Tissue adhesive for use in a treatment method in which an ophthalmological implant is implanted in a human or animal patient, and ophthalmological implantation system

Abstract

The disclosure relates to a tissue adhesive for use in a treatment method in which an ophthalmological implant is implanted in a human or animal patient and the ophthalmological implant is connected, at least partially in an integrally bonded manner, to eye tissue of the patient via the tissue adhesive. The disclosure also relates to an ophthalmological implantation system including an ophthalmological implant for implantation in a human or animal eye and to a tissue adhesive via which the ophthalmological implant is connectable, at least partially in an integrally bonded manner, to eye tissue of the patient.

Claims

1. A tissue adhesive comprising a hydrogel, wherein the tissue adhesive in an uncured state and is formed as an interpenetrating network and/or a semi-interpenetrating network, wherein the hydrogel is an active ingredient release system which comprises: (i) MeTro (methacrylated recombinant tropoelastin) prepolymer, and/or (ii) a GeIMA (methacrylated gelatin) combined with N-(2-aminoethyl)-4-(4-(hydroxymethyl)-2-methoxy-5-nitrosophenoxy)butanamide), wherein the active ingredient promotes and/or inhibits proliferation, migration, and/or differentiation of eye cells, and wherein the active ingredient is one or more of 5-fluorouracil, thapsigargin, paclitaxel, growth factors angiogenesis inhibitors, and (meth)acrylates.

2. The tissue adhesive of claim 1, wherein the active ingredient is bonded covalently to the hydrogel.

3. The tissue adhesive of claim 1, further comprising a biopolymer.

4. An ophthalmological implantation system comprising an ophthalmological implant and the tissue adhesive of claim 1, wherein the ophthalmological implant is an intraocular lens or an artificial capsular bag.

5. The tissue adhesive of claim 1, wherein the active ingredient is transforming growth factor β (TGFβ).

6. The tissue adhesive of claim 3, wherein the biopolymer comprises hyaluronic acid.

7. The tissue adhesive of claim 1, further comprising one or more hydrophilic polymers selected from alginic acid, carboxymethylcellulose, chitosan, dextran, dextran sulfate, pentosan polysulfate, carrageenan, pectin, pectin derivatives, cellulose, cellulose derivatives, glucosaminoglycans, especially hyaluronic acid, dermatan sulfate, chondroitin sulfate, dermatan sulfate, keratan sulfate, heparan sulfate, heparin, heparan sulfate, hyaluronan, agarose, starch, methylcellulose, polymannuronic acid, polyguluronic acid, polyglucuronic acid, amylose, amylopectin, callose, polygalactomannan, xanthan, poly(ethylene oxide), poly(ethylene glycol), collagen, gelatin, fibrin, fibrinogen, fibronectin, vitronectin, poly(ethylene oxide), poly(acrylic acid), poly(methacrylic acid), poly(acrylamide), polyvinylpyrrolidone, poly(amino acids); poly(amines), and poly(imines).

8. A method of implanting an ocular implant into an eye of a subject in need thereof, which comprises: providing an implant comprising a surface, providing a tissue adhesive, applying the tissue adhesive to a surface of the implant, contacting the eye of the subject with the implant surface, thereby cohesively bonding the implant to the eye of the subject, wherein the tissue adhesive comprises a hydrogel, which is in an uncured state and is formed as an interpenetrating network and/or a semi-interpenetrating network, wherein the hydrogel is an active ingredient release system which comprises: (i) MeTro (methacrylated recombinant tropoelastin) prepolymer, and/or (ii) a GeIMA (methacrylated gelatin) combined with N-(2-aminoethyl)-4-(4-(hydroxymethyl)-2-methoxy-5-nitrosophenoxy)butanamide), wherein the active ingredient promotes and/or inhibits proliferation, migration, and/or differentiation of eye cells, and wherein the active ingredient is one or more of 5-fluorouracil, thapsigargin, paclitaxel, growth factors angiogenesis inhibitors, and (meth)acrylate.

9. The method of claim 8, further comprising crosslinking the tissue adhesive.

10. The method of claim 8, wherein crosslinking is achieved by anaerobic curing, UV light-curing, anionical curing, activator-curing, moisture-curing, and/or thermal curing.

11. A tissue adhesive for use in attaching an ophthalmological implant to a human or animal patient, wherein the ophthalmological implant is at least partly cohesively bonded to the patient's eye tissue via the tissue adhesive, wherein the tissue adhesive in an uncured state is formed as an interpenetrating network and/or a semi-interpenetrating network, wherein the adhesive is provided as a composition with an active ingredient release system which is designed to release at least one active pharmacological ingredient when implanted, wherein the at least one active ingredient is designed to promote and/or inhibit at least one aspect from the group consisting of: proliferation, migration and differentiation of cells that occur in the human or the animal eye, and wherein the at least one active ingredient is selected from the group consisting of: 5-fluorouracil, thapsigargin, paclitaxel, growth factors, angiogenesis inhibitors, (meth)acrylate-modified compounds, isomers, and mixtures thereof.

