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WO2024258996A1 - Administration de médicament oculaire - Google Patents

Administration de médicament oculaire Download PDF

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Publication number
WO2024258996A1
WO2024258996A1 PCT/US2024/033654 US2024033654W WO2024258996A1 WO 2024258996 A1 WO2024258996 A1 WO 2024258996A1 US 2024033654 W US2024033654 W US 2024033654W WO 2024258996 A1 WO2024258996 A1 WO 2024258996A1
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WO
WIPO (PCT)
Prior art keywords
corneal
nin
ocular
eye
therapeutic agents
Prior art date
Application number
PCT/US2024/033654
Other languages
English (en)
Inventor
Crystal S. SHIN
Ghanashyam Acharya
Original Assignee
Baylor College Of Medicine
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 Baylor College Of Medicine filed Critical Baylor College Of Medicine
Publication of WO2024258996A1 publication Critical patent/WO2024258996A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/04—Artificial tears; Irrigation solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F9/00—Methods or devices for treatment of the eyes; Devices for putting in contact-lenses; Devices to correct squinting; Apparatus to guide the blind; Protective devices for the eyes, carried on the body or in the hand
    • A61F9/0008—Introducing ophthalmic products into the ocular cavity or retaining products therein
    • A61F9/0017—Introducing ophthalmic products into the ocular cavity or retaining products therein implantable in, or in contact with, the eye, e.g. ocular inserts
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • 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
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A61K9/0051—Ocular inserts, ocular implants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics

Definitions

  • This disclosure relates at least to the fields of biology, ophthalmology, cell biology, molecular biology, devices, and medicine.
  • An optically transparent and clear cornea is essential for vision [1] Injuries to eyes including corneal perforations, deep corneal abrasions, chemical burns, and persistent ulceration are the major causes of destructive corneal scarring that result in vision loss [2], Each year approximately 2.4 million eye injuries occur in the United States with more than 20% of these injuries resulting in vision loss [3], Corneal scars block the light transmission and impair the visual function [4,5], The scarred and damaged corneas need to be surgically replaced with corneal transplants (penetrating keratoplasty) to restore vision [6], However, a short supply of donor corneas limits the number of corneal transplant procedures.
  • Embodiments of the disclosure include compositions, methods, and kits that are utilized for treatment of one or more ocular medical conditions.
  • the ocular medical condition(s) may be treated topically.
  • the ocular medical condition(s) may be treated on the surface of the eyeball.
  • One or more eyes in a mammal may be affected.
  • one or more therapeutic agents that will treat the one or more ocular medical conditions is provided to the eye with a device.
  • the device may comprise the one or more therapeutic agents on part or all of its surface and/or within the structure(s) of the device itself.
  • the device is utilized as a scaffold for delivery of the one or more therapeutic agents.
  • the device is 3D-printed which may allow for control of structure of the device.
  • the present disclosure concerns the fabrication of an antifibrotic drug-loaded membrane (referred to herein as theramem) and its efficacy on scarless corneal wound healing (FIG. 1).
  • an antifibrotic Nintedanib (NIN)- loaded theramem (NIN-theramem) was fabricated by 3D-bioprinting strategy.
  • NIN is a broad tyrosine kinase inhibitor with known modulatory activity on platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), and vascular endothelial growth factor (VEGF) receptors.
  • PDGF platelet-derived growth factor
  • FGF fibroblast growth factor
  • VEGF vascular endothelial growth factor
  • NIN has been approved by the FDA for the treatment of idiopathic pulmonary fibrosis (IPF) and systemic sclerosis associated interstitial lung disease.
  • IPF idiopathic pulmonary fibrosis
  • OB mouse alkali induced ocular burn
  • Embodiments of the disclosure include a device, comprising 3D-printed material comprising one or more ocular therapeutic agents.
  • the device comprises a membrane.
  • the ocular therapeutic agent treats or prevents corneal fibrosis.
  • the device may be or may comprise a wafer, a nanowafer, a scaffold, a film, or a combination thereof.
  • the device comprises a configuration of filaments that may comprise the one or more ocular therapeutic agents on their surface, within the filaments, or both.
  • the configuration of filaments is random, whereas in other cases the configuration of filaments is ordered.
  • the device comprises both random and ordered filaments.
  • the interior of the filaments may be hollow or solid.
  • the interior of the filaments comprises two or more coaxial layers.
  • the ordered configuration of filaments comprises multiple intersections of fibers, each intersection comprising an angle between about 1-179°.
  • the ordered configuration of filaments comprises multiple intersections of fibers having 90° angles, in some embodiments.
  • the device may or may not comprise apertures. In embodiments wherein the device comprises one or multiple apertures, the multiple apertures may or may not be substantially the same size.
  • the shape of multiple apertures may generally be a polygon (e.g., a square, a rectangle, a diamond, a hexagon, etc.), or a circle. In some embodiments, the device comprises a circular shape comprising a diameter between about 1.0 mm and 15.0 mm.
  • the device comprises a polygonal shape comprising a width or diameter between about 1.0 mm and 15.0 mm.
  • the device is comprised in a liquid, such as a pharmaceutically acceptable solution.
  • the liquid may comprise one or more ocular therapeutic agents, and the one or more ocular therapeutic agents in the liquid may be the same as the one or more ocular therapeutic agents of the device. In certain cases, one or more ocular therapeutic agents of the liquid is not the same one or more ocular therapeutic agents of the device.
  • the therapeutic agent comprises a tyrosine kinase inhibitor. In some embodiments, the device comprises between about 1 pg to 12 pg of the tyrosine kinase inhibitor.
  • the tyrosine kinase inhibitor is nintedanib.
  • the device comprises between about 1 pg to 12 pg of nintedanib.
  • the material of the device comprises a polymer having a charge that will affect release kinetics of the one or more therapeutic agents and/or polymer(s) from the device.
  • the material of the device may comprise a polymer having a charge that will induce a synergistic effect on release kinetics of the one or more therapeutic agents and/or polymer(s) from the device.
  • the release kinetics comprise release of the ocular therapeutic agent at an average rate of about 50 ng to 1000 ng per hour, or any range derivable thereof.
  • Embodiments of the disclosure include methods of treating an ocular medical condition in an individual, comprising the step of applying any device encompassed herein to at least one eye of the individual.
  • the ocular medical condition may affect one eye or both eyes.
  • the ocular medical condition may affect the cornea.
  • the ocular medical condition may or may not be corneal fibrosis, trauma, a genetic defect of the individual, a burn, corneal neovascularization, pterygium, meibomian gland dysfunction, an allergy, conjunctivitis, bacterial conjunctivitis, viral conjunctivitis, asthenopia, corneal injury, chemical exposure, infectious keratitis, bacterial keratitis, viral keratitis, ulcers, alkali burn, keratoconus, Fuchs' endothelial dystrophy, bullous keratopathy, ocular inflammation, ocular pain, dry eye, ocular infection, need for regenerative healing of the eye, corneal perforation, deep corneal abrasion, eye surgery, or a combination thereof.
  • the device comprises one or more antifibrotic agents.
  • the therapeutic agent may or may not be nintedanib, pirfenidone, nilotinib, dexamethasone, or a combination thereof.
  • the device is comprised in a liquid, such as a pharmaceutically acceptable solution.
  • the device is applied to the eye of the individual prior to onset of the ocular medical condition.
  • the device may be applied to the eye of the individual following onset of the ocular medical condition.
  • the device is applied to the eye of the individual prior to onset of scarring of the cornea.
  • the device may be applied to an individual at risk for having scarring of the cornea.
  • the device is applied once to the affected eye or eyes, or it may be applied more than once to the affected eye or eyes, such as daily, weekly, multiple times during a week, or monthly.
  • the individual is a mammal, such as a human.
  • the method further comprises the step of producing the device, such as by 3D printing of at least part of the device, including producing coaxial layers of filaments of the device.
  • the 3D printed material of the device comprises one or more therapeutic agents.
  • the device may or may not comprise one or more nerve regenerating factors and one or more neurotrophic factors.
  • the therapeutic agent may be leteprinim.
  • the device comprises one or more of each of an analgesic, anesthetic, antibiotic, antiviral, and/or nerve-blocking agent.
  • the analgesic is pregabalin, gabapentin, bupivacaine, proparacaine, lidocaine, oxybuprocaine, tetracaine, or a combination thereof.
  • the device comprises antibiotics.
  • the antibiotics comprise bacteriostatic or bactericidal antibiotics.
  • the device comprises an antiviral.
