WO2018152065A1 - Greffe de tissu mécaniquement anisotrope et impression 3d d'une greffe de tissu mécaniquement anisotrope - Google Patents

Greffe de tissu mécaniquement anisotrope et impression 3d d'une greffe de tissu mécaniquement anisotrope Download PDF

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WO2018152065A1
WO2018152065A1 PCT/US2018/017837 US2018017837W WO2018152065A1 WO 2018152065 A1 WO2018152065 A1 WO 2018152065A1 US 2018017837 W US2018017837 W US 2018017837W WO 2018152065 A1 WO2018152065 A1 WO 2018152065A1
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tissue graft
block copolymer
deposited
graft
filament
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PCT/US2018/017837
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English (en)
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Nicole L. BLACK
Jennifer A. Lewis
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President And Fellows Of Harvard College
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    • 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
    • A61L27/58—Materials at least partially resorbable by the body
    • 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
    • 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
    • A61L27/3808—Endothelial 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
    • A61L27/36—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
    • A61L27/36—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
    • A61L27/383—Nerve cells, e.g. dendritic cells, Schwann 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
    • A61L27/36—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
    • A61L27/3834—Cells able to produce different cell types, e.g. hematopoietic stem cells, mesenchymal stem cells, marrow stromal cells, embryonic stem 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
    • A61L27/507—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials for artificial blood vessels
    • 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
    • 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
    • A61L2430/06—Materials or treatment for tissue regeneration for cartilage reconstruction, e.g. meniscus
    • 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
    • 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
    • A61L2430/32—Materials or treatment for tissue regeneration for nerve reconstruction

Definitions

  • the present disclosure is related generally to three-dimensional (3D) printing and more particularly to 3D printing of mechanically anisotropic tissue grafts.
  • the human body contains a wide variety of structurally and mechanically anisotropic soft tissues whose functions rely on this anisotropy.
  • the tympanic membrane eardrum
  • radial stiffness plays a role in allowing the tympanic membrane to conduct sounds at both low and high frequencies.
  • the alignment and directional elongation of cells themselves may have a
  • a mechanically anisotropic tissue graft and a method of 3D printing a mechanically anisotropic tissue graft are described in this disclosure.
  • the method entails flowing a polymeric ink formulation into a deposition nozzle, where the polymeric ink formulation includes (a) a block copolymer with hydrogen bonding segments and (b) a volatile solvent.
  • a continuous filament comprising the polymeric ink composition is extruded from the deposition nozzle, and the volatile solvent evaporates rapidly upon extrusion.
  • the continuous filament is deposited on a substrate as a deposited filament comprising the block copolymer while the deposition nozzle moves relative to the substrate in a print direction. Due to the rapid evaporation, at least a surface region of the deposited filament is substantially absent the volatile solvent.
  • a mechanically anisotropic tissue graft comprises one or more deposited filaments arranged in a 2D or 3D architecture, where each of the deposited filaments comprises a block copolymer with densified hydrogen bonding segments.
  • the densified hydrogen bonding segments are aligned along a longitudinal axis of the respective deposited filament.
  • Each of the deposited filaments has higher average stiffness along the longitudinal axis thereof than along a direction transverse to the longitudinal axis, and thus the one or more deposited filaments are configured to induce cell elongation along a path of the 2D or 3D architecture.
  • FIG. 1 is a schematic of an exemplary 3D printing process.
  • FIG. 2A illustrates 3D printing of a polymeric ink formulation that comprises (a) a block copolymer with hydrogen bonding segments and (b) a volatile solvent; the inset figures illustrate the densification of the hydrogen bonding (or hard) segments that occurs during filament deposition.
  • FIG. 2B shows a larger-scale view of the 3D printing process of FIG.
  • FIG. 3 is a schematic of an exemplary reaction of hard and soft segments and a chain extender to form a block copolymer with hydrogen bonding segments; in this example the block copolymer is a polyurethane.
  • FIG. 4 shows viscosity versus shear rate for three exemplary polymeric ink formulations to demonstrate the shear-thinning behavior of the ink formulations.
