[go: up one dir, main page]

WO2020002625A1 - Système d'hydrogel biohybride à cellules d'actionneur - Google Patents

Système d'hydrogel biohybride à cellules d'actionneur Download PDF

Info

Publication number
WO2020002625A1
WO2020002625A1 PCT/EP2019/067379 EP2019067379W WO2020002625A1 WO 2020002625 A1 WO2020002625 A1 WO 2020002625A1 EP 2019067379 W EP2019067379 W EP 2019067379W WO 2020002625 A1 WO2020002625 A1 WO 2020002625A1
Authority
WO
WIPO (PCT)
Prior art keywords
hydrogel
hydrogel matrix
cells
light
matrix
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/EP2019/067379
Other languages
German (de)
English (en)
Inventor
Christine Selhuber-Unkel
Anne STAUBITZ
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.)
Christian Albrechts Universitaet Kiel
Original Assignee
Christian Albrechts Universitaet Kiel
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 Christian Albrechts Universitaet Kiel filed Critical Christian Albrechts Universitaet Kiel
Priority to EP19735293.3A priority Critical patent/EP3813857A1/fr
Publication of WO2020002625A1 publication Critical patent/WO2020002625A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • C12N5/0068—General culture methods using substrates
    • 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
    • A61K35/34—Muscles; Smooth muscle cells; Heart; Cardiac stem cells; Myoblasts; Myocytes; Cardiomyocytes
    • 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
    • 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
    • A61L27/3826—Muscle cells, e.g. smooth muscle 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
    • A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
    • C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
    • C08J3/075—Macromolecular gels
    • 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
    • C12N5/0657—Cardiomyocytes; Heart 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
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/30—Materials or treatment for tissue regeneration for muscle 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

