WO2024226778A2 - Systèmes et procédés d'électrofilage par impression 3d - Google Patents

Systèmes et procédés d'électrofilage par impression 3d Download PDF

Info

Publication number
WO2024226778A2
WO2024226778A2 PCT/US2024/026244 US2024026244W WO2024226778A2 WO 2024226778 A2 WO2024226778 A2 WO 2024226778A2 US 2024026244 W US2024026244 W US 2024026244W WO 2024226778 A2 WO2024226778 A2 WO 2024226778A2
Authority
WO
WIPO (PCT)
Prior art keywords
integrated
electrospinning system
electrospinning
component
printhead
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2024/026244
Other languages
English (en)
Other versions
WO2024226778A3 (fr
Inventor
Mohammed MANIRUZZAMAN
Yu Zhang
Faez ALKADI
Ishaan Duggal
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.)
University of Texas System
University of Texas at Austin
Original Assignee
University of Texas System
University of Texas at Austin
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by University of Texas System, University of Texas at Austin filed Critical University of Texas System
Publication of WO2024226778A2 publication Critical patent/WO2024226778A2/fr
Publication of WO2024226778A3 publication Critical patent/WO2024226778A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • 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
    • D01D5/0015—Electro-spinning characterised by the initial state of the material
    • D01D5/003—Electro-spinning characterised by the initial state of the material the material being a polymer solution or dispersion

