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WO2023121614A2 - Greffon vasculaire naturel, elastique et bioactif - Google Patents

Greffon vasculaire naturel, elastique et bioactif Download PDF

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Publication number
WO2023121614A2
WO2023121614A2 PCT/TR2022/051234 TR2022051234W WO2023121614A2 WO 2023121614 A2 WO2023121614 A2 WO 2023121614A2 TR 2022051234 W TR2022051234 W TR 2022051234W WO 2023121614 A2 WO2023121614 A2 WO 2023121614A2
Authority
WO
WIPO (PCT)
Prior art keywords
vascular graft
hyaluronic acid
bio
alginate
ink
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.)
Ceased
Application number
PCT/TR2022/051234
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English (en)
Other versions
WO2023121614A3 (fr
Inventor
Burak DERKUS
Ece KARAKAYA
Melis ISIK
Emel EMREGUL
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.)
TC Ankara Universitesi
Original Assignee
TC Ankara Universitesi
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 TC Ankara Universitesi filed Critical TC Ankara Universitesi
Publication of WO2023121614A2 publication Critical patent/WO2023121614A2/fr
Publication of WO2023121614A3 publication Critical patent/WO2023121614A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/507—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials for artificial blood vessels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/44—Vessels; Vascular smooth muscle cells; Endothelial cells; Endothelial progenitor cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/20—Polysaccharides
    • 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
    • A61L27/36—Materials 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
    • A61L27/3604—Materials 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
    • A61L27/3625—Vascular tissue, e.g. heart valves
    • 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
    • A61L27/36—Materials 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
    • A61L27/3604—Materials 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
    • A61L27/3633—Extracellular matrix [ECM]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B33—ADDITIVE MANUFACTURING TECHNOLOGY
    • B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
    • B33Y80/00—Products made by additive manufacturing
    • 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
    • A61F2/04—Hollow or tubular parts of organs, e.g. bladders, tracheae, bronchi or bile ducts
    • A61F2/06—Blood vessels
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B33—ADDITIVE MANUFACTURING TECHNOLOGY
    • B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
    • B33Y10/00—Processes of additive manufacturing
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B33—ADDITIVE MANUFACTURING TECHNOLOGY
    • B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
    • B33Y70/00—Materials specially adapted for additive manufacturing