Definitions

  • the present invention relates to a biohybrid hydrogel system with actuator cells such as muscle cells.
  • the “soft robots” can interact with their environment in a much more finely graded manner, they feel much more natural to a human user and they are inherently safer than hard, inflexible robots.
  • Approaches to development are often pursued that transfer successful, naturally occurring concepts to “soft robotics” and are based on a biomimetic approach.
  • a special branch of research is concerned with the development of biohybrid systems, i.e. with the development of functional materials that combine living biological cells on the one hand and synthetic materials on the other to achieve a synergistic interaction that combines the respective advantages of the different materials.
  • the movement of a living being can be simulated by integrating living material into an actuator system.
  • biohybrid actuators There are not many successful biohybrid actuators at the moment, but they represent an important step in the further development of the rigid robots, which are still rigid and clearly functionally restricted, into a new era.
  • the biohybrid actuators developed so far are based on muscle cells as a living component.
  • the American patent US 9,383,350 B2 describes a targeted cell growth of muscle cells on a polymeric layer and an application of this material for the treatment of damaged tissue, in particular muscle tissue as a wound dressing.
  • biohybrid system which realizes an activation by living cells which can be stimulated to contract by an external stimulus.
  • Different, controllable degrees of contraction should be possible, so that dynamic, controlled adjustable actuator movements can be achieved on the macro scale. In this way it should be possible to provide a new type of actuator based on the biohybrid system.
  • biohybrid hydrogel system comprising a combination of
  • the hydrogel matrix being biocompatible for the actuator cells
  • the hydrogel matrix can be reversibly and locally limited in its mechanical property as a function of an external stimulus, that the actuator cells are only activated by the change in the mechanical property of the hydrogel matrix, and that the actuator cells then in dependence on the change in those surrounding them perform a reversible contraction of the local mechanical property of the hydrogel matrix.
  • the hydrogel system of the present invention initially comprises a combination of a porous hydrogel matrix and actuator cells.
  • hydrogels that are biocompatible for the actuator cells can be considered as the hydrogel matrix.
  • hydrogels or hydrogel matrix are materials that comprise a water-containing but water-insoluble polymer, the molecules of which are chemically, for example, by covalent or ionic bonds, or physically, for example by looping the polymer chains, are linked to form a three-dimensional network.
  • hydrogels For the selection and suitability of the hydrogels, it is also essential in the present case that their mechanical properties can be reversibly changed depending on an external stimulus in a locally limited manner, in particular locally with regard to the microscale.
  • the mechanical property that can be changed locally as a function of an external stimulus is viscosity.
  • Viscosity generally refers to the viscosity or viscosity of liquids and gases. The greater the viscosity, the more viscous, ie less fluid, the fluid; the lower the viscosity, the less viscous it is.
  • the viscosity of liquids can be measured with a viscometer, for example according to EN ISO 3219.
  • a rheometer also enables other rheological properties, including those of solids, to be determined. Therefore, the viscosity of the materials according to the present invention is determined with a rheometer.
  • a suitable device is, for example, a Malvern Kinexus pro + from Malvern.
  • the mechanical property that can be changed as a function of an external stimulus is the modulus of elasticity.
  • the term change in the modulus of elasticity is understood to mean any local change in the mechanical properties of the hydrogel material which is brought about by a change in the local molecular structure.
  • Elasticity is generally the property of a body or material to change its shape under the action of force and to return to its original shape when the force acting is lost.
  • linear-elastic behavior which is described by Hooke's law, which generally occurs with small deformations
  • non-linear-elastic behavior in which the stress is non-linearly dependent on the deformation.
  • a typical example here is the rubber elasticity for larger deformations.
  • the polymer relaxes only incompletely after removal of the external force, the remaining energy is broken down in the form of flow processes.
  • the elasticity of materials can be described in detail with the elasticity module; it generally describes the context between tension and elongation when deforming a solid material with linear elastic behavior.
  • the modulus of elasticity E the tensile, bending and compression tests are used in the quasi-static plastic test using a universal testing machine.
  • the modulus of elasticity is determined as a tangent module in the origin of the stress-strain diagram
  • the secant module of plastics is determined for standards-compliant testing, for example in accordance with DIN EN ISO 527-1 or 527-2.
  • Another example is the determination of the local change in the mechanical property with microindentation methods, for example with an atomic force microscope “JPK Nanowizard 3”.
  • the mechanical property which can be changed as a function of an external stimulus is the density.
  • the density is defined as the quotient of the mass and volume of a substance.
  • Optical methods, immersion methods or bending vibration methods are suitable as measuring methods.
  • a change in the density of a material can be determined in accordance with the regulations of the standards DIN EN ISO 845 and / or DIN EN ISO 1183-1.
  • the mechanical property that can be changed as a function of an external stimulus is volume.