Definitions

  • This present disclosure is in the field of electrospinning.
  • This present disclosure relates generally to devices, systems, and methods for electrospinning of fibers including various components.
  • Fibers are a form of string-like material that is characterized by a large length to width ratio. Fibers are ubiquitous in nature and are widely developed in synthetic forms. Natural fibers present in hair, fur of animals, and in bird feathers consisting mainly of proteins, provide essential functionality, such as protection, sensing, regulation, etc. Silk, produced by spiders, worms, and other species, is also a protein-based fiber with an extremely high strength-to-weight ratio. Fiberlike cellulose filaments, with diameters ranging from micrometers to nanometers, present in the cellular walls of plants serve as the base component of paper and cardboard. Plant fibers in various forms are also used in textiles and for nutrition.
  • Man-made fibers are produced with higher uniformity and reproducibility in order to enable a more predictable manufacturing process.
  • membranes containing fibers with nanometer diameters provide an extremely high surface area and high porosity material, presenting useful properties in terms of mechanical strength, breathability, sensitivity to external stimuli, and biomimetic environment.
  • Electrospinning is a fiber fabrication method combining electrospraying and conventional solution dry spinning fibers.
  • the process uses electric force to draw charged threads of polymer solutions, or polymer melts up to form fibers.
  • the formed fiber diameter can range from hundred nanometers to a few micrometers.
  • electrospinning avoids using coagulation chemistry or high temperature to produce solid threads from a solution. Also, this method prevents the final product containing any solvent.
  • Fibers featuring large length-to-width ratios and strength-to-weight ratios have emerged as powerful tools in pharmaceutical science and tissue engineering. Without the involvement of coagulation chemistry or high temperature, electrospinning is capable of fabricating fibers or mats of electrospun fibers including large and complex molecules by applying electric force to a solution droplet. Integrated with printheads and mechanical arms, a continuous, safe, and efficient fiber production system can be achieved.
  • electrospinning is a versatile and effective technique for producing polymer fibers with diameters ranging from several nanometers to several micrometers. This method can be useful in the pharmaceutical industry for applications relating to drug delivery and tissue engineering.
  • electrospinning can be used to create drug-loaded fibers with controlled release properties. These fibers can be used as a platform for drug delivery systems that can be implanted in the body or applied topically to the skin. Electrospun fibers have a high surface area-to-volume ratio, which can improve drug release kinetics, enhance drug bioavailability, and reduce the frequency of drug administration.
  • General steps involved in using electrospinning for drug delivery may include: (1) polymer selection that includes choosing a suitable polymer that can be electrospun and is compatible with the drug to be delivered. The polymer should also have appropriate mechanical and chemical properties for the intended application. General steps may further include (2) drug incorporation that includes dissolving the drug in the polymer solution before electrospinning. The concentration of the drug in the polymer solution should be optimized for the desired release rate. General steps may further include (3) electrospinning that includes using an electrospinning apparatus to produce nanofibers from the polymer solution. The electrospinning parameters, such as voltage, flow rate, and distance between the spinneret and the collector, should be optimized to obtain uniform and fine nanofibers.
  • General steps may further include (4) cross-linking including cross-linking the electrospun nanofibers to improve their stability and prevent the drug from leaching out.
  • the cross-linking method may depend on the polymer used and the intended application.
  • General steps may further include (5) drug release evaluation including evaluating the drug release kinetics from the electrospun nanofibers using in vitro or in vivo methods. The release rate can be adjusted by modifying the polymer composition, fiber diameter, and drug loading.
  • General steps may further include (6) formulation development includes developing the drug delivery system based on the electrospun nanofibers, such as patches, implants, or dressings, depending on the intended application. Electrospinning is a versatile technique that can be used for drug delivery. The success of the technique may depend on the choice of polymer, drug loading, electrospinning parameters, and the intended application.
  • electrospinning and 3D printing are both innovative technologies that have shown great potential in the field of tissue engineering. Combining these two technologies can offer new opportunities for the development of tissue-engineered constructs with enhanced mechanical and biological properties.
  • One approach is to use 3D printing technology to fabricate a 3D structure or scaffold and then electrospin fibers onto the scaffold to create a hybrid structure. This can provide a more complex structure than can be achieved with electrospinning alone, allowing for more advanced tissue engineering constructs.
  • the electrospun fibers can provide a high surface area-to-volume ratio, which can improve cell attachment, proliferation, and differentiation.
  • Another approach is to use electrospinning to create fibers and then 3D print the fibers into a desired shape or structure.
  • scale-up one challenge of electrospinning is the difficulty in scaling up the process to produce large quantities of nanofibers for drug delivery. Scaling up can be challenging due to issues such as nozzle clogging, inconsistent fiber size, and decreased electrospinning efficiency. Scaling up of electrospinning may require careful consideration of several factors including the number of nozzles, size of the collector, voltage power supply and the flow rate amongst others. The scaling up of electrospinning may benefit tremendously by using a mechanical arm.
  • the mechanical arm can be programmed to move the spinneret over the collector in a precise pattern, and to maintain a consistent distance between the spinneret and the collector.
  • the mechanical arm can help to achieve the following roles: 1) controlling the range of motions in 6 dimensions, 2) improved control on speed to ensure fiber quality is not damaged, and 3) improved control of precision.
  • the challenges that can be addressed to successfully use this technique in pharmaceutical science may further include (2) reproducibility: another challenge is ensuring the reproducibility of the electrospinning process, which can be affected by various factors such as environmental conditions, polymer properties, and electrospinning parameters. Reproducibility is important for the development of consistent and reliable drug delivery systems.
  • the challenges that can be addressed to successfully use this technique in pharmaceutical science may additionally include (3) drug stability: the incorporation of drugs into electrospun nanofibers can also be challenging, as drugs may degrade or lose activity during the electrospinning process or during storage. The selection of a suitable polymer and the optimization of the drug loading and release rate may be important to maintaining drug stability.
  • the electrospun nanofibers should be biocompatible and non-toxic to avoid adverse reactions or inflammation when used for drug delivery in vivo. Biocompatibility testing should be performed before using electrospun nanofibers for drug delivery.
  • Cost finally, the cost of electrospinning equipment and materials can be a significant barrier to using this technique for drug delivery. The cost of materials, equipment, and labor should be carefully considered when developing electrospun drug delivery systems. While electrospinning is a promising technique for drug delivery, there are several challenges that should be addressed to ensure its successful use in pharmaceutical science. Addressing these challenges may require continued research and development to optimize electrospinning parameters, improve drug stability, ensure biocompatibility, and reduce costs. The techniques described in the present disclosure may overcome one or more of these challenges.
  • the challenges include (1) mimicking native tissue structure: tissue engineering may employ the creation of biomimetic scaffolds that can mimic the natural structure of the target tissue. Electrospinning can produce nanofibers with high surface area-to-volume ratios, but achieving the desired three-dimensional structure can be challenging.
  • the challenges may further include (2) mechanical properties: the mechanical properties of electrospun scaffolds, such as stiffness, strength, and elasticity, should be carefully controlled to ensure compatibility with the target tissue. Achieving the desired mechanical properties while maintaining biocompatibility and drug release can be difficult.
  • the challenges may further include (3) cell infiltration: the electrospun scaffolds should support the growth and proliferation of cells and allow for cell infiltration and integration with the host tissue. Achieving optimal cell infiltration and integration can be challenging due to the small pore size of the nanofibers.
  • the challenges may further include (4) long-term stability: electrospun scaffolds should maintain their structural and functional properties over an extended period to support tissue regeneration. Achieving long-term stability can be challenging due to factors such as degradation of the polymer, inflammatory response, and mechanical stress.
  • the challenges may further include (5) standardization: standardization of the electrospinning process and scaffold properties is important for reproducibility and scalability of tissue engineering applications. Achieving standardized electrospinning protocols can be challenging due to the complex and dynamic nature of the process.
  • a fiber fabrication device integrates an electrospinning device, printheads containing linkers, and a mechanical arm to obtain large-scale manufacturing of fibers.
  • An example system includes a plurality of supply containers for preparing or storing a respective component comprising a polymer or a non-polymeric excipient, a solvent, or an active pharmaceutical ingredient (API), a printhead in fluid communication with the plurality of supply containers, the printhead comprises a plurality of linkers, wherein each linker is in fluid communication with a supply outlet of one of the plurality of supply containers, a fluid mixer for mixing components from the plurality of linkers into a mixture, and one or more outlets in fluid communication with the fluid mixer, and a spinneret in fluid communication with the one or more outlets, a high- voltage power supply in electrical communication with the spinneret to form electrospun fibers, and a collector to collect the electrospun fibers.
  • a printhead in fluid communication with the plurality of supply containers, the printhead comprises a plurality of linkers, wherein each linker is in fluid communication with a supply outlet of one of the plurality of supply containers, a fluid mixer for mixing components from the plurality of
  • the collector further comprises a stage, a mechanical arm, and/or a conveyor belt.
  • the integrated electrospinning system further comprises an environmental simulator, wherein the environmental simulator comprises a temperature chamber, refrigerated chambers, humidity chamber, vacuum chamber, freeze-thaw chambers, environmental exposure chambers, growth chamber, light control, pressure controlled, thermal cycling, hypoxia chamber, electrostatic discharge chamber, electrochemical test chambers, antistatic charge chamber, environmental exposure chamber, acceleration test chamber, biochemical test chambers, vibration chamber, stability chamber, salt spray chamber, thermal shock chamber, altitude chamber, anechoic chamber, gas-controlled chamber, air quality-controlled chambers and/or sterilization chamber.
  • the environmental simulator comprises a temperature chamber, refrigerated chambers, humidity chamber, vacuum chamber, freeze-thaw chambers, environmental exposure chambers, growth chamber, light control, pressure controlled, thermal cycling, hypoxia chamber, electrostatic discharge chamber, electrochemical test chambers, antistatic charge chamber, environmental exposure chamber, acceleration test chamber, biochemical test chambers, vibration chamber, stability chamber, salt spray chamber,
