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WO2019018443A1 - Échafaudages pour interface os-tissu mou et leurs procédés de fabrication - Google Patents

Échafaudages pour interface os-tissu mou et leurs procédés de fabrication Download PDF

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Publication number
WO2019018443A1
WO2019018443A1 PCT/US2018/042559 US2018042559W WO2019018443A1 WO 2019018443 A1 WO2019018443 A1 WO 2019018443A1 US 2018042559 W US2018042559 W US 2018042559W WO 2019018443 A1 WO2019018443 A1 WO 2019018443A1
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WO
WIPO (PCT)
Prior art keywords
bone
phase
fibers
soft tissue
electrospinning
Prior art date
Application number
PCT/US2018/042559
Other languages
English (en)
Inventor
Christina Salas
Sherif Hassan Abdelkader ABOUBAKR
Steven NERY
Christopher BUKSA
Alexander Hamilton
Original Assignee
Stc.Unm
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 Stc.Unm filed Critical Stc.Unm
Priority to US16/632,313 priority Critical patent/US20200163752A1/en
Publication of WO2019018443A1 publication Critical patent/WO2019018443A1/fr
Priority to US18/609,914 priority patent/US20240261084A1/en

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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B33—ADDITIVE MANUFACTURING TECHNOLOGY
    • B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
    • B33Y80/00—Products made by additive manufacturing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/08—Muscles; Tendons; Ligaments
    • 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
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B33—ADDITIVE MANUFACTURING TECHNOLOGY
    • B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
    • B33Y10/00—Processes of additive manufacturing
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B33—ADDITIVE MANUFACTURING TECHNOLOGY
    • B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
    • B33Y30/00—Apparatus for additive manufacturing; Details thereof or accessories therefor

Definitions

  • An optimal interface scaffold would be tri-phasic, including the bone, ligament (tendon, cartilage, or other soft tissue), and the hard/ soft tissue interface region. It would be histologically and
  • ligament-bone interface The insertions of ligaments onto bone (ligament-bone interface) are specially adapted to allow proper distribution and dissipation of stresses at this interface. However, significant force is transmitted through this interface, so injury and tissue damage most often occur (avulsion) .
  • This interface (enthesis) consists of gradients in mechanical properties, chemical properties and cell phenotypes, and structurally continuous over four compositionally distinct regions: ligament, non-mineralized fibrocartilage, mineralized fibrocartilage and bone. The interface exhibits a gradual increase in mineral content with gradual decrease in collagen fiber organization.
  • fibrocartilage acts as a barrier to cell communication between ligament's fibroblasts and bone's osteocytes, as fibrocartilage is poorly vascularized and fibrochondrocytes do not express connexins and do not form gap junctions, therefore the intercellular communication occurs indirectly through cell-matrix interaction or soluble factors, these contribute to poor healing response at interface.
  • Tendons conversely, have been shown to heal at the midsubstance when common suturing techniques and biologies are used for repair. Yet, tendon avulsions (rupture at the bone interface) require a repair technique similar to that of the ligament where bone tunnels are used to reattach the tendon to the bone.
  • the enthesis for tendons varies slightly by skeletal attachment site but is similar to that for ligaments. It consists of gradients in mechanical properties, chemical properties and cell phenotypes, and is structurally continuous over multiple compositionally distinct regions. Fibrous entheses (bony or periosteal) are common in tendons that attach to the diaphysis of long bones and are characterized by dense fibrous connective tissue.
  • Fibrocartilaginous entheses are common in tendons that attach at the epiphyses and apophyses and have four distinct regions that provide a structurally continuous gradient from bone to tendon: dense fibrous connective tissue, unmineralized fibrocartilage, mineralized fibrocartilage, bone.
  • Tendon and ligament are soft-tissues whose primary function is to stabilize and resist tensile loading.
  • the interface of tendon/ligament to bone are specially adapted to allow for dissipation of stresses during loading.
  • Current surgical repair/reconstruction techniques fail to adequately reproduce this interface and are prone to secondary failure at the interface.
  • 3D bioprinting can be defined as the printing of biopolymers, biocompatible synthetic polymers, and high-concentration cell solutions. Typically, a 10 to 1000 ⁇ resolution is required to form the internal structure of these tissue-like scaffolds, with higher-viscosity materials often providing structural support for the printed structure and lower-viscosity materials providing a suitable environment for maintaining cell viability and function. Laboratories across the world have designed and created 3D bioprinters to fabricate replacement human-scale tissues and organs, often with structural integrity and biological function similar to native tissues.
  • the electrospinning fabrication technique uses high voltage to create an electric field between a droplet of polymer solution (typically at the tip of a syringe needle (406)) and a conductive collector plate (490).
  • the main forces acting on the polymer droplet are the electrostatic field and the electrostatic repulsion of charges. These forces are opposed by the surface tension of the droplet, and the viscoelastic forces of polymer.
