WO2016100355A1 - Hydrogels biocompatibles, systèmes comprenant les hydrogels et procédés d'utilisation et de formation associés - Google Patents

Hydrogels biocompatibles, systèmes comprenant les hydrogels et procédés d'utilisation et de formation associés Download PDF

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WO2016100355A1
WO2016100355A1 PCT/US2015/065842 US2015065842W WO2016100355A1 WO 2016100355 A1 WO2016100355 A1 WO 2016100355A1 US 2015065842 W US2015065842 W US 2015065842W WO 2016100355 A1 WO2016100355 A1 WO 2016100355A1
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hydrogel
composition
hydrogel composition
polymers
polymer
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Inventor
Devatha P. Nair
Malik Y. Kahook
Naresh MANDAVA
Christopher Bowman
Saikripa RADHAKRISHNAN
Srinidhi RADHAKRISHNAN
Amir H. TORBATI
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University of Colorado System
University of Colorado Colorado Springs
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University of Colorado Colorado Springs
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    • 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
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/14—Eye parts, e.g. lenses or corneal implants; Artificial eyes
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/043—Mixtures of macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/26—Mixtures of macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/52—Hydrogels or hydrocolloids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/06—Flowable or injectable implant compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/16—Materials or treatment for tissue regeneration for reconstruction of eye parts, e.g. intraocular lens, cornea

Definitions

  • BIOCOMPATIBLE HYDROGELS BIOCOMPATIBLE HYDROGELS, SYSTEMS INCLUDING THE HYDROGELS, AND METHODS OF USING AND FORMING SAME
  • the present disclosure generally relates to hydrogel compositions and to methods of forming and using the hydrogel compositions. More particularly, the disclosure relates to hydrogel compositions having a first polymer network including ionic bonds and a second polymer network having covalent bonds, to methods of forming the polymers and compositions, and to methods of using the compositions.
  • the vitreous material in the eye resides in the space between the lens and the retina.
  • the vitreous is a gel material, comprised primarily of water and is generally clear.
  • the vitreous serves several functions, including as a barrier to disease, providing or maintaining desired intraocular pressure, holding the retina and/or other tissue in place, circulating metabolites, maintaining the shape of the eye, and the like.
  • vitreous tends to degrade with age, trauma, and/or disease, becoming less gelatinous and more liquid. If left untreated, deteriorating vitreous can lead to posterior vitreous detachment, which can lead to retinal tears or detachment and intravitreal hemorrhaging. In addition, the vitreous can form fibers, sometimes referred to as "floaters" that can interfere with vision. Accordingly, several attempts have been made to find a suitable vitreous substitute.
  • Some of the first attempts of vitreous substitution included transplanting healthy vitreous from animal donors, such as calves and rabbits. Such techniques were further extended to human donors. However, these methods were generally unsuccessful, because they caused immune responses within a patient's eye, causing inflammation and further complications.
  • vitreous substitutes that mimic biomechanical properties of a (e.g., human) vitreous that can maintain desired properties for an extended period of time are desirable.
  • compositions that can be injected into a vitreous region of an eye including those that can be used to deliver drugs and/or be used as an adhesive, are desired.
  • the present disclosure generally relates to hydrogels and to methods of forming and using the hydrogels. More particularly, the disclosure relates to biocompatible hydrogels that can be used for various applications, including vitreous substitutes, adhesives, and drug delivery compositions. While the ways in which the compositions and methods address various drawbacks of prior compositions and methods will be discussed in greater detail below, in general, exemplary compositions have desirable properties, such as clarity, refractive index, viscosity and elastic modulus (e.g., that are the same or similar to the same properties of a healthy vitreous in an eye), and can be injected through a relatively small needle and retain or reform as a hydrogel. The inventors surprisingly were able to develop a clear, transparent composition with a desired refractive index and other desirable properties, wherein the composition has or exhibits the desirable properties after injection.
  • desirable properties such as clarity, refractive index, viscosity and elastic modulus
  • a hydrogel composition includes a first network comprising covalently bonded first polymers and a second network comprising second polymers, wherein the hydrogel comprises a sacrificial bond (e.g., a bond between the second polymers and/or a bond between the second polymers and the first polymers) selected from the group consisting of one or more of an ionic bond, an electrostatic bond, and a hydrogen bond.