  • the environmental simulator includes a plurality of environmental parameters, wherein the plurality of environmental parameters comprises temperature, humidity, gas, optical conditions, and/or stability.
  • the stage is adjustable in six degrees of freedom.
  • the stage includes a roller and/or a spinning roller.
  • the stage is adjustable along a first axis, a second axis, and/or a third axis.
  • the mechanical arm is assembled with the stage.
  • the stage comprises a collecting surface that rotates or translates to collect the electrospun fibers.
  • the integrated electrospinning system includes further comprises equipment for maintaining the plurality of supply containers, the printhead, and/or the collector in a sterile environment.
  • the mechanical arm comprises multiple metal joints. In some examples, the mechanical arm has six degrees of freedom. In some examples, at least one of the respective components include particles. In some examples, the particles having diameters of from 10 nm to 1100 pm. In some examples, the electrospun fibers include particles. In some examples, at least one of the respective components include live cells.
  • the polymer is a biodegradable polymer selected from the group consisting of poly(lactide-co-glycolide), polylactide (PLA), polyglycolide (PGA), poly caprolactone (PCL), pluronic Fl 27, sodium alginate, hyaluronic acid, chitosan, cyclodextrin, dextran, agarose, gelatin, albumin, collagen, lipids, a polyethylene glycol (PEG) derivative, a pharmaceutical grade polymer, poly(hydroxy butyrate), poly(P-malic acid), or poly(L-lysine).
  • the integrated electrospinning system further comprises a continuous belt system to deliver the electrospun fibers to a downstream process.
  • the integrated electrospinning system further comprises at least one pneumatic pump and/or syringe stress pump to facilitate fluidic motion of the respective component of the plurality of supply containers.
  • the fluid mixer comprises a coaxial arrangement of a first fluidic channel in fluid communication with a first linker and a second fluid channel in fluid communication with a second linker, wherein the first component is provided to the first linker, and wherein the second component is provided to the second linker.
  • the fluid mixer comprises a stirrer.
  • the integrated electrospinning system further comprises an electric field or a magnetic field for activating the stirrer.
  • the stirrer rotates about an axis parallel to a flow direction of the mixture through the one or more outlets.
  • the stirrer rotates about an axis perpendicular to a flow direction of the mixture through the one or more outlets.
  • the fluid mixer is characterized by a fluidic arrangement providing the first component and the second component in a coaxial flow configuration, a biaxial flow configuration, or a triaxial or higher axial flow configuration.
  • the fluid mixer comprises a mixing architecture characterized by an “S” shape or a helix shape.
  • the integrated electrospinning system further comprises one or more temperature sensors or temperature controllers for monitoring or controlling a temperature of mixture in the fluid mixer.
  • the mixture comprises or further comprises one or more of a cosolvent, a surfactant, a preservative, live cells, polymer, thickeners, diluents, biologically active polynucleotides, cellular components, an additional active ingredient, a salt, a preservative, a protein, a peptide, an amino acid, or a nucleic acid component.
  • the API comprises a protein, an antibody, a nucleic acid, messenger ribonucleic acid (mRNA) molecules, a lipid nanoparticle, clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (Cas9), transcription activator-like effector nucleases (TALENs), zinc-finger nucleases (ZFNs), homing endonucleases or meganucleases, a growth factor, a plasmid, a hydrophilic pharmaceutical, a lipophilic pharmaceutical, a viral particle, a virus-like particle, a live yeast cell, a live recombinant yeast cell, a live fungus, a live bacterial cell, a live recombinant bacterial cell, a live insect cell, a live mammalian cell, or a live mesenchymal stem cell.
  • CRISPR clustered regularly interspaced short palindromic repeats
  • TALENs transcription activator-like effector
  • the polymer is a biodegradable polymer selected from the group consisting of poly(lactide-co-glycolide), polylactide (PLA), polyglycolide (PGA), poly caprolactone (PCL), pluronic Fl 27, sodium alginate, hyaluronic acid, chitosan, cyclodextrin, dextran, agarose, gelatin, albumin, collagen, lipids, a polyethylene glycol (PEG) derivative, a pharmaceutical grade polymer, poly(hydroxy butyrate), poly(P-malic acid), or poly(L-lysine).
  • PEG polyethylene glycol
  • PEG polyethylene glycol
  • the non-polymeric excipient is a hydrophilic substance, a hydrophobic substance, a non-reducing sugar, trehalose, sucrose, a polyol, mannitol, sorbitol, xylitol, an amino acid, leucine, or L-arginine.
  • the integrated electrospinning system further comprises one or more mixing vessels in fluid communication with the plurality of supply containers for preparing and providing components to the plurality of supply containers.
  • the integrated electrospinning system further comprises one or more sensors monitoring a concentration of the API.
  • the one or more sensors comprise a UV probe.
  • the plurality of linkers comprises a Luer lock, a Luer slip, or a slip tip. In some examples, the plurality of linkers is configured to couple with an outlet of an additional printhead. In some examples, the plurality of linkers is characterized by a diameter of less than or about 5.0 mm. In some examples, a first respective component comprises a first API and a second respective component comprises a second API that is different from the first API. In some examples, a first respective component has a first polarity and a second respective component has second polarity that is different from the first polarity, wherein the first respective component and the second respective component are immiscible.
  • An example method comprises providing a first component to a first linker of a plurality of linkers of a printhead, providing a second component to a second linker of the plurality of linkers of the printhead, combining the first component and the second component in a fluid mixer of the printhead, forming a mixture of the first component and the second component in the printhead, delivering the mixture to a spinneret in fluid communication with the printhead, applying voltage to the mixture at the spinneret to form fibers, and collecting the fibers by using a controlled collector.
  • the first component comprises a first solvent and the second component comprises a second solvent having a different polarity from the first solvent.
  • the first component comprises a first active pharmaceutical ingredient (API) and the second component comprises a second API that is different from the first API.
  • An example integrated electrospinning system comprises a plurality of supply containers for preparing or storing a respective component comprising a polymer or a non-polymeric excipient, a solvent, or an active pharmaceutical ingredient (API), a plurality of spinnerets in fluid communication with the plurality of supply containers to form a plurality of electrospinning droplets, a high-voltage power supply in electrical communication with the plurality of spinnerets to form electrospun fibers from the plurality of electrospinning droplets, and a collector including a stage and a mechanical arm.
  • the integrated electrospinning system further comprises a printhead in fluid communication with the plurality of supply containers, wherein the printhead comprises a plurality of linkers, wherein each linker is in fluid communication with a supply outlet of one of the plurality of supply containers, a fluid mixer for mixing components from the plurality of linkers into a mixture, and one or more printhead outlets in fluid communication with the fluid mixer and the plurality of spinnerets.
  • the API comprises a protein, an antibody, a nucleic acid, messenger ribonucleic acid (mRNA) molecules, a lipid nanoparticle, clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (Cas9), transcription activator-like effector nucleases (TALENs), zinc-finger nucleases (ZFNs), homing endonucleases or meganucleases, a growth factor, a plasmid, a hydrophilic pharmaceutical, a lipophilic pharmaceutical, a viral particle, a virus-like particle, a live yeast cell, a live recombinant yeast cell, a live fungus, a live bacterial cell, a live recombinant bacterial cell, a live insect cell, a live mammalian cell, or a live mesenchymal stem cell.
  • CRISPR clustered regularly interspaced short palindromic repeats
  • TALENs transcription activator-like effector
  • the respective component is semi-permeable.
  • the polymer is a biodegradable polymer selected from the group consisting of poly(lactide-co-glycolide), polylactide (PLA), polyglycolide (PGA), poly caprolactone (PCL), pluronic Fl 27, sodium alginate, hyaluronic acid, chitosan, cyclodextrin, dextran, agarose, gelatin, albumin, collagen, lipids, a polyethylene glycol (PEG) derivative, a pharmaceutical grade polymer, poly(hydroxy butyrate), poly(P-malic acid), or poly(L-lysine).
  • PEG polyethylene glycol
  • PEG polyethylene glycol
  • the non-polymeric excipient is a hydrophilic substance, a hydrophobic substance, a non-reducing sugar, trehalose, sucrose, a polyol, mannitol, sorbitol, xylitol, an amino acid, leucine, or L-arginine.
  • An example electrospun fiber comprises a first segment including a first component, and a second segment including a second component, wherein the first segment and the second segment have uniform diameters.
  • the second segment coaxially surrounds the first segment.
  • the first segment is characterized by a first axis and the second segment is characterized by a second axis.
  • the electrospun fiber further comprises a third segment.
  • the second segment coaxially surrounds the first segment and the third segment coaxially surrounds the first segment and the second segment.
  • the first segment is characterized by a first axis
  • the second segment is characterized by a second axis
  • the third segment is characterized by a third axis.
  • the electrospun fiber further comprises live cells.
  • the electrospun fiber is edible.
  • the first segment and the second segment are configured to overcome phase segregation and separation.
  • An example system comprises an environmental simulator including at least one simulating component, wherein the simulating component includes a simulating fluid, and a simulating fiber disposed in the environmental simulator, wherein the simulating fiber comprises an inner layer, an inter layer surrounding the inner layer, and an outer layer surrounding the inter layer and the inner layer.
  • the simulating fiber comprises a hydrophobic material and a hydrophilic material.
  • the simulating fiber is semi- permeable to only allow a selected group of materials to pass through.
  • the at least one simulating component comprises a temperature chamber, humidity chamber, vacuum chamber, vibration chamber, stability chamber, salt spray chamber, thermal shock chamber, altitude chamber, anechoic chamber, gas-controlled chamber, and/or sterilization chamber.
  • an integrated electrospinning system includes a plurality of supply containers for preparing or storing a respective component comprising a polymer or a non-polymeric excipient, a solvent, or an active pharmaceutical ingredient (API); a first printhead in fluid communication with the plurality of supply containers, the first printhead comprising a first linker, a second linker, and a first coil; a second printhead in fluid communication with the first printhead, the second printhead comprising a third linker, a second coil, and a connecting linker in fluid connection with the first printhead, the second coil, and a spinneret; a high-voltage power supply in electrical communication with the spinneret to form electrospun fibers; and a collector to collect the electrospun fibers.
  • API active pharmaceutical ingredient
  • the third linker is in fluid communication with a respective component comprising a polymer or a non-polymeric excipient, a solvent, or an active pharmaceutical ingredient (API).
  • the first coil is configured to fabricate nanoparticles or microparticles, and wherein the second coil is configured to mix the nanoparticles or microparticles fabricated in the first coil with a respective component delivered from the third linker.
  • FIG. l is a schematic illustration of an integrated electrospinning system according to some examples.
  • FIG. 2 provides schematic illustrations of printheads for component mixing and corresponding electrospun fibers according to some examples.
  • FIG. 3 provides schematic illustrations of a printhead for multi-component fabrication of an electrospun fiber according to some examples.
  • FIG. 4 is a schematic illustration of an integrated electrospinning system including multiple spinnerets according to some examples.