  • electrospinning processes can produce structures with excellent micro/nano structural porosity, density and tensile strength, while lacking macroscale geometric control. These characteristics contrast to those of the 3D -bioprinting process that allows for excellent macroscale geometric control but is limited in the ability to produce structures resistant to high tensile loads.
  • the engineered hierarchical scaffold of the present invention may match the tensile and viscoelastic properties of the native ligament and provide a ligament/tendon-bone region that allows for the regeneration of a graded transition from soft to hard tissue for integration into existing structures.
  • the present invention provides a scaffold with fiber alignment along the direction of applied tensile load while addressing all mechanical, biochemical and biophysical requirements for tissue growth.
  • the present invention provides a scaffold fabricated by a combination of 3D bioprinting and aligned electrospinning process to allow for a functionally graded transition from soft tissue to bone.
  • the present invention uses synthetic and/or natural polymers for electrospinning fibers that constitute the main component of the dense fibrous connective tissue (ligament, tendon, cartilage, meniscus, etc.) phase.
  • the present invention provides a functional tissue scaffold that allows for regeneration of native tissue without the morbidity associated with harvesting of material from other regions of the body.
  • the present invention provides a scaffold that introduces a hydrogel made from decellularized ligament/tendon/bone as polymer bioinks coupled with synthetic and/or natural electrospun polymers to promote cell adhesion and growth along the fibers.
  • the present invention provides a hydrogel that may be reinforced with Hydroxyapatite (HAp) nanoparticles in the soft tissue to bone interface region to aid in providing the graded mechanical properties needed to transition from soft tissue to bone.
  • HAp is a calcium phosphate mineral that constitutes the main material of bones.
  • the present invention uses an optimization procedure to design an architecture for 3D printed bone and interface phases that will provide the graded structural properties needed to transition from soft tissue to bone.
  • the present invention uses bioceramics and natural and/or synthetic polymers as bioinks for 3D printing the bone, interface (mineralized fibrocartilage and unmineralized fibrocartilage) phase of the scaffold.
  • the present invention provides a method for
  • a ligament comprising: a scaffold that is functionally-graded from the bone phase to the ligament phase.
  • This can be extended to any other connective soft tissue (such as tendon, cartilage, meniscus, etc.) at bone insertion, and not limited only to ligaments.
  • the present invention provides a device for regenerating a ligament comprising: a scaffold that is functionally-graded from the bone phase to the ligament phase.
  • a scaffold that is functionally-graded from the bone phase to the ligament phase.
  • This can be extended to any other connective soft tissue (such as tendon, cartilage, meniscus, etc) at bone insertion, and not limited only to ligaments.
  • the present invention provides a method and device wherein the scaffold includes hierarchical layers of 3D printed materials such as thermoplastics, bioceramics, and polymer bioinks (B) and electrospun fibers (F), alternated in a variety of thicknesses, patterns and architectures, optimized for anatomical region and mechanical properties of native tissue.
  • 3D printed materials such as thermoplastics, bioceramics, and polymer bioinks (B) and electrospun fibers (F), alternated in a variety of thicknesses, patterns and architectures, optimized for anatomical region and mechanical properties of native tissue.
  • the present invention provides a device and method wherein the 3D printed materials provide structural support for the bone and interface phases and support for cell viability, while fibers provide structural integrity for the ligament (soft tissue) and interface phases.
  • the present invention provides a device and method wherein microstructure and mechanical properties are optimized for stem cell differentiation and proliferation. Moreover, it will aid fibroblast, osteoblast, chondroblast, and other cell proliferation for tissue regeneration with regional cellular population, density distribution and function of the native tissue.
  • the present invention provides a device and method wherein multi-materials are used for functional gradation discretely or continuously. This may be achieved by multi-extrusion additive manufacturing (3D -printing) with varied concentration, mixtures and compounds of bioinks, and dispersed particles.
  • 3D -printing multi-extrusion additive manufacturing
  • the present invention provides a device and method wherein dispersed micro/nanoparticles concentrations are used to all extra levels of functional gradation, to alter microstructural, rheological and mechanical properties of bioinks.
  • the present invention provides a device and method for regenerating a ligament comprising: an engineered hierarchical scaffold that matches the viscoelastic and mechanical properties of the native ligament and provides a ligament- bone region that allows for the regeneration of a graded transition from soft to hard tissue for integration into existing native soft and hard tissue.
  • the present invention provides a device and method for regenerating a ligament comprising: a manufacturing technology or combination of technologies that allows for the fabrication of a hierarchical ligament-bone complex with fiber alignment along the direction of applied tensile load while addressing mechanical, biochemical and biophysical requirements for tissue regeneration.
  • the present invention provides a device and method for regenerating a ligament comprising: a functional tissue scaffold that allows for regeneration of native tissue without the morbidity associated with harvesting of tissue from other regions of the body.