  • the composition can also include water, such as deionized water— e.g., about 80 wt% to about 95 wt% water.
  • the hydrogel composition can pass through a 25-gauge or smaller needle and reform as a hydrogel.
  • the hydrogel composition has a refractive index between about 1.33 and about 1.35. In accordance with further aspects, the hydrogel composition has a viscosity between about 300 cp and about 2000 cp. In accordance with yet further aspects, the elastic modulus (G') of the composition is between about 1.6 pa and about 14.8 pa. In accordance with yet further aspects, the composition is clear and/or transparent. In accordance with yet further exemplary aspects, the specific gravity of the hydrogel composition is between about 1.0053 and about 1.0089.
  • the first polymers include one or more polymers selected from the group consisting of methacrylate, and acrylamide.
  • the second polymer can include, for example, alginate (e.g., derived from sodium alginate) or chitosan.
  • alginate e.g., derived from sodium alginate
  • chitosan e.g., chitosan
  • Exemplary compositions can be used as a vitreous substitute, an ocular adhesive, and/or as a drug delivery system.
  • a system includes a delivery device and a composition, namely a hydrogel composition, as described herein.
  • the delivery device can include, for example, a syringe— e.g., a syringe having a 25- gauge or smaller needle.
  • the system can be used to inject the composition directly into a vitreous cavity or other area.
  • a method of forming a hydrogel composition includes the steps of providing a first polymer that forms a first network comprising covalent bonds, providing a second polymer having side chains that form sacrificial (e.g. ionic , electrostatic, and/or hydrogen bonds) providing a salt, providing water, providing an initiating system, mixing the first polymer, the second polymer and a first portion of the water to form a first mixture, mixing the salt, the initiating system and a second portion of the water to form a second mixture, and mixing the first mixture and the second mixture to form a hydrogel.
  • sacrificial e.g. ionic , electrostatic, and/or hydrogen bonds
  • the first polymer comprises a polymer selected from the group consisting of one or more of methacrylate and acrylamide.
  • the second polymer comprises one or more of alginate and chitosan.
  • the method can further include mixing a covalent crosslinker, such as PEGDA 575, with the first mixture.
  • the resulting composition can have one or more of the hydrogel composition properties described herein.
  • Additional exemplary embodiments of the disclosure relate to the use of a hydrogel, such as the hydrogel compositions described herein, in the manufacture of a medicament for treatment of an eye.
  • exemplary hydrogel compositions can be used as a vitreous substitute, a drug delivery system, and/or as an ocular adhesive.
  • a hydrogel composition includes a first network comprising covalent bonds between side chains of a first polymer selected from the group consisting of acrylamides methacrylate, acrylates, allyl ether, norbornenes and vinyl ethers and other monomers containing vinyl group and a second network comprising sacrificial bonds (e.g., ionic, electrostatic, and/or hydrogen bonds) between the second polymers and/or the second polymers and the first polymers, the second polymers selected from the group consisting of alginate and chitosan, wherein the first network and the second network are linked to form a hydrogel composition.
  • a first polymer selected from the group consisting of acrylamides methacrylate, acrylates, allyl ether, norbornenes and vinyl ethers and other monomers containing vinyl group
  • a second network comprising sacrificial bonds (e.g., ionic, electrostatic, and/or hydrogen bonds) between the second polymers and/or the second polymers and the first poly
  • the hydrogel further comprises water, e.g., deionized water.
  • the water can be present in an amount of about 80 wt% to about 95 wt% water.
  • the hydrogel composition can pass through a 25-gauge needle and reform as a hydrogel.
  • the hydrogel composition has a refractive index between about 1.33 and about 1.35.
  • the hydrogel composition has a viscosity between about 300 cp and about 2000 cp.
  • the elastic modulus (G') of the composition is between about 1.6 pa and about 14.8 pa.
  • the composition is clear and/or transparent.
  • the specific gravity of the hydrogel composition is between about 1.0053 and about 1.0089.
  • Exemplary compositions can be used as a vitreous substitute, an ocular adhesive, and/or as a drug delivery system.
  • a method of forming a hydrogel composition includes the steps of providing positively charged methacrylated alginate, providing negatively charged alginate, and mixing the positively charged methacrylated alginate with the negatively charged alginate in water to form an ionically crosslinked network.
  • the method further includes a step of covalently crosslinking the negatively charged alginate and the positively charged methacrylated alginate to form a highly crosslinked network and an ionically crosslinked network.
