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WO2025065004A2 - Systèmes, procédés et contenants pour la formation et la collecte de fibres polymères de dimension micrométrique et nanométrique - Google Patents

Systèmes, procédés et contenants pour la formation et la collecte de fibres polymères de dimension micrométrique et nanométrique Download PDF

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Publication number
WO2025065004A2
WO2025065004A2 PCT/US2024/047995 US2024047995W WO2025065004A2 WO 2025065004 A2 WO2025065004 A2 WO 2025065004A2 US 2024047995 W US2024047995 W US 2024047995W WO 2025065004 A2 WO2025065004 A2 WO 2025065004A2
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WO
WIPO (PCT)
Prior art keywords
collection
polymer
reservoir
ejection
collection member
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Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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PCT/US2024/047995
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English (en)
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WO2025065004A3 (fr
Inventor
Kevin Kit Parker
Yichong Wang
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Harvard University
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Harvard University
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Publication of WO2025065004A2 publication Critical patent/WO2025065004A2/fr
Publication of WO2025065004A3 publication Critical patent/WO2025065004A3/fr
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    • D—TEXTILES; PAPER
    • D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
    • D01D—MECHANICAL METHODS OR APPARATUS IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS
    • D01D5/00—Formation of filaments, threads, or the like
    • D01D5/18—Formation of filaments, threads, or the like by means of rotating spinnerets
    • D—TEXTILES; PAPER
    • D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
    • D01D—MECHANICAL METHODS OR APPARATUS IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS
    • D01D5/00—Formation of filaments, threads, or the like
    • D01D5/06—Wet spinning methods
    • D—TEXTILES; PAPER
    • D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
    • D01D—MECHANICAL METHODS OR APPARATUS IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS
    • D01D7/00—Collecting the newly-spun products

Definitions

  • Embodiments of the disclosure relate systems and methods for generating and collecting one or more micron or nanometer dimension polymer fibers.
  • Natural organisms serve as a rich source of inspiration for the development of new materials, offering innovative ideas based on millions of years of evolutionary refinement. Amidst the vast array of biological materials, some stand out for their extraordinary mechanical properties, demonstrating behaviors such as low stiffness combined with high strength and flaw insensitivity. Noteworthy examples include tendons, chordae tendineae, spider silk, cocoon silk, and bamboo. The mechanical behavior of these natural materials is intimately linked to their hierarchical structure, featuring anisotropic fibers and fibrils structures across various length scales. At the smallest length scale, monomers assemble to form long chains. Within these chains, specific regions give rise to hydrophobic structures or crystalline zones, forming phase-separated hard nanophases.
  • Covalent crosslinking between chains stabilizes the structures, and enhance their stiffness and strength.
  • the organization of these molecular components results in the formation of nanofibrils, which aggregate to form macro fibrous bundles. This hierarchical assembly imparts anisotropic properties and remarkable mechanical strength to the tissues.
  • Electrospinning is a common conventional process for fabricating polymeric fibers. Electrospinning uses high voltages to create an electric field between a droplet of polymer solution at the tip of a needle and a collection device. One electrode of the voltage source is placed in the solution and the other electrode is connected to the collection device. This exerts an electrostatic force on the droplet of polymer solution. As the voltage is increased, the electric field intensifies, thus increasing the magnitude of the force on the pendant droplet of polymer solution at the tip of the needle. The increasing electrostatic force acts in a direction opposing the surface tension of the droplet and causes the droplet to elongate, forming a conical shape known as a Taylor cone.
  • a charged continuous jet of polymer solution is ejected from the cone.
  • the jet of polymer solution accelerates towards the collection device, whipping and bending wildly.
  • the jet rapidly thins and dries as the solvent evaporates.
  • a non-woven mat of randomly oriented solid polymeric fibers is deposited on the surface of the grounded collection device.
  • RJS devices permit the formation of polymeric fibers by essentially ejecting a polymer solution through an orifice of a reservoir into air. Air drag extends and elongates the jets into fibers as the solvent in the material solution rapidly evaporates.
  • An aspect of the invention provides a system for generation and collection of a micron or nanometer micron or nanometer dimension polymeric fiber.
  • the system includes a reservoir configured to hold a polymer and including an ejection surface having one or more orifices for ejecting the polymer for fiber formation, and a reservoir motion generator configured to impart rotational motion to the reservoir about a reservoir rotational axis. The rotational motion of the reservoir causing ejection of the polymer from the reservoir through the one or more orifices in a direction perpendicular to the reservoir rotational axis.
  • the system also includes a collection member configured to hold a liquid.
  • the collection member has a first end into which the reservoir can be inserted and includes a sidewall having an inner surface facing the ejection surface of the reservoir during polymer ejection.
  • the collection member includes an overhang portion with an inner diameter smaller that a largest diameter of the inner surface of the sidewall.
  • the system also includes a collection motion generator configured to rotate the collection member holding the liquid about a collection rotational axis at a rotation rate to form a liquid layer disposed on the inner surface of the sidewall. The overhang portion of the collection member prevents the liquid layer from flowing out of the first end of the collection member during rotation of the collection member.
  • At least a portion of a front surface of the liquid layer facing the ejection surface of the reservoir has a normal within 10 degrees of perpendicular to the collection rotational axis.
  • the normal of at least the portion of the front surface of the liquid layer facing the ejection surface of the reservoir is within 5 degrees of perpendicular to the collection rotational axis during polymer ejection. In some embodiments, the normal of at least the portion of the front surface of the liquid layer facing the ejection surface of the reservoir is within 3 degrees of perpendicular to the collection rotational axis during polymer ejection. In some embodiments, the normal of at least the portion of the front surface of the liquid layer facing the ejection surface of the reservoir is within 2 degrees of perpendicular to the collection rotational axis during polymer ejection.
  • a cross-sectional profile of the front surface of at least the portion of the liquid layer facing the ejection surface of the reservoir taken in a cross-sectional plane that includes the second collection rotational axis is within 10 degrees of vertical during polymer ejection. In some embodiments, the cross-sectional profile of the front surface of at least the portion of the liquid layer facing the ejection surface is within 5 degrees of vertical during polymer ejection. In some embodiments, the cross-sectional profile of the front surface of at least the portion of the liquid layer facing the ejection surface is within 3 degrees of vertical during polymer ejection. In some embodiments, the cross-sectional profile of the front surface of at least the portion of the liquid layer facing the ejection surface is within 2 degrees of vertical during polymer ejection.
  • the liquid layer is substantially static or substantially immobile with respect to the inner surface of the sidewall during polymer ejection. In some embodiments, the front surface of the liquid layer is substantially static or substantially immobile with respect to the inner surface of the sidewall during polymer ejection.
  • the collection member is configured for draining the liquid after formation of the micron or nanometer dimension polymeric fiber.
  • the liquid layer is disposed directly on the inner surface of the sidewall, and the collection member is a container configured to contain the formed micron or nanometer dimension polymeric fiber.
  • the collection member is further configured to receive a removable liner, at least a portion of the removable liner having a surface corresponding to the inner surface of the sidewall and the overhang portion of the collection member.
  • the received removable liner is positioned between the inner surface of the sidewall and the reservoir during ejection of the jet of polymer.
  • the liquid layer is disposed directly on the removable liner overlaying the inner surface of the sidewall during ejection of the polymer layer.
  • the removable liner is a container configured to be removed from the collection member while containing the formed micron or nanometer dimension polymeric fiber.
  • the collection member includes a collection support portion and a removable container portion, with the removable container portion disposed between the collection support portion and the reservoir during use.
  • the removable container portion forms the inner surface of the sidewall of the collection member, and the collection support portion is configured to engage or be engaged by the collection motion generator.
  • the liquid layer is disposed directly on the removable container portion during ejection of the polymer layer.
  • the removable container portion is a container configured to be removed from the collection support portion while containing the formed micron or nanometer dimension polymeric fiber.
  • the container is further configured to drain the liquid after formation of the micron or nanometer dimension polymeric fiber.
  • the container is configured for storage of the formed micron or nanometer dimension polymeric fiber.
  • the container is configured for storage of the liquid and the formed micron or nanometer dimension polymeric fiber.
  • the container is configured for storage of a second liquid or a second gel and the formed micron or nanometer dimension polymeric fiber after formation.
  • the container is configured to be sealed to contain the formed micron or nanometer dimension polymeric fiber.
  • the collection container is configured to be sealed to contain the formed micron or nanometer dimension polymeric fiber and a liquid.
  • the reservoir motion generator is further configured to move the reservoir in a direction parallel to the first rotational axis during polymer ejection. In some embodiments, movement of the reservoir motion generator in a direction parallel to the first rotational axis controls an area of the liquid layer that receives the jet and/or controls a density of coverage of the formed polymeric fiber.
  • ejection of the polymer into the liquid layer causes precipitation of the micron or nanometer dimension polymeric fiber.
  • ejection of the polymer into the layer causes cross-linking of the micron or nanometer dimension polymeric fiber.
  • ejection of the polymer into the layer causes coagulation of the micron or nanometer dimension polymeric fiber.