  • FIG. 5A is a schematic illustration of an integrated electrospinning system according to some examples.
  • FIG. 5B is a schematic illustration of a system including a first printhead and a second printhead according to some examples.
  • FIG. 5C is a schematic illustration of a system including a first printhead and a second printhead according to some examples.
  • FIG. 6 provides a schematic illustration of an environmental simulator according to some examples.
  • FIG. 7 provides scanning electron microscopy images of electrospun fiber mats according to some examples.
  • FIG. 8 provides a scanning electron microscopy image of electrospun fiber mats according to some examples.
  • FIG. 9 provides a scanning electron microscopy image of electrospun fiber mats according to some examples.
  • FIG. 10A provides data showing attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR) of electrospun fibers according to some examples.
  • FIG. 10B provides data showing attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR) of electrospun fibers according to some examples.
  • ATR-FTIR attenuated total reflectance-Fourier transform infrared spectroscopy
  • FIG. 11 A provides data showing attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR) of electrospun fibers according to some examples.
  • FIG. 1 IB provides data showing attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR) of electrospun fibers according to some examples.
  • FIG. 11C provides data showing attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR) of electrospun fibers according to some examples.
  • FIG. 12 provides a scanning electron microscopy image of electrospun fiber mats according to some examples.
  • FIG. 13 provides data showing thermogravimetric analysis (TGA) of raw materials and mixtures according to some examples.
  • FIG. 14 provides DSC thermograms of electrospun fibers according to some examples.
  • FIG. 15A provides a bar chart showing the hydration of electrospun fibers according to some examples.
  • FIG. 15B provides a bar chart showing the entrapment efficiency of CUR and RTV of electrospun fibers according to some examples.
  • FIG. 16A contains a graph showing the cumulative drug release of RTV from electrospun fibers according to some examples in 0. IN HC1 (pH 1.2) with dialysis tube at 120 minutes.
  • FIG. 16B contains a graph showing the cumulative drug release of RTV from electrospun fibers according to some examples in 0. IN HC1 (pH 1.2) with dialysis tube at 7200 minutes (120 hours).
  • FIG. 16C contains a graph showing the cumulative drug release of RTV from electrospun fibers according to some examples in 0. IN HC1 (pH 1.2) with dialysis tube.
  • FIG. 16D contains a graph showing the cumulative drug release of RTV from electrospun fibers according to some examples in 0. IN HC1 (pH 1.2) without dialysis tube.
  • FIG. 17A provides shear stress and viscosity as a function of shear rate for the RTV electrospinning inks according to some examples in the lamellar region of the phase diagram.
  • FIG. 17B provides shear stress and viscosity as a function of shear rate for the CUR electrospinning inks according to some examples in the lamellar region of the phase diagram.
  • FIG. 18 provides schematic images of a biaxial printhead according to some examples and schematic images of the solo shape, alongside shape, and mixing shape of electrospinning bifibers according ot some examples.
  • Described herein are systems, methods, and techniques for electrospinning fibers, including multi-component fibers as well as fiber-based products, such as 3D-shaped fiber-based products (e.g., mats, filters, pharmaceutical dosage forms, thin films, 3D scaffolds, etc.).
  • the disclosed systems, methods, fibers, and products are useful for a variety of applications in pharmaceutical science and tissue engineering.
  • the disclosed systems and methods allow for continuous production of electrospun fibers of a variety of compositions and geometries, such as by using different printing nozzles, feedstocks, collection arrangements, or the like.
  • the produced electrospun fibers and fiber-based products can include pharmaceutically loaded fibers, hydrophobic fibers, hydrophilic fibers, live cell-loaded fibers, biocompatible polymer-based fibers, mixed-component fibers, or the like, such as by employing electrospinning nozzles or spinnerets fed by or incorporating multi-component printheads.
  • Dynamically controlled collection of the electrospun fibers for example using a multi-dimensionally controlled collection stage, such as a collection stage that includes up to 6 degrees of freedom (e.g., X, Y, Z, ⁇ I>, 9, ), can allow for creation of fiber-based products of any desirable geometry.
  • FIG. l is a schematic illustration of an integrated electrospinning system according to some examples.
  • the integrated electrospinning system 100 includes a plurality of supply containers 110, at least one printhead 120, a spinneret 140, a power supply 150, and a collector 160.
  • the integrated electrospinning system 100 includes the plurality of supply containers 110 (e.g., 110a, 110b, and 110c) for preparing or storing a respective component, such as a polymer or a non-polymeric excipient, a solvent, or an active pharmaceutical ingredient (“API”).
  • a respective component such as a polymer or a non-polymeric excipient, a solvent, or an active pharmaceutical ingredient (“API”).
  • API active pharmaceutical ingredient
  • the component may include, but is not limited to, poly(a-hydroxy acids) (“PAHAs”), lactic acids, polyglycolide or poly(glycolic acid) (“PGA”), poly(s-caprolactone), poly(ethylene glycolcaprolactone), poly(lactide)(“PLA”), poly(aminoacid alkyl ester) phosphazene, poly(caprolactone- co-ethyl ethylene phosphate), poly(carbonate), poly(caprolactone) (“PCL”), poly(ethylene glycol) (“PEG”), polyethyleneimine (“PEI”), poly(urethane) (“PU”), poly(vinyl alcohol) (“PVA”), poly(lactide-co-glycolide) (“PLGA”), poly(L-lactide) (“PLLA”), hydroxyapatite (“HA”), polypropylene carbonate) (“PPC”), poly(cyclohexyl carbonate), silicate, polyphosphazenes.
  • the printhead 120 may include a plurality of linkers (122a, 122b, 122c, and 122d) defining inlets of the printhead 120.
  • the printhead 120 may include a fluid mixer 124 in fluid communication with the plurality of linkers 122a, 122b, 122c, 122d for mixing components from the inlets into a mixture.
  • the fluid mixer 124 may be in fluid communication with the plurality of linkers 122a, 122b, 122c, 122d via a plurality of fluid lumens.
  • the printhead 120 may be connected to any components to facilitate the movement of the respective component.
  • the component may be a pressure pump.
  • the mixture may include a cosolvent, a surfactant, a preservative, live cells, polymer, thickeners, diluents, biologically active polynucleotides, cellular components, an additional active ingredient, a salt, a preservative, a protein, a peptide, an amino acid, or a nucleic acid component.
  • the printhead 120 may further include sub-printhead(s) 130.
  • the subprinthead ⁇ ) 130 may further include linkers (e.g., 122a, 122b), sub-printhead fluid mixer 134 and sub-printhead outlet 136.
  • sub-printhead outlet 136 may be an outlet linker that is coupled to linker 122d.
  • One or more of the plurality of linkers 122a, 122b, 122c, 122d may include a Luer lock, a Luer slip, a slip tip, or other couplers for establishing sealable fluid communication. As shown in FIG. 1, the plurality of linkers 122a, 122b, 122c, 122d may be various types of couplings or connectors.
  • each of the plurality of linkers 122a, 122b, 122c, 122d may be the same type of coupling or connector.
  • the linkers 122a, 122b, 122c, 122d may be characterized by a diameter of less than or about 5.0 mm, such as less than or about 4.5 mm, less than or about 4.0 mm, less than or about 3.5 mm, less than or about 3.0 mm, less than or about 2.5 mm, less than or about 2.0 mm, less than or about 1.5 mm, less than or about 1.4 mm, less than or about 1.3 mm, less than or about 1.2, mm, less than or about 1.1 mm, less than or about 1.0 mm, less than or about 0.9 mm, less than or about 0.8 mm, less than or about 0.7 mm, less than or about 0.6 mm, less than or about 0.5 mm, or less.
  • the fluid mixer 124 may have a coaxial arrangement of a first fluidic channel in fluid communication with a first linker (e.g., linker 122c) and a second fluid channel in fluid communication with a second linker (e.g., linker 122d).
  • the fluid mixer 124 may include a stirrer.
  • the stirrer may be activated using any means.
  • the stirrer may be activated by an electric field or a magnetic field.
  • the stirrer may be disposed at an upstream location of the fluid mixer 124 or at any location along the fluid mixer 124.
  • the fluid mixture 124 may include a plurality of stirrers to form the mixture.
  • the fluid mixer 124 may include a mixing architecture characterized by a “Y” shape, an “S” shape, a helix shape, or any other desirable shape to establish a desired amount of mixing of components introduced from various linkers.
  • the fluid mixer 124 may include a co-blender and/or a similar functional system.
  • the printhead 120 may include a printhead outlet 126 in fluid communication with the fluid mixer 124 via a one or more fluid lumens.
  • the printhead outlet 126 may also be in fluid communication with a spinneret 140 that forms droplets suitable for electrospinning via a printhead outlet 126.
  • the spinneret 140 may be a single-needle spinneret, a multi-needle spinneret, any co-axial spinneret (e.g., bi-axial, tri-axial), or the like.
  • the spinneret 140 may be fluidly connected to a pump (e.g., a syringe stress pump), such as via the printhead 120.
  • a pump e.g., a syringe stress pump
  • the printhead outlet 126 may further include an outlet linker and/or a nozzle.
  • the outlet linker and the nozzle may be separate components.
  • the outlet linker and/or the nozzle may form a unitary structure with the fluid mixer 124 (e.g., no outlet linker is present, and the nozzle is joined to the fluid mixer 124).
  • Various nozzle configurations may be used as appropriate.
  • the nozzle may include a plurality of nozzle ports.
  • the printhead outlet 126 the outlet linker (e.g., sub-printhead outlet 136), and/or any other nozzle may be characterized by a diameter of less than or about 5.0 mm, such as less than or about 4.5 mm, less than or about 4.0 mm, less than or about 3.5 mm, less than or about 3.0 mm, less than or about 2.5 mm, less than or about 2.0 mm, less than or about 1.5 mm, less than or about 1.4 mm, less than or about 1.3 mm, less than or about 1.2, mm, less than or about 1.1 mm, less than or about 1.0 mm, less than or about 0.9 mm, less than or about 0.8 mm, less than or about 0.7 mm, less than or about 0.6 mm, less than or about 0.5 mm, or less.
  • a droplet formed by the spinneret 140 may be subject to a high voltage (e.g., 5 to 50 kV) for electrospinning.
  • a power supply 150 may be used to apply high voltage over the droplet.
  • the high voltage may create a high electric field surrounding the formed droplet, thereby electrifying the droplet.
  • the accumulation of charge may cause a protrusion to appear at the tip of the droplet, thereby distorting the droplet from a hemispherical shape to a conical shape.
  • the distorted conical part of the droplet may be referred to as a “Taylor cone.”
  • a jet of charged liquid or liquid particles is formed at the “Taylor cone” of the droplet.
  • the jet is a very thin fiber of charged liquid or liquid particles.
  • the very thin fiber may have a diameter ranging from micrometers to nanometers.
  • the jet then undergoes a stretching and whipping process under the high electric field, forming a long thread of the very thin fiber 145.
  • the long thread of the very thin fiber 145 may be referred to as an “electrospun fiber.” Additional portions of the fluid from the spinneret may be continuously ejected and join the ejected thread to create a continuous electrospun fiber.
  • the integrated electrospinning system 100 may use the collector 160 to collect the long thread of the very thin fiber formed by the electrospinning process.
  • the collector 160 may include a collecting surface upon which the long thread of the very thin fiber is collected.
  • the collector may be a static collector or a rotating collector.
  • the collector 160 may include at least one stage that translates and/or rotates along at least one axis.
  • the at least one stage may include a roller, a spinning roller, a three-axis (e.g., x-axis, y-axis, z-axis) adjustable stage, and/or a four, five, or six degrees of freedom adjustable stage.
  • the collector 160 may arrange the long thread of the very thin fiber in any structure (e.g., a mat, a semi -permeable membrane including multiple layers of electrospun fibers, a 3 -dimensional scaffold including electrospun fibers loaded with cells, tissues, organs, edible matter, food, etc.) as desired.
