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WO2025073993A1 - Implant en couches et système pour réparer une perforation dans une membrane tympanique - Google Patents

Implant en couches et système pour réparer une perforation dans une membrane tympanique Download PDF

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Publication number
WO2025073993A1
WO2025073993A1 PCT/EP2024/078121 EP2024078121W WO2025073993A1 WO 2025073993 A1 WO2025073993 A1 WO 2025073993A1 EP 2024078121 W EP2024078121 W EP 2024078121W WO 2025073993 A1 WO2025073993 A1 WO 2025073993A1
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WO
WIPO (PCT)
Prior art keywords
thin film
film layer
implant
porous body
layered implant
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/EP2024/078121
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English (en)
Inventor
Fergal O'brien
John Gleeson
Eamon SHEEHY
Cian O'CONNOR
Cian O'LEARY
Andrew Cameron
Ronaldo DO AMARAL
Elizabeth SAINSBURY
Alec BLANEY
Irina PASCU
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Royal College of Surgeons in Ireland
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Royal College of Surgeons in Ireland
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Filing date
Publication date
Application filed by Royal College of Surgeons in Ireland filed Critical Royal College of Surgeons in Ireland
Publication of WO2025073993A1 publication Critical patent/WO2025073993A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
    • A61L27/222—Gelatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/20—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
    • A61L27/24—Collagen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/26—Mixtures of macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/56—Porous materials, e.g. foams or sponges
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/58—Materials at least partially resorbable by the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/14—Materials or treatment for tissue regeneration for ear reconstruction or ear implants, e.g. implantable hearing aids

Definitions

  • the tympanic membrane also known as the eardrum, is a thin tissue responsible for transmitting sound vibrations from the outer parts of the ear to the inner parts of the ear, which will eventually stimulate sensory nerve cells enabling us to hear.
  • Ruptures in the eardrum can eventually result in hearing loss.
  • those ruptures heal by themselves without the need of specific treatment.
  • a surgery known as tympanoplasty is the only treatment option.
  • the thin film layer generally comprises collagen and is generally formed by dehydration so that it is substantially non-porous.
  • the porous body generally comprises collagen and is generally formed by freeze-drying such that it is highly porous and resiliently compressible, providing the spring-back functionality required to allow the implant to be compressed for delivery through a perforation and then self-expand to a deployed configuration where it anchors the implant with the thin film adjacent to the tympanic membrane.
  • the thin film layer is of low porosity.
  • the thin film layer is dehydrated. In any embodiment, the thin film layer is mounted on and integrated with the porous body.
  • the layered implant is resorbable in-vivo.
  • the porous body is resiliently compressible.
  • the biopolymer of the porous body and dehydrated thin film layer are each, independently, selected from collagen, hyaluronic acid, and gelatin.
  • the biopolymer of the freeze-dried matrix of the porous body and dehydrated thin film layer comprises collagen.
  • the biopolymer of the freeze-dried matrix of the porous body comprises collagen, elastin, hyaluronic acid and a gelling agent.
  • the biopolymer of the dehydrated thin film layer comprises collagen, elastin and hyaluronic acid.
  • the dehydrated thin film layer comprises or is coated with one or more extracellular matrix proteins.
  • extracellular matrix proteins examples include collagen Type IV, Elastin and vitronectin.
  • the porous body comprises a distal end, a proximal and, and a sidewall, and in which the dehydrated thin film layer is mounted on and integrated with the proximal end of the porous body.
  • the porous body may be cylindrical and may taper inwardly towards a distal end or a proximal end.
  • the cylinder may have a cross-sectional profile that is round, oval, rectangular, square, hexagonal,
  • the layered implant has a height of 4-8mm and a width of 4- 10mm.
  • the dehydrated thin film layer has a thickness of less than 1000, 500, 400, 300, 200, 100, 75 or 50 microns.
  • the dehydrated thin film layer is a laminate having a plurality of thin film layers.
  • the laminate comprises biopolymer fibres disposed between at least two thin film layers of the laminate.
  • the biopolymer fibres are collagen fibres.
  • the porous body is cylindrical.
  • the cylindrical porous body may taper towards a distal or proximal end, or may have a waisted section.
  • porous body has a cross-sectional profile that is round or oval.