  • Such a change in volume can, for example, be determined optically, that is to say macroscopically document the respective x, y, z dimension.
  • it can be caused by a swelling of the activated point of the hydrogel, for example by a changed polarity, which results in a greater local water attraction.
  • the hydrogel matrix of the present invention also has the essential property that it must be biocompatible for the actuator cells.
  • biocompatible is used here and below with regard to the hydrogel matrix understood that the hydrogels have no negative impact on the living actuator cells. They prefer to support cell growth and allow nutrients to reach the cells. In addition, they preferably form a framework that protects the cells from mechanical stress and / or negative external influences. In order to enable targeted, controllable actuation, the hydrogels should support actuator force generation and force transmission from the actuator cells to the base material.
  • suitable hydrogels are selected from the group of three-dimensional, porous hydrogels.
  • Three-dimensional porous materials are fundamentally easier to deform than solid non-porous materials.
  • porous materials offer the ability to allow the diffusion of nutrients to the living cells and the transportation of waste products away from the cells.
  • Such three-dimensional porous hydrogels have controllable mechanical properties that affect not only the flexibility of the material but also such parameters as cell growth, for example through the choice of the size of the pores or the possibility of introducing channels.
  • salt washing or hydrolyzing ceramic microstructures and 3-D printing are known for producing such materials.
  • EP 3 090 862 Ai which describes suitable hydrogels and their preparation.
  • Microporous polyurethanes containing gold nanowire are also an example of possible hydrogel materials.
  • the hydrogel matrix can also be based on other polymers.
  • polyolefins such as, for example, acrylamide polymers, polyacrylates and polyacrylate copolymers, such as, for example, poly (2-hydroxyethyl methacrylate-co-methacrylic acid (pHEMA-co-MAA), polyvinylpyrrolidones (PVP) , the liquid crystalline elastomers, the polydimethylsiloxanes, the silicones, the polycondensation polymers such as, for example, the polyurethanes, the polyamides or the polyureas, the polyethers, the polyesters, the gelatin-based polymers, the chemically modified biopolymers such as, for example, the light-crosslinkable gelatin Methacrylates (GelMA) and the alginate / hyaluronic acid hydrogel systems, the PNIPAM hydrogels, or mixtures thereof.
  • polyolefins such as, for example, acrylamide polymers, polyacrylates and polyacrylate copolymers, such as
  • soft hydrogels with a high water content that are mechanically robust against repeated deformation are particularly preferred.
  • gel formers There are generally two different types of gel formers.
  • gel formation based on small molecular units with hydrogen bonds as supramolecular structure generation can take place
  • weakly crosslinked polymer materials can be used.
  • the hydrogel material has a very robust structural integrity even with repeated deformations.
  • polymer materials are preferably used.
  • electrically conductive additives can be introduced into the hydrogel matrix, for example by adding carbon nanotubes or particles, polyaniline and metal particles, in particular gold particles.
  • the hydrogel matrix of the present invention also has the property that its mechanical property can be changed locally to a limited extent when exposed to an external stimulus.
  • This property can be achieved, for example, by light-switchable molecules or parts of molecules, for example in the main chain or in the side chain of the polymers of the hydrogel matrix.
  • the switchability of individual molecules that is, the change in the mechanical properties of the molecules to an external stimulus
  • it can be made reversible and, on the other hand, it can be transferred in such a way that the entire mechanical material properties can be switched at least locally.
  • the photomechanical effect of liquid crystalline elastomers based on azobenzene derivative could be demonstrated.
  • the photomechanical effect of the liquid crystalline elastomer can be increased significantly if a porous instead of a solid structure of the hydrogel matrix is provided.
  • a porous hydrogel matrix the larger the pores in the porous hydrogel matrix are selected, the more the photomechanical effect of the corresponding light-activatable repeat units has an effect on the behavior of the entire material.
  • a pore size on the micrometer scale that is from a few micrometers to several hundred micrometers, has proven to be very suitable.
  • a repeating unit can be provided in the main chain of the hydrogel polymer, which has a photomechanical or electromechanical switchability.
  • examples include azobenzene units, spiropyran units or dithienylene units.
  • the provision of such units in the main chain of the polymer has the advantage that the local change in the mechanical properties has a direct effect on the entire polymer. A higher efficiency of the copolymer can therefore be expected.
  • a photomechanical or electromechanical repetition unit can be installed as - or in - a side chain of the hydrogel polymer.
  • this has the advantage that less energy is required to change the mechanical properties of the overall polymer, also and / or in particular locally limited. This applies both to the azobenzene units mentioned and to the spiropyrans and the dithienyl units.
  • the actuator cells can perform a reversible contraction depending on the local elastic modulus of the hydrogel matrix surrounding them.
  • the action of an external stimulus can be used in such a way that a reversible local change in the mechanical properties of the hydrogel matrix occurs, that is to say the modulus of elasticity as defined above. This change in the hydrogel matrix surrounding them locally then leads to the actuator cells performing a contraction.
