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WO2015007797A1 - Treillis tridimensionnel fonctionnalisé avec des micro-tissus pour la régénération tissulaire - Google Patents

Treillis tridimensionnel fonctionnalisé avec des micro-tissus pour la régénération tissulaire Download PDF

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Publication number
WO2015007797A1
WO2015007797A1 PCT/EP2014/065301 EP2014065301W WO2015007797A1 WO 2015007797 A1 WO2015007797 A1 WO 2015007797A1 EP 2014065301 W EP2014065301 W EP 2014065301W WO 2015007797 A1 WO2015007797 A1 WO 2015007797A1
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WO
WIPO (PCT)
Prior art keywords
bone
scaffold
microtissues
poly
biomaterial
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/EP2014/065301
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English (en)
Inventor
Nadia BENKIRANE-JESSEL
Sandy EAP
Laetitia KELLER
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.)
Institut National de la Sante et de la Recherche Medicale INSERM
Universite de Strasbourg
Original Assignee
Institut National de la Sante et de la Recherche Medicale INSERM
Universite de Strasbourg
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 Institut National de la Sante et de la Recherche Medicale INSERM, Universite de Strasbourg filed Critical Institut National de la Sante et de la Recherche Medicale INSERM
Priority to US14/905,190 priority Critical patent/US20160136330A1/en
Priority to EP14739200.5A priority patent/EP3021880A1/fr
Priority to JP2016526611A priority patent/JP2016524967A/ja
Publication of WO2015007797A1 publication Critical patent/WO2015007797A1/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
    • A61L27/14—Macromolecular materials
    • A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—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
    • A61L27/38—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 containing added animal cells
    • A61L27/3804—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 containing added animal cells characterised by specific cells or progenitors thereof, e.g. fibroblasts, connective tissue cells, kidney cells
    • A61L27/3821—Bone-forming cells, e.g. osteoblasts, osteocytes, osteoprogenitor 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
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/52—Hydrogels or hydrocolloids
    • 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
    • A61L27/56—Porous materials, e.g. foams or sponges
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0652—Cells of skeletal and connective tissues; Mesenchyme
    • C12N5/0654—Osteocytes, Osteoblasts, Odontocytes; Bones, Teeth
    • 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
    • A61L2430/24—Materials or treatment for tissue regeneration for joint reconstruction
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2533/00—Supports or coatings for cell culture, characterised by material
    • C12N2533/30—Synthetic polymers
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2533/00—Supports or coatings for cell culture, characterised by material
    • C12N2533/70—Polysaccharides
    • C12N2533/74—Alginate
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2533/00—Supports or coatings for cell culture, characterised by material
    • C12N2533/70—Polysaccharides
    • C12N2533/80—Hyaluronan