  • the antiviral comprises a protease inhibitor, reverse transcriptase inhibitor, integrase inhibitor, viral entry inhibitor, and/or maturation inhibitors.
  • Embodiments of the disclosure include methods of producing any device encompassed herein, comprising the step of 3D printing a water-soluble polymer, optionally with one or more therapeutic agents mixed therein.
  • the polymer may be polyvinyl alcohol (PVA).
  • the polymer may be mucoadhesive.
  • the polymer may be dissolvable on the eye.
  • kits comprising any device encompassed herein, wherein said device is housed in a suitable container.
  • the kit may or may not comprise one or more ocular therapeutic agents.
  • the kit further comprises one or more ocular therapeutic agents housed separately from the device.
  • FIGS. 1A-1E NIN-theramem.
  • FIG. 1A shows a bright field image of an NIN- theramem
  • FIG. IB shows a fluorescence image of an NIN-theramem
  • FIG. 1C shows an NIN-theramem applied on a mouse eye.
  • FIG. ID shows an XRD analysis of an NIN-Theramem. Scale bar: 1000 pm.
  • FIG. IE shows examples of BioCAD designs and projections of a 3D- bioprinted device, e.g., a theramem.
  • FIGS. 2A-2I NIN-theramem safety on the ocular surface.
  • FIGS. 1A shows a bright field image of an NIN- theramem
  • FIG. IB shows a fluorescence image of an NIN-theramem
  • FIG. 1C shows an NIN-theramem applied on a mouse eye.
  • FIG. ID shows an XRD analysis of an NIN-Theram
  • FIG. 2A-2B show results of an evaluation of NIN-theramem toxicity and maximum tolerated drug dose in human corneal epithelial cells and human corneal fibroblasts in vitro (for each plot, bars from left to right represent untreated (UT), NIN-theramem 3 pg, NIN-theramem 6 pg, NIN-theramem 9 pg, and NIN- theramem 12 pg, respectively).
  • Whole eye images and H&E-stained corneal sections of healthy eyes FIGGS. 2C-2F
  • alternate day q.o.d.
  • NIN-theramem treated FIGS. 2D-2G
  • FIG. 21 shows a plot depicting the corneal thickness. *P ⁇ 0.05 and *** ⁇ 0.001
  • FIGS. 3A-3G NIN-theramem was more effective in enhancing the NIN drug diffusion into the cornea compared to the topical NIN-eyedrops.
  • NIN eyedrop instilled on the mouse eye Fluorescence image (FIGS. 3A-3B), and Negative ion mode DESI-MS image of m/'z 538.25 corresponding to NIN (FIG. 3C); and NIN-theramem applied on the mouse eye: Fluorescence image (FIGS. 3D-3E), and Negative ion mode DESI image of m/z 538.25 corresponding to NIN (FIG. 3F).
  • FIGS. 4A-4R NIN-theramem promotes scarless corneal wound healing in ocular alkali burn (OB)-induced mouse model.
  • BSS Balanced Saline Solution
  • FIGS. 4A-4D Representative bright field and fluorescence images of Balanced Saline Solution (BSS) eyedrops (FIGS. 4A-4D), NIN-eyedrops (FIGS. 4E-4H), and NIN-theramem treated mouse eyes (FIGS. 4I-4L).
  • H&E-stained sections of healthy cornea FIG. 4M
  • OB corneas treated with BSS eyedrops (control) FIG. 4N
  • OB corneas treated with NIN- eyedrops FIG. 40
  • FIG. 4P shows a plot depicting the cornea
  • FIGS. 5A-5F NIN-theramem modulates corneal fibrosis in alkali induced ocular burn mouse model.
  • FIGS. 6A-6F NIN-theramem treatment promotes corneal wound healing.
  • Corneal sections stained with Ki67 for dividing epithelial cells (white, FIGS. 6A-6C) and keratin-13 (white, FIGS. 6D-6F).
  • Healthy corneas (FIG. 6A and FIG. 6D); BSS-ey edrops treated corneas (control) (FIG. 6B and FIG. 6E); and NIN-theramem treated OB corneas (FIG. 6C and FIG. 6F).
  • Scale bar 50pm
  • FIGS. 7A-7H NFS! regulated corneal keratocyte to myofibroblast differentiation.
  • hCK human corneal keratocyte
  • FIG. 7A Untreated hCK (control) (FIG. 7A); hCK treated with TGF-0 (FIG. 7B); and hCK treated with TGF-P and NIN (FIG. 7C).
  • FIG. 7D Healthy
  • PBS treated control
  • FIG. 7F NIN-theramem treated corneas
  • 7G shows quantitative flow cytometry analysis demonstrating the NIN-theramem ability to attenuate the fibroblast to myofibroblast differentiation (for each plot, left bar: healthy; middle bar: BSS; right bar: NOIN-theramem). Scale bar: 100 pm. Mean differences of the groups were considered significant at **P ⁇ 0.01.
  • FIG. 8 NIN-theramem downregulate the proangiogenic and profibrotic molecular mediators. *P ⁇ 0.05, **P ⁇ 0.01, ***P ⁇ 0.001. NIN-theramem treatment downregulates the TGF- P expression level compared to the BSS treated mouse OB corneas (control) (FIG. 8A; for each plot, left bar: BSS (ctrl); right bar: NIN-theramem). Ctrl: control.
  • FIGS. 9A-9H NIN-theramem treatment reversed the established corneal scars.
  • Bright field and fluorescence images of BSS treated FIGS. 9A-9D
  • NIN-theramem treated OB mouse eyes FIGS. 9E-9H.
  • FIGS. 10A-10F Coaxially bioprinted ocular drug delivery 3D-scaffold.
  • FIG. 10A shows a fluorescence image of an NIN-scaffold.
  • FIG. 10B shows a confocal image of a tubular coaxial filament showing the outer shear and inner core.
  • FIG. 10C shows a 3D-scaffold applied on a mouse eye.
  • FIG. 10D shows a coaxially 3D-printed scaffold.
  • FIG. 10E shows a microfilament structure of the 3D-scaffold under high magnification.
  • FIG. 10F shows a 3D- printed scaffold on a fingertip. Scalebar 8 mm.
  • FIG. 11 3D-scaffold drug delivery of NIN was more effective in enhancing the drug diffusion into the cornea compared to the topical NIN eyedrops. Bars represent the amount of drug released at the respective timepoint. Lines represent the cumulative amount of drug released over time. The darker portion of each bar represents NIN-drops while the lighter portion of each bar represents NIN-scaffold.
  • FIGS. 12A-12G NIN-scaffold safety on the ocular surface.
  • Whole eye and H&E- stained corneal sections of Healthy eyes (FIGS. 12A-12B); eyes treated with NIN-scaffold on alternate days (q.o.d.) for 14 days (FIGS. 12C-12D); and eyes treated daily (q.d.) with NTN- scaffold for 14 days (FIGS. 12E-12F).
  • FIG. 12G shows a plot depicting the corneal thickness.
  • FIG. 13 A plot depicting corneal thickness (for each plot, left bar: healthy cornea; middle bar: NIN-drops; and right bar: NIN-scaffold).
  • FIGS. 14A-14F NIN-scaffold modulated corneal fibrosis in alkali-induced ocular burned mouse eyes.
  • COL1A1 and Fibronectin-stained mouse corneal sections of healthy FIG. 14A and FIG, 14D
  • BSS-ey edrops treated FIG. 14B and FIG. 14E
  • NIN-scaffold treated FIG. 14C and FIG. 14F.
  • Scale bar 50 pm.
  • FIG. 15 Flow cytometry analysis of corneal myofibroblast densities in the corneal tissue. For each plot, left bar: healthy; middle bar: BSS (control); and right bar: NIN-scaffold.
  • FIGS. 16A-16K NIN-theramem treatment aided in reversing established corneal scar.
  • FIGS. 16A-16D show BSS treated OB mouse eyes.
  • FIGs. 16E-16H show NIN-theramem treated OB mouse eyes.
  • FIGS. 16I-16K show representative H&E images of harvested mouse cornea at day 21 : Healthy (FIG. 161), BSS Treated (FIG. 16J), and NIN-theramem Treated (FIG. 16K). Scale bar: 50pm
  • A, B, and/or C includes: A alone, B alone, C alone, a combination of A and B, a combination of A and C, a combination of B and C, or a combination of A, B, and C.
  • A, B, and/or C includes: A alone, B alone, C alone, a combination of A and B, a combination of A and C, a combination of B and C, or a combination of A, B, and C.
  • “and/or” operates as an inclusive or.