  • a shape of the inner surface of the sidewall is configured to determine a corresponding shape of at least a portion of an article comprising the micron or nanometer dimension polymeric fiber.
  • Another aspect provides a collection member configured for use with any of the systems or in any methods described herein.
  • Another aspect provides a removable liner configured for use with any of the systems or in any methods described herein.
  • the method includes providing a polymer, and providing a reservoir configured to hold the polymer and including an ejection surface having or more orifices for ejecting the polymer for fiber formation.
  • the method also includes providing a collection member configured to hold a liquid.
  • the collection member has a first end into which the reservoir can be inserted and includes a sidewall having an inner surface facing the reservoir.
  • the collection member includes an overhang portion with an inner diameter smaller that a largest diameter of the inner surface of the sidewall.
  • the method also includes disposing a liquid in the collection member and rotating the collection member about a collection rotational axis in a first direction to form a liquid layer on the sidewall inner surface.
  • a front surface of the liquid layer facing the ejection surface of the reservoir with the overhang portion of the collection member prevents the liquid layer from flowing out of the first end of the collection member during rotation of the collection member. At least a portion of a front surface of the liquid layer facing the ejection surface of the reservoir has a normal within 10 degrees of perpendicular to the collection rotational axis.
  • the method also includes, during rotation of the collection member, rotating the reservoir holding the polymer about a reservoir rotational axis causing ejection of the polymer in a jet.
  • the method also includes receiving the polymer jet at the front surface of the liquid layer and collecting the polymer jet in the liquid layer, thereby forming thereby forming the micron or nanometer dimension polymeric fiber.
  • the normal of at least the portion of the front surface of the liquid layer facing the ejection surface of the reservoir is within 5 degrees of perpendicular to the collection rotational axis during polymer ejection. In some embodiments, the normal of at least the portion of the front surface of the liquid layer facing the ejection surface of the reservoir is within 2 degrees of perpendicular to the collection rotational axis during polymer ejection. In some embodiments, the normal of at least the portion of the front surface of the liquid layer facing the ejection surface of the reservoir is within 1 degree of perpendicular to the collection rotational axis during polymer ejection.
  • a cross-sectional profile of the front surface of at least the portion of the liquid layer facing the ejection surface of the reservoir, taken in a cross-sectional plane that includes the collection rotational axis is within 10 degrees of vertical during polymer ejection. In some embodiments, the cross-sectional profile is within 5 degrees of vertical during polymer ejection. In some embodiments, the cross-sectional profile is within 3 degrees of vertical during polymer ejection. In some embodiments, the cross-sectional profile is within 2 degrees of vertical during polymer ejection. In some embodiments, the cross-sectional profile is within 1 degree of vertical during polymer ejection.
  • the liquid layer is substantially static or substantially immobile with respect to the inner surface of the sidewall during polymer ejection. In some embodiments, the front surface of the liquid layer is substantially static or substantially immobile with respect to the inner surface of the sidewall during polymer ejection.
  • the collection member is configured as a container, and the method also includes containing the formed micron or nanometer dimension polymeric fiber within the collection member container after removal of the reservoir from the collection member.
  • the collection member includes a collection support portion and a removable portion configured as a container with the removable portion disposed between the collection support portion and the reservoir during ejection of the polymer.
  • the removable portion forms the inner surface of the sidewall of the collection member, and the collection support portion is configured to engage or be engaged by the collection motion generator.
  • the removable portion is removed from the collection support portion after formation of the micron or nanometer dimension polymeric fiber, forming a container for the polymeric fiber.
  • the collection member is further configured to receive a removable liner, at least a portion of the removable liner having a surface corresponding to the inner surface of the sidewall and the overhang portion of the collection member.
  • the method further comprises providing the removable liner that is positioned between the inner surface of the sidewall and the reservoir during ejection of the jet of polymer.
  • the liquid layer is disposed directly on the removable liner overlaying the inner surface of the sidewall during ejection of the polymer layer.
  • the method also includes removing the removable liner after formation of the polymeric fiber while holding the polymeric fiber, the removable liner forming a container for holding polymeric fiber.
  • the method also includes sealing the formed micron or nanometer dimension polymeric fiber within the container.
  • the contents of the collection member container are sterile prior to or during sealing of the container. In some embodiments, or the contents of the container are sterilized prior to or during sealing of the container.
  • the method also includes transporting the sealed container. In some embodiments, the method also includes draining the liquid after formation of the micron or nanometer dimension polymeric fiber while keeping the micron or nanometer dimension polymeric fiber within the container.
  • the method also includes vertically translating the reservoir parallel to the reservoir rotational axis during ejection of the polymer jet to control an area and/or a density of fiber deposition in the liquid layer.
  • the method also includes removing the liquid from the collection member after formation of the polymeric fiber while retaining the polymeric fiber in the collection member and introducing a second liquid into the collection member. In some embodiments, the method also includes rotating the collection member to form a layer of the second liquid on an inner surface of the sidewall of the collection member. In some embodiments, the method also includes introducing a second polymer to the reservoir. In some embodiments, the method also includes during rotation of the collection member, rotating the reservoir holding the second polymer about the reservoir rotational axis causing ejection of the second polymer in a jet.
  • the method also includes receiving the jet of the second polymer jet at a front surface of the layer of the second liquid and collecting the jet of the second polymer in the layer of the second thereby forming a micron or nanometer dimension polymeric fiber from the second polymer.
  • the method also includes vertically translating the reservoir parallel to the reservoir rotational axis during ejection of the jet of the second polymer to control an area and/or a density of fiber deposition in the layer of the second liquid.
  • FIG. 1 A schematically depicts a side cross-sectional view of a system for polymer fiber generation and collection in accordance with some embodiments
  • FIG. IB schematically depicts a side cross-sectional view of the collection member of the system of FIG. 1 A holding liquid while the collection member is not being rotated, in accordance with some embodiments.
  • FIG. 1C schematically depicts a perspective view of the system of FIG. 1A during use, in accordance with some embodiments.
  • FIG. 2 is an image of a perspective view of an example prototype collection member holding a liquid that is being rotated to form a liquid layer with the liquid dyed for better visualization in accordance with some embodiments.
  • FIG. 3 A is an image of a perspective view of a first prototype system with a collection member holding a liquid that is being rotated to form a liquid layer in accordance with some embodiments.
  • FIG. 3B is an image of the first prototype system in use forming fibers in accordance with some embodiments.
  • FIG. 4A schematically depicts movement of the reservoir parallel to the reservoir rotational axis during fiber formation in accordance with some embodiments.
  • FIG. 4B schematically depicts movement of the collection member parallel to the collection rotational axis during fiber formation in accordance with some embodiments.
  • FIG. 5 schematically depicts steps in formation and collection of fibers of two different polymers, in accordance with some embodiments.
  • FIG. 6 schematically depicts a method including formation of fibers and packaging of fibers in accordance with some embodiments.
  • FIG. 7 schematically depicts a removable liner used with a collection member in accordance with some embodiments.
  • FIG. 8 schematically depicts a collection member with a collection support portion and a removable container portion in accordance with some embodiments.
  • FIG. 9A schematically depicts a second prototype system employed in the Example in accordance with some embodiments.
  • FIG. 9B schematically depicts the reservoir of the second prototype system employed in the Example in accordance with some embodiments.
  • FIG. 10 schematically depicts a perspective view of the second prototype system in use in accordance with some embodiments.
  • FIG. 11 includes images of PVA fibers generated with the second prototype system at different magnifications with a 0.5 cm scale bar in the (i) image and with a 10 micron scale bar in the (ii) image.
  • FIG. 12 is a graph of fiber diameter frequencies for the PVA fibers in the dehydrated state (measured data in bars and solid line fit) and the hydrated state (dashed line fit, measured data not shown).
  • FIG. 13 is a scanning electron microscope (SEM) image of dried formed PVA fibers.
  • FIG. 14 is a scanning electron microscope (SEM) image of dried formed PVA fibers at higher magnification.
  • FIG. 15 includes images of formed and collected fibers at various magnifications including images of fibers dispersed in the ethanol bath and images of fibers dried.
  • FIG. 16 schematically depicts a mechanism for anisotropic crystalline PVA morphology in the formed fibers.
  • FIG. 17A includes small-angle X-ray scattering (SAXS) measurements of PVA fiber morphology in the produced PVA fibers.
  • SAXS small-angle X-ray scattering
  • FIG. 17B includes graphs of polarized Raman spectroscopy measurements of the formed fibrous PVA and homogeneous PVA with the fibrous PVA demonstrating crystalline anisotropy in the formed fibers.
  • FIG. 18 including images of cellulose and chitosan fibers formed with the prototype system.
  • polymer fiber and “polymeric fiber” refer to a fiber including a polymer.
  • the fiber may also include some non-polymer components.
  • a micron or nanometer dimension fiber refers to a fiber having a diameter of less than about 10 pm.
  • this substantial movement of liquid in the vortex generated by the spin bar motion generator in the liquid bath results in instabilities in the liquid movement and exerts additional force on the fibers after they enter the bath that could potentially cause reduced continuity and reproducibility in produced fibers, some fiber wrapping and distortion, some unstable fibers diameters from a swelling effect, and reduced control of geometry and alignment of collected fibers.
