability to the tissue. The properties of elastin are critical to specific tissue functions (e.g. dermis, blood vessels, muscle). In addition, some evidence suggests that soluble elastin facilitates tissue regeneration by promoting angiogenesis. Therefore, the porcine small intestine submucosa and elastin composite can be used for bionic repair of abdominal wall structure and composition.
At present, a hernia repair material which can actively resist bacteria and can be applied to polluted and infected wounds is urgently needed. Abdominal wall defects under the conditions of pollution and infection are very common under the conditions of war wounds, traffic injuries, intestinal tract operations and the like, at present, most of the abdominal wall defects are firstly debrided and secondly fixed by materials, so that the treatment time is prolonged, the patient is suffered from pain for a long time, and the loss of sanitary, economic and social labor force is caused. To solve the above problems, it is necessary to introduce an antibacterial material into the abdominal wall repair material. The chitosan is a degradable material, belongs to natural polycation biological polysaccharide, and has broad-spectrum antibacterial effect. There are mainly 2 views on the antibacterial mechanism of chitosan. One is a mechanism proposed based on the polycationic nature of chitosan, targeting bacterial negatively charged cell membranes, which indicates that protonated ammonium in chitosan molecules interact with cellular negatively charged cell membranes, adsorbing bacteria, causing them to sag, deform and leak; the other is an antibacterial mechanism targeting DNA in bacterial molecules, which indicates that chitosan enters the cell after penetrating the damaged cell wall, further interacting with the cytoplasm, disrupting transcription of the bacterial DNA molecule. The chitosan also has good biocompatibility and biodegradability, can obviously improve the proliferation and migration speed of fiber cells, can promote the synthesis of extracellular matrix, and can create a good healing environment for the defect part.
Disclosure of Invention
The invention aims to provide a bionic antibacterial abdominal wall repair material which is suitable for surgical repair of hernia and abdominal wall and effectively improves the treatment effect of clinical abdominal wall defect repair.
In order to solve the technical problems, the invention is specifically realized by the following technical scheme:
a bionic antibacterial abdominal wall repairing material comprises a porcine small intestine submucosa and a chitosan-elastin fiber net layer, wherein the chitosan-elastin fiber net layer is covered on one side of the porcine small intestine submucosa in a covering mode.
The chitosan-elastin fiber net layer is a nano-scale chitosan-elastin fiber net layer, the fiber diameter of the chitosan-elastin fiber net layer is 80-230 nanometers, and the thickness of the chitosan-elastin fiber net layer is 50-300 micrometers. The nano-scale chitosan-elastin fiber net is beneficial to better exerting the antibacterial effect of the chitosan-elastin fiber layer on the porcine small intestine submucosa repairing effect.
The chitosan-elastin fiber net layer is prepared by adopting an electrostatic spinning method, and is combined with a porcine small intestine submucosa covering film, so that the medical performance of the abdominal wall repairing material is further optimized.
The porcine small intestine submucosa is 4 layers of acellular porcine small intestine submucosa materials.
The invention has the beneficial effects that:
the chitosan-elastin fiber net layer is combined with the porcine small intestine submucosa coating, so that the obtained abdominal wall repairing material has bionic property, antibacterial property and biological activity. Meanwhile, the mechanical strength and the degradation performance of the abdominal wall repairing material meet the abdominal wall repairing requirement, can promote angiogenesis to facilitate tissue regeneration, is beneficial to solving the existing technical bottleneck of the abdominal wall repairing material, and effectively improves the treatment effect of abdominal wall defect repair.
Drawings
FIG. 1 is a schematic structural diagram of a bionic antibacterial abdominal wall repair material in example 1 of the present invention; wherein 1 is porcine small intestine submucosa, and 2 is chitosan-elastin fiber net layer;
FIG. 2 is a scanning electron micrograph of submucosa of small intestine of swine according to example 1 of the present invention, wherein FIG. 2(a) is a low magnification and FIG. 2(b) is a high magnification;
FIG. 3 is a cross-sectional view of a porcine small intestine submucosa in accordance with example 1 of the present invention;
FIG. 4 is a scanning electron microscope image of the bionic antibacterial abdominal wall repair material of example 1, wherein FIG. 4(a) is at low magnification and FIG. 4(b) is at high magnification;
FIG. 5 is a cross-sectional view of the bionic antibacterial abdominal wall repair material of example 1 of the present invention.
Detailed Description
The technical solutions of the present invention will be described clearly and completely with reference to specific embodiments of the present invention, and it should be understood that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
A bionic antibacterial abdominal wall repairing material is shown in figure 1, and comprises porcine small intestine submucosa and chitosan-elastin fiber net layer coated on one side of the porcine small intestine submucosa.
The thickness of the chitosan-elastin fiber net layer is 50 microns, the fiber diameter of the nano-scale chitosan-elastin fiber is 100 nanometers, and the nano-scale chitosan-elastin fiber net is prepared by adopting electrostatic spinning. As shown in fig. 2 and 3, the porcine small intestine submucosa is 4 layers of decellularized porcine small intestine submucosa material.
As shown in fig. 4 and 5, in the scanning electron microscope images of the prepared bionic antibacterial abdominal wall repair material, it can be seen from fig. 4 that the chitosan-elastin fibers in the bionic antibacterial abdominal wall repair material have smooth surfaces and nano-scale fiber diameters; as can be seen from FIG. 5, the two layers of the bionic antibacterial abdominal wall repair material are tightly combined.
Example 2
A bionic antibacterial abdominal wall repairing material comprises porcine small intestine submucosa and chitosan-elastin fiber net layer coated on one side of the porcine small intestine submucosa
In this embodiment, the thickness of the nano-sized chitosan-elastin fiber web layer is 100 microns, the fiber diameter of the nano-sized chitosan-elastin fiber is 150 nanometers, and the nano-sized chitosan-elastin fiber web is prepared by electrostatic spinning. The porcine small intestine submucosa in this embodiment is a 4-layer decellularized porcine small intestine submucosa material.
Example 3
A bionic antibacterial abdominal wall repairing material comprises a porcine small intestine submucosa and a nano chitosan-elastin fiber net layer coated on one side of the porcine small intestine submucosa.
In this embodiment, the thickness of the nano-sized chitosan-elastin fiber web layer is 150 microns, the fiber diameter of the nano-sized chitosan-elastin fiber is 200 nanometers, and the nano-sized chitosan-elastin fiber web is prepared by electrostatic spinning. The porcine small intestine submucosa in this embodiment is a 4-layer decellularized porcine small intestine submucosa material.
Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.

