Ophthalmic implantation system with an ophthalmic implant and a tissue adhesive, as well as an ophthalmic implant

Abstract

The invention relates to an ophthalmic implantation system (10) comprising an ophthalmic implant (12) for implantation into the eye of a human or animal patient and a tissue adhesive (18) by means of which the ophthalmic implant (12) is to be connected to the patient's ocular tissue after its implantation, wherein the tissue adhesive (18) comprises aldehyde and / or keto groups which can form imines upon condensation with amino groups, and wherein the ophthalmic implant (12) has a base body (14) consisting of at least one monomer group (A) which has at least one amino group. The invention further relates to an ophthalmic implant (12) for such an ophthalmic implantation system (10).

Description

[0001] The invention relates to an ophthalmic implantation system comprising an ophthalmic implant for implantation into the eye of a human or animal patient and a tissue adhesive by means of which the ophthalmic implant is to be bonded to the patient's eye tissue after its implantation. The invention further relates to an ophthalmic implant for such an ophthalmic implantation system. State of the art

[0002] Several tissue adhesives are known that can be used to fix medical implants and create a bond, for example, between an intraocular lens (IOL) or a capsular tension ring (CTR) and the adjacent tissue, particularly the capsular bag. An implant "glued" in this way can no longer rotate or decenter, which significantly improves its stability after implantation. A cohesive bond, for example, between an ophthalmic implant and the adjacent tissue (e.g., the capsular bag), can also form a barrier to migrating cells, preventing the development of posterior capsule opacification (PCO, secondary cataract). PCO is a postoperative clouding of the lens capsule following the surgical extraction of a natural lens.The remaining lens epithelial cells (E cells) in the equatorial region of the capsular bag are mitotically active and can transform into fibroblasts. These then trigger a type of wound healing process, resulting in the formation of collagenous connective tissue. Since some fibroblast subtypes not only migrate to the inner surface of the capsular bag but can also contract, wrinkling occurs within the capsular bag. The clouding of the capsule is thus a consequence of a wound healing process and the associated scarring. Because the resulting lens opacity has a different cause than the original cataract, it is referred to as a "posterior capsule opacification" or "secondary cataract." Clinically significant posterior capsule opacification can lead to a reduction in visual acuity, color perception, and contrast sensitivity, as well as increased glare sensitivity.

[0003] Similarly, for example, a CTR can be glued into the equatorial region of the capsular bag to embed the lens epithelial cells (LEC) and prevent their transformation into fibroblasts.

[0004] Furthermore, with various accommodative intraocular lens (AIOL) designs, it is advantageous to fix at least part of such an ophthalmic implant to the inner surface of the capsular bag using tissue adhesive in order to improve or even enable accommodative functionality. Here, too, it is important to prevent the development of polycystic ovary syndrome (PCO) or fibrosis from the remaining cells of the capsular bag prepared for IOL implantation, so as not to impair the functionality of the IOL, especially an accommodative IOL, and thus the patient's vision.

[0005] Finally, tissue adhesive can also be used to create capsulorhexis. For this purpose, a so-called patch of a defined size can be glued onto the capsular sac and then torn off to create a defined rhexis.

[0006] In all these approaches, a strong and reliable connection between the ophthalmic implant and the tissue is crucial. Description of the invention

[0007] The object of the present invention is to provide an ophthalmic implantation system that ensures a strong and reliable connection between an ophthalmic implant and the surrounding tissue after implantation. A further object of the invention is to provide a suitable ophthalmic implant for such an ophthalmic implantation system.

[0008] The problems are solved according to the invention by an ophthalmological implantation system according to claim 1 for use in a treatment method in which an ophthalmological implant is implanted into a human or animal patient, and by an ophthalmological implant according to claim 5 for such an implantation system. Advantageous embodiments with expedient configurations of the invention are specified in the respective dependent claims, wherein advantageous configurations of each aspect of the invention are to be regarded as advantageous configurations of the other aspects of the invention.

[0009] A first aspect of the invention relates to an ophthalmic implantation system comprising an ophthalmic implant for implantation into the eye of a human or animal patient and a tissue adhesive by means of which the ophthalmic implant is to be bonded to the patient's ocular tissue after implantation. According to the invention, a strong and reliable bond between the ophthalmic implant and the surrounding tissue after implantation is ensured by the fact that the tissue adhesive comprises aldehyde and / or keto groups which can form imines upon condensation with amino groups, and that the ophthalmic implant has a base body consisting of at least one monomer group (A) which has at least one amino group.In other words, according to the invention, the tissue adhesive and the ophthalmic implant of the implantation system are designed to react covalently with each other to form Schiff bases, thus creating a stable, metallurgical bond. For this purpose, the tissue adhesive has aldehyde and / or keto groups, while the ophthalmic implant has a base body that consists partially or completely of monomers of monomer group A), each of which has one or more amino groups. The general condensation reaction is shown by way of example using an amino and a keto compound in formula (I):

