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WO2025120597A1 - Biomatériau fait à partir de sécrétome, son procédé de fabrication et ses utilisations - Google Patents

Biomatériau fait à partir de sécrétome, son procédé de fabrication et ses utilisations Download PDF

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Publication number
WO2025120597A1
WO2025120597A1 PCT/IB2024/062331 IB2024062331W WO2025120597A1 WO 2025120597 A1 WO2025120597 A1 WO 2025120597A1 IB 2024062331 W IB2024062331 W IB 2024062331W WO 2025120597 A1 WO2025120597 A1 WO 2025120597A1
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WIPO (PCT)
Prior art keywords
secretome
cells
cell
based biomaterial
biomaterial according
Prior art date
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Pending
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PCT/IB2024/062331
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English (en)
Inventor
João Filipe COLARDELLE DA LUZ MANO
Mariana Braga De Oliveira
Ana María SANTOS COQUILLAT
Dora Cristina SILVA COSTA
Beatriz GUAPO NEVES
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.)
Universidade de Aveiro
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Universidade de Aveiro
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Application filed by Universidade de Aveiro filed Critical Universidade de Aveiro
Publication of WO2025120597A1 publication Critical patent/WO2025120597A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/0012—Cell encapsulation
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0652—Cells of skeletal and connective tissues; Mesenchyme
    • C12N5/0662—Stem cells
    • C12N5/0667—Adipose-derived stem cells [ADSC]; Adipose stromal stem cells

