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WO2025034706A1 - Compositions fibreuses cœur-écorce et procédés associés - Google Patents

Compositions fibreuses cœur-écorce et procédés associés Download PDF

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Publication number
WO2025034706A1
WO2025034706A1 PCT/US2024/041041 US2024041041W WO2025034706A1 WO 2025034706 A1 WO2025034706 A1 WO 2025034706A1 US 2024041041 W US2024041041 W US 2024041041W WO 2025034706 A1 WO2025034706 A1 WO 2025034706A1
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WIPO (PCT)
Prior art keywords
polymer
plga
polymeric
nanofibrous structure
pcl
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PCT/US2024/041041
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English (en)
Inventor
Sahar VAHABZADEH
Nicholas POHLMAN
Matthew KLESZYNSKI
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Northern Illinois Research Foundation
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Northern Illinois Research Foundation
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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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0092—Hollow drug-filled fibres, tubes of the core-shell type, coated fibres, coated rods, microtubules or nanotubes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/65—Tetracyclines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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
    • A61L27/50—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
    • D—TEXTILES; PAPER
    • D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
    • D01D—MECHANICAL METHODS OR APPARATUS IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS
    • D01D1/00—Treatment of filament-forming or like material
    • D01D1/02—Preparation of spinning solutions
    • D—TEXTILES; PAPER
    • D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
    • D01D—MECHANICAL METHODS OR APPARATUS IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS
    • D01D5/00—Formation of filaments, threads, or the like
    • D01D5/0007—Electro-spinning
    • D—TEXTILES; PAPER
    • D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
    • D01D—MECHANICAL METHODS OR APPARATUS IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS
    • D01D5/00—Formation of filaments, threads, or the like
    • D01D5/06—Wet spinning methods
    • D—TEXTILES; PAPER
    • D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
    • D01D—MECHANICAL METHODS OR APPARATUS IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS
    • D01D5/00—Formation of filaments, threads, or the like
    • D01D5/28—Formation of filaments, threads, or the like while mixing different spinning solutions or melts during the spinning operation; Spinnerette packs therefor
    • D01D5/30—Conjugate filaments; Spinnerette packs therefor
    • D01D5/34—Core-skin structure; Spinnerette packs therefor
    • D—TEXTILES; PAPER
    • D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
    • D01F—CHEMICAL FEATURES IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS; APPARATUS SPECIALLY ADAPTED FOR THE MANUFACTURE OF CARBON FILAMENTS
    • D01F1/00—General methods for the manufacture of artificial filaments or the like
    • D01F1/02—Addition of substances to the spinning solution or to the melt
    • D01F1/10—Other agents for modifying properties
    • D—TEXTILES; PAPER
    • D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
    • D01F—CHEMICAL FEATURES IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS; APPARATUS SPECIALLY ADAPTED FOR THE MANUFACTURE OF CARBON FILAMENTS
    • D01F6/00—Monocomponent artificial filaments or the like of synthetic polymers; Manufacture thereof
    • D01F6/58—Monocomponent artificial filaments or the like of synthetic polymers; Manufacture thereof from homopolycondensation products
    • D01F6/62—Monocomponent artificial filaments or the like of synthetic polymers; Manufacture thereof from homopolycondensation products from polyesters
    • D01F6/625—Monocomponent artificial filaments or the like of synthetic polymers; Manufacture thereof from homopolycondensation products from polyesters derived from hydroxy-carboxylic acids, e.g. lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/906—Zingiberaceae (Ginger family)
    • A61K36/9066—Curcuma, e.g. common turmeric, East Indian arrowroot or mango ginger
    • 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
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/12—Nanosized materials, e.g. nanofibres, nanoparticles, nanowires, nanotubes; Nanostructured surfaces
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y40/00—Manufacture or treatment of nanostructures
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Definitions

  • the invention relates to nanofibers comprising two different polymers.