  • the present invention provides a device and method for regenerating a ligament comprising: a scaffold that uses a hydrogel made from
  • decellularized biomaterial as a bioink coupled with synthetic and/or natural electrospun polymer fibers.
  • the present invention provides a device and method wherein the hydrogel is reinforced with Hydroxyapatite (HAp) particles in the ligament- bone interface region to provide the graded mechanical properties needed to transition from ligament to bone.
  • HAp Hydroxyapatite
  • the present invention provides a device and method wherein in order to replicate the biochemical and biophysical gradient at the ligament- bone interface, an additional mineral component of HAp may be included in the stepwise formation of the ligament- bone scaffold.
  • the present invention provides a device and method wherein dual deposition of isolated decellularized ligament and/or bone and/or tendon and/or cartilage hydrogel and isolated HAp in solution is used to form a continuously graded transition region.
  • the present invention provides a device and method for regenerating a ligament comprising: a scaffold that acts as a template for ligament and bone regeneration.
  • the present invention provides a device and method wherein the scaffold is seeded with cells, and growth factors, and subjected to stimuli.
  • the present invention provides a device and method wherein the scaffold cultured in-vitro and then implanted or implanted directly into the injured site where regeneration is induced in-vivo.
  • the present invention provides a device and method wherein the scaffold has a functionally-graded characteristic that provides a gradual transition from the bone phase to ligament phase then back to the bone phase using polymers with a varying concentration of dispersed particles (i.e. Hydroxyapatite) and other necessary material modifiers.
  • dispersed particles i.e. Hydroxyapatite
  • the present invention provides a device and method wherein the scaffold has a functionally-graded characteristic that provides a gradual transition from the bone phase to tendon, cartilage, meniscus, or other soft tissue interfacing with bone using polymers with a varying concentration of dispersed particles (i.e. Hydroxyapatite) and other necessary material modifiers.
  • dispersed particles i.e. Hydroxyapatite
  • the present invention provides a device and method for regenerating a ligament comprising: bulk scaffolds that vary vertically and horizontally and are made from alternating layers of bioinks with optimized architecture at each phase and aligned or unaligned fibers.
  • the present invention provides a device and method wherein the bioinks include biodegradable hydrogel or decellularized tissue and are tuned to serve as a viable extracellular matrix environment to support cell migration, growth, and proliferation.
  • the present invention provides a device and method wherein the fibers are tuned (non-aligned vs. aligned orientation, porosity, fiber diameter, fiber spacing, length, etc.) to support high tensile loads such as those experienced by the native ligament.
  • the present invention provides a device and method for regenerating a ligament comprising: a 3D bioprinter and electrospinner - in conventional and near-field configurations.
  • the present invention provides a device and method that includes print heads and abstract material processing tools, including but not limited to, filament extruders, syringe pumps, electrospinner, router, etc.
  • print heads may be provided for applying varied printing materials, bioinks, and electrospinning solutions that include but are not limited to molten polymers, cell-laden hydrogels, and polymer solutions.
  • the present invention provides a device and method wherein the printer is controlled by one or more multi-axis motor controllers. Multiple motors may also be used: two for the X, Y build plate motion, one each for Z positioning of the abstract tools (3D print heads, electrospinner head, router, filament extrusion head, etc.). Furthermore, the material dispensing syringes (one for each print head, one for electrospinner, etc.) may be controlled using motors, pneumatic dispensers, or hydraulic dispensers.
  • the present invention provides a device and method wherein the printer is controlled by one or more multi-axis motor controllers. Multiple motors may also be used: two motors can be used for X, Y positioning of the abstract tools and print heads and one motor can be used for Z positioning of the build plate.
  • the material dispensing syringes may be controlled using motors, pneumatic dispensers, or hydraulic dispensers.
  • the present invention provides a device and method that are adaptable for additional print heads or abstract tools as necessary by application and properties of printing material.
  • the present invention provides a device and method further including an X-Y stage that enables positioning and adjusting of the build plate under the 3D bioprinter or electrospinner deposition heads, respectively and successively, and multiple Z axes vertically mounted to the frame of the printer, allowing for height control (i.e. material deposition thickness and build plate out-of-plane patterns and architectures) of the abstract tools (print heads, electrospinner head, router, filament extruder head, etc.) .
  • the present invention provides a device and method further including an X-Y stage enables positioning and adjusting of the deposition heads and a Z axis that allows for height control of the build plate.
  • the present invention provides a device and method further including a build plate designed as a surface for printed material, containing a grounded collector for the electrospinner of the system.
  • the grounded collector is made from high conductivity materials including, but not limited to, copper, steel, indium tin oxide, and/or carbon.
  • the present invention provides a device and method wherein the build plate is a layered system of electrical and thermal conductive and insulating materials supported by leveling screws.
  • One layer or more may include a heated element.
  • An air gap may also be provided between the build plate and linear stage configured to reduce unwanted conductivity from the electrified collector plate during electrospinning.