  • any structure e.g., a mat, a semi -permeable membrane including multiple layers of electrospun fibers, a 3 -dimensional scaffold including electrospun fibers loaded with cells, tissues, organs, edible matter, food, etc.
  • the collector 160 may include one or more pressure sensors or pressure controllers, temperature sensors or temperature controller, position sensors, or other sensors or controllers.
  • the collector 160 may be connected to a mechanical arm 170 having up to six degrees of freedom (“DOF”).
  • DOF degrees of freedom
  • the DOF may include translation along the x, y, and z axes, as well as rotation around these axes.
  • the mechanical arm 170 may further include an assistive component to facilitate the gathering of the electrospun fiber.
  • the assistive component may be a static or dynamic collecting device.
  • the assistive component may be a cylindrical or a flat collector that is attached to an end effector of the mechanical arm 170.
  • the collector 160 may further include a conveyor belt or any continuous belt system that continuously transports products (e.g., electrospun fibers) of the integrated electrospinning system 100.
  • the integrated electrospinning system 100 may further comprise an environmentally controlled or sterile compartment to sterilize or maintain sterility of any of the plurality of supply containers 110, the at least one printhead 120, the spinneret 140, the power supply 150, and the collector 160.
  • FIG. 2 provides schematic illustrations of printheads for component mixing and corresponding electrospun fibers according to some examples.
  • Printhead 201 is a bi-axial printhead including a first linker 210 and a second linker 220.
  • the first linker 210 may be characterized by a first axis and the second linker 220 may be characterized by a second axis that is different from the first axis.
  • the first linker 210 and the second linker 220 may be respectively connected to a first supply container and a second supply container (not shown).
  • the first supply container includes a first component
  • the second supply container includes a second component.
  • the first component is different from the second component.
  • An integrated electrospinning device e.g., the integrated electrospinning system 100 using the printhead 201 may fabricate an electrospun fiber 230.
  • the electrospun fiber 230 includes a first fiber part 231 and a second fiber part 232.
  • the first part 231 includes the first fiber component and the second part 232 includes the fiber second component.
  • Printhead 202 is a tri-axial printhead including a first linker 240, a second linker 250, and a third linker 260.
  • the first linker 240 may be characterized by a first axis
  • the second linker 250 may be characterized by a second axis that is different from the first axis
  • the third linker 230 may be characterized by a third axis that is different from the first axis and the second axis.
  • the first linker 240, the second linker 250, and the third linker 260 may be respectively connected to a first supply container, a second supply container, and a third supply container (not shown).
  • the first supply container includes a first component
  • the second supply container includes a second component that is different from the first component
  • the third supply container includes a third component that is different from the first component and the second component.
  • An integrated electrospinning device e.g., the integrated electrospinning system 100
  • the electrospun fiber 270 includes a first fiber part 271, a second fiber part 272, and a third fiber part 273.
  • the first fiber part 271 includes the first component
  • the second fiber part 272 includes the second component
  • a third fiber part 273 includes the third component.
  • FIG. 3 provides a schematic illustration of a printhead for component mixing and a corresponding electrospun fiber according to some examples.
  • Printhead 300 is a co-biaxial printhead including a first printhead 310 and a second printhead 320.
  • the first printhead 310 is in fluid communication with the second printhead 320.
  • the first printhead 310 further includes a first linker 311, a second linker 312, a co-axial fluid mixer 313 in fluid communication with the first linker 311 and the second linker 312, and a first outlet 314 in fluid communication with the co-axial fluid mixer 313.
  • the first printhead 310 may be a co-axial printhead.
  • the co-axial fluid mixer 313 may include two capillaries that share an axis.
  • Each of the two capillaries may respectively be in fluid communication with the first linker 311 that is in fluid communication with a first component and the second linker 312 that is in fluid communication with a second component.
  • the first printhead 310 allows for the injection of the second component as a core part 331 into the first component as a coat part 332, thereby forming a co-axial fiber 330 that includes the coat part 332 continuously surrounding the core part 331.
  • the core part 331 and the coat part 332 may have any cross-sectional geometry as desired (e.g., circle, oval, rectangular, triangular, etc.).
  • the second printhead 320 includes a third linker 321 and a fourth linker 322.
  • the third linker 321 may be in fluid connection with a third component. In some examples, the third component is different from the first component and the second component. In some examples, the fourth linker 322 may be in fluid communication with the first outlet 314 to receive the co-axial fiber 330 as an input component.
  • the second printhead 320 further includes a bi-axial fluid mixer 324.
  • the bi-axial fluid mixer 324 includes a first channel in fluid connection with the third linker 321 and a second channel in fluid connection with the fourth linker 322.
  • the first channel is characterized by a first axis and the second channel is characterized by a second axis that is different from the first axis.
  • the second printhead 320 allows for the injection of the third component as bi-axial fiber 340 that is adjacent to the co-axial fiber 330, thereby forming a co-biaxial fiber that includes the co-axial fiber 330 and the bi-axial fiber 340.
  • the bi-axial fiber 340 and the co-biaxial fiber may have any cross-sectional geometry as desired (e.g., circle, oval, rectangular, triangular, etc.).
  • the co-axial fiber 330 and the bi-axial fiber 340 in the co-biaxial fiber may respectively include a first API and a second API that is different from the first API.
  • the release rate of the first API loaded in the co-axial fiber 330 is equal to the release rate of the second API loaded in the bi-axial fiber 340.
  • FIG. 4 is a schematic illustration of an integrated electrospinning system 400 including multiple spinnerets according to some examples.
  • the integrated electrospinning system 400 includes a plurality of supply containers 410 (e.g., 410a, 410b, and 410c), a plurality of spinnerets 420 (e.g., 420a, 420b, and 420c), a collector 440, and a mechanical arm 450.
  • the plurality of supply containers 410 e.g., 410a, 410b, and 410c
  • can prepare or store a respective component 412 e.g., 412a, 412b, and 412c).
  • the respective component 412 may be a polymer or a non-polymeric excipient, a solvent, or an active pharmaceutical ingredient (“API”).
  • the respective component 412 may include a lipidic material, an aqueous material, a porous material, and the like.
  • each respective components 412 can be optionally substituted by a multi-component nozzle and associated supply container, such as depicted in FIG. 1.
  • Each of the plurality of spinnerets 420 e.g., 420a, 420b, and 420c
  • the plurality of spinnerets 420 may form droplets of the respective component 412 (e.g., 412a, 412b, and 412c) that are suitable for electrospinning.
  • the integrated electrospinning system 400 may inject a first component (e.g., 412a) toward a first spinneret (e.g., 420a) to form droplets of the first component.
  • a first component e.g., 412a
  • a first spinneret e.g., 420a
  • the integrated electrospinning system 400 forms electrospun fibers including the first component and the electrospun fibers may be collected at the collector 440.
  • the collector 440 may further include a collecting surface 442 and a rotating element 444 that revolves and translates at a controlled speed.
  • the rotating element 444 gathers the electrospun fibers around the rotating element and aligns the electrospun fibers to form a first aligned fiber mat.
  • the first aligned fiber mat may be referred as an inner layer 430a.
  • the rotating element 444 may be coupled to an end effector 452 of the mechanical arm 450.
  • the integrated electrospinning system 400 may form a multi-layer fiber that includes the inner layer 430a, an inter layer 430b surrounding the inner layer 430a, and an outer layer 430c that surrounding the inner layer 430a and the inter layer 430b. Similar to the inner layer 430a, to form the inter layer 430b, the integrated electrospinning system 400 may inject a second component (e.g., 412b) toward a second spinneret (e.g., 420b) to form droplets of the second component (e.g., 412b).
  • a second component e.g., 412b
  • a second spinneret e.g., 420b
  • the integrated electrospinning system 400 forms electrospun fibers including the second component and the electrospun fibers may be collected by the collector 440, thereby disposing a second aligned fiber mat, or the inter layer 430b, surrounding the inner layer 430a.
  • the integrated electrospinning system 400 may inject a third component (e.g., 412c) toward a third spinneret (e.g., 420c) to form droplets of the third component (e.g., 412c).
  • the integrated electrospinning system 400 forms electrospun fibers including the third component and the electrospun fibers may be collected by the collector 440, thereby disposing a third aligned fiber mat, or the outer layer 430c, surrounding the inner layer 430a and the inter layer 430b.
  • the multi-layer fiber including the inner layer 430a, the inter layer 430b, and the outer layer 430c may be used as a semipermeable membrane, a membrane filter, etc.
  • the inner layer 430a, the inter layer 430b, and the outer layer 430c may have any cross-sectional geometry as desired (e.g., circle, oval, rectangular, triangular, etc.).
  • FIG. 5 A is a schematic illustration of an integrated electrospinning system according to some examples.
  • the integrated electrospinning system 500A includes a plurality of supply containers 510 (e.g., 510a, 510b, and 510c), a first printhead including a first linker 522 and a second linker 524, a second printhead including a third linker 532 and a connecting linker 526 in fluid connection with the first printhead, a mixer 534, and a spinneret 540.
  • the plurality of supply containers 510 e.g., 510a, 510b, and 510c
  • can prepare or store a respective component 512 e.g., 512a, 512b, and 512c).
  • the respective component 512 may be a polymer or a non-polymeric excipient, a solvent, or an active pharmaceutical ingredient (“API”).
  • the respective component 512 may include a lipidic material, an aqueous material, a porous material, and the like.
  • the respective component 512c may include particles (e.g., microparticles or nanoparticles that include APIs, or cells) as desired. The particles may have any cross-sectional geometry as desired (e.g., circle, oval, rectangular, triangular, etc.).
  • APIs may include a protein, an antibody, a nucleic acid, messenger ribonucleic acid (mRNA) molecules, a lipid nanoparticle, clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (Cas9), transcription activator-like effector nucleases (TALENs), zinc-finger nucleases (ZFNs), homing endonucleases or mega-nucleases, a growth factor, a plasmid, a hydrophilic pharmaceutical, a lipophilic pharmaceutical, a viral particle, a virus-like particle, a live yeast cell, a live recombinant yeast cell, a live fungus, a live bacterial cell, a live recombinant bacterial cell, a live insect cell, a live mammalian cell, or a live mesenchymal stem cell.
  • CRISPR clustered regularly interspaced short palindromic repeats
  • TALENs transcription activator-like
  • a weight ratio of the API to the polymer or the non -polymeric excipient in the mixture may be from 1 :8 to 1 : 15, such as from 1 :8 to 1 :9, from 1 :9 to 1 : 10, from 1 : 10 to 1 : 11, from 1 : 11 to 1 : 12, from 1 : 12 to 1 : 13, from 1 : 13 to 1 : 14, or from 1 : 14 to 1 : 15.
  • the particles may be a polymer, and the polymer may be a biodegradable polymer.
  • the biodegradable polymer may include, but is not limited to, poly(lactide-co-glycolide), polylactide (PLA), polyglycolide (PGA), polycaprolactone (PCL), Pluronic Fl 27, sodium alginate, hyaluronic acid, chitosan, cyclodextrin, dextran, agarose, gelatin, albumin, collagen, lipids, a polyethylene glycol (PEG) derivative, a pharmaceutical grade polymer, poly(hydroxy butyrate), poly(P-malic acid), or poly(L-lysine).