  • the invention includes compositions and methods, and formulations for fabricating nanofibers with two different polymers.
  • Polymer nanofibers are used in various tissue engineering and drug delivery applications. Typically, polymer nanofibers are made by electrospinning a single polymer and are utilized for the controlled release of biomolecules depending on the material properties of that polymer. However, there is a need for more complex drug delivery and tissue engineering structures comprising materials with different chemical and physical characteristics.
  • This disclosure is directed to a nanofiber comprising a core-shell structure using two polymers that allow the nanofiber to have multi-functional properties.
  • Fig. 1 is an embodiment of a core-shell nanofibrous structure
  • Fig. 2A is a scanning electron microscopy image illustrating the morphology of monoaxial PCL fibers at 10 kV;
  • Fig. 2B is a scanning electron microscopy image illustrating the morphology of monoaxial PCL fibers at 11 kV;
  • Fig. 2C is a scanning electron microscopy image illustrating the morphology of monoaxial PCL fibers at 12 kV;
  • Fig. 2D is a scanning electron microscopy image illustrating the morphology of monoaxial PLGA fibers at 10 kV;
  • Fig. 2E is a scanning electron microscopy image illustrating the morphology of monoaxial PLGA fibers at 11 kV;
  • Fig. 2F is a scanning electron microscopy image illustrating the morphology of monoaxial PLGA fibers at 12 kV;
  • Fig. 3A is a scanning electron microscopy image illustrating the morphology of monoaxial PCL fibers with 2.5% doxycycline at 10 kV;
  • Fig. 3B is a scanning electron microscopy image illustrating the morphology of monoaxial PCL fibers with 2.5% doxycycline at 11 kV;
  • Fig. 3C is a scanning electron microscopy image illustrating the morphology of monoaxial PCL fibers with 5% doxycycline at 10 kV;
  • Fig. 3D is a scanning electron microscopy image illustrating the morphology of monoaxial PCL fibers with 5% doxycycline at 11 kV;
  • Fig. 3E is a scanning electron microscopy image illustrating the morphology of monoaxial PCL fibers with 7.5% doxycycline at 10 kV;
  • Fig. 3F is a scanning electron microscopy image illustrating the morphology of monoaxial PCL fibers with 7.5% doxycycline at 11 kV;
  • Fig. 4A is a scanning electron microscopy image illustrating the morphology of a polymeric core-shell nanofibrous structure comprising a PCL core and 65:35 PLGA shell that is electrospun at 9 kV;
  • Fig. 4B is a scanning electron microscopy image illustrating the morphology of a polymeric core-shell nanofibrous structure comprising a PCL core and 65:35 PLGA shell that is electrospun at 10 kV;
  • Fig. 5A is a scanning electron microscopy image illustrating the morphology of a polymeric core-shell nanofibrous structure comprising a PCL core with 7.5% doxycycline and 65:35 PLGA shell that is electrospun at 10 kV;
  • Fig. 5B is a scanning electron microscopy image illustrating the morphology of a polymeric core-shell nanofibrous structure comprising a PCL core with 7.5% doxycycline and 65:35 PLGA shell that is electrospun at 11 kV;
  • Fig. 6 is a graph illustrating FTIR data from PCL fibers, PCL/PLGA coaxial fibers, and PCL + 7.5% doxycycline / PLGA coaxial fibers;
  • Fig. 7 is a graph illustrating FTIR data from PCL/PLGA coaxial fibers, fibers loaded with 2.5%, 5%, and 7.5% doxycycline;
  • Fig. 8 shows PCL monoaxial fibers loaded with doxycycline and PCL/PLGA core-shell fibers with PCL core loaded with 7.5% doxycycline in bacteria culture after 1, 2, 3, and 4 days;
  • Fig. 9 shows 7.5% w/v PCL spun with about 7.5% w/v curcumin
  • Fig. 10 shows 7.5% w/v PCL spun with about 2.5% w/v quercetin
  • Fig. 11 shows scanning electron microscopy image illustrating the morphology of a polymeric core-shell nanofibrous structure including 7.5% w/v PCL with about 7.6% w/v CuSO4 as core and 30% w/v of 65:35 PLGA shell that is electrospun at 9kV.