12. The tissue adhesive of claim 11, wherein the adhesive is provided as a composition with an active ingredient release system designed, in the implanted state of the tissue adhesive, to release at least one active pharmacological ingredient in a controlled manner, and/or in that the tissue adhesive is provided as a composition with an active pharmacological ingredient immobilized on the tissue adhesive.

13. The tissue adhesive of claim 11, wherein the active ingredient is bonded covalently to the tissue adhesive via a (meth)acrylate group, and/or wherein the active ingredient and the tissue adhesive are in the form of the interpenetrating network.

14. The tissue adhesive of claim 11, wherein in the uncured state the adhesive is in the form of a hydrogel, the interpenetrating network, and/or the semi-interpenetrating network, and/or wherein the adhesive can be cured by at least one mechanism selected from the group consisting of: anaerobic curing, UV light-curing, anionic curing, activator-curing, moisture-curing, and thermally curing.

15. The tissue adhesive of claim 11, wherein the adhesive comprises a MeTro (methacrylated recombinant tropoelastin) prepolymer and/or a GeIMA (methacrylated gelatin)/NB (N-(2-aminoethyl)-4-(4-(hydroxymethyl)-2-methoxy-5-nitrosophenoxy)butanamide)-containing polymer, and/or wherein the adhesive comprises the adhesive comprises a MeTro (methacrylated recombinant tropoelastin) prepolymer and/or the GeIMA (methacrylated gelatin)/NB (N-(2-aminoethyl)-4-(4-(hydroxymethyl)-2-methoxy-5-nitrosophenoxy)butanamide)-containing polymer, combined with a biopolymer, wherein the biopolymer is hyaluronic acid (HA).

16. The tissue adhesive of claim 11, wherein the at least one active ingredient is TGFβ.

17. The tissue adhesive of claim 11, wherein the at least one active ingredient is bonded covalently to the tissue adhesive via a (meth)acrylate group.

18. An ophthalmological implantation system comprising an ophthalmological implant for implantation in a human or animal eye and a tissue adhesive via which the ophthalmological implant is at least partly cohesively bondable to the patient's eye tissue, wherein the tissue adhesive is as claimed in claim 11.

19. The ophthalmological implantation system of claim 18, wherein the ophthalmological implant is an intraocular lens or an artificial capsular bag.

20. The ophthalmological implantation system of claim 18, wherein the ophthalmological implant comprises, on an outside thereof, free amino groups via which the ophthalmological implant is cohesively bondable to the eye tissue via the tissue adhesive.

Description

BRIEF DESCRIPTION OF DRAWINGS

[0025] The invention will now be described with reference to the drawings wherein:

[0026] FIG. 1 shows a reaction for formation of methacrylated gelatin (GeIMA);

[0027] FIG. 2 shows a crosslinking reaction of GeIMA and modified hyaluronic acid (HA-NB) to produce a first network;

[0028] FIG. 3 shows a second network produced by crosslinking of the first network;

[0029] FIG. 4 shows a coupling reaction of thapsigargin to GeIMA;

[0030] FIG. 5 shows a coupling reaction of a (meth)acrylate-modified thapsigargin derivative to GeIMA; and,

[0031] FIG. 6 shows a basic diagram of an ophthalmological implantation system of the disclosure.

DETAILED DESCRIPTION

[0032] Hong, Y., Zhou, F., Hua, Y. et al. (A strongly adhesive hemostatic hydrogel for the repair of arterial and heart bleeds. Nat Commun 10, 2060 (2019)) discloses a hydrogel tissue adhesive which is similar to the composition of the extracellular matrix of biological connective tissue and is suitable for use in a method of treatment in which an eye lens of a human or animal patient is replaced by an ophthalmological implant and the ophthalmological implant is cohesively bonded to a capsular bag of the patient via the tissue adhesive. The method of treatment may, for example, be a cataract operation. This tissue adhesive forms a hydrogel and consists of about 5% methacrylated gelatin (GeIMA) and about 1.25% N-(2-aminoethyl)-4-(4-(hydroxymethyl) methoxy-5-nitrosophenoxy)butanamide (NB), bonded to the glycosaminoglycan hyaluronic acid (HA) (HA-NB). FIG. 1 shows a schematic of a reaction for formation of GeIMA in which gelatin is mixed with methacrylic anhydride and optionally kept at 50° C. in DPBS (Dulbecco's phosphate-buffered saline) while stirring for 48 hours. NB is in turn bound to HA and crosslinked with GeIMA in order to form a first GelMA/HA-NB network. The crosslinking reaction is started by UV photoactivation of the polymerization initiator lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP) (0.1%). The crosslinking reaction of GeIMA and modified hyaluronic acid (HA-NB) to produce a first network is shown schematically in FIG. 2.

