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WO2025076043A1 - Compositions et méthodes pour une régénération tissulaire améliorée - Google Patents

Compositions et méthodes pour une régénération tissulaire améliorée Download PDF

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Publication number
WO2025076043A1
WO2025076043A1 PCT/US2024/049533 US2024049533W WO2025076043A1 WO 2025076043 A1 WO2025076043 A1 WO 2025076043A1 US 2024049533 W US2024049533 W US 2024049533W WO 2025076043 A1 WO2025076043 A1 WO 2025076043A1
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Prior art keywords
myofibroblast
binding agent
receptor binding
wound site
tissue wound
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Ioannis V. Yannas
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Massachusetts Institute of Technology
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Massachusetts Institute of Technology
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/39—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
    • 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
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
    • A61L26/0028—Polypeptides; Proteins; Degradation 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
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
    • A61L26/0028—Polypeptides; Proteins; Degradation products thereof
    • A61L26/0033—Collagen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0061—Use of materials characterised by their function or physical properties
    • A61L26/0066—Medicaments; Biocides
    • 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
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0061—Use of materials characterised by their function or physical properties
    • A61L26/0076—Sprayable compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
    • A61L27/24—Collagen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/78—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin or cold insoluble globulin [CIG]
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/412—Tissue-regenerating or healing or proliferative agents

Definitions

  • Wounds in mammals are closed by wound contraction and scar formation.
  • Wound contraction typically reduces the size of an injured area
  • scar formation typically seals the area and achieves secure closure.
  • INTEGRA® matrix wound dressing (Integra LifeSciences, USA) is a (if not the) leading treatment for regenerating skin in humans, e.g.. victims of bums, congenital nevi, chronic skin wounds, and other instances of skin loss.
  • the process of manufacturing INTEGRA® matrix wound dressing (Integra LifeSciences, USA), however, is complex and expensive.
  • the use or application of INTEGRA® matrix wound dressing (Integra LifeSciences, USA) also typically requires the sen-ices of a surgeon or other well-trained medical practitioner.
  • MFB myofibroblasts
  • AJs adherence junctions
  • MFB-MFB binding transforms the MFB inside a healing wound into a continuous MFB netw ork, which transfers mechanical forces rapidly and efficiently across the space of the entire wound.
  • This finding contradicts prevailing views of wound contraction, which assume that MFB apply contractile forces independently of each other, thereby requiring separate, extensive cell-by-cell blocking in order to achieve an effective treatment.
  • cell contraction activity is a “cooperative” process that likely depends, at least partially, on close synergy among the MFB.
  • methods of controlling, e.g., preventing or reducing, wound contraction include reducing or eliminating a contractile force applied at a tissue wound site by a continuous myofibroblast network.
  • the methods include contacting a tissue wound site and an amount of a myofibroblast receptor binding agent.
  • a continuous myofibroblast network may be present at the tissue wound site, and the amount of the myofibroblast receptor binding agent may be effective to (i) fracture the continuous myofibroblast network at one or more locations of the continuous myofibroblast network, (ii) reduce or eliminate a contractile force applied at the tissue wound site by the continuous myofibroblast network, or (iii) a combination thereof.
  • compositions are provided, such as compositions that may be used to block or reduce wound contraction.
  • the compositions include a biocompatible liquid, and a myofibroblast receptor binding agent dispersed in the biocompatible liquid.
  • the myofibroblast receptor binding agent may be soluble or partially soluble in the biocompatible liquid.
  • a material such as a myofibroblast receptor binding agent, is “soluble” in a liquid when the material has a solubility in the liquid of at least 1 g per 100 mL at room temperature and pressure.
  • a material is “partially soluble” in a liquid when the material has a solubility in the liquid that is greater than 0. 1 g and less than 1 g per 100 mL at room temperature and pressure.
  • kits of parts include a reservoir and an applicator, such as a nozzle or a needle.
  • the applicator such as the nozzle or the needle, may be attachable to the reservoir.
  • Any composition disclosed herein may be disposed (e.g., contained, stored, etc.) in the reservoir. The composition may be dispensed from the reservoir with the aid of the applicator.
  • FIG. 1A depicts an example of myofibroblasts contracting a wound.
  • FIG. IB depicts an example of myofibroblasts contracting a wound.