Definitions

  • a biomaterial comprising a nanofibrous scaffold which is functionalized by microtissues.
  • Such biomaterials advantageously create a second three dimensional tissue regeneration system within the three dimensional scaffold.
  • the biocompatible polymer is preferably selected from poly(e-caprolactone), poly- (lactic acid), poly(glycolic acid), poly(ethylene glycol) terephthalate, poly(butylene terephthalate), collagen, fibrin, hyaluronic acid, hydroxyapatite, chondroitine sulfate, chitosan, copolymers and mixtures thereof.
  • biomaterial devoid of a growth factor refers to a biomaterial devoid of added growth factor.
  • the scaffold comprises or consists of collagen.
  • microtissues The preparation of microtissues is known in the art, and described in detail notably in WO 2012/014047 A1 .
  • Particularly preferred in the framework of the present invention is the preparation of microtissues in an automated hangingdrop platform, using a GravityPLUSTM plate (sold by InSphero, Zurich, Switzerland).
  • GravityPLUSTM plate sold by InSphero, Zurich, Switzerland.
  • Such microtissues are well calibrated in size, form and number of cells and thus ensure a homogeneous colonisation and subsequent tissue growth.
  • Microtissues are also available commercially, notably at InSphero, Zurich, Switzerland.
  • the microtissues are used in form of a suspension in a liquid medium, generally an aqueous solution and most often a buffer solution.
  • a liquid medium generally an aqueous solution and most often a buffer solution.
  • the microtissues may also be introduced into a hydrogel before contacting with the scaffold.
  • a very convenient and simple means to put the scaffold in contact with the microtissues is to deposit the suspension of microtissues onto the scaffold, for instance by spraying, or to dip the scaffold into the suspension and to let the suspension impregnate the scaffold with the assistance of capillary forces.
  • the biomaterial according to the invention may be equilibrated (e.g. by bringing it in contact with serum-free medium).
  • the biomaterial according to the invention may be produced without adding growth factor.
  • the bone and/or cartilage defect is a subchondral bone defect.
  • the invention thus provides a biomaterial described in the above paragraphs for use in subchondral bone regeneration and/or for use in the treatment of a subchondral bone defect.
  • the individual and/or patient to be treated is preferably a human individual and/or patient.
  • the biomaterials according to the invention also find use in the field of veterinary medicine.
  • Figure 2 Fluorescence micrographs of human primary osteoblasts microtissue stained with DAPI (DNA) and phalloidin (actin) (A, B, C) and of the living microtissue nesting in the scaffold according to Example 2 (D).
  • DAPI DNA
  • actin phalloidin
  • Figure 4 In vitro proliferation of human osteoblasts single cells and microtissues growing on the surface of the scaffold according to Example 1 after 3 days, 7 days, 14 days, 21 days and 28 days (A). Bone induction and mineralization (alizarin red staining) after 21 days in vitro culture of human osteoblasts single cells (C) and microtissues after 21 days (D) and 28 days (E). Control without cells (B).
  • Figure 5 In vivo bone induction of the scaffold functionalized with human primary osteoblasts single cells (according to Comparative Example, A and C) and microtissues (according to Example 2, B and D) after 4 weeks calvaria implantations in nude mice.
  • a and B cell nucleus in dark grey, bone collagen matrix in light grey
  • HB host bone
  • NB new bone.
  • C and D cell nucleus in dark grey with DAPI, bone in formation in light grey with calcein.
  • Figure 6 Schematic representation of an osteochondral implant prepared according to example 4.
  • PCL Poly(e-caprolactone)
  • DCM/DMF 40/60 vol/vol dichloromethane/dimethylformamide
  • the PCL solution was poured into a 5 mL syringe and ejected through a 21 G needle of 0.8 mm diameter at a flow rate of 1 .2 mlJh thanks to a programmable pump (ProSense).
  • the electrospun hjet was focused thjanks to the use of a poly(methyl metacrylate) (PMMA) plate of 2,5 mm thick pierced with a hole (25 mm in diameter) placed over the conductive collector.
  • the collector was placed at a distance from the needle of 16 cm.
  • Chondrocytes were seeded in GravityPLUSTM plate (from InSphero, Zurich, Switzerland) to produce microtissues. 1 x10 4 cells per microtissue were seeded in these plates and cultivated during 5 days.
  • chondrocytes microtissues were then suspended in a solution of alginate (12 mg mL "1 ) / hyaluronic acid (3 mg mL "1 ) hydrogel.
  • the alginate was then polymerized in a solution of CaCI 2 at 102 mM during 15 minutes at 37 ⁇ C.
  • the microtissues embedded with alginate/AH were then cultured in medium complemented with 1 mM of CaCI 2 .
  • AlamarBlue® (Serotec) was used to assess cellular proliferation.
  • the Alamar Blue test is a non-toxic, water-soluble, colorimetric redox indicator that changes color in response to cell metabolism.
  • Alizarin Red S powder was dissolved in distilled water in a concentration of 2 g for 100 mL. The samples were incubated in the Alizarin Red solution for 20 min and then rinsed with distilled water several times. The samples were embedded in Tissue-Tek OCTTM Compound to be cut in sections (35 ⁇ ) with a cryostat (LEICA JUNG CM 3000). The sections were then observed under the optical microscope (LEICA DM 4000 B).