  • 3D-printing and “3D-bioprinting” may be used interchangeably throughout the specification and refer to a method of forming a three-dimensional (3D) structure by laminating materials, such as powders, liquids, or polymers, layer-by-layer as to form the 3D structure.
  • wafer or “nanowafer” refer to structures containing reservoirs, e.g., nanosized reservoirs, for improved delivery of a substance, such as a drug.
  • membrane refers to a thin film.
  • a membrane may be prepared by 3D bioprinting, casting, or any other method commonly known in the art.
  • sold refers to a hollow or solid 3D-printed core-shell polymer for deliver substances, such as drugs.
  • compositions and methods for their use can “comprise,” “consist essentially of,” or “consist of’ any of the ingredients or steps disclosed throughout the specification. Compositions and methods “consisting essentially of’ any of the ingredients or steps disclosed limits the scope of the claim to the specified materials or steps which do not materially affect the basic and novel characteristic of the claimed invention.
  • VHI Vision Health Initiative
  • the World Health Organization estimates that corneal opacity accounts for over 4% of blindness worldwide, leading to around 1.5-2 million cases yearly (McKay et al., Eye volume 34, pages 271-278 (2020)). Corneal fibrosis develops in response to injury, infection, postsurgical complications, or underlying systemic disease that disrupts the tissue's homeostasis, leading to irregular extracellular matrix deposition within the stroma.
  • the present disclosure provides herein a novel 3D-printed drug-comprising scaffold, such as to be used as an alternative to transplants (for example) for treating any ocular medical condition.
  • a novel 3D-printed drug-comprising scaffold such as to be used as an alternative to transplants (for example) for treating any ocular medical condition.
  • Such medical conditions may affect the cornea, such as corneal fibrosis.
  • Embodiments of the disclosure include devices that are used for delivery of at least one therapeutic drug to the surface of an eye.
  • the device is 3D-printed.
  • the device is a drug-delivering wafer or nanowafer.
  • the device is a membrane.
  • the device may be an ocular drug delivery wafer, nanowafer, or membrane that is therapeutic to treat any ocular medical condition, including at least medical diseases or injuries that affect the cornea.
  • the device is an antifibrotic drug-loaded wafer, nanowafer, or membrane, although the membrane may comprise apertures.
  • the device is a 3D-printed drug delivery modality.
  • the device will dissolve over time following placement on the eye, whereas in alternative embodiments the device is not dissolvable.
  • the device is comprised of multiple filaments, such as in an array of filaments.
  • the filaments may or may not be hollow.
  • the device comprises a configuration of filaments.
  • the filaments may comprise the one or more ocular therapeutic agents on their surface, within the filaments, or both.
  • the device may have a particular configuration of filaments, and the configuration may be determined by the need of the individual receiving the device. In some cases, the configuration of filaments is random, whereas in other cases, the configuration of filaments is ordered.
  • the configuration of filaments may be such that there are apertures in the device, and the apertures may be of any shape, including a polygon (e.g., a square, a rectangle, a diamond, a hexagon, etc.), a circle, or there may be no particular or repeating shape to the aperture. Multiple apertures of the device may or may not be of the same shape and size.
  • an ordered configuration of filaments comprises multiple intersections of fibers, wherein the intersections have 90° angles.
  • multiple filaments may be perpendicular to other multiple filaments. In such cases, the filaments may be perpendicular with respect to an edge of the device, and in other cases the filaments may be non-perpendicular with respect to an edge of the device.
  • an ordered configuration of filaments comprises multiple intersections of fibers, wherein the intersections have an acute angle, e.g., 1°, 2°, 3°, 4°, 5°, 6°, 7°, 8°, 9°, 10°, 11°, 12°, 13°, 14°, 15°, 16°, 17°, 18°, 19°, 20°, 21°, 22°, 23°, 24°, 25°, 26°, 27°, 28°,
  • an acute angle e.g., 1°, 2°, 3°, 4°, 5°, 6°, 7°, 8°, 9°, 10°, 11°, 12°, 13°, 14°, 15°, 16°, 17°, 18°, 19°, 20°, 21°, 22°, 23°, 24°, 25°, 26°, 27°, 28°,
  • an ordered configuration of filaments comprises multiple intersections of fibers, wherein the intersections have an obtuse angle, e.g., 91°, 92°, 93°, 94°, 95°, 96°, 97°, 98°, 99°, 100°, 101°, 102°, 103°, 104°, 105°, 106°, 107°, 108°, 109°, 110°, 111°, 112°, 113°, 114°, 115°,
  • an ordered configuration of filaments comprises multiple intersections of fibers, wherein the intersections comprise acute and oblique angles.
  • the device is fabricated by 3D printing of tubular filaments, and a drug-polymer matrix comprises its inner core.
  • the polymer matrix may comprise one or more drugs, one or more biologies, one or more polymeric particles, one of more biologically-derived polymers, one or more synthetic polymers, one or more drug diffusion (penetration) enhancers, and/or one or more drug loaded polymer micro/nanoparticles.
  • the device is configured and/or comprised of suitable material(s) to allow for the device to adhere to an ocular surface.
  • suitable material(s) to allow for the device to adhere to an ocular surface.
  • the device is configured and/or is comprised of suitable material(s) to allow for elution of one or more therapeutic agents over a duration of time, such as over 1-24 hours, 1-7 days, 1-28 days, 1-4 weeks, and so forth.
  • the duration of time is 1-28, 1-25, 1-20, 1-14, 1-10, 1-7, 2- 28, 2-25, 2-20, 2-14, 2-10, 2-7, 4-28, 4-25, 4-20, 4-14, 4-10, 4-7, 7-28, 7-25, 7-20, 7-14, 7-10, 10- 28, 10-25, 10-20, 10-14, 14-28, 14-25, 14-20, 20-28, 20-25, or 25-28 days.
  • one or more therapeutic agents elutes from a suitable material in 1-4 hours.
  • the drug is released from the device as the device itself dissolves.
  • the drug molecules are homogeneously dispersed within the device, including in the matrix of the device in some cases, although alternative embodiments they are not.
  • the material of the 3D-printed device may be fabricated with any material suitable for therapeutic use, but in specific embodiments the device is made with a poly(vinyl alcohol) (PVA) solution, Polyvinyl pyrrolidone (PVP), methylcellulose, ethylcellulose, hydroxypropyl methylcellulose, polyacrylic acid, poly(lactic-co-glycolic) acid (PLGA), poly lactic acid (PLA), poly glycolic acid (PGA), hyaluronic acid, gelatin, polyethylene glycol (PEG), dextran, any polysaccharide, Calcium Stearate, polyvinylidene fluoride (PVDF), polyhydroxyethyl methacrylate (pHEMA), silicone, silicone hydrogels (e.g., galyfilcon, senofdcon, comfilcon, enfilcon), Arginine derivatives, chitosan derivatives, cyclodextrins, carboxymethylcellulose, polycaprolactone, alg
  • the device may have any shape, including but not limited to a polygon or a circle.
  • the diameter of the device may be between about 1 mm to about 15 mm.
  • the diameter of the device may be 1.0 mm, 1.1 mm, 1.2 mm, 1.3 mm, 1.4 mm, 1.5 mm, 1.6 mm, 1.7 mm, 1.8 mm, 1.9 mm, 2.0 mm, 2.1 mm, 2.2 mm, 2.3 mm, 2.4 mm, 2.5 mm, 2.6 mm, 2.7 mm, 2.8 mm, 2.9 mm, 3.0 mm, 3.1 mm, 3.2 mm, 3.3 mm, 3.4 mm, 3.5 mm, 3.6 mm, 3.7 mm, 3.8 mm, 3.9 mm, 4.0 mm, 4.1 mm, 4.2 mm, 4.3 mm, 4.4 mm, 4.5 mm, 4.6 mm, 4.7 mm, 4.8
  • the thickness of the device may range between about 60 gm to about 100 gm. In some embodiments, the thickness of the device may be 60 gm, 61 gm, 62 gm, 63 gm, 64 gm, 65 gm, 66 gm, 67 gm, 68 gm, 69 gm, 70 gm, 71 gm, 72 gm, 73 gm, 74 gm, 75 gm, 76 gm, 77 gm, 78 gm, 79 gm, 80 gm, 81 gm, 82 gm, 83 gm, 84 gm, 85 gm, 86 gm, 87 gm, 88 gm, 89 gm, 90 gm, 91 gm,
  • the device is flat. In some embodiments, the device is curved. In some embodiments, the device is concave. In some embodiments, the device has a base curve between about 8.0 mm to about 10.0 mm. In some embodiments, the base curve may be 8.0 mm,
  • the device is housed in a liquid, such as an aqueous liquid that is sterile.