  • FIG. 2A depicts an example of myofibroblasts distributed at an embodiment of a wound site.
  • FIG. 2B depicts an example of my ofibroblasts distributed at an embodiment of a wound site.
  • FIG. 3A depicts an example of myofibroblasts in a wound grafted with an embodiment of a dermis regeneration template.
  • FIG. 3B depicts an example of myofibroblasts in a wound grafted with an embodiment of a dermis regeneration template.
  • FIG. 4A depicts an embodiment of a collagen scaffold of a first regenerative activity.
  • FIG. 4B depicts an embodiment of a collagen scaffold of a second regenerative activity.
  • FIG. 5 depicts a possible configuration of integrin binding to an embodiment of a collagen ligand.
  • FIG. 6 depicts an embodiment of a porous graft copolymer.
  • compositions, methods, and kits of parts that benefit from the surprising discovery that a myofibroblast (MFB), during normal wound closure by contraction, does not apply a contractile force individually (i.e., separately from other cells). Instead, these contractile cells are believed to act cooperatively by forming a continuous network, which can transfer mechanical forces over most, if not all, of a wound space rapidly and effectively, leading to efficient wound closure.
  • MFB myofibroblast
  • Fracturing the spatially continuous MFB network can be a simpler route towards deactivation of contraction and blocking scar formation than previously used processes, which include capturing individual MFB cells and deactivating them separately (which is done routinely with INTEGRA® matrix wound dressing (Integra LifeSciences, USA)).
  • compositions, kits, and methods described herein can permit a continuous MFB network to be fractured readily by applying an agent, such a collagen hexapeptide, without (i) the need to employ INTEGRA® matrix wound dressing (Integra LifeSciences, USA), and/or (ii) the sendees of a surgeon or other highly-trained medical practitioner.
  • an agent such as a collagen hexapeptide
  • the methods include reducing or eliminating a contractile force applied at a tissue wound site by a continuous myofibroblast network.
  • the reducing or eliminating of the contractile force may be achieved by any manner described herein.
  • the methods include contacting a tissue wound site and an amount of a myofibroblast receptor binding agent.
  • a continuous myofibroblast network may be present at the tissue wound site, and the amount of the myofibroblast receptor binding agent may be effective to (i) fracture the continuous myofibroblast network at one or more locations of the continuous myofibroblast network, (ii) reduce or eliminate a contractile force applied at the tissue wound site by the continuous myofibroblast network, or (iii) a combination thereof.
  • the methods provided herein prevent or reduce scar formation at the tissue wound site.
  • the prevention or reduction of scar formation may eliminate or reduce the risk of fibrosis.
  • a myofibroblast receptor binding agent may be applied independently of any other material, or the myofibroblast receptor binding agent may be applied in combination with at least one other material.
  • a myofibroblast receptor binding agent may be present in a liquid prior to the contacting of the tissue wound site. Therefore, the contacting of a tissue wound site and a myofibroblast receptor binding agent may include contacting the liquid and a tissue wound site in any manner, such as by injecting the liquid, spraying the liquid, applying the liquid by brush, dropper, or roller, etc.
  • the liquid for example, may be sprayed with any known apparatus onto a tissue wound site directly or indirectly, such as by spraying a bandage or other material that is applied to the tissue wound site.
  • the liquid may be injected.
  • the injection may occur at any location (e.g., at or near a tissue wound site) that is effective to contact the liquid and the tissue wound site.
  • a myofibroblast receptor binding agent may be soluble or partially soluble in the liquid.
  • compositions include a biocompatible liquid, and a myofibroblast receptor binding agent dispersed in the biocompatible liquid.
  • the biocompatible liquid may be an aqueous liquid or an organic liquid, and may include any one or more pharmaceutically acceptable additives, such as a preservative, a buffer, a pharmaceutical agent, a propellant, or a combination thereof.
  • a myofibroblast receptor binding agent is soluble or partially soluble in the biocompatible liquid.
  • a myofibroblast receptor binding agent may be present in a liquid at any concentration, such as at least 1 wt%, at least 5 wt%, at least 10 wt%, at least 25 wt%, or at least 50 wt%, based on the total weight of the liquid and the myofibroblast receptor binding agent.