Claims (5)

1. The bionic antibacterial abdominal wall repair material is characterized by comprising a porcine small intestine submucosa and a chitosan-elastin fiber net layer, wherein the chitosan-elastin fiber net layer is covered on one side of the porcine small intestine submucosa.
2. The biomimetic antibacterial abdominal wall repair material as recited in claim 1, wherein the chitosan-elastin fiber mesh layer is a nano-scale chitosan-elastin fiber mesh layer.
3. The bionic antibacterial abdominal wall repair material as claimed in claim 2, wherein the chitosan-elastin fiber net layer has a fiber diameter of 80-230 nm and a thickness of 50-300 μm.
4. The bionic antibacterial abdominal wall repair material as claimed in claim 3, wherein the chitosan-elastin fiber mesh layer is prepared by electrospinning.
5. The biomimetic antibacterial abdominal wall repair material according to claim 1, wherein the porcine small intestine submucosa is a 4-layer decellularized porcine small intestine submucosa material.
CN201811426674.2A 2018-11-27 2018-11-27 Bionic antibacterial abdominal wall repair material Active CN109276759B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201811426674.2A CN109276759B (en) 2018-11-27 2018-11-27 Bionic antibacterial abdominal wall repair material

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201811426674.2A CN109276759B (en) 2018-11-27 2018-11-27 Bionic antibacterial abdominal wall repair material

Publications (2)

Publication Number Publication Date
CN109276759A CN109276759A (en) 2019-01-29
CN109276759B true CN109276759B (en) 2020-11-24

Family

ID=65173214

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201811426674.2A Active CN109276759B (en) 2018-11-27 2018-11-27 Bionic antibacterial abdominal wall repair material

Country Status (1)

Country Link
CN (1) CN109276759B (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114984323B (en) * 2022-06-15 2023-09-12 上海交通大学医学院附属第九人民医院 Abdominal wall defect repair material and preparation method thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1237913A (en) * 1996-11-20 1999-12-08 清水庆彦 Collagen material and process for producing the same
CN201664349U (en) * 2009-06-30 2010-12-08 中国人民解放军第二军医大学 Novel composite hernia and body wall repairing piece
CN102488926A (en) * 2011-12-16 2012-06-13 东华大学 Tissue engineering scaffold for urethra reconstruction and preparation method thereof