  • PEG polyethylene glycol
  • PEG polyethylene glycol
  • the particles may be a non-polymeric excipient, and the non- polymeric excipient may be a hydrophilic substance or a hydrophobic substance.
  • the non-polymeric excipient may include, but is not limited to, a non-reducing sugar, such as trehalose, or sucrose, a polyol, such as mannitol, sorbitol, xylitol, or an amino acid, such as leucine, or L-arginine.
  • the first linker 522 and the second linker 524 may be respectively in fluid connection with the respective component 512b and 512c.
  • the respective component 512c may be a secondary material that can coat the particles included in the respective component 512b.
  • the first printhead including the first linker 522 and the second linker 524 generates a plurality of composite particles 528.
  • the plurality of composite particles 528 may include at least one API and at least one secondary material.
  • the plurality of composite particles 528 may flow into the second printhead via the connecting linker 526.
  • the third linker 532 may be in fluid connection with the respective component 512a.
  • the respective component 512a may be base material within which the plurality of composite particles 528 can be embedded.
  • the integrated electrospinning system 500A mixes the plurality of composite particles 528 and the respective component 512a at the mixer 534.
  • the mixer 534 is in fluid communication with the spinneret 540.
  • the spinneret 540 forms droplets including the respective component 512a and the plurality of composite particles 528 that are suitable for electrospinning.
  • high voltage 545 is applied to the droplets at the spinneret 540 to form electrospun fiber 550 toward the collector 560.
  • the electrospun fiber 550 includes a fiber body 552 including the respective component 512a as a fiber body and a plurality of embedded or loaded particles 554.
  • the plurality of embedded particles 554 includes the plurality of composite particles 528.
  • the electrospun fiber 550 may have any cross- sectional geometry as desired (e.g., circle, oval, rectangular, triangular, etc.).
  • FIG. 5B is a schematic illustration of a system 500B including a first printhead 570 and a second printhead 580 according to some examples.
  • the system 500B may be incorporated to the integrated electrospinning system 500A.
  • the first printhead 570 and the second printhead 580 may correspond to the first printhead and the second printhead in the integrated electrospinning system 500A.
  • the first printhead 570 may perform a first process to fabricate nanoparticles and/or microparticles as described in relation to FIG. 5A.
  • the second printhead 580 may perform a second process to mix a polymer and the nanoparticles and/or microparticles to form a mixture for a subsequent process.
  • the subsequent process may be an electrospinning process.
  • FIG. 5C is a schematic illustration of a system 500C including a first printhead 590 and a second printhead 595 according to some examples.
  • the first printhead 590 may include a coil 590a.
  • the second printhead may include a coil 595a.
  • the first printhead 590 and the second printhead 595 may correspond to the first printhead and the second printhead in the integrated electrospinning system 500A.
  • the first printhead 590 may perform a first process to fabricate nanoparticles and/or microparticles as described in relation to FIG. 5A.
  • nanoparticles and/or microparticles are fabricated in coil 590a.
  • the second printhead 595 may perform a second process to mix a polymer and the nanoparticles and/or microparticles to form a mixture for a subsequent process.
  • the nanoparticles and/or microparticles generated in coil 590a are mixed with one or more polymers in coil 595a to form a mixture for the subsequent process.
  • the subsequent process may be an electrospinning process.
  • the first printhead or the second printhead may resemble a printhead (e.g., FIG. 9) described in WO 2024/026039, filed July 27, 2023, the entire contents of which are incorporated herein by reference for all purposes. [0068]
  • Each of coil 590a and coil 595a may have a number of turns.
  • Coil 590a and coil 595a may each independently have a number of turns. Each turn may represent a full revolution.
  • the number of turns in a coil may be from 2 to 5, from 5 to 10, from 10 to 15, from 15 to 20.
  • the inner diameter of the tube of the coil may be from 1 to 2 mm, from 2 to 3 mm, from 3 to 4 mm, from 4 to 5 mm, or over 5 mm.
  • the length from the beginning of the coil to the end of the coil may be from 5 to 10 mm, 10 to 15 mm, 15 to 20 mm, 20 to 25 mm, 25 to 30 mm, or greater than 30 mm.
  • the radius of the turns of the coil may be from 1 to 5 mm, 5 to 10 mm, 10 to 15 mm, 15 to 20 mm, 20 to 25 mm, 25 to 30 mm, or greater than 30 mm.
  • a coil may be referred to as a helix.
  • the coil may be replaced by a (repeating) S-shape.
  • One difference with an S-shape from a coil may be that the S-shape does not appear as a circle when viewed from a certain perspective.
  • coil 590a may be separated from coil 595a by a predominantly straight section or a section without a coil.
  • the embodiment of FIG. 5C may help with particle generating and mixing for electrospinning.
  • the coils in FIG. 5C may be part of a fluid mixer described herein.
  • FIG. 6 provides a schematic illustration of an environmental simulator according to some examples.
  • the environmental simulator 600 includes a stomach simulator 610, an intestine simulator 620, and a simulating fiber 630.
  • the environmental simulator 600 may control various parameters as desired. In some examples the parameters include, but are not limited to, temperature, humidity, gas, light, and stability.
  • the simulating fiber 630 may be the electrospun fiber 145 (FIG. 1), the electrospun fiber 230 (FIG. 2), the electrospun fiber 270 (FIG. 2), the co-biaxial fiber that includes the co-axial fiber 330 and the bi-axial fiber 340 (FIG.
  • the simulating fiber 630 may include a hydrophobic material and/or a hydrophilic material.
  • the simulating fiber 630 may be a semi-permeable membrane that includes an inner layer, an inter layer surrounding the inner layer, and an outer layer 430c surrounding the inner layer and the inter layer. Each of the inner layer, the inter layer and the outer layer may have different permeabilities to materials. In some examples, the simulating fiber 630 may only allow a selected group of materials to pass through.
  • the stomach simulator 610 includes a stomach compartment 612 and at least one sensor
  • the stomach compartment 612 may include fasted state simulated gastric fluid (FASSGF) with a pH value of 1.6 to mimic a stomach environment.
  • the at least one sensor 614 may be programmed compression probe (e.g., UV sensor probe) to monitor mechanical properties of interest (e.g., compression, stress, etc.) during the dissolution of a disintegrated test drug 608.
  • the environmental simulator 600 may include a feeding pump 618 to facilitate the transportation of the test drug 608 toward the intestine simulator 620.
  • the intestine simulator 620 may include an extraluminal compartment 622 and an intraluminal compartment 623.
  • the extraluminal compartment 622 may include at least one FASSGF fluid with a pH value of 6.5 to simulate intestinal conditions.
  • the extraluminal compartment 622 may be connected to a buffer compartment 640 that contains at least one physiologically relevant buffer as desired.
  • the at least one physiologically relevant buffer may be contained in a reactor tank.
  • the at least one physiologically relevant buffer may be a phosphate buffer having a pH value of 6.5.
  • the at least one physiologically relevant buffer may be transported from the buffer compartment 640 into the simulating fiber 630 to adjust simulating parameters or a simulating environment as desired.
  • the simulating fiber 630 is hollow.
  • the physiologically relevant buffer is transported via a buffer channel 631 that passes inside and through the hollow simulating fiber 630.
  • the buffer channel 631 may have any length or shape as desired.
  • the buffer channel 631 may be in fluid communication with an intermediate compartment 624 that receives any fluid or matter flowing from the buffer compartment 640.
  • the intermediate compartment 624 may be in fluid communication with the intraluminal compartment 623.
  • the intermediate compartment 624 may include any component and/or device as desired.
  • the component and the device may include a feeding pump, a vacuum, a UV sensor probe, etc.
  • the buffer compartment 640 may further include any component or device as needed.
  • the component or device may be a feeding pump, a vacuum, an agitation system, and/or sensor (e.g., UV sensor probe).
  • the environmental simulator 600 may include a pump to facilitate the transportation of the test drug 608 toward the intraluminal compartment 623.
  • the simulating fiber 630 may be disposed into the FASSGF fluid of the extraluminal compartment 622 and the test drug 608 diffuses or permeates across a part (e.g., a layer, a specific surface of the simulating fiber 630) of the simulating fiber 630.
  • the extraluminal compartment 622 may monitor properties related to the diffusion or permeation (e.g., diffusion rate, permeation rate, etc.) of the test drug 608 by a sensor.
  • the sensor may be a UV sensor probe, a dynamic light scattering (“DLS”) sensor, and the like.
  • the sensor may be disposed in the extraluminal compartment 622 for continuous monitoring of the absorbance of the test drug 608.
  • the simulating fiber 630 may be disposed or immersed in the extraluminal compartment 622 to allow the test drug 608 to diffuse across any part of the simulating fiber 630.
  • the intraluminal compartment 623 of the environmental simulator 600 may receive fluid and/or matter from the extraluminal compartment 622, the intraluminal compartment 623, and/or the intermediate compartment 624.
  • a mixture of the fluid and/or matter may be referred to as “waste.”
  • a pump may be disposed between the extraluminal compartment 622 and the intraluminal compartment 623 to facilitate the transportation of fluid or any matter from the extraluminal compartment 622 toward the intraluminal compartment 623.
  • a pump may be disposed between the intermediate compartment 624 and the intraluminal compartment 623 to facilitate the transportation of fluid or any matter from the intermediate compartment 624 toward the intraluminal compartment 623.
  • the system 600 may include a plurality of special simulating components, and each of the plurality of special simulating components may be an independent chamber.
  • the plurality of special simulating components may include a temperature chamber, refrigerated chambers, humidity chamber, vacuum chamber, freeze-thaw chambers, environmental exposure chambers, growth chamber, light control, pressure controlled, thermal cycling, hypoxia chamber, electrostatic discharge chamber, electrochemical test chambers, antistatic charge chamber, environmental exposure chamber, acceleration test chamber, biochemical test chambers, vibration chamber, stability chamber, salt spray chamber, thermal shock chamber, altitude chamber, anechoic chamber, gas-controlled chamber, air quality- controlled chambers and/or sterilization chamber.
  • Biaxial Electrospun Fibers (Biaxial-NFs).
  • Biaxial NFs were prepared from Eudragit® SI 00 (ESI 00) and Eudragit® EPO (EPO) to encapsulate Ritonavir (RTV) and Curcumin (CUR), respectively.
  • Curcumin produced by Tokyo Chemical Industry Co., Ltd.
  • Ritonavir was purchased from Nexconn Pharmatechs Ltd. (Shenzhen, China).
  • Methacrylic acid- Methyl methacrylate copolymer (1 :2) (Eudragit® SI 00) and butyl methacrylate, dimethyl aminoethyl methacrylate, methyl methacrylate copolymer (Eudragit® EPO) were procured from Evonik Rohm Pharma GmbH, Darmstadt, Germany. Absolute ethanol was purchased from Fischer Scientific UK.
  • FIG. 18 shows the schematic images of the printhead which contains three parts: the two inputs, microfluid system, and one output.
  • the input was designed as the female luer locker while the output was designed as the male luer locker.
  • the ink flows go through a tube with the inner diameter of 3 mm, then the diameter of the tube was down to 2 mm and through the ‘Janus’ half tube (radius 1 mm). The Janus line finally goes through the standard 14- and 18-gauge stainless needles.
  • NFs were collected on a collector plate covered with aluminum foil placed at 12 cm from the spinneret. All experiments were performed under ambient conditions (25 ⁇ 2°C; 57 ⁇ 6% relative humidity).