  • FIGs. 5A-5C show a 3D printed tympanic membrane tissue graft before (FIGs. 5A-5B) and after (FIG. 5C) seeding with cells; the tissue graft is printed from a biodegradable polymeric ink formulation comprising poly(ester urethane urea) (PEUU) in acetone.
  • PEUU poly(ester urethane urea)
  • PCL polycaprolactone
  • FIG. 7 shows stress-strain curves and stiffness values for tensile specimens prepared by 3D printing and strained either along the print path or transverse to the print path.
  • FIGs. 8A-8C show a comparison of GFP-HNDF (GFP-expressing human neonatal dermal fibroblast) alignment on a control PCL material as compared to PEUU on a cast sheet, a circular print path, and a parallel line print path. Cellular alignment is apparent on each of the printed PEUU grafts along the print path, but not on the PCL grafts.
  • GFP-HNDF GFP-expressing human neonatal dermal fibroblast
  • FIG. 9A shows the print path (parallel lines) for 3D printing of polymeric ink formulations composed of PEUU mixed at 30 wt.% in solvents of different vapor pressures, specifically, acetone (FIG. 9B), HFIP (FIG. 9C), and ethyl acetate (FIG. 9D).
  • FIG. 9B shows an image of a graft 3D printed from PEUU/acetone after 7 days in culture with GFP-HNDFs.
  • FIG. 9C shows an image of a graft 3D printed from PEUU/HFIP after 7 days in culture with GFP-HNDFs.
  • FIG. 9D shows an image of a graft 3D printed from PEUU/ethyl acetate after 7 days in culture with GFP-HNDFs.
  • FIGs. 10A and 10B show PEUU/acetone ink formulations 3D printed in straight lines to form a tissue graft.
  • FIG. 10C shows the tissue graft of FIGs. 10A and 10B after seeding with cells on the underside of the tissue graft.
  • FIGs. 10D and 10E show PEUU/acetone ink formulations 3D printed in a circular/radial architecture to form a tissue graft.
  • FIG. 10F shows the 3D printed graft of FIGs. 10D and 10E after seeding with cells on the underside of the tissue graft.
  • FIGs. 1 1 A and 1 1 B are images of a tissue graft printed in the shape of an "H" and seeded with HNDF cells; the images reveal that the cells tend to align along the print path of the graft.
  • FIG. 12A shows the structure of the temporomandibular joint (TMJ) cartilage disc.
  • FIG. 12B shows a schematic of the approximate collagen structure of the TMJ disc.
  • FIG. 12C shows a TMJ graft 3D printed from a PEUU/acetone ink formulation; the graft shows increased stiffness in the anterior-posterior (AP) direction.
  • FIG. 12D shows Live/Dead confocal images of hMSCs differentiated into chondrocytes on the 3D printed TMJ graft of FIG. 12C.
  • Block copolymers that have hydrogen bonding segments can exhibit "densification hardening” or "strain hardening” under mechanical deformation, which leads to an increased stiffness along the direction of strain.
  • the inventors have discovered that 3D printing of an ink formulation comprising a strain-hardenable block copolymer and a rapidly evaporating solvent can provide a means to manipulate the stiffness anisotropy of printed filaments, thereby enabling the fabrication of anisotropic tissue grafts or scaffolds that promote elongation of cells along a desired direction (e.g., the path of filament deposition).
  • Block copolymers may further have degradation rates and biocompatibility well suited for use in tissue engineering applications.
  • FIG. 1 A shows a close-up schematic of an exemplary 3D printing process, which may also be referred to as direct ink writing.
  • Ink formulations that are suitable for 3D printing can be readily extruded through a deposition nozzle 102 moving relative to a substrate 104 to form a continuous filament 106 that substantially maintains its shape once deposited.
  • suitable ink formulations exhibit shear-thinning behavior.
  • the deposition nozzle 102 can be moved at a constant or variable speed along a desired print direction 114 while the substrate 104 remains stationary.
  • the substrate 104 may be moved while the deposition nozzle 102 remains stationary, or both the deposition nozzle 102 and the substrate 104 may be moved.
  • the method entails flowing a polymeric ink formulation 110 comprising a block copolymer with hydrogen bonding segments and a volatile solvent into a deposition nozzle 102.
  • a continuous filament 106 comprising the polymeric ink composition 110 is extruded from the deposition nozzle 102, and the volatile solvent evaporates rapidly.