  • mice were anesthetized and implanted with a PCL three-dimensional scaffold seeded with human single cell osteoblasts on one side of calvaria and a PCL three- dimensional scaffold seeded with osteoblasts microtissues on the other side. Five mice per group were used. Implantations have been carried out with the same protocol as above. After 2 or 4 weeks of calvaria implantation, the mice were sacrificed and the samples extracted for analysis.
  • mice were anesthetized and implanted with a PCL three-dimensional scaffold seeded with human single cell osteoblasts and a PCL three-dimensional scaffold seeded with osteoblasts microtissues.
  • the samples were implanted between skin and muscles behind the ears of mice. Five mice per group were used. After 4 weeks of calvaria implantation, the mice were sacrificed and the samples extracted for analysis.
  • the implants were fixed with Bouin Hollande solution during two days. Then, they were dehydrated through a series of increasing ethanol concentrations, cleared with toluene and embedded in paraffin wax. Sections were cut at 7 ⁇ using a sledge microtome and mounted on glass slides. After the removal of paraffin wax, sections of the calvaria and subcutaneous implants were stained using Mallory coloration during two days.
  • the scaffolds were gold-coated (Edwards Sputter Coater) and observed with a scanning electron microscope (SEM Hitachi TM1000) in conventional mode (high vacuum).
  • Samples seeded with human osteoblast as single cells or osteoblasts microtissues were cultivated for 21 days. Then, they were fixed with 4% PFA over 1 h, permeabilized with 0.1 % Triton X-100 for 1 h and incubated for 30 min with Alexa Fluor 546-conjugated phalloidin (Molecular Probes) for F-actin labelling and 5 min with 200 nM DAPI (Sigma) for nuclear staining.
  • Alexa Fluor 546-conjugated phalloidin Molecular Probes
  • Bone growth induction was measured by assaying expression of osteocalcin and BSPII, using polyclonal goat anti-oscteocalcin (1/200; Santa Cruz Biotechnology) and monoclonal mouse anti-BSPII (1 /200; Santa Cruz Biotechnology) overnight at 4 ⁇ C. After washing with PBS, the samples were incubated with secondary anti-goat or anti-mouse antibodies conjugated to Alexa Fluor 488 (Invitrogen). The samples were observed under a fluorescent microscope (LEICA DM 4000 B).
  • the three-dimensional scaffold was an electrospun PCL (Poly ( ⁇ - caprolactone) nanofibers implant (689 ⁇ 45 ⁇ fiber diameter) with a thickness of 1 mm was manufactured ( Figure 1 ). Human primary osteoblasts after Live-Dead fluorescent staining were visualized before incorporation into the three-dimensional implants.
  • PCL Poly ( ⁇ - caprolactone) nanofibers implant (689 ⁇ 45 ⁇ fiber diameter) with a thickness of 1 mm
  • the comparative Example was repeated, except that the scaffold was seeded with living human osteoblasts microtissues instead of living human osteoblasts single cells.
  • microtissues were prepared according to the protocol indicated above, using a GravityPLUSTM plate for hanging-drop cell culture from InSphero AG (Zurich, Switzerland).
  • mice calvaria implantations have been carried out with the same conditions in nude mice to confirm the subcutaneous results.
  • both implants showed good osteo-integration, large cell colonization and even mineralized bone matrix.
  • the scaffold functionalized with microtissues presented a large newly mineralized area.
  • biomaterial according to the invention functionalized with microtissues, provides for fast and in depth tissue engineering, without the need for a growth factor and including for scaffolds having a thickness of over 50 ⁇ .
  • An implant useful for the regeneration of the bone-cartilage unit is prepared as follows.
  • the nanofibrous three-dimensional scaffold was an electrospun PCL (Poly ( ⁇ - caprolactone) nanofibers implant (689 ⁇ 45 ⁇ fiber diameter) with a thickness of 50 ⁇ or 1 mm.
  • the three-dimensional scaffold was covered with an alginate hydrogel comprising chondrocyte microtissues or mesenchymal stem obtained according to the protocol indicated above.
  • the implant for regeneration of the bone-cartilage unit was then implanted in nude mice for cartilage regeneration as described above.
  • the osteochondral implant (1 ) comprises a nanofibrous three-dimensional scaffold (2) covered with a hydrogel (alginate) and hyaluronic acid (3) comprising microtissues of chondrocytes or mesenchymal stem cells (4). Osteoblasts (5) do not necessarily need to be seeded as they may be recruited from the implantation site.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Dermatology (AREA)
  • Transplantation (AREA)
  • Animal Behavior & Ethology (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Cell Biology (AREA)
  • Zoology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Organic Chemistry (AREA)
  • Dispersion Chemistry (AREA)
  • Biotechnology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Genetics & Genomics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Wood Science & Technology (AREA)
  • Rheumatology (AREA)
  • General Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Microbiology (AREA)
  • Urology & Nephrology (AREA)
  • Botany (AREA)
  • Materials For Medical Uses (AREA)