  • a plurality of syringe pumps may be included.
  • the electrospinner may also consist of a syringe, metallic needle, conductive plates of the collector, and one or more variable high-voltage power supplies.
  • the present invention provides a device and method wherein one lead of the power supply clamps to the collector of the build plate, and the other lead connects directly to the needle of the mounted syringe, as voltage is applied, material fibers collect on the surface of the collector.
  • the present invention provides a device and method further including one or more polymer filament extruders to allow for deposition of thermoplastic and/or thermoset polymers to print custom patterns, architectures and multi-materials structures.
  • FIG. 1A illustrates a functional tissue scaffold that allows for regeneration of native tissue subject to high tensile loads for an embodiment of the present invention.
  • Figure IB illustrates a section that may be repeated to form a functional tissue scaffold that allows for regeneration of native tissue subject to high tensile loads for an embodiment of the present invention.
  • Figure 2A illustrates a functional tissue scaffold that allows for regeneration of native tissue subject to high tensile loads for another embodiment of the present invention.
  • Figure 2B illustrates a section that may be repeated to form a functional tissue scaffold that allows for regeneration of native tissue subject to high tensile loads for an embodiment of the present invention.
  • Figure 3 illustrates a functional tissue scaffold that allows for regeneration of native tissue subject to high compressive loads for an embodiment of the present invention.
  • Figure 4 is a schematic of a 3D bioprinting and electrospinning dual apparatus.
  • Figure 5A is a schematic of a 3D bioprinting and electrospinning dual apparatus in an alternate configuration. Note that the top plate and vertical front supports have been removed from the image so that internal structure can be viewed.
  • Figure 5B is a schematic of a 3D bioprinting and electrospinning dual apparatus in the alternate configuration of Figure 5A, but top plate, vertical front supports, side walls, door, and windows are included.
  • Figure 6A illustrates how unaligned fibers may be created for the scaffolds of the present invention using electrospinning.
  • Figure 6B illustrates how aligned fibers may be created for the scaffolds of the present invention using electrospinning.
  • FIG. 1A and IB A representative schematic of a scaffold 100 for an embodiment of the present invention is shown in Figures 1A and IB.
  • One or more electrospun fibers 110A, HOB and HOC may be made from a plurality of synthetic and/or natural polymer.
  • Layers 110A and HOC, as well as others in the scaffold, form the top and bottom of the scaffold with the other layers sandwiched in-between to form a composite of layers of different electrospun and/or 3D printed materials.
  • the fibers may be a composite of one or more collagen-rich layers (120A-120D) to improve adhesion to the other layers and facilitate cell activity.
  • One or more 3D printed polymer sections represent the soft tissue phase of the scaffold and are made using biomaterials that are mechanically, chemically, and histologically similar to the soft tissue targeted for regeneration.
  • One or more 3D printed sections represent the bone phase of the scaffold and are made using biomaterials that are mechanically, chemically, and histologically similar to bone.
  • Also provided are one or more functionally graded interfaces 150A and 150B. These interfaces will be materially and architecturally graded to transition from the soft-tissue (ligament, tendon, cartilage, etc.) phase (140) to the bone phase on each end (130A and 130B).
  • layers or sections (110A, 120C, 130A, 130B, 150A, 150B, and 140) form a section 160 that may be repeated to form a plurality of sections as shown in Figure 1A.
  • layers 120A-120D include collagen-rich PLGA to improve adhesion to the hydrogel and facilitate cell attachment.
  • collagen-rich PLGA layer 12 OA and 120B are located on both sides of layer HOB.
  • fibers 110A, HOB and HOC may be made from polylactic-co-glycolic acid (PLGA).
  • FIGS 2 A and 2B illustrate another embodiment of the present invention.
  • two or more different materials may be used to fabricate the soft tissue-bone scaffold (200). These materials may form: i) one or more electrospun fibers (210-217), ii) one or more coatings to promote cell adhesion, iii) one or more 3D printed soft tissue phase layers (220-224), iv) one or more 3D printed bone tissue phase layers (230-232, 290A, and 290B) and v) one or more functionally graded soft tissue-bone interfaces (240-242).
  • the fibrous phase of the scaffold may be conventionally or near-field electrospun from a solution of synthetic and/or natural polymers.
  • 3D printed layers (220-224), as well as the others shown, may be made from decellularized bone, hydroxyapatite (Hap), and/or other functional nano/micro particles in a synthetic and/or natural polymer solution.
  • Bone-soft tissue interfaces (240-242) may be considered as a third phase. These layers may be printed in a functionally graded manner near the electrospun fiber ends to form a bone-ligament- bone scaffold.
  • layers 220-224 may be hydrogels made from a decellularized ligament-derived hydrogel (LDH), which is an optimal milieu of macromolecules conducive to native material regeneration.