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020131933A1 (en) * 1996-01-16 2002-09-19 Yves Delmotte Biopolymer membrane and methods for its preparation
CN100569299C (en) * 2006-08-29 2009-12-16 北京华世本全科技有限公司 Degradable compound biomaterial membrane for medical purpose
US20090163936A1 (en) * 2007-12-21 2009-06-25 Chunlin Yang Coated Tissue Engineering Scaffold
CN101849850B (en) * 2010-04-12 2013-03-06 苏州博创同康生物工程有限公司 Bionic in-situ regeneration repair nano sticking patch and preparation method and application thereof
CN103272274B (en) * 2013-05-28 2015-04-15 北京博辉瑞进生物科技有限公司 Biological repair tablet for herniae and preparation method thereof
WO2015089020A1 (en) * 2013-12-09 2015-06-18 Boston Scientific Scimed, Inc. Compositions, devices, kits and methods for attaching surgical meshes to tissue
CN105194734A (en) * 2015-07-27 2015-12-30 烟台海安药物研发有限公司 Chitosan-extracellular matrix tissue repairing membrane and preparation method thereof
CN106552294B (en) * 2015-09-25 2021-06-01 上海市东方医院 Biological patch material for heart repair
CN106492272B (en) * 2015-11-27 2019-07-02 广州迈普再生医学科技股份有限公司 Tissue repair tunica fibrosa and its preparation method and application and tissue repair product
CN108066821A (en) * 2016-11-10 2018-05-25 上海中医药大学附属曙光医院 A kind of compound bio sticking patch for abdominal-wall defect reparation
CN106975106A (en) * 2017-03-31 2017-07-25 北京化工大学 A kind of double-deck Bone Defect Repari membrane material and preparation method thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1237913A (en) * 1996-11-20 1999-12-08 清水庆彦 Collagen material and process for producing the same
CN201664349U (en) * 2009-06-30 2010-12-08 中国人民解放军第二军医大学 Novel composite hernia and body wall repairing piece
CN102488926A (en) * 2011-12-16 2012-06-13 东华大学 Tissue engineering scaffold for urethra reconstruction and preparation method thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Repair and Regeneration of the Abdominal Wall Musculofascial Defect Using Silk Fibroin一Chitosan Blend;ANDREA S et al;《Tissue Engineering》;20061231;第3383-3394页 *

Also Published As

Publication number Publication date
CN109276759A (en) 2019-01-29

Similar Documents

Publication Publication Date Title
JP3233326U (en) Composite material for soft tissue repair with stable repair area
Chen et al. Recent advances in electrospun nanofibers for wound healing
Kargozar et al. “Hard” ceramics for “Soft” tissue engineering: Paradox or opportunity?
Wolf et al. Naturally derived and synthetic scaffolds for skeletal muscle reconstruction
Aramwit Introduction to biomaterials for wound healing
Anton-Sales et al. Opportunities of bacterial cellulose to treat epithelial tissues
KR100860896B1 (en) Bioabsorbable Wound Dressing
Brennan et al. Antibacterial activity within degradation products of biological scaffolds composed of extracellular matrix
US10245353B2 (en) Hydrophilic electrospinning biological composite stent material used for tissue regeneration and preparation method and application thereof
EP2921136B1 (en) Fiber membranes for repairing tissue and products and preparation method thereof
CN102580166A (en) Medical bionic transparent film implanting material, and preparation method and application of material
BRPI1006250B1 (en) dura mater and artificial production method
Cao et al. Prevascularized bladder acellular matrix hydrogel/silk fibroin composite scaffolds promote the regeneration of urethra in a rabbit model
Liao et al. A biomimetic triple-layered biocomposite with effective multifunction for dura repair
CN109276759B (en) Bionic antibacterial abdominal wall repair material
Subramanian et al. Skin tissue regeneration
Zhao et al. The latest progress of tympanic membrane repair materials
Naghibzadeh Nanofibers for Skin Regeneration.
CN112972064A (en) Bolt type soft tissue repair patch and preparation method thereof
Liu et al. The microstructures and materials of nerve conduits used in peripheral nerve regeneration
DE20122661U1 (en) Wound dressing for chronic wounds, comprises porous bioabsorbable layer as scaffold for cell attachment and proliferation, and absorbent gel forming layer as barrier for cell adhesion and penetration
Tornello et al. Micro/nanofiber-based scaffolds for soft tissue engineering applications: Potential and current challenges
Faccendini NANOCOMPOSITE SCAFFOLDS FOR TISSUE ENGINEERING
Bhat et al. Soft Tissue Applications
SethurAmAn Skin tissue regeneration

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
GR01 Patent grant
GR01 Patent grant