  • the step of covalently crosslinking includes applying UV light to the crosslinked network.
  • a method of treating an eye of an animal includes the steps of providing a hydrogel composition, such as a hydrogel composition described herein, and injecting the hydrogel composition into the eye.
  • a hydrogel composition such as a hydrogel composition described herein
  • Exemplary methods can be used for vitreous substitution, for providing a drug delivery system including the hydrogel composition and a therapeutic agent, and/or providing an ocular adhesive.
  • a method can include injecting the hydrogel composition through a small- gauge needle, such as a 25-gauge needle or smaller.
  • exemplary hydrogel compositions such as those described herein provide one or more of an antioxidant capacity, a free radical trap, and biological molecule trap.
  • FIG. 1 is an illustration of a human eye.
  • FIGS. 2(a), 2(b) and 2(c) illustrate ionic and covalent bonds within exemplary hydrogels in accordance with various embodiments of the disclosure.
  • FIG. 3 illustrates modulus data for hydrogel compositions in accordance with exemplary embodiments of the disclosure.
  • FIG. 4 illustrates exemplary refractive index values of exemplary hydrogels in accordance with various embodiments of the disclosure.
  • FIG. 5 illustrates an exemplary method of forming methacrylated alginate in accordance with exemplary embodiments of the disclosure.
  • FIG. 6 illustrates an exemplary method of forming an exemplary hydrogel in accordance with further exemplary embodiments of the disclosure.
  • FIG. 7(a) illustrates a hydrogel after injection of an uncured sample through a 27- gauge needle in accordance with exemplary embodiments of the disclosure.
  • FIGS. 7(b) and 7(c) illustrate the hydrogel illustrated in FIG. 7(a) after UV curing.
  • exemplary embodiments of the disclosure provide a hydrogel suitable for use in a variety of applications.
  • exemplary hydrogels can be used as a vitreous substitute, an adhesive (e.g., an ocular adhesive), and/or as part of a drug delivery system that further includes one or more therapeutic agents.
  • Exemplary therapeutic agents include: anti- fibrotic agent, anti-inflammatory agent, immunosuppressant agent, anti-neoplastic agent, migration inhibitors, anti-proliferative agent, rapamycin, triamcinolone acetonide, everolimus, tacrolimus, paclitaxel, actinomycin, azathioprine, dexamethasone, cyclosporine, bevacizumab, an anti-VEGF agent, an anti-IL-1 agent, canakinumab, an anti-IL-2 agent, viral vectors, beta blockers, alpha agonists, muscarinic agents, steroids, antibiotics, non-steroidal anti-inflammatory agents, prostaglandin analogues, ROCK inhibitors, nitric oxide, endothelin, matrixmetalloproteinase inhibitors, CNPA, corticosteroids, an antibody-based immunosuppressants, apatmers, medications that decrease eye pressure, medications that decrease edema in and around the eye, medications that treat n
  • exemplary hydrogel compositions are transparent, optically clear, and when used as a vitreous substitute are thought to not cause inflammation, cataracts, glaucoma or scar tissue. Furthermore, exemplary hydrogels do not degrade or emulsify, and can therefor maintain an ocular volume over a sustained period of time (e.g., in in- vitro experiments, they have been observed to stay cohesive for up to 6 months), while providing desired clarity. Further, hydrogel compositions as described herein can exhibit globe stability, and are suitable for visual function.
  • the physical properties of various exemplary hydrogel compositions exhibit a refractive index, transparency, specific gravity, and/or viscosity that match or substantially match (e.g., within about 5% or 10%) such properties of a healthy vitreous; this allows use of such compositions for long-term optical applications, such as vitreous substitution, ocular adhesive, and/or long-term (e.g., 6 weeks) drug delivery systems.
  • the hydrogel compositions allow for in situ polymerization using various modes of polymerization to allow for low rates of free monomers in an aqueous and oxygen rich environment.
  • the in-situ polymerization also allows for in-situ varying the physical properties of the hydrogel composition— e.g., polymerization or crosslinking of the composition after the composition has been injected into the vitreous cavity allows for additional tuning of physical properties of the hydrogel.
  • exemplary hydrogel compositions can be injected through a relatively small needle, such as 25-gauge, or smaller (e.g., 26- to 34- gauge) and form and/or reform a hydrogel after injection into a site.