  • a myofibroblast receptor binding agent may be present in the liquid at a concentration of about 1 ⁇ 1% to about 60 wt%, about 1 ⁇ 1% to about 50 wt%, about 1 wt% to about 40 wt%, about 1 wt% to about 30 wt%, about 1 wt% to about 20 wt%, or about 1 wt% to about 10 wt%, based on the total weight of the liquid and the myofibroblast receptor binding agent.
  • kits of parts include a reservoir and an applicator.
  • the applicator may be attachable to the reservoir.
  • the applicator may be configured to dispense a composition from the reservoir.
  • the applicator includes a nozzle, a needle, a brush, a dropper, a roller, etc.
  • compositions described herein may be disposed (e.g., contained, stored, etc.) in the reservoir.
  • the reservoir may be a reservoir of a spray bottle.
  • the spraybottle may be an aerosol or non-aerosol spray bottle.
  • the reservoir may be a reservoir of a syringe.
  • the applicator may include a nozzle.
  • the nozzle may be attachable to the reservoir, and configured for spraying the composition directly or indirectly, as described herein, on a tissue wound site.
  • the applicator also may include a needle.
  • the needle may be attachable to a reservoir, and configured for injecting the composition.
  • a myofibroblast receptor binding agent used in the methods, compositions, and kits provided herein may include any agent that binds a myofibroblast receptor.
  • a myofibroblast receptor binding agent may bind to integrin a2pi, integrin a2(12, or a combination thereof.
  • the myofibroblast receptor binding agent includes a hexapeptide, such as a collagen hexapeptide.
  • a collagen hexapeptide may include GFOGER (glycine-phenylalanine-hydroxyproline-glycine-glutamic acid-arginine) and/or GLOGER (gly cine-1 eucine-hydroxyproline-glycine-glutamic acid-arginine).
  • a tissue wound site may be present in or on a mammal, such as a human or non-human mammal.
  • An organ such as a human organ, may include a tissue wound site.
  • a tissue wound site may be present in or on a heart, a kidney, or a liver. Other tissues are envisioned, however, such as nerves, skin. etc.
  • the present disclosure may address one or more of the problems and deficiencies of known methods and processes. However, it is contemplated that various embodiments may prove useful in addressing other problems and deficiencies in a number of technical areas. Therefore, the present disclosure should not necessarily be construed as limited to addressing any of the particular problems or deficiencies discussed herein.
  • a myofibroblast receptor binding agent may be present in the liquid at a concentration of about 1 wt% to about 10 wt%, based on the total w eight of the liquid and the myofibroblast receptor binding agent. This disclosure should be interpreted as including concentrations of “about 1 wt%” and “about 10 wt%”.
  • the term “about” means plus or minus 10 % of the numerical value of the number with which it is being used.
  • Embodiment 1 A method of preventing or reducing wound contraction, the method comprising, consisting essentially of, or consisting of - [0054] contacting a tissue wound site and an amount of a myofibroblast receptor binding agent; [0055] wherein a continuous myofibroblast network is present at the tissue wound site.
  • Embodiment 2 A method of preventing or reducing wound contraction, the method comprising, consisting essentially of, or consisting of -
  • Embodiment 3 The method of Embodiment 2, wherein the reducing or the eliminating of the contractile force prevents or reduces scar formation at the tissue wound site.
  • Embodiment 4 A composition comprising, consisting essentially of, or consisting of -
  • a liquid such as a biocompatible liquid
  • a myofibroblast receptor binding agent dispersed in the liquid.
  • Embodiment 5 A kit of parts comprising, consisting essentially of, or consisting of -
  • a reservoir in which the composition of Embodiment 4 is disposed e.g., contained, stored, etc.
  • the applicator includes (a) a nozzle that is attachable to the reserv oir. and configured for spraying the composition, or (b) a needle that is attachable to the reservoir, and configured for injecting the composition.
  • Embodiment 6 The method or composition of any of the preceding Embodiments, wherein the myofibroblast receptor binding agent is present in a liquid, such as the biocompatible liquid, at a concentration of at least 1 wt%, at least 5 wt%, at least 10 wt%, at least 25 wt%, or at least 50 wt%, based on the total weight of the liquid and the myofibroblast receptor binding agent.