  • Fig. 12 shows scanning electron microscopy image illustrating the morphology of a polymeric core-shell nanofibrous structure including 7.5% w/v PCL with about 7.6% w/v MgSO4 as core and 30% w/v of 65:35 PLGA shell that is electrospun at 9kV;
  • Fig. 13 shows the FTIR of monoaxial PLGA and monoaxial PCL + MgSO4 (400-4000 cm’ 1 );
  • Fig. 14 shows the FTIR of monoaxial PLGA and monoaxial PCL + CuSO4 (400- 4000 cm 1 );
  • Fig. 15 shows the FTIR of monoaxial PLGA and monoaxial PCL+ curcumin (400-4000 cm’ 1 );
  • Fig. 16 shows the FTIR of PCL + MgSO4/PLGA core/shell (400-4000 cm- 1 );
  • Fig. 17 shows the FTIR of (PCL + CuSO4)/PLGA core/shell (400-4000 cm’ 1 );
  • Fig. 18 shows the FTIR of PCL+ curcumin (monoaxial) and PCL + curcumin/PLGA core/shell (400-4000 cm 1 );
  • Fig. 19 shows the EDS of PCL + 7.6% CuSO4 /PLGA core/shell
  • Fig. 20 shows EDS of PCL + 7.6% MgSCU /PLGA core/shell.
  • the present disclosure relates to a polymeric core-shell nanofibrous structure comprising different polymers.
  • the disclosure also related to a method for electrospinning polymeric composites with a core-shell configuration, using an electrospinning technique.
  • the method is directed to the synthesis of the polymeric core-shell nanofibrous structure or a polymeric core-shell fiber 100 using blending or laying techniques in electrospinning.
  • the polymeric core-shell nanofibrous structure 100 shown in FIG. 1, includes a core 102 and a shell 104.
  • the polymeric core-shell nanofibrous structure 100 comprises two polymers that have distinct physical and chemical characteristics.
  • the core 102 can comprise a first polymer and the shell 104 can comprise a second polymer.
  • Such polymeric core-shell nanofibrous structure 100 can be utilized in tissue engineering and drug delivery applications that require different delivery regimes.
  • the polymeric core-shell nanofibrous structure 100 with a core-shell structure can be loaded with hydrophilic and/or hydrophobic molecules.
  • the polymeric core-shell nanofibrous structure 100 can have increased stability and specificity compared to a nanofiber made of one material.
  • the two polymers of the polymeric core-shell nanofibrous structure 100 can have different degradation rates. In some embodiments, the two polymers of the polymeric core-shell nanofibrous structure 100 can have different electrical charges. In some embodiments, the two polymers of the polymeric core-shell nanofibrous structure 100 can have differing hydrophilicity. In some embodiments, the two polymers of the polymeric coreshell nanofibrous structure 100 can have different chemical compositions. In some embodiments, the two polymers of the polymeric core-shell nanofibrous structure 100 can have different degradation rates. Such differing characteristics can enable the use of the polymeric core-shell nanofibrous structure 100 in applications that require interaction with different tissues. In some embodiments, the two polymers of the polymeric core-shell nanofibrous structure 100 can include additives including but not limited to biomolecules, drugs, elements, and/or other chemicals dispersed in them.
  • the hydrophilicity of the polymeric core-shell nanofibrous structure 100 can be adjusted by altering or managing a ratio of two polymers in a solvent, formation of the core-shell sequence, and/or the molecular weight of the two polymers.