[0010] The tissue adhesive can therefore react with the amino groups of the implant body on the one hand, and with amino groups of the surrounding tissue on the other, primarily with lysine, forming covalent bonds. This ensures a correspondingly stable, covalent bond between the implant and the surrounding tissue. This reliably prevents problems frequently encountered during treatment procedures, such as decentration, tilting, rotation, or detachment of the implant. The possibility of this covalent bond between the implant and the ocular tissue using the tissue adhesive reliably prevents the infiltration of the implant by lens epithelial cells and the like.Any lens epithelial cells and other cell types that may remain in the eye after surgery can no longer cause polycystic ovary syndrome (PCOS), fibrosis, or similar complications that could impair the vision and functionality of an implant, such as an intraocular lens (IOL), particularly an accommodating IOL, or an artificial capsular bag. Preferably, the amino groups are present not only on the surface of the base body but throughout its entire surface. This is particularly advantageous when the base body is manufactured from a semi-finished product using a separation process, such as turning or machining from a blank, because in this case, without further processing of the base body, it is always ensured that it presents amino groups on its surface, enabling the described reaction with the tissue adhesive.In preferred embodiments, the base body therefore has no coating bonded to it, in particular no coating containing amino groups and not removable without damage. Depending on the embodiment, the ophthalmic implant can have an optical part and a haptic part, which may be made of the same or different materials. In this case, it may be provided that only the optical part, or preferably only the haptic part, contains monomer groups of type A). The ophthalmic implant can also be generally hydrophobic or hydrophilic and / or hydrated or hydratable. The tissue adhesive can generally be applied to the entire surface of the ophthalmic implant or only to a part of the surface, in particular only to a part of the surface that contains free amino groups.For example, an IOL can be coated with tissue adhesive only in the peripheral region of its optical area or only in a haptic area and glued into the capsular bag of the patented device to form a tight seal around the optical part and to keep the posterior capsular bag free of cells. The ophthalmic implant and the tissue adhesive are preferably packaged separately to prevent premature reaction and to increase shelf life. The two packages are, in turn, preferably packaged together in a common outer packaging for the ophthalmic implantation system so that they can be used together as a kit and to avoid confusion. Generally, "a / an" in this disclosure is to be read as an indefinite article, i.e., unless expressly stated otherwise, always also as "at least one / at least one". Conversely, "a / an" can also be understood as "only one / only one".Within the context of this disclosure, the term "comprise" is generally to be interpreted as meaning that the relevant features are included, but the presence of other features is not excluded. Conversely, within the context of this disclosure, the term "comprise" can also be interpreted as "consisting of" or "consisting essentially of," meaning that, in addition to the features mentioned following this formulation, no further features ("consisting of") can be present, or that certain further features can be present, namely those that do not significantly alter the essential features of the invention ("consisting essentially of").

[0011] In an advantageous embodiment of the invention, the amino groups of monomer group A) are at least partially protected by at least one amino protecting group, wherein the amino protecting group is preferably selected from 9-fluorenylmethylcarbamate (FMOC), t-butylcarbamate (Boc), benzylcarbamate (Cbz / Z), acetamide (Ac), trifluoroacetamide, phthalimide, benzylamine (Bn), triphenylmethylamine (tritylamine, Tr), benzylideneamine, p-toluenesulfonamide (tosylamide, Ts), or a mixture thereof. In other words, it is provided that some or all of the existing amino groups are initially protected by a protecting group. A protecting group is a substituent that is introduced into a molecule to temporarily protect a specific functional group and prevent unwanted reactions at that group. The protecting group can then be cleaved off once its function is no longer required.By at least partially protecting the amino groups of the ophthalmic implant with a protecting group, potential problems of monomer group A) regarding its chemical composition and possible charge, depending on the polymerization method chosen and the properties of any comonomers used in the production of the base body, can be avoided. To achieve a high polymerization rate and prevent interference with other chemical manufacturing steps, the amino group-containing monomers A) can thus be used in a protected form and, after polymerization, reactivated at least on the surface of the base body by partially or completely removing the protecting group(s). Alternatively or additionally, the durability and shelf life of the ophthalmic implant can also be advantageously increased by partially or completely removing the protecting group(s) only during the implantation procedure.This occurs shortly beforehand. This also helps to avoid unwanted or premature reactions of the amino groups. The choice of protecting group depends primarily on the desired stability and the conditions under which it is cleaved.

[0012] In a further advantageous embodiment of the invention, the ophthalmic implantation system further comprises cleaving agents for the partial or complete cleaving of the at least one amino protecting group. This allows all components required for the intended use of the ophthalmic implant to be contained within or provided by the implantation system. The cleaving agent(s) are preferably tailored to the protecting group(s). For example, Boc can be cleaved by 2,2,2-trifluoroacetic acid, CBz can be cleaved by hydrogenation with Pd-C, and FMOC can be cleaved by piperidine or other bases. Further cleaving agents and the respective required reaction conditions are described, for example, in T.W. Green, P.M. Wuts, Protective Groups in Organic Synthesis (Wiley-Interscience, New York, 1999, 503-507, 736-739).