  • a liquid such as the biocompatible liquid
  • Embodiment 7 The method or composition of any of the preceding embodiments, wherein the myofibroblast receptor binding agent is present in a liquid, such as the biocompatible liquid, at a concentration of about 1 wt% to about 60 wt%. about 1 wt% to about 50 wt%, about 1 wt% to about 40 wt%, about 1 wt% to about 30 wt%, about 1 wt% to about 20 wt%, or about 1 wt% to about 10 wt%, based on the total weight of the myofibroblast receptor binding agent and the liquid.
  • Embodiment 8 The method or composition of any of the preceding Embodiments, wherein the amount of the myofibroblast receptor binding agent is effective to-
  • Embodiment 9 The method or composition of any of the preceding Embodiments, wherein the contacting of the tissue wound site and the amount of the myofibroblast receptor binding agent prevents or reduces scar formation at the tissue wound site.
  • Embodiment 10 The method or composition of any of the preceding Embodiments, wherein the contacting of the tissue wound site and the amount of the myofibroblast receptor binding agent eliminates or reduces fibrosis, such as fibrosis at the tissue wound site.
  • Embodiment 11 The method or composition of any of the preceding Embodiments, wherein the myofibroblast receptor binding agent is present in a liquid, such as the biocompatible liquid, prior to the contacting of the tissue wound site.
  • Embodiment 12 The method or composition of any of the preceding Embodiments, wherein the contacting of the tissue wound site and the amount of the myofibroblast receptor binding agent comprises, consists essentially of, or consists of- [0076] (i) spraying the liquid,
  • Embodiment 13 The method or composition of any of the preceding Embodiments, wherein the myofibroblast receptor binding agent is soluble in the liquid or partially soluble in the liquid.
  • Embodiment 14 The method or composition of any of the preceding Embodiments, wherein the myofibroblast receptor binding agent comprises, consists essentially of, or consists of a collagen hexapeptide.
  • Embodiment 15 The method or composition of any of the preceding Embodiments, wherein the collagen hexapeptide comprises, consists essentially of, or consists of-
  • GFOGER glycine-phenylalanine-hydroxyproline-glycine-glutamic acid- arginine
  • GLOGER glycine-leucine-hydroxyproline-glycine-glutamic acid- arginine
  • Embodiment 16 The method or composition of any of the preceding Embodiments, wherein the myofibroblast receptor binding agent binds to integrin a2pi, integrin a2p2, or a combination thereof.
  • Embodiment 17 The method or composition of any of the preceding Embodiments, wherein the tissue wound site is present in or on a mammal.
  • Embodiment 18 The method or composition of any of the preceding Embodiments, wherein the mammal is a human.
  • Embodiment 19 The method or composition of any of the preceding Embodiments, wherein the tissue wound site is in or on an organ.
  • Embodiment 20 The method or composition of any of the preceding Embodiments, wherein the organ is a heart, a kidney, or a liver.
  • Regeneration was induced by grafting the wound site with a contractionblocking scaffold based on a highly porous scaffold based on Type I collagen copolymerized with a glycosaminoglygan (GAG), named the dermis regeneration template (DRT) (I. V. Yannas, et al. Proc Nat. Acad Sci USA 86. 933-937 (1989); and I. V. Yannas, Tissue and organ regeneration in adults, Extension of the paradigm to several organs (Springer, ed. 2, 2015)).
  • DTT dermis regeneration template
  • npj Regen Med 5, 1-14 (2020) can become clinical treatments for several terminally diseased organs, as well as contribute to resolution of fibrosis.
  • the physiological wound contraction process requires the presence of differentiated fibroblasts, known as myofibroblasts (MFB) (G. Gabbiani, et al. Experientia 27, 549-550 (1971); O Skalli, et al. J Cell Biol 103. 2787-2796 (1986); 1. Darby, et al. Lab Invest 63, 21-29. (1990), B. Hinz, et al. Mol Biol Cell 12. 2730-2741 (2001 )).
  • myofibroblasts known as myofibroblasts (MFB)
  • a well-known characteristic feature of MFB during wound contraction is the presence of stress fibers, which are muscle-like filaments containing alpha-smooth muscle actin (alpha-SMA), which is a widely recognized MFB marker (O. Skalli, et al. J Cell Biol 103, 2787-2796 (1986), I. Darby, et al. Lab Invest 63, 21-29. (1990); B. Hinz, et al. Mol Biol Cell 12, 2730-2741 (2001 )).