  • the hydrophilicity of the polymeric core-shell nanofibrous structure 100 directly impacts the integration of any biomolecules, drugs, elements, and/or other chemicals within the polymeric core-shell nanofibrous structure 100 and the release of the biomolecules, drugs, elements, and/or other chemicals in a biological environment surrounding the polymeric core-shell nanofibrous structure 100. Such release of biomolecules, drugs, elements, and/or other chemicals may affect the treatment of conditions including but not limited to infection and inflammation.
  • the nanofiber with a core-shell structure 100 can be used for drug delivery and/or tissue engineering applications.
  • the polymeric core-shell nanofibrous structure 100 can be used for energy storage where the electrical charge of each of two polymers is based on the ratio of the polymers in the solvent, formation of the core-shell sequence, and/or the molecular weight of the two polymers.
  • the first polymer is PCL and the second polymer is PLGA.
  • the first polymer is PLGA and the second polymer is PCL.
  • other combinations of polymers may be used.
  • a method of treating conditions such as infection and inflammation can include using the polymeric core-shell nanofibrous structure 100.
  • a method of creating the polymeric core-shell nanofibrous structure 100 by electrospinning two polymers is described in detail herein.
  • the two polymers may comprise different chemical compositions, electrical charges, and/or degradation behavior.
  • the interaction of the polymeric core-shell nanofibrous structure 100 with different tissues can be adjusted and/or managed based on the degradation rate of each polymer.
  • the method can include managing the hydrophilicity of the polymeric core-shell nanofibrous structure 100 by changing the ratio of the polymers in the solvent, managing the formation of the core-shell sequence, and/or identifying different molecular weights of the two polymers.
  • the hydrophilicity of the polymeric core-shell nanofibrous structure 100 can directly impact the integration of any biomolecules, drugs, elements, and/or other chemicals loaded within each polymer, and the release of the said biomolecules, drugs, elements, and/or other chemicals in the biological environment.
  • the method of fabricating the polymeric core-shell nanofibrous structure 100 can comprise utilizing the same solvent or polymer-based solutions for the two polymers during electrospinning.
  • the polymer-based solution may comprise solvents including but not limited to acetone, chloroform, dioxane, and hexafluoroisopropanol (HFIP).
  • the method of fabricating the polymeric core-shell nanofibrous structure 100 can comprise coaxial electrospinning. Coaxial electrospinning for the fabrication of the polymeric core-shell nanofibrous structure 100 can be optimized by optimizing the monoaxial electrospinning of the two polymer-based solutions.
  • electrospinning may be utilized to fabricate the polymeric core-shell nanofibrous structure 100 comprising a PCL core and a PLGA shell. In other embodiments, electrospinning may be utilized to fabricate the polymeric core-shell nanofibrous structure 100 comprising a PLGA core and a PCL shell. In one embodiment, a dual nozzle system is utilized to fabricate the polymeric core-shell nanofibrous structure 100.
  • the core of the polymeric core-shell nanofibrous structure 100 may comprise about 5% w/v PCL to about 10% w/v PCL, including any value or range comprised therein. In one embodiment, the core may comprise about 7.5 w/v PCL.
  • the method may include dispersing biomolecules, drugs, elements, and/or other chemicals in one or both polymers used to comprise the polymeric coreshell nanofibrous structure 100.
  • the biomolecules, drugs, elements, and/or other chemicals may include but are not limited to antibiotics, inhibitors, receptor agonists or antagonists, and/or agents to promote wound healing, vascularization, tissue engineering, and inflammation control.
  • the polymeric core-shell nanofibrous structure 100 may comprise curcumin and/or quercetin.
  • curcumin and/or quercetin may be dispersed in the PCL core.
  • the PCL core may comprise 2% to about 10% curcumin including any percentage or range comprised therein.
  • the PCL core may comprise about 2% to about 2.5% curcumin, about 2.5% to about 5% curcumin, about 5% to about 7.5% curcumin, or about 7.5% to about 10% curcumin.