  • the device comprises at least one therapeutic agent of any kind.
  • the therapeutic agent or agents may be therapeutic or preventative for an ocular medical condition, including one that stems from disease, genetics, or injury.
  • the therapeutic agent may comprise one or more of a small molecule, a protein, nucleic acid, an antibody, a cell (including engineered cells), an enzyme, and so forth.
  • the therapeutic agent may be an antifibrotic agent, an anti-inflammatory agent, an analgesic, an antibiotic, etc.
  • the therapeutic agent is a tyrosine kinase inhibitor, such as a VEGFR-2 tyrosine kinase inhibitor.
  • the therapeutic agent is a corticosteroid (Dexamethasone, Prednisolone, and/or FluoromethoIone).
  • the therapeutic agent may be nintedanib, pirfenidone, nilotinib, dexamethasone, or a combination thereof, in specific embodiments.
  • the therapeutic agent is mitomycin C
  • the therapeutic agent inhibits fibroblast differentiation into myofibroblasts.
  • the amount of therapeutic agent associated with the device will be an amount that is not cytotoxic or have deleterious effects for the individual receiving the device. In certain embodiments, a particular amount of therapeutic agent is utilized, including no more than a certain level, and depending on the therapeutic agent.
  • one or more of the following therapeutic agents may be utilized with the device for any indication: Acetazolamide for glaucoma, Acetylcysteine for dry eyes, Aciclovir eye ointment, Antazoline and xylometazoline eye drops, Apraclonidine eye drops, Atropine eye drops, Azelastine eye drops for allergies, Azithromycin eye drops, Betamethasone eye drops, Betaxolol eye drops for glaucoma, Bimatoprost eye drops, Brimonidine eye drops for glaucoma, Brinzolamide eye drops for glaucoma, Bromfenac eye drops, Carbomer liquid eye gels, Carmellose sodium for dry eyes, Carteolol eye drops for glaucoma, Chloramphenicol for eye infections, Ciprofloxacin eye preparations, Cyclopentolate eye drops, Dexamethasone eye drops for inflammation, Diclofenac eye drops, Dorzolamide eye drops,
  • the therapeutic agent may comprise (1) Corticosteroids, such as dexamethasone, prednisolone, fluormethoIone, and/or loteprednol etabonate; (2) Non-steroidal anti-inflammatory drugs (NSAIDs), such as Ketorolac tromethamine, bromfenac, nepafenac, flurbiprofen, and/or diclofenac; (3) Anti-infection therapeutic agents, such as fungal -amphotericin B, fluconazol, voriconazole, and/or natamycine; (4) anti-bacterial therapeutic agents, such as ciprofloxacin, ofloxacin, moxifloxacin, polymyxin b/trimethoprim, levofloxacin, gatifloxacin, azithromycin, bacitracin, and/or erythromycin; anti-viral therapeutic agents, such as ganciclovir, triflu
  • the therapeutic agent may comprise bacteriostatic antibiotics (e.g., glycylcyclines, tetracyclines, lincosamides, macrolides, oxazolidinones, and sulfoamides) or bactericidal antibiotics (e.g., aminoglycosides, beta-lactams, fluoroquinolones, glycopeptides, cyclic lipopeptides, and nitroimidazoles).
  • bacteriostatic antibiotics e.g., glycylcyclines, tetracyclines, lincosamides, macrolides, oxazolidinones, and sulfoamides
  • bactericidal antibiotics e.g., aminoglycosides, beta-lactams, fluoroquinolones, glycopeptides, cyclic lipopeptides, and nitroimidazoles.
  • the therapeutic agent comprises an antiviral, such as a protease inhibitor (e g., telapivir, atazanavir, darunavir, simeprevir, lopinavir, ritonavir, boceprevir, ritonavir, indinavir, nelfinavir, fosamprenavir, saquinavir, and tipranavir), which may target enzymes involved in viral replication and/or assembly; reverse transcriptase inhibitors, including nucleoside reverse transcriptase inhibitors (NRTIs), nucleotide reverse transcriptase inhibitors (NtRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) (e.g., nevirapine, penciclovir, tenofovir disoproxil, zidovudine, foscarnet, efavirenz, stavudine, delavirdine, lamivudine, and ade
  • the device comprises between about 0.001 to about 500 pg, or any range deliverable therein, of the therapeutic agent.
  • the device comprises 0.001 pg, 0.01 pg, 0.1 pg, 0.2 pg, 0.3 pg, 0.4 pg, 0.5 pg, 0.6 pg, 0.7 pg, 0.8 pg, 0.9 pg, 1.0 pg, 2.0 pg, 3.0 pg, 4.0 pg, 5.0 pg, 6.0 pg, 7.0 pg, 8.0 pg, 9.0 pg, 10.0 pg, 11.0 pg, 12.0 pg, 13.0 pg, 14.0 pg, 15.0 pg, 16.0 pg, 17.0 pg, 18.0 pg, 19.0 pg, 20.0 pg, 21.0 pg, 22.0 pg, 23.0 pg, 24.0 pg,
  • Embodiments of the disclosure concern methods of use of a drug delivery device for any ocular medical condition, including for the treatment or prevention of any ocular medical condition.
  • the ocular medical condition directly or indirectly affects the cornea.
  • the ocular medical condition may be the result of disease, genetic defects, or injury, as examples.
  • the device of the disclosure is well-suited to overcome ocular surface barriers (OSB) because the device adheres to the wet surface of the eye and is stable.
  • OSB ocular surface barriers
  • the device avoids rapid clearance, such as with eye drops, allowing for enhanced bioavailability of the drug to the eye.
  • the device dissolves, allowing for continual exposure of the cornea to the drug.
  • Examples of ocular medical conditions include at least glaucoma, corneal fibrosis, corneal injury (such as from impact with a foreign object), chemical exposure, infectious keratitis, ulcers, corneal neovascularization, alkali burn, meibomian gland dysfunction, pterygium, keratoconus, Fuchs' endothelial dystrophy, bullous keratopathy, ocular inflammation, ocular pain, dry eye, ocular infections (viral, bacterial, fungal, etc ), need for regenerative healing of the eye, corneal perforations, deep corneal abrasions, chemical burns, eye surgery, and persistent ulceration and so forth.
  • Embodiments of the disclosure include methods of treating or preventing corneal scarring and/or opacification that can result in significant and irreversible vision loss and blindness.
  • any of the methods reduce enlargement or swelling of the stroma and epithelium.
  • an individual avoids a corneal transplant by utilizing the methods encompassed herein.
  • any of the methods encompassed herein may delay the onset of corneal scarring and/or opacification and/or reduce the severity of corneal scarring and/or opacification.
  • Embodiments of the disclosure include treatment or prevention of an ocular inflammation-related disease.
  • there are methods of treating or preventing cornea neovascularization including reducing the risk of cornea neovascularization.
  • Certain methods include treating corneal burn, such as corneal alkali burn.
  • Methods for inhibiting corneal fibrosis are encompassed herein.
  • methods include those that promote scarless corneal wound healing.
  • compositions encompassed herein may be at risk for scarring in the eye for any reason.
  • the methods and compositions prevent corneal scarring and allow for regression of already-established corneal scars.
  • the device allows for promotion of regenerative repair of corneal wounds or diseased tissue.
  • Embodiments of the disclosure include methods of reducing the risk for having corneal scars as a result of any cause. In specific embodiments, there are methods of reducing the severity of a corneal scar. In some embodiments, there are methods of reducing the size of a corneal scar. A corneal scar may be smaller in size with the treatment in comparison to not having the treatment. [0063] Embodiments of the disclosure include methods of avoiding partial or full vision loss for any reason, including related to the cornea. Specific cases include methods of avoiding the risk for or avoiding the need for a corneal transplant. Particular embodiments include methods of minimizing corneal fibrosis.
  • methods of the disclosure result in, or enhance the ability for, corneas to remain clear with no (or reduced) haze and/or opacification (upon onset or risk for an ocular medical condition) compared to when the methods are not employed.
  • the methods of the disclosure allow for uniform epithelial layer formation upon healing from an ocular medical condition.
  • Methods and compositions of the disclosure allow for corneal re- epithelialization, including without a risk for scarring.
  • the 3D-printed drug delivery device of the present disclosure is configured to allow the drug delivery to overcome the ocular surface barrier and facilitate drug diffusion into the cornea.