  • the thin film layer is attached to a proximal end of the porous body and comprises a flange portion that extends radially outwardly of the proximal end of the porous body.
  • a diameter of the thin film may be 5 to 100% greater than a diameter of the proximal end of the porous body.
  • the flange portion of the thin film is annular.
  • the porous body comprises at least 40% or 50% gelling agent (e.g., gelatin) (w/w).
  • gelling agent e.g., gelatin
  • the porous body comprises 1 to 5% hyaluronic acid (w/w).
  • the porous body comprises 20-40% collagen, 50-80% gelling agent (e.g., gelatin) and 1 -5% hyaluronic acid (w/w).
  • gelling agent e.g., gelatin
  • hyaluronic acid w/w
  • the porous body comprises about 27-37% collagen, about 60- 70% gelling agent (e.g., gelatin) and about 1 -5% hyaluronic acid (w/w).
  • gelling agent e.g., gelatin
  • hyaluronic acid w/w
  • the dehydrated thin film layer comprises 1 to 20%, 5 to 15%, or about 10% hyaluronic acid (w/w).
  • the dehydrated thin film layer comprises about 90-95% collagen and 5-10% hyaluronic acid (w/w).
  • the thin non-porous regenerative film layer comprises a laminate of at least two thin film layers.
  • the implant has a width of 2 to 20 mm.
  • the implant comprises three or more layers.
  • the implant is not crosslinked or cured.
  • the collagen employed in the present invention is bovine or porcine collagen.
  • the collagen employed in the present invention is microfibrillar collagen, preferably microfibrillar bovine tendon collagen.
  • the disclosure also provides a layered implant according to the invention, in a rehydrated form.
  • the disclosure also provides a method of forming a layered implant (for example, a layered implant according to the disclosure), the method comprising the steps of: dehydrating a first slurry comprising a biopolymer to provide a dehydrated thin film layer; re-hydrating the dehydrated thin film layer; pouring a second slurry comprising a biopolymer on top of the re-hydrated regenerative film layer; and freeze-drying the re-hydrated regenerative film layer and second slurry together to form the layered implant.
  • the rehydrated thin film layer is frozen prior to the freeze-drying step.
  • the thin film layer is laminated prior to the step of pouring the second slurry.
  • the thin film layer is laminated prior to or after re-hydration (or after re-hydration and freezing) of the thin film layer.
  • the thin film layer is laminated in a method comprising the steps of: optionally, rehydrating the dehydrated thin film layer; preparing a third slurry comprising a biopolymer; pouring the third slurry on top of the dehydrated or rehydrated thin film layer; and dehydrating the third slurry and the dehydrated or rehydrated thin film layer to form the laminated dehydrated thin film layer.
  • the biopolymer is selected from collagen, elastin, hyaluronic acid and gelatin.
  • biopolymer fibres are embedded between the layers of the laminated dehydrated thin film layer.
  • the fibres may be collagen fibres.
  • the fibres may be placed on the dehydrated or rehydrated thin film layer prior to the step of pouring the third slurry.
  • the fibres may be directionally aligned.
  • the lamination step may be repeated one or more times.
  • the first biopolymer comprises collagen and hyaluronic acid.
  • the first slurry comprises 0.1% to 1 .0% of biopolymer (e.g., collagen) (w/v).
  • biopolymer e.g., collagen
  • the first slurry comprises 0.01% to 0.1 % hyaluronic acid (w/v).
  • the first slurry comprises 0.03% to 0.07%, 0.04% to 0.05%, or about 0.044% hyaluronic acid (w/v).
  • the second slurry comprises hyaluronic acid. In any embodiment, the second slurry comprises collagen, hyaluronic acid and optionally a gelling agent.
  • the gelling agent is gelatin.
  • the first slurry and/or second slurry comprises a collagen to hyaluronic acid weight ratio of 5:1 to 20:1 or 8:1 to 13:1 or about 11 :1.
  • the second slurry comprises collagen to gelatin weight ratio of 1 :1 to 1 :3 or about 1 :2 (w/w).
  • the second slurry comprises a gelatin to hyaluronic acid weight ratio of 20:1 to 25:1 or about 23:1 (w/w).
  • the second slurry comprises 0.3% to 0.7%, 0.4% to 0.6%, or about 0.5% collagen (w/v).
  • the second slurry comprises 0.01% to 0.1% hyaluronic acid (w/v).