  • stress fibers which are muscle-like filaments containing alpha-smooth muscle actin (alpha-SMA), which is a widely recognized MFB marker (O. Skalli, et al. J Cell Biol 103, 2787-2796 (1986), I. Darby, et al. Lab Invest 63, 21-29. (1990); B. Hinz, et al. Mol Biol Cell 12, 2730-2741 (2001 )).
  • MFB clusters extended across large swaths of the healing wound in skin (FIG. 2A) and nerve (FIG. 2B), an observation that led to the hypothesis that DRT disrupted a “mechanically coherent” organization of MFB (I. V. Yannas, Wound repair regen 6, 518- 523 (1998)).
  • a related hypothesis of intercellular transmission of MFB -mediated contractile force across a distance was independently supported experimentally. (B. Hinz, et al. Mol Biol Cell 15, 4310-4320 (2004)). Indeed, wound closure by cell-cell transfer of mechanical contraction forces across the entire span of the wound perimeter was most simply explained by cell-cell cooperativity. It appeared futile to contemplate wound closure by invoking individual cell activity 7 .
  • FIG. 1A and FIG. IB depict myofibroblasts contracting examples of wounds physiologically in two animal wound models. In physiologically healing skin wounds and peripheral nen e wounds myofibroblasts close wounds by contraction.
  • FIG. 1A depicts a fullthickness excised dorsal skin wound (guinea pig) 10 days post injury.
  • FIG. IB depicts a stump of transected sciatic nerve (rat) 7 days post injury.
  • MFB myofibroblasts stained with antibody to alpha-SMA. Scale bars: 100 micron.
  • FIG. 2B depict myofibroblasts distributed around wounds physiologically in skin and peripheral nen e, respectively; specifically, the figures depict longitudinal section views of physiologically healing skin wounds and peripheral nerve wounds. Myofibroblasts were abundantly present while closing wounds by contraction.
  • FIG. 2A depicts a longitudinal section of an excised full-thickness skin wound (guinea pig, 10 days post injury). Skin wounds contracted in a plane stress field (Vertical arrows). Skin wound edges prior to full-thickness excision were indicated.
  • FIG. 2B depicts longitudinal sections of a transected peripheral nerve (rat) inserted in a silicone tube, relatively inactive regeneratively and used as control (initially 10-mm gap between stumps, specimen was harvested midway between stumps 11 days post injury).
  • MFB density was very high, which facilitated cell-cell contacts; extensive MFB clustering took place, which permitted the formation of a dense AJ-bonded network throughout the wound; and long axes of MFB were oriented along a wound axis, which suggested the presence of a macroscopic force vector that directed wound closure.
  • the presumptive force vector was planar in skin wounds and circumferential in a nerve stump following transection.
  • DRT dermis regeneration template
  • FIG. 3A Immunohistochemical staining data, are shown in FIG. 3A for a skin wound and in FIG. 3B for a peripheral nerve wound, and additionally in the excised rabbit eye conjunctiva (I. V. Yannas, et al, npj Regen Med 6, 39 (2021)).
  • FIG. 3A and FIG. 3B depict myofibroblasts in wounds grafted with an embodiment of a dermis regeneration template (DRT).
  • FIG. 3A depicts a full-thickness excised dorsal skin wound grafted with DRT (guinea pig, 10 days post injury).
  • FIG. 3B depicts a stump of a transected sciatic nen e tubulated with DRT (rat, 7 days post injury ).
  • Myofibroblasts were stained with antibody to aSMA.
  • F fibroblasts. Arrows, DRT scaffold struts. Scale bars: 100 pm. (I. V. Yannas, Tissue and organ regeneration in adults, Extension of the paradigm to several organs (Springer, ed. 2, 2015)).
  • FIG. 5 depicts integrin binding to a collagen ligand on a DRT surface.
  • the image is based on a cry stallographic study of a complex between the I domain of integrin a2[31 (510) and a critical GFOGER motif (530) located in the triple helical collagen molecule (520) (J. Emsleyet al. Cell 101, 47-56).
  • GFOGER is abbreviation for the collagen hexapeptide glycine-phenylalanine-hydroxyproline-glycine-glutamic acid-arginine (I. V. Yannas, Tissue and organ regeneration in adults, Extension of the paradigm to several organs (Springer, ed. 2, 2015)).
