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WO2024229363A1 - Produits médicaux revêtus, et leurs méthodes de préparation et d'utilisation - Google Patents

Produits médicaux revêtus, et leurs méthodes de préparation et d'utilisation Download PDF

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Publication number
WO2024229363A1
WO2024229363A1 PCT/US2024/027693 US2024027693W WO2024229363A1 WO 2024229363 A1 WO2024229363 A1 WO 2024229363A1 US 2024027693 W US2024027693 W US 2024027693W WO 2024229363 A1 WO2024229363 A1 WO 2024229363A1
Authority
WO
WIPO (PCT)
Prior art keywords
coating
product
polymeric substance
porous sheet
substrate
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/US2024/027693
Other languages
English (en)
Inventor
Hunter LAVOINE
Brayden SMITH
Jessica BENDELL
Alycia G. BERMAN
Joshua BRODY
Sydney E. HOLLINGSHEAD
Brooke L. MARTINDALE
Tyler A. NOVAK
Alex DE POIX
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Cook Biotech Inc
Original Assignee
Cook Biotech Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cook Biotech Inc filed Critical Cook Biotech Inc
Publication of WO2024229363A1 publication Critical patent/WO2024229363A1/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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/146—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
    • A61L27/28—Materials for coating prostheses
    • A61L27/34—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/3604—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the human or animal origin of the biological material, e.g. hair, fascia, fish scales, silk, shellac, pericardium, pleura, renal tissue, amniotic membrane, parenchymal tissue, fetal tissue, muscle tissue, fat tissue, enamel
    • A61L27/3633—Extracellular matrix [ECM]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/52—Hydrogels or hydrocolloids
    • 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/005—Ingredients of undetermined constitution or reaction products thereof
    • 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A61L31/10—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/145—Hydrogels or hydrocolloids

Definitions

  • aspects of the present disclosure relate to medical devices incorporating a porous sheet substrate such as an extracellular matrix material that carries a coating material including one or more polymeric substances, and to methods for their preparation and use.
  • a variety of medical products include a porous substrate that is coated with one or more polymeric substances.
  • the coating may provide adhesive properties, anti-tissue-adhesion properties, lubriciousness, and/or bioactivity to the product, among other things. Both the substances used in the coating and the techniques to by which those substances are combined with a substrate can impact the final form of the coating and of the coated product as a whole, as well as performance properties thereof.
  • the present disclosure relates to coated medical products that include a porous sheet substrate and a polymeric coating material, where the substrate and coating material are combined to provide unique product configurations that can be beneficial in use of the coated medical products.
  • the coating material is distributed over and within the porous sheet substrate to provide a stratified structure having compositionally distinct domains through a thickness of the coated medical product from a first face to a second face opposite the first face.
  • coated medicai products that include a porous sheet substrate having a first side surface, a second side surface opposite the first side surface and a thickness between the first side surface and the second side surface.
  • the products include a first coating including one or more polymeric substances at the first side surface and penetrating only partially through the thickness of the porous sheet substrate, and a second coating including the one or more polymeric substances and penetrating only partially through the thickness of the porous sheet substrate.
  • coated medical products including a porous sheet substrate having a first side surface, a second side surface opposite the first side surface, and a thickness extending from the first side surface to the second side surface.
  • the products include a first coating including one or more polymeric substances on the first side surface and a second coating including one or more polymeric substances on the second side surface.
  • the first coating and the second coating can have been separately applied and/or can be distinct from one another.
  • the coated medical products can be in a flat condition absent externally applied force.
  • the polymeric substance(s) of the first coating include at least one hydrogel-forming polymeric substance and/or the polymeric substance(s) of the second coating include at least one hydrogel-forming polymeric substance.
  • coated medical products that include a porous sheet substrate having a first side surface, a second side surface opposite the first side surface, and a thickness extending from the first side surface to the second side surface.
  • the products include a first coating including one or more polymeric substances on the first side surface.
  • the products further include a second coating including one or more polymeric substances on the second side surface, wherein the second coating and the first coating are not segments of a single, uniform coating formed on the porous sheet substrate, for example where the second coating and the first coating are distinct and have been separately formed on the porous sheet substrate.
  • the coated medical products, absent externally applied force, are desirably in a flat condition.
  • coated medical products that include a porous sheet substrate having a first side surface, a second side surface opposite the first side surface, and a thickness extending from the first side surface to the second side surface.
  • the products also include a polymeric coating material carried by the porous sheet substrate, the coating material including one or more polymeric substances.
  • the coating material is configured to become lubricious on wetting with water and further: (i) penetrates only partially through the thickness of the substrate; and/or (ii) has a first coating surface that is contoured to the first side surface of the substrate; and/or (iii) has a first coating surface formed by self-coalescing of the polymeric substance(s) during drying of a liquid coating medium including the polymeric substance(s) while horizontal to gravity; and/or (I v) has at least 60% by dry weight, or optionally at least 70% by dry weight, of the polymeric substance(s) of the coating material occurring externa! of the substrate.
  • coated medical products including a porous sheet substrate including a plurality of layers of decelluiarized extracellular matrix material laminated together, the substrate having a first side surface, a second side surface, and a thickness occurring between the first side surface and the second side surface.
  • Polymeric coating material is carried by the porous sheet substrate.
  • the polymeric coating material includes a plurality of polymeric substances in admixture, and the plurality of polymeric substances Includes at least two hydrogel-forming polymeric substances.
  • the polymeric coating material includes an Internalized coating material portion positioned within the porous sheet substrate and an externalized coating material portion positioned external of the porous sheet substrate.
  • the externalized coating material portion includes at least 60% by dry weight of the plurality of polymeric substances of the polymeric coating material.
  • the present disclosure relates to methods for preparing coated medical products, where a substrate and a polymeric coating material are combined under controlled conditions to provide unique product configurations that can be beneficial in use of the coated medical products.
  • the controlled conditions provide unique distributions of the polymeric coating material relative to the substrate of the product, unique conformational features to the product, and/or unique surface properties to the product.
  • methods for preparing a coated extracellular matrix material that include first applying a first liquid coating medium containing one or more polymeric substances to a first side surface of a porous sheet substrate so that the liquid medium penetrates pores of the porous sheet substrate only partially through a thickness of the porous sheet substrate between the first side surface of the porous sheet substrate and a second side surface of the porous sheet substrate opposite the first side surface.
  • the methods also include first treating the first liquid coating medium to form a first coating including the one or more polymeric substances of the first liquid coating medium, the first coating providing amounts of the polymeric substance(s) of the first liquid coating medium at the first side surface and penetrating only partially through the thickness of the porous sheet substrate.
  • the methods include second treating the second liquid coating medium to form a second coating including the one or more polymeric substances of the second liquid coating medium, the second coating providing amounts of the polymeric substance(s) of the second liquid coating medium at the second side surface and penetrating only partially through the thickness of the porous sheet substrate.
  • the first treating and second treating preferably include drying the first liquid coating medium and the second liquid coating medium, respectively.
  • methods for preparing a coated medical product include first applying a first liquid coating medium containing one or more polymeric substances to a first side surface of a flat, dried porous sheet substrate, so as to form a layer of the first liquid coating medium.
  • the methods also include first drying the first liquid coating medium by exposure to a first drying atmosphere to form a first coating including the one or more polymeric substances of the first liquid coating medium, where the first drying is conducted while the porous sheet substrate is secured in a flat condition with a surface of the layer of the first liquid coating medium freely exposed to the drying atmosphere.
  • methods for preparing a coated medical product include first applying a first liquid coating medium containing one or more polymeric substances to a first side surface of a porous sheet substrate, where the first side surface to which the first liquid coating medium is applied is enclosed within a frame circumferentially surrounding the first side surface.
  • the methods also include first treating the first liquid coating medium to form a first coating including the one or more polymeric substances of the first liquid coating medium.
  • the first treating desirably includes drying.
  • the frame compresses the porous sheet substrate to create a compressed substrate periphery that can be less porous than the substrate region underlying the first side surface to which the first liquid coating medium is applied, and/or the first treating is conducted while the porous sheet substrate is secured in a flat condition by the frame, and/or the first treating includes first drying while a surface of a layer of the applied first liquid coating medium is freely exposed to a first drying atmosphere.
  • corresponding steps can be conducted in respect of a second side surface of the porous sheet substrate opposite the first side surface, to form a second coating including one or more polymeric substances of a second liquid coating medium.
  • methods for preparing a coated medical product include applying a volume of a first liquid coating medium containing one or more polymeric substances to a first side surface of a porous sheet substrate mechanically held in a flat, horizontal condition (for example by a frame), and allowing the volume of the first liquid coating medium to self-level to gravity.
  • the methods also include treating the volume of the first liquid coating medium to form a first coating including the one or more polymeric substances of the first liquid coating medium.
  • the treating desirably includes drying.
  • the applying is conducted by gravitational flow of the first liquid coating medium onto the first side surface of the porous sheet substrate and gravitationally-generated spreading and leveling of the first liquid coating medium, e.g.
  • the treating can include drying while a surface of a layer of the applied first liquid coating medium is freely exposed to a drying atmosphere and/or while the substrate is mechanically held in a flat, horizontal condition (for example by a frame) and/or while a substrate periphery that surrounds the first side surface to which the first liquid coating medium has been applied is compressed (for example by a frame).
  • corresponding steps can be conducted in respect of a second side surface of the porous sheet substrate opposite the first side surface, to form a second coating including one or more polymeric substances of a second liquid coating medium.
  • FIG. 1 provides an exploded view of one embodiment of a frame and porous sheet substrate combination useful for preparing a coated medical product.
  • FIG. 2 provides a top perspective view of the assembled frame and porous sheet substrate combination depicted in FIG. 1.
  • FIG. 3 provides a cross sectional view of the combination of FIG. 2.
  • FIG. 4 provides a cross-sectional view showing the layup construct shown in FIG. 3 after gravity-directed application, spreading and leveling of a first liquid coating medium on a first side surface of the porous sheet substrate.
  • FIG. 5 provides a cross-sectional view showing the layup construct shown in FIG. 4 after treating to form a first coating from the first liquid coating medium.
  • FIG. 6 provides a cross-sectional view showing the combination shown in FIG. 5 after inversion and then gravity-directed application, spreading and leveling of a second liquid coating medium on a second side surface of the porous sheet substrate opposite the first side surface.
  • FIG. 7 provides a cross-sectional view showing the layup construct shown in FIG. 6 after treating to form a second coating from the second liquid coating medium.
  • FIG. 8 provides a cross-sectional view of a coated medical product cut from the coated porous sheet substrate shown in FIG. 7 and including the first coating and the second coating.
  • FIG. 9 provides a cross-sectional view of one embodiment of a multilaminate porous sheet substrate for use in preparing a coated medical product in accordance with the present disclosure.
  • FIG. 10 provides a cross-sectional view showing the multilaminate porous sheet substrate of FIG. 9 after application of a volume of a first liquid coating medium to a first side surface thereof.
  • FIG. 11 provides a cross-sectional view of the multilarrnnate porous sheet substrate of FIG. 10 after treating to form a first coating.
  • FIG. 12 provides a cross-sectional view showing the construct of FIG. 11 after inversion and application of a volume of a second liquid coating medium to a second side surface thereof.
  • FIG. 13 provides a cross-sectional view showing the construct of FIG. 12 after treating to form a second coating.
  • FIG. 14 provides a cross-sectional view showing the multilaminate porous sheet substrate of FIG. 9 after application of a volume of a first liquid coating medium to a first side surface thereof and deep penetration of amounts of the first liquid coating medium into the substrate.
  • FIG. 15 provides a cross-sectional view of the multilaminate porous sheet substrate of FIG. 14 after treating to form a first coating.
  • FIG. 16 provides a cross-sectional view showing the construct of FIG. 15 after inversion and application of a volume of a second liquid coating medium to a second side surface thereof and deep penetration of amounts of the second liquid coating medium into the substrate to mix with substance(s) of the first liquid coating medium.
  • FIG. 17 provides a cross-sectional view showing the construct of FIG. 16 after treating to form another embodiment of a coated medical product of the present disclosure with a stratified compositional structure including an intermediate stratum containing a mixture of polymeric substances resultant of a first coating application and a second coating application.
  • FIG. 18 provides a cross-sectional view of one embodiment of a coated medical product conformed against a cylindrical shaping surface useful for post-coating- processing to impart a new shape memory to the coated medical product.
  • FIG. 19 provides a perspective view of the reshaped coated medical product shown in FIG. 18.
  • FIG. 20 provides a cross-sectional view of another embodiment of a coated medical product conformed against a cylindrical shaping surface useful for post-coatingprocessing to impart a new shape memory to the coated medical product.