Definitions

  • the present invention relates to the field of medicine, namely with the use of biomaterials in regenerative medicine strategies, and tissue engineering, mainly to treat diseases that require immunomodulation, regeneration of tissues, or modulation of fibrosis.
  • Other biomedical and biological applications include cell expansion, organoid or 3D culture, disease modeling, induction of differentiation and drug delivery.
  • Biomaterials are substances engineered to interact with biological systems for therapeutic or diagnostic purposes. In the realm of tissue engineering and regenerative medicine, biomaterials are instrumental in restoring, maintaining, or improving tissue function.
  • Scaffolds and hydrogels are two primary classes of biomaterials extensively researched and utilized for tissue regeneration due to their ability to mimic the natural extracellular matrix (ECM) and provide a conducive environment for cell growth and tissue formation.
  • ECM extracellular matrix
  • Hydrogels have found extensive use as fillers, drug or cell carriers, coatings, and substrates for in vitro culture of cells, tissues, or organoids 1 . Primarily, hydrogels sourced from synthetic or naturally derived animal materials have been created.
  • the secretome effect on regeneration and tissue repair has been described in the past years as it can modulate immune responses, differentiation, and angiogenesis, among many others 3,4 .
  • Another aim is to develop cost-effective, consistent, and reproducible methods which are suitable for large-scale production and regulatory approval.
  • the present invention proposes a secretome-based biomaterial, i.e., a biomaterial comprising secreted soluble factors and extracellular vesicles that are released to the cell culture medium or other fluids by cells of therapeutic interest.
  • a secretome-based biomaterial i.e., a biomaterial comprising secreted soluble factors and extracellular vesicles that are released to the cell culture medium or other fluids by cells of therapeutic interest.
  • the biomaterial herein disclosed in completely autologous or derives from a compatible donor. It is also an object of the present invention the method for its production and uses thereof.
  • the international application WO2018213795A1 relates to methods of delivering secreted factors from stem cells to tissues in order to immobilize and concentrate such secreted factors at or under the surface of damaged tissue to promote tissue regeneration.
  • US20220218873A1 patent application discloses the formulation of a bioink for application to the cornea comprising hyaluronic acid, gelatin, and exosomes derived from mesenchymal stem cells primed with a corneal stromal stem cell derived-conditioned medium.
  • US2022088274A1 relates to compositions and methods for repairing or regenerating damaged tissue, more specifically, methods of delivering secreted factors from stem cells to tissues in order to immobilize and concentrate such secreted factors at or under the surface of damaged tissue to promote tissue regeneration.
  • the international application WO2022159878A9 discloses a method for treating or preventing a cardiac injury in a subject comprising delivering a hydrogel-based composition into a portion of a pericardial cavity of a subject and improving at least one aspect of myocardial cells or tissue in the subject.
  • the biomaterial includes other heterologous materials (such as polymers) which could induce an undesired physical and chemical / biological feature.
  • the present invention relates to a secretome-based biomaterial, wherein the secretome is cell secretome selected from secreted soluble factors, apoptotic bodies, small extracellular vesicles or microvesicles that are released from cells of therapeutic interest to the cell culture medium or other fluids or combinations thereof.
  • the invention further relates to a method for the production of the secretome-based biomaterial and to the use thereof for the treatment of diseases requiring tissue regeneration and / or immunomodulation.
  • biomaterials may lack the necessary biological cues required for optimal cell adhesion, recruitment, proliferation, differentiation, and phenotype modulation.
  • the inability to tailor the material properties based on specific pre-conditioning or stimuli applied to parent cells limits the versatility and applicability of the biomaterials in diverse medical and research settings.
  • the present invention offers a comprehensive solution to the problems identified in the state of the art by introducing a novel biomaterial generated from secreted soluble factors, apoptotic bodies, small extracellular vesicles or microvesicles released by cells of therapeutic interest.
  • the invention proposes an optimized purification process that effectively discards other components of the cell culture medium or fluids, resulting in a highly pure product.
  • the material maintains essential properties necessary for effective cell interaction and modulation, contrasting therefore with traditional methods that may compromise the functionality due to impurities or processing conditions.
  • the invention provides a material rich in natural factors that actively guide cell behavior.
  • the present invention meets the needs unmet by current technologies.
  • the optimized purification method disclosed in the present invention ensures that other components of the medium or fluids are discarded, resulting in a highly pure product with conserved biological properties. This high level of purity enhances the material’s biocompatibility and effectiveness in clinical applications.
  • the invention allows the biomaterial to be prepared in various forms, including particles, membranes, capsules, bioinks, foams, hydrogels, sponges, cream, ointments, patches, adhesives, fibers, 3D printed constructs, or discs.
  • Each form contains biological cues essential for maintaining cell adhesion, promoting cell recruitment, supporting proliferation and differentiation, facilitating degradation, and modulating cell phenotype.
  • the ability to customize the material based on the pre-conditioning or stimuli applied to the parent cells adds a significant level of versatility. This adaptability enables the material to be tailored for specific applications such as cell expansion, organoid culture, disease modeling, and the induction of cell differentiation.
  • the invention offers a biomaterial that more closely mimics the natural extracellular matrix, with enhanced purity and customizable properties, overcoming the shortcomings of existing technologies in tissue engineering and regenerative medicine.
  • FIG. 1 graphically illustrates the rheological kinetics of the crosslinking process of secretome
  • A is an schematic representation of the preparation of secretome samples and their crosslinking
  • (b) and (c) are the rheological analysis of the crosslinking process of secretome (obtained from naive ASCs) at a concentration of 10% (w/v) and 5% with genipin, respectively
  • (d) is the rheological analysis of the crosslinking process of secretome (obtained from IFN-gamma-modulated ASCs) at a concentration of 5% (w/v) with genipin
  • (e) is a summary data of the data obtained from three independent replicates from the rheology assays shown in (b) and (c).
  • a timelapse analysis of the storage modulus ( G’ ) and loss modulus ( G’’ ) is shown.
  • C166-GFP mouse endothelial cell
  • A 10% w/V hydrogel
  • B and C C166-GFP growing on the surface of the hydrogel after 7 days in contact
  • RAW 264.7 mouse macrophages adhered to the hydrogel after 48 h of culture, stained for nuclei (DAPI), actin and CD68 (D).
  • the present invention discloses, in a first aspect, a secretome-based biomaterial, wherein the secretome is cell secretome selected from secreted soluble factors, apoptotic bodies, small extracellular vesicles or microvesicles that are released from cells to the cell culture medium (adequate for animal cell culture) or other fluids or combinations thereof.