  • the continuous filament 106 is deposited on the substrate 104 as a deposited filament 108 comprising the block copolymer while the deposition nozzle 102 moves relative to the substrate 104 in a print direction 114.
  • the extrusion of the continuous filament 106 continues during deposition. Because the volatile solvent evaporates rapidly from the
  • the extrusion and/or deposition induces elongation of the block copolymer and densification (or strain hardening) of the hydrogen bonding segments, as shown schematically in FIG. 2A; thus, the deposited filament 108 exhibits an increased stiffness along the print direction 114.
  • the stiffness of the deposited filament 108 along the print direction 114 may be at least about 20% higher, or at least about 40% higher, than the stiffness of the deposited filament 108 transverse to the print direction 114.
  • the deposited filament 108 may exhibit an average stiffness of at least about 60 MPa along the print direction 114.
  • the deposited filament 108 may be said to exhibit stiffness anisotropy. Rapid evaporation of the solvent is essential for manipulation of the stiffness and other mechanical properties of the deposited filament 108 since strain hardening may not occur while the block copolymer is solvated. Since evaporation occurs more rapidly from the surface of the continuous filament 106 than from the interior, it is possible that strain hardening is enhanced within the surface region of the deposited filament 108.
  • the deposited filament 108 with directional mechanical properties is arranged in a predetermined architecture 1 12 that defines a mechanically anisotropic tissue graft or scaffold 1 16, as shown for example in FIG. 2B.
  • a predetermined architecture 1 12 that defines a mechanically anisotropic tissue graft or scaffold 1 16, as shown for example in FIG. 2B.
  • complex 3D patterns and high aspect ratio structures may be printed layer by layer.
  • Various 2D and 3D architectures 1 12 can be printed to form mechanically anisotropic tissue grafts 1 16, as further described below. It is preferred but not necessary for the block copolymer of the deposited filament(s) 108 to be biodegradeable.
  • Block copolymers suitable for use in the polymeric ink formulation include hydrogen bonding segments or "hard segments” that can crystallize with each other through hydrogen bonding or other another weaker bonding interaction (e.g., pi stacking, ionic bonding, polar bonding, van der Waals bonding, or disulfide bonding). Polymers can hydrogen-bond between their chains if they contain both a hydrogen donor and a hydrogen acceptor.
  • Amide bonds such as urethane, urea, and nylon, are the most common source of hydrogen bonding in block copolymers because these bonds usually contain both a hydrogen acceptor through the oxygen and a hydrogen donor through the nitrogen in the secondary amine.
  • Block copolymers that include hydrogen bonding segments and which may be suitable for the polymeric ink formulation include polyurethane, nylon, polyurea, polyparaphenylene terephthalamide (Kevlar), cellulose, and proteins.
  • the block copolymer When the block copolymer is strained, the polymer chains tend to reorganize in the most energetically feasible way possible. This usually means that weaker interactions or links between polymer chains break and reform to create as many interactions or links as possible, a process referred to as densification. Densification during straining leads to an increased stiffness along the strain direction and may be referred to as densification hardening or strain hardening. In polyurethanes, urethane hard segments tend to density transverse to the strain direction. This makes the polymer stiffer in the strain direction, as more covalent bonds are oriented with the strain direction, and less stiff in the transverse direction, which is connected mainly by weaker hydrogen bonds.
  • Polyurethanes may be formed by reacting a hydrogen bonding segment or hard segment comprising a diisocyanate with a "soft segment" comprising a polyol.
  • Diisocyanates tend to hydrogen-bond and crystallize with other diisocyanates in nearby polymer chains, giving polyurethane its elastomer-like properties.
  • a chain extender may be included in the reaction to link polyurethane chains together to form a high molecular weight polymer.
  • An exemplary two-step reaction of soft and hard segments and a chain extender is shown schematically in FIG. 3 and described in detail in the Examples below. Referring to FIG. 3, IPDI represents isophorene diisocyanate, a hard segment; PCL represents polycaprolactone diol, a soft segment; PU
  • a suitable molar ratio of components is 1 :2:1 (soft segment: hard segment: chain extender). Other possible molar ratios may be selected from the following, where the chain extender is optional: 0.5-2 : 1 -5 : 0-2.