  • FIG. 21 provides a perspective view of the reshaped coated medical product shown in FIG. 20.
  • FIG. 22 provides a schematic illustration of one embodiment of a medical product according to the present disclosure including a sterile barrier package in which is sterilely contained a coated medical product of the present disclosure.
  • coated medical products include a porous sheet substrate and polymeric coating material carried by the porous sheet substrate, for example including at least a first coating including one or more polymeric substances applied to the porous sheet substrate and in some forms also a second coating including one or more polymeric substances applied to the porous sheet substrate.
  • FIGs. 1-8 are illustrative of methods for preparing coated medical products and coated medical products that may be obtained thereby.
  • a porous sheet substrate 20 to be coated a frame including a first frame component 100 cooperable with a second frame component 102, and an insert plate 104.
  • Porous sheet substrate 20 includes a first side surface 22 and a second side surface 24 opposite the first side surface 22.
  • Porous sheet substrate 20 also Includes first, second, third and fourth edges 26, 28, 30 and 32, respectively. It will be understood that while substrate 20 shown is rectangular including four edges 26,28,30,32, other shapes including polygonal shapes having multiple edges or circular or ovoid shapes having a continuous edge, may also be used.
  • the frame components 100 and 102 define respective openings 106 and 108. Openings 106 and 108 are bounded and closed on all sides by walls of the frame components 100 and 102, and the openings 106 and 108 can be of the same shape and dimensions as one another, as illustrated.
  • the walls of the frame components 100 and 102 define inner wall surfaces 110 and 112, respectively, that in the assembled state with the porous sheet substrate 20 extend transversely to and outward (e.g.
  • the inner wall surfaces 110 and 112 can thereby form respective liq u id-pooling volumes bounded by circumscribing by inner wall surfaces 110 and 112 in combination, respectively, with the first side surface 22 and second side surface 24 of the porous sheet substrate 20,
  • the first side surface 22 and second side surface 24 of such an assembled combination can in sequence be positioned facing upward and horizontal with respect to gravity for sequential coating operations in which liquid coating mediums are applied and allowed to self-level to gravity, for example as discussed further hereinbelow.
  • the frame components 100 and 102 In the assembled state, the frame components 100 and 102 have aligned surfaces that face each other and contact the first side surface 22 and second side surface 24 of the substrate 20, respectively.
  • the frame components 100 and 102 may be held together under compression, with the compression for example provided by magnets embedded in or otherwise associated with one or both components 100 and 102 (e.g. with magnet-to-magnet attraction and/or with magnet-to-metal attraction in the case of metallic frame(s)).
  • Other mechanism for holding the frame components 100 and 102 together, potentially under compression may also be used, including for example mechanical clamps, pins extending through corresponding openings in frame components 100 and 102, and others.
  • the compressed band of the porous substrate 20 can exhibit a lower tendency to absorb a liquid coating medium as compared to the inner region of the porous sheet substrate 20, which can facilitate maintenance of liquid coating medium applied within the defined pooling volumes upon and within the inner region of the porous sheet substrate (e.g. preventing or diminishing any wicking of the liquid coating medium into the surrounding compressed, less porous band). This in turn can facilitate the formation of a dried coating for which the polymeric substance(s) of the applied liquid coating medium remain upon and within the inner regions of the substrate 20 that occur within the openings 106 and 108.
  • the porous sheet substrate 20 can be positioned upon and pinned to frame component 102 around a periphery of porous sheet substrate 20.
  • a plurality of pins 114 positioned about the external edge of frame component 102 are used for this purpose. Pins 114 penetrate the substrate 20 at corresponding locations to hold it in place.
  • substrate 20 can be positioned on component 102 and held under tension, for example biaxial tension, using pins 114 or any other suitable mechanism to secure the substrate 20 to the frame component 102.
  • the substrate 20 is in a wetted condition (for example with high purity water) when applied and/or as secured to the frame component 102
  • the substrate 20 is a multilaminate substrate including a plurality of layers laminated to one another (see e.g, discussions below), and the layers can be individually applied and secured in sequence to the frame component 102, Again, those layers can be in a wetted condition when applied and/or as secured to the frame component 102, Thereafter, the frame component 100 can be assembled to the frame component 102/substrate 20 combination for example as discussed above.
  • the creation of a continuous, compressed peripheral band of the substrate surrounding the side surface of the substrate 20 to be coated can eliminate stress concentration regions in the substrate 20 that might otherwise occur during drying operations for the coating and substrate 20 (e.g. stress concentration regions aligned with discretely located pins 114). It has been found that such stress concentration regions can lead to the formation of undesirable wrinkles in the substrate 20 and/or the formed coating 40C as discussed below.
  • the insert plate 104 can be positioned against the first side surface 22 or second side surface 24 of the substrate 20.
  • the assembly is subjected to conditions to dry the porous sheet substrate 20 (in wetted condition) prior to the coating operation(s).
  • Any suitable drying technique can be used, including as examples air drying, oven drying, convection drying, lyophilization and/or vacuum pressing, Drying conducted at temperatures not exceeding about 50°C, for example at a temperature in the range of about 20X to about 50 c C, will be preferred in some aspects. Drying conditions that result in a decreased thickness and a decreased porosity of the of the porous sheet substrate 20, and in particular of the inner region of the porous sheet substrate 20 that occurs within openings 106 and 108, are preferred.
  • Such drying condition can include drying while compressing the porous sheet substrate, for example as may be achieved by vacuum pressing the frame/substrate 20 assembly, thereby resulting in a vacuum pressed porous sheet substrate 20.
  • insert plate 104 received in one of openings 106 and 108 and against the corresponding first side surface 22 or second side surface 24 of the porous sheet substrate 20, thereby drying the substrate 20 against a surface of the insert plate 104.
  • such surface of the insert plate 104 can be a generally planar surface and can thereby facilitate the formation of a dried, flat inner region of porous sheet substrate 20 occurring within openings 106 and 108 to be coated.
  • FIG. 3 in particular provides a cross-sectional view of the assembly of FIG. 2 positioned with the first side surface 22 of substrate 20 positioned facing upwardly and generally horizontally with respect to gravity. This provides a pooling volume bounded by first side surface 22 and the inner wall surfaces 110 of frame component 100, As shown in FIG, 4, a volume of a first liquid coating medium 40L containing one or more polymeric substances has been applied to the first side surface 22 of the substrate 20.
  • the first liquid coating medium 40L can be applied in any suitable manner.
  • the first coating medium 401 will be applied in a controlled volume from a volume-measuring device.
  • the volume measuring device can be any suitable such a device, including, for example, a syringe, a pipette, or the like.
  • the volume of the first liquid coating medium 401 will be applied by gravitational flow onto the first side surface 22. The applied volume of the first liquid coating medium 401 can then be caused to level on the first side surface 22 of the substrate 20 thereby forming a first liquid coating medium surface 40L-S.
  • the applied volume of the first liquid coating medium 401 is allowed to level to gravity without contacting the liquid coating medium with any mechanical element that applies a force to spread the liquid coating medium on the first side surface 22 and/or to drive the liquid coating medium into the porous structure of the porous sheet substrate 20.
  • the use of such a mechanical element could remove amounts of the applied volume of the first liquid coating medium 40L that adhere to the mechanical element, thus diminishing the ability to control the volume of the first liquid coating medium 401 that is dried and/or otherwise treated to form a coating (see discussions below) and thus the level of loading of the polymeric substance(s) in the coating, in some aspects, the spreading of the applied volume of the first liquid coating medium 401 upon the first side surface 22 may be facilitated by methods that apply forces to the liquid coating medium 401 that are other than gravity in a direction normal (perpendicular) to the first side surface 22, but that avoid contact of the liquid coating medium 401 with a mechanical element configured for spreading the liquid coating medium. Such processes may for example include vibration, tilting the substrate 20 (e.g.
  • the spread liquid coating medium 401 can in some aspects then be allowed to self-level to gravity with the first side surface 22 positioned horizontal to gravity. In other aspects, such non-mechanical-contact spreading methods are not used, and the applied volume of the liquid coating medium 401 is allowed to spread and level to gravity with the substrate 20 remaining static in position with the first side surface 22 horizontal to gravity and without the use of any mechanical element that contacts the liquid coating medium 401 to spread it after it has been applied to the first side surface 22. As shown for example in FIG.
  • the leveled volume of the first coating medium can in some forms pool on the first side surface 22 of the substrate 20, contact the peripherally-bounding inner wall surfaces 110 of the frame component 100, and form a leveled liquid coating medium surface 401-S directly interfacing an overlying gaseous atmosphere.
  • the viscosity of the first liquid coating medium 401 can be controlled to facilitate its spreading and/or leveling, and in particular aspects its self-leveling to gravity.
  • the viscosity can be controlled by any suitable means, including as examples the molecular weight of the polymer substance(s) contained in the first liquid coating medium 401, the concentration of the polymeric substance(s) contained in the first liquid coating medium 401, the temperature of the first liquid coating medium 401, and/or other factors.
  • self-leveling to gravity of the first liquid coating medium 401 it is preferred to control its viscosity so that self-leveling occurs within about five minutes, more desirably within about three minutes, and even more desirably within about two minutes.
  • the self-leveled first liquid coating medium 401 can have a first portion that has penetrated into pores of the porous sheet substrate 20, but preferably not completely through the thickness of the porous sheet substrate 20, and a second portion residing above the first side surface 22 of the porous sheet substrate 20.
  • the frame/substrate assembly can be subjected to conditions to treat the first liquid coating medium 401 to form a first coating 40C, for example including drying conditions to remove solvent from the first liquid coating medium 401 and form a first coating 40C including the polymeric substance(s) that were in the first liquid coating medium 401.
  • Other treating conditions may also be used in forming the first coating 40C, for example including crosslinking polymeric substance(s) of the coating medium 401 (potentially combined with drying) or cooling and thereby solidifying molten polymeric substance(s) of the coating medium 40L.
  • any suitable drying conditions may be employed.
  • convection drying is particularly useful to provide a suitable rate of drying to benefit the qualities of the formed first coating on the substrate 20.
  • Convection drying or other drying techniques are desirably conducted at relatively moderate temperatures, for example, temperatures not exceeding about 50° C.
  • Preferred are convection drying or other drying methods during which the liquid surface 401-S of the first liquid coating medium 40L is freely exposed to and forms a liquid-gas interface with a gaseous drying atmosphere.
  • a drying method during which the liquid surface 40L-S is impinged and covered by a solid material, for example a gas-permeable solid film pressed against the first liquid coating medium 40L and interposed between the first liquid coating medium 401 and a gaseous drying atmosphere.
  • a solid material for example a gas-permeable solid film pressed against the first liquid coating medium 40L and interposed between the first liquid coating medium 401 and a gaseous drying atmosphere.
  • convection drying or other drying methods that are conducted at atmospheric pressure and/or above atmospheric pressure.
  • the dried first coating 40C penetrates only partially through the thickness of the porous sheet substrate 20.
  • the applied first liquid coating medium 401 can be dried and/or otherwise treated to form first coating 40C without having penetrated through the entire thickness of the porous sheet substrate 20.
  • the level of penetration of the coating medium 401 can be controlled, for example, by the viscosity of the medium 401, the porosity of the substrate 20, the forces or lack of ferees imparted on the applied medium 401 (e.g.
  • the dried first coating 40C includes a conforms! layer of the polymeric substance(s) occurring overtop the first side surface 22 of the substrate 20.
  • the conformal layer of the polymeric substance(s) can be characterized as molecules of the polymeric substance(s) self-coalesced onto the first side surface 22 under the force of gravity.
  • a self-coalesced polymeric substance(s) layer can be prepared using drying methods as discussed above in which the liquid surface 40L-S of the first liquid coating medium 40L is freely exposed to and forms a liquid-gas interface with a gaseous drying atmosphere. In this manner, the coating surface 40C-S of the dried coating 40C takes a form resultant of self-coalescing of molecules of the polymeric substance(s) under the force of gravity as the solvent of the first liquid coating medium 40L is evaporated or otherwise removed.
  • the insert plate 104 can be positioned underneath and against the second side surface 24 of the substrate 20. It has been found that the presence of the insert plate 104 during these coating steps facilitates maintaining a flat condition of the substrate 20 and obtaining a flat product having the substrate 20 and the first coating 40C thereon.
  • a coated medical product can include the substrate 20 and the coating 40C, and can be free from any coating on the second side surface 24 of the substrate 20,
  • the substrate 20 with coating 40C thereon as depicted in FIG. 5, or a segment thereof can be isolated and further processed herein (e.g. packaged and/or sterilized as described below) to provide a coated medical product.