  • the secretome is cell secretome selected from secreted soluble factors, apoptotic bodies, small extracellular vesicles or microvesicles that are released from cells to the cell culture medium (adequate for animal cell culture) or other fluids or combinations thereof.
  • the cell secretome is crosslinked via chemical crosslinking, physical crosslinking, guest-host interactions, enzymatic crosslinking via transglutaminase, photopolymerized or combinations thereof and is present in a concentration that ranges from 1-20 % (w secretome /V biomaterial ), preferably from 1-15% w/V, more preferably 5-10% w/V.
  • the secreted soluble factors, apoptotic bodies, small extracellular vesicles or microvesicles are chemically modified or reacted with other molecules to enable intermolecular click chemistry selected from azide-dibenzocyclooctyne (DBCO) (strain-promoted azide-alkyne cycloaddition, SPAAC) or tetrazine based (inverse electron-demand Diels–Alder reaction, IEDDA), Schiff base, Diels-Alder (normal and inverse electron-demand) reactions, photochemical crosslinking in the presence or absence of photo initiators, and metal coordination complexes formation.
  • DBCO azide-dibenzocyclooctyne
  • SPAAC strain-promoted azide-alkyne cycloaddition
  • tetrazine based inverse electron-demand Diels–Alder reaction, IEDDA
  • Schiff base Diels-Alder (normal and inverse
  • the secreted soluble factors are selected from growth factors, interleukins, cytokines, structural proteins and proteins from secreted vesicles.
  • the cells are cells of animal origin selected from stem cells, immune cells, or other cells of therapeutic interest that can be in their native state, immortalized cell lines, cells primed with physical, chemical or biological stimuli, gene edited cells or a combination thereof.
  • the stem cells are selected from induced pluripotent cells and mesenchymal stromal cells and the immune cells are selected from T lymphocytes, dendritic cells, macrophages and NK cells.
  • the cell culture When the cell culture is stimulated during growth, its release profile is modulated and, consequently, the biological properties of the resulting biomaterial can be tailored.
  • the physical stimuli are selected from hypoxia (in the range of 0.1-7% O 2 ), low-level lasers, mechanical stretch, silica, pulsed electromagnetic fields, 3D culture, or combinations thereof.
  • the chemical stimuli are selected from metabolic acidosis, BAY 11-708, LL-37, dimethyloxalylglycine, JI-34, sevoflurane, atorvastatin, oxytocin, cyclophosphamide or combinations thereof.
  • the biological stimuli are selected from migration inhibitory factor, IFN- ⁇ , TGF- ⁇ 1, interleukin (IL)-1 ⁇ / ⁇ , IL-25, IL-6, TNF- ⁇ , IL-17, IFN- ⁇ , stromal-derived factor 1, gene modification, polyinosinic-polycytidylic acid, lipopolysaccharide or combinations thereof.
  • migration inhibitory factor IFN- ⁇ , TGF- ⁇ 1, interleukin (IL)-1 ⁇ / ⁇ , IL-25, IL-6, TNF- ⁇ , IL-17, IFN- ⁇ , stromal-derived factor 1, gene modification, polyinosinic-polycytidylic acid, lipopolysaccharide or combinations thereof.
  • the cell culture medium is selected from Minimum Essential Medium, Dulbecco Modified Eagle Medium, RPMI 1640, DMEM/F12 and formulations supplemented with fetal bovine serum, platelet lysates, xenogeneic-free supplements for cell expansion.
  • the fluids are selected from plasma, serum, urine, menstrual blood, amniotic fluid or combinations thereof.
  • the cell secretome is chemically crosslinked via genipin, glutaraldehyde, formaldehyde, and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide / N-hydroxy succinimide.
  • the cell secretome is physically crosslinked via tripolyphosphate and calcium chloride.
  • the secretome-based biomaterial further comprises a therapeutic or biologically active agent.
  • the therapeutic agent is selected from a biomolecule, a diagnostic marker, a probe or a combination thereof and the biologically active agent is selected from a cell, a protein or a combination thereof.
  • the secretome-based biomaterial has a reconfigurable shape.
  • the biomaterial is selected from the group consisting of particles, membranes, capsules, bioinks, foams, hydrogels, sponges, cream, ointments, patches, adhesives, fibers, 3D printed constructs, or discs.
  • step (c) subjecting the product obtained in step (c) to freeze-drying
  • step (d) dissolving and crosslinking the product obtained in step (d) to generate the secretome-based biomaterial.
  • step (a) the cell secretome is collected from a patient fluid or after culturing the patient cells in vitro , as the supernatant of cultured cells for at least 4 hours.
  • step (b) the cell secretome is ultrafiltrated or dialyzed using a membrane having a value threshold (cut-off value) equal to or less than 3 kDa.
  • this step takes places prior to the crosslinking step.
  • the secretome-based biomaterial is for use in tissue regeneration, immune-mediated diseases or conditions, transplantation and post-transplantation.
  • Other biomedical and biological applications include cell expansion, organoid or 3D culture, disease modeling, induction of differentiation and drug delivery.
  • the secretome-based biomaterial is tailored by changing the percentage of weight used in the formulation, crosslinking degree, or crosslinking strategies.
  • Tuneable mechanical properties are defined as adjustable Young's modulus, brittleness, viscoelasticity, and stress relaxation.
  • Tuneable degradation properties refer to the ability to control the stability of the biomaterial over time, through the tailoring of crosslinking extension, or the use of on-demand reversible crosslinking chemistries.
  • the secretome-based biomaterial of the present invention must present tuneable mechanical properties and be non-cytotoxic, biocompatible, and suitable for cell culture of different cell types.
  • the secreted fraction (growth factors, interleukins, small extracellular vesicles and microvesicles) from a serum-deprived culture media is collected from human mesenchymal stem cells isolated from the adipose tissue.
  • the resulting medium is ultrafiltrated or dialyzed using a membrane having a value threshold (cut-off value) equal to or less than 3,000 Daltons, thus concentrating the sample at least 10x times.
  • the resulting purified medium is then passed through a size-exclusion column (desalting columns containing Sephadex G-25 resin) to remove the remaining components of the cell media.
  • the purified product is evaluated by dynamic light scattering for size and z-potential measurements.
  • the sample consists of different sizes with three predominant peaks around 10, 100, and 1000 nm ( A).
  • the zeta potential is negative (-3.52 mV) correlating with small extracellular vesicles’ negative charge and an overall negative charge of the protein content ( B).
  • the freeze-dried product is weighted and dissolved in Dulbecco's Phosphate Buffered Saline (DPBS) to a final concentration of 5% and 10% w/V, and then genipin (0.5% w/V in deionized water (dH 2 O): dimethyl sulfoxide (DMSO), 4:1 mixture): is added to the solution ( ).
  • DPBS Dulbecco's Phosphate Buffered Saline
  • the assay was designed following the ISO 10993-5:2009.
  • Endothelial mouse cells (C166-GFP) are able to grow and proliferate after 7 days of contact with the biomaterials ( B and 5 C).
  • Mouse macrophages (RAW 264.7) are able to attach, grow, and proliferate after 48 h of seeding (20.000 cells/cm 2 ) into the biomaterials ( D).
  • the secretome-derived biomaterials produced by naive (control) or IFN-gamma-induced ASCs lead to the organization of human umbilical vein endothelial cells, indicating their in vitro pro-angiogenic properties. This is consistent with their potential biocompatibility and effectiveness in clinical applications.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Wood Science & Technology (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Biotechnology (AREA)
  • Zoology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Genetics & Genomics (AREA)
  • Microbiology (AREA)
  • Cell Biology (AREA)
  • Biochemistry (AREA)
  • General Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Developmental Biology & Embryology (AREA)
  • Rheumatology (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)