  • the second slurry comprises 0.03% to 0.07%, 0.04% to 0.05%, or about 0.044% hyaluronic acid (w/v).
  • the second slurry comprises:
  • the third slurry comprises a collagen, elastin, hyaluronic acid, and a gelling agent.
  • the method comprises: placing the rehydrated (non-porous) film layer in a base of a mould; pouring the second slurry on top of the re-hydrated (non-porous) film layer; and freeze-drying the re-hydrated (non-porous) film layer and second slurry together to form the implant.
  • the mould comprises a porous body shaped recess.
  • the method comprises: placing the rehydrated thin film layer on the top surface of the base part; placing the second part of the mould on top of the base part such that the rehydrated thin film layer is sandwiched between the top part and bottom part of the base and the at least one porous body shaped through-hole is disposed over a part of the rehydrated thin film layer; pouring the second slurry into the at least one porous body shaped through- hole. and freeze-drying the re-hydrated thin film layer and second slurry together to form the layered implant comprising the dehydrated thin film layer adhered to the porous body.
  • the method comprises removing the implant from the mould, and cutting excess dehydrated thin film layer away.
  • the cutting step comprises cutting excess dehydrated thin film layer away to leave a flange of dehydrated thin film layer around a base of the porous structural support scaffold.
  • the disclosure also provides a mould to form a layered implant of the invention comprising a base part having a top surface and a top part configured to abut the base part and comprising at least one porous body shaped through-hole.
  • the porous body shaped through-holes have a depth of 4-6 mm and a width of 4-8 mm.
  • the porous body shaped through-holes are inwardly tapered towards a base of the top plate.
  • the top part of the mould is configured to be secured to the bottom part of the mould.
  • the disclosure also provides a system to repair a perforation in a body membrane, for example a tympanic membrane, comprising: a layered implant according to the disclosure; and a delivery device for the layered implant configured to hold the layered implant and deliver the layered implant in a radially compressed form into a perforation in a tympanic membrane via the ear canal.
  • the delivery device comprises: a handle; an elongated tube having a proximal end coupled to the handle and a distal end comprising a lumen; an ejection element disposed within the elongated tube and configured for axial movement along the elongated tube to eject the layered implant distally from the distal end of the lumen in a resiliently deformed (e.g., radially compressed) form; and optionally, an optic fibre camera to remotely view the distal end of the elongated tube.
  • a handle an elongated tube having a proximal end coupled to the handle and a distal end comprising a lumen
  • an ejection element disposed within the elongated tube and configured for axial movement along the elongated tube to eject the layered implant distally from the distal end of the lumen in a resiliently deformed (e.g., radially compressed) form
  • an optic fibre camera to remotely view the distal end of the elongated tube.
  • all or part of the lumen is inwardly tapered towards a distal end thereof.
  • the elongated stem is angled intermediate its ends at an angle 0 of 20° to 40° to a longitudinal axis of the elongated stem.
  • elongated stem comprises a proximal stem part detachably attachable to a distal stem part, wherein the distal stem part comprises a funnel shaped section, distal tip with distal opening, and a proximal opening dimensioned to receive the implant in an uncompressed configuration.
  • the method comprises a step of cutting around all or part of a periphery of the perforation in the membrane.
  • the delivery device for the layered implant comprises a cutting blade configured to cut around all or part of a periphery of the perforation in the membrane.
  • the cartridge comprises the cutting blade.
  • the cutting blade is a curved blade.
  • the eustachian canal plug comprises gelatin. In any embodiment, the eustachian canal plug has a conical or frustoconical shape.
  • the disclosure also provides a method comprising: providing a layered implant according to the disclosure; providing a cartridge for the layered implant comprising a cylindrical body with open ends, a sidewall and an internal lumen; inserting the layered implant into the internal lumen of the cylindrical body; coupling the cartridge to a delivery device for the layered implant.
  • the method comprises the steps of immersing the cartridge containing the layered implant into an implant rehydration fluid for a suitable period of time to rehydrate the layered implant prior to coupling the cartridge to the delivery device.
  • the layered implant in a relaxed un-compressed configuration is too large to fit within the internal lumen of the cylindrical body without being resiliently deformed, wherein the method comprises resiliently deforming the layered insert and inserting the layered insert into the hollow cylindrical body in a resiliently deformed form.