Definitions

  • the invention relates to a natural, elastic, and bioactive vascular graft for use in the technical field of vascular surgery to repair or bypass veins with occlusion, impaired integrity, or aneurysmal degeneration, comprising decellularized extracellular matrices and biomaterials as raw materials, and the production of this vascular graft and the use of the said vascular graft.
  • prosthetic grafts which are used in vascular surgery to repair or bypass the veins with occlusion, impaired integrity, or aneurysmal degeneration. With the experience of vascular surgery in its first years of development, its ideal graft characteristics were determined. The success of the clinical use of vascular grafts depends upon the physical properties of these prostheses. Grafts are classified as synthetic and natural according to their structure and composition. When choosing grafts, factors such as patency rates, suitability for the surgery to be performed and the patient, absence of complications, and high cost should be taken into consideration.
  • Ischemic diseases such as atherosclerotic cardiovascular disease remain one of the leading causes of mortality and morbidity worldwide.
  • Demand for vascular ducts is increasing to solve vascular occlusion problems.
  • Bypass surgery in which an artificial or autologous tube is inoculated into an existing vein to restore blood flow around the occluded or damaged part of the vein, is one of the most common treatments for such diseases.
  • Synthetic grafts were developed with tissue engineering approaches to replace occluded arterial veins, but these synthetic vascular grafts could not significantly reduce overall mortality and morbidity.
  • the invention with patent number EP09887998 relates to tissue decellularization and especially a method for treating tissues such as heart valves, tendons, and ligaments, in such a way as to decellularize them and thereby limit mineralization and/or immunoreactivity upon in vivo administration.
  • the invention with patent number W02007048831 A2 relates to the addition of discontinuous Extra Cellular Matrix (abbreviated as ECM) regions to a biodegradable scaffold.
  • ECM Extra Cellular Matrix
  • the optimal amount of separate ECM material for each application is described, and this concentration is evenly distributed within the dressing, thus avoiding unnecessary high ECM concentrations.
  • the porous structure of the base material provides the cells with a structure for growth.
  • the present invention relates to the acquisition of natural vascular grafts which eliminates the disadvantages in the related technical field and offers additional technical solutions and advantages for the related technical field.
  • the object of the invention is to provide vascular grafts obtained from completely natural components.
  • Another object of the invention is to provide a vascular graft with elastic and bioactive properties.
  • the invention relates to obtaining natural vascular grafts from regenerative biomaterials.
  • the invention is to present a new method for obtaining the natural vascular graft.
  • the invention relates to a natural, bioactive, and elastic vascular graft for use in vascular surgery to repair or bypass the veins with occlusion, impaired integrity, or aneurysmal degeneration, comprising
  • Hyaluronic acid to provide elasticity properties
  • Decellularized extracellular matrix to provide bioactivity and functionality.
  • a preferred embodiment of the invention is that the alginate component is cross-linked with the calcium chloride compound.
  • a preferred embodiment of the invention is that hyaluronic acid is polymerized with the tyramine compound.
  • a preferred embodiment of the invention is that the tyramine-hyaluronic acid compound is cross-linked with the hydrogen peroxide compound.
  • a preferred embodiment of the invention is that it comprises a decellularized extracellular matrix obtained from bone, cartilage, nerve, muscle, skin, cardiac tissue, and aortic vein tissue.
  • a preferred embodiment of the invention is the aortic vein tissues of the decellularized extracellular matrix.
  • a preferred embodiment of the invention is that the decellularized extracellular matrix obtained from the aortic tissues is cross-linked.
  • the invention also relates to the production of the characterized natural vascular graft.
  • the said production method is characterized in that it comprises the steps of i) obtaining bio-ink containing hyaluronic acid, alginate, and decellularized extracellular matrix as components and ii) producing the resulting bio-ink in tubular form by means of a 3D printer.
  • it comprises the mixture of alginate:hyaluronic acid:decellularized extracellular matrix in the ratio of 1 .5:1 :1 by weight in the said bio-ink.
  • the mixture of alginate:hyaluronic acid:decellularized extracellular matrix is incubated at temperatures of 36-37°C before the bio-ink is obtained.
  • the incubation process takes at least 45 minutes.
  • the production method of the invention includes the following process steps; i. Preparing alginate and tyramine-hyaluronic acid solutions, ii. Adding aortic gels to the solution obtained in step i), iii. Incubating the mixture obtained in step ii) and obtaining the bio-ink, iv. Placing the mixture incubated in step iii) in the syringe to be used in the 3D printer as bio-ink, v. Producing the bio-ink obtained in the process step iv) in the tubular form in a 3D printer.
  • the number of coating of the 3D printer is 20 layers.
  • the extruder width of the 3D printer is in the range of 0.2 to 0.4 mm.
  • the thickness of the product obtained by the application of the 3D printer is in the range of 10 to 20 mm.
  • the speed of the 3D printer is in the range of 8 to 12 mm/second.
  • the pressure of the 3D printer is in the range of 50 to 60 kPa.
  • the subject of the invention relates to a natural, elastic, and bioactive vascular graft for use in the technical field of vascular surgery to repair or bypass veins with occlusion, impaired integrity, or aneurysmal degeneration, comprising decellularized cellular matrices and biomaterials as raw materials, and it is explained with examples that do not have any limiting effect only for a better understanding of the subject.
  • the vascular graft of the invention is a composite material containing natural biomaterials.
  • the said composite material contains regenerative and biocompatible biomaterials. In this way, natural vascular grafts with highly elastic and mechanical strength and bioactive properties can be obtained.
  • the vascular graft of the invention contains an alginate component.
  • Alginate' 1 is a polysaccharide that is hydrophilic and is widely dispersed in the cell walls of brown algae, which when hydrated form a viscous gum.
  • the alginate component is included in the vascular graft of the invention due to its positive properties such as being biocompatible, hydrophilic, and cost-effective, being biologically absorbable, not being immunogenic, and ease of gelling.
  • the alginate component has the appropriate mechanical strength for sewing.
  • the alginate compound in the vascular graft of the invention can preferably be cross-linked by means of cross-linking solutions. With cross-linking, alginate can reach high mechanical strength values. Calcium chloride ionic solution is used for cross-linking of the alginate compound.
  • the vascular graft of the invention contains hyaluronic acid as a component.