  • a composition can be a hydrogel, and pass through a needle or other high shear-force delivery device, where sacrificial bonds within the composition may break. The sacrificial bonds can then reform after injection, whereby the composition can reform as a hydrogel. Additional crosslinking of the composition after injection can also occur. The additional crosslinking can be used to fine-tune desired properties, such as viscosity and elastic modulus of the composition after injection.
  • FIG. 1 illustrates an eye 100, including a lens 102, a retina 104, and a vitreous humor 106 (also referred to herein as a vitreous or vitreous material) that resides within a vitreous cavity 108.
  • vitreous humor 106 can degrade with time, disease, or trauma. In such circumstances, it may be desirable to remove and replace vitreous humor 106.
  • exemplary hydrogel compositions exhibit clarity, transparency, a refractive index, a viscosity, and/or an elastic modulus value that is the same as or similar to the respective values for a healthy vitreous.
  • a hydrogel composition includes a first polymer and a second polymer crosslinked with the fist polymer.
  • a hydrogel composition includes a first network comprising covalently bonded first polymers and a second network comprising second polymers, wherein the hydrogel comprises a sacrificial bond, selected from the group consisting of one or more of an ionic bond, an electrostatic bond, and a hydrogen bond, between one or more of the polymers of the second network and the polymers of the second network and the polymers of the first network.
  • the composition can also include water, such as deionized water, salt, such as calcium sulfate, polymerization initiators, such as APS and TEMED, described below, and/or covalent crosslinker(s), such as PEGDA 575.
  • the sacrificial bonds can be reversible, such that as the composition passes through a high shear-force delivery device (e.g., a needle having a 25-gauge or smaller needle), the sacrificial bonds break, while the covalent bonds of the hydrogel composition remain substantially intact.
  • the sacrificial bonds can then reform after injection into a site, thereby forming or reforming the hydrogel.
  • the first polymers comprise one or more polymers selected from the group consisting of acrylamides methacrylates, acrylates, allyl ether, norbornenes and vinyl ethers and other monomers containing vinyl group.
  • FIG. 2(a) illustrates ionic bonds 202 formed between first polymers (e.g., acrylamide polymers) 204.
  • the ionic bonds can include a cation 203, such as Ca 2+ from a salt.
  • the ionic bonds can be reversibly broken and illustrate one form of sacrificial bond.
  • the second polymers can include, for example, one or more of alginate (e.g., alginate derived from sodium alginate, available from Sigma-Aldrich) and chitosan.
  • FIG. 2(b) illustrates covalent bonds 206 that form between second polymers (e.g., alginate polymers) 208.
  • the covalent bonds form between side chains of the second polymer, thereby facilitating gel formation.
  • bonds 210 between the first and second polymers do cleave and therefore, the hydrogel does not undergo phase separation; thus, the hydrogel remains as an intact system. The multiple bonds fortify the hydrogel and minimize degradation of the hydrogel over time.
  • a hydrogel includes a first network comprising covalent bonds between side chains of a first polymer selected from the group consisting of acrylamides methacrylate, acrylates, allyl ether, norbornenes and vinyl ethers and other monomers containing vinyl group and second network comprising sacrificial bonds (e.g., ionic bonds) between the second polymers— e.g., selected from the group consisting of alginate and chitosan, wherein the first network and the second network form a hydrogel— e.g., are linked to form a hydrogel composition.
  • the hydrogel composition can also suitably include about 80-95 or 90-95 wt% (e.g., deionized) water, one or more salts, and/or one or more crosslinking and/or initiating system agents as noted herein.
  • methods of forming a hydrogel composition include the steps of: providing a first polymer that forms a first network comprising covalent bonds, providing a second polymer having side chains that form sacrificial bonds (e.g., ionic, electrostatic, and/or hydrogen bonds) providing a salt, providing water, providing an initiating system, mixing the first polymer, the second polymer and a first portion of the water to form a first mixture, mixing the salt, the initiating system and a second portion of the water to form a second mixture, and mixing the first mixture and the second mixture to form a hydrogel.
  • the first and second polymers can be the same as the first and second polymers noted herein.
  • Exemplary methods can additionally include a step of adding a crosslinker (e.g., PEGDA 575), such as a first polymer crosslinker to the first mixture.
  • the hydrogel includes methacrylated alginate.