[0033] The UV irradiation converts hydroxymethyl groups of NA to keto groups, which react with free amino groups of GeIMA to give Schiff bases, and in so doing form a second network. The resulting second network is shown schematically in FIG. 3. The resulting tissue adhesive binds strongly to moist biological tissue surfaces after UV photoactivation of the LAP.

[0034] The cytotoxin thapsigargin which is shown in FIG. 4 is an inhibitor of the calcium-ATPase inhibitor of the endoplasmic reticulum, which greatly reduces cell growth in the capsular bag at low concentrations (100 nM) and induces cell death at higher concentrations (10-100 μM). It can therefore be used in principle for prevention of PCO and fibrosis. Free thapsigargin which is released into the aqueous humor in the anterior chamber, but can damage the epithelial cell layer of the cornea.

[0035] In order to prevent uncontrolled release of thapsigargin, according to FIG. 4, the acrylate groups of thapsigargin are bound covalently to GeIMA. For this purpose, the thapsigargin is added to the aforementioned tissue adhesive, such that the thapsigargin likewise binds covalently to the GeIMA through the employment of UV and LAP, which is used for curing the tissue adhesive.

[0036] The bound thapsigargin cannot display any toxic effect because it has to get into the cells to do so. The aqueous humor of the eye contains matrix metalloproteinases, the concentration of which rises during the cataract operation owing to an elevated TGFβ level. Matrix metalloproteinases are gelatinases that digest collagens and gelatin. In the presence of these matrix metalloproteinases, thapsigargin-containing GeIMA is degraded with time, which can achieve controlled release of thapsigargin in an active ingredient release system. As a result of the incorporation into the tissue adhesive, a small amount of thapsigargin is released over an adjustable period of time only in the immediate proximity of the tissue adhesive and hence in the immediate proximity of PCO- and fibrosis-causing cells, without damaging other tissue.

[0037] It should be emphasized that it is also possible to provide other active pharmacological ingredients, which are incorporated in these or other suitable tissue adhesives, are covalently bound thereto, or form a composition therewith in some other way. The composition may be produced before, during and/or after the ultimate mixing of the tissue adhesive components and the curing by LAP/UV. The active ingredient(s) need not necessarily bind to the acryloyl groups of the tissue adhesive; alternatively or additionally, a bond to the free amino groups of the GeIMA may also be provided.

[0038] FIG. 5 shows a schematic coupling of modified thapsigargin to GeIMA. The thapsigargin in the present case is bound covalently by an acrylate group to GeIMA or to the tissue adhesive 14. This has the benefit of lower steric hindrance and a correspondingly simpler reaction regime with higher and faster conversion. For this purpose, the thapsigargin is first derivatized with methacrylic anhydride at about 50° C. for 48 hours in phosphate-buffered salt solution (DPBS—Dulbecco's Phosphate-Buffered Saline). The methacrylate group binds here to free OH groups of thapsigargin. Subsequently, the derivatized thapsigargin binds covalently via that methacrylate group to a corresponding methacrylate group in the modified gelatin (GeIMA). After the eye operation and the implantation of the implant 12, the already described degradation by matrix metalloproteinases (MMP) results in slow release of the thapsigargin in the operation region.

[0039] FIG. 6 shows a basic diagram of an ophthalmological implantation system 10 of the disclosure. The implantation system 10 includes an ophthalmological implant 12, via which the lens of a patient's eye is replaceable. The implant 12 may take the form, for example, of an accommodating intraocular lens. Alternatively, the implant 12 may also be a different type of implant, for example a non-accommodating IOL, an (optionally accommodating) IOL with one or more tactile portions or an artificial capsular bag (not shown). A suitable artificial capsular bag in which an IOL is implantable in turn is known, for example, from U.S. Pat. No. 8,900,300 B1. In addition, the implantation system 10 includes a tissue adhesive 14, via which the ophthalmological implant 12, after implantation thereof, is cohesively bondable to a patient's capsular bag. The tissue adhesive 14 may take the form as described above and be stored in a suitable pack 16 until use thereof. Alternatively, the tissue adhesive 14 may already have been applied to the implant 12. In that case, the implant 12 and the tissue adhesive 14 are preferably stored so as to prevent premature curing of the tissue adhesive 14, that is, curing during storage or before implantation.

[0040] The parameter values specified in the documents to define process and measurement conditions for the characterization of specific properties of the subject matter of the disclosure should also be considered to be encompassed by the scope of the disclosure within the scope of variances—for example due to measurement errors, system errors, weighing errors, and the like.

[0041] It is understood that the foregoing description is that of the preferred embodiments of the invention and that various changes and modifications may be made thereto without departing from the spirit and scope of the invention as defined in the appended claims.

LIST OF REFERENCE SYMBOLS

[0042] 10 implantation system [0043] 12 implant [0044] 14 tissue adhesive [0045] 16 pack