  • the disclosed ocular drug delivery device enhances the drug bioavailability in the corneal tissue compared to conventional eye drop formulations that do not remain on the surface of the eye for sufficient time to allow sufficient healing, including to avoid scar prevention.
  • the 3D-scaffold upon application on the eye will release the drug for an extended period of time, thus increases the drug residence time on the ocular surface and promotes drug transport through the ocular surface barriers into the corneal tissue to enhance the drug bioavailability and efficacy.
  • the device may be employed prior to, during, and/or following onset of any ocular medical condition.
  • the device may be used following the injury, and in cases wherein an individual is subject to a scheduled surgery, the device may be used prior to, during, and/or following the surgery.
  • the device may be utilized at least prior to its onset.
  • the device improves the drug bioavailability to a part of an eye.
  • the device may be applied topically, in specific embodiments, and the application may or may not be applied to the surface of the eye in a pharmaceutically acceptable liquid.
  • the device is applied in an eye drop(s).
  • the device may also be applied similar to that of applying a contact to the eyeball.
  • Any of the methods encompassed herein may utilize one or more of the following steps (or similar steps): treating one or more ocular medical conditions; preventing one or more ocular medical conditions; preparing a device; 3D-printing a device; 3D-printing a device comprising one or more therapeutic agents; identifying an ocular medical condition; applying a device to the surface of an eye; applying a dissolvable device to the surface of an eye; and so forth IV.
  • Embodiments of the disclosure include methods of producing a 3D-printed drug delivery device for treatment or prevention of at least one ocular medical condition.
  • the production method fabricates a drug delivery device comprising a structure that comprises one or more therapeutic agents on the surface of the structure, within the structure itself, or both.
  • the therapeutic agent is within the structure material as it is being 3D printed. In alternative cases, the therapeutic agent is applied to the device following its printing.
  • the selection of the material for the 3D printing is done for the purpose of allowing the structure of the device to be dissolvable once placed onto the surface of the eye.
  • the selection of the configuration of the structure of the device is such that the device applies a sufficient amount of the therapeutic agent(s) to the surface of the eye, including over time, such as including over the duration of time that the device structure dissolves.
  • the 3D printing of the device produces an array of filaments for the device, and in some cases the pattern of the array of filaments facilitates release of the therapeutic agent.
  • the 3D printing produces an array of filaments comprising multiple apertures produced as the filaments are printed.
  • the apertures may be of any size or shape, including a polygon (e.g., a square, rectangle, triangle, diamond, etc.), a circle, or there may be randomly shaped apertures.
  • the interior of the filaments may be solid or hollow.
  • the production methods generate an antifibrotic drug delivery 3D-scaffold, such as for scarless corneal wound healing.
  • the antifibrotic 3D-scaffolds are fabricated by coaxially 3D-bioprinting the filaments that, in specific embodiments, enables the fabrication of 3D-scaffolds comprising arrays of drug-encapsulated filaments (tubular, in some aspects) with programmable drug release kinetics.
  • the filaments may be monolithic or coaxial, in certain embodiments, which further enables the tunability/programmability of the drug release kinetics of the device.
  • the filament orientation affects the release kinetics.
  • the filament diameter and/or the number of coaxial layers affects the release kinetics.
  • the width of the filament is about, or is substantially exactly, 50-200 pm. In some embodiments, the width of the filament is about, or substantially exactly, 50- 200, 50-175, 50-150, 50-100, 50-75, 75-200, 75-175, 75-150, 75-100, 100-200, 100-175, 100-150, 150-200, 150-175, or 175-200 pm in width. In specific embodiments, the width of the filament is about, or is substantially exactly, 50, 75, 100, 125, 150, 175, or 200 pm in width. In some embodiments, the filaments have 1 or multiple layers, including 3-5, 3-4, or 4-5 layers. The number of layers may be 1, 2, 3, 4, or 5, or more. The layers may be configured coaxially.
  • Eye injuries leading to corneal scarring are a major cause of vision loss and a significant disabling concern among the patient population.
  • eye injuries are treated with eyedrop formulations of anti-inflammatory and antibiotics drugs with limited success in preventing scarring.
  • injured patients need corneal transplants to restore vision.
  • the ineffectiveness of current pharmacotherapies and the scarcity of donor corneas emphasize the critical unmet need to develop efficacious antifibrotic therapeutics to prevent corneal scarring and obviate the need for a corneal transplant.
  • NIN nintedanib
  • the inventors fabricated nintedanib-loaded theramem (NIN-theramem) by a 3D-bioprinting strategy.
  • the NIN-theramem rapidly adhered to the wet ocular surface and released NIN for longer than the eyedrop.
  • NIN-theramem treatment enhanced corneal healing and prevented scarring by reducing corneal keratocyte to myofibroblast transformation. This demonstrated the development of a 3D-bioprinted NIN-theramem with controlled drug release attributes and enhanced efficacy in preventing scarring of the injured corneas.
  • the antifibrotic NIN-theramems were fabricated using a poly(vinyl alcohol) (PVA) solution by 3D-bioprinting strategy.
  • PVA poly(vinyl alcohol)
  • PVA is a water-soluble, mucoadhesive polymer and its aqueous solutions are commonly used in ophthalmic formulations, particularly as artificial tears [28,29].
  • the inventors first prepared a PVA solution (10%, 5mL) and dissolved (20mg) NIN, which was used for layer-by-layer printing. It was determined that a 2 mm circular NIN-theramem contained 3 pg by HPLC analysis.
  • the printed theramem comprised an array of filaments.
  • the NIN-theramems thus fabricated were characterized by optical microscopy, which demonstrated a uniform array of microfilaments in the theramem (FIGS. 1A and IB).
  • X-ray diffraction analysis revealed that the drug molecules are homogeneously dispersed in the PVA matrix of the theramem (FIG. ID)
  • Theramem was safe on the corneal cell lines in vitro.
  • hCEC human corneal epithelial
  • hCF human corneal fibroblast
  • NIN treatment had negligible effect on live hCF cells, however a higher NIN concentration (>9 pg) produced cytotoxic effect and an approximately 50% decrease in live hCF cells was observed with 12 pg of NIN treatment, indicating that the hCF cells can safely tolerate up to 6 pg of NIN (FIGS. 2A and 2B).
  • NIN-theramem was safe on the ocular surface.
  • the in vivo safety of the NIN-theramems was evaluated on healthy mouse eyes.
  • Gross examination indicated the absence of corneal haze, redness, or swelling in q.o.d and q.d. treated eyes compared to the healthy eyes (FIGS. 2C-2E). Histological analysis was performed of the H&E-stained corneal eye sections which also revealed no change in the corneal thickness or integrity.
  • Theramem enabled drug molecular transport into the cornea.
  • the inventors performed Desorption electrospray ionization mass spectrometry (DESI-MS) imaging that allowed for the detection of NIN directly from samples and further provided visualization of its spatial distribution within the cornea [30,31].
  • DESI-MS Desorption electrospray ionization mass spectrometry
  • the inventors applied either NIN- theramem or NIN-eyedrop on the healthy mouse corneas then corneas were separated 3 hours postapplication.
  • the DESI-MS images showed a high relative abundance of NIN, detected in the negative ion mode at m/z 538.25, localized to the center of theramem applied corneas (FIG. 3F) compared to eye drop instilled corneas (FIG. 3C).
  • the inventors further evaluated NIN-theramem driven drug pharmacokinetics in the corneas of healthy mice.
  • 24 wildtype mice were randomly selected and divided into 6 groups (4 mice/group), and a single NIN-theramem containing 3 pg of NIN was applied on the right eye of each mouse.
  • a group of 4 mice were used for each timepoint.
  • the corneas were collected at 1-, 2-, 3-, 6-, 12-, and 24-hours after the NIN-theramem application and the NIN concentration was quantified by liquid chromatograph mass spectrometry (LCMS).
  • LCMS liquid chromatograph mass spectrometry
  • NIN-theramem promoted scarless corneal wound healing.
  • the H&E-stained corneal sections revealed that the NIN-theramem treated corneas completely healed with a uniform epithelial layer formation (FIG. 4P) compared to the NIN eyedrop treated sections that contained several voids in the cornea indicating an incomplete epithelium formation (FIG. 40).
  • the BSS treated corneal sections have swollen stroma (edema) and irregular corneal epithelium (FIG. 4N) compared to the NIN-theramem treated eyes. Thickness of the NIN-theramem treated corneas was close to the healthy corneas (FIG. 4Q). NIN-theramem treatment improved the recovery of corneal sensitivity.
  • Corneal sensitivity was measured using a Cochet-Bonnet aesthesiometer using a 12/100 nylon thread [32], Pressure response was tested twice with two observers confirming the occurrence of a blink.