  • a segment of the coated substrate 20 as depicted in FIG. 5 is cut away, for example by die cutting, from a remainder of the coated substrate 20.
  • the segment can for example substantially correspond to the inner segment of the coated substrate occurring within the aligned openings 106 and 108 of the frame components 100 and 102.
  • Such products can in some forms thus have coating 40C coinciding with the entire first side surface 22 of the substrate 20, with all peripheral edges of the products presenting an edge of the coating 40C and an edge of the substrate 20.
  • a coating will also be applied to the second side surface 24 of substrate 20 to provide a coated medical product.
  • a coating can be compositionally the same as the coating 40C or can be compositionally different from the coating 40C.
  • FIGs. 6-8 one embodiment of a method for preparing such coated medical products will be described. Generally, such a method can include repeating the above-described steps for applying coating 40C to first side surface 22 in respect of the second side surface 24, with the same liquid coating medium or a different liquid coating medium.
  • FIG. 6 shown in FIG. 6 is a view of the frame/substrate assembly of FIG. 5 in an inverted position and having insert plate 104 removed.
  • second side surface 24 of substrate 20 is positioned upward and generally horizontal relative to gravity. This provides a pooling volume bounded by second side surface 24 and the inner wall surfaces 112 of frame component 102,
  • a volume of a second liquid coating medium 42L containing one or more polymeric substances which can be compositionally the same as or different from the first liquid coating medium 40L, has been applied to the second side surface 24 of the substrate 20.
  • the second liquid coating medium 421 can be applied in any suitable manner.
  • the second liquid coating medium 42L will be applied in a controlled volume from a volume-measuring device.
  • the volume-measuring device can be any suitable such a device, including, for example, a syringe, a pipette, or the like.
  • the volume of the second liquid coating medium 421 will be applied by gravitational flow onto the second side surface 24.
  • the applied volume of the second liquid coating medium 42L can then be caused to level on the second side surface 24 of the substrate 20 thereby forming a second liquid coating medium surface 42L-S.
  • the applied volume of the second liquid coating medium 42L is allowed to level to gravity without contacting the liquid coating medium with any mechanical element that applies a force to spread the liquid coating medium on the second side surface 24 and/or to drive the liquid coating medium into the porous structure of the porous sheet substrate 20.
  • any mechanical element that applies a force to spread the liquid coating medium on the second side surface 24 and/or to drive the liquid coating medium into the porous structure of the porous sheet substrate 20.
  • the use of such a mechanical element could remove amounts of the applied volume of the second liquid coating medium 42L that adhere to the mechanical element, thus diminishing the ability to control the volume of the second liquid coating medium 42L that is dried and/or otherwise treated to form a coating (see discussions below) and thus the level of loading of the applied polymeric substance(s) in the coating.
  • the spreading of the applied volume of the second liquid coating medium 42L upon the second side surface 24 may be facilitated by methods that apply forces to the liquid coating medium 421 that are other than gravity in a direction normal (perpendicular) to the second side surface 24, but that avoid contact of the liquid coating medium 42L with a mechanical element configured for spreading the liquid coating medium.
  • Such processes may for example include vibration, tilting the substrate 20 (e.g. by tilting the frame/substrate assembly as described herein) relative to horizontal to gravity, application of forced air or other gas, and/or other such methods.
  • the spread liquid coating medium 421 can in some aspects then be allowed to self-level to gravity with the second side surface 24 positioned horizontal to gravity.
  • the applied volume of the liquid coating medium 421 is allowed to spread and level to gravity with the substrate 20 remaining static in position with the second side surface 24 horizontal to gravity and without the use of any mechanical element that contacts the liquid coating medium 421 to spread it after it has been applied to the second side surface 24.
  • the leveled volume of the second liquid coating medium 421 can in some forms pool on the second side surface 24 of the substrate 20, contact the peripherally-bounding inner wall surfaces 112 of the frame component 102, and form a leveled liquid coating medium surface 42L-S directly interfacing an overlying gaseous atmosphere.
  • the viscosity of the second liquid coating medium 421 can be controlled to facilitate its spreading and/or leveling, and in particular aspects its self-leveling to gravity.
  • the viscosity can be controlled by any suitable means, including as examples the molecular weight of the polymer substance(s) contained in the second liquid coating medium 42L, the concentration of the polymeric substance(s) contained in the second liquid coating medium 421, the temperature of the second liquid coating medium 421, and/or other factors.
  • self-leveling to gravity of the second liquid coating medium 421 it is preferred to control its viscosity so that self-leveling occurs within about five minutes, more desirably within about three minutes, and even more desirably within about two minutes.
  • the self-leveled second liquid coating medium 421 can have a first portion that has penetrated into pores of the porous sheet substrate 20, but preferably not completely through the thickness of the porous sheet substrate 20, and a second portion residing above the second side surface 24 of the porous sheet substrate 20.
  • the frame/substrate assembly can be subjected to drying and/or other treating conditions to form a second coating 42C including the polymeric substance(s) that were in the second liquid coating medium 42L.
  • Other treating conditions that may be used in forming the second coating 42C include for example crosslinking polymeric substance(s) of the coating medium 421 (potentially combined with dryingj or cooling and thereby solidifying molten polymeric substance(s) of the coating medium 421.
  • any suitable drying conditions may be employed. These may include, for example, air drying, oven drying, vacuum drying, convection drying, or another drying technique, or combinations thereof.
  • convection drying is particularly useful to provide a suitable rate of drying to benefit the qualities of the formed second coating on the substrate 20.
  • Convection drying or other drying techniques are desirably conducted at relatively moderate temperatures, for example, temperatures not exceeding about 50” C.
  • Preferred are convection drying or other drying methods during which the liquid surface 42L-S of the second liquid coating medium 421 is freely exposed to and forms a liquid-gas interface with a gaseous drying atmosphere. This is contrasted to a drying method during which the liquid surface 42L-S is impinged and covered by a solid material, for example a gas-permeable solid film pressed against the second liquid coating medium 421 and interposed between the second liquid coating medium 42L and a gaseous drying atmosphere.
  • convection drying or other drying methods that are conducted at atmospheric pressure and/or above atmospheric pressure.
  • the second coating 42C penetrates only partially through the thickness of the porous sheet substrate 20.
  • the applied second liquid coating medium 421 can be dried and/or otherwise treated to form second coating 42C without having penetrated through the entire thickness of the porous sheet substrate 20.
  • the level of penetration of the coating medium 42L can be controlled, for example, by the viscosity of the medium 421, the porosity of the substrate 20, the presence of polymeric substance(s) of the first coating 40C in pores within the thickness of substrate 20, the forces or lack of forces imparted on the applied medium 42L (e.g.
  • any mechanical spreading element such as a blade or a roller, that also imparts a driving force to the medium 421 that causes it to penetrate into the thickness of the substrate 20
  • the time period between application of the medium 42L to the second side surface 24 and drying and/or other treatment of the medium 421 to obtain a non-flowable state can be controlled to form a second coating 42C that penetrates only partially through the thickness of the porous sheet substrate.
  • the second coating 42C includes a conformal layer of its polymeric substance(s) occurring overtop the second side surface 24 of the substrate 20.
  • the conformal layer of such polymeric substance(s) can be characterized as molecules of the polymeric substance(s) seif-coalesced onto the second side surface 24 under the force of gravity.
  • Such a self-coalesced polymeric substance(s) layer can be prepared using drying methods as discussed above in which the liquid surface 42L-S of the second liquid coating medium 42L is freely exposed to and forms a iiquid-gas interface with a gaseous drying atmosphere, in this manner, the coating surface 42C-S of the dried second coating 42C takes a form resuitant of seif-coalescing of moiecuies of its polymeric substance(s) under the force of gravity as the solvent of the second liquid coating medium 42L is evaporated or otherwise removed.
  • This is contrasted to a coating surface form defined by a surface of a film or other solid materia! impinging upon the second liquid coating medium 42L during drying.
  • peripherally securing the region of the substrate 20 within the opening 108 against shrinkage in the plane of the substrate 20 with the frame components 100 and 102 during drying and/or other treatment of the liquid coating medium 421 can be beneficially used to facilitate obtaining a fiat product with a wrinkle-free coating surface 42C-S.
  • the insert piate 104 can be absent (e.g. where there is no support positioned underneath and against the first coating 40C on the substrate 20), It has been found that flat coated medical products including substrate 20 and coatings 40C and 42C can be prepared. Also, in this way, contact of the first coating 40C with any solid surface during steps for forming second coating 42C can be avoided. It wiil be understood, however, that in other embodiments the insert plate 104 or another similar or different support may be positioned beneath and against the first coating 40C during step(s) for forming the second coating 42C.
  • the substrate 2G with coatings 40C and 42C thereon as depicted in FIG. 7, or a segment thereof can be isolated and further processed herein (e.g. packaged and/or sterilized as described below) to provide a coated medical product.
  • a segment of the coated substrate 20 as depicted in FIG. 7 is cut away, for example by die cutting, from a remainder of the coated substrate 20.
  • the segment can for example substantially correspond to the inner segment of the coated substrate occurring within the aligned openings 106 and 108 of the frame components 100 and 102.
  • FIG. 8 depicts one such coated medical product 50 including the substrate 20, coating 40C presenting surface 40C-S, and coating 42C presenting surface 42C-S.
  • Such products can in some forms thus have coating 40C coinciding with the entire first side surface 22 of the substrate 20 and coating 42C coinciding with the entire second side surface 24 of substrate 20, with all peripheral edges of the product 50 presenting an edge 40E of the coating 40C, an edge 20E of the substrate 20, and an edge 42E of the coating 42C.
  • coated medical products having coating 40C but not coating 42C can have the same features shown in FIG. 8, except lacking coating 42C (and thus also lacking its surface 42C-S and edge 42Ej.
  • Such coated medical products can instead have second side surface 24 of substrate 20 exposed as an outermost surface of the coated medical product.
  • a flat coated medical product may deform from its flat condition and/or develop wrinkles in the substrate or coating(s). This may especially be the case where the substrate relaxes (loses stiffness) and/or swells in the presence of the applied liquid coating medium(s) which wet the substrate, and then develops stress and/or shrinks as it is thereafter dried and/or otherwise treated to form a coating. Differential shrinking between the applied coating(s) and the substrate during drying/treating operation(s) may also contribute to the deformation and/or wrinkles.
  • the coated medical product is preferably held to its desired shape, such as a flat shape, for example by a circumferential frame as discussed herein.
  • a flat or other shaped coated medical product may deform from its fiat or other shaped condition as it equilibrates to the moisture level (humidity) of its surrounding atmospheric environment, for example a manufacturing environment. Accordingly, in some embodiments, after the drying and/or other treating operation, the coated medical product is held to its desired shape, such as a flat shape or a non-flat shape e.g. as discussed herein, for a time period for moisture equilibration to its surrounding atmospheric environment. Such time period may for exampie be for five minutes to ten hours.
  • coated medical products manufactured using frames as discussed may be retained in their frames after the drying operation and during the moisture equilibration period, after which they may be isolated from their frames (e.g. cut or otherwise removed) as discussed above and will retain their desired (e.g. flat) shape.
  • their respective penetration depths through the thickness of the substrate 20 can be such that the coatings 40C and 42C to not overlap in the thickness of the substrate 20.
  • the coated medical product 50 can include an interior region of the substrate 20, for example a thickness stratum, in which the pores of the substrate 20 are not filled with any polymeric substance(s), but rather can be open pores, e.g. providing an open porous stratum within the thickness of the substrate 20.
  • Such open pores or open porous stratum can facilitate cellular invasion into the substrate 20 upon implantation of the coated medical product 50.
  • an open porous stratum is present in product 50, it can in some embodiments represent at least about 10% of the thickness of the substrate 20, for example with this value being in the range of about 10% to about 80% of the thickness of the substrate 20.
  • coatings 40C and 42C are both included, their respective penetration depths partially through the thickness of the substrate 20 can be such that the coatings overlap in the thickness of the substrate 20.
  • the coated medical product 50 can include an interior region of the substrate 20, for example a thickness stratum, in which the pores of the substrate 20 contain and are potentially filled with a polymeric substance mixture including the polymeric substance(s) of both coatings 40C and 42C. Such a polymeric substance mixture can be present within a stratum of the thickness of the substrate.
  • the intermediate., first and second thickness strata can differ from one another in respect of the types of polymeric substance(s) that are present.
  • the intermediate, first and second thickness strata can differ from one another in respect of the ratio of multiple polymeric substance(s) to one another, in respect of the abundance of the polymeric substance(s) present (e.g. expressed in terms of dry weight parts of the polymeric substance(s) per unit surface area of the substrate 20 and/or in terms of the dry weight parts of the polymeric substance(s) per dry weight parts of the substrate 20), in some forms.