  • Scanning electron microscopy SEM. Scanning electron microscopy (Quanta FEG 650 ESEM, FEI Company, Hillsboro, OR, USA) was employed to observe the surface of the electrospinning (NFs). The thin piece of NFS was sheared from the center using a sharp razor blade and fixed on aluminum stubs with conductive double-sided tape. The samples were coated with gold by vacuum sputtering (EMS Sputter Coater, Hatfield, PA, USA) before observation under SEM. Microscope images were captured at a working distance of ⁇ 9 mm, an accelerated voltage of 10 kV, and an emission current of 15 pA.
  • FIG. 7 provides scanning electron microscopy images of electrospun fiber mats according to some examples (701 (Sample 1, Table 1), 702 (Sample 2, Table 1), 703 (Sample 3, Table 1), and 704 (Sample 4, Table 1)).
  • Table 1 Exemplary Formulation and Processing Conditions
  • FIG. 8 provides a scanning electron microscopy image of an electrospun fiber mat according to some examples.
  • the electrospun fiber mat includes a plurality of bi-axial electrospun fibers.
  • a design of experimental (DoE) modeling was utilized to optimize the electrospinning of the biaxial NFs using a custom design using I-Optimal design as an optimality criterion.
  • DoE modeling was conducted using the custom design platform in JMP 16 software developed by the SAS institute.
  • Table 2 The processing conditions of example electrospun fibers are summarized in Table 2. As seen in Table 2, each process factor was studied at four levels while the inner needle diameter was included as numerical factor (two levels).
  • the model parameters specified is a traditional response surface design (RSM) is listed as: applied voltage (kV) & RS, flow rate (mL/h) & RS, gap distance (cm) & RS, Nozzle diameter (gauge), applied voltage (kV)*applied voltage (kV), applied voltage (kV)*flow rate (mL/h), flow rate (mL/h)*flow rate (mL/h), applied voltage (kV)*gap distance (Cm), flow rate (mL/h)*gap distance (cm), gap distance (cm)*gap distance (cm), applied voltage (kV)*Nozzle diameter (gauge), flow rate (mL/h)*Nozzle diameter (gauge), and gap distance (cm)*Nozzle diameter (gauge).
  • the controllable processing parameters defined as factors included flow rate (1 to 2 mL/h), inner needle diameter (18, 14 gauge), applied voltage (15 to 25 KV), and distance between the tip of the needle and the foil surface (20 to 25 cm
  • the SEM images presented in FIG. 9 illustrates the biaxial nanofibers (NFs) with smooth surfaces, randomly distributed, and displaying distinct features. Alongside their lengths, the NFs exhibit a bicylindrical shape.
  • a predetermined dissolved organic solvent e.g., ethanol, chloroform, acetone, or combinations thereof
  • 4 wt. % EPO in ethanol e.g., ethanol, chloroform, acetone, or combinations thereof
  • FIG. 9 the bi-axial fibers shown in 901, 902, and 903 were formed by combining two inks: EPO dissolved in ethanol and ES100 dissolved in chloroform, exhibiting a relative polarity difference of 0.395.
  • the biaxial fibers shown in 904, 905, and 906 were created by employing another set of two inks: EPO dissolved in ethanol and ES100 dissolved in acetone, with a relative polarity difference of 0.299.
  • no split sole fibers were observed among the bi-axial fibers, confirming formation of biaxial NFs.
  • FIG. 10A (1001 and 1002) and FIG. 10B (1003 and 1004) provide data showing attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR) of electrospun fibers according to some examples.
  • ATR-FTIR of the electrospun fibers may be collected using a modular NicoletTM iSTM 50 FTIR system (ThermoFisher Scientific, Waltham, Massachusetts, USA).
  • the preparation of the electrospun fibers includes weighing 20-25 mg of sample electrospun fibers, the sample electrospun fibers may be analyzed for percentage transmittance from 4000 to 400 cm’ 1 at a resolution of 4 cm’ 1 and 64 scans per run. The absorbance mode was used. OMNICTM series software (Version 9.0 ThermoFisher Scientific, Waltham, MA, USA) was used to capture and analyze the spectra.
  • Table 3 Exemplary Formulation and Physical Form
  • Samples No. 5-8 are Samples No. 1-4 dissolved in ethanol, respectively.
  • Sample 9 and Sample 10 represent InkA and InkB, respectively, prepared as described herein.
  • Samples 11-22 are electrospun fibers obtained from three electrospinning processes (corresponding to No. 4, 8, 19 in Table 2) and the optimized process derived from the Design of Experiments (DoE) experiments described herein. Utilizing these four electrospinning processes (corresponding to No. 4, 8, 19 in Table 2), fibers were fabricated using InkA and InkB, respectively, through a single needle, resulting in samples 14-16 and 21 (prepared using InkA), and samples 17-19 and 22 (prepared using InkB), respectively. Subsequently, the same four process parameters were applied to produce bi-fibers via the Xspin biaxial electrospinning system, yielding samples 11-13 and 20.
  • the main absorption peaks correspond to the following intramolecular and intermolecular interactions of liquid ethanol: 3000-3500 cm’ 1 -OH bond; 2700-3000 cm’ 1 -valent CH bond; 1400-1000 cm’ 1 -skeleton vibrations of the C-O-H group, and CH bond; 700-1000 cm’ 1 - deformational vibrations of the CH bond.
  • FIG. 11 provides Fourier transform infrared spectroscopy (FT-IR) spectra of (1101) Eudragit E100 powder/dissolved in ethanol, (1102) RTV/dissolved in ethanol, (1103) CUR and CUR dissolved in ethanol, (1104) CUR and EPO dissolved in ethanol, (1105) InkA and InkB, and (1106) RTV/ES100 and CUR@EPO electrospun bi-fibers (Samples 20 customized). Cur@EPO 16% and Cur@EPO 20%.
  • RTV and Eudragit El 00 InkA
  • CUR and EPO InkB
  • FIG. 11 A (1101), FIG. 11B( 1105 and 1106), NH-0 stretching vibration that appeared at 1755 cm 1 in anhydrous form disappears on hydration.
  • the band at 1670 cm 1 that is assigned to NH-N stretching became less intense and shifted towards lower wavenumber on hydration.
  • N N stretching band at 1495 cm 1 disappeared after the drug exposure to higher humidity.
  • O-H stretching peak observed at 1440 cm 1 in anhydrous form became sharp at higher humidity. This may be due to the hydrogen bonding on hydrate formation.
  • the structural changes in the RTV sulfate exposure to higher humidity may be associated with hydrate/pseudo polymorphic transition of the drug.
  • EPO was chosen for its positive charge, which was believed to facilitate electrostatic interactions with CUR's negative charge, in order to enhance the solubility and stability of CUR. This hypothesis was based on the aim of improving CUR's bioavailability and potential therapeutic effects.
  • FIG. 1 IB (1103 and 1104) and FIG. 11C (1105)
  • FTIR spectra of CUR, EPO, CUR and EPO fibers (CUR-EPO) samples are depicted. The spectra of CUR-EPO samples showed some significant changes.
  • the carboxylic group was determined as belonging to the sodium acetate which was introduced from the buffer solution during the freeze drying treatment.
  • FTIR results also suggest that the formation of hydrogen bonding involved the carbonyl group in the EPO polymer that accepted the H atom from OH group of CUR.
  • FTIR spectrum shows the bi-fibers of all the identified materials including RTV, CUR, EPO, and E100.
  • FIG. 12 provides SEM images of some electrospun bi-fibers listed in Table 3: (1201), (1202), and (1203) were bi-fibers for Samples No. 11, No. 12, and No. 13 of Table 3, and FIG. 12 (1204) is the customized bi-fiber (Sample No. 20) listed in Table 3. All SEM images distinctly portray a side-by-side structure with a smooth surface for the electrospun nanofibers (NFs). Notably, the ribbon-like fibers are useful for buoyant pharmaceutical dosage forms, such as capsules, tablets, or scaffolds.
  • FIG. 13 provides data showing thermogravimetric analysis (TGA) of raw materials and mixtures according to some examples.
  • TGA thermogravimetric analysis
  • the thermal properties of the raw materials and physical mixtures may be determined through a Mettler-Toledo TGA/DSC1 analyzer (Mettler-Toledo, Schwerzenbach, Switzerland).
  • Sample raw materials and physical mixtures may be placed in an open ceramic crucible and ramped from 35°C to 600 °C at a rate of 10 °C /min.
  • a furnace may be purged using ultra-purified nitrogen at a flow rate of 50 mL/min.
  • Table 4 Exemplary Formulation and Physical Form
  • TGA Therm ogravimetric analysis
  • the TGA curve of EPO (Line No. 2, FIG. 13,) displayed two major thermal weight losses. The first occurred between 225 and 320 °C, followed by a second weight loss (-60%) between 380 and 460 °C.
  • the TGA curve of RTV (Line No. 4, FIG. 13) demonstrated a major weight loss between 200 and 250 °C, with a second weight loss (-50%) occurring between 300 and 395 °C. Comparing the working temperature of the maximum rate of weight reduction and the terminating decomposition temperature, it was observed that the bi-fibers had higher values than EPO and RTV but lower values than ESI 00 and CUR. This indicated that the ES100-CUR fibers improved the thermal stability of the EPO-RTV fibers in the form of bi-fibers.
  • DSC Differential scanning calorimetry
  • a purge gas (Nitrogen) at a flow rate of 50 mL/min was used for all the experiments.
  • the data were collected by TA advantage software (Q series, Version 2007 build 13029.20308) and analyzed by TA instruments Universal Analysis 2000. The results were presented as a plot of temperature (°C) versus heat flow (mW).
  • the differential scanning calorimeter (DSC) analysis was conducted to investigate the physical state of the bioactive compounds, as shown in FIG. 14.
  • the DSC curves of pure CUR and RTV exhibited distinct sharp endothermic peaks at temperatures of 175 and 122 °C, respectively. These peaks corresponded to the melting of the crystalline form of CUR and RTV, indicating that the model drugs were present in a crystalline state.
  • Nanofibrous mats (1 x 1 cm 2 ) were placed in flask containing 100 ml of 0.1 N HC1 (pH 1.2) at 37 °C.
  • the time necessary for test samples to go from the bottom to the surface of dissolution medium was called floating lag time (FLT). Additionally, the time duration of mats continuously floated on the surface of dissolution media was considered as the “Total Floating Time” (TFT). All measurements were carried out three times.
  • entrapment efficiency (EE%). Twenty -five mg of the freeze-dried Biaxial NFs (samples no. 4,8,19, and customized) were cut and dissolved in 45 mL methanol using a magnetic stirrer (Heidolph, USA) for 5 min until complete dissolution of the NFs. The drug content was analyzed spectrophotometrically using UV/VIS spectrophotometer microplate reader (BioTek Synergy Hl) at 238 and 420 nm for RTV and CUR, respectively. The experiment was done in triplicate and the mean values were calculated. The entrapment efficiency percent (EE%) was calculated according to the following equation:
  • the evaluation of drug-loaded (NFs) includes the measurement of entrapment efficiency (EE%).
  • EE% entrapment efficiency
  • FIG. 15 A in the case of EPO NFs containing CUR, the EE% exceeded 87% (w/w) across all the prepared biaxial NF samples.
  • ES 100 NFs containing RTV the EE% was above 84% in all four samples.
  • these observed entrapment efficiencies may be due to the substantial surface area of the biaxial NFs and the incorporation of the drugs into the polymeric solution, which subsequently solidifies during the electrospinning process.
  • Ritonavir release from biaxial NFs with dialysis tube demonstrated a gradual and sustained pattern, with approximately 30% of the drug released within the initial 5 -hour period for all four samples, gradually increasing but remaining below 50% over the subsequent five days. Without being limited by theory, this sustained-release behavior is attributed to the prolonged diffusion of the drug from the acidic and insoluble Eudragit SI 00 nanofibers.
  • the developed biaxial NFs improved aqueous solubility and sustained RTV release, reaching around 30% within the first 2 hours, compared to less than 10% from ritonavir tablets, showcasing enhanced solubility and dissolution properties through the electrospinning technique's amorphous drug preparation.
  • the biaxial nanofibers with a higher surface area to volume ratio due to electrospinning, offer sustained Ritonavir release over an extended period, demonstrating their suitability for controlled drug delivery applications.
  • FIG. 16C and FIG. 16D illustrate the in vitro release profiles of Curcumin from various biaxial nanofiber (NF) formulations.
  • NF biaxial nanofiber
  • FTIR Fourier Transform Infrared
  • FIG. 17A and FIG. 17B show the results obtained from rheological characterization of the inks.
  • the graphs show the viscosity of the inks that are exposed to various shear rates ranging from 0.01 s' 1 to 300 s' 1 .
  • the prepared InkA and InkB tend to exhibit non-Newtonian behavior, viscosity increases with increasing shear rate (shear thickening) shown in FIG. 17A and FIG. 17B.
  • These flow curves would indicate that both InkA and InkB that increase at higher rates of shear velocity rate, stress. Without being limited by theory, this is the phenomenon of shear thickening and usually due to structure rearrangements as a result of the applied shear.