  • the filament pressure is inversely proportional to the sensitivity and a lower filament pressure indicates an increased corneal sensitivity.
  • the NIN-theramem treated eyes required a lower filament pressure close to that of the healthy mice to elicit a blink response compared to the BSS and NTN-eyedrops treated mice (FIG. 4R).
  • NIN-theramem controlled corneal fibrosis NIN-theramem controlled corneal fibrosis.
  • NIN-theramem promoted corneal re-epithelialization.
  • the corneal cross sections were stained with Ki67 antibody and imaged to assess the dividing corneal epithelial cells. This study revealed that in the NIN-theramem treated sections an increased number dividing epithelial cells were observed, compared to the BSS treated corneal sections (FIGS. 6A-6C). The corneal cross sections also indicated a uniform layer of keratin 13 formation (FIGS. 6D-6F). These results demonstrated corneal re-epithelialization and a normal wound healing process with NIN-theramem treatment.
  • NIN regulated corneal keratocyte to myofibroblast differentiation NIN regulated corneal keratocyte to myofibroblast differentiation.
  • TGF-P induced corneal keratocyte (CKC) to myofibroblast (MFB) differentiation the inventors treated CKC with TGF-P (lOng/ml) followed by NIN (lOpg) for 72 hours.
  • the TGF-P+NIN treated CKCs did not exhibit a-SMA antibody staining compared to the only TGF-P treated CKCs (control), indicating that NIN attenuates the TGF-P induced CKC to MFB differentiation (FIG. 7A-C).
  • the inventors further characterized the CKC to MFB differentiation in vivo in a mouse OB model.
  • the OB mice were treated with NIN-theramems on alternate days for 14 days.
  • the corneal sections were subjected to a-SMA antibody staining (green fluorescent) to differentiate the MFB from FB.
  • the NIN-theramem treated corneas have fewer MFBs compared to the BSS treated corneas (control) (FIGS. 7D-F).
  • the MFB density in the NIN- theramem treated sections was comparable to the healthy corneas.
  • a flow cytometry analysis of the corneal tissue was performed. The OB mice were treated with NIN-theramems every alternate day for 10 days.
  • the corneas were collected, cells were isolated and subjected to flow cytometry analysis.
  • the corneas treated with BSS eyedrops were used as controls.
  • the u-SMA-expressing myofibroblasts are the key contributors to scar formation [33-36]
  • Theramem regulated corneal scarring at the molecular level.
  • NIN-theramem treatment downregulated the expression levels of proangiogenic VEGFR1, VEGFR2, PDGFR-A, and PDGFR-B, and profibrotic TGF- , COL1A1, CTGF, and ACTA2 (FIG. 8).
  • a patient will be treated several days after the corneal injury, and often the drug treatment will begin only after the visual diagnosis of haze formation or opacification.
  • OB were generated as previously described and OB eyes were treated with BSS or NIN-theramem on post-OB day 7 and continued for 14 days.
  • the progress of corneal healing and wound closure was monitored by fluorescein staining (FIGs. 16A-H) and corneal epithelium morphology was assessed by H&E staining (FIG. 16I-K).
  • NIN-theramem treated corneas showed continuous corneal epithelium comparable to Healthy (FIG. 16I-K).
  • the BSS treated cornea shows irregular epithelial formation along with severe edema to the stroma (FIG. 16I-K).
  • the body’s first and immediate response to injury is to rapidly seal the wound by excessive secretion of extracellular matrix (ECM) materials and prevent fluid loss and infection [37]
  • ECM extracellular matrix
  • the corneal wound healing response involves a sequence of events that usually contribute to the spontaneous resolution of opacity during the wound healing process leading to the return of a clear cornea with normal function [33-36]
  • an abnormal wound healing response results in a persistent corneal scar with a loss of corneal transparency [33]
  • the quiescent corneal keratocytes (CK) in the stroma transform into myofibroblasts (MFB) to repair the damage by secreting extracellular matrix (ECM) [39]
  • Myofibroblast differentiation has been identified as the critical factor that leads to corneal fibrosis [33]
  • CK are relatively quiescent strom
  • Corneal fibrosis is characterized by a high density of type I collagen-producing aSMA- positive MFBs and an excessive secretion of ECM proteins at the wound site [33], These underlying events result in fibrosis and scar formation.
  • an effective approach to modulate corneal fibrosis is to target the trans-differentiation pathway responsible for the conversion of quiescent CK or fibroblasts to activated, profibrotic MFBs [34], Drugs capable of blocking the fibroblast conversion to activated MFBs could prevent the progression of corneal fibrosis [41], Moreover, pharmacologic agents capable of inhibiting the formation of MFBs in the presence of transforming growth factor-fBl (TGF-pi) without directly inhibiting TGF-pi signaling itself, may have an advantage over direct suppression of TGF-pi, which has the potential to exacerbate immune responses [41], Hence, modulating the CK differentiation into MFBs with pharmacologic agents that do not suppress TGF-pi expression could be an effective strategy to prevent corneal fibrosis and obviate the need for corneal transplant.
  • TGF-pi transforming growth factor-fBl
  • NIN Nintedanib
  • PDGF platelet-derived growth factor
  • FGF fibroblast growth factor
  • VEGF vascular endothelial growth factor
  • a 3D-bioprinting strategy was employed to fabricate NIN-theramems with a water-soluble polymer, polyvinyl alcohol (PVA) as a delivery system to increase the drug residence time on the cornea and demonstrated its efficacy in promoting scarless corneal wound healing in a mouse ocular burn (OB) induced model.
  • PVA polyvinyl alcohol
  • OB mouse ocular burn
  • the NIN-theramem rapidly adheres to the wet mucosal surface of the eye.
  • the mucoadhesive hydrogel forming PVA polymer in the theramem enables its rapid wetting and adhesion to the ocular surface without being displaced due to constant blinking and minimizes foreign body sensation in the eye.
  • the antifibrotic drug loaded theramems can function as a drug delivery system and as an ocular surface lubricant.
  • the NIN-theramem can be applied on the ocular surface with a fingertip like a contact lens.
  • the studies have confirmed that when NIN-theramems applied on the eyes of healthy mice, released the drug for an extended time (up to 24 hours), increased the drug residence time on the ocular surface and promoted the drug diffusion into the corneal tissue.
  • a longer drug residence time on the ocular surface provides sufficient time for the drug molecules to diffuse through the ocular surface barriers (OSB) such as tear-film mucus barrier, epithelial tight junctions and diffuse into the corneal tissue, thus improving the drug bioavailability.
  • OSB ocular surface barriers
  • NIN-theramems when applied on the eyes of alkali induced severe OB mouse model have demonstrated a reduction in the MFB density in the injured corneas compared to the NIN-eyedrop and BSS treatment groups, as confirmed by the fluorescence imaging, q-PCR, and flowcytometry analysis, respectively. Taken together, these results confirm that NIN-theramem treatment is highly effective in attenuating corneal fibrosis in the injured corneas and do not interfere with the normal corneal healing process.
  • the inventors have demonstrated the development of an innovative 3D- bioprinted antifibrotic drug delivery NIN-theramem and established the repurposing potential of NIN for the scarless healing of corneal injuries.
  • the development of antifibrotic NIN-theramems is a major advancement in the treatment of corneal fibrosis and fulfils a hitherto unmet clinical need.
  • the ocular drug delivery theramem is broadly applicable, as it can be loaded with other antiinflammatory and/or antibiotic drugs for the treatment of corneal inflammation, infections, and dry eye.
  • NIN -theramem Fabrication of NIN -theramem: Theramem was fabricated by layer-by-layer 3D- bioprinting (3DDiscovery; regenHU, Switzerland) of a homogenous solution of PVA and NIN in water using a pressure-gradient printhead. The spacing and thickness of the theramem can be tuned by adjusting printing parameters like array design, needle gauge, line spacing and number of layers printed. Here, a 27-gauge needle with an inner diameter of 0.2 mm was used to continuously extrude the polymer drug solution onto the glass slide at a needle pressure of 0.025 MPa and collector velocity of 12 mms' 1 . After printing, the theramem was left on the stage for 60 mins to dry.
  • 3D-bioprinting 3DDiscovery; regenHU, Switzerland
  • NIN-Theramem ability to regulate corneal scarring in vitro: The ability of NIN-theramem to regulate corneal scarring was evaluated by determining the effect of NIN on modulating TGF-0 induced transition of corneal keratocyte (CKC) to myofibroblasts.
