WO2023075203A1 - Matrice tridimensionnelle pour restauration de la peau - Google Patents

Matrice tridimensionnelle pour restauration de la peau Download PDF

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Publication number
WO2023075203A1
WO2023075203A1 PCT/KR2022/015263 KR2022015263W WO2023075203A1 WO 2023075203 A1 WO2023075203 A1 WO 2023075203A1 KR 2022015263 W KR2022015263 W KR 2022015263W WO 2023075203 A1 WO2023075203 A1 WO 2023075203A1
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WO
WIPO (PCT)
Prior art keywords
skin
peg
vinylsulfone
polyethylene glycol
wound
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PCT/KR2022/015263
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English (en)
Korean (ko)
Inventor
이승태
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강원대학교산학협력단
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Publication of WO2023075203A1 publication Critical patent/WO2023075203A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • 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
    • 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
    • A61L27/227—Other specific proteins or polypeptides not covered by A61L27/222, A61L27/225 or A61L27/24
    • 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
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/56—Porous materials, e.g. foams or sponges
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/60—Materials for use in artificial skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • 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
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/252—Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/34—Materials or treatment for tissue regeneration for soft tissue reconstruction

Definitions

  • the present invention relates to a three-dimensional scaffold for skin restoration, and more particularly, to a biodegradable three-dimensional scaffold containing polyethylene glycol (PEG), a crosslinking agent, and MFG-E8.
  • PEG polyethylene glycol
  • MFG-E8 polyethylene glycol
  • Skin transplantation is commonly used for patients with extensive skin defects, and skin regeneration in the damaged area is induced with treatments using xenograft, allogeneic skin graft, and autologous skin graft.
  • xenodermal skin transplantation has limitations in that immune rejection occurs after transplantation and complete engraftment to the treatment site is difficult. There is a limitation that it can be used only when the aspect of is small. Therefore, allograft treatment technology is currently being used as an emergency treatment method rather than a complete treatment purpose.
  • partial-thickness skin grafting technology using autologous skin cells has been widely used for skin defect treatment, but it shows a big difference in engraftment rate depending on the condition of the surgical site for skin transplantation, and at the same time, the transplanted part has high contractility, so this technology is suitable for children. is difficult to apply.
  • 3D scaffolds made of synthetic materials are also problematic due to the absence of cell-friendly materials that can effectively promote the physiological functions of endogenous skin constituent cells and the remaining problem of implanted materials in skin tissues due to low biodegradability after skin regeneration.
  • cell-friendly materials that can effectively promote the physiological functions of endogenous skin constituent cells
  • implanted materials in skin tissues due to low biodegradability after skin regeneration.
  • skin cancer resection patients or patients with more than 3rd degree deep burns should regenerate severely damaged blood vessels and nerves along with skin regeneration.
  • the development of biomaterials that can be used is insufficient.
  • one aspect of the present invention is to provide a biodegradable three-dimensional scaffold for skin restoration.
  • the three-dimensional scaffold for biodegradable skin restoration may include polyethylene glycol-vinylsulfone (PEG-VS), a crosslinking agent, and MFG-E8.
  • PEG-VS polyethylene glycol-vinylsulfone
  • MFG-E8 polyethylene glycol-vinylsulfone
  • the PEG-VS polyethylene glycol-vinylsulfone
  • the PEG-VS may be 4-arm PEG-VS (polyethylene glycol-vinylsulfone).
  • the crosslinking agent may be an MMP-1 specific crosslinking agent.
  • the biodegradable three-dimensional scaffold for skin restoration may further include an attachment protein.
  • the adhesion protein may be one or more selected from the group consisting of RGD and LDV.
  • a pharmaceutical composition for wound treatment includes a first component including polyethylene glycol-vinylsulfone (PEG-VS); and a second component including a crosslinking agent; and at least one selected from the group consisting of the first component and the second component may include MFG-E8.
  • PEG-VS polyethylene glycol-vinylsulfone
  • MFG-E8 MFG-E8
  • the PEG-VS polyethylene glycol-vinylsulfone
  • the PEG-VS may be 4-arm PEG-VS (polyethylene glycol-vinylsulfone).
  • the crosslinking agent may be an MMP-1 specific crosslinking agent.
  • the pharmaceutical composition for treating wounds may further include an attachment protein.
  • the adhesion protein may be one or more selected from the group consisting of RGD and LDV.