  • an intermediate thickness stratum is present in product 50 including a polymeric substance mixture including the polymeric substance(s) of both coatings 40C and 42C
  • it can in some embodiments represent at least about 10% of the thickness of the substrate 20, for example with this value being in the range of about 10% to about 80% of the thickness of the substrate 20.
  • the polymeric substance(s) of coating 40C and/or 42C can be more abundant in regions external of the first and second side surfaces 22 and 24 (externalized portions of the coating 40C and/or 42C) than within the substrate 20 (internalized portions of the coating 40C and/or 42C).
  • At least about 60% by dry weight, or at least about 70% by dry weight, of the total load of the polymeric substance(s) of the coating 40C and/or the coating 42C will be present in the externalized portion of the coating that occurs atop the first side surface 22 and/or the second side surface 24, respectively.
  • a distribution of the polymeric substance(s) toward the regions external of and/or adjacent the first and second side surfaces 22 and 24 can be particularly advantageous where the first and second coatings 40C and 42C have a purpose of modulating the interaction of surfaces of the coated medical product SO with surrounding patient tissue upon implantation, for example, where the first and second coatings 40C and 42C are lubricious coatings, anti-tissue-adhesion coatings, or adhesive coatings.
  • Such lubricious, anti-tissue-adhesion, or adhesive coatings can in some forms be provided by the inclusion of hydrogel-forming polymeric substance(s) in or as the first and second coatings 40C and 42C.
  • frame components 100 and 102 define a pooling volume on each side of the substrate 20
  • one or more frame components can be used that define a pooling volume on only one side of the substrate 20.
  • a frame component similar to frame component 102 except lacking the opening 108 e.g, being a solid sheet across its width and breadth
  • Such frame components could be used in the preparation of a substrate 20 coated only on one side, e.g.
  • frame components 100 and 102 each define only a single pooling volume, it will be understood that in other embodiments frame component 100 and/or frame component 102 can define multiple discrete openings to provide multiple pooling volumes. Such multiple-opening frame component(s) can be used to prepare substrates 20 coated (e.g. with coating 40C and/or coating 42C ⁇ in multiple discreet regions corresponding to the multiple openings of the frame component(s).
  • Such coated substrates 20 could be further processed to provide coated medical products with coating patterns thereon having discrete coated regions or could be cut at or within the edges of the coated regions to isolate the multiple coated regions as multiple separate coated medical products having coating(s) coinciding with their entire first side and/or their entire second side.
  • coated products of the present disclosure include a porous sheet substrate.
  • a porous sheet substrate Generally speaking, a wide variety of porous sheet substrates are known and can be used.
  • the porous sheet substrate is a collagenous (i.e. coliagen- containing) sheet substrate and/or is conformable to patient tissue when wet.
  • remodelable materials can be provided by a collagen- containing materials, e.g., provided in a reconstituted or non-reconstituted form, for example where the collagen has been obtained from a warm-blooded vertebrate, and especially a mammal, including as examples a porcine, bovine, ovine, or caprine mammal.
  • Isolated collagen-containing materials can be processed so as to have remodelable, angiogenic properties and promote cellular invasion and ingrowth, and in this regard, inventive constructs comprising a remodelable material can be effective upon implantation to stimulate ingrowth of adjacent tissues into the construct such that the remodelable material gradually breaks down and becomes replaced by new patient tissue so that a new, remodeled tissue structure is generated.
  • Suitable remodelable materials that can be included in or that can constitute the porous sheet substrate can be decellularized membranous tissue segments, which can be provided by collagenous extracellular matrix (ECM) materials.
  • suitable collagenous materials include ECM materials such as those comprising submucosa, renal capsule membrane, amnion, dermal collagen, dura mater, pericardium, fascia lata, serosa, peritoneum or basement membrane layers, including liver basement membrane.
  • Suitable submucosa materials for these purposes include, for instance, intestinal submucosa including small intestinal submucosa, stomach submucosa, urinary bladder submucosa, and uterine submucosa.
  • Collagenous sheet substrates comprising submucosa (potentially along with other associated tissues) useful in aspects of the present disclosure can be obtained by harvesting such tissue sources and delaminating the submucosa-containing matrix from smooth muscle layers, mucosal layers, and/or other layers occurring in the tissue source. Collagenous sheet substrates that are pliable when wet so as to be easily conformable to patient tissue will be beneficially useful in certain aspects herein.
  • Remodelable ECM tissue materials harvested as intact sheets from a mammalian source and processed to remove cellular debris advantageously retain at least a portion of and potentially ali of the native collagen microarchitecture of the source extracellular matrix.
  • This matrix of collagen fibers provides a scaffold to facilitate and support tissue ingrowth, particularly in bioactive ECM implant materials, such as porcine small intestinal submucosa or SIS (Surgisis® BiodesignTM, Cook Medical, Bloomington IN), that are processed to retain an effective level of growth factors and other bioactive constituents from the source tissue.
  • bioactive ECM implant materials such as porcine small intestinal submucosa or SIS (Surgisis® BiodesignTM, Cook Medical, Bloomington IN)
  • a submucosa-containing or other ECM tissue used in the invention is preferably highly purified, for example, as described in U.S, Patent No, 6,206,931 to Cook et al. or in U.S. Patent No. 8,192,763 of Cook Biotech Incorporated.
  • preferred ECM material will exhibit an endotoxin level of less than about 12 endotoxin units (Ell) per gram, more preferably less than about 5 EU per gram, and most preferably less than about 1 EU per gram.
  • the submucosa or other ECM material may have a bioburden of less than about 1 colony forming units (CFU) per gram, more preferably less than about 0.5 CPU per gram.
  • Fungus levels are desirably similarly low, for example less than about 1 CFU per gram, more preferably less than about 0.5 CFU per gram.
  • Nucleic acid levels are preferably less than about 5 pg/mg, more preferably less than about 2 pg/mg, and virus levels are preferably less than about 50 plaque forming units (PFU) per gram, more preferably less than about 5 PFU per gram.
  • a typical layer thickness for an as-isolated submucosa or other ECM tissue layer that can be used in embodiments herein ranges from about 50 to about 250 microns when fully hydrated, more typicaliy from about 50 to about 200 microns when fully hydrated, although isolated layers having other thicknesses may also be obtained and used. These layer thicknesses may vary with the type and age of the animal used as the tissue source. As well, these layer thicknesses may vary with the source of the tissue obtained from the animal source. As disclosed herein, in certain embodiments, porous sheet substrates will include or be provided by a laminate of multiple layers of submucosacontaining ECM material and/or other ECM material.
  • a decellularized submucosa or other remodelable ECM tissue material for use herein as or in the porous sheet substrate may retain one or more growth factors native to a source tissue for the tissue material, such as but not limited to basic fibroblast growth factor (FGF-2), transforming growth factor beta (TGF-beta), epidermal growth factor (EGF), cartilage derived growth factor (CDGF), and/or platelet derived growth factor (PDGF).
  • FGF-2 basic fibroblast growth factor
  • TGF-beta transforming growth factor beta
  • EGF epidermal growth factor
  • CDGF cartilage derived growth factor
  • PDGF platelet derived growth factor
  • submucosa or other ECM materials when used in the invention may retain other bioactive agents native to the source tissue such as but not limited to proteins, glycoproteins, proteoglycans, and glycosaminoglycans.
  • ECM materials may include retained heparin, heparin sulfate, hyaluronic acid, fibronectin, and/or cytokines, native to a source tissue.
  • Submucosa-containing or other ECM materials when used as or in a porous sheet substrate herein, can be derived from any suitable organ or other tissue source, usually sources containing connective tissues.
  • the ECM materials processed for use in the invention will typically include abundant collagen, most commonly being constituted at least about 80% by weight collagen on a dry weight basis.
  • Such naturally-derived ECM materials will for the most part include collagen fibers that are non-randomly oriented, for instance occurring as generally uniaxial or multi-axial but regularly oriented fibers.
  • the ECM material When processed to retain native bioactive factors, the ECM material can retain these factors interspersed as solids between, upon and/or within the collagen fibers.
  • Particularly desirable naturally-derived ECM materials for use in the invention will include significant amounts of such interspersed, non-collagenous solids that are readily ascertainable under light microscopic examination with appropriate staining.
  • Such non- collagenous solids can constitute a significant percentage of the dry weight of the ECM material in certain inventive embodiments, for example at least about 1%, at least about 3%, and at least about 5% by weight in various embodiments of the invention.
  • a submucosa-containing or other ECM material that can be used in embodiments of the present disclosure may also exhibit an angiogenic character and thus be effective to induce angiogenesis in a host engrafted with the material.
  • angiogenesis is the process through which the body makes new blood vessels to generate increased blood supply to tissues.
  • angiogenic materials when contacted with host tissues, promote or encourage the formation of new blood vessels into the materials.
  • Methods for measuring in vivo angiogenesis in response to biomaterial implantation have recently been developed. For example, one such method uses a subcutaneous implant model to determine the angiogenic character of a material. See, C. Heeschen et al., Nature Medicine 7 (2001), No. 7, 833-839.
  • nan-native bioactive substances such as those synthetically produced by recombinant technology or other methods (e.g., genetic materia! such as DMA), may be incorporated into an ECM material.
  • non-native bioactive substances may be naturally-derived or recombinantly produced proteins that correspond to those natively occurring in an ECM tissue, but perhaps of a different species. These non-natlve bioactive substances may also be drug substances.
  • Illustrative drug substances that may be added to materials include, for example, anticlotting agents, e.g. heparin, antibiotics, statins, anti-inflammatory agents, thrombuspromoting substances such as blood clotting factors, e.g., thrombin, fibrinogen, and the like, and anti-proliferative agents, e.g. taxol derivatives such as paclitaxel.
  • anticlotting agents e.g. heparin
  • antibiotics e.g., statins
  • anti-inflammatory agents e.g., thrombuspromoting substances such as blood clotting factors, e.g., thrombin, fibrinogen, and the like
  • anti-proliferative agents e.g. taxol derivatives such as paclitaxel.
  • Such nonnative bioactive components can be incorporated into and/or onto ECM material in any suitable manner, for example, by surface treatment (e.g., spraying) and/or impregnation (e
  • Porous sheet substrates herein can incorporate or in some forms be constituted of xenograft material (i,e., cross-species material, such as tissue material from a nonhuman donor to a human recipient), allograft material (i.e., interspecies material, with tissue material from a donor of the same species as the recipient), and/or autograft material (i.e., where the donor and the recipient are the same individual).
  • xenograft material i,e., cross-species material, such as tissue material from a nonhuman donor to a human recipient
  • allograft material i.e., interspecies material, with tissue material from a donor of the same species as the recipient
  • autograft material i.e., where the donor and the recipient are the same individual.
  • any exogenous bioactive substances incorporated into an ECM material may be from the same species of animal from which the ECM material was derived (e.g. autologous or allogenic relative to the ECM material) or may be from
  • ECM material of the substrate will be xenogenic relative to the patient receiving the graft, and any added exogenous material(s) will be from the same species (e.g. autologous or allogenic) as the patient receiving the graft.
  • human patients may be treated with xenogenic ECM materials (e.g. porcine-, bovine- or ovine-derived) that have been modified with exogenous human material(s) as described herein, those exogenous materials being naturally derived and/or recombinantly produced.
  • ECM materials or decellularized membranous tissue segments may be essentially free of additional, non-native crosslinking, or may contain additional crosslinking.
  • Such additional crosslinking may be achieved by photo-crosslinking techniques, by chemical crosslinkers, or by protein crosslinking induced by dehydration or other means.
  • certain crosslinking techniques, certain crosslinking agents, and/or certain degrees of crosslinking can destroy the remodeiable properties of a remodelable material, where preservation of remodelable properties is desired, any crosslinking of the remodelable ECM material can be performed to an extent or In a fashion that allows the material to retain at least a portion of its remodelable properties.
  • Chemical crosslinkers that may be used include for example aldehydes such as glutaraldehydes, diimides such as carbodiimides, e.g., l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, ribose or other sugars, acyl-azide, sulfo-N-bydroxysuccinamide, or polyepoxide compounds, including for example poiyglycidyl ethers such as ethyleneglycol diglycidyl ether, available under the trade name DENACOL EX810 from Nagese Chemical Co., Osaka, Japan, and glycerol polyglycerol ether available under the trade name DENACOL EX 313 also from Nagese Chemical Co. Typically, when used, polyglycerol ethers or other polyepoxide compounds will have from 2 to about 10 epoxide groups per molecule.