  • the spin bar must be removed from the collection device or the fibers removed from the collection device after generation of the fibers and before storage or packaging of the fibers, which introduces an additional complexity to the process of fiber formation and collection.
  • Some embodiments provide systems and methods that employ a collection member configured to hold a liquid and a collection motion generator configured to rotate the collection member to form a liquid layer disposed on an inner surface of the sidewall of the collection member by centripetal force exerted on the liquid by the sidewall during rotation of the collection member.
  • the collection member includes an overhang portion that prevents the liquid from flowing out the top of the collection member during initial acceleration or “spin up” of the collection member and during constant velocity rotation of the collection member.
  • the liquid layer is only in contact with a surface or surfaces of the collection member that all move at the same rotational speed, meaning that there little to no motion of any portion of the liquid in the liquid layer relative to another portion of the liquid layer after the initial acceleration of the collection member and formation of the liquid layer on the sidewall.
  • This may be described herein as a “static” liquid layer even if the layer exhibits small amounts of movement of some liquid relative to other liquid in the layer, and even though the entire layer is rotating at a constant velocity. Ejecting one or more polymer jets into the static liquid layer may provide increased continuity and reproducibility in produced fibers, prevent or reduce fiber wrapping and distortion, increased stability of fiber diameters, and/or increased control of geometry and alignment of collected fibers in some embodiments. Additionally, in some embodiments, the static liquid layer results in an increased density of a fiber mat collected in the collection member.
  • the collection member, a removable liner inserted in the collection member, or a removable container portion of the collection member is configured to have a surface upon which the liquid layer is directly formed, and is also configured to be a container removable from the system or from the rest of the system for storage of the formed fiber or fibers.
  • collection member, a removable liner inserted in the collection member, or a removable container portion of the collection member is configured to be a container removable from the system or from the rest of the system for storage of the liquid and the formed micron or nanometer dimension polymeric fiber.
  • the container is configured to be sealable after formation of the micron or nanometer dimension polymeric fiber.
  • the container is further configured to drain the liquid after formation of the micron or nanometer dimension polymeric fiber or fibers.
  • FIGS. 1 A to 1C A system 10 for formation and storage of one or more micron or submicron dimension polymer fibers is depicted in FIGS. 1 A to 1C in accordance with some embodiments. Methods of forming and storing one or more micron or submicron dimension polymer fibers in accordance with some embodiments, are explained with respect to the system of FIGS. lA to 1C.
  • the system 10 includes a reservoir 12 configured to hold a polymer and including an ejection surface 14 having one or more orifices 16 for ejecting the polymer for fiber formation (see FIGS. 1 A and 1C).
  • the system also includes a reservoir motion generator (e.g., a motor) 18 configured to impart rotational motion to the reservoir 12 about a reservoir rotational axis A (see FIG. 1A).
  • the system 10 also includes a collection member 20 configured to hold a liquid 22, which may also be described herein as a liquid material, a bath material, or a liquid bath material herein.
  • the collection member has a first end 24a, which may also be referred to herein as an upper end or a top end, that includes an opening 26.
  • the reservoir 12 may be inserted into the collection member 20 via the opening 26 (see FIGS. 1 A and 1C).
  • the collection member 20 includes a sidewall 28 that has an inner surface 30 facing the ejection surface 14 of the reservoir during polymer ejection (see FIG. 1A).
  • the collection member 20 includes an overhang portion 32 having an inner diameter Di o smaller than a largest (e.g., maximum) diameter of the inner surface of the sidewall Di_ max _s see FIG.
  • the system 10 also includes a collection motion generator (e.g., a motor) configured to rotate the collection member 20 holding the liquid 22 about a collection rotational axis Ac at a rotational rate sufficient to form a liquid layer 32, also referred to herein as a liquid bath layer, disposed on the inner surface of the sidewall 30, (see FIGS. 1 A and 1C).
  • a collection motion generator e.g., a motor
  • the rotational rate is sufficient for a cross-sectional profile 40 of the front surface 38 of the liquid layer (taken with the collection rotational axis laying in the cross-sectional plane) to have an orientation of within 10 degrees of parallel to the collection rotational axis (see FIGS. 1 A and
  • the collection motion generator 34 is configured to rotate the collection member 20 at a sufficient speed for the cross-sectional profile 40 of the front surface 38 of the liquid layer to be within 5 degrees of parallel to the collection rotational axis, within 3 degrees of parallel to the collection rotational axis, within 2 degrees of parallel to the collection rotational axis, or within 1 degree of parallel to the collection rotational axis. Alternatively, this may be described as at least a portion of a front surface 38 of the liquid layer facing the ejection surface 14 of the reservoir having a normal N within 10 degrees, within 5 degrees, within 3 degrees, within 2 degrees, or within 1 degree of perpendicular to the collection rotational axis. If the collection rotational axis is defined as vertical, this may be described as the liquid layer front surface having a cross-sectional profile within 10 degrees, within 5 degrees, within 3 degrees, within 2 degrees or within 1 degree of vertical.
  • FIG. 2 is an image of a prototype collection member 20 holding a liquid that is being rotated to form a liquid layer 36 where the liquid is dyed for better visualization.
  • the liquid layer 36 is smooth with no visible ripples due to fluid flow instabilities (see also FIG. 3 A). The lack of visible ripples in the liquid layer indicates that the liquid layer is substantially static or substantially immobile with respect to the inner surface of the sidewall during polymer ejection.
  • the liquid layer is substantially static or substantially immobile with respect to inner surface of the sidewall.
  • the front surface of the liquid bath layer is also substantially static or substantially immobile with respect to the inner surface of the collection member in accordance with some embodiments. This may also be confirmed in a trial run using visible small particles in the liquid.
  • a sufficient collection member rotational rate may depend on a size and geometry of the collection member being employed. In the Example presented below 200 rotations per minute (rpm) was a sufficient rotational rate to form a static liquid layer. A sufficient rotational rate for a specific collection member can be determined visually by increasing a rotational velocity of the collection member until the liquid layer shows a smooth appearance (see FIGS. 2 and 3A).
  • a polymer is supplied to the reservoir 12 and the reservoir is rotated about the reservoir rotational axis AR to eject the polymer radially outward, with respect to the reservoir rotational axis, in one or more jets 42 from the one or more orifices 16 (see FIG. 1C).
  • the polymer jet 42 undergoes elongation and is received by the liquid layer 36 on the front surface 38 and interacts with the liquid layer 36 to form the polymeric fiber 44 (see FIGS. 1C and 3B).
  • the reservoir may be moved along an axis (e.g., along an axis parallel to the reservoir rotational axis) to deposit fibers at different heights in the collection member during fiber generation (see FIG. 4A).
  • the collection member may be moved along an axis (e.g., along an axis parallel to the collection rotational axis) to deposit fibers at different heights in the collection member during fiber generation (see FIG. 4A). In some embodiments, this may be used to control fiber layer thickness or density as a function of height.
  • the collection member may include a drainage feature 48 for draining the liquid (see FIG. 5).
  • a second polymer may be employed to generate fibers of the second polymer in the same collection member after generation of the fibers of the first polymer and drainage of the liquid bath (see FIG. 5).
  • the second polymer fibers may be deposited on a liquid layer of a second bath over or partially overlying the first polymers (see FIG. 5).
  • the reservoir may be moved along the reservoir rotational axis or the collection member may be moved along the collection rotational axis, during generation of the polymer fibers and/or during generation of the second polymer fibers to obtain a pattern of the fibers (see FIG. 5).
  • the liquid layer may be employed for polymers that require precipitation to form fibers, polymers that require extension in air and precipitation to form fibers, polymers that require on-contact crosslinking, and polymers that require extension in air and on-contact crosslinking to form fibers.
  • the liquid includes one or more components for precipitation, or components for cross-linking.
  • the collection member may include one or more engagement features 46 for being coupled to or engaged by the collection motion generator (see FIGS. 1 A-1C). In other embodiments, the collection member need not include such engagement features. In some embodiments, the engagement feature may have a different design. In some embodiments, a collection member may not include a specific engagement feature for engaging with the collection motion generator.
  • the collection member is also configured to be a container removable from the system or from the rest of the system for storage of the formed polymeric fiber or fibers.
  • the collection member may have extensions that can be used to cover the top end and enclose the collection member.
  • the collection member may have features to facilitate packaging, sealing or being sealed.
  • the collection member may have features to facilitate post processing in the collection member.
  • the collection member may have features to packing or shipping of the fibers (e.g., dry, in the bath liquid, or in some other liquid or gel), (see FIG. 5).
  • the collection member may be designed as a disposable storage and packaging container for the fibers.
  • the liquid layer is deposed directly on the inner surface of the sidewall.
  • the collection member may have a sidewall surface upon which the liquid layer is directly formed (see FIGS. 1 A to 1C), and is also configured to be a container removable from the system or from the rest of the system for storage of the formed fiber or fibers.