  • Fig. 9 illustrates a polymeric core-shell nanofibrous structure 100 comprising about 7.5% w/v PCL in the core with about 2.5% w/v curcumin.
  • the fibers have an average diameter of about 1.26 pm.
  • the PCL core may comprise 2% to about 10% quercetin including any percentage or range comprised therein.
  • the PCL core may comprise about 2% to about 2.5% quercetin, about 2.5% to about 5% quercetin, about 5% to about 7.5% quercetin, or about 7.5% to about 10% quercetin.
  • Fig. 10 illustrates a polymeric core-shell nanofibrous structure 100 comprising about 7.5% w/v PCL in the core with about 2.5% w/v quercetin.
  • the fibers have an average diameter of 1 .13 pm
  • the polymeric core-shell nanofibrous structure 100 may be comprised in a membrane, a patch, or in any other application for wound healing and/or tissue regeneration.
  • the polymeric core-shell nanofibrous structure 100 can include trace elements such as Cu and Mg in the core.
  • the polymeric coreshell nanofibrous structure 100 may be used to coat an implant (e.g., orthopaedic implant) and or soft tissue or organ to enhance regeneration or healing.
  • the polymeric core-shell nanofibrous structure 100 may comprise compounds comprising copper and/or magnesium.
  • the polymeric core-shell nanofibrous structure 100 may comprise compounds including but not limited to CuSO4 or MgSO4.
  • the core may comprise about 0.5 % to about 20 % C0SO4 or MgSC including any percentage or range comprised therein.
  • the core may comprise about 0.5 % to about 1 % CuSO4, about 1 % to about 2 % CuSO4, about 2 % to about 3 % CuSO4, about 3 % to about 4 % CuSO4, about 4 % to about 7.5 % CuSC , about 7.5 % to about 10 % Q1SO4, about 10 % to about 15 % CuSC>4, or about 15 % to about 20 % Q1SO4.
  • the core may comprise about 1 % CuSO 4 , 2 % CuSO 4 , 3.8 % CuSO 4 , about 7.6 % CuSO 4 , about 11.4 % CuSO 4 , or about 15 % CuSO4.
  • Fig. 11 illustrates a polymeric core-shell nanofibrous structure 100 comprising about 7.5% w/v PCL in the core with about 7.6% w/v CuSO4.
  • the fibers have an average diameter of about 1.8 pm.
  • the core may comprise about 0.5 % to about 1 % MgSCU, about 1 % to about 2 % MgSO4, about 2 % to about 3 % MgSO4, about 3 % to about 4 % MgSO4, about 4 % to about 7.5 % MgSC , about 7.5 % to about 10 % MgSC , about 10 % to about 15 % MgSO4, or about 15 % to about 20 % MgSCU.
  • the core may comprise about 1 % MgSC , 2 % MgSC , 3.8 % MgSCh, about 7.6 % MgSC , about 11.4 % MgSO4, or about 15 % MgSO4.
  • Fig. 11 illustrates a polymeric core-shell nanofibrous structure 100 comprising about 7.5% w/v PCL in the core with about 7.6% w/v MgSCL.
  • the fibers have an average diameter of about 1.97 pm.
  • the polymeric core-shell nanofibrous structure 100 can be coated on manufactured Ti alloys, a polymeric compound, or a ceramic compound.
  • the polymeric core-shell nanofibrous structure 100 can be used wherever a transition from hard tissue (such as bone and dental) to soft tissue (mainly muscle and skin) is required. The soft electrospun layer can minimize skin irritation due to metallic implants.
  • the polymeric core-shell nanofibrous structure 100 is used instead of microspheres because a high aspect ratio of the polymeric core-shell nanofibrous structure 100 decreases the amount of antibiotics needed.
  • the Inovenso NS1 Nanospinner (Inovenso Inc, MA, USA) electrospinning system was used.
  • PCL and PLGA (65:35) solutions were prepared by dissolving a polymeric precursor in HFIP at concentrations of 7.5% w/v and 30% w/v, respectively, for 45 minutes.