  • aldehydes such as
  • Remodelable ECM materials having a relatively more open matrix structure are capable of exhibiting different material properties than those having a relatively more closed or collapsed matrix structure.
  • an ECM material having a relatively more open matrix structure is generally softer and more readily compliant to an implant site than one having a relatively more closed matrix structure.
  • the rate and amount of tissue growth in and/or around a remodelable material can be influenced by a number of factors, including the amount of open space available in the material's matrix structure for the invasion and support of a patients tissue-forming components, such as fibroblasts. Therefore, a more open matrix structure can provide for quicker, and potentially more, growth of patient tissue in and/or around the remodelable materia!, which in turn, can lead to quicker remodeling of the material by patient tissue.
  • the porosity of a layer or layers of ECM material of the sheet substrate to be coated as described herein is reduced by drying the material(s) under compression, in general, compressing a pliable open matrix material, such as a pliable ECM material, increases the material's density and reduces the material's porosity by collapsing pores of the open matrix.
  • a pliable open matrix material such as a pliable ECM material
  • the open matrix structure can become somewhat fixed in this relatively higher density, lower porosity state (i.e., in a relatively more collapsed pore state).
  • the density of these or other materials of the sheet substrate can be conventionally determined.
  • the volume and the weight occupied by an amount of the material(s) can be determined, and the volume divided by the weight to provide a density expressed as a unit volume/unit weight (e.g. in grams/cubic centimeter) of the material.
  • the porosity of a materlal(s) of the sheet substrate can be conventionally determined.
  • mercury intrusion porosimetry can be used to determine the porosity of the material(s), e.g. as described by Janis et al., J. Biomater. Appi., May 2012, Vol. 26 No. 8, 1013-1033.
  • Sheet substrates used in certain embodiments of the present disclosure can include a plurality of ECM material layers bonded together, a plurality of non-ECM material layers bonded together, or a combination of one or more ECM material layers and one or more non-ECM material layers bonded together, illustratively, two or more ECM segments can be fused or bonded together using a bonding technique, such as chemical cross-linking or vacuum pressing during dehydrating conditions.
  • An adhesive, glue or other bonding agent may also be used in achieving a bond between material layers to form the laminated segment(s) of the pouch products disclosed herein.
  • a combination of bonding technique(s) and bonding agent(s) may also be used to bond ECM material sheets or layers, or other sheets of material, to one another in a laminate structure.
  • Sheet substrates used in certain embodiments of the present disclosure can include a plurality of ECM materia! layers bonded together, a plurality of non-ECM materia! layers bonded together, or a combination of one or more ECM material Sayers and one or more non-ECM material Sayers bonded together.
  • Deceiiularized collagenous ECM materia! layers for example used in laminate porous sheet substrates herein, will in some forms include a compact collagen sublayer formed by relatively densely packed collagen fibers adjacent to a loose collagen sublayer formed by less densely packed collagen fibers, with the compact collagen sublayer being less porous than the loose collagen sublayer.
  • deceiiularized collagenous ECM material layers that include submucosal tissue can include as such a compact sublayer a collagenous lamina intestinal sublayer or a collagenous stratum compactum sublayer, attached to an adjacent collagenous sublayer having less densely packed fibers than those of the lamina limba sublayer or collagenous stratum compactum sublayer.
  • the presence of the included compact sublayers can provide less porous strata distributed through the thickness of the substrate. This can impact the extent of penetration of a first liquid coating medium and/or second liquid coating medium as discussed herein into the porous sheet substrate and thus the resulting compositional structure of the coated medical product.
  • dehydration-induced bonding methods can be used to fuse ECM or other material layers together in forming a multilaminate porous sheet substrate.
  • multiple layers or other pieces of ECM material and/or other sheet material as described herein are compressed under dehydrating conditions.
  • dehydrating conditions can include any mechanical or environmental condition which promotes or induces the removal of water from the material.
  • at least one of the two surfaces received directly against and compressing the sheet material can be water permeable in some embodiments. Dehydration of the material can optionally be further enhanced by applying blotting material, heating the matnx structure or blowing air, or other inert gas, across the exterior of the compressing surfaces.
  • One particularly useful method of dehydration bonding materials, and preferably collagen-containing materials, is lyophilization.
  • the lyophilization includes first freezing the materials and then subjecting the frozen materials to lyophilization conditions in which frozen liquid within the materials is removed by sublimation.
  • Another method of dehydration bonding comprises pulling a vacuum on the layers to be laminated while simultaneously pressing the layers together. In some forms, this can be done by vacuum pressing.
  • vacuum pressing dehydration of the layers in forced contact with one another effectively bonds the materials to one another, even in the absence of other agents for achieving a bond, although such agents can be used while also taking advantage at least in part of the dehydration-induced bonding.
  • the layers can be caused to form a generally unitary multilaminate porous sheet substrate.
  • the porous sheet substrate may include or be constituted of one or more synthetic polymeric materials.
  • synthetic polymeric materials including but not limited to bioresorbable and/or non-bioresorbable polymeric materials can be used.
  • Bioresorbable polymers that may be used include, but are not limited to, polyfl- lactic acid), polycaprolactone, poly(lactide-co-glycolide), poly(hydroxybutyrate), poly(hydroxybutyrate-co-vaierate), poiydioxanone, polyorthoester, polyanhydride, polyfglycolic acid), poly(D,L-lactic acid), polyfglycolic acid-co-trimethylene carbonate), polyhydroxyalkanaates, polyphosphoester, polyphosphoester urethane, polyfamino acids), cyanoacrylates, polyftrimethylene carbonate), polyfiminocarbonate), copoiy(ether-esters) (e.g., PEO/PLA), polyalkylene ox
  • Non-bioresorbable polymers that may be used include, but are not limited to, polytetrafluoroethylene (PTFE) (including expanded PTFE), polyethylene terephthalate (PET), polyurethanes, silicones, and polyesters and other polymers such as, but not limited to, polyolefins, polyisobutylene and ethylene-alphaolefin copolymers; acrylic polymers and copolymers, vinyl halide polymers and copolymers, such as polyvinyl chloride; polyvinyl ethers, such as polyvinyl methyl ether; polyvinylidene halides, such as polyvinylidene fluoride and polyvinylidene chloride; polyacrylonitrile, polyvinyl ketones; polyvinyl
  • Preferred embodiments of the present disclosure are coated medical products that include a multilaminate porous sheet substrate, especially a multilaminate porous sheet substrate including a plurality of deceliularlzed ECM layers, for example any of those discussed herein, laminated together.
  • the lamination of the layers together can be achieved by any suitable technique described herein but is preferably achieved by vacuum pressing or another technique that Involves compression of the layers against one another under dehydrating conditions, which can beneficially reduce the porosity of the starting layers used in the lamination.
  • FIGS. 9-13 described will be an illustrative embodiment of a coated medical product including a multilaminate porous sheet substrate and its preparation.
  • the steps, materials e.g.
  • first and second liquid coating media and their respective polymeric substance(s)) and equipment e.g. frame components and insert
  • first and second liquid coating media and their respective polymeric substance(s)) and equipment e.g. frame components and insert
  • first and second liquid coating media and their respective polymeric substance(s)) and equipment e.g. frame components and insert
  • frame components and insert e.g. frame components and insert
  • FIG. 9 provides a cross-sectional view illustrating an embodiment of a multilaminate porous sheet substrate 60 including a plurality of deceliularlzed ECM layers (four layers In the specific depicted embodiment) 60a, 60b, 60c and 60d laminated together.
  • Porous sheet substrate 60 has a first side surface 62 and a second side surface 64 opposite the first surface.
  • FIG. 10 depicts a volume of a first liquid coating medium 66L applied to the multi laminate porous sheet substrate 60 and including a first portion 66L-a pooled above the surface 62 and a second portion 66L-b infiltrating pores of the substrate 60 and extending only partially through the thickness of the substrate 60 ⁇ in the illustrated embodiment being confined to within the outermost ECM layer 60a providing the first side surface 62),
  • the volume of the first liquid coating medium 66L forms a liquid surface 66L-S, for example self-leveled to gravity as discussed hereinabove.
  • treating conditions can be used to form a first coating 66C including the polymeric substance(s) that were in the first liquid coating medium 66L, for example drying conditions can be applied to remove solvent from the first liquid coating medium SSL and form a first coating 66C including the polymeric substance(s) that were in the first liquid coating medium 66L,
  • the first coating 66C includes a conformal layer 66C-a of the polymeric substance(s) occurring overtop the first side surface 62 of the multilaminate porous sheet substrate 60.
  • the conformal layer 66C ⁇ a of the polymeric substance(s) can in some forms be characterized as molecules of the polymeric substance(s) self-coalesced onto the first side surface 62 under the force of gravity.
  • a self-coalesced polymeric substance(s) layer 66C-a can be prepared using drying methods as discussed above in which the liquid surface 66L-S of the first liquid coating medium 66L is freely exposed to and forms a liquid-gas interface with a gaseous drying atmosphere. In this manner, the coating surface 66C-S of the dried coating 66C takes a form resultant of self-coalescing of molecules of the polymeric substance(s) under the force of gravity as the solvent of the first liquid coating medium 66L is evaporated or otherwise removed.
  • the first coating 66C also includes an infiltrating portion 66C-b including molecules of the polymeric substance(s) from the first liquid coating medium 66L infiltrating pores of the substrate 60 and extending only partially through the thickness of the substrate 60 (in the illustrated embodiment being confined to within the outermost ECM layer 60a providing the first side surface 62).
  • a coated medical product can include the substrate 60 and the coating 66C, and can be free from any coating on the second side surface 64 of the substrate 60.
  • the substrate 60 with coating 66C thereon as depicted in FIG. 11, or a segment thereof can be isolated and further processed herein (e.g. packaged and/or sterilized as described below) to provide a coated medical product.
  • a segment of the coated substrate 60 as depicted in FIG. 11 is cut away, for example by die cutting, from a remainder of the coated substrate 60.
  • the segment can for example substantially correspond to the inner segment of the coated substrate occurring within the aligned openings 106 and 108 of the frame components 100 and 102 ( see FIGs. 1-3) .
  • Such products can in some forms thus have coating 66C coinciding with the entire first side surface 62 of the substrate 60, with ail peripheral edges of the products presenting an edge of the coating 66C and an edge of the substrate 60.
  • a coating will also be applied to the second side surface 64 of substrate 60 to provide a coated medical product.
  • a coating can be compositionally the same as the coating 66C or can be compositionally different from the coating 66C.
  • FIGs. 12-13 one embodiment of a method for preparing such coated medical products will be described. Generally, such a method can include repeating the above-described steps for applying coating 66C to first side surface 62 in respect of the second side surface 64, with the same liquid coating medium or a different liquid coating medium.
  • FIG. 12 shown in FIG. 12 is a view of the substrate 60 and coating 66C of FIG. 10 in an inverted position.
  • second side surface 64 of substrate 60 is positioned upward and generally horizontal reiative to gravity.
  • a volume of a second liquid coating medium 681 containing one or more polymeric substances which can be compositionally the same as or different from the first liquid coating medium 661, has been applied to the second side surface 64 of the substrate 60.
  • the applied volume of the second liquid coating medium 681 includes a first portion 681-a pooled above the surface 64 and a second portion 681-b infiltrating pores of the substrate 60 and extending only partially through the thickness of the substrate 60 (in the illustrated embodiment being confined to within the outermost ECM layer 60d providing the second side surface 64).
  • the volume of the second liquid coating medium 681 forms a liquid surface 68L-S, for example self-leveled to gravity as discussed herein.
  • treating conditions can be used to form a second coating 68C including the polymeric substance(s) that were in the second liquid coating medium 68L, for example drying conditions can be applied to remove solvent from the second liquid coating medium 68L and form a second coating 68C including the polymeric substance(s) that were in the second liquid coating medium 68L.
  • the second coating 68C includes a conformal layer 68C-a of the polymeric substance(s) occurring overtop the second side surface 64 of the multilaminate porous sheet substrate 60.
  • the conformal layer 68C-a of the polymeric substance(s) can in some forms be characterized as molecules of the polymeric substance(s) self-coalesced onto the second side surface 64 under the force of gravity.
  • Such a seif-coalesced polymeric substance(s) layer 68C-a can be prepared using drying methods as discussed above in which the liquid surface 68L-S of the second liquid coating medium 68L is freely exposed to and forms a liquid-gas interface with a gaseous drying atmosphere. In this manner, the coating surface 68C-S of the dried coating 68C takes a form resultant of self -coalescing of molecules of the polymeric substance(s) under the force of gravity as the solvent of the second liquid coating medium 68L is evaporated or otherwise removed.