  • the internal lumen of the hollow cylindrical body is dimensioned to receive the layered implant in an un-compressed relaxed configuration, wherein the internal lumen is inwardly tapered towards a distal end of the device such that when the layered implant is advanced distally along the internal lumen it is resiliently deformed.
  • the delivery device is configured to resiliently compress the implant during ejection of the implant.
  • the distal end of the delivery device may comprise a funnel configured to radially compress the implant during ejection.
  • the delivery device comprises an elongated stem and a cartridge having a lumen to receive the layered implant and configured for detachable coupling to a distal end of the elongated stem
  • the method comprises inserting a layered implant into the lumen of the cartridge, optionally immersing the cartridge containing the layered implant into a rehydration liquid, and then coupling the cartridge containing the optionally-hydrated layered implant to the distal end of the elongated stem.
  • the method comprises viewing using an imaging module the delivery of the layered implant, the imaging module may be an optic fibre camera forming part of the delivery device.
  • the method comprises delivering a resiliently deformable eustachian canal plug into the eustachian canal to temporarily block the eustachian canal.
  • the method comprises a step of cutting around all or part of a periphery of the perforation in the membrane.
  • the cartridge comprises a cutting blade.
  • Hyaluronic acid has a number of benefits in this application, (i) improved mechanical stability and integrity of the membrane i.e., marginal stiffness augmentation but good control of biodegradation timing which is important for healing. Also serves as a better anchor during the crosslinking stiffening process i.e. works better than just collagen on its own, (ii) it can help with the small amount of fluid absorption at the wound site to encourage infiltration of local healing cells and (iii) it actively encourage cell infiltration to the centre of the scaffolds and membranes, a critical thing to help discouraging avascular necrosis of the healed tissue, i.e. improves patency of healing tissue and stops early unwanted cell death.
  • the porous body may comprise a gelling agent such as gelatin.
  • a gelling agent such as gelatin.
  • An important function of the porous body is to be as elastic as possible i.e., allow it to be compressed to a high degree but then that it can expand rapidly and firmly back to its original shape, to act as an anchor for the implant.
  • the gelling agent gives a much better and firmer springback.
  • FIG. 1 A illustrates a thin regenerative film layer forming part of the implant of the invention.
  • FIG.1C illustrates a bilayered implant according to the invention.
  • FIG. 4A to 4C illustrate the use of one embodiment of a system of the invention to treat a perforation in a tympanic membrane of the human ear showing a hydrated implant according to Figure 3 in an elongated tube of a delivery device in a radially inwardly compressed form (FIG. 4A), a plunger pushing the implant distally out of the distal end of the elongated tube and through the perforation in the tympanic membrane where a distal end of the implant expands after it has passed through the tympanic membrane (FIG. 4B), and the implant fully released with the expended distal end of the implant anchoring the implant in the perforation and the regenerative film at this distal end flush with tympanic membrane around the perforation. (FIG. 4C).
  • FIG. 5A to 5C illustrate the use of another embodiment of a system of the invention to treat a perforation in a tympanic membrane of the human ear showing a hydrated implant in an elongated tube of a delivery device (FIG. 3A), a plunger pushing the implant distally toward a distal tip of the elongated tube with consequent radial compression of the implant in the inwardly tapering funnel section of the tube (FIG. 3B), and the hydrated implant after being ejected from the tip of the tube through the perforation where the implant springs-back to a deployed radially expanded configuration where the regenerative thin film layer abuts and spans the perforation causing the membrane to self-regenerate (FIG. 3C).
  • FIG. 7 illustrates a system comprising a delivery device according to one embodiment of the invention in use delivering an implant through a perforation in the tympanic membrane.
  • FIG. 8 illustrates a system comprising a delivery device according to one embodiment of the invention in use delivering an implant through a perforation in the tympanic membrane.
  • FIG. 9 illustrates a system comprising a delivery device according to one embodiment of the invention in use delivering an implant through a perforation in the tympanic membrane.
  • FIG. 10 illustrates a system comprising a delivery device according to one embodiment of the invention in use delivering an implant through a perforation in the tympanic membrane.
  • FIG. 11 illustrates a delivery device of the invention comprising a detachable cartridge having a lumen for holding a layered implant in a compressed form and a plurality of windows to allow hydration of the layered implant while it is inside the cartridge.