  • the diisocyanate may be selected from among isophorene diisocyanate (IPDI), methyl diphenyl diisocyanate (MDI), l-lysine diisocyanate (LDI), 1 ,4-butane diisocyanate (BDI), hexamethylene diisocyanate (HDI), and trimethylhexamethylene diisocyanate (TMDI).
  • IPDI isophorene diisocyanate
  • MDI methyl diphenyl diisocyanate
  • LLI l-lysine diisocyanate
  • BDI hexamethylene diisocyanate
  • TMDI trimethylhexamethylene diisocyanate
  • the chain extender may combine individual polyurethane chains through urea bonds or additional urethane bonds.
  • the chain extender may comprise a diol or a diamine, such as ethylene glycol, 1 ,4-butanediol, 1 ,4-cyclohexanedimethanol, 1 ,2- ethanediamine, 1 ,4-butanediamine, combinations including 2-amino-1 - butanol, or another degradable linkage such as 2-hydroxyethyl-2- hydroxyproponoate.
  • a diol or a diamine such as ethylene glycol, 1 ,4-butanediol, 1 ,4-cyclohexanedimethanol, 1 ,2- ethanediamine, 1 ,4-butanediamine, combinations including 2-amino-1 - butanol, or another degradable linkage such as 2-hydroxyethyl-2- hydroxyproponoate.
  • hydrolysable bonds such as esters, ethers, or carbonates
  • polyurethanes may include a diol (polyol) formed from polycaprolactone (PCL), poly(ethylene glycol) (PEG), poly(hexamethylene carbonate) (PHC), poly(ethylene oxide) (PEO), poly(propylene oxide) (PPO), polylactide, (PLA), polyglycolide (PGA), poly(hydroxybutyrate) (P3HB and P4HB), or amino acids.
  • PCL polycaprolactone
  • PEG poly(ethylene glycol)
  • PLC poly(hexamethylene carbonate)
  • PEO poly(ethylene oxide)
  • PPO poly(propylene oxide)
  • PLA polyglycolide
  • P3HB and P4HB poly(hydroxybutyrate)
  • the viscosity and flow properties of the polymeric ink formulation may be influenced by the molecular weight of the block copolymer as well as the amount or concentration of the block copolymer dissolved in the volatile solvent.
  • a wide range of molecular weights may be suitable for 3D printing. Longer polymer chains may increase viscosity, which may promote solvent evaporation during extrusion, but it is also possible to utilize shorter chains and lower amounts of solvent.
  • the molecular weight of the block copolymer may range from about 1 kDa to about 100 kDa, where the molecular weight is more typically in the range from about 25 kDa to about 100 kDa after chain extension and from about 1 kDa to about 3 kDa before chain extension.
  • the concentration of the block copolymer in the polymeric ink formulation is at least about 20 wt.% and may be as high as about 60 wt.%, depending on the molecular weight (chain length) of the block copolymer. Concentrations of at least about 30 wt.% or at least about 40 wt.% are typical.
  • the volatile solvent may account for from about 40 wt.% to about 80 wt.% of the polymeric ink formulation.
  • Suitable volatile solvents evaporate rapidly (relative to water) and are capable of solubilizing the block copolymer. Solvent evaporation occurs nearly instantaneously from the surface of the continuous filament upon extrusion, where "nearly instantaneously” refers to a time scale typically in a range from about 0.01 second to about 1 second. Rapid solvent evaporation ensures that at least the surface region of the deposited filament is
  • substantially solvent-free i.e., substantially absent the volatile solvent
  • the extent of the surface region may be understood to be at least about 1 % and less than about 50% of the deposited filament in terms of volume, where the remaining volume of the filament (from 50 vol.% to less than about 99 vol.%) is considered to be the interior. Evaporation may also occur rapidly from the interior of the filament, depending on the diameter of the filament, the volatile solvent used, etc.
  • substantially absent the volatile solvent means that no more than about 5 wt.% volatile solvent remains (e.g., in the surface region of the deposited filament) due to the rapid evaporation that occurs upon extrusion.
  • at least the surface region of (and possibly an entirety of) the deposited filament includes the volatile solvent at a
  • the volatile solvent employed in the polymeric ink formulation may be an organic solvent.