  • a pharmaceutical composition for treating wounds according to another embodiment of the present invention includes a first component including polyethylene glycol-vinylsulfone (PEG-VS); a second component comprising a crosslinking agent; and a third component including MFG-E8.
  • PEG-VS polyethylene glycol-vinylsulfone
  • MFG-E8 MFG-E8
  • the three-dimensional scaffold for skin restoration according to the embodiments of the present invention can be used as a covering material for skin wounds and the like to restore the skin while being decomposed in vivo.
  • 5 is a graph showing the wound area on the 5th day in the experimental results according to Experimental Example 2.
  • a peptide containing an amino acid sequence specifically cleaved by matrix metalloproteinase (MMP) and having cysteine at both ends as a crosslinker is an amino acid sequence specifically cleaved by MMP1 (Ac-GCRD-VPMSMRGG-DRCG- A crosslinker having NH2; SEQ ID NO: 1) was synthesized by Peptron (Daejeon, Korea).
  • adhesion proteins having amino acid sequences of Ac-GCGWGRGDSPG-NH2 (SEQ ID NO: 2) and Ac-GCRRDPEILDVPSTVRRD-NH2 (SEQ ID NO: 3) were synthesized from Peptron ( Daejeon, Korea).
  • 4-arm PEG-VS was dissolved in Dulbecco'phosphate-buffered saline (DPBS; Welgene), prepared as a stock, and the MMP1-specific crosslinking agent having the amino acid sequence of SEQ ID NO: 1 and the amino acid sequences of SEQ ID NO: 2 and SEQ ID NO: 3
  • Each branch attachment protein was dissolved in pH 8.0 0.3M HEPES buffer and prepared as a stock.
  • the PEG-VS stock solution and the attached protein stock solution were mixed and reacted for 30 minutes to bind the attached protein to PEG-VS. Thereafter, the PEG-VS solution coupled with the attached protein and the crosslinking agent stock solution were mixed, and 250 ng/ml of MFG-E8 was added before gelation to prepare a 7.5% (w/v) 4-arm PEG-based hydrogel.
  • a 7.5% (w / v) 4-arm PEG-based hydrogel was prepared in the same manner as in Example 1, except that MFG-E8 was not added.
  • a solution was prepared by diluting 250 ng/ml of MFG-E8 in DPBS without PEG-based hydrogel.
  • a solution was prepared by diluting 500 ng/ml of MFG-E8 in DPBS without PEG-based hydrogel.
  • a wound with a diameter of 6 mm was made on the skin of the back of the mouse, and the hydrogels of Comparative Example 1 and Examples 1 to 3 were transplanted into the wound. Then, the degree of skin wound reduction over time was confirmed.
  • FIG. 1 is a photograph of the wound area showing the experimental results according to Experimental Example 1
  • FIG. 2 is a graph showing the area of the wound area on the 5th day from the experimental results according to Experimental Example 1
  • FIG. It is a graph showing the area of the primary wound site.
  • the range of wounds transplanted with PEG hydrogel (Examples 2 and 3) to which 250 ng/ml or more MFG-E8 was added from day 5 was transplanted with the PEG hydrogel of Comparative Example 1 Compared to the extent of the wound, it can be seen that it is rapidly reduced.
  • Figure 4 is a picture of the wound area showing the experimental results according to Experimental Example 2
  • Figure 5 is a graph showing the wound area on the 5th day from the experimental results according to Experimental Example 2
  • Figure 6 is the experimental result according to Experimental Example 2 10 It is a graph showing the area of the primary wound site. 4 to 6 together, when MFG-E8 was used alone (Comparative Examples 3 and 4), the range of wounds on both the 5th and 10th days compared to Comparative Example 2 without the addition of MFG-E8 was relatively You can see that it is not reduced, but rather wider.
  • a wound with a diameter of 6 mm was made on the skin of the back of the mouse, and the hydrogel of Comparative Example 1 and Example 2 was transplanted into the wound. Then, on the 28th day after the wound occurred, the degree of blood vessel and nerve regeneration was confirmed through immunohistological analysis using the antibodies CD31 (vascular) and MBP (nerve).
  • Example 7 is a comparative photograph showing blood vessel and nerve regeneration results of Experimental Example 3. Referring to Figure 7, in the case of Example 2 compared to Comparative Example 1, it was confirmed that regeneration of blood vessels (white arrows) and nerves (black arrows) in damaged skin tissue was effectively promoted.
  • a wound with a diameter of 6 mm was made on the skin of the back of the mouse, and the hydrogels of Examples 2 and 4 were transplanted into the wound. Then, on the 28th day after the wound occurred, whether or not the PEG hydrogel remained was confirmed through histological staining.
  • FIG 8 is a comparative photograph showing the results of whether or not the PEG hydrogel remains in Experimental Example 4.
  • the PEG hydrogel of Example 2 fabricated without adhesive protein was transplanted to a skin wound, some PEG hydrogel (arrow A) remained in the skin tissue even after wound healing, but the PEG hydrogel of Example 4 with adhesive protein added When transplanted to the skin wound site, it can be confirmed that there is no PEG hydrogel remaining in the skin tissue after wound healing (B).
  • Example 2 and Example 4 did not show a significant difference in wound healing rate.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Dermatology (AREA)
  • Transplantation (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Dispersion Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Materials For Medical Uses (AREA)