Landscapes

  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Textile Engineering (AREA)
  • Dispersion Chemistry (AREA)
  • Mechanical Engineering (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Spinning Methods And Devices For Manufacturing Artificial Fibers (AREA)

Abstract

L'invention concerne des techniques, des systèmes et des procédés impliquant l'emploi d'électrofilage, de têtes d'impression comportant de multiples lieurs et d'un bras mécanique qui facilite un système de production en continu, sûr et efficace de fibres et/ou de tapis de fibres. Les têtes d'impression peuvent être en communication fluidique avec une filière pour former des gouttelettes appropriées pour l'électrofilage. Les fibres électrofilées peuvent comprendre des structures complexes. Dans certains exemples, les fibres électrofilées peuvent comprendre de multiples couches, des particules (par exemple, des microparticules, des nanoparticules, etc.) et/ou différents composants de fibre ayant des structures souhaitées (par exemple, des fibres bi-axiales, des fibres tri-axiales, des fibres co-axiales, des fibres co-biaxiales, etc.). Les fibres électrofilées peuvent être disposées dans un simulateur environnemental pour imiter la libération d'un médicament de test désintégré dans une membrane semi-perméable.
PCT/US2024/026244 2023-04-26 2024-04-25 Systèmes et procédés d'électrofilage par impression 3d Ceased WO2024226778A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202363498383P 2023-04-26 2023-04-26
US63/498,383 2023-04-26

Publications (2)

Publication Number Publication Date
WO2024226778A2 true WO2024226778A2 (fr) 2024-10-31
WO2024226778A3 WO2024226778A3 (fr) 2025-02-06

Family

ID=93257481

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2024/026244 Ceased WO2024226778A2 (fr) 2023-04-26 2024-04-25 Systèmes et procédés d'électrofilage par impression 3d

Country Status (1)

Country Link
WO (1) WO2024226778A2 (fr)

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7762801B2 (en) * 2004-04-08 2010-07-27 Research Triangle Institute Electrospray/electrospinning apparatus and method
WO2007143047A1 (fr) * 2006-06-01 2007-12-13 Ecolab Inc. Capteur fluorométrique uv et son procédé d'utilisation
US8372057B2 (en) * 2008-10-10 2013-02-12 Coeur, Inc. Luer lock adapter
CN101929035B (zh) * 2009-06-24 2011-11-16 中国科学院理化技术研究所 经纬双向静电纺丝制膜设备及设备的应用方法
EP3606754A1 (fr) * 2017-04-06 2020-02-12 Regenhu AG Dispositif et procédé d'impression par électrofilage
US11618975B1 (en) * 2019-07-10 2023-04-04 American Nano Llc. Electrospinning apparatus and methods

Also Published As

Publication number Publication date
WO2024226778A3 (fr) 2025-02-06

Similar Documents

Publication Publication Date Title
Wang et al. Electrospun Janus zein–PVP nanofibers provide a two-stage controlled release of poorly water-soluble drugs
Gaydhane et al. Electrospun nanofibres in drug delivery: advances in controlled release strategies
Zupančič Core-shell nanofibers as drug-delivery systems
CN108992432B (zh) 用作药物递送系统的无纺布膜
Angkawinitwong et al. A novel transdermal protein delivery strategy via electrohydrodynamic coating of PLGA microparticles onto microneedles
Nath et al. Preparation and characterization of PLGA microspheres by the electrospraying method for delivering simvastatin for bone regeneration
Yu et al. Electrospun nanofiber-based drug delivery systems
Domingues et al. Nanoparticle synthesis and their integration into polymer-based fibers for biomedical applications
Dhanka et al. Injectable methotrexate loaded polycaprolactone microspheres: physicochemical characterization, biocompatibility, and hemocompatibility evaluation
Patel et al. Review on electrospray nanoparticles for drug delivery: Exploring applications
CN104114349B (zh) 用于制造聚合物纤维的系统、装置和方法
Chen et al. Electrospun core–sheath nanofibers with a cellulose acetate coating for the synergistic release of zinc ion and drugs
Yu et al. Self-assembled liposomes from amphiphilic electrospun nanofibers
Kulkarni et al. Synthesis of polymeric nanomaterials for biomedical applications
WO2007052042A2 (fr) ,dispositif biocompatible de delivrance de medicaments
Zare et al. Current progress of electrospun nanocarriers for drug delivery applications
Haidar et al. Electrospun nanofibers for dual and local delivery of neuroprotective drugs
Fathi-Azarbayjani et al. Single and multi-layered nanofibers for rapid and controlled drug delivery
Rehman et al. Designing sustained release from nanofiber patch for paclitaxel as prospective localized nanotherapeutic delivery in breast cancer
CN115920126B (zh) 负载植物外泌体的聚羟基脂肪酸酯微球及其制备方法
WO2024226778A2 (fr) Systèmes et procédés d'électrofilage par impression 3d
Lee et al. Rosin microparticles as drug carriers: Influence of various solvents on the formation of particles and sustained-release of indomethacin
Thakkar et al. Electrospray particles as drug delivery systems: concepts, strategies, and applications
Pan et al. Poly (lactic acid)-aspirin microspheres prepared via the traditional and improved solvent evaporation methods and its application performances
Shi et al. Development of curcumin-loaded methoxy poly (ethylene glycol)-block-poly (caprolactone)-block-poly (1, 4, 8-Trioxa [4.6] spiro-9-undecanone) nanoparticles and studies on their in vitro anti-tumor activities

Legal Events

Date Code Title Description
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 24797939

Country of ref document: EP

Kind code of ref document: A2