  • FIG. 12 illustrates a delivery device according to one embodiment of the invention having a plurality of different plungers.
  • FIG. 14 illustrates a number of plunger types.
  • FIG. 16 illustrates a delivery device with a detachable cartridge incorporating a funnel shaped section that functions as an implant hydration part.
  • an implant is inserted into a proximal end of the cartridge, which is then placed in a hydrating liquid, and once the implant is fully hydrated the cartridge is attached to a distal end of the elongated stem for delivery of the implant.
  • FIG. 17 and 18 are images of the delivery device of FIG. 16 with the detachable distal part detached from the elongated tune (FIG. 17) and attached to the elongated tube (FIG. 18).
  • FIG. 19 is an image of the detachable distal part of the delivery device of FIG. 16 containing an implant
  • FIG. 20 shows the detachable distal part immersed in a hydration solution
  • FIG. 21 shows the detachable distal part about to be attached to a distal end of the elongated tube.
  • FIG. 27 illustrates a method of forming a layered implant according to the invention comprising the steps of: pouring a first slurry into a first mould (FIG. 27A); dehydrated thin film layer (FIG. 27B); rehydrating (or freezing) the thin film layer (FIG. 27C); placing the rehydrated (or frozen) thin film layer in a base of a second mould (FIG.
  • FIG. 27D pouring a second slurry into the second mould
  • FIG. 27E freeze-drying the thin film and second slurry to form the layered implant
  • FIG. 27G the layered implant after removal from the second mould
  • FIG. 29 illustrates a first method of preparing a layered implant for delivery.
  • FIG. 30 illustrates a second method of preparing a layered implant for delivery.
  • the term “comprise,” or variations thereof such as “comprises” or “comprising,” are to be read to indicate the inclusion of any recited integer (e.g. a feature, element, characteristic, property, method/process step or limitation) or group of integers (e.g. features, element, characteristics, properties, method/process steps or limitations) but not the exclusion of any other integer or group of integers.
  • the term “comprising” is inclusive or open- ended and does not exclude additional, unrecited integers or method/process steps.
  • the term “disease” is used to define any abnormal condition that impairs physiological function and is associated with specific symptoms.
  • the term is used broadly to encompass any disorder, illness, abnormality, pathology, sickness, condition or syndrome in which physiological function is impaired irrespective of the nature of the aetiology (or indeed whether the aetiological basis for the disease is established). It therefore encompasses conditions arising from infection, trauma, injury, surgery, radiological ablation, age, poisoning or nutritional deficiencies.
  • treatment refers to an intervention (e.g., the administration of an agent to a subject) which cures, ameliorates or lessens the symptoms of a disease or removes (or lessens the impact of) its cause(s).
  • the term is used synonymously with the term “therapy”.
  • treatment refers to an intervention (e.g., the administration of an agent to a subject) which prevents or delays the onset or progression of a disease or reduces (or eradicates) its incidence within a treated population.
  • treatment is used synonymously with the term “prophylaxis”.
  • biopolymer refers to a polymer produced by the body or a derivative thereof, for example a collagen, a glycosaminoglycan such as hyaluronic acid, or a collagen by-product such as gelatin.
  • the film layer is usually formed by dehydration without sublimation, and then re-hydrated prior to placing in a mould.
  • a slurry is then poured into the mould on top of the film layer, and the contents of the mould is then freeze-dried which enables the film layer adhere to the porous matrix layer.
  • freeze-drying ice crystals do not form in the film layer as it is too thin (thus, no sublimation) and the resultant construct comprises a film layer that is dehydrated and substantially non-porous.
  • the rehydrated film layer is frozen before slurry is poured on top.
  • the thin-film layer is typically regenerative.
  • the term “regenerative” as applied to the film layer means that it comprises a material that is capable of supporting host cell migration and proliferation.
  • An example is a collagen, gelatin, or a mixture of collagen or gelatin, and hyaluronic acid.
  • Other materials suitable for use in the regenerative film layer include chondroitin sulfate and chitosan.
  • implant advancement module should be understood to mean a system for advancing the implant along the elongated tube of the delivery device. It is generally a plunger, but may also be provided by a hydraulic or pneumatic force generator configured to push the implant along the tube.
  • the implant is a bilayered implant comprising a regenerative thin-film layer 2 (FIG. 1 A) and a cylindrical porous body 3 (FIG. 1 B).