  • a collection member, a removable liner inserted in the collection member, or a removable container portion of the collection member is configured to be a container removable from the system or from the rest of the system for storage of the liquid and the formed micron or nanometer dimension polymeric fiber.
  • the container is configured to be sealable after formation of the micron or nanometer dimension polymeric fiber (e.g., see sealing flap 50 of FIG. 7).
  • the container is further configured to drain the liquid after formation of the micron or nanometer dimension polymeric fiber or fibers.
  • a collection member 60 is further configured to receive a removable liner 62, at least a portion of the removable liner 62 having a surface corresponding to the inner surface of the sidewall and the overhang portion of the collection member.
  • the received removable liner 62 is positioned between the inner surface of the sidewall during ejection of the jet of polymer.
  • the liquid layer is disposed directly on the removable liner overlaying the inner surface of the sidewall during ejection of the polymer.
  • the removable liner 62 is configured to be removed from the collection member 60 while containing the formed micron or nanometer dimension polymeric fibers (see FIG. 7).
  • the collection member 70 includes a collection support portion 72 and a removable container portion 74 (see FIG. 8).
  • the removable container portion 74 is disposed between the collection support portion 72 and the reservoir during use.
  • the removable container portion 74 forms the inner surface of the sidewall of the collection member 70.
  • the collection support portion 72 is configured to engage or be engaged by the collection motion generator as well as support the removable container portion 74.
  • the liquid layer is disposed directly on the removable container portion 74 during ejection of the polymer layer.
  • the removable container portion 74 is a container configured to be removed from the collection support portion 74 while containing the formed micron or nanometer dimension polymeric fiber.
  • the entire collection member, the removable liner, or the removable container portion can be designed as disposable, as a packing device for the fibers inside.
  • this process for generation of polymeric fibers can be easily achieved in a mass production pipeline, and the collection member, removable liner, or removable container portion can be designed as sterile/disposable to meet certain packaging requirements.
  • a collection member, a removable liner inserted in the collection member, or a removable container portion of the collection member is configured to be a container removable from the system or from the rest of the system for storage of the liquid and the formed micron or nanometer dimension polymeric fiber.
  • the container is configured to be sealable after formation of the micron or nanometer dimension polymeric fiber.
  • the container is further configured to drain the liquid after formation of the micron or nanometer dimension polymeric fiber or fibers.
  • the generated and collected fibers may be used in the form of a a mat or a sheet formed during the formation of the fibers.
  • the inner surface of the sidewall may have a shape configured to achieve a desired shape in the collected generated fibers.
  • a plurality of micron or nanometer dimension polymeric fibers are formed.
  • the plurality of micron or nanometer dimension polymeric fibers may be of the same diameter or of different diameters.
  • the methods result in the fabrication of a plurality of aligned (e.g., uniaxially aligned) micron or nanometer dimension polymeric fibers, (e.g., a sheet of polymeric fibers).
  • aligned e.g., uniaxially aligned
  • nanometer dimension polymeric fibers e.g., a sheet of polymeric fibers
  • Suitable polymers for use in exemplary devices and methods include water soluble polymers (i.e., polymers dissolved in slowly evaporating solvents, e.g., aqueous solvents), polymers that require on-contact cross-linking (e.g., alginate) and/or polymers that cannot be readily dissolved at a high enough concentrations to provide sufficient viscosity for random entanglement and solvent evaporation to form polymeric fibers (e.g., deoxyribonucleic acid, polyurethane-polyurea copolymer, and polyacrylonitrile), and/or polymers that require precipitation (e.g., deoxyribonucleic acid), and/or polymers dissolved in water at low concentrations (e.g., below 2%) and/or polymers that require both extension in air and precipitation (e.g., polyamides, e.g., liquid crystalline polymers, e.g., poly-paraphenylene terephthalamide and poly(p-
  • Suitable polymers may be biocompatible or non-biocompatible, synthetic or natural, e.g., biogenic polymers, e.g., proteins, polysaccharides, lipids, nucleic acids or combinations thereof.
  • Exemplary polymers which require on-contact crosslinking include, for example, alginate, gelatin, collagen, chitosan, polyvinyl alcohols, polyacrylamides, starches, and polyethylene oxides, copolymers and derivatives thereof
  • Exemplary polymers which require precipitation include, for example, deoxyribonucleic acid, ribonucleic acid.
  • Exemplary polymers which require extension in air and precipitation include, for example, polyamides, e.g., liquid crystalline polymers, e.g., poly-paraphenylene terephthalamide, e.g., 1,4-phenylene-diamine (para-phenyl enediamine)and terephthaloyl chloride, and poly(p-phenylene benzobisoxazole)).
  • polyamides e.g., liquid crystalline polymers, e.g., poly-paraphenylene terephthalamide, e.g., 1,4-phenylene-diamine (para-phenyl enediamine)and terephthaloyl chloride, and poly(p-phenylene benzobisoxazole)).
  • the polymers for use in the devices and methods of the invention may be mixtures of two or more polymers and/or two or more copolymers. In one embodiment the polymers for use in the devices and methods of the invention may be a mixture of one or more polymers and or more copolymers. In another embodiment, the polymers for use in the devices and methods of the invention may be a mixture of one or more synthetic polymers and one or more naturally occurring polymers.
  • the polymer is fed into the reservoir as a polymer solution, i.e., a polymer dissolved in an appropriate solution. In this embodiment, the methods may further include dissolving the polymer in a solvent prior to feeding the polymer into the reservoir.
  • the polymer may be fed into the reservoir as a polymer melt and, thus, in one embodiment, the reservoir is heated at a temperature suitable for melting the polymer, e.g., heated at a temperature of about 100°C-300°C, 100°C-200°C, about 150-300°C, about 150-250°C, or about 150-200°C, 200°C-250°C, 225°C-275°C, 220°C-250°C, or about 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, or about 300°C. Ranges and temperatures intermediate to the recited temperature ranges are also part of the invention. In such embodiments,
  • fiber and “polymeric fiber” are used herein interchangeably, and both terms refer to fibers having micron, submicron, and nanometer dimensions.
  • a “chemically and physically stable polymeric fiber” is one that shows substantially no signs of, e.g., loss of strength measured by, e.g., uniaxial tensile testing, and/or degradation rate in culture with media or cells measured by, e.g., weight of the fibers over time.
  • Exemplary devices and methods may be used to form a single, continuous polymeric fiber or a plurality of polymeric fibers of the same or different diameters, e.g., diameters about 25 nanometers to about 50 micrometers, about 100 nanometers to about 1 micrometer, about 500 nanometers to about 100 micrometers, 25 micrometers to about 100 micrometers, or about 5, 20, 25, 30, 35,40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 33, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 5
  • the methods of the invention result in the fabrication of a plurality of aligned (e.g., uniaxially aligned) micron or nanometer dimension polymeric fibers.
  • Rotational speeds of the reservoir in exemplary embodiments may range from about 1,000 rpm to about 400,000 rpm, e.g., about 1,000, 3,000, 5,000, 10,000, 50,000, 55,000, 60,000, 65,000, 70,000, 75,000, 80,000, 85,000, 90,000, 95,000, 100,000, 105,000, 110,000, 115,000, 120,000, 125,000, 130,000, 135,000, 140,000, 145,000, 150,000 rpm, about 200,000 rpm, 250,000 rpm, 300,000 rpm, 350,000 rpm, or about 400,000 rpm. Ranges and values intermediate to the above recited ranges and values are also contemplated to be part of the invention.
  • Exemplary orifice lengths that may be used in some exemplary embodiments range between about 0.001 m and about 0.1 m, e.g., about 0.0015, 0.002, 0.0025, 0.003, 0.0035, 0.004, 0.0045, 0.005, 0.0055, 0.006, 0.0065, 0.007, 0.0075, 0.008, 0.0085, 0.009, 0.0095, 0.01, 0.015, 0.02, 0.025, 0.03, 0.035, 0.04, 0.045, 0.05, 0.055, 0.06, 0.065, 0.07, 0.075, 0.08, 0.085, 0.09, 0.095, or about 0.1 m. Ranges and values intermediate to the above recited ranges and values are also contemplated to be part of the invention.
  • Exemplary orifice diameters that may be used in some exemplary embodiments range between about 0.05 pm and about 1000 pm, e.g., about 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.15, 0.2, 0.225, 0.25, 0.275, 0.3, 0.325, 0.35, 0.375, 0.4, 0.425, 0.45, 0.475, 0.5, 0.525, 0.55, 0.575, 0.6, 0.625, 0.65, 0.675, 0.7, 0.725, 0.75, 0.075, 0.8, 0.825, 0.85, 0.825, 0.9, 0.925, 0.95, 0.975, 1.0, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900
  • the reservoir may further include a first nozzle provided on a first of the one or more orifices of the reservoir
  • le polymers for use in exemplary devices and methods include water soluble polymers (i.e., polymers dissolved in slowly evaporating solvents, e.g., aqueous solvents), polymers that require on-contact cross-linking (e.g., alginate) and/or polymers that cannot be readily dissolved at a high enough concentrations to provide sufficient viscosity for random entanglement and solvent evaporation to form polymeric fibers (e.g., deoxyribonucleic acid, polyurethane-polyurea copolymer, and polyacrylonitrile), and/or polymers that require precipitation (e.g., deoxyribonucleic acid), and/or polymers dissolved in water at low concentrations (e.g., below 2%) and/or polymers that require both extension in air and precipitation e.g., polyamides, e.g.,
  • the plurality of micron or nanometer dimension polymeric fibers are contacted with additional agents, e.g., a plurality of living cells, e.g., muscle cells, neuron cells, endothelial cells, and epithelial cells; biologically active agents, e.g., lipophilic peptides, lipids, nucleotides; fluorescent molecules, metals, ceramics, nanoparticles, and pharmaceutically active agents.