  • a robust hydrogel composition can be formed by additional covalent crosslinks between the methacrylated alginate and the vinyl groups present within the hydrogel network.
  • FIGS. 5 and 6 illustrate exemplary methods of forming methacrylated alginate and a hydrogel including the methacrylated alginate.
  • the methacrylated alginate can be prepared accordingly by reacting sodium alginate with 2-aminoethyl methacrylate in the presence of N- hydroxy succinimide (NHS) and l -ethyl-3-(3-dimethylaminopropyl carbodiimide hydrochloride (EDC).
  • NHS N- hydroxy succinimide
  • EDC l -ethyl-3-(3-dimethylaminopropyl carbodiimide hydrochloride
  • An exemplary method of forming methacrylated alginate is disclosed in Jeon, O.; Bouhadir, K. H. ; Mansour, J. M. ; Alsberg, E. Biomaterials 2009, 30, 2724-2734, the contents of which are hereby incorporated herein by reference to the extent such contents do not conflict with the present disclosure.
  • a hydrogel composition including the methacrylated alginate can be prepared by mixing the positively charged methacrylated alginate with the negatively charged calcium sulfate alginate in water. Initially, the calcium sulfate and methacrylated alginate can form an ionically crosslinked network. During the injection of vitreous substitute by, for example, a 27-gauge needle, the ionic bonds break down to ease the injection procedure. Once the vitreous substitute is set in the eye, the ionic bonds are reformed and the methacrylated alginate can also be further crosslinked covalently by a UV light to form a highly crosslinked network, as illustrated in FIG. 6.
  • HOA 2-hydroxyethyl acrylate
  • PEGDA 575 Poly(ethylene glycol) diacrylate
  • methacrylated alginate and sodium alginate can be used in conjunction with methacrylated alginate and sodium alginate to change the overall properties of the vitreous substitute.
  • Examples 1 -3 [00044] To create the hydrogel, the appropriate masses of alginate and acrylamide are added to half of the amount of DI water and vortexed this system. In a separate tube, we added the appropriate masses of calcium disulfate dihydrate (CaSO4*2H20), ammonium persulfate (APS), N,N-methylenebisacrylamide (MBAA), and ⁇ , ⁇ , ⁇ ', ⁇ '- tetramethylethylenediamine (TEMED) in the remaining amount of DI water. After mixing both of these samples, we let it sit for 24 hours in a sealed tube. Various gels formed using this techniques are presented in the table below.
  • CaSO4*2H20 calcium disulfate dihydrate
  • APS ammonium persulfate
  • MBAA N,N-methylenebisacrylamide
  • TEMED ⁇ , ⁇ , ⁇ ', ⁇ '- tetramethylethylenediamine
  • hydrogels noted above were transparent, clear, and colorless.
  • the samples with 95% water appear to maintain an appearance most similar to a natural, healthy human vitreous for the longest period of time.
  • FIG. 3 illustrates elastic modulus values for the hydrogel compositions formed according to examples 1-3.
  • modifying the mass of alginate and its crosslinker affected the swelling of the hydrogel created, thus affecting the degradability of the hydrogel.
  • Altering the mass of acrylamide and its activator affected the stiffness and transparency of the hydrogel. Halving the mass of alginate (1/2 alginate) and quartering the mass of CaSO4*2H20 (1/4 CaSO4*2H20) helped the hydrogel maintain its shape and its heterogeneity. As well, reducing the acrylamide to two thirds of the normal amount (2/3 acrylamide) and its activator most closely mimicked the vitreous of a human.
  • a hydrogel composition including 95 wt% DI water, with 1/2 algin, 1/4 CaSO4*2H20, and 1/2 acrylamide was formed according to the above method.
  • a hydrogel was formed according to the following procedure: in a vial, add in 4ml of water via syringe; add the appropriate measurements of alginate, then mix via vortex and add HEA and vortex. Care was taken to not move the vial after HEA was added so bubbles would not form.
  • Example 6 The composition of Example 6 was formed using the method described above connection with Example 5.
  • Example 7 The composition of Example 7 was formed using the method described above in connection with Example 5.
  • Example 8 The composition of Example 8 was formed using the method described above in connection with Example 5.
  • FIGS. 7(a)-7(c) illustrate formulation no. 4 after inj ection of uncured sample through a 27-gauge needle. The sample is then cured under UV, between glass slides, for 5 minutes using the Omnicure 2000 series UV light source at the intensity of 320 mW/cm2.