  • LDH ligament-derived hydrogel
  • ligament-bone interfaces 230-232 may be made of LDH reinforced with nano-HAp. These layers may be configured in a functionally graded manner at the electrospun fiber ends to form a bone-ligament-bone scaffold.
  • the fibers extend parallel to bone, gradient and soft-tissue phases. Alternately, the fibers extend through the bone, gradient, and soft-tissue phases.
  • the fibrous material phase may be formed through aligned electrospinning by adjusting the parameters of the system in a near-field electrospinning configuration ( ⁇ 2 cm needle to collector distance, ⁇ 5 kV, moving collector and/or tool head).
  • the ratio of synthetic and/or natural polymers, fibers, and nano/micro particle constituents governs the mechanical properties, degradation rate, and hydrophobicity of the scaffold.
  • electrospun fibers addresses the biomechanical properties of the native ligament, it is necessary to provide an environment conducive to cellular attachment, growth, migration, and proliferation. This may be achieved through addition of a polymer matrix deposited in an alternating fiber-polymer-fiber fashion via 3D bioprinting.
  • an additional mineral component of decellularized bone, Hap, or other biocompatible nano/micro particles may be included in the stepwise formation of the scaffold.
  • HAp an inorganic salt, has excellent osteoconductivity and biocompatibility and has been shown to induce osteoblast proliferation.
  • Figure 3 illustrates another embodiment of the scaffold (300).
  • the direction of the functionally-graded regions may change.
  • this embodiment shows the bone (310) at the bottom, moving vertically through the interface region (320), and further vertically showing the alternating 3D printing (340- 342)/electrospun fiber layers (330-333).
  • This is the preferred embodiment for other bone - soft tissue scaffolds such as cartilage and meniscus where the primary mode of external loading is compressive.
  • Electrospinners require a high voltage power supply (up to 30 kV), a syringe with a needle and a conducting collector. An electrode is placed in the syringe with the polymer solution or attached to the needle to provide a uniform charge to the liquid, and the other electrode is attached to the collector plate.
  • the polymer experiences electrostatic repulsion on its surface due to the applied charge and is also attracted to the collector plate via a Coulombic attraction. These forces work against the surface tension of the polymer solution to create a cone of fluid, known as a Taylor Cone, at the tip of the metal syringe. Above a threshold voltage, the electrostatic forces are enough to overcome the surface tension and a thin jet of fluid is ejected toward the collector plate. This technique has been used on over 50 polymers to create fibers with diameters ranging from ⁇ 3nm to over 1 ⁇ and lengths up to several kilometers.
  • the diameter of the fibers can be controlled to some degree by varying parameters of the system, most notably the viscosity of the solution, distance from needle to collector, strength of the applied electric field, electrical conductivity of the collector surface, and feeding rate for the solution. Varying the concentration of polymer in the solution can alter the viscosity of the solution.
  • the diameter of the fiber increases with the viscosity of the solution, though at very low viscosities defects such as beads can appear along the fibers. Increasing the electrical conductivity helps to significantly reduce the diameter of the fibers possible without defects.
  • the fiber diameter also increases with feeding rate. However, the correlation between electric field strength and fiber diameter is not well established.
  • the diameter of the fibers may be tailored for use in specific applications. In a preferred embodiment of the present invention, aligned electrospun fibers with diameters between 1 and 15 microns may be used to facilitate MSC differentiation into the ligament lineage and associated with spindle-shaped morphology in human ligament fibroblasts.
  • a hybrid 3D bioprinter and electrospinner system 400 is provided.
  • the system (400) is configured to accommodate the polymer bioinks, filament extruders, and electrospinner polymers for composite scaffold formation.
  • Motion of the tool heads (405 and 406) is controlled using rails (410-411) that allow for Z-axis control of carriages that engage the rails supporting the tool heads.
  • X-Y axis motion of the build plate (450) is controlled by perpendicularly positioned stepper motors and linear screw drives, which carries the x-y module (460-461).
  • An air gap (470) is included between the build plate/collector and the non-conductive support engaging the linear rails to limit interference from the high voltage power supply (480).
  • the collector (490) is positioned centrally in/on the build plate. One electrical lead is connected from the power supply (480) to the collector (490) and the other is connected from the power supply to the needle of the electrospinning syringe.
  • a hybrid 3D bioprinter and electrospinner system (500) is provided.
  • the system (500) is configured to accommodate the polymer bioinks, filament extruders, and electrospinner polymers for composite scaffold formation.
  • Motion of the attached tool/print heads (510 and 511) is controlled using perpendicularly positioned rails 520 and 521 that allows for X-Y axis control of the carriage (530) that engages the tool heads.
  • Z axis motion of the build plate/collector (540) is controlled by a stepper motor and linear screw drive (522, partially hidden), which carries the Z carriage engaging the build plate.
  • the collector (550) is positioned centrally in/on the build plate.