  • additional agents e.g., a plurality of living cells, e.g., muscle cells, neuron cells, endothelial cells, and epithelial cells
  • biologically active agents e.g., lipophilic peptides, lipids, nucleotides
  • fluorescent molecules e.g., metals, ceramics, nanoparticles, and pharmaceutically active agents.
  • the polymeric fibers contacted with living cells are cultured in an appropriate medium for a time until, e.g., a living tissue is produced.
  • the polymer is contacted with living cells during the fabrication process such that fibers populated with cells or fibers surrounded (partially or totally) with cells are produced.
  • the polymer may also be contacted with additional agents, such as proteins, nucleotides, lipids, drugs, pharmaceutically active agents, biocidal and antimicrobial agents during the fabrication process such that functional micron or nanometer dimension polymeric fibers are produced which contain these agents.
  • additional agents such as proteins, nucleotides, lipids, drugs, pharmaceutically active agents, biocidal and antimicrobial agents during the fabrication process such that functional micron or nanometer dimension polymeric fibers are produced which contain these agents.
  • alginate fibers including living cells may be fabricated by providing living cells in a solution of cell media that contains calcium chloride at a concentration that maintains cell viability and is sufficient to crosslink the alginate polymer.
  • embodiments provide the polymeric fibers produced using the methods and devices of the invention, as well as tissues, membranes, filters, biological protective textiles, biosensor devices, food products, and drug delivery devices including the polymeric fibers of the invention.
  • embodiments provide methods for identifying a compound that modulates a tissue function.
  • the methods include, providing a tissue produced according to the methods of the invention; contacting the tissue with a test compound; and determining the effect of the test compound on a tissue function in the presence and absence of the test compound, wherein a modulation of the tissue function in the presence of the test compound as compared to the tissue function in the absence of the test compound indicates that the test compound modulates a tissue function, thereby identifying a compound that modulates a tissue function.
  • the methods include applying a stimulus to the tissue.
  • a plurality of living tissues is contacted with a test compound simultaneously.
  • the fibers produced according to the methods disclosed herein can be, for example, used as extracellular matrix and, together with cells, may also be used in forming engineered tissue. Such tissue is useful not only for the production of prosthetic devices and regenerative medicine, but also for investigating tissue developmental biology and disease pathology, as well as in drug discovery and toxicity testing.
  • the polymeric fibers of the invention may also be combined with other substances, such as, therapeutic agents, in order to deliver such substances to the site of application or implantation of the polymeric fibers.
  • the polymeric fibers produced according to the methods disclosed herein may also be used to generate food products, thread, fabrics, membranes and filters.
  • Exemplary fiber formation devices may have many applications including, but not limited to, mass production of polymer fibers, production of ultra-aligned scaffolds, biofunctional scaffolds for in vitro tissue engineering applications, bio-functional scaffolds for in vivo tissue engineering applications, bio-functional suture threads, ultra-strong fiber and fabric production, bio-functional protein or polymer filters, protective clothing or coverings, etc.
  • a plurality of polymeric fibers may be contacted, e.g., seeded, with a plurality of living cells, e.g., vascular smooth muscle cells, myocytes (e.g., cardiac myocytes), skeletal muscle, myofibroblasts, airway smooth muscle cells, osteoblasts, myoblasts, neuroblasts, fibroblasts, glioblasts, germ cells, hepatocytes, chondrocytes, keratinocytes, connective tissue cells, glial cells, epithelial cells, endothelial cells, vascular endothelial cells, hormone-secreting cells, cells of the immune system, neural cells, and cells that will differentiate into contractile cells (e.g., stem cells, e.g., embryonic stem cells or adult stem cells, progenitor cells or satellite cells).
  • a plurality of living cells e.g., vascular smooth muscle cells, myocytes (e.g., cardiac myocytes), skeletal muscle, myofibroblast
  • polymeric fibers treated with a plurality of living cells may be cultured in an appropriate medium in vitro. Such cultured cells exhibit characteristics and functions typical of such cells in vivo.
  • the plurality of living cells may include one or more types of cells, such as described in U.S. Provisional Application No. 61/306,736 and PCT Application No. PCT/US09/060224, entitled “Tissue Engineered Mycocardium and Methods of Productions and Uses Thereof’, filed October 9, 2009, the entire contents of each of which are incorporated herein by reference.
  • progenitor cell is used herein synonymously with “stem cell.”
  • stem cell refers to an undifferentiated cell which is capable of proliferation and giving rise to more progenitor cells having the ability to generate a large number of mother cells that can in turn give rise to differentiated, or differentiable daughter cells.
  • the daughter cells themselves can be induced to proliferate and produce progeny that subsequently differentiate into one or more mature cell types, while also retaining one or more cells with parental developmental potential.
  • stem cell refers to a subset of progenitors that have the capacity or potential, under particular circumstances, to differentiate to a more specialized or differentiated phenotype, and which retains the capacity, under certain circumstances, to proliferate without substantially differentiating.
  • the term stem cell refers generally to a naturally occurring mother cell whose descendants (progeny) specialize, often in different directions, by differentiation, e.g., by acquiring completely individual characters, as occurs in progressive diversification of embryonic cells and tissues.
  • Cellular differentiation is a complex process typically occurring through many cell divisions.
  • a differentiated cell may derive from a multipotent cell which itself is derived from a multipotent cell, and so on. While each of these multipotent cells may be considered stem cells, the range of cell types each can give rise to may vary considerably.
  • Some differentiated cells also have the capacity to give rise to cells of greater developmental potential. Such capacity may be natural or may be induced artificially upon treatment with various factors.
  • stem cells are also “multipotenf ’ because they can produce progeny of more than one distinct cell type, but this is not required for “sternness.”
  • Self-renewal is the other classical part of the stem cell definition. In theory, selfrenewal can occur by either of two major mechanisms. Stem cells may divide asymmetrically, with one daughter retaining the stem state and the other daughter expressing some distinct other specific function and phenotype. Alternatively, some of the stem cells in a population can divide symmetrically into two stems, thus maintaining some stem cells in the population as a whole, while other cells in the population give rise to differentiated progeny only.
  • embryonic stem cell is used to refer to the pluripotent stem cells of the inner cell mass of the embryonic blastocyst (see US Patent Nos. 5,843,780, 6,200,806, the contents of which are incorporated herein by reference). Such cells can similarly be obtained from the inner cell mass of blastocysts derived from somatic cell nuclear transfer (see, for example, US Patent Nos. 5,945,577, 5,994,619, 6,235,970, which are incorporated herein by reference). The distinguishing characteristics of an embryonic stem cell define an embryonic stem cell phenotype.
  • a cell has the phenotype of an embryonic stem cell if it possesses one or more of the unique characteristics of an embryonic stem cell such that that cell can be distinguished from other cells.
  • Exemplary distinguishing embryonic stem cell characteristics include, without limitation, gene expression profile, proliferative capacity, differentiation capacity, karyotype, responsiveness to particular culture conditions, and the like.
  • the term “adult stem cell” or “ASC” is used to refer to any multipotent stem cell derived from non- embryonic tissue, including fetal, juvenile, and adult tissue. Stem cells have been isolated from a wide variety of adult tissues including blood, bone marrow, brain, olfactory epithelium, skin, pancreas, skeletal muscle, and cardiac muscle.
  • Each of these stem cells can be characterized based on gene expression, factor responsiveness, and morphology in culture.
  • Exemplary adult stem cells include neural stem cells, neural crest stem cells, mesenchymal stem cells, hematopoietic stem cells, and pancreatic stem cells.
  • progenitor cells suitable for use in the claimed devices and methods are Committed Ventricular Progenitor (CVP) cells as described in PCT Application No. PCT/US09/060224, entitled “Tissue Engineered Mycocardium and Methods of Productions and Uses Thereof’, filed October 9, 2009, the entire contents of which are incorporated herein by reference.
  • CVP Committed Ventricular Progenitor
  • Cells for seeding can be cultured in vitro, derived from a natural source, genetically engineered, or produced by any other means. Any natural source of prokaryotic or eukaryotic cells may be used.
  • Embodiments in which the polymeric fibers contacted with a plurality of living cells are implanted in an organism can use cells from the recipient, cells from a conspecific donor or a donor from a different species, or bacteria or microbial cells.
  • a plurality of polymeric fibers is contacted with a plurality of muscle cells and cultured such that a living tissue is produced.