  • the volatile solvent may be selected from among acetone, toluene, hexafluoroisopropanol, ethyl acetate, diethyl ether, hexane, isopropanol, methylene chloride, ethanol, and methyl ethyl ketone.
  • volatile solvent as used herein may refer to an organic solvent that evaporates more rapidly than water.
  • the polymeric ink formulation comprises a strain-rate dependent viscosity, and thus may be described as viscoelastic. More specifically, the polymeric ink formulation may be shear-thinning, a characteristic that provides a low viscosity at high shear rates (e.g., while passing through the deposition nozzle) and a higher viscosity at low shear rates (e.g., when deposited).
  • the flow properties of exemplary polymeric ink formulations are shown in FIG. 4. Rapid evaporation of the volatile solvent further ensures an increase in viscosity and rigidity of the deposited filament.
  • block copolymers with hydrogen bonding segments may also exhibit desirable mechanical properties for soft tissue engineering applications.
  • Current tissue grafts are typically fabricated from hard, brittle polymers such as poly(capro-lactone) (PCL) and poly(lactic acid) (PLA), which have Young's moduli of 300-5,000 MPa, or from soft, ductile hydrogels such as gelatin or fibrinogen, which have Young's moduli of 1 -100 kPa.
  • PCL poly(capro-lactone)
  • PLA poly(lactic acid)
  • the elastic modulus of most collagenous tissues in the human body is between the range of these commonly used materials, at around 1-1 ,000 MPa.
  • tissue graft should be able to integrate well into the mechanics of the surrounding tissue to prevent stress shielding if it is too stiff or tearing apart if it is too soft. Additionally, grafts that are too stiff may have difficulty being bent,
  • the polyurethanes and other block copolymers described in this disclosure have Young's modulus values (stiffnesses) much closer to the range of human soft tissues.
  • Young's modulus values typically between about 10 MPa and about 1000 MPa.
  • a 3D printed mechanically anisotropic tissue graft 1 16 comprises one or more deposited filaments 108 arranged in a 2D or 3D architecture or pattern 1 12, where each of the deposited filaments 108 comprises a block copolymer with densified hydrogen bonding segments.
  • the graft 1 16 shown in the photographic image of FIG. 5A is also shown schematically in FIG. 2B, with reference numerals).
  • the tissue graft 116 is printed from a biodegradable polymeric ink formulation comprising poly(ester urethane urea) (PEUU) in acetone.
  • the densified hydrogen bonding segments are aligned along a longitudinal axis of the respective deposited filament 108.
  • the deposited filaments 108 exhibit stiffness anisotropy, with each deposited filament 108 having a higher average stiffness along the longitudinal axis thereof than along a direction transverse to the longitudinal axis.
  • the average stiffness along the longitudinal axis may be at least about 20% higher, or at least about 40% higher, than the average stiffness along the direction transverse to the longitudinal axis. Consequently, the one or more deposited filaments 108 are configured to induce cell elongation along a path of the 2D or 3D architecture 112, which coincides with the print path during 3D printing.
  • the mechanically anisotropic tissue graft 116 may be a tympanic membrane graft, as shown in FIGs. 5A-5C, or an articular cartilage graft, a muscle tissue graft, a nerve tissue graft, a vascular graft, or another type of tissue graft.
  • the block copolymer with "densified" hydrogen bonding segments that makes up the mechanically anisotropic tissue graft may have any of the characteristics described above for the block copolymer with hydrogen bonding segments.
  • the block copolymer may be biodegradable.
  • the block copolymer may comprise polyurethane and the densified hydrogen bonding segments may comprise a diisocyanate, such as isophorene diisocyanate (IPDI), methyl diphenyl diisocyanate (MDI), I- lysine diisocyanate (LDI), 1 ,4-butane diisocyanate (BDI), hexamethylene diisocyanate (HDI), or trimethylhexamethylene diisocyanate (TMDI).