  • the central idea of the present invention is not to activate or deactivate the actuator cells directly with a stimulus.
  • no electrical stimulus is required solely for contraction of the actuator cells, which in many aspects simplifies the previously known soft robotics systems with actuator cells, in particular with muscle cells.
  • the material of the hydrogel matrix can even be used in such a way that it controls how hard the cells beat.
  • the hydrogel matrix constitutes an intrinsic control unit, which is additionally achieved by e.g. the electrical stimulus would be controlled.
  • the quantity that is to say the intensity of the movement
  • the quantity can also be controlled, for example via the size of the area to which the stimulus is applied or via the intensity of the stimulus.
  • the positioning and density of those in the Actuator cells introduced into the matrix can be used to achieve control and thus dynamic movement. It is only essential for the selection of the living cells that they are able to carry out the contraction described above as a function of the change in the mechanical properties of the matrix surrounding them. Both rapidly contracting and slowly contracting muscle cells can be mentioned as examples of such suitable cells.
  • the actuator cells of the present invention are preferably muscle cells, especially cardiac muscle cells.
  • smooth muscle cells and cardiac muscle cells it has already been shown that it is possible to stimulate them to contract due to an external stimulus even in a synthetic environment.
  • previously isolated cells were brought to controlled adhesion by means of defined substrate conditioning and that after filling in the limited adhesive areas and the formation of cell-cell contacts, functional syncytia were formed in which the individual cells coupled both electrochemically and mechanically. It is therefore assumed that these cells are particularly suitable for the intended purpose, since they show good stability in a synthetic environment and have good responsiveness to external stimuli.
  • the present invention is based on the provision of a hydrogel system with actuator cells integrated therein, which, due to one or more external stimuli, can reversibly change its mechanical properties locally in such a way that dynamically controllable softer and harder areas can be produced in a single material.
  • the external stimulus is a light stimulus.
  • a light stimulus regardless of whether wavelengths in the visible and / or invisible range are selected depending on the matrix material, can be controlled very precisely both locally and in terms of its intensity. It therefore offers great advantages in handling.
  • one or more OLED arrays can be used as the light source.
  • the hydrogel matrix is based on a synthetic biocompatible polymer which has light-activatable repeat units in the polymer which locally change the elastic modulus.
  • the hydrogel matrix can, for example, on an acrylamide copolymer with 2-vinyl-4,6-diamino-i, 3,5-triazine (VDT), preferably with polyethylene glycol crosslinking, or on a poly (N-vinyl-2- pyrrolidone) (PVP) based.
  • VDT 2-vinyl-4,6-diamino-i, 3,5-triazine
  • PVP poly (N-vinyl-2- pyrrolidone)
  • other biocompatible hydrogels such as other polyolefins, polycondensation polymers such as polyurethanes or polyamides, polyethylene glycol, polyvinyl alcohols or polyesters are also conceivable.
  • hydrogel polymers specifically mentioned it has already been shown that they have good biocompatibility with muscle cells.
  • the essential property of the hydrogel matrix of the present invention is that it must be biocompatible.
  • biocompatible is understood here and below with regard to the hydrogel matrix that the hydrogels have no negative influence on living cells or other living tissue. They prefer to support cell growth and allow nutrients to get to the cells or tissues. In addition, they preferably form a framework that can protect the cells from mechanical stress and / or negative external influences.
  • the biocompatibility of the polymers mentioned can already be present in the polymer itself.
  • RGD sequence which mediates cell adhesion and which generates a mechanical anchorage of cells on the surface being treated in each case.
  • the RGD sequence can be linked via thiol anchor or Amino groups take place.
  • other peptide sequences for integrin-mediated cell adhesion are known.
  • the functionalization option offers not only the setting of the hardness, but also the synthetic connection of switchable repeat units with photo- or electromechanical behavior.
  • the light-activatable repeating units which change the mechanical property locally can preferably be azobenzene units or spiropyran units.
  • the azobenzene units or the spiropyran units can be suitably functionalized on the one hand to support the porous structure of the hydrogel matrix and on the other hand to have a desired polarity, for example.
  • Functionalization can also be provided in such a way that the repeating units can either be introduced synthetically into the main chain of the hydrogel polymer or as a side chain.
  • functionalizations with terminal double bonds or other end groups known in macromolecular chemistry such as, for example, hydroxyl groups, which are esterified or etherified in accordance with the functionalities of the hydrogel polymer, are suitable for binding to the polymer of the hydrogel matrix.
  • this change in length leads locally to a change in the modulus of elasticity by swelling or else by a local change in volume to shrink the polymer strand.
  • switchable repeat units show good chemical stability.
  • switchability of the repetition units can also be influenced, for example, by functionalization or by additives in such a way that it does not take place in the UV range but in a lower-energy wavelength range.
  • a preferred use of a hydrogel system according to the invention can be in a soft-robotics application, or as a dynamically controllable valve, or in a dynamically controllable gripping tool.