  • a plurality of polymeric fibers is contacted with a plurality of muscle cells and cultured such that a living tissue is produced, and the living tissue is further contacted with neurons, and cultured such that a living tissue with embedded neural networks is produced.
  • the living tissue is an anisotropic tissue, e.g., a muscle thin film.
  • a plurality of polymeric fibers is contacted with a biologically active polypeptide or protein, such as, collagen, fibrin, elastin, laminin, fibronectin, integrin, hyaluronic acid, chondroitin 4-sulfate, chondroitin 6-sulfate, dermatan sulfate, heparin sulfate, heparin, and keratan sulfate, and proteoglycans.
  • the polypeptide or protein is lipophilic.
  • the polymeric fibers are contacted with nucleic acid molecules and/or nucleotides, or lipids.
  • a plurality of polymeric fibers may also be contacted with a pharmaceutically active agent.
  • suitable pharmaceutically active agents include, for example, anesthetics, hypnotics, sedatives and sleep inducers, antipsychotics, antidepressants, antiallergics, antianginals, antiarthritics, antiasthmatics, antidiabetics, antidiarrheal drugs, anticonvulsants, antigout drugs, antihistamines, antipruritics, emetics, antiemetics, antispasmodics, appetite suppressants, neuroactive substances, neurotransmitter agonists, antagonists, receptor blockers and reuptake modulators, beta-adrenergic blockers, calcium channel blockers, disulfiram and disulfiram-like drugs, muscle relaxants, analgesics, antipyretics, stimulants, anticholinesterase agents, parasympathomimetic agents, hormones, anticoagulants, antithrombotics, thrombolytics,
  • growth factors and cytokines include growth factors and cytokines.
  • Growth factors useful in embodiments include, but are not limited to, transforming growth factor-a (“TGF-a”), transforming growth factor-P (“TGF-P”), platelet-derived growth factors including the AA, AB and BB isoforms (“PDGF”), fibroblast growth factors (“FGF”), including FGF acidic isoforms 1 and 2, FGF basic form 2, and FGF 4, 8, 9 and 10, nerve growth factors (“NGF”) including NGF 2.5s, NGF 7.0s and beta NGF and neurotrophins, brain derived neurotrophic factor, cartilage derived factor, bone growth factors (BGF), basic fibroblast growth factor, insulin-like growth factor (IGF), vascular endothelial growth factor (VEGF), granulocyte colony stimulating factor (G-CSF), insulin like growth factor (IGF) I and II, hepatocyte growth factor, glial neurotrophic growth factor (GDNF), stem cell factor (SCF), keratinocyte growth
  • Cytokines useful in embodiments include, but are not limited to, cardiotrophin, stromal cell derived factor, macrophage derived chemokine (MDC), melanoma growth stimulatory activity (MGSA), macrophage inflammatory proteins 1 alpha (MIP-1 alpha), 2, 3 alpha, 3 beta, 4 and 5, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, TNF-a, and TNF-p.
  • Immunoglobulins useful in embodiments include, but are not limited to, IgG, IgA, IgM, IgD, IgE, and mixtures thereof.
  • agents that may be used to contact the polymeric fibers of the invention, include, but are not limited to, growth hormones, leptin, leukemia inhibitory factor (LIF), tumor necrosis factor alpha and beta, endostatin, angiostatin, thrombospondin, osteogenic protein- 1, bone morphogenetic proteins 2 and 7, osteonectin, somatomedin-like peptide, osteocalcin, interferon alpha, interferon alpha A, interferon beta, interferon gamma, interferon 1 alpha, amino acids, peptides, polypeptides, and proteins, e.g., structural proteins, enzymes, and peptide hormones.
  • LIF leukemia inhibitory factor
  • any nucleic acid can be used to contact the polymeric fibers.
  • examples include, but are not limited to deoxyribonucleic acid (DNA), ent- DNA, and ribonucleic acid (RNA).
  • Embodiments involving DNA include, but are not limited to, cDNA sequences, natural DNA sequences from any source, and sense or anti-sense oligonucleotides.
  • DNA can be naked (e.g., U.S. Pat. Nos. 5,580,859; 5,910,488) or complexed or encapsulated (e.g., U.S. Pat. Nos. 5,908,777; 5,787,567).
  • DNA can be present in vectors of any kind, for example in a viral or plasmid vector.
  • nucleic acids used will serve to promote or to inhibit the expression of genes in cells inside and/or outside the polymeric fibers.
  • the nucleic acids can be in any form that is effective to enhance uptake into cells.
  • Magnetically or electrically reactive materials are examples of other agents that are optionally used to contact the polymeric fibers of embodiments.
  • magnetically active materials include but are not limited to ferrofluids (colloidal suspensions of magnetic particles), and various dispersions of electrically conducting polymers. Ferrofluids containing particles approximately 10 nanometers in diameter, polymer-encapsulated magnetic particles about 1-2 microns in diameter, and polymers with a glass transition temperature below room temperature are particularly useful.
  • electrically active materials are polymers including, but not limited to, electrically conducting polymers such as polyanilines and polypyrroles, ionically conducting polymers such as sulfonated polyacrylamides are related materials, and electrical conductors such as carbon black, graphite, carbon nanotubes, metal particles, and metal-coated plastic or ceramic materials.
  • Suitable biocides for contacting the polymeric fibers of the invention include, but are not limited to, organotins, brominated salicylanilides, mercaptans, quaternary ammonium compounds, mercury compounds, and compounds of copper and arsenic.
  • Antimicrobial agents which include antibacterial agents, antiviral agents, antifungal agents, and anti-parasitic agents, may also be used to contact the polymeric fibers of the invention.
  • the present invention is also directed to the polymeric fibers produced using the methods and device of the invention, as well as, tissues, membranes, filters, and drug delivery device, e.g., polymeric fibers treated with, e.g., a pharmaceutically active agent, including the polymeric fibers of the invention.
  • exemplary fibers include, but are not limited to, manufacture of engineered tissue and organs, including structures such as patches or plugs of tissues or matrix material, prosthetics, and other implants, tissue scaffolding for, e.g., fractal neural and/or vascular networks, repair or dressing of wounds, hemostatic devices, devices for use in tissue repair and support such as sutures, surgical and orthopedic screws, and surgical and orthopedic plates, natural coatings or components for synthetic implants, cosmetic implants and supports, repair or structural support for organs or tissues, substance delivery, bioengineering platforms, platforms for testing the effect of substances upon cells, cell culture, catalytic substrates, photonics, filtration, protective clothing, cell scaffolding, drug delivery, wound healing, food products, enzyme immobilization, use in a biosensor, forming a membrane, forming a filter, forming a fiber, forming a net, forming a food item, forming a medicinal item, forming a cosmetic item, forming a fiber structure inside a body cavity, forming a non-lethal
  • Biogenic polymer assemblies with defined dimensional scales formed by exemplary fiber formation devices, systems and methods may be used as a wound healing patch to enhance healing processes by providing essential proteins on or in the wound area to significantly shorten the healing time.
  • Biogenic polymers formed by exemplary fiber formation devices, systems and methods may be used as biofunctional textiles.
  • polymeric fibers of some embodiments disclosed herein can be used to tightly control the biotic/abiotic interface.
  • the polymeric fibers of the invention can be used to direct the growth and/or development of specific cell and/or tissue types.
  • the polymeric fibers of the invention may be used to prepare a membrane, which is useful as, for example, a dressing for wounds or injuries of any type.
  • Stem cells, fibroblasts, epithelial cells, and/or endothelial cells may be included to allow tissue growth.
  • use of the polymeric fibers will, in addition to providing support, will direct and/or impede desired cells types to the area of a wound or injury.
  • use of the polymeric fibers to repair the heart may include the addition of any suitable substance that will direct cells to differentiate into, for example, myocytes, rather than, for example, fibroblasts, and/or encourage the migration of a desired cell type to migrate to the area of the wound. Such methods will ensure that the repair is biologically functional and/or discourage, for example restonosis.
  • Such use of the polymeric fibers may be combined with other methods of treatment, repair, and contouring.
  • a polymeric fiber membrane can be inserted as a filler material into wounds to enhance healing by providing a substrate that does not have to be synthesized by fibroblasts and other cells, thereby decreasing healing time and reducing the metabolic energy requirement to synthesize new tissue at the site of the wound.
  • membranes of embodiments may be used to make tissue or orthopedic screws, plates, sutures, or sealants that are made of the same material as the tissue in which the devices will be used.
  • polymeric fiber membranes may be used to form, e.g., a sleeve to use as reinforcement for aneurysms or at the site of an anastamosis. Such sleeves are placed over the area at which reinforcement is desired and sutured, sealed, or otherwise attached to the vessel. Polymeric fiber membranes may also be used as hemostatic patches and plugs for leaks of cerebrospinal fluid. Yet another use is as an obstruction of the punctum lacryma for a patient suffering from dry eye syndrome.
  • Polymeric fiber membranes may also be used to support or connect tissue or structures that have experienced injury, surgery, or deterioration.