  • the implant FIG. 1 A
  • the regenerative thin-film layer 2 comprises collagen and hyaluronic acid and is formed from a collagen-hyaluronic acid aqueous slurry that is dehydrated in a mould as described below.
  • the cylindrical porous body 3 is formed from a slurry comprising collagen, hyaluronic acid and gelatin which is freeze-dried as described below, making the porous body spongy and resiliently compressible when rehydrated.
  • FIG. 3 illustrates another embodiment of an implant according to the invention in which parts described with reference to the previous embodiment are assigned the same reference numerals.
  • the implant indicated by the reference numeral 10
  • the cylindrical porous body 3 has a proximal end 13 having a greater diameter that the distal end 12, a distal frustoconical section 14 and a proximal cylindrical section 15.
  • Figures 5A to 5C illustrate the use of a second system of the invention to treat a perforation in a tympanic membrane of the human ear.
  • the system comprises the implant 1 of Figures 1 and 2 (e.g., without the flange section) and a delivery device 30.
  • the delivery device comprises an elongated tube 31 with a distal funnel shaped section 32 having a distal end with a distal aperture 34.
  • Figure 5A shows the distal end 7 approaching a tympanic membrane 23 of a human ear having a perforation 24.
  • An implant 1 (which has been hydrated
  • FIG. 5B shows the delivery device advanced towards the tympanic membrane and a plunger 25 pushing the implant distally toward a distal tip of the elongated tube with consequent radial compression of the implant in the inwardly tapering funnel section 32.
  • FIG. 5C shows the implant 1 after being ejected from the tip of the tube through the perforation where the implant springs- back to a deployed radially expanded configuration where the regenerative thin film layer 2 abuts and spans the perforation 24 causing the membrane to selfregenerate by the formation of new tissue (not shown).
  • FIG. 6 illustrates the anatomy of a human ear showing the external auditory canal 37 separated from the internal auditory canal 38 by a tympanic membrane 23 with a perforation 24, and an otoscope 39 positioned to view the tympanic membrane.
  • FIG. 8 illustrates a system comprising a delivery device according to another embodiment of the invention in use delivering an implant through a perforation in the tympanic membrane, in which parts described with reference to the previous embodiment are assigned the same reference numerals.
  • the elongated tube 31 is a rigid plastic tubing with a distal part with a narrow internal diameter (2mm) and a funnel shaped proximal part 32, a handle part 40 with an external sliding button 41 , and a plunger 25 with a proximal end 42 coupled to the sliding button 41 for axial movement therewith.
  • a user can hold the handle in their hand and actuate the movement of the plunger axially along the lumen of the tube 31 with their thumb.
  • FIG. 9 illustrates a system comprising a delivery device according to another embodiment of the invention in use delivering an implant through a perforation in the tympanic membrane, in which parts described with reference to the previous embodiment are assigned the same reference numerals.
  • the elongated tube 31 is a rigid plastic tubing with a distal part 50 with a narrow internal diameter (2mm), a proximal part 51 cranked an at angle 0 of about 70° to the distal part, and a funnel shaped proximal end 52.
  • the plunger 25 is made from flexible tubing.
  • FIG. 10 is similar to the embodiment of FIG. 9 with the exception of the elongated tube 31 being a flexible tube and having a steel mandrel 45 dimensioned to be inserted into and run the length pf the elongated tube.
  • the steel mandrel can be shaped into a desired configuration that suits the anatomy of the patient’s ear, and then inserted into the elongated tube which will then adapt the elongated shape of the mandrel.
  • FIG. 11 illustrates a system comprising a delivery device according to another embodiment of the invention, in which parts described with reference to the previous embodiment are assigned the same reference numerals.
  • the delivery device 60 comprises an elongated tube 61 with a distal end 62 and an implant receiving cartridge 63 coupled to the distal end 62 of the elongated tube 61 .
  • the cartridge 63 has a hollow cylindrical body with a proximal opening 64, a distal opening 65, and a sidewall 66 comprising a plurality of windows 67.
  • An implant 1 is shown loaded into the cartridge 63.