  • one of the core effects of the present invention is to provide a flexible material that can not only perform one type of movement but controllably movements of different types and forms, it is possible for the first time to use this dynamic movement in a soft-robotic application, as a valve or to use as a flexible actuator element in a gripping tool.
  • the material can be used, for example, in combination with a hard material. It can be used not only to switch between “open” and “close” in a valve, but also to dynamically control intermediate states such as “half open”, “quarter closed”, and this in a way that is modeled on nature , This also applies to the use in a gripping tool, which due to the flexibility of the material of the mechanics or the actuator can show a completely different dynamic response behavior than with a mechanical actuator made of hard material.
  • a hydrogel system of the present invention can particularly preferably be used in a hand prosthesis.
  • Such a hand prosthesis can be constructed in such a way that the hydrogel system according to the invention is preferably used in the joint areas of the fingers and is combined with hard and other non-functional flexible materials. In this way, a finger movement can be made possible, which allows a more natural, dynamic movement of the individual finger segments.
  • the invention further relates to a light-activatable hydrogel system comprising a porous three-dimensional hydrogel matrix network, the hydrogel matrix being based on is based on a synthetic polymer which is selected, for example, from the group of polyolefins, such as polyacrylamide copolymers, for example with polyethylene glycol crosslinking, polyurethanes, polyesters or poly (N-vinyl-2-pyrrolidone) e (PVP) , the polyether (polyethylene glycol) and the polyamides, wherein the synthetic polymer has light-activatable groups and / or repeating units in its main or side chain, which in response to an external light stimulus a local change in length and / or change in polarity and thus Cause swelling.
  • a synthetic polymer which is selected, for example, from the group of polyolefins, such as polyacrylamide copolymers, for example with polyethylene glycol crosslinking, polyurethanes, polyesters or poly (N-vinyl-2-pyr
  • a material is made available for the first time which can reversibly change its mechanical properties in whole or locally due to an external light stimulus. In this way, dynamically controllable softer areas and harder areas can be created, which can be reversibly regressed.
  • the hydrogel matrix is selected, for example, from the group of polyolefins, such as, for example, acrylamide copolymers with 2-vinyl-4,6-diamino-i, 3,5-triazine (VDT), for example with polyethylene glycol crosslinking, the polyurethanes, the polydimethylsiloxanes, the polyester or the poly (N-vinyl-2-pyrrolidone) e (PVP).
  • VDT 2-vinyl-4,6-diamino-i, 3,5-triazine
  • PVP poly (N-vinyl-2-pyrrolidone) e
  • porous hydrogels are much easier to deform than solid hydrogels. Further functionalization of the material, for example by means of electrically conductive groups or additives, is also easily possible.
  • the biocompatibility of the polymers mentioned can already be present in the polymer itself. Alternatively or additionally, however, it can also be brought about or improved by a method which is generally known to the person skilled in the art, such as, for example, by treating with or applying suitable ones Peptide solutions.
  • a method which is generally known to the person skilled in the art such as, for example, by treating with or applying suitable ones Peptide solutions.
  • commercially available is, for example, an RGD sequence that mediates cell adhesion and that generates a mechanical anchorage of cells on the surface being treated.
  • the RGD sequence can be linked via thiol anchors or amino groups.
  • other peptide sequences for integrin-mediated cell adhesion are known.
  • the light-activatable groups and / or repeating units in the main or side chain of the hydrogel system reference is made in full to the above examples of the azobenzene units, the spiropyran units and the dithienyl units.
  • the invention is not restricted to this, only the mode of action of the light-switchable, that is to say photomechanical, groups is important in the present case.
  • a preferred light-activatable hydrogel system can comprise a hydrogel matrix which has azobenzene units or spiropyran units as light-activatable groups and / or repeating units in its main or side chain.
  • Azobenzenes and spiropyrans can be easily functionalized, so that they can be built into both the main chain of the matrix polymer and the side chain of the matrix polymer. Both repetition units can be activated specifically by UV light and their change in length is comparatively large, so that an efficient effect can be achieved in the matrix.
  • the azobenzene units or the spiropyran units can be suitably functionalized on the one hand to support the porous structure of the hydrogel matrix and on the other hand to have a desired polarity, for example.
  • Functionalization can also be provided in such a way that the repeating units can either be introduced synthetically into the main chain of the hydrogel polymer or as a side chain.
  • functionalizations with terminal double bonds or other end groups known in macromolecular chemistry such as, for example, are suitable for binding to the polymer of the hydrogel matrix Hydroxy groups that are esterified or etherified according to the functionalities of the hydrogel polymer.
  • this change in length locally leads to a change in the modulus of elasticity due to swelling or through a locally greater crosslinking or shrinkage of the polymer strand.
  • switchable repeat units show good chemical stability.
  • switchability of the repetition units can also be influenced, for example, by functionalization or by additives in such a way that it does not take place in the UV range but in a lower-energy wavelength range.
  • a preferred use of a light-activatable hydrogel system according to the above-described embodiment of the invention can be in medical technology, in sensor technology or in micromechanics.