  • Hyaluronic acid is a linear polysaccharide consisting of sodium D-glucuronate and N-acetyl- D-glucosamine and having recurrent disaccharide units.
  • Naturally occurring glycosaminoglycan is a component of the skin, joint fluid, and subcutaneous tissues.
  • Hyaluronic acid can be metabolically excreted from the body and plays a role in protecting cells and maintaining the structural integrity of tissues.
  • Hyaluronic acid is used in the art in various material designs to prevent tissue adhesion after surgery.
  • Hyaluronic acid is biocompatible, bio-absorbable/non-immunogenic, polyanionic, hydrophilic, and anti-fibrotic.
  • the hyaluronic acid component is present in the inventive vascular graft as a hyaluronic acid- tyramine biomaterial, preferably obtained by polymerization with tyramine.
  • Tyramine is HTA polymerized by oxidative bonding reaction of hydrogen peroxide (H2O2) and horseradish peroxidase (HRP) compound and HTA hydrogel is formed.
  • the hyaluronic acid-tyramine bio-component provides high elasticity for the vascular graft according to the invention.
  • the vascular graft of the invention is subjected to cross-linking processes with hyaluronic acid, preferably cross-linking compounds.
  • the hydrogen peroxide compound is used as the cross-linking component.
  • the vascular graft of the invention contains an aortic extracellular matrix that is free of cells.
  • the decellularized extracellular matrix (ECM) provides bioactivity and functionality for the vascular graft of the invention. It is obtained from tissues, not tumorigenic.
  • the inventors have provided the extracellular matrix component that has been decellularized by decellularization of the aortic vein.
  • the process of decellularizing the said aortic vein comprises the following steps:
  • the aortic vein obtained is first mechanically separated, Undesirable residues such as fat, blood, etc. are removed from the mechanically separated aortic vein and thoroughly washed with phosphate buffer (PBS),
  • PBS phosphate buffer
  • the aortic artery is cut into small pieces so that it can be easily separated from its cells
  • DMEM Dulbecco's Modified Eagle Medium
  • aortic samples are rinsed again with ultrapure water and aortic gels are obtained.
  • the aortic vein is preferably divided into 2*4 cm pieces. In this way, the surface area of the aortic samples is increased and faster and more precise reactions are achieved for the aortic gel to be obtained.
  • the said trizma hydrochloride preferably has a concentration of 5 to 15 millimoles (mM).
  • the said EDTA solution is a solution of 0.05% to 0.2% by weight.
  • the aortic samples in the said trizma hydrochloride-EDTA solution are subjected to mixing in a magnetic stirrer for at least 1 hour.
  • the said stirring is preferably carried out at room temperature.
  • the concentration of the said dimethylsulfoxide compound is in the range of 0.5 M to 2 M.
  • the sodium dodecyl sulfate solution contains 1% by weight of the dimethylsulfoxide compound.
  • the said magnetic stirring is carried out for at least 3 hours. Magnetic stirring is carried out at room temperature.
  • Dulbecco's Modified Eagle Medium (abbreviated as DMEM) solution contains 3% by weight of antibiotic/antimycotic components. Preferably, the DMEM solution is changed every 12 hours.
  • Aortic gels obtained with the information given in the invention can be cross-linked if preferred. The aortic gels are incubated for cross-linking and the temperature of the said incubation is carried out at 36-37°C.
  • the vascular graft of the invention comprises decellularized aortic gels, hyaluronic acid, and alginate components obtained with the information provided in the invention.
  • the vascular graft of the invention comprises decellularized aortic gels, hyaluronic acid- tyramine, and alginate components obtained with the information provided in the invention.
  • the vascular graft of the invention comprises decellularized aortic gels, cross-linked hyaluronic acid-tyramine, and cross-linked alginate components obtained with the information provided in the invention.
  • the invention also provides a method for the production of vascular grafts.
  • the vascular graft comprises the process steps of producing the components in the form of grafts by means of a 3D printer with the bio-ink obtained after obtaining the components as bio-ink.
  • the following process steps are performed for the production of the vascular graft according to the invention; i. Preparing alginate and tyramine-hyaluronic acid solutions, ii. Adding aortic gels to the solution obtained in step i), iii. Incubating the mixture obtained in step ii), iv. Placing the mixture incubated in step iii) in the syringe to be used in the 3D printer as bio-ink, v. Producing the bio-ink obtained in the process step iv) in the tubular form in a 3D printer.
  • the alginate obtained in process step ii) is in the form of 1.5:1 :1 by weight of the mixture of tyramine-hyaluronic acid:aortic gel.
  • the incubation process is carried out at a temperature of 36-37°C in process step iii). Preferably, the incubation is carried out for 40 to 60 minutes.
  • the vascular graft of the invention can be cross-linked using cross-links if the vascular graft is preferred in the tubular form obtained by applying the process steps of the production method.
  • Solutions containing one or both H2O2 and/or CaCh solutions are used as crosslinkers in the invention.
  • Solutions preferably containing H2O2 and CaCh compounds together are used as cross-linkers in the invention.
  • H2O2:CaCl2 solution prepared with 1 :10 (v:v) value by volume is used as a crosslinker.
  • the cross-linking process is carried out for at least 2 hours.
  • the vascular graft of the invention is preferably subjected to UV-sterilization processes to increase its optical permeability after cross-linking.
  • the raw materials of the vascular graft of the invention can be obtained easily and their costs are quite low.
  • the unit production cost of the final product vascular graft to be obtained in this way is quite low.
  • the vascular graft of the invention contains completely natural components.
  • Vascular graft obtained from natural components is not tumorigenic, supports angiogenesis, and can be used as both gel and tissue scaffolding.
  • the vascular graft of the invention can be biocompatible and bioactive thanks to the natural components it contains.
  • the vascular graft of the invention has high flexibility.
  • the vascular graft obtained is unbreakable, unbreakable thanks to its elastic structure, and is a candidate for use instead of natural vascular tissue.
  • the vascular graft of the invention has mechanical strength and elasticity at the level that can be used instead of the vein at the same time.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Transplantation (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Dermatology (AREA)
  • Vascular Medicine (AREA)
  • Zoology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Molecular Biology (AREA)
  • Cell Biology (AREA)
  • Botany (AREA)
  • Urology & Nephrology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Surgery (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Virology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Developmental Biology & Embryology (AREA)
  • Biotechnology (AREA)
  • Biophysics (AREA)
  • Manufacturing & Machinery (AREA)
  • Materials Engineering (AREA)
  • Prostheses (AREA)
  • Materials For Medical Uses (AREA)