  • IPDI isophorene diisocyanate
  • MDI methyl diphenyl diisocyanate
  • LLI I- lysine diisocyanate
  • BDI hexamethylene diisocyanate
  • TMDI trimethylhexamethylene diisocyanate
  • the block copolymer may further include a soft segment comprising a diol formed from polycaprolactone (PCL), poly(ethylene glycol) (PEG), poly(hexamethylene carbonate) (PHC), poly(ethylene oxide) (PEO), poly(propylene oxide) (PPO), polylactide, (PLA), polyglycolide (PGA), poly(hydroxybutyrate) (P3HB and P4HB), or amino acids, and a chain extender comprising a diol or a diamine.
  • PCL polycaprolactone
  • PEG poly(ethylene glycol)
  • PLC poly(hexamethylene carbonate)
  • PEO poly(ethylene oxide)
  • PPO poly(propylene oxide)
  • PVA polyglycolide
  • P3HB and P4HB poly(hydroxybutyrate)
  • the mechanically anisotropic tissue graft may be seeded with cells for in vitro or in vivo remodeling.
  • the cells selected for seeding depend on the architecture and intended function of
  • mesenchymal stem cells smooth muscle cells, cardiac muscle cells, and/or skeletal muscle cells.
  • some or all of the cells deposited on the graft may become elongated along the print direction (or along the longitudinal axis of the deposited filament ("filament axis"), which coincides with the print direction).
  • filament axis the cells are elongated along the radial and circumferential directions of the graft.
  • the alignment of cells may be crucial for the alignment of fibrillar extracellular matrix proteins.
  • cell elongation and spreading direction impacts the direction of collagen deposition.
  • Atomic force microscopy (AFM) imaging of a 3D printed graft (prepared from a PEUU/acetone ink formulation) after 3 months of cellular remodeling reveals bands of what appear to be collagen fibers along the print path (or filament axis). This suggests that controlling cell alignment along the print path in turn affects collagen deposition and eventual collagen fiber organization also.
  • AFM Atomic force microscopy
  • Synthesis of an exemplary biodegradable polyurethane is done through a two-step melt reaction to create poly(ester urethane urea) (PEUU), where the soft segment is polycaprolactone diol (PCL) with hydrolysable ester bonds, the hard segment is isophorene diisocyanate (IPDI), and the chain extender is 1 ,4-diaminobutane (putrescine, PU), as shown schematically in FIG. 3. They are combined in a molar ratio of 1 :2:1 soft segment : hard segment : chain extender.
  • the reaction product is purified in water and ethyl acetate to remove residual monomers and dried in a vacuum oven at 70°C to obtain the final polymer, which in this example is PEUU.
  • PEUU final polymer
  • the soft segment, hard segment, and chain extender employed to form the biodegradable polyurethane can be varied as described above.
  • polymers that may be formed (e.g., by varying the soft segments) are poly(ester carbonate urethane urea) (PECUU), using PHC, and poly(ester ether urethane urea) (PEEUU), using PEG.
  • PHC poly(ester carbonate urethane urea)
  • PEUU poly(ester ether urethane urea)
  • the reaction can be modified to be done under argon or vacuum and for variations in temperature and time scale for each of the two steps.
  • the entire reaction can also be conducted under a solvent such as dimethyl sulfoxide (DMSO) in lieu of the first step being performed as a melt reaction.
  • DMSO dimethyl sulfoxide
  • the block copolymer may be combined with a volatile solvent to prepare the polymeric ink formulation.
  • a volatile solvent such as toluene, hexafluoroisopropanol, and methyl ethyl ketone, may also or alternatively be used.
  • the block copolymer is generally combined in a Thinky cup with the volatile solvent at concentration between 20 wt.% and 60 wt.%, depending on its chain length and properties.
  • the two components can be heated below the solvent's boiling point (56°C for acetone) or mixed in the Thinky planetary centrifugal mixer. Together, these components give a shear-thinning ink as shown for example in FIG. 4, which is ideal for filamentary extrusion 3D printing.
  • Rheology measurements were performed on a Discovery Series Hybrid Rheometer-3 (Texas Instruments) using a 40 mm flat cone geometry.
  • the ink can be loaded into a syringe for filamentary extrusion 3D printing.
  • the printer used in this investigation is a custom multimaterial printer (Aerotech), but others can also be used.
  • a straight (or tapered) nozzle is connected to one side of the syringe (Nordson).