Landscapes

  • 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)
  • Zoology (AREA)
  • Medicinal Chemistry (AREA)
  • Cell Biology (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Veterinary Medicine (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Organic Chemistry (AREA)
  • Dermatology (AREA)
  • Biotechnology (AREA)
  • Transplantation (AREA)
  • Genetics & Genomics (AREA)
  • Wood Science & Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dispersion Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Developmental Biology & Embryology (AREA)
  • General Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Microbiology (AREA)
  • Urology & Nephrology (AREA)
  • Botany (AREA)
  • Cardiology (AREA)
  • Rheumatology (AREA)
  • Polymers & Plastics (AREA)
  • Molecular Biology (AREA)
  • Vascular Medicine (AREA)
  • Immunology (AREA)
  • Virology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Composite Materials (AREA)
  • Materials Engineering (AREA)
  • Prostheses (AREA)

Abstract

L'invention concerne un système d'hydrogel biohybride, comprenant une combinaison d'une matrice d'hydrogel poreuse, et de cellules d'actionneur, lesquelles sont agencées dans la matrice d'hydrogel, la matrice d'hydrogel étant biocompatible pour les cellules d'actionneur, caractérisé en ce que la matrice d'hydrogel peut être modifiée de manière réversible et limitée localement en fonction d'un stimulus extérieur en ce qui concerne sa propriété mécanique, en ce qu'une activation des cellules d'actionneur se produit d'abord par la modification de la propriété mécanique de la matrice d'hydrogel, et en ce que les cellules d'actionneur exercent alors une contraction réversible en fonction de la modification de la propriété mécanique de la matrice d'hydrogel qui les entoure localement. L'invention concerne également une application en technique de médecine, en technologie des capteurs ou en micromécanique, en particulier dans une application de robotique molle, ou en tant que soupape commandable dynamiquement, ou dans un outil de saisie commandable dynamiquement.
PCT/EP2019/067379 2018-06-29 2019-06-28 Système d'hydrogel biohybride à cellules d'actionneur Ceased WO2020002625A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP19735293.3A EP3813857A1 (fr) 2018-06-29 2019-06-28 Système d'hydrogel biohybride à cellules d'actionneur

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102018210709.2A DE102018210709A1 (de) 2018-06-29 2018-06-29 Biohybrides Hydrogelsystem mit Aktuatorzellen
DE102018210709.2 2018-06-29

Publications (1)

Publication Number Publication Date
WO2020002625A1 true WO2020002625A1 (fr) 2020-01-02