  • DOX doxycycline
  • doxycycline was added to the PCL solution after the polymer solution was stirred for 45 minutes.
  • the amount of doxycycline added to the polymer corresponded to values in the range from about 2.5% w/w to 7.5% w/w with respect to the polymer amount.
  • the solution was stirred for about 20 minutes until the doxycycline was completely dissolved.
  • the solution was then transferred to an electrospinning apparatus.
  • the polymeric core-shell nanofibrous structure 100 was fabricated by optimizing spinning parameters for monoaxial electrospinning of PCL and PLGA.
  • the parameters that were adjusted include polymer concentration, voltage, feed rate, and the distance between the nozzle and the collector.
  • Prior to electrospinning polymers were dissolved in HFIP for 45 min, transferred to a syringe, and connected to an electrospinner.
  • the microstructure of PCL and PLGA was evaluated by scanning electron microscopy (SEM), and the diameters of the fibers were measured.
  • PCL concentration of about 5% (w/v) resulted in poor morphology and inconsistent PCL fiber formation.
  • Optimized PCL fiber was formed using a PCL concentration of about 7.5% (w/v) that was electrospun at about 8 kV and at a distance of about 10 cm between the nozzle and collector.
  • PCL and PLGA were electrospun simultaneously using two different nozzles.
  • coaxial electrospinning of PCL and 50:50 PLGA at the above-described parameters was undertaken.
  • the polymeric core-shell nanofibrous structure 100 was fabricated without any defects at PLGA feed rates of about 0.9 ml/hr, 1.1 ml/hr, and 1.3 ml/hr. In one embodiment, the polymeric core-shell nanofibrous structure 100 was fabricated without any defects at a PCL feed rate of about 1.5 ml/hr. In one embodiment, the polymeric core-shell nanofibrous structure 100 was fabricated without any defects at a voltage of about 8 kV. In one embodiment, the polymeric core-shell nanofibrous structure 100 was fabricated without any defects when electrospinning was performed at a nozzle-collector distance of about 10 cm. Transmission electron microscopy (TEM) illustrated that the polymeric core-shell nanofibrous structure 100 comprised a uniform fibrous PCL coating around a PLGA shell.
  • TEM Transmission electron microscopy
  • the polymeric core-shell nanofibrous structure 100 was fabricated. To produce the polymeric core-shell nanofibrous structure 100, two separate solutions were made. PCL or PCL+ doxycycline was made for forming the core and PLGA (65:35) was made for forming the shell.
  • FIGS. 2A-2F illustrate the morphology of monoaxial PCL and PLGA fibers electrospun at voltages of about 10, 11, and 12 kV.
  • Fiber diameters were measured at 2500x and 15 kV.
  • Table #2 shows the diameters of the PCL fibers at the three different voltages.
  • the fiber diameters for PCL that have previously been produced typically show smaller fiber diameters.
  • PCL diameters in previous studies were around 295 ⁇ 148 nm (7 kV, 6 mL/h, 15 cm) and 250 ⁇ 80 nm (22 kV, 3 mL/h, 10 cm). These differences can be related to various parameters including voltage, flow rate, distance, and solvent used.
  • increased voltage results in increased fiber diameter while increased flow rates result in a decrease in fiber diameter.
  • Increasing the distance between the nozzle and collector also causes a decrease in fiber diameter. Implementation of these parameters results in fibers with larger diameters.
  • the use of HFIP instead of acetone affects fiber morphology. Table #2
  • FIGS. 3A-3F shows the electrospun PCL fibers loaded with three concentrations of doxycycline (2.5, 5, 7.5% w/w).
  • the fiber diameter for the doxycycline- loaded fibers was similar to the unloaded PCL at diameters of about 600 ⁇ 200 nm. (See Tables# 3-5). Other studies have shown that PCL diameter decreases with the addition of molecules. However, as shown in Table #3, the size of the fibers does not significantly change due to the use of a lower concentration of the drug.