  • nozzles with inner diameters (openings) from about 5 microns to about 200 microns are used to allow for faster evaporation of the solvent from the polymer because of a higher surface to volume ratio.
  • the polymeric ink formulation is extruded via pneumatics onto a glass slide or a slide coated with a nonstick polymer, with pressures typically ranging from 5-100 psi depending on the block copolymer, solvent, and wt.% of the block copolymer in the ink formulation. Aerobasic G-code is used to program the print path of the nozzle in three dimensions. As the polymeric ink formulation is extruded, the solvent rapidly evaporates, leaving deposited filaments comprising just the block copolymer. Thus, as the nozzle translates, it pulls the deposited filament with it, densifying the hard segments (domains) of the block copolymer.
  • the graft can be removed from the glass side and plasma treated (Diener ATTO) for 60 seconds on each side to make it more hydrophilic prior to cell seeding.
  • the plasma treatment also works to clean the samples by killing bacteria on the surface.
  • the mechanical properties of the biodegradable PEUU are determined by tensile tests of tensile specimens 3D printed from a polymeric ink formulation containing 30 wt.% PEUU in acetone using a 330-micron diameter nozzle. The cross-sectional areas are measured with micrometers, and then the specimens, shown schematically in FIG. 7, are subjected to tensile testing (Instron).
  • the tensile specimen having a print path along the vertical direction, or along the longitudinal axis of the tensile specimen yields the data along the upper stress-strain curves
  • the tensile specimen having a print path along the horizontal direction, or transverse to the longitudinal axis of the tensile specimen yields the data along the lower stress-strain curves.
  • Young's moduli values are calculated for each specimen from the stress-strain curves. The results show approximately a 179% increase in stiffness for the PEUU specimen having a print path aligned with the longitudinal axis instead of transverse to (e.g., normal to) the longitudinal axis. In the case of PLA control samples printed with the same vertical and horizontal print paths, the increase is only 119%.
  • Grafts are cast from both the PEUU and PCL ink formulations as well as printed in circular and parallel line print paths, as shown in FIGs. 8A- 8C.
  • GFP-HNDFs showed random spreading for both cast sheets (FIG. 8A). They also spread randomly on the confluent 3D printed PCL grafts independent of the print path (filament axis), suggesting that 3D printing of any polymer alone in a rapidly evaporating solvent may be insufficient to generate the mechanical anisotropy required to obtain cell elongation along a preferred direction.
  • the GFP-HNDFs oriented strongly along the direction of the print path/filament axis.
  • FIGs. 9B-9D were taken after 7 days in culture with GFP-HNDFs, where FIG. 9B shows the seeded graft printed from the acetone-containing ink formulation, FIG. 9C shows the seeded graft printed from the HFIP-containing ink formulation, and FIG. 9D shows the seeded graft printed from the ethyl acetate-containing ink formulation.
  • FIG. 9B shows the seeded graft printed from the acetone-containing ink formulation
  • FIG. 9C shows the seeded graft printed from the HFIP-containing ink formulation
  • FIG. 9D shows the seeded graft printed from the ethyl acetate-containing ink formulation.
  • Only the tissue grafts prepared from the acetone-containing ink formulation showed strong cell elongation along the print path. It appears that only acetone, which has the highest vapor pressure of the three solvents, evaporates rapidly enough following extrusion to permit straining and densification of the
  • polymeric ink formulations comprising PEUU and acetone are 3D printed in straight lines (FIGs. 10A and 10B) and in a circular/radial architecture (FIGs. 10D and 10E). Cells are then seeded on the underside of the tissue grafts, which are fundamentally flat due to compression on the glass. Despite the absence of fiber curvature on the underside of the deposited filaments, the cells still aligned along the print path or filament axis of the bottom-most layer of the grafts, as can be seen in FIGs. 10C and 10F.
  • TM grafts 3D printed from various polymers e.g., PDMS, PLA, and PCL
  • TM grafts 3D printed from PEUU/acetone ink formulations in an architecture that includes circu inferential ly directed lines on the bottom of the graft and radially directed lines on top of the graft are able to induce cell alignment, as shown in FIGs. 5A-5C.
  • the temporomandibular joint contains an articular cartilage disc with a fibrous collagen structure that gives it anisotropic mechanical properties.