Family

ID=67139743

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2019/067379 Ceased WO2020002625A1 (fr) 2018-06-29 2019-06-28 Système d'hydrogel biohybride à cellules d'actionneur

Country Status (3)

Country Link
EP (1) EP3813857A1 (fr)
DE (1) DE102018210709A1 (fr)
WO (1) WO2020002625A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024165004A1 (fr) * 2023-02-10 2024-08-15 The University Of Hong Kong Système composite d'hydrogels auto-cicatrisants et procédés associés
CN119700210A (zh) * 2024-12-23 2025-03-28 西安交通大学医学院第一附属医院 湿粘附可穿戴抓取设备、制备方法及用途

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005072334A2 (fr) * 2004-01-23 2005-08-11 Arizona Board Of Regents For And On Behalf Of Arizona State University Hydrogels photosensibles
US20070249044A1 (en) * 2006-01-30 2007-10-25 University Of Illinois At Chicago Microstructures in three dimensional gel suspensions for growth of cells
US20090292325A1 (en) * 2008-05-02 2009-11-26 Cederna Paul S Hybrid bioelectrical interface device
JP2010046012A (ja) * 2008-08-21 2010-03-04 Konica Minolta Holdings Inc 細胞培養基材及び細胞培養方法
WO2010036800A1 (fr) * 2008-09-24 2010-04-01 President And Fellows Of Harvard College Hydrogels électroactifs poreux et utilisations de ceux-ci
US20110256628A1 (en) * 2010-04-20 2011-10-20 The University Of Washington Through Its Center For Commercialization Adaptive tissue engineering scaffold
US8748181B2 (en) 2008-05-23 2014-06-10 President And Fellows Of Harvard College Methods of generating patterned soft substrates and uses thereof
US9383350B2 (en) 2006-02-03 2016-07-05 President And Fellows Of Harvard College Engineered cell growth on polymeric films and biotechnological application thereof
EP3090862A1 (fr) 2015-05-07 2016-11-09 Christian-Albrechts-Universität zu Kiel Hydrogels microporeux

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005072334A2 (fr) * 2004-01-23 2005-08-11 Arizona Board Of Regents For And On Behalf Of Arizona State University Hydrogels photosensibles
US20070249044A1 (en) * 2006-01-30 2007-10-25 University Of Illinois At Chicago Microstructures in three dimensional gel suspensions for growth of cells
US9383350B2 (en) 2006-02-03 2016-07-05 President And Fellows Of Harvard College Engineered cell growth on polymeric films and biotechnological application thereof
US20090292325A1 (en) * 2008-05-02 2009-11-26 Cederna Paul S Hybrid bioelectrical interface device
US8748181B2 (en) 2008-05-23 2014-06-10 President And Fellows Of Harvard College Methods of generating patterned soft substrates and uses thereof
JP2010046012A (ja) * 2008-08-21 2010-03-04 Konica Minolta Holdings Inc 細胞培養基材及び細胞培養方法
WO2010036800A1 (fr) * 2008-09-24 2010-04-01 President And Fellows Of Harvard College Hydrogels électroactifs poreux et utilisations de ceux-ci
US20110256628A1 (en) * 2010-04-20 2011-10-20 The University Of Washington Through Its Center For Commercialization Adaptive tissue engineering scaffold
EP3090862A1 (fr) 2015-05-07 2016-11-09 Christian-Albrechts-Universität zu Kiel Hydrogels microporeux