  • Coaxial fiber processing of the polymeric core-shell nanofibrous structure 100 was performed using optimized parameters from monoaxial fiber (PCL, PLGA, PCL+ doxycycline) processing, with the addition of a coaxial nozzle.
  • polymeric core-shell nanofibrous structures 100 comprising PCL/PLGA (65:35) were produced.
  • the polymeric core- shell nanofibrous structures 100 as shown in FIGS. 4A-4B have no defects in the form of spindles or beads and are continuous.
  • FIG. 4A illustrates the morphology of the polymeric core-shell nanofibrous structure 100 electrospun at 9 kV.
  • FIG. 4B illustrates the morphology of polymeric core-shell nanofibrous structure 100 electrospun at 10 kV.
  • the diameters of such polymeric core-shell nanofibrous structure 100 is about 779 ⁇ 248 nm for 9 kV and 780 + 232 nm at 10 kV (see Table #6). These values were in between that of PCL and PLGA monoaxial fibers, which is expected as the coaxial solution is a combination of the two polymers. Similar to monoaxial fibers, coaxial fiber structure varies based on voltage, flow rate, distance to the collector, and solution composition. As there are multiple solutions in use at one time, the viscosity of the solutions should be similar. Viscosity is important for electrospinning to occur and is a critical factor in determining the quality of the interface between the core and shell of the fibers. If the viscosity of the solutions is incorrect, forces from electrospinning can cause unfavorable fiber structures, like beading. Additionally, there may be cyclical dripping of the solution out of the nozzle instead of spraying.
  • doxycycline-loaded coaxial fibers consisting of PCL+ doxycycline (7.5%) core and PLGA (65:35) shell (FIGS. 5A-5B) were produced.
  • PLGA was used as the shell because PLGA has a faster degradation rate than PCI.
  • Electrospinning parameters were similar to those for unloaded PCL/PLGA fibers. Flow rates of about 1.3 ml/h were used for the PCL+ doxycycline core and about 1.6 ml/h were used for the PLGA shell. Fibers were produced at voltages of about 10 kV and 11 kV and at a distance of about 10 cm.
  • PCL/PLGA core-shell fibers with doxycycline had a diameter of about at 673 ⁇ 241 nm (see Table #7).
  • 10 kV voltage consistently allowed for the creation of nanofibers for both monoaxial and coaxial fibers, 10 kV was chosen as the optimal voltage. Further characterization of fibers, including FTIR and an antibacterial study, was done using fibers made at 10 kV voltage.
  • FIG. 8 shows electrospun fibers in bacteria culture after 1 , 2, 3, and 4 days. PCL monoaxial and PCL/PLGA core-shell fibers were used as control fibers.
  • Region A illustrates PCL monoaxial fibers loaded with 2.5% doxycycline
  • region B PCL monoaxial fibers loaded with 5% doxycycline
  • region C PCL monoaxial fibers loaded with 7.5% doxycycline
  • region D illustrates PCL/PLGA core-shell fibers with PCL core loaded with 7.5% doxycycline
  • region E illustrates unloaded PCL monoaxial fibers
  • region F illustrates unloaded PCL/PLGA core-shell fibers.
  • the images show clear areas around the doxycycline-loaded fibers, indicating antibacterial properties against all five bacteria strains apart from P. aeruginosa 27312, which showed no reaction to the presence of fibers.
  • the resistance of P. aeruginosa to doxycycline has been shown in other studies and does not change the overall antibacterial properties of the fibers.
  • control fibers also had some antibacterial effects, the doxycycline-loaded fibers show a larger effect as indicated by the increase in clear areas (zone of influence) around the fiber.
  • the Shimadzu IRAffinity-lS FTIR was used to determine molecular concentrations of PCL, PCL+ doxycycline, PCL/PLGA polymeric core-shell nanofibrous structure 100, and PCL+ doxycycline/PLGA polymeric core-shell nanofibrous structure 100.