Abstract

La présente invention concerne un biomatériau dépourvu de facteur de croissance comprenant : - un treillis tridimensionnel constitué d'un polymère biocompatible, et - de cellules vivantes, lesdites cellules vivantes étant sous forme de micro-tissus et le treillis tridimensionnel nanofibreux étant un treillis nanofibreux. Elle concerne en outre un procédé pour fabriquer ce type de biomatériau. Elle concerne enfin un biomatériau destiné à être utilisé pour traiter un défaut osseux et/ou cartilagineux.
PCT/EP2014/065301 2013-07-17 2014-07-16 Treillis tridimensionnel fonctionnalisé avec des micro-tissus pour la régénération tissulaire Ceased WO2015007797A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
US14/905,190 US20160136330A1 (en) 2013-07-17 2014-07-16 Three-Dimensional Scaffold Functionalized with Micro-Tissues for Tissue Regeneration
EP14739200.5A EP3021880A1 (fr) 2013-07-17 2014-07-16 Treillis tridimensionnel fonctionnalisé avec des micro-tissus pour la régénération tissulaire
JP2016526611A JP2016524967A (ja) 2013-07-17 2014-07-16 組織再生のための微細組織を用いて機能化された三次元スキャフォールド

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201313944245A 2013-07-17 2013-07-17
US13/944,245 2013-07-17
EP13306027 2013-07-17
EP13306027.7 2013-07-17

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WO2015007797A1 true WO2015007797A1 (fr) 2015-01-22

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JP (1) JP2016524967A (fr)
WO (1) WO2015007797A1 (fr)

Cited By (4)

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WO2017005927A1 (fr) 2015-07-08 2017-01-12 Paris Sciences Et Lettres - Quartier Latin Dispositif de culture cellulaire
WO2017150371A1 (fr) * 2016-02-29 2017-09-08 国立大学法人大阪大学 Agent thérapeutique pour lésion tissulaire
CN115702953A (zh) * 2021-08-10 2023-02-17 上海交通大学医学院附属第九人民医院 一种骨组织单元-支架材料复合体及其构建方法与应用
WO2024246778A1 (fr) 2023-06-01 2024-12-05 Consejo Nacional De Investigaciones Científicas Y Técnicas (Conicet) Procédé d'obtention d'un produit de thérapie cellulaire avancé au moyen de la culture de cellules souches mésenchymateuses conditionnées avec de l'acide hyaluronique et des dérivés sulfatés, pour des lésions osseuses

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KR20200070247A (ko) * 2017-10-17 2020-06-17 고쿠리츠다이가쿠호진 히로시마다이가쿠 골연골 수복을 유도하는 다능성 간세포
EP3695856A1 (fr) * 2019-02-13 2020-08-19 Institut National De La Sante Et De La Recherche Medicale (Inserm) Biomatériaux comprenant un échafaudage contenant un composé de minéraux et leurs utilisations en tant que substituts osseux
WO2023210765A1 (fr) * 2022-04-28 2023-11-02 株式会社クラレ Dispositif d'immunoisolation

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017005927A1 (fr) 2015-07-08 2017-01-12 Paris Sciences Et Lettres - Quartier Latin Dispositif de culture cellulaire
WO2017150371A1 (fr) * 2016-02-29 2017-09-08 国立大学法人大阪大学 Agent thérapeutique pour lésion tissulaire
CN115702953A (zh) * 2021-08-10 2023-02-17 上海交通大学医学院附属第九人民医院 一种骨组织单元-支架材料复合体及其构建方法与应用
WO2024246778A1 (fr) 2023-06-01 2024-12-05 Consejo Nacional De Investigaciones Científicas Y Técnicas (Conicet) Procédé d'obtention d'un produit de thérapie cellulaire avancé au moyen de la culture de cellules souches mésenchymateuses conditionnées avec de l'acide hyaluronique et des dérivés sulfatés, pour des lésions osseuses

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JP2016524967A (ja) 2016-08-22
EP3021880A1 (fr) 2016-05-25

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