  • the second coating 68C also includes an infiltrating portion 68C-b including molecules of the polymeric substance(s) from the second liquid coating medium 681 infiltrating pores of the substrate 60 and extending only partially through the thickness of the substrate 60 (in the illustrated embodiment being confined to within the outermost ECM layer 60d providing the second side surface 64).
  • the substrate 60 with coatings 66C and 68C thereon as depicted in FIG. 13, or a segment thereof can be isolated and further processed herein (e.g. packaged and/or sterilized as described below) to provide a coated medical product.
  • a segment of the coated substrate 60 as depicted in FIG. 13 is cut away, for example by die cutting, from a remainder of the coated substrate 60.
  • the segment can for example substantially correspond to the inner segment of the coated substrate occurring within the aligned openings 106 and 108 of the frame components 100 and 102 (see FIGs. 1-7).
  • Such coated medical products can include the substrate 60, coating 66C presenting surface 66C-S, and coating 68C presenting surface 68C-S.
  • coated medical products can have coating 66C coinciding with the entire first side surface 62 of the substrate 60 and coating 68C coinciding with the entire second side surface 64 of substrate 60, with all peripheral edges of the product presenting an edge of the coating 66C, an edge of the substrate 60, and an edge of the coating 68C.
  • coated medical products having coating 66C but not coating 68C can have coating 66C coinciding with the entire first side surface 62 of the substrate 60, with all peripheral edges of the product presenting an edge of the coating 66C and an edge of the substrate 60, and with second side surface 64 of substrate 60 exposed as an outermost surface of the coated medical product.
  • the first coating 66C and when included the second coating 68C each only partially penetrate through the thickness of the multilaminate porous sheet substrate 60.
  • their respective penetration depths through the thickness of the substrate 60 can be such that the coatings 66C and 68C to not overlap in the thickness of the substrate 60.
  • the coated medical product can include an interior region of the substrate 60, for example a thickness stratum, in which the pores of the substrate 60 are not filled with any polymeric substance(s), but rather can be open pores, e.g. providing an open porous stratum within the thickness of the substrate 60.
  • Such open pores or open porous stratum can facilitate cellular Invasion into the substrate 60 upon implantation of the coated medical product.
  • an open porous stratum can in some embodiments represent at least about 10% of the thickness of the substrate 60, for example with this value being in the range of about 10% to about 80% of the thickness of the substrate 60.
  • such an open porous stratum can include the entirety of at least one ECM layer of a multilaminate porous sheet substrate including at least three, for example three to ten, ECM layers laminated together (in the depicted embodiment including two such layers 60b and 60c) and/or the infiltrating portions 66C-b and 68C-b of coatings 66C and 68C, respectively, can be limited to occurring within respective outermost ECM layers (e.g. 60a and 60d) of the multilaminate porous sheet substrate (e.g. 60) that provide first and second outer surfaces (e.g. 62 and 64) of the multilaminate porous sheet substrate.
  • ECM layers laminated together in the depicted embodiment including two such layers 60b and 60c
  • the infiltrating portions 66C-b and 68C-b of coatings 66C and 68C, respectively can be limited to occurring within respective outermost ECM layers (e.g. 60a and 60d) of the multilaminate porous sheet substrate (e
  • the first liquid coating medium 66L and/or the second liquid coating medium 681 can be applied to the substrate 60 in any suitable manner.
  • the first liquid coating medium 66L and/or the second liquid coating medium 68L will be applied in a controlled volume from a volume-measuring device.
  • the volume-measuring device can be any suitable such a device, including, for example, a syringe, a pipette, or the like.
  • the volume of the liquid coating medium 661 and/or 681 will be applied by gravitational flow onto the respective side surface 62 or 64.
  • the applied volume of the liquid coating medium 661 and/or 681 can then be caused to level on the respective first or second side surface 62 or 64 of the substrate 60 thereby forming a respective first and/or second liquid coating medium surface 661- S/68L-S.
  • the applied volume of the first and/or second liquid coating medium 66L/68L Is allowed to level to gravity without contacting the liquid coating medium with any mechanical element that applies a force to spread the liquid coating medium on the respective first or second side surface 62/64 and/or to drive the liquid coating medium into the porous structure of the multilaminate porous sheet substrate 60.
  • the spreading of the applied volume of the first and/or second liquid coating medium 66L/68L upon the respective first or second side surface 62/64 may be facilitated by methods that apply forces to the liquid coating medium 661/681 that are other than gravity in a direction normal to the respective first or second side surface 62/64, but that avoid contact of the liquid coating medium 66L/68L with a mechanical element configured for spreading the liquid coating medium.
  • Such processes may for example include vibration, tilting the substrate 60 (e.g. by tilting a frame/substrate assembly as described herein) relative to horizontal to gravity, application of forced air or other gas, and/or other such methods.
  • the spread liquid coating medium 66L/68L can in some aspects then be allowed to self-level to gravity with the respective first or second side surface 62/64 positioned horizontal to gravity, in other aspects, such non- mechanical-contact spreading methods are not used, and the applied volume of the liquid coating medium 66L/68L is allowed to spread and level to gravity with the substrate 60 remaining static in position with the respective first or second side surface 62/64 horizontal to gravity and without the use of any mechanical element that contacts the liquid coating medium 66L/68L to spread it after it has been applied to the respective first or second side surface 62/64.
  • FIG. 14 provides a cross-sectional view illustrating an embodiment of a multilaminate porous sheet substrate 80 including a plurality of deceilularized ECM layers (four layers in the specific depicted embodiment) 80a, 80b, 80c and 80d laminated together.
  • Porous sheet substrate 80 has a first side surface 82 and a second side surface 84 opposite the first surface.
  • FIG. 14 also depicts a volume of a first liquid coating medium 861 applied to the multilaminate porous sheet substrate 80 and including a first portion 86L-a pooled above the surface 82 and a second portion 86L-b infiltrating pores of the substrate 80 and extending only partially through the thickness of the substrate 80 (in the illustrated embodiment being confined within the substrate 80 such that it does not penetrate into the opposite outermost ECM layer 80d providing the second side surface 84).
  • the volume of the first liquid coating medium 861 forms a liquid surface 86L-S, for example self-leveled to gravity as discussed hereinabove.
  • the first coating 86C includes a conformal layer 86C-a of the polymeric substance(s) occurring overtop the first side surface 82 of the multilaminate porous sheet substrate 80.
  • the conformal layer 86C-a of the polymeric substance(s) can in some forms be characterized as molecules of the polymeric substance(s) self-coalesced onto the first side surface 82 under the force of gravity.
  • Such a self-coalesced polymeric substance(s) layer 86C-a can be prepared using drying methods as discussed above in which the liquid surface 86L-S of the first liquid coating medium 861 is freely exposed to and forms a liquid-gas interface with a gaseous drying atmosphere. In this manner, the coating surface 86C-S of the coating 86C takes a form resultant of self-coalescing of molecules of the polymeric substance(s) under the force of gravity as the solvent of the first liquid coating medium 861 is evaporated or otherwise removed.
  • the first coating 86C also includes an infiltrating portion 86C-b including molecules of the polymeric substance(s) from the first liquid coating medium 861 infiltrating pores of the substrate 80 and extending only partially through the thickness of the substrate 80 (in the illustrated embodiment being confined within the substrate 80 outermost ECM layer 60a providing the first side surface 62).
  • a coating will also be applied to the second side surface 84 of substrate 80 to provide the coated medical product.
  • a coating can be compositionally the same as the coating 86C or can be compositionally different from the coating 86C.
  • the second coating can be applied by repeating the above-described steps for applying coating 86C to first side surface 82 in respect of the second side surface 84, with the same liquid coating medium or a different liquid coating medium.
  • FIG. 16 shown in FIG. 16 is a view of the substrate 80 and coating 86C of FIG. 15 in an inverted position.
  • second side surface 84 of substrate 80 is positioned upward and generally horizontal relative to gravity.
  • a volume of a second liquid coating medium 88L containing one or more polymeric substances, which can be compositionally the same as or different from the first liquid coating medium 861, has been applied to the second side surface 84 of the substrate 80.
  • the applied volume of the second liquid coating medium 88L includes a first portion 88L-a pooled above the surface 84 and a second portion 88L-b infiltrating pores of the substrate 80 and extending only partially through the thickness of the substrate 80 ⁇ in the illustrated embodiment being confined within substrate 80 such that it does not penetrate into the outermost ECM layer 80a providing the first side surface 82 of the substrate 80).
  • the volume of the second liquid coating medium 881 forms a liquid surface 88L-S, for example self-leveled to gravity as discussed herein.
  • the thus- prepared product includes an intermediate thickness stratum 90M intermediate to a first thickness stratum 90-86C and a second thickness stratum 90-881.
  • the intermediate thickness stratum 90M includes a mixture of polymeric substance(s) molecules from the second liquid coating medium 881 and the previously-applied first coating 86C.
  • the intermediate thickness stratum 90M may also include solvent from the second liquid coating medium 88L, and it will be understood that in some cases this solvent may redissolve some or all of the polymeric substance(s) molecules of the previously-applied first coating 86C.
  • the first thickness stratum 90-86C will include polymeric substance(s) molecules of the first coating 86C but not of the second liquid coating medium 881.
  • the second thickness stratum 90-881 will include polymeric substance(s) molecules of the second liquid coating medium 88L but not of the first coating 86C.
  • drying and/or other treating conditions can be applied to form a second coating 88C including the polymeric substance(s) that were in the second liquid coating medium 881.
  • the second coating 88C includes a conformal layer 88C-a of the polymeric substance(s) occurring overtop the second side surface 84 of the multilaminate porous sheet substrate 80.
  • the conformal layer 88C-a of the polymeric substance(s) can in some forms be characterized as molecules of the polymeric substance(s) self-coalesced onto the second side surface 84 under the force of gravity.
  • Such a self-coalesced polymeric substance(s) layer 88C-a can be prepared using drying methods as discussed above in which the liquid surface 881- S of the second liquid coating medium 88L is freely exposed to and forms a liquid-gas interface with a gaseous drying atmosphere. In this manner, the coating surface 88C-S of the coating 88C takes a form resultant of self-coalescing of molecules of the polymeric substance(s) under the force of gravity as the solvent of the second liquid coating medium 88L is evaporated or otherwise removed.
  • the second coating 88C also includes an infiltrating portion 88C-b including molecules of the polymeric substance(s) from the second liquid coating medium 881 infiltrating pores of the substrate 80 and extending only partially through the thickness of the substrate 80 (in the illustrated embodiment being confined within substrate 80 such that it does not penetrate into the opposite outermost ECM layer 80a providing the first side surface 82 of the substrate 80).
  • the thus- prepared product includes an intermediate thickness stratum 90MC intermediate to first thickness stratum 90-86C and second thickness stratum 90-88C.
  • the intermediate thickness stratum 90MC includes a mixed coating including polymeric substance(s) of both the second coating 88C and the first coating 86C.
  • the first thickness stratum 90- 86C includes polymeric substance(s) of the first coating 86C but not of the second coating 88C.
  • the second thickness stratum 90-88C includes polymeric substance(s) of the second coating 88C but not of the first coating 86C.
  • the intermediate, first and second thickness strata 90MC, 90*86C and 90-88C can differ from one another in respect of the types of polymeric substance(s) that are present.
  • the intermediate, first and second thickness strata 90MC, 90-86C and 90-88C can differ from one another in respect of the ratio of multiple polymeric substance(s) to one another and/or in respect of the abundance of the polymeric substance(s) present (e.g.
  • Intermediate thickness stratum 90MC can in some embodiments represent at least about 10% of the thickness of the substrate 80, for example with this value being in the range of about 10% to about 80% of the thickness of the substrate 80.
  • the first stratum 90-86C can include at least the entire thickness of an outermost ECM layer of substrate 80 providing side surface 82 and/or the second stratum 90-88C can include at least the entire thickness of an outermost ECM layer of the substrate 80 providing second side surface 84.
  • muitilaminate substrate 80 has four ECM layers, it will be understood that these features can also be present for example in multilaminate substrates having other numbers of ECM layers laminated together, for example at least three and in some forms three to ten ECM layers laminated together.
  • the substrate 80 with coatings 86C and 88C thereon as depicted in FIG, 17, or a segment thereof can be isoiated and further processed herein (e.g. packaged and/or sterilized as described below) to provide a coated medical product.
  • a segment of the coated substrate 80 as depicted in FIG. 17 is cut away, for example by die cutting, from a remainder of the coated substrate 80.
  • the segment can for example substantially correspond to the inner segment of the coated substrate occurring within the aligned openings 106 and 108 of the frame components 100 and 102 (see FIGs. 1-7).
  • Such coated medical products can include the substrate 80, coating 86C presenting surface 86C-S, and coating 88C presenting surface 88C-S.