  • the FTIR graphs from the first set of PCL and PCL+ doxycycline polymeric core-shell nanofibrous structure 100 at 2.5, 5, and 7.5% w/w concentrations are illustrated in FIG. 6.
  • the data from this study determined that the major peaks for PCL were at 1100- 1200, 1727, 2865, and 2943 cm-1.
  • FIG. 7 shows the FTIR data from PCL/PLGA polymeric core-shell nanofibrous structure 100 with and without doxycycline.
  • the additional peaks for PLGA were previously measured and located to be at about 1762.6 cm-1 and in the range of about 1089-1186 cm- 1.191. For this study, there were noticeable peaks at these same locations. However, as there was PCL and/or doxycycline present in the fibers, the peaks for PLGA were combined with the peaks from the other materials present.
  • PCL and doxycycline peaks were similar to other data in this study, doxycycline was located in the range of about 1400 and 1700 cm-1. PCL had major peaks at locations previously identified. The major peak for PCL was combined with that for PLGA, but it was possible to determine the presence of both. Since there was no difference in FTIR data in comparison to previous experiments, the electrospinning process does not alter the polymers or drugs. The comparison between polymer solution and electrospun fibers also proves there was no crosslinking of polymers during the solution preparation.
  • FTIR analysis was performed on monoaxial and coaxial electrospun fibers.
  • the Shimadzu IR Affinity- IS FTIR spectrometer was used to determine the presence of the polymers and molecules in the fibers.
  • the FTIR transmittance spectrum was recorded over the range of 400-4000 c
  • Monoaxial electrospun fibers were prepared with MgSCL concentrations of about 1%, 2%, 3.8%, and/or 7.6% w/w.
  • the electrospinning parameters comprised 9 kV voltage, a distance of 10 cm, and a flow rate of 1.5 ml/h (Fig. 13).
  • monoaxial electrospun fibers were prepared with CuSO4 concentrations of 1%, 2%, 3.8%, and 7.6% w/w, under the same conditions of 9 kV, 10 cm distance, and 1.5 ml/h flow rate (Fig. 14).
  • Monoaxial electrospun fibers were prepared with 2.5%, 5%, and 7.5% w/w of curcumin, at 9 kV, 10 cm, and 1.5 ml/h (Fig. 15).
  • Coaxial electrospun fibers were prepared with PCL and PLGA using an electrospinning parameters comprising 9 kV, 10 cm distance, and flow rates of 1.5 ml/h and 1.9 ml/h.
  • the PCL core comprised about 2% or about 7.6% w/w MgSCh (Fig. 16).
  • the PCL core comprised about 2%, or 7.6% w/w CuSCU (Fig. 17).
  • FITR peaks for PCL and PLGA confirm presence of both polymers. Presence of MgSO4 or Q1SO4 (1.0%, 2.0%, 3.8%, and 7.6%) in monoaxial electrospun PCL fibers do not change the peak position, and do not introduce new peaks, which indicates that no new material or functional group has been introduced. By adding PLGA to the PCL+ MgS04 and PCL+ CuSC>4 samples, no significant alterations in the peak positions at 1,165 cm or within the 2800-3000 cm 1 range were observed. These findings indicate that the molecular environments at these specific wavelengths remained unchanged, suggesting stability in the chemical composition of the samples.
  • EDS Energy dispersive spectroscopy

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Abstract

L'invention concerne une structure de nanofibres comprenant une structure cœur-écorce utilisant deux polymères qui permettent à la structure de nanofibres d'avoir des propriétés multifonctionnelles, et un procédé de fabrication de ladite nanofibre.
PCT/US2024/041041 2023-08-07 2024-08-06 Compositions fibreuses cœur-écorce et procédés associés Pending WO2025034706A1 (fr)

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