  • This stiffness difference is 76 MPa in the anterior-posterior (AP) direction and only 3 MPa in the medial-lateral (ML) direction, as can be understood in view of FIG. 12A.
  • This disc is composed of mainly of fibroblasts, which make up about 70% of the cells, and chondrocytes which make up about 30% of the cells.
  • an Aerobasic G-code print path shown in FIG. 12B was designed with lines parallel to the AP direction in the center with a border of radial and circular fibers at the edges.
  • the program allows for parameters, such as length, width, fiber spacing, and number of layers, to be rapidly varied and customized.
  • the overall dimensions of the TMJ disc were taken from previous literature to be a width of 13 mm and length of 19 mm, with a thickness of 1-2 mm.
  • An exemplary 3D printed TMJ disc is shown in FIG. 12C.
  • the ability of human mesenchymal stem cells (hMSCs) differentiated into chondrocytes to proliferate and elongate on the PEUU grafts was examined.
  • Preliminary Live/Dead imaging shows potential for the chondrocytes to grow on both PCL printed filaments and PEUU printed filaments.
  • the cells elongate only on the PEUU filaments, as expected, and spread randomly on the PCL filaments.
  • the hMSCs appear to elongate along the print direction (longitudinal axis) for the different filament

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Abstract

La présente invention concerne un procédé d'impression 3D d'une greffe de tissu mécaniquement anisotrope qui comprend l'écoulement d'une formulation d'encre polymère dans une buse de dépôt, la formulation d'encre polymère comprenant (a) un copolymère séquencé avec des segments de liaison hydrogène et (b) un solvant volatil. Un filament continu comprenant la composition d'encre polymère est extrudé à partir de la buse de dépôt, et le solvant volatil s'évapore rapidement lors de l'extrusion. Le filament continu est déposé sur un substrat sous la forme d'un filament déposé comprenant le copolymère séquencé tandis que la buse de dépôt se déplace par rapport au substrat dans une direction d'impression. En raison de l'évaporation rapide, au moins une région de surface du filament déposé est sensiblement absente du solvant volatil. Le dépôt et/ou l'extrusion induisent un allongement du copolymère séquencé et la densification des segments de liaison hydrogène, et ainsi le filament déposé présente une rigidité moyenne plus élevée dans la direction d'impression que dans une direction transversale à la direction d'impression. Lors de l'achèvement du dépôt, un ou plusieurs des filaments déposés sont agencés selon une architecture prédéterminée sur le substrat, définissant ainsi une greffe de tissu mécaniquement anisotrope imprimée en 3D.
PCT/US2018/017837 2017-02-14 2018-02-12 Greffe de tissu mécaniquement anisotrope et impression 3d d'une greffe de tissu mécaniquement anisotrope WO2018152065A1 (fr)

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CN110016214A (zh) * 2019-04-11 2019-07-16 林元钦 一种用于3d打印的pla共混改性材料及其制备方法
CN110964379A (zh) * 2019-12-18 2020-04-07 江南大学 一种3d打印用抗菌墨水及其制备方法
CN111454458A (zh) * 2020-04-23 2020-07-28 万华化学集团股份有限公司 一种新型尼龙材料、制备方法及其在3d打印上的应用
WO2021119501A1 (fr) * 2019-12-12 2021-06-17 Massachusetts Eye And Ear Infirmary Encres d'impression 3d pouvant être extrudées à l'état fondu

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110016214A (zh) * 2019-04-11 2019-07-16 林元钦 一种用于3d打印的pla共混改性材料及其制备方法
WO2021119501A1 (fr) * 2019-12-12 2021-06-17 Massachusetts Eye And Ear Infirmary Encres d'impression 3d pouvant être extrudées à l'état fondu
EP4072607A4 (fr) * 2019-12-12 2024-01-10 Massachusetts Eye and Ear Infirmary Encres d'impression 3d pouvant être extrudées à l'état fondu
CN110964379A (zh) * 2019-12-18 2020-04-07 江南大学 一种3d打印用抗菌墨水及其制备方法
CN111454458A (zh) * 2020-04-23 2020-07-28 万华化学集团股份有限公司 一种新型尼龙材料、制备方法及其在3d打印上的应用

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