  • FIG. 7(b) illustrates the optical clarity of cured sample while FIG. 7(c) illustrates the durability and flexibility of cured sample.
  • Exemplary hydrogels formed according to the techniques described above can pass through a 25-gauge to 32-gauge needle and form a hydrogel after injection.
  • Exemplary hydrogels have a refractive index between about 1.33 and about 1.35 or between 1.33 and 1.34.
  • exemplary hydrogels have a viscosity between about 300 cp and about 2000 cp or between 400 cp and 1800 cp.
  • the elastic modulus of the hydrogel composition can be between about 1.6 Pa and about 14.8 Pa or between 1.5 Pa and 15 Pa.
  • the specific gravity of the composition can be between about 1.0053 and about 1.0089 or between 1.006 and 1.009.
  • the hydrogels of the above examples were clear and transparent.
  • the pH of the composition can be between about 7.0 and about 7.4 or between 7 and 7.5.
  • Exemplary hydrogel composition as described herein when used as a vitreous substitute will decrease the rate of cataract formation seen with current vitrectomy and vitreous substitutes by leveraging anti-oxidant capabilities within the vitreous scaffold.
  • Methods for imparting anti-oxidant capabilities include both long-term and short-term solutions. Short-term solutions include addition of anti-oxidants such as ethyl pyruvate to the scaffold. Long-term solutions include the addition of oxygen radical scavengers to the backbone of the vitreous scaffold.
  • Drug delivery- Exemplary hydrogel compositions have chemical properties, which allow for slow release of drug to the retina, choroid, ciliary body, trabecular meshwork, lens, and cornea.
  • the drug delivery can be, for example, via molecular donating or molecular trapping.
  • Long-term tamponade agent-exemplary hydrogel compositions have the appropriate physical properties to allow for long-term tamponade of retinal breaks and retina and use of such compositions have fewer complications. This will prevent re-detachment of the retina.
  • Current vitreous substitutes are fraught with complications, as they do not match the physical characteristics of natural human vitreous. Inflammation, scar tissue formation, emulsification, and damage to retina secondary to compressive effects of the tamponade agents are common with long-term instillation of agents such as silicone oil and liquid perfluorocarbons.
  • Exemplary vitreous substitutes as described herein result in less of all of these complications due to matching of the physical properties measured in natural, healthy human vitreous.
  • compositions as described herein include the use of a composition as described herein in the manufacture of a medicament.
  • the medicament can be used for, for example, a vitreous substitute, an ocular adhesive, and/or a drug delivery system that includes a therapeutic agent.
  • a system e.g., a drug delivery system
  • a hydrogel composition as described herein and a delivery device.
  • exemplary delivery devices include syringes, such as syringes having a 25-, 26- 26s-, or 27- to 34-gauge needle.
  • a hydrogel composition comprising:
  • hydrogel comprises a sacrificial bond, selected from the group consisting of one or more of an ionic bond, an electrostatic bond, and a hydrogen bond, between one or more of the polymers of the second network and the polymers of the second network and the polymers of the first network.
  • a sacrificial bond selected from the group consisting of one or more of an ionic bond, an electrostatic bond, and a hydrogen bond, between one or more of the polymers of the second network and the polymers of the second network and the polymers of the first network.
  • hydrogel composition of example 1 further comprising water.
  • An ocular adhesive comprising the composition of any of examples 1-21.
  • a vitreous substitute comprising the composition of any of examples 1-21.
  • a drug delivery system comprising the composition of any of examples 1-21 and a therapeutic agent.
  • the therapeutic agent is selected from the group consisting of anti-fibrotic agent, anti-inflammatory agent, immunosuppressant agent, anti-neoplastic agent, migration inhibitors, anti-proliferative agent, rapamycin, triamcinolone acetonide, everolimus, tacrolimus, paclitaxel, actinomycin, azathioprine, dexamethasone, cyclosporine, bevacizumab, an anti-VEGF agent, an anti-IL-1 agent, canakinumab, an anti-IL-2 agent, viral vectors, beta blockers, alpha agonists, muscarinic agents, steroids, antibiotics, non-steroidal anti-inflammatory agents, prostaglandin analogues, ROCK inhibitors, nitric oxide, endothelin, matrixmetalloproteinase inhibitors, CNPA, corticosteroids, an antibody
  • a system comprising:
  • a method of forming a hydrogel composition comprising the steps of: providing a first polymer that forms a first network comprising covalent bonds;
  • the first polymer comprises a polymer selected from the group consisting of one or more of acrylamides methacrylate, acrylates, allyl ether, norbornenes and vinyl ethers and other monomers containing vinyl group.