  • Figure 5B shows the system (500) of Figure 5A with outer walls and windows used to control temperature, humidity, and pressure within the system. Additionally, the lower region of the internal structure of the system will contain a system for UV polymerization of polymers. The enclosed system will shield the user from exposure to UV radiation.
  • the system is controlled by electronics that provide control to the X, Y, and Z rail positioners.
  • the syringe toolheads may be dispensed using motors, pneumatic dispensers, hydraulic dispensers, or other similar mechanism for dispensing.
  • One or more high voltage power supplies (1-35 kV) provide the voltage source for conventional and near-field electrospinning.
  • the electronics may control syringe dispensing, the filament extruder, the power supplies, and other onboard accessories that may be added to the system including but not limited to an ultraviolet (UV) light chamber for polymerization, the other abstract tool heads, and devices for controlling temperature, humidity, and pressure.
  • UV ultraviolet
  • Figure 6 A illustrates how unaligned fibers may be created for the scaffolds of the present invention using the conventional electrospinning technique (>2 cm needle to collector distance, >5kV) from source 600 onto collector 610.
  • Figure 6B illustrates how aligned fibers may be created for the scaffolds of the present invention using near-field electrospinning ( ⁇ 2 cm needle to collector distance, ⁇ 5 kV, and X, Y, Z positioning of the syringe/needle and/or the collector) from source 600 onto collector 610.
  • the figure shows arrows representing Figure 4 configuration of linear rails (620, 621, and 622) moving the build plate/collector in the X-Y axes and the print heads in the Z axis.
  • the present invention takes into consideration the fact that ligament healing is not efficient and often results in weak scar tissue that influences the graft stability in the bone tunnel.
  • the present invention provides a tissue-engineering strategy that provides functionally-graded scaffolds from soft to hard tissue.
  • the functionally-graded characteristic may allow a gradual transition from the bone phase 290A to ligament (or other soft tissue) phase 295 then back to the bone 290B phase using natural and/or synthetic polymers with a varying concentration of micro/nanoparticles (i.e.
  • the bulk scaffolds may vary vertically made from alternating layers of bioinks (synthetic and/or natural polymers are 3D printed with optimized architecture at each phase) and fibers (i.e. electrospun collagen and/or natural or synthetic biopolymers).
  • the bioinks which may also include hydrogel biomaterials or decellularized tissue may be tuned to serve as a viable extracellular matrix environment to support cell migration, growth, and proliferation.
  • the fibers may be tuned (non-aligned vs. aligned orientation, porosity, fiber diameter, fiber spacing, length, etc.) to support high tensile loads such as those experienced by the native ligament; these fibers provide most of the mechanical stability and strength of the bulk scaffold.
  • Multiscale material and structural optimization can be used to control microstructure, mechanical properties, and biodegradation rates of the scaffold.
  • the 3D printed aspect of this approach enables macroscale structural features of the replacement tissue to match that of the targeted native tissue.
  • the present invention fabricates 3D hierarchical, functionally-graded scaffolds and tunes the biodegraded scaffold mechanical properties to comply with the ligament regeneration rate to maintain mechanical properties at a satisfactory level during the tissue growth period and thereafter.
  • the scaffold may act as a template for ligament regeneration and is typically seeded with cells, and growth factors, and subjected to stimuli.
  • the scaffolds may be either cultured in- vitro and then implanted or implanted directly into the injured site where regeneration is induced in-vivo.
  • the present invention provides a modular 3D
  • Bioprinter and Electrospinner system for targeted fabrication of scaffolds for tissue engineering and other biomedical applications.
  • the hybrid system aims to merge the positive aspects of each technology.
  • the present invention is particularly useful for creation of tissue scaffolds which are configured to resist high tensile loads (i.e. ligament, tendon, bone-ligament interface, etc.).
  • the present invention is designed using a control system similar to 3D printers, but with modification to input software files to control for alternating deposition of materials from the 3D printing side and the electrospinner side of the system.
  • This allows for the creation of hierarchical scaffolds with alternating layers of 3D printed bioinks, extruded polymer filaments, and electrospun materials.
  • the print heads can be tuned to deliver bioinks in the form of synthetic or natural polymers including hydrogels or decellularized tissue solutions with various concentrations of macro/micro/nanoscale particles for targeted deposition of materials depending on the tissue type.
  • This deposition is meant to serve as an optimal microenvironment for encouraging cell growth, migration, proliferation and can include growth factors and cells in solution as a bioink that can be deposited from one or more print heads (or abstract tools) in any defined architecture.
  • the present invention may be comprised of one or more of the following components depending on the desired application and use:
  • the system is controlled by a multi-axis stepper motor controller with flexible software configuration.
  • the system is designed to be extensible, adapting to various hardware and software configurations.
  • the system uses motors: for X, Y, and/or Z positioning of the abstract tools (3D print heads, electrospinner head, router, filament extrusion head, etc.) and build plate/collector, and one each to drive custom syringe pumps (one for each print head, one for electrospinner, etc.), filament extruder, and other abstract tools.