  • such membranes may be used in a bladder neck suspension procedure for patients suffering from postpartum incontinence. Rectal support, vaginal support, hernia patches, and repair of a prolapsed uterus are other illustrative uses.
  • the membranes may be used to repair or reinforce weakened or dysfunctional sphincter muscles, such as the esophageal sphincter in the case of esophageal reflux.
  • Other examples include reinforcing and replacing tissue in vocal cords, epiglottis, and trachea after removal, such as in removal of cancerous tissue.
  • membranes of the invention include preparing an obstruction or reinforcement for an obstruction to a leak, for example, to seal openings in lungs after lung volume reduction (partial removal).
  • Another exemplary us of the polymeric fibers of the invention is as a barrier for the prevention of post-operative induced adhesion(s).
  • Yet another exemplary use of the polymeric fibers of the invention is to serve as a template for nerve growth.
  • the polymeric fibers may be used to prepare a filter.
  • filters are useful for filtration of contaminants, biological agents and hazardous but very small particles, e.g., nanoparticles.
  • a polymeric fiber filter of the invention may be used to purify liquids, such as water, e.g., drinking water, oil, e.g., when used in an automobile oil filter.
  • a polymeric fiber filter may be used to purify air when used in, e.g, a face mask, to filter out viruses, bacteria and hazardous nanoparticles.
  • the polymeric fibers may be used to prepare textiles.
  • the textiles are biological protective textiles, e.g., textiles that provide protection from toxic agents, e.g., biological and chemical toxins.
  • the polymeric fibers may include, e.g., chlorhexidine, which can kill most bacteria, or an oxime that can break down organophosphates, chemicals that are the basis of many pesticides, insecticides and nerve gases.
  • the polymeric fibers of the invention may be used to prepare furniture upholstery.
  • polymeric fibers of the invention may be used to form or manufacture medical devices.
  • the ability to seed the polymeric fibers of the invention with living cells also provides the ability to build tissue, organs, or organ-like tissues.
  • Cells included in such tissues or organs can include cells that serve a function of delivering a substance, seeded cells that will provide the beginnings of replacement tissue, or both.
  • polymeric fibers contacted or seeded with living cells are combined with a drug such that the function of the implant will improve.
  • a drug such that the function of the implant will improve.
  • antibiotics, anti-inflammatories, local anesthetics or combinations thereof can be added to the cell-treated polymeric fibers of a bioengineered organ to speed the healing process.
  • bioengineered tissue examples include, but are not limited to, bone, dental structures, joints, cartilage, (including, but not limited to articular cartilage), skeletal muscle, smooth muscle, cardiac muscle, tendons, menisci, ligaments, blood vessels, stents, heart valves, corneas, ear drums, nerve guides, tissue or organ patches or sealants, a filler for missing tissues, sheets for cosmetic repairs, skin (sheets with cells added to make a skin equivalent), soft tissue structures of the throat such as trachea, epiglottis, and vocal cords, other cartilaginous structures such as articular cartilage, nasal cartilage, tarsal plates, tracheal rings, thyroid cartilage, and arytenoid cartilage, connective tissue, vascular grafts and components thereof, and sheets for topical applications, and repair of organs such as livers, kidneys, lungs, intestines, pancreas visual system, auditory system, nervous system, and musculoskeletal system.
  • cartilage including, but
  • a plurality of polymeric fibers are contacted with a plurality of living muscle cells and cultured under appropriate conditions to guide cell growth with desired anisotropy to produce a muscle thin film (MTF) or a plurality of MTFs prepared as described in U.S. Patent Publication Nos. 20090317852 and 20120142556, and PCT Application No. PCT/US2012/068787. The entire contents of each of the foregoing are incorporated herein by reference.
  • MTF muscle thin film
  • Polymeric fibers contacted with living cells can also be used to produce prosthetic organs or parts of organs. Mixing of committed cell lines in a three dimensional polymeric fiber matrix can be used to produce structures that mimic complex organs. The ability to shape the polymeric fibers allows for preparation of complex structures to replace organs such as liver lobes, pancreas, other endocrine glands, and kidneys. In such cases, cells are implanted to assume the function of the cells in the organs. Preferably, autologous cells or stem cells are used to minimize the possibility of immune rejection.
  • polymeric fibers contacted with living cells are used to prepare partial replacements or augmentations.
  • organs are scarred to the point of being dysfunctional.
  • a classic example is hepatic cirrhosis.
  • cirrhosis normal hepatocytes are trapped in fibrous bands of scar tissue.
  • the liver is biopsied, viable liver cells are obtained, cultured in a plurality of polymeric fibers, and re-implanted in the patient as a bridge to or replacement for routine liver transplantations.
  • pancreatic islet by growing glucagon secreting cells, insulin secreting cells, somatostatin secreting cells, and/or pancreatic polypeptide secreting cells, or combinations thereof, in separate cultures, and then mixing them together with polymeric fibers, an artificial pancreatic islet is created. These structures are then placed under the skin, retroperitoneally, intrahepatically or in other desirable locations, as implantable, long-term treatments for diabetes.
  • hormone-producing cells are used, for example, to replace anterior pituitary cells to affect synthesis and secretion of growth hormone secretion, luteinizing hormone, follicle stimulating hormone, prolactin and thyroid stimulating hormone, among others.
  • Gonadal cells such as Leydig cells and follicular cells are employed to supplement testosterone or estrogen levels.
  • Specially designed combinations are useful in hormone replacement therapy in post and perimenopausal women, or in men following decline in endogenous testosterone secretion.
  • Dopamine-producing neurons are used and implanted in a matrix to supplement defective or damaged dopamine cells in the substantia nigra.
  • stem cells from the recipient or a donor can be mixed with slightly damaged cells, for example pancreatic islet cells, or hepatocytes, and placed in a plurality of polymeric fibers and later harvested to control the differentiation of the stem cells into a desired cell type.
  • thyroid cells can be seeded and grown to form small thyroid hormone secreting structures. This procedure is performed in vitro or in vivo. The newly formed differentiated cells are introduced into the patient.
  • Bioengineered tissues are also useful for measuring tissue activities or functions, investigating tissue developmental biology and disease pathology, as well as in drug discovery and toxicity testing.
  • embodiments also provide methods for identifying a compound that modulates a tissue function.
  • the methods include providing a bioengineered tissue produced according to the methods of the invention, such as a muscle thin film; contacting the bioengineered tissue with a test compound; and determining the effect of the test compound on a tissue function in the presence and absence of the test compound, wherein a modulation of the tissue function in the presence of the test compound as compared to the tissue function in the absence of the test compound indicates that the test compound modulates a tissue function, thereby identifying a compound that modulates a tissue function.
  • embodiments also provide methods for identifying a compound useful for treating or preventing a disease.
  • the methods include providing a bioengineered tissue produced according to the methods of the invention, e.g., a muscle thin film; contacting a bioengineered tissue with a test compound; and determining the effect of the test compound on a tissue function in the presence and absence of the test compound, wherein a modulation of the tissue function in the presence of the test compound as compared to the tissue function in the absence of the test compound indicates that the test compound modulates a tissue function, thereby identifying a compound useful for treating or preventing a disease.
  • Some methods include determining the effect of a test compound on a bioengineered tissue as a whole, however, the methods of the invention may include further evaluating the effect of a test compound on an individual cell type(s) of the bioengineered tissue.
  • Some methods may involve contacting a single bioengineered tissue with a test compound or a plurality of bioengineered tissues with a test compound.
  • modulate are intended to include stimulation (e.g., increasing or upregulating a particular response or activity) and inhibition (e.g., decreasing or downregulating a particular response or activity).
  • the term "contacting" is intended to include any form of interaction (e.g., direct or indirect interaction) of a test compound and a bioengineered tissue.
  • the term contacting includes incubating a compound and a bioengineered tissue (e.g., adding the test compound to a bioengineered tissue).
  • Test compounds may be any agents including chemical agents (such as toxins), small molecules, pharmaceuticals, peptides, proteins (such as antibodies, cytokines, enzymes, and the like), and nucleic acids, including gene medicines and introduced genes, which may encode therapeutic agents, such as proteins, antisense agents (i.e., nucleic acids including a sequence complementary to a target RNA expressed in a target cell type, such as RNAi or siRNA), ribozymes, and the like.
  • chemical agents such as toxins
  • small molecules such as pharmaceuticals, peptides, proteins (such as antibodies, cytokines, enzymes, and the like)
  • nucleic acids including gene medicines and introduced genes, which may encode therapeutic agents, such as proteins, antisense agents (i.e., nucleic acids including a sequence complementary to a target RNA expressed in a target cell type, such as RNAi or siRNA), ribozymes, and the like.
  • antisense agents i.e., nucleic acids including a sequence
  • the test compound may be added to a bioengineered tissue by any suitable means.
  • the test compound may be added drop-wise onto the surface of a bioengineered tissue of the invention and allowed to diffuse into or otherwise enter the bioengineered tissue, or it can be added to the nutrient medium and allowed to diffuse through the medium.
  • each of the culture wells may be contacted with a different test compound or the same test compound.
  • the screening platform includes a microfluidics handling system to deliver a test compound and simulate exposure of the microvasculature to drug delivery.