Abstract

La présente invention concerne un biomatériau fait à partir de sécrétome, le sécrétome étant un sécrétome cellulaire choisi parmi les facteurs solubles sécrétés, les corps apoptotiques, les petites vésicules extracellulaires ou les microvésicules qui sont libérées par les cellules d'intérêt thérapeutique dans le milieu de culture cellulaire ou d'autres fluides ou des combinaisons de ces derniers. L'invention concerne en outre un procédé de production du biomatériau fait à partir de sécrétome et son utilisation pour le traitement de maladies nécessitant une régénération tissulaire et/ou une immunomodulation.
PCT/IB2024/062331 2023-12-06 2024-12-06 Biomatériau fait à partir de sécrétome, son procédé de fabrication et ses utilisations Pending WO2025120597A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
PT11910123 2023-12-06
PT119101 2023-12-06
PT11988524 2024-12-05
PT119885 2024-12-05

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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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WO2018213795A1 (fr) 2017-05-18 2018-11-22 The Board Of Trustees Of The Leland Stanford Junior University Administration thérapeutique in situ ciblée de facteurs sécrétés à partir de cellules souches pour le traitement de tissus lésés
WO2019023584A1 (fr) * 2017-07-27 2019-01-31 Cornell University Fixation et rétention de vésicules extracellulaires
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WO2021055013A1 (fr) * 2018-09-21 2021-03-25 Aufbau Medical Innovations Limited Procédés et agents contre le glaucome
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WO2022159878A9 (fr) 2021-01-25 2023-10-12 North Carolina State University Compositions et procédés d'administration de produits thérapeutiques dans le coeur

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120189584A1 (en) * 2010-12-02 2012-07-26 University Of Vermont And State Agricultural College Genipin cross-linked fibrin gels
WO2018213795A1 (fr) 2017-05-18 2018-11-22 The Board Of Trustees Of The Leland Stanford Junior University Administration thérapeutique in situ ciblée de facteurs sécrétés à partir de cellules souches pour le traitement de tissus lésés
US20220088274A1 (en) 2017-05-18 2022-03-24 The Board Of Trustees Of The Leland Stanford Junior University Targeted in Situ Therapeutic Delivery of Secreted Factors from Stem Cells for Treatment of Damaged Tissue
WO2019023584A1 (fr) * 2017-07-27 2019-01-31 Cornell University Fixation et rétention de vésicules extracellulaires
WO2021055013A1 (fr) * 2018-09-21 2021-03-25 Aufbau Medical Innovations Limited Procédés et agents contre le glaucome
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US20220218873A1 (en) 2019-07-26 2022-07-14 Pandorum Technologies Private Limited Hyaluronic acid and gelatin-containing formulations
WO2022159878A9 (fr) 2021-01-25 2023-10-12 North Carolina State University Compositions et procédés d'administration de produits thérapeutiques dans le coeur
CN116549719A (zh) * 2023-05-15 2023-08-08 华中科技大学 负载间充质干细胞外泌体的双交联水凝胶、制备与应用

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