  • the system is adaptable for additional print heads or abstract tools as necessary by application.
  • the other inputs of the controller could also run several systems for temperature, humidity, UV polymerization, heated beds, and other system accessories.
  • Linear Stages High precision linear stages are used for X, Y, and Z axis movement to control for resolution, accuracy and repeatability. Each stage may be fitted with stepper motors. The leadscrew configuration of the linear stages allows for precise movement.
  • the X stage enables positioning of the build plate/collector under the 3D bioprinter or electrospinner deposition heads or the deposition heads above the build plate/collector.
  • the Y stage is mounted orthogonally to the X stage for front-to-back positioning of either the deposition heads or the build plate/collector.
  • the Z axis may be vertically mounted to the frame of the system, allowing for height control of the deposition heads or build plate/collector
  • the build plate (print bed) is designed as a surface for printed material and as an electrical conductor for the electrospinner of the system.
  • the build plate is a layered system of conductive and electrically-insulating materials supported by leveling screws.
  • the electrically-conductive layer can be made using copper, steel, indium tin oxide, and any other conductive material that enables high resolution deposition and control of electrospun fibers.
  • an air gap is formed between the build plate and linear stage.
  • the build plate may be attached to the linear stage using nylon screws or other non- or minimally-conductive material to further reduce unwanted electrical charge throughout the system.
  • FIG. 4 Another embodiment of the present invention as shown in Figure 4, includes a build plate (450) that includes a non-conducting material (452) that allows for deposition of materials from the tool heads, but limits conductivity for the electrospinner outside of the conductive collector region.
  • the new collector surface for electrospinning are one or more high-conductive sections (490) which may be in the shape of raised bars, inset plates or coatings in the build plate, or other geometries.
  • the one or more conductive sections (490) are placed on or in non-conductive surface (452) to allow for fiber deposition from the electrospinner side of the system.
  • the voltage and needle to collector distance determines the type of fiber deposition (uncontrolled or aligned) to be deposited on the collector.
  • Syringe Dispensers/3D printing tool heads The extrusion system consists of two or more syringe holders that may be constructed using custom or commercially available off-the-shelf hardware (rails, bolts, nuts, etc.). The fixture that holds the syringe allows access to slide bearings and improves the grip on the plunger of the syringe during deposition. Each syringe may be dispensed using motors, pneumatic dispensers, hydraulic dispensers, or any similar dispensing system.
  • Electrospinner tool head The electrospinner tool head consists of a syringe, steel syringe tip/needle, the conductive collector of the build plate, and one or more 1 to 35-kV variable high -voltage power supplies.
  • the power supply has positive and negative leads the attach to the needle of the syringe and to the collector plate to apply a voltage from needle to collector plate during deposition.
  • the syringe may be dispensed using motors, pneumatic dispensers, hydraulic dispensers, or any similar dispensing system.
  • one lead of the power supply clamps directly to the conductive collector plate, and the other lead connects directly to the steel needle of the mounted syringe.
  • an electric field is created between the syringe needle and collector. Solution exiting the syringe becomes charged and quickly collects on the surface of the charged collector plate.
  • 3D-Modeling Software Any commercially available 3D modeling software can be used to create the input files.
  • the current hardware configuration is not limited to any 3D modeling software.
  • Slicing Software The current configuration of the system works with any commercially available slicing software. For more complex scaffold geometries and to enable alternating deposition of 3D printed and electrospun fibers it is necessary to use the custom slicing software or modify the source code of commercially available software. It is highly recommended that a more sophisticated software that allows for voxelization of the scaffold (discretizing the structure into elements to define elemental material properties) be used.
  • Filament Extruders The system contains one or more polymer filament extruders to allow for deposition of thermoplastic polymers to print custom
  • a Peltier cooler can be used to reduce the temperature of the materials in each syringe prior to deposition if necessary by application.
  • a flexible heat bed can be used to increase the temperature of the materials in each syringe prior to deposition if necessary by application.
  • the system uses additional temperature, humidity, and pressure controlling hardware to maintain a suitable environment for deposition.
  • the present invention provides a method for fabricating a device for regenerating musculoskeletal tissue comprising the steps of: creating scaffold or other structure having an aligned fiber layer adapted to provide mechanical integrity to the scaffold in the form of increased tensile and compressive resistance; creating an interface layer comprised of one or more bone phases that is adapted to resemble the biophysical and biochemical structure of bone, one or more soft tissue phases adapted to resemble the biophysical and biochemical structure of the soft tissue to be regenerated, and one or more gradient phases adapted to resemble the biophysical and biochemical interface between the bone and said soft tissue; each of the phases created using one or more materials; and repeating the above steps as needed.
  • the aligned fiber layer is created by near-field electrospinning and the interface layer is created by 3D- printing.
  • the aligned fiber layer is created by the use of a print head and print bed configured to suppress the formation of a Taylor cone.