  • CKC corneal keratocyte
  • the cells were then treated with lOng/ml TGF-01 followed by NIN-theramem for 72 hours. After 72 hours the cells were fixed in 4% PF A, blocked, permeabilized and incubated with oc-SMA primary antibody at 4°C overnight. This was followed by incubation with fluorescent secondary antibody protected from light for 40 mins at room temperature. The slides were mounted with Fluoromount G and sealed with glass cover slip before imaging using Nikon AR confocal microscope (Nikon Instruments, Melville, NY, USA). The cells treated with TGF-01 + NIN- Theramem was compared against cells treated with only TGF-01 and untreated controls.
  • NIN-theramems were placed on the corneas of healthy C57BL/6 mice (6-8 weeks old). Nintedanib is a green-fluorescent drug, and the efficiency of transport of this drug molecule by the theramem was evaluated by fluorescent imaging every hour for 3 hours using SMZ imaging system.
  • DESI-MS imaging the corneas were harvested after 3 hours of treatment with either NIN eyedrop or NIN-theramem. The fresh corneas were flat-mounted on glass slide for analysis. DESI-MS analyses were performed using a DESI-XS source paired with a Xevo G2-XS Q-TOF mass spectrometer (Waters Corporation) operated in sensitivity mode with a mass range m z 100 to 1500. DESI-MS imaging of cornea samples was performed at a spatial resolution of 100 pm in the positive and negative ion modes using a spray solvent of MeOH at a flow rate of 3 pL/min. DESI-MS ion images were constructed using HDI (Waters Corporation) software. Ions were identified based on high mass accuracy measurements.
  • NIN-Theramem pharmacokinetic study on the corneal surface Pharmacokinetic analysis for NIN-theramem was done at 1-, 2-, 3-, 6-, 12-, and 24-hours after the NIN-theramem application on the cornea. For this study, 24 wildtype mice were randomly divided into 6 groups with 4 mice in each group for each timepoint and a NIN-theramem containing 3 pg of NIN was applied on the right eye of each mouse. At each time point the mice were euthanized and the corneas were collected. The NIN concentration on the harvested corneas were quantified using liquid chromatograph mass spectrometry (LC-MS). Here, the eyes treated with NIN eye drops were used as control.
  • LC-MS liquid chromatograph mass spectrometry
  • Corneal Sensitivity Measurement The inventors evaluated the corneal sensitivity to tactile sensation by gently applying pressure using a Cochet-Bonnet aesthesiometer (nylon thread, 12/100 mm, Luneau Ophthalmologies, France). This measurement was performed at least three times by two independent observers. The length of the filament is inversely proportional to the pressure applied.
  • Histology Flash-frozen eye tissue samples were sectioned at 10 um thickness using a cryostat (LEICA CM 1850, Leica Biosystems, Buffalo Grove, IL, USA) at -20 °C and collected on a glass microscope slide. The tissue-mounted glass slides were stained with hematoxylin for 4 mins and eosin for 1 minute, followed by dehydration and cleaning in ethanol and xylene. The slides were mounted using toluene-based synthetic resin mounting medium (e.g., PermountTM mounting solution) and sealed with a cover slip. The sections were imaged and analyzed using Nikon eclipse TE2000-U microscope (Nikon Instruments, Melville, NY, USA). The corneal thickness of the OB theramem treated mice were calculated from the H&E images using NIKON AR software and compared with a healthy and BSS eye drop treated group.
  • LICA CM 1850 Leica Biosystems, Buffalo Grove, IL, USA
  • Immunofluorescence Tissues sectioned at 10 um thickness were used for all the immunofluorescence study. Sections were fixed with 4% PFA, permeabilized, blocked, and incubated with the following primary antibodies: Ki67, keratin-13, ot-SMA, fibronectin and COL1A1 at 4°C, followed by fluorescent secondary antibody staining in a dark chamber for 40 mins at room temperature. The tissues were then mounted using a water soluble, non-fluorescing mounting medium (e.g., Fluoromount GTM) and sealed using a glass cover slip. The tissues were imaged and analyzed using Nikon AR confocal microscope.
  • a water soluble, non-fluorescing mounting medium e.g., Fluoromount GTM
  • Flow cytometry After separating the corneas, corneal cells were isolated followed by digestion for 2 h at 37°C. The obtained single-cell suspension was stained for viability using blue live/dead fixable cell stain kit. The cells were then fixed and permeabilized overnight at 4 °C (Fixation/Permeabilization, Affymetrix, Santa Clara, USA). On the next day, cells were stained with anti-oc-SMA, SI 00, SCA1 (Invitrogen, Thermo Sciences). A BD LSRII cytometer was used for data acquisition and data was analyzed using BD Diva Software (BD Pharmingen) and FlowJo software.
  • First strand cDNA was synthesized from 1.0 ug of RNA with Ready-To- Go-You-Prime-First-Strand Beads and random hexamers (Applied Biosystems, Thermo Fisher Scientific, USA). Equal amounts of synthesized cDNA were used to measure specific gene expression by RT-PCR using a TaqMan Fast Advanced Master Mix (Applied Biosystems, Thermo Fisher Scientific, USA) for specific primers: VEGFR1, VEGFR2, PDGFR-A, PDGFR-B, TGF-p, COL1 Al, CTGF, and ACTA2 from Applied Biosystems on Quantstudio 5 Real-Time PCR system (Applied Biosystems, Thermo Fisher Scientific, USA).
  • Embodiments of the disclosure encompass development of an ocular drug delivery 3D- scaffold by coaxial 3D-bioprinting strategy.
  • this strategy enables the fabrication of 3D-scaffolds containing tubular filaments with an inner core composed of drug- polymer matrix and an outer sheath of mucoadhesive polymer.
  • the 3D- scaffold releases the drug in a tightly controlled fashion and enhances the drug molecular diffusion into the cornea.
  • the drug-polymer ratio, polymer molecular weight, the outer sheath thickness and diameter of the tubular filaments its drug release kinetics can be programmed.
  • By optimizing the wettability and lubricity of the 3D-scaffold its ocular comfort and compliance is improved. This strategy enables the incorporation of biologies into the 3D-scaffold without compromising their stability and biological activity.
  • 3D-bioprinted NIN-scaffolds were fabricated by coaxial bioprinting strategy, which enables the fabrication of tubular filaments with inner core of drug-polymer matrix and an outer sheath of mucoadhesive polymer, unlike the monolithic fibers printed by current 3D-printers.
  • the inventors designed a square patterned 3D- scaffold using BioCAD software for co-axial bioprinting with a water soluble mucoadhesive polyvinyl alcohol (PVA) polymer.
  • PVA water soluble mucoadhesive polyvinyl alcohol
  • the inner core of the filament was loaded with red fluorescent dye and PVA while the outer sheath with green-fluorescent dye mixed PVA to demonstrate the ability to coaxially bioprint arrays of tubular filaments with two different fluorescent dyes (FIGS. 10A and 10B).
  • the microfilaments in the 3D-scaffold enable rapid wetting and adhesion to the ocular surface without being displaced because of constant blinking and minimizes foreign body sensation in the eye (FIGS. 10D-10F).
  • the controlled release of drug molecules from the NIN-PVA microfilaments of the 3D-scaffold increases the drug residence time on the corneal surface. A longer residence time on the corneal surface provides sufficient time for the drug molecules to diffuse into the corneal through the ocular surface barriers.
  • NIN-scaffold enhanced the drug transport into the cornea: A Nintedanib (NIN) loaded 3D-scaffold was fabricated by coaxial 3D-bioprinting strategy in which the outer sheath of the tubular filament was made of PVA sheath, and the inner core is formed of NIN-PVA matrix (2: 10 w/w).
  • the NIN loaded 3D-scaffolds (NIN-scaffolds) were used to evaluate the NIN-scaffold efficacy in promoting the drug transport into the cornea.
  • the inventors randomly selected 24 wildtype mice and divided them into 6 groups (4 mice/group) and a single NIN-scaffold containing 3 pg of NIN was applied on the right eye of each mouse.
  • mice were used for each timepoint.
  • the corneas were collected at 1-, 2-, 3-, 6-, 12-, and 24-hours after the NIN-scaffold application and the NIN concentration was quantified by mass spectrometry.
  • the mouse eyes treated with NIN-eyedrops of same drug concentration (3 pg/3 pL) contained less amount of drug (226 ng) in the first hour and no drug was detected after 12 h.
  • NIN- scaffold surmounts the ocular surface barriers and enables the drug diffusion into the cornea compared to the eye drop treatment (FIG. 11).