  • FIG. 6 depicts an embodiment of a DRT scaffold. Scanning electron microscopic view of DRT, synthesized as a highly porous graft copolymer of type I collagen and chondroitin 6-sulfate. Regenerative activity 7 requires optimization of average pore diameter (range 20-125 gm); half-life for degradation (14 ⁇ 7 days); and presence of an estimated minimal ligand density' (200 pM) for integrins aipi or a2(31 on the collagen surface of DRT. Scale bar 100 pm. (A Kourgiantaki, et al. npj Regen Med 5. 1 -14 (2020)).
  • the transected sciatic nerve was regenerated in the rat using DRT tubes that connected the two stumps across a 10-mm gap (L. J. Chamberlain et al. Exp Neurology’ 154, 315-329 (1998)).
  • the quality of peripheral nerve regeneration was studied over a period of 60 weeks using histomorphometry and electrophysiological measurements of A-fiber, B- fiber, and C-fiber peaks of the evoked action potentials.
  • the series of studies eventually demonstrated that the regenerated rat sciatic nerve was equivalent in functional quality to that of the nerve autograft.
  • the researchers measured the kinetics of force generated by fibroblasts in vitro seeded at different levels of cell density over a period of 22 hours. Two observations defined the absence of cooperativity in this model. First, the asymptotic force developed by the cells was observed to be linearly proportional to the density of fibroblasts. The data indicated that the contractile force per cell, observed to be of order 1 nN/fibroblast, was independent of cell density. In addition, the value of the time constant observed at different fibroblast density' levels remained approximately constant, indicating that the kinetics of force generation were also independent of fibroblast density'. These results suggested that the fibroblasts in this study acted independently of each other, thereby denying a hypothesis of cooperativity for this in vitro experimental system.
  • fibrosis a condition which can lead to disruption of organ architecture and loss of tissue function (J-I Jun, et al. J Clin Invest 128, 97-107 (2016)). Organ failure due to fibrosis has been confirmed in the liver (Y.

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Abstract

L'invention concerne des méthodes, des compositions et des kits de pièces pour prévenir ou réduire la contraction des plaies. L'invention concerne des méthodes qui peuvent comprendre la réduction ou l'élimination d'une force contractile appliquée au niveau d'un site de plaie tissulaire par un réseau de myofibroblastes continu. Les compositions peuvent comprendre un liquide biocompatible, et un agent de liaison au récepteur des myofibroblastes dispersé dans le liquide biocompatible. Des kits de pièces peuvent comprendre un réservoir et un applicateur, tel qu'une buse, une aiguille, une brosse, un compte-gouttes ou un rouleau.
PCT/US2024/049533 2023-10-02 2024-10-02 Compositions et méthodes pour une régénération tissulaire améliorée Pending WO2025076043A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007017671A1 (fr) * 2005-08-09 2007-02-15 Cambridge Enterprise Limited Peptides collagenes, procedes et utilisations
US20100215710A1 (en) * 2005-04-08 2010-08-26 The Regents Of The University Of California Beta-2 Adrenergic Receptor Agonists and Antagonists and Modulation of Wound Healing
US20100291058A1 (en) * 2002-10-04 2010-11-18 Virginia Commonwealth University Sealants for Skin and Other Tissues

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100291058A1 (en) * 2002-10-04 2010-11-18 Virginia Commonwealth University Sealants for Skin and Other Tissues
US20100215710A1 (en) * 2005-04-08 2010-08-26 The Regents Of The University Of California Beta-2 Adrenergic Receptor Agonists and Antagonists and Modulation of Wound Healing
WO2007017671A1 (fr) * 2005-08-09 2007-02-15 Cambridge Enterprise Limited Peptides collagenes, procedes et utilisations

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
YANNAS IOANNIS V., TZERANIS DIMITRIOS S., SO PETER T. C.: "Regeneration of injured skin and peripheral nerves requires control of wound contraction, not scar formation", WOUND REPAIR AND REGENERATION, JOHN WILEY & SONS, INC., HOBOKEN, USA, vol. 25, no. 2, 1 April 2017 (2017-04-01), Hoboken, USA, pages 177 - 191, XP093302911, ISSN: 1067-1927, DOI: 10.1111/wrr.12516 *

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