  • the Taylor cone is suppressed by applying a voltage to the print head and print bed. The Taylor cone may also be suppressed by applying a voltage to the print head and print bed and separating the print head and print bed a sufficient distance.
  • a technique for near-field electrospinning may also be used by using the following parameters: the needle to collector distance is ⁇ 2cm, the voltage between the needle and the collector plate is ⁇ 5kV, and the collector and/or the needle can translate in X and Y directions, while the other moves in the Z direction.
  • the present invention provides a system for 3D printing and electrospinning materials on the same build platform with a single control system by defining the parameters for each deposition.
  • the system may include a 3D printer with one or more tool heads that are used for electrospinning and the build platform can move in the X, Y and/or Z directions. Also, the one or more tool heads can move in the X, Y, and/or Z directions.
  • the system may also include tool heads which can be one or more of the following: syringes w/needles and filament extruders (hot ends) which can be controlled by one or more of the following: pneumatic pumps, hydraulic pumps, and motors.
  • a high voltage power supply is connected to the collector plate and to the needle or filament extruder to create a circuit between the two objects allowing for
  • the system may also include a sub-chamber containing ultraviolet (UV) lights that enables polymerization of said 3D printed or electrospun materials.
  • the collector plate can be made from one or more of the following materials: steel, silver, aluminum, copper, carbon, silicon, indium tin oxide.

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Abstract

L'invention concerne un dispositif de régénération de tissu musculo-squelettique ayant un échafaudage constitué de couches de fibres conçues pour fournir une intégrité mécanique à l'échafaudage sous la forme d'une résistance accrue à la traction et à la compression et une ou plusieurs autres couches conçues pour fournir une intégrité mécanique et pour fournir un environnement biochimique approprié.
PCT/US2018/042559 2017-07-17 2018-07-17 Échafaudages pour interface os-tissu mou et leurs procédés de fabrication WO2019018443A1 (fr)

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CN109734434A (zh) * 2019-03-01 2019-05-10 北京工业大学 一种基于3d打印技术的极小曲面结构磷酸三钙/钛酸锶钡复合生物陶瓷的制备方法
CN109853054A (zh) * 2019-02-27 2019-06-07 上海交通大学医学院附属第九人民医院 一种同轴静电纺丝三维打印生物支架的装置及搭建方法
CN110042058A (zh) * 2019-05-24 2019-07-23 北京化工大学 一种制备有效搭桥细胞支架的熔体静电纺丝直写装置
CN110466153A (zh) * 2019-09-05 2019-11-19 上海交通大学医学院附属第九人民医院 一种采用低温成型生物电纺3d打印装置及其制备方法
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CN113152018A (zh) * 2021-03-12 2021-07-23 张凤英 一种碳化硅基体碳纤维复合材料人工肋骨处理装置
CN113476660A (zh) * 2021-05-17 2021-10-08 重庆医科大学 一种模拟肌腱-骨界面的高仿生复合支架的制备方法
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CN114870087A (zh) * 2022-06-01 2022-08-09 万绵水 一种脱细胞支架及其制备方法
CN114949353A (zh) * 2022-01-24 2022-08-30 东华大学 一种生物功能差异化的适配肌骨系统修复体及其制备方法
CN115068687A (zh) * 2022-07-08 2022-09-20 重庆科技学院 梯度纳/微纤维支架及其制备方法与应用
US20220339879A1 (en) * 2019-07-10 2022-10-27 Jong Young Kim Deposition data collection apparatus and three-dimensional object manufacturing system including the same
EP4119169A1 (fr) 2021-07-16 2023-01-18 Lietuvos Sveikatos Mokslu Universitetas Construction pour la régénération du cartilage articulaire et son procédé de préparation
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CN115887071A (zh) * 2022-09-15 2023-04-04 哈尔滨工业大学（威海） 一种连续多界面仿生梯度骨软骨支架及其制备方法
CN116328030A (zh) * 2023-02-09 2023-06-27 南昌大学第二附属医院 一种亲水生物支架及其制备方法
CN117695443A (zh) * 2024-02-05 2024-03-15 四川大学华西医院 一种负泊松比结构人工椎间盘及其制备方法

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CN109734434A (zh) * 2019-03-01 2019-05-10 北京工业大学 一种基于3d打印技术的极小曲面结构磷酸三钙/钛酸锶钡复合生物陶瓷的制备方法
CN110042058A (zh) * 2019-05-24 2019-07-23 北京化工大学 一种制备有效搭桥细胞支架的熔体静电纺丝直写装置
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US12214555B2 (en) * 2019-07-10 2025-02-04 Jong Young Kim Deposition data collection apparatus and three-dimensional object manufacturing system including the same
US20220339879A1 (en) * 2019-07-10 2022-10-27 Jong Young Kim Deposition data collection apparatus and three-dimensional object manufacturing system including the same
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