  • the implant 1 Before the cartridge is coupled to the elongated tube 61 of the delivery device, the implant 1 is radially compressed and inserted one end of the cartridge where it is held within the cartridge in a radially compressed form. The cartridge containing the implant may then be immersed in a hydration liquid where the windows 67 facilitate access of the hydration liquid to the implant. Once the implant has been hydrated, the cartridge is coupled to the distal end of the elongated tube.
  • FIG. 12 illustrates a system comprising a delivery device according to another embodiment of the invention in which parts described with reference to the previous embodiment are assigned the same reference numerals.
  • the elongated tube 71 has a distal part 72 and a funnel shaped proximal part 73 configured to couple together.
  • a plurality of plungers 25 having different diameters are provided to assist advancing the implant through the inwardly tapering funnel shaped proximal part 73.
  • FIG. 13 illustrates different designs of plungers, one with a convex end (FIG. 13A) and one with base and sidewalls (FIG. 13B).
  • FIG. 14 illustrates more designs of plungers of different length and bore size, and including different design of plunger heads including a spherical head, a flat head, and a convex head.
  • FIG. 15A illustrates a shuttle 80 comprising a split tube 81 with an internal lumen 82 dimensioned to receive an implant 1 in a non-radially compressed configuration and configured for radial contraction as it is advanced distally along a funnel shaped section of the delivery device.
  • FIG. 15B illustrates an elongated tube 84 of a delivery device with the shuttle 80 containing an implant 1 inserted into a proximal end of the tube. As the shuttle is advanced along the funnel shaped tube, it compressed radially compressing the implant contained in the shuttle. A distal end of the tube 84 defines a radially inward step which in practice acts as a stop for the shuttle allowing the radially compressed implant 1 to be advanced out of the distal end of the tube.
  • FIG. 19 shows the detachable distal tube part being attached to a distal end of the proximal tube part
  • FIG. 20 shows the plunger advancing the hydrated implant distally along the funnel shaped section of the detachable distal tube part
  • FIG. 21 shows the implant deployed proud of the distal tip of the detachable distal tube part where it has expanded radially to a deployed configuration.
  • FIG. 22 shows the distal tube part containing an implant and detached from the proximal tube part.
  • FIG. 23 shows the distal tube part containing the implant immersed in a hydration liquid.
  • FIG. 24 shows the distal part of the elongated tube being attached to the proximal end of the elongated tube after the implant has been hydrated.
  • a layered implant (not shown) is loaded into a proximal end of the cartridge 96 in an un-compressed form and the cartridge housing the implant is immersed in a hydration liquid to hydrate the implant.
  • the delivery device is than assembled by coupling the first and second elongated tubes together and then coupling the proximal end of the cartridge to the distal end of the second elongated tube.
  • the second elongated tube may then be inserted into the ear canal of a patient under guidance and advanced until the distal end of the cartridge is disposed adjacent a perforation in the patient’s tympanic membrane.
  • the button 100 on the handle is then pressed to actuate the plunger and advance the implant along the funnel- shaped section of the cartridge to eject the implant in a radially compressed form into the perforation.
  • the implant Once released from the cartridge, the implant self-expends to anchor the implant in the perforation with the thin film layer disposed almost flush with the periphery of the tympanic membrane.
  • FIG. 27 illustrates a method of forming a layered implant according to the invention comprising the steps of pouring a first slurry 110 into a first mould 1 11 to a depth of about 0.5mm (FIG. 27A), dehydrated the first slurry in the mould to form a dehydrated thin film layer 2 (FIG. 27B), placing the thin film layer 2 into a rehydration bath 112 containing a hydration liquid 113 to rehydrate the thin film layer (FIG. 27C). Once fully re-hydrated, the thin film layer 2 is placed onto a base 115 of a second mould 116 (FIG. 27D), a second slurry 117 is poured into the second mould 116 (FIG. 27E), before the mould is placed on a shelf of a freeze- dryer 118 to freeze-dry the thin film and second slurry (FIG. 27F), before the layered implant 10 is removed from the second mould (FIG. 27G).
  • FIG. 28 illustrates another method and apparatus for forming a layered implant according to the invention that employs a mould apparatus have a bottom plate 120 having a top surface 121 and a top plate 122 configured to be coupled together with the bottom plate in a face-to-face relationship.
  • the top plate 122 comprises a plurality of porous body shaped through-holes 123.
  • FIG. 28A shows a dehydrated thin film layer 2 after dehydration.