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CORO ECHEVERRIA ET AL: "Functional Stimuli-Responsive Gels: Hydrogels and Microgels", GELS, vol. 4, no. 2, 12 June 2018 (2018-06-12), pages 54, XP055619513, DOI: 10.3390/gels4020054 *
FRANCIS WAYNE ET AL: "Spiropyran based hydrogels actuators-Walking in the light", SENSORS AND ACTUATORS B: CHEMICAL, vol. 250, 3 May 2017 (2017-05-03), pages 608 - 616, XP085055195, ISSN: 0925-4005, DOI: 10.1016/J.SNB.2017.05.005 *
MICHAEL C. KOETTING ET AL: "Stimulus-responsive hydrogels: Theory, modern advances, and applications", MATERIALS SCIENCE AND ENGINEERING: R: REPORTS, vol. 93, 1 July 2015 (2015-07-01), AMSTERDAM, NL, pages 1 - 49, XP055602110, ISSN: 0927-796X, DOI: 10.1016/j.mser.2015.04.001 *
TAKEMURA R ET AL: "Chemical switching of jellyfish-shaped micro robot consisting only of cardiomyocyte gel", 2011 16TH INTERNATIONAL SOLID-STATE SENSORS, ACTUATORS AND MICROSYSTEMS CONFERENCE (TRANSDUCERS 2011) ; BEIJING, CHINA; 5 - 9 JUNE 2011, IEEE, PISCATAWAY, NJ, 5 June 2011 (2011-06-05), pages 2442 - 2445, XP031910968, ISBN: 978-1-4577-0157-3, DOI: 10.1109/TRANSDUCERS.2011.5969661 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024165004A1 (fr) * 2023-02-10 2024-08-15 The University Of Hong Kong Système composite d'hydrogels auto-cicatrisants et procédés associés
CN119700210A (zh) * 2024-12-23 2025-03-28 西安交通大学医学院第一附属医院 湿粘附可穿戴抓取设备、制备方法及用途

Also Published As

Publication number Publication date
DE102018210709A1 (de) 2020-01-02
EP3813857A1 (fr) 2021-05-05

Similar Documents

Publication Publication Date Title
Shi et al. Bioactuators based on stimulus-responsive hydrogels and their emerging biomedical applications
DE69931474T2 (de) Formgedächtnis-polymer
DE68912268T2 (de) Elastomere polypeptide als vaskulare prothesematerialien.
EP1948263B1 (fr) Tuyaux de guidage pour les nerfs
WO1993025266A1 (fr) Dilatateur tissulaire autodilatable
WO2010036800A1 (fr) Hydrogels électroactifs poreux et utilisations de ceux-ci
DE3012233A1 (de) Verfahren zum einkapseln von lebensfaehigem gewebe in eine membran
WO2008043484A2 (fr) Séparation de callosité artificielle tridimensionnelle
Liu et al. Biomimetic self-deformation of polymer interpenetrating network with stretch-induced anisotropicity
EP3813857A1 (fr) Système d'hydrogel biohybride à cellules d'actionneur
Mandal et al. Mechanically robust anisotropic hydrogel–organogel conjugates for soft actuators with fast response time and diverse bi-axial programmable folding ability
DE69111245T2 (de) Knochenwachstumsstimulator.
Gong et al. Hydrogel Fabrication Techniques for Advanced Artificial Sensory Systems
EP2356215A1 (fr) Substrats permettant de sélectionner et d'influencer spécifiquement le fonctionnement de cellules
WO2014130449A1 (fr) Gradients chimiques
DE102007006843A1 (de) Verfahren und Stützstruktur zum Kultivieren lebender Zellen
EP2686028B1 (fr) Mélange de granulats, comprenant deux granulats différents, pour distraction de cal artificielle
EP2477667B1 (fr) Mélange de granulés comprenant deux types de granulés différents pour distraction de cal artificielle
WO2009115251A1 (fr) Dispositif comprenant un agent de gonflement et une enveloppe pour la distraction du cal artificielle
DE4312970A1 (de) Mikrokapsel sowie Verfahren und Vorrichtung zu ihrer Herstellung
KR101616932B1 (ko) 히알루론산-인산칼슘 복합체의 제조방법
Sonn et al. 3D fabrication of artificial cell microenvironments for mechanobiology
DE102008014560A1 (de) Vorrichtung, umfassend ein Quellmittel und eine Ummantelung, zur künstlichen Kallusdistraktion
Moatsou et al. Mechanically adaptive nanocomposites inspired by sea cucumbers
EP0681834B1 (fr) Microcapsule, ainsi qu'un procédé et un appareil pour la produire

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19735293

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2019735293

Country of ref document: EP