  • the second polymer comprises one or more of alginate and chitosan.
  • a hydrogel composition comprising:
  • a first network comprising covalent bonds between side chains of a first polymer selected from the group consisting of acrylamides methacrylate, acrylates, allyl ether, norbornenes and vinyl ethers and other monomers containing vinyl group; and
  • a second network comprising sacrificial bonds between the second polymers selected from the group consisting of alginate and chitosan, wherein the first network and the second network are linked to form a hydrogel composition.
  • the hydrogel composition of example 37 further comprising water.
  • hydrogel composition of any of examples 37 and 38, wherein the hydrogel composition can pass through a 25-gauge needle and reform as a hydrogel.
  • hydrogel composition of any of examples 37-39, wherein the hydrogel composition has a refractive index between about 1.33 and about 1.35.
  • hydrogel composition of any of examples 37-44, wherein the elastic modulus (G ) of the composition is between 1.5 Pa and 15 Pa.
  • hydrogel composition of any of examples 38-51 wherein the water is deionized water.
  • a method of forming a hydrogel composition comprising the steps of: providing positively charged methacrylated alginate;
  • a method of treating an eye of an animal comprising the steps of:
  • a vitreous tamponade agent comprising a hydrogel composition of any of examples 1-21, 37-51 that carries surface tension and other physical properties that allow the retina to remain attached and prevent fluid from traveling through a retinal break.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Transplantation (AREA)
  • Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Engineering & Computer Science (AREA)
  • Vascular Medicine (AREA)
  • Dermatology (AREA)
  • Medicinal Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Surgery (AREA)
  • Dispersion Chemistry (AREA)
  • Cardiology (AREA)
  • Materials For Medical Uses (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne des compositions d'hydrogel et des procédés de formation et d'utilisation des compositions d'hydrogel. Des compositions d'hydrogel données à titre d'exemple sont biocompatibles et peuvent être utilisées dans diverses applications, y compris des substituts vitreux, des adhésifs et des compositions d'administration médicamenteuse. En outre, les compositions d'hydrogel données à titre d'exemple possèdent des propriétés souhaitables, telles que la transparence, l'indice de réfraction, la viscosité et le module élastique qui sont identiques ou similaires aux mêmes propriétés du corps vitré sain de l'œil.
PCT/US2015/065842 2014-12-15 2015-12-15 Hydrogels biocompatibles, systèmes comprenant les hydrogels et procédés d'utilisation et de formation associés Ceased WO2016100355A1 (fr)

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WO2020077173A1 (fr) 2018-10-12 2020-04-16 President And Fellows Of Harvard College Adhésifs résistants dégradables bio-inspirés pour diverses surfaces humides
CN113646014A (zh) * 2019-02-08 2021-11-12 俄亥俄州创新基金会 释放抗氧化剂的玻璃体替代物以及其用途
US20230414838A1 (en) * 2016-07-13 2023-12-28 Massachusetts Eye And Ear Infirmary Methods and polymer compositions for treating retinal detachment and other ocular disorders
US20240016972A1 (en) * 2019-09-20 2024-01-18 President And Fellows Of Harvard College Tough gel-based drug delivery compositions and methods thereof
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US12029829B2 (en) 2016-03-22 2024-07-09 President And Fellows Of Harvard College Biocompatible adhesives and methods of use thereof
US20230414838A1 (en) * 2016-07-13 2023-12-28 Massachusetts Eye And Ear Infirmary Methods and polymer compositions for treating retinal detachment and other ocular disorders
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CN113646014A (zh) * 2019-02-08 2021-11-12 俄亥俄州创新基金会 释放抗氧化剂的玻璃体替代物以及其用途
US20240016972A1 (en) * 2019-09-20 2024-01-18 President And Fellows Of Harvard College Tough gel-based drug delivery compositions and methods thereof
US12605480B2 (en) * 2019-09-20 2026-04-21 President And Fellows Of Harvard College Tough gel-based drug delivery compositions and methods thereof

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