  • the polymeric fiber tissues of the invention can be used in contractility assays for muscular cells or tissues, such as chemically and/or electrically stimulated contraction of vascular, airway or gut smooth muscle, cardiac muscle or skeletal muscle.
  • the differential contractility of different muscle cell types to the same stimulus e.g., pharmacological and/or electrical
  • the bioengineered tissues of embodiments can be used for measurements of solid stress due to osmotic swelling of cells. For example, as the cells swell the polymeric fiber tissues will bend and as a result, volume changes, force and points of rupture due to cell swelling can be measured.
  • the bioengineered tissues of embodiments can be used for pre-stress or residual stress measurements in cells.
  • vascular smooth muscle cell remodeling due to long term contraction in the presence of endothelin-1 can be studied.
  • bioengineered tissues of embodiments can be used to study the loss of rigidity in tissue structure after traumatic injury, e.g., traumatic brain injury. Traumatic stress can be applied to vascular smooth muscle bioengineered tissues as a model of vasospasm. These bioengineered tissues can be used to determine what forces are necessary to cause vascular smooth muscle to enter a hyper-contracted state. These bioengineered tissues can also be used to test drugs suitable for minimizing vasospasm response or improving post-injury response and returning vascular smooth muscle contractility to normal levels more rapidly.
  • the bioengineered tissues of embodiments can be used to study biomechanical responses to paracrine released factors (e.g., vascular smooth muscle dilation due to release of nitric oxide from vascular endothelial cells, or cardiac myocyte dilation due to release of nitric oxide).
  • paracrine released factors e.g., vascular smooth muscle dilation due to release of nitric oxide from vascular endothelial cells, or cardiac myocyte dilation due to release of nitric oxide.
  • the bioengineered tissues of the invention can be used to evaluate the effects of a test compound on an electrophysiological parameter, e.g., an electrophysiological profile including a voltage parameter selected from the group consisting of action potential, action potential duration (APD), conduction velocity (CV), refractory period, wavelength, restitution, bradycardia, tachycardia, reentrant arrhythmia, and/or a calcium flux parameter, e.g., intracellular calcium transient, transient amplitude, rise time (contraction), decay time (relaxation), total area under the transient (force), restitution, focal and spontaneous calcium release.
  • a decrease in a voltage or calcium flux parameter of a bioengineered tissue including cardiomyocytes upon contacting the bioengineered tissue with a test compound would be an indication that the test compound is cardiotoxic.
  • the bioengineered tissues of embodiments can be used in pharmacological assays for measuring the effect of a test compound on the stress state of a tissue.
  • the assays may involve determining the effect of a drug on tissue stress and structural remodeling of the bioengineered tissues.
  • the assays may involve determining the effect of a drug on cytoskeletal structure and, thus, the contractility of the bioengineered tissues.
  • the bioengineered tissues of embodiments can be used to measure the influence of biomaterials on a biomechanical response. For example, differential contraction of vascular smooth muscle remodeling due to variation in material properties (e.g., stiffness, surface topography, surface chemistry or geometric patterning) of bioengineered tissues can be studied.
  • material properties e.g., stiffness, surface topography, surface chemistry or geometric patterning
  • the bioengineered tissues of embodiments can be used to study functional differentiation of stem cells (e.g., pluripotent stem cells, multipotent stem cells, induced pluripotent stem cells, and progenitor cells of embryonic, fetal, neonatal, juvenile and adult origin) into contractile phenotypes.
  • stem cells e.g., pluripotent stem cells, multipotent stem cells, induced pluripotent stem cells, and progenitor cells of embryonic, fetal, neonatal, juvenile and adult origin
  • the polymeric fibers of the invention are treated with undifferentiated cells, e.g., stem cells, and differentiation into a contractile phenotype is observed by thin film bending.
  • Differentiation can be observed as a function of: co-culture (e.g., co-culture with differentiated cells), paracrine signaling, pharmacology, electrical stimulation, magnetic stimulation, thermal fluctuation, transfection with specific genes and biomechanical perturbation (e.g., cyclic and/or static strains)
  • the bioengineered tissues of the invention may be used to determine the toxicity of a test compound by evaluating, e.g., the effect of the compound on an electrophysiological response of a bioengineered tissue.
  • opening of calcium channels results in influx of calcium ions into the cell, which plays an important role in excitation-contraction coupling in cardiac and skeletal muscle fibers.
  • the reversal potential for calcium is positive, so calcium current is almost always inward, resulting in an action potential plateau in many excitable cells.
  • These channels are the target of therapeutic intervention, e.g., calcium channel blocker sub-type of anti -hypertensive drugs.
  • Candidate drugs may be tested in the electrophysiological characterization assays described herein to identify those compounds that may potentially cause adverse clinical effects, e.g., unacceptable changes in cardiac excitation, that may lead to arrhythmia.
  • unacceptable changes in cardiac excitation that may lead to arrhythmia include, e.g., blockage of ion channel requisite for normal action potential conduction, e.g., a drug that blocks Na + channel would block the action potential and no upstroke would be visible; a drug that blocks Ca 2+ channels would prolong repolarization and increase the refractory period; blockage of K + channels would block rapid repolarization, and, thus, would be dominated by slower Ca 2+ channel mediated repolarization.
  • metabolic changes may be assessed to determine whether a test compound is toxic by determining, e.g., whether contacting a bioengineered tissue with a test compound results in a decrease in metabolic activity and/or cell death.
  • detection of metabolic changes may be measured using a variety of detectable label systems such as fluormetric/chrmogenic detection or detection of bioluminescence using, e.g., AlamarBlue fluorescent/chromogenic determination of REDOX activity (Invitrogen), REDOX indicator changes from oxidized (non-fluorescent, blue) state to reduced state(fluorescent, red) in metabolically active cells; Vybrant MTT chromogenic determination of metabolic activity (Invitrogen), water soluble MTT reduced to insoluble formazan in metabolically active cells; and Cyquant NF fluorescent measurement of cellular DNA content (Invitrogen), fluorescent DNA dye enters cell with assistance from permeation agent and binds nuclear chromatin.
  • the following exemplary reagents are used: Cell-Titer Gio luciferase-based ATP measurement (Promega), a thermally stable firefly luciferase glows in the presence of soluble ATP released from metabolically active cells.
  • the bioengineered tissues of the invention are also useful for evaluating the effects of particular delivery vehicles for therapeutic agents e.g., to compare the effects of the same agent administered via different delivery systems, or simply to assess whether a delivery vehicle itself (e.g., a viral vector or a liposome) is capable of affecting the biological activity of the bioengineered tissue.
  • delivery vehicles may be of any form, from conventional pharmaceutical formulations, to gene delivery vehicles.
  • the devices of the invention may be used to compare the therapeutic effect of the same agent administered by two or more different delivery systems (e.g., a depot formulation and a controlled release formulation).
  • the bioengineered tissues of the invention may also be used to investigate whether a particular vehicle may have effects of itself on the tissue.
  • the bioengineered tissues of embodiments may be used to investigate the properties of delivery systems for nucleic acid therapeutics, such as naked DNA or RNA, viral vectors (e.g., retroviral or adenoviral vectors), liposomes and the like.
  • nucleic acid therapeutics such as naked DNA or RNA, viral vectors (e.g., retroviral or adenoviral vectors), liposomes and the like.
  • the test compound may be a delivery vehicle of any appropriate type with or without any associated therapeutic agent.
  • a bioengineered tissue of the invention may be bathed in a medium containing a candidate compound, and then the cells are washed, prior to measuring a tissue activity (e.g., a biomechanical and/or electrophysiological activity) as described herein.
  • a tissue activity e.g., a biomechanical and/or electrophysiological activity
  • Any alteration to an activity determined using the bioengineered tissue in the presence of the test agent is an indication that the test compound may be useful for treating or preventing a tissue disease, e.g., a neuromuscular disease.

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  • Engineering & Computer Science (AREA)
  • Mechanical Engineering (AREA)
  • Textile Engineering (AREA)
  • Nonwoven Fabrics (AREA)
  • Spinning Methods And Devices For Manufacturing Artificial Fibers (AREA)
  • Artificial Filaments (AREA)

Abstract

L'invention concerne des systèmes et des procédés de production et de collecte d'une ou de plusieurs fibres polymères de dimension micrométrique ou nanométrique ainsi que des matériaux à base de telles fibres. Certains modes de réalisation utilisent une couche de bain liquide alignée sensiblement verticale produite par un élément de collecte rotatif pour la formation et la collecte des fibres.
PCT/US2024/047995 2023-09-22 2024-09-23 Systèmes, procédés et contenants pour la formation et la collecte de fibres polymères de dimension micrométrique et nanométrique Pending WO2025065004A2 (fr)

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US3353378A (en) * 1965-09-14 1967-11-21 Leo M Kahn Apparatus for cleaning clothes and treating wash liquid
WO2010132636A1 (fr) * 2009-05-13 2010-11-18 President And Fellows Of Harvard College Procédés et dispositifs pour la fabrication de fibres polymères en 3d
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