Abstract

Matrice 3D biodégradable pour la restauration de la peau selon la présente invention, comprenant un complexe polyéthylène glycol-vinylsulfone (PEG-VS), un agent de réticulation et du MFG-E8. Lorsqu'elle est utilisée comme matériau de recouvrement de plaies cutanées, la matrice 3D pour la restauration de la peau de la présente invention peut restaurer la peau tout en étant décomposée in vivo.
PCT/KR2022/015263 2021-10-26 2022-10-11 Matrice tridimensionnelle pour restauration de la peau WO2023075203A1 (fr)

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KR1020210143483A KR20230059380A (ko) 2021-10-26 2021-10-26 피부 복원용 3차원 스캐폴드
KR10-2021-0143483 2021-10-26

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20180047433A (ko) * 2016-10-31 2018-05-10 주식회사 세바바이오텍 Peg-기반 하이드로젤을 포함하는 3차원 세포배양 시스템
KR102172344B1 (ko) * 2019-06-19 2020-11-03 주식회사 한스파마 신경줄기세포 배양액을 유효성분으로 포함하는 피부 개선용 조성물
KR102264607B1 (ko) * 2014-07-17 2021-06-14 더 리전트 오브 더 유니버시티 오브 캘리포니아 생물의학적 적용을 위한 제어가능한 자기-어닐링 마이크로겔 입자

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR102264607B1 (ko) * 2014-07-17 2021-06-14 더 리전트 오브 더 유니버시티 오브 캘리포니아 생물의학적 적용을 위한 제어가능한 자기-어닐링 마이크로겔 입자
KR20180047433A (ko) * 2016-10-31 2018-05-10 주식회사 세바바이오텍 Peg-기반 하이드로젤을 포함하는 3차원 세포배양 시스템
KR102172344B1 (ko) * 2019-06-19 2020-11-03 주식회사 한스파마 신경줄기세포 배양액을 유효성분으로 포함하는 피부 개선용 조성물

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ADELOW, C. SEGURA, T. HUBBELL, J.A. FREY, P.: "The effect of enzymatically degradable poly(ethylene glycol) hydrogels on smooth muscle cell phenotype", BIOMATERIALS, vol. 29, no. 3, 22 October 2007 (2007-10-22), AMSTERDAM, NL , pages 314 - 326, XP022338914, ISSN: 0142-9612, DOI: 10.1016/j.biomaterials.2007.09.036 *
GONG ZHE, WANG CHENGGUI, NI LICHENG, YING LIWEI, SHU JIAWEI, WANG JINGKAI, YU CHAO, XIA KAISHUN, CHENG FENG, SHI KESI, XU GUOPING,: "An injectable recombinant human milk fat globule–epidermal growth factor 8–loaded copolymer system for spinal cord injury reduces inflammation through NF-κB and neuronal cell death", CYTOTHERAPY, vol. 22, no. 4, 1 April 2020 (2020-04-01), GB , pages 193 - 203, XP093060799, ISSN: 1465-3249, DOI: 10.1016/j.jcyt.2020.01.016 *

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