  • coated medical products can have coating 86C coinciding with the entire first side surface 82 of the substrate 80 and coating 88C coinciding with the entire second side surface 84 of substrate 80, with all peripheral edges of the product presenting an edge of the intermediate thickness stratum 90MC, an edge of the first thickness stratum 90-86C, and an edge of the second thickness stratum 90-88C.
  • coated medical products shaped as a flat sheet are desirable for many applications, for other applications the coated medical product may benefit from having a shape other than a flat sheet. Additional embodiments of the present disclosure relate to such coated medical products having a shape other than a flat sheet, to methods for their preparation, and to methods for their use.
  • Such coated medical products may have a curved sheet shape, for example having an elongate curl shape in which the coated substrate forms walls curving circumferentially to less than or equal to 360 degrees so as to present longitudinally-extending edges in a non-overiapped condition, or having an elongate curl shape in which the coated substrate forms walls curving circumferentially to greater than 360 degrees so as to present longitudinally- extending edges in an overlapped condition, in some forms, these or other coated medical products having a shape other than a flat sheet can be prepared by re-shaping a starting coated medical product that is in a flat sheet form, for example a flat coated medical product as described herein and/or prepared using a method as described herein.
  • a dried starting coated medical product that is in a flat sheet form can be moistened with a liquid, for example an aqueous liquid such as water, and dried while holding the product in a shape other than a flat sheet form, to impart memory for a shape other than a flat sheet form, for example a shape as described above.
  • the starting coated medical product can be moistened before and/or after positioning it to the shape other than a flat sheet.
  • the moistening can be achieved by subjecting the coated medical product to a gaseous atmosphere including a vapor of the moistening liquid, for example a gaseous atmosphere humidified with water.
  • the moistening of the coated medical product will be controlled to increase conformability of and remove shape memory of the product for the flat sheet form but avoid causing the coating(s) on the substrate to become flowable, for example under the force of gravity.
  • This can be beneficial in preserving qualities of the coating(s) in the transition from the shape of a fiat sheet to a shape other than a fiat sheet.
  • FIG. 18 provides a cross-sectional view of a coated medical product 120 mounted and held in a curled shape having walls curving circumferentially to less than 360 degrees.
  • Coated medical product 120 has a porous sheet substrate as described herein, preferably a multilaminate porous sheet substrate including or constituted of a plurality of decelluiarized ECM layers laminated together.
  • Coated medical product 120 also includes at least a first coating including polymeric substance(s), e.g.
  • the coated medical product 120 is held in the curled shape mounted on an inner support 122, such as a tube.
  • Inner support 122 has a convexly-curved (e.g. cylindrical) outer surface 124 against which is received a concavely-curved inner surface 126 of the product 120,
  • An outer member 128 holds the product 120 in place with its surface 126 against the outer surface 124 of support 122.
  • outer member 128 includes a concavely- curved (e.g. cylindrical) inner surface 130 received against a convexly-curved outer surface 132 of the product 120.
  • outer member 128 and/or inner support 122 can be permeable to a gas including a moistening vapor as discussed below that is used to moisten the product 120.
  • outer member 128 and/or inner support 122 can as examples be porous or perforated.
  • outer member 128 and/or inner support 122 can be composed of a porous film of spunbound polymer (e.g. polyethylene) fibers, for example as occurs in Tyvek® films, that is permeable to the gas including the moistening vapor.
  • spunbound polymer e.g. polyethylene
  • the product layup shown in FIG. 18 can be subjected to any suitable conditions to moisten the product 120.
  • the product layup is exposed to a gas environment, for example within an environmentally-controlled chamber, that includes a vapor that condenses upon and moistens the product 120.
  • a humidified (i.e, with water) gas such as humidified air
  • Humidified air or other gas having a relative humidity level of at least 90%, or at least 95% can be used, for example such humidity level being in the range of 90-100% or in the range of 95-100% in some aspects.
  • the humidified air or other gas, or other moistening gas environment can be at any suitable temperature, with temperatures in the range of about 4°C to about GO'X, or about 15°C to about 40°C, being used in some embodiments.
  • the period of time for exposure of the product layup to the moistening gas environment will typically be at least about 3 minutes, or at least about 10 minutes, and in some aspects in the range of about 3 minutes to about 24 hours or about 20 minutes to about 5 hours.
  • these and other conditions of the moistening operation will desirably be controlled to increase conformability of and remove shape memory of the product 120 for a flat sheet form but avoid rendering flowable the coating(s) on the substrate of the product 120.
  • the product layup of FIG. 18 can be subjected to drying conditions. Any suitable drying conditions can be used, including as examples air drying, oven drying, convection drying, lyophilization and/or vacuum pressing. Drying conducted at temperatures not exceeding about 50 c C, for example at a temperature in the range of about 20°C to about 50 'C, wili be preferred in some aspects.
  • the dried product 120 will have shape memory for a shape other than a flat shape, for example for a curled shape having walls curving circumferentially to less than 360 degrees. Such curled shape may be as product 120 was shaped around inner support 122 or a curled shape after product has partially but not completely rebounded toward a flat shape.
  • the support 122, product 120 layup, moistening and drying conditions can be controlled so that the relaxed shape of the completed product 120, absent applied external forces, is the desired shape.
  • product 120 has walls that curve circumferentially less than 360 degrees, for example walls that curve to circumferentially extend greater than 270 degrees but no more than about 355 degrees, so as to leave a first longitudinally-extending edge 134 and a second longitudinally-extending edge 136 that are not circumferentially overlapped with respect to one another, defining a gap 138 therebetween.
  • Product 120 has a concavely- curved inner surface 126 and an opposite convexly-curved outer surface 132.
  • product 120 includes a porous sheet substrate, for example any of those disclosed herein, and at least a first coating including polymeric substance(s), for example any of those disclosed herein.
  • Beneficial coated medical products 120 can be formed from coated medical products as described hereinabove In conjunction with FIGs. 8-17.
  • the concavely-curved inner surface 126 of the product 120 is provided by the surface of the first coating (e.g. coating surface 40C-S or 66C-S as described above), and in other forms the convexly-curved outer surface 132 of the product 120 is provided by the surface of the first coating (e.g. coating surface 40C-S or 66C-S as described above).
  • the product 120 includes both a first coating including polymeric substance(s) and a second coating including polymeric substance(s), each of which penetrates only partially through the porous sheet substrate
  • the concavely-curved inner surface 126 of the product 120 is provided by the surface of the first coating (e.g. coating surface 40C-S or 66C-S as described above) while the convexly- curved outer surface 132 of the product 120 is provided by the surface of the second coating (e.g.
  • the concavely-curved inner surface 126 of the product 120 is provided by the surface of the second coating (e.g, coating surface 42C-S or 68C-S as described above) while the convexly-curved outer surface 132 of the product 120 is provided by the surface of the first coating (e.g. coating surface 40C-S or 66C-S as described above).
  • FIG. 20 provides a cross-sectional view of a coated medical product 140 mounted and held in a curled shape having walls curving circumferentially to greater than 360 degrees.
  • Coated medical product 140 has a porous sheet substrate as described herein, preferably a multilaminate porous sheet substrate including or constituted of a plurality of decellularized ECM layers laminated together.
  • Coated medical product 140 also includes at least a first coating including polymeric substance(s), e.g. as described herein, in some forms only a first coating including polymeric substance(s), e.g.
  • the coated medical product 140 is held in the curled shape mounted on an inner support 142, such as a tube.
  • Inner support 142 has a convexly -curved (e.g. cylindrical) outer surface 144 against which is received a concavely-curved inner surface 146 of the product 140.
  • An outer member 148 holds the product 140 in place with its surface 146 against the outer surface 144 of support 142.
  • outer member 148 includes a concavely- curved inner surface 150 received against a convexly-curved outer surface 1S2 of the product 140.
  • the product 140 is held in a curled shape having curved walls that circumferentially extend greater than 360 degrees, providing an overlap region 154 in which the product 140 overlaps itself.
  • the overlap region 154 is moderate in extent, for example wherein the curved walls of product 140 circumferentially extend greater than 360 degrees but no more than about 450 degrees, or no more than about 400 degrees.
  • a layer of the outer member 148 is interposed between the adjacent surfaces of the product 140.
  • outer member 148 and/or inner support 142 can be permeable to a gas Including a moistening vapor as discussed below that is used to moisten the product 140.
  • outer member 148 and/or inner support 142 can as examples be porous or perforated.
  • outer member 148 and/or inner support 142 can be composed of a porous film of spunbound polymer (e.g. polyethylene) fibers, for example as occurs in Tyvek® films, that is permeable to the gas including the moistening vapor.
  • spunbound polymer e.g. polyethylene
  • the product layup shown in FIG. 20 can be subjected to any suitable conditions to moisten the product 140, for example any of those conditions disclosed above with respect to the product layup shown in FIG. 18. As disclosed above, these and other conditions of the moistening operation will desirably be controlled to increase conformability of and remove shape memory of the product 140 for a flat sheet form but avoid rendering flowable the coating(s) on the substrate of the product 140.
  • the product layup of FIG. 20 can be subjected to drying conditions. Any suitable drying conditions can be used, including for example any of those disclosed above with respect to the product layup shown in FIG. 18.
  • the dried product 140 will have shape memory for a shape other than a flat shape, for example for a curled shape having walls curving circumferentially to greater than 360 degrees, providing an overlap region 154 in the dried product.
  • Such curled shape, and the overlap region 154 may be as product 140 was shaped around inner support 142 or a curled shape after product has partially but not completely rebounded toward a flat shape, leaving a reduced but nonetheless present overlap region 154.
  • the dried product includes a first longitudinally extending edge 156 and a second longitudinally-extending edge 158 (shown in phantom in FIG. 21), with the overlap region 154 defined between them.
  • the dried product 140 is not bonded to itself in the overlap region 154 and thus can be forced from an original set shape to uncurl the product 140 sufficiently to remove the overlap region 154 and provide a longitudinally- extending opening (e.g. for receiving an elongate tissue structure within the product 140).
  • the force can thereafter be discontinued whereupon the product will re-curl at least toward its original set shape having overlap region 154, potentially to again provide at least some extent an of overlap region, or in some forms whereupon the product will re-curl to its original set shape having overlap region 154.
  • the support 142, product 140 layup, moistening and drying conditions can be controlled so that the relaxed shape of the completed product 140 after drying, absent applied external forces, is a desired shape having a desired overlap region 154.
  • product 140 includes a porous sheet substrate, for example any of those disclosed herein, and at least a first coating including polymeric substance(s), for example any of those disclosed herein.
  • Beneficial coated medical products 140 can be formed from coated medical products as described hereinabove in conjunction with FIGs. 8-17.
  • the concavely-curved inner surface 146 of the product 140 is provided by the surface of the first coating (e.g. coating surface 40C-S or 66C-S as described above), and in other forms the convexly-curved outer surface 152 of the product 140 is provided by the surface of the first coating ⁇ e.g. coating surface 40C-S or 66C-S as described above).
  • the concavely-curved inner surface 146 of the product 140 is provided by the surface of the first coating (e.g. coating surface 40C-S or 66C-S as described above) while the convexly- curved outer surface 152 of the product 140 is provided by the surface of the second coating (e.g. coating surface 42C-S or 68C-S as described above), and in other forms the concavely-curved inner surface 146 of the product 140 is provided by the surface of the second coating (e.g.
  • the exposure of the product layup of FIG, 18 or FIG, 20 (or otherwise a product layup constraining the coated medical product to a desired non-flat shape) to a gas environment to moisten the product (e.g. 120 or 140) can occur partially or completely within a controlled environment chamber in which the product (e.g, 120 or 140) is also sterilized, for example by exposure to a humidified gas atmosphere containing ethylene oxide vapor (e.g, at a relative humidity above 90%, or above 95%).
  • a humidified gas atmosphere containing ethylene oxide vapor e.g, at a relative humidity above 90%, or above 95%).
  • Such exposure to moisten the product can occur before, during and/or after a period in which the gas atmosphere within the chamber contains the ethylene oxide vapor.
  • the product e.g. 120 or 140
  • the product layup for example as depicted in FIG. 18 or FIG. 20, can be enclosed within sterile barrier packaging that is permeable to the humidified gas atmosphere(s) used. Drying of the product (e.g.
  • the product (e.g. 120 or 140) after such moistening processes can include any suitable drying method, and in some forms may be or include conditions for degassing the product (e.g. 120 or 140) to remove residual ethylene oxide from the sterilization.