Abstract

L'invention concerne un greffon vasculaire naturel, élastique et bioactif destiné à être utilisé dans le domaine technique de la chirurgie vasculaire pour réparer ou contourner des veines avec occlusion, intégrité altérée, ou dégénérescence anévrismale, comprenant des matrices extracellulaires décellularisées et des biomatériaux en tant que matières premières, ainsi que la production de ce greffon vasculaire et l'utilisation dudit greffon vasculaire.
PCT/TR2022/051234 2021-12-22 2022-11-03 Greffon vasculaire naturel, elastique et bioactif Ceased WO2023121614A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2021/020673 2021-12-22
TR2021/020673A TR2021020673A2 (tr) 2021-12-22 2021-12-22 Doğal, elasti̇k, bi̇yoakti̇f özelli̇klerde bi̇r damar grefti̇

Publications (2)

Publication Number Publication Date
WO2023121614A2 true WO2023121614A2 (fr) 2023-06-29
WO2023121614A3 WO2023121614A3 (fr) 2023-08-24

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PCT/TR2022/051234 Ceased WO2023121614A2 (fr) 2021-12-22 2022-11-03 Greffon vasculaire naturel, elastique et bioactif

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WO (1) WO2023121614A2 (fr)

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102908207B (zh) * 2012-10-30 2015-04-22 南通大学 生物打印技术制备的组织工程神经移植物及其制备方法
WO2016033337A1 (fr) * 2014-08-27 2016-03-03 The Cleveland Clinic Foundation Greffe de tissu biocompatible
CN111655451A (zh) * 2017-11-29 2020-09-11 奥里根生物治疗公司 无菌增材制造系统
KR102253724B1 (ko) * 2019-11-26 2021-05-20 주식회사 티앤알바이오팹 회전형 3d 프린팅 조형판 및 이를 포함하는 3d 프린터
WO2021177503A1 (fr) * 2020-03-06 2021-09-10 주식회사 엘앤씨바이오 Composition utilisant une encre biologique à base de composant cartilagineux pour construire une structure à des fins de traitement de microtie, et procédé de préparation associé

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WO2023121614A3 (fr) 2023-08-24
TR2021020673A2 (tr) 2022-01-21

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