  • NIN-scaffold promoted scarless corneal wound healing.
  • the inventors evaluated the efficacy of the NIN-scaffolds in alkali induced severe ocular burn (OB) mouse model.
  • OB alkali induced severe ocular burn
  • an alternate day NIN-wafer treatment regimen was designed to minimize the drug overdosing.
  • the NIN wafers were applied soon after the OB creation and the treatment continued once every alternate day for 14 days.
  • the eyes were monitored on alternate days by bright field microscopy during the course of the NIN-scaffold treatment.
  • the NIN-wafer treated corneas were clear with no haze or opacification (FIG. 4I-4L).
  • FIG. 40 The BSS treated corneal sections have swollen stroma (edema) and irregular corneal epithelium (FIG. 4N) compared to the healthy and NIN- wafer treated eyes (FIGS. 4M and 4P). Thickness of the NIN-scaffold treated corneas was close to the healthy corneas compared to the NIN-eyedrops treated corneas (FIG. 13).
  • NIN-scaffold treatment improved the recovery of corneal sensitivity: Corneal sensitivity was measured using a Cochet-Bonnet aesthesiometer using a 12/100 nylon thread [42], The threshold pressure response (g/mm 2 ) for the central cornea was obtained by starting at a pressure too low for detection and then systematically increasing the pressure by shortening the filament length until a blink was observed. Pressure response was tested twice with two observers confirming the occurrence of a blink. The filament pressure is inversely proportional to the sensitivity and a lower filament pressure indicates an increased corneal sensitivity. The NIN- scaffold treated eyes required a lower filament pressure close to that of the healthy mice to elicit a blink response compared to the BSS and NIN-eyedrops treated mice (FIG. 4R).
  • keratocytes migrate to the injury site and a subset of these keratocytes in the stroma will differentiate into fibroblast (FB) and myofibroblasts (MFB) by the activation of TGF-P and PDGF secreted by the epithelial cells.
  • the MFB produce ECM at the wound site to repair the damaged cornea.
  • the stromal MFB undergo apoptosis and the keratocytes populate the stroma to enable the structural and functional recovery of the cornea.
  • a sustained secretion of TGF-P at the wound site transform the quiescent stromal cells to MFB and prevents the repopulation of keratocytes in the stroma.
  • the MFB continue to secrete an excessive disorganized ECM that result in a permanent corneal scarring.
  • the inventors deciphered the mechanism through which NIN acts as an antifibrotic drug, i.e., if the antifibrotic effect of NIN is by modulating the persistent secretion of TGF-P and the MFB differentiation at the wound site or directly targeting the MFB and trigger their apoptosis. Studies were performed to elucidate the antifibrotic mechanism of NIN.
  • NIN regulated in vitro FB to MFB differentiation To determine the effect of NIN on regulating the TGF-P induced FB to MFB transformation, keratocytes were treated with TGF- P (10 ng/ml) followed by NIN (10 pg) for 72 hours. The TGF-P+NIN treated keratocytes did not exhibit a-SMA antibody staining compared to the only TGF-P treated keratocytes (control) indicating that NIN plays a key role in attenuating the TGF-P induced keratocyte transformation to MFB (FIGS. 7A-7C).
  • NIN-scaffold modulated the in vivo MFB differentiation: To evaluate the antifibrotic efficacy of the NIN-scaffold, the OB mice were treated with NIN-scaffolds on alternated days for 14 days. The corneal sections were subjected to green fluorescent a-SMA antibody staining to differentiate the MFB from FB. The NIN-wafer treated corneas had fewer MFBs compared to the BSS treated corneas (control). The MFB density in the NIN-scaffold treated sections was close to the healthy corneas (FIGS. 7D-7F).
  • NIN-scaffold treatment also reduced the fibrotic COL1 Al and fibronectin content in the corneal sections, further confirming its antifibrotic effect (FIGS. 14A-14F). These results demonstrated the efficacy of the NIN-scaffold on reducing the MFB density in the corneas compared to the BSS treated corneas (control).
  • NIN-scaffold promoted corneal re-epithelialization: The Ki67 stained NIN-scaffold treated corneal cross sections contained an increased number of dividing epithelial cells compared to the BSS treated corneal sections (FIGS. 6A-6C). The corneal cross sections stained for Keratin 13 indicated a uniform layer of keratin 13 formation (FIGS. 6D-6F). Together, these results demonstrated the corneal re-epithelialization and a normal wound healing process with NIN- scaffold treatment.
  • NIN-scaffold regulated profibrotic mediator expression q-PCR analysis revealed that the expression levels of profibrotic factors COL1 Al, CTGF, and ACTA2 were down regulated in the NIN-scaffold treated corneas compared to the BSS treated control group, indicating that NIN-scaffold operates by downregulating the expression levels of TGF-0 and profibrotic factors (FIG. 8)
  • fibroblasts 3 subsets of fibroblasts were quantified: a-SMA positive myofibroblasts associated with haze and scar formation, S100 positive fibroblasts that promote angiogenesis, and Sca-1 positive fibroblasts associated with progenitor mesenchymal stromal cells.
  • a-SMA positive myofibroblasts associated with haze and scar formation
  • S100 positive fibroblasts that promote angiogenesis
  • Sca-1 positive fibroblasts associated with progenitor mesenchymal stromal cells.
  • This study revealed that, the NIN-scaffold treated corneas exhibited a decrease in the myofibroblast density compared to the OB group (FIG. 15).
  • the BSS eyedrops treated mice exhibited a persistent corneal haze even after complete corneal healing (after 24 days) (FIGS. 9A-9D).
  • the NIN-scaffold treated mice exhibited clear and smooth corneas devoid of any haze or scar.
  • the data demonstrated the capability to fabricate coaxially 3D-bioprinted NIN-scaffolds with controlled drug release attributes and enhanced efficacy in preventing corneal fibrosis and restoration of corneal sensitivity towards a regenerative wound repair process.
  • LiQD Cornea Pro-regeneration collagen mimetics as patches and alternatives to corneal transplantation. Sci Adv 2020; 6, eaba2187. DOI: 10.1126/sciadv.aba2187 S Chameettachal, D Prasad, Y Parekh, S Basu, V Singh, KK Bokara, F Pati.
  • Dextran sulfate polymer wafer promotes corneal wound healing.

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Abstract

Des modes de réalisation de la divulgation concernent des dispositifs thérapeutiques oculaires, y compris ceux qui sont imprimés en 3D. Dans des modes de réalisation spécifiques, la divulgation concerne l'administration d'un médicament bio-imprimé en 3D pour des affections oculaires de n'importe quel type. Dans des modes de réalisation particuliers, la divulgation concerne l'administration d'un médicament antifibrotique bio-imprimé en 3D avec un échafaudage 3D pour le traitement de pathologies associées à la cornée, telles que la fibrose cornéenne.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180228725A1 (en) * 2010-05-17 2018-08-16 Novaer Holdings, Inc. Drug delivery devices for delivery of ocular therapeutic agents
US20190340957A1 (en) * 2014-10-24 2019-11-07 The Trustees Of The University Of Pennsylvania Methods and Devices for Modeling the Eye
US20200405538A1 (en) * 2019-06-27 2020-12-31 Layerbio, Inc. Ocular device delivery methods and systems
US20210236336A1 (en) * 2018-05-09 2021-08-05 North Carolina State University Applicator for corneal therapeutics

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180228725A1 (en) * 2010-05-17 2018-08-16 Novaer Holdings, Inc. Drug delivery devices for delivery of ocular therapeutic agents
US20190340957A1 (en) * 2014-10-24 2019-11-07 The Trustees Of The University Of Pennsylvania Methods and Devices for Modeling the Eye
US20210236336A1 (en) * 2018-05-09 2021-08-05 North Carolina State University Applicator for corneal therapeutics
US20200405538A1 (en) * 2019-06-27 2020-12-31 Layerbio, Inc. Ocular device delivery methods and systems

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Title
IOANNOU NICOLE, LUO JINYUAN, QIN MENGQI, DI LUCA MATTEO, MATHEW ESSYROSE, TAGALAKIS ARISTIDES D, LAMPROU DIMITRIOS A, YU-WAI-MAN C: "3D-printed long-acting 5-fluorouracil implant to prevent conjunctival fibrosis in glaucoma", JOURNAL OF PHARMACY AND PHARMACOLOGY, vol. 75, no. 2, 1 February 2023 (2023-02-01), GB , pages 276 - 286, XP093259938, ISSN: 0022-3573, DOI: 10.1093/jpp/rgac100 *

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