  • the product layup e.g. as depicted in FIG. 18 or FIG. 20
  • the re-shaped product e.g. 120 or 140
  • the outer member e.g. 128 or 1408
  • inner support e.g. 122 or 142
  • the product (e.g. 120 or 140) can thereafter be implanted in a patient.
  • coated medical product e.g. 120 or 140
  • coated products herein will include a first coating including polymeric substance(s) and/or a second coating including polymeric substance(s) associated with the porous sheet substrate.
  • a wide variety of polymeric substance ⁇ s ⁇ will be suitable in the formation of coatings herein. These include as examples naturally-derived polymeric substances and/or synthetic polymeric substances.
  • the polymeric substance(s) can likewise provide a wide variety of functions to the coated medical product. These include for example providing an adhesive coating for example as described in U.S. Patent No. 10,500,309 issued December 10, 2019 or U.S. Patent No. 8,920,443 issued December 30, 2014, or U.S. Patent Application Publication No. US2022023489A1 dated January 27, 2022, a polymer hydrogel layer for example as described in U.S. Patent Application Publication No. US2001031974A1 dated October 18, 2001, an adhesive and/or lubricating polymer hydrogel coating for example as described in U.S. Patent Application Publication No. US2021046221A1 dated February 18, 2021, a drug-eluting coating for example as described in U.S.
  • Patent No. 11,065,368 issued July 20, 2021 an analgesic coating for example as described in U.S. Patent Application Publication No. US2009142400A1 dated June 4, 2009, an anti-tissue-adhesion coating for example as described in U.S. Patent Application Publication No. US2006251702A1 dated November 9, 2006, or other functional coating(s).
  • analgesic coating for example as described in U.S. Patent Application Publication No. US2009142400A1 dated June 4, 2009
  • an anti-tissue-adhesion coating for example as described in U.S. Patent Application Publication No. US2006251702A1 dated November 9, 2006, or other functional coating(s).
  • Coated medical products of the present disclosure may be configured for and may have any of a wide variety of medical applications. These include for example as bolster materials for reinforcing staple lines, e.g. wherein the coating(s) provide an adhesive function for adhering the porous sheet substrate to a stapler arm, for the repair or reconstruction of patient tissue structures such as body wall structures, e.g. wherein the coating(s) provide anti-tissue-adhesion properties and/or the local delivery of one or more drugs or other bioactive agents, or tendons, ligaments or nerves, e.g. wherein the coating(s) provide lubricating and/or anti-tissue-adhesion properties and/or the local delivery of one or more drugs or other bioactive agents (e.g. heparin, dermatan sulfate, FGF-2 or a neural growth stimulating agent), and others.
  • bioactive agents e.g. heparin, dermatan sulfate, FGF-2 or a neural growth stimulating agent
  • the polymeric substance(s) of the first coating and/or second coating will be or include a hydrogel-forming polymeric substance or a combination of hydrogelforming polymeric substances.
  • suitable hydrogel-forming polymeric substances may include, but are not limited to, poly-anion polymers (net negative charge to the polymer), including for example polysaccharide polymeric substances such as chondroitin sulfate and/or hyaluronic acid.
  • Additional anionic polymeric substances that may be used include for example chondroitin, alginate, alginic acid, oxidized cellulose (e.g. non -regenerated oxidized cellulose), heparin, and sulfated versions of these polymers, and combinations thereof.
  • the first coating and/or the second coating as disclosed herein will include, as hydrogel -form! ng polymeric substances, a combination of alginic acid or a salt thereof (e.g. sodium alginate) and hyaluronic acid or a salt thereof (e.g. sodium hyaluronate).
  • alginic acid or a salt thereof e.g. sodium alginate
  • hyaluronic acid or a salt thereof e.g. sodium hyaluronate
  • Cationic polymeric substances that may be used in embodiments of the present disclosure include for example poly-lysine, poly-ornithine, polyhexamethylene biguanide (PHMB), polyethyieneimine (PEI), diethylaminoethyl-dextran (DEAE-dextran), poly(amidoamine) (PAMAM), and quaternary ammonium versions of these polymers, and combinations thereof.
  • PHMB polyhexamethylene biguanide
  • PEI polyethyieneimine
  • DEAE-dextran diethylaminoethyl-dextran
  • PAMAM poly(amidoamine)
  • quaternary ammonium versions of these polymers and combinations thereof.
  • Porous sheet substrates of the present disclosure may be associated with the hydrogel-forming or other polymeric substance in various ways.
  • physical binding of the coating to the porous sheet substrate may be obtained by wetting the substrate with a liquid coating medium containing the polymeric substance(s), preferably in solvated form in the liquid medium, and thereafter drying the liquid coating medium.
  • the porous sheet substrate can be wetted with an aqueous liquid coating medium, for example an aqueous sol-gel, including the one or more hydrogel-forming polymeric substances prior to drying, resulting in an interpenetrating network of the polymeric substance(s) entrained in pores of the porous sheet substrate and preferably also a layer or layers of the polymeric substance(s) residing above a surface or surfaces of the substrate.
  • an aqueous liquid coating medium for example an aqueous sol-gel, including the one or more hydrogel-forming polymeric substances prior to drying, resulting in an interpenetrating network of the polymeric substance(s) entrained in pores of the porous sheet substrate and preferably also a layer or layers of the polymeric substance(s) residing above a surface or surfaces of the substrate.
  • the porous sheet substrate may be wetted with a solution of the hydrogel-forming and/or other polymeric substance(s) prior to drying and sterilization.
  • the polymeric substance(s) may be present on the surface of the porous sheet substrate, as well as within internal pores the substrate, and in some forms will not be covalently bound to the porous sheet substrate.
  • This may allow the hydrogel-forming and/or other polymeric substances to be retained at the surface of the porous sheet substrate and may allow migration and diffusion of the polymeric substances(s) within and around the substrate, in such an embodiment no reactive species may be needed between the polymeric substance(s) and the substrate, as the binding interaction may be physical intertangling of chains of the polymeric substance(s). if alginate or another ionic cross-linking polymeric substance is present, this physical intertangling effect can be further increased by introducing cross-link causing ions, for example calcium ions, to ionically cross-link the polymeric substance(s).
  • covalent linkages may be introduced between the polymeric substance(s) and the substrate.
  • aldehyde reactive groups on the polymeric substance(s) may form covalent linkages by their reaction with primary amine groups on the substrate, for example where the substrate includes a polypeptide containing primary amine groups, such as collagen.
  • the aldehyde reactive groups may be formed by oxidizing groups on the polymeric substance(s) in the presence of an oxidation agent.
  • the hydrogel-forming or other polymeric substance may be bound to the porous sheet substrate via other known binding techniques.
  • EDC l-Ethyl-3- ⁇ 3-dimethylaminopropyl ⁇ carbodiimide
  • NHS N- hydroxysuccinimide
  • sulfo-NHS N-hydroxysulfoxuccinimide
  • Porous sheet substrates with aldehyde reactive groups such as primary amine, tertiary amines, quartenary amines, or substituents with similar chemical properties, may be used in embodiments of the present disclosure. These sheet substrates may be similarly reacted with hydrogel-forming or other polymeric substances to form bonds with the aldehyde groups, or equivalent binding substituents, in the formation of a coated product as described herein.
  • the polymeric substance(s) can include both a positively charged polymeric substance and a negatively charged polymeric substance.
  • polyelectrolyte complexation may occur to result in a sol i d/ge I .
  • this may occur at physiological conditions when chitosan and hyaluronic acid are used in mixture as or in the polymeric substance(s) of a coating material herein.
  • the polymeric substance(s) utilized may have any suitable molecular weight. ! certain forms, the weight average molecular weight of the polymeric substance(s) will be in the range of about 10,000 Daltons (Da) to 4,000,000 Da, or in the range of about 1,000,00 to 2,000,000 Da.
  • coated medical products having a relatively high degree of lubricity may be provided by way of physical interpenetrations of the polymeric substance(s) at least in part into the porous sheet substrate.
  • a porous sheet substrate such as a multilaminate ECM layer substrate as discussed herein, may be coated with in an aqueous liquid coating medium including hyaluronic acid and alginate to at least partially diffuse the liquid coating medium into the membrane, if an ionic geliing polymer is used, care can be taken to avoid calcium or other multivalent cations during coating of the liquid coating medium onto the substrate, as the coating medium may gel prematurely.
  • the substrate and coating medium can be dried, for example using any of those coating and drying operations described elsewhere herein.
  • the alginate may provide some degree of ionic cross-linking in the presence of calcium ions and/or other divalent cations.
  • divalent cation sources include but are not limited to calcium chloride, calcium acetate, magnesium chloride, and magnesium acetate.
  • the ionic cross-linking may improve the retention of the hyaluronic acid and alginate over time, and may provide increased lubricity for the treated membrane over time, as compared to embodiments with lower degrees, or no, ionic cross-linking.
  • the polymeric substance(s) may include high molecular weight hyaluronic acid (e.g. 1 million Da or more), for example to provide a biocompatible lubricating layer.
  • hyaluronic acid e.g. 1 million Da or more
  • alginate may also provide some lubricity on its own. Further, alginate may perform as an ionically crosslinking polymer that may facilitate retaining the hyaluronate at the site of implant for a longer period.
  • the dried coating(s) containing polymeric substance(s) on the substrate may provide a reversible adhesive layer that is non-tacky in the dried state but becomes tacky when wetted with water or an otherwise biocompatible aqueous solution such as saline.
  • a coated medical device as described herein can be packaged and shipped in a dried state, and then wetted at the point of use (e.g. by attending medical personnel) to render the implantable material tacky.
  • suitable polymeric substance(s) for such dried coating(s) include polyvinyl pyrrolidones, polyvinyl alcohols, polyvinyl acetates, vinyl acetate esters, starches, dextrins, dextrans, carboxymethyl cellulose, carboxy methyl ethyl cellulose, hyaluronic acid, alginates, chondroitin sulfates, poly-lactides, gelatin, polyethylene glycols, poloxamers, carbomers, or blends or combinations thereof.
  • Additional polymeric substance(s) that may be used include hydroxypropyl cellulose, pullulan, gellan, carrageenan, xantham gum, and/or guar gum.
  • the level of loading of the polymeric substance(s) on the porous sheet substrate may vary with many factors including for example the particular polymeric substance(s) used, the intended function(s) of the applied coating(s), and the intended end use for the coated medical product.
  • a coating on the coated medical product will include the polymeric substance(s) at a level of about 0.25 mg/cm 2 to about 10 mg/cm 2 of the coating, more typically about 0.5 mg/cm 2 to about 5 mg/cm 2 of the coating. It will be understood that such levels may apply to a single coating when the coated medical product includes only a single coating, or may apply separately to multiple (e.g. two) separate coatings when the coated medical product includes multiple separate coatings.
  • a liquid coating medium as disclosed herein can include any suitable liquid solvent, including in some forms a mixed solvent.
  • the liquid solvent will be an aqueous liquid solvent.
  • the hydrogelforming polymeric substance(s) and the aqueous liquid solvent will form an aqueous colloidal liquid coating medium, which may in some aspects help to limit the penetration of the liquid coating medium into the substrate and thereby help to modulate the distribution of the polymeric substance(s) relative to the substrate as discussed herein.
  • the aqueous liquid solvent may for example be water, water mixed with one or more water-miscible organic solvents such as an alcohol (e.g. methanol) or ketone (e.g. acetone).
  • the liquid solvent of the coating medium will solvate the polymeric substance(s) of the coating medium.
  • the polymeric substance(s) in the liquid coating medium may be present at any suitable concentration.
  • the polymeric substance(s) of the coating medium, taken together when multiple polymeric substances are used, will be present at about 0.1% to about 20% by weight of the coating medium.
  • coated medical products as described herein can be provided sterile in a sterile barrier package, for example as illustrated in FIG. 22.
  • the sterile barrier package "P" which can for exampie be a single pouch or multiple pouch package, contains a coated medical product "CMP" as described herein, for example where product CMP is a product as depicted and discussed in conjunction with FIG. 8, FIG. 11, FIG. 13, FIG. 15, FIG. 17, FIG, 18, FIG. 19, FIG. 20, or FIG. 21.
  • the coated medical product CMP is terminally sterilized in the sterile barrier package P, for example by exposure to ethylene oxide gas or to sterilizing radiation.

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Abstract

L'invention concerne des produits médicaux revêtus comprenant au moins un premier revêtement composé d'une ou plusieurs substances polymères et, sous certaines formes, un second revêtement composé d'une ou plusieurs substances polymères, sur un substrat poreux en feuille tel qu'un substrat multicouche comportant une pluralité de couches de matrice extracellulaire décellularisée stratifiées. L'invention concerne également des méthodes de préparation et d'utilisation de tels produits médicaux revêtus.
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