  • FIG. 28B shows the thin film 2 placed on the top surface 121 of the bottom plate 120.
  • FIG. 28C shows the top plate 122 having forty- nine porous body forming through-holes 124.
  • FIG. 28D shows the top plate 122 placed on top of the bottom plate 120 sandwiching the dehydrated thin film 2 between the plates.
  • FIG. 28F shows a sheet of layered implants 128 after removal from the mould and
  • FIG. 28G shows a single layered implant 129 cut out of the sheet of layered implants 128.
  • FIG. 29 illustrates a method of preparing a layered implant for delivery to a target locus in the body.
  • the implant 1 is radially compressed by applying a force in the direction of the arrows marked A as illustrated in FIG. 29A from a diameter of about 8mm to a diameter of about 4mm (FIG. 29B).
  • the implant is then inserted into a cartridge 130 in a radially compressed form (FIG. 29C), and the cartridge 130 is then immersed into a hydration fluid 131 in a hydration bath 132 (FIG. 29D). In one embodiment, this hydration step is not required.
  • the cartridge 130 is then attached to a distal end of an elongated tube 133 of a delivery device (FIGS. 29E and 29F).
  • FIG. 30 illustrates a further method of preparing a layered implant for delivery to a target locus in the body.
  • the cartridge 140 has a lumen comprising a proximal lumen section 141 that is dimensioned to receive the implant 10 in an uncompressed form and a distal funnel-shaped lumen section 142 configured to radially compress the implant as it is advanced through the distal funnel-shaped lumen section 142.
  • the implant 10 (FIG. 30A) is inserted into the proximal lumen section 141 of the cartridge 140 (FIG. 30B).
  • Films can be stores at room temperature in an aluminum foil pocket

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Transplantation (AREA)
  • Medicinal Chemistry (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Dermatology (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Dispersion Chemistry (AREA)
  • Biophysics (AREA)
  • Prostheses (AREA)

Abstract

La présente invention porte sur un implant en couches pour réparer une perforation dans une membrane tympanique qui comprend une couche de film mince déshydratée comprenant un biopolymère, et un corps poreux comprenant une matrice lyophilisée comprenant un biopolymère. La couche de film mince déshydratée est montée sur le corps poreux et intégrée au corps poreux, et le corps poreux est résorbable in vivo et élastiquement compressible. La couche de film mince fonctionne comme un échafaudage régénératif pour la membrane tympanique, et le corps poreux permet à l'implant d'être comprimé de manière élastique dans un dispositif de distribution pour permettre son administration dans une perforation dans une membrane tympanique, et une fois délivré, le retour élastique à sa forme d'origine où il ancre l'implant et positionne la couche de film mince adjacente à la perforation permettant à la couche de film mince de supporter la régénération de la membrane de film mince pour fermer la perforation. L'invention concerne également un dispositif d'administration pour l'implant.
PCT/EP2024/078121 2023-10-05 2024-10-07 Implant en couches et système pour réparer une perforation dans une membrane tympanique Pending WO2025073993A1 (fr)

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EP23201992.7 2023-10-05
EP23201992 2023-10-05

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110110987A1 (en) * 2008-06-26 2011-05-12 shin-ichi Kanemaru Agent for regenerating tympanic membrane or external auditory canal
US20140303727A1 (en) * 2011-07-11 2014-10-09 Ear Science Institute Australia Device for ear drum repair
US20160199537A1 (en) * 2014-08-28 2016-07-14 Mimedx Group, Inc. Collagen reinforced tissue grafts
WO2023113584A1 (fr) * 2021-12-14 2023-06-22 Top Health, S.A.P.I. De C.V. Membrane tympanique au collagène humain pour la réparation de lésions du tympan

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110110987A1 (en) * 2008-06-26 2011-05-12 shin-ichi Kanemaru Agent for regenerating tympanic membrane or external auditory canal
US20140303727A1 (en) * 2011-07-11 2014-10-09 Ear Science Institute Australia Device for ear drum repair
US20160199537A1 (en) * 2014-08-28 2016-07-14 Mimedx Group, Inc. Collagen reinforced tissue grafts
WO2023113584A1 (fr) * 2021-12-14 2023-06-22 Top Health, S.A.P.I. De C.V. Membrane tympanique au collagène humain pour la réparation de lésions du tympan

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