[0013] Further advantages arise from the tissue adhesive comprising a MeTro (methacrylated recombinant tropoelastin) prepolymer and / or a GelMA (methacrylated gelatin) / HA-NB (N-(2-aminoethyl)-4-(4-(hydroxymethyl)-2-methoxy-5-nitrosophenoxy)butanamide)-containing polymer. This results in a highly elastic, strongly adhesive, and biocompatible tissue adhesive that adheres well to the soft tissue of the capsular bag. The preparation of a suitable MeTro prepolymer is generally known, for example, from Annabi et al. (“Engineering a highly elastic human protein-based sealant for surgical applications”, Sci. Transl. Med. 9, eaai7466 (2017)). MeTro prepolymers can be synthesized using recombinant human tropoelastin and methacrylic anhydride. For example, MeTro prepolymers with a methacryloyl substitution degree of 54% (low), 76% (medium) and 82% (high) can be synthesized using 8, 15 and 15 respectively.20% (v / v) methacrylic anhydride can be synthesized. However, different weight and volume fractions are also possible. The resulting MeTro hydrogels can then be photocrosslinked with UV light (6.9 mW / cm²). 2The tissue adhesive can be cured at 360 to 480 nm for various exposure times of 30 to 180 s. For example, [2-Hydroxy-1-(4-(Hydroxyethoxy)phenyl)-2-methyl-1-propanone (Irgacure 2959); 0.5% w / v] can be used as a photoinitiator. Alternatively or additionally, the tissue adhesive can comprise or consist of a polymer containing GelMA (methacrylated gelatin) / NB (N-(2-aminoethyl)-4-(4-(hydroxymethyl)-2-methoxy-5-nitrosophenoxy)butanamide). This is a photoreactive polymer that mimics the composition of the extracellular matrix (ECM). This matrix hydrogel, also based on biomacromolecules, can be rapidly cured after UV irradiation to bond the implant to the capsular bag. This polymer can additionally be bonded to a hydrophilic polymer by means of up to 0.1% or more of a polymerization initiator, for example lithium phenyl 2,4,6-trimethylbenzoylphosphinate (LAP).which is preferably selected from a group comprising alginic acid, carboxymethylcellulose, chitosan, dextran, dextran sulfate, pentosan polysulfate, carrageenan, pectin, pectin derivatives, cellulose, cellulose derivatives, glucosaminoglycans, in particular 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 gum, 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(amine), Poly(imine),a mixture thereof and / or copolymers thereof and / or pharmacologically acceptable salts thereof. For example, the hydrophilic polymer may be hyaluronic acid (HA). A suitable tissue adhesive and its preparation are known, for example, from 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)) (see pages 7-9, Methods). For example, the tissue adhesive may comprise 1%-10%, in particular 5%, methacrylated gelatin (GelMA) and 0.5%-3%, in particular 1.25%, N-(2-Aminoethyl)-4-(4-(hydroxymethyl)-2-methoxy-5-nitrosophenoxy)butanamide (NB), wherein the NB is bound to HA via LAP (HA-NB). Generally, percentages given in this disclosure are to be understood as mass percentages unless otherwise stated.

[0014] A second aspect of the invention relates to an ophthalmic implant for an ophthalmic implantation system of the first aspect of the invention. The ophthalmic implant has a base body consisting of at least one monomer group A) which has at least one amino group. In other words, according to the invention, the ophthalmic implant of the implantation system is designed to react covalently with the tissue adhesive of the ophthalmic implantation system, forming Schiff bases and thus creating a stable, metallurgical bond. For this purpose, the ophthalmic implant has a base body that consists partially or completely of monomers of monomer group A), each of which has one or more amino groups.This enables the implant according to the invention, in conjunction with the tissue adhesive of the ophthalmic implantation system, to form a strong and reliable bond with the surrounding tissue after implantation. Further features and their advantages can be found in the descriptions of the first aspect of the invention, whereby advantageous embodiments of the first aspect of the invention are to be regarded as advantageous embodiments of the second aspect of the invention and vice versa.

[0015] In an advantageous embodiment of the invention, the base body consists at least predominantly or entirely of aliphatic and / or aromatic poly(meth)acrylate (co)monomers. For the purposes of this disclosure, the term (meth)acrylate generally refers to acrylates, methacrylates, and any mixtures thereof. This allows the material properties of the base body or implant, such as water absorption capacity, refractive index, solvation tendency, deformability, etc., to be optimally adapted to the respective application.

[0016] Further advantages arise from the fact that monomer group A) is, or forms after polymerization, a highly branched polymer with at least two amino groups. Highly branched polymers are polymeric structures characterized by a branched structure and high functionality, i.e., in this case, a high density of functional amino groups. Preferably, monomer group A) is, or forms, a dendrimer, a star polymer, a comb polymer, a structurally and molecularly heterogeneous highly branched polymer, or a so-called "starburst" or "hyperbranched polymer." For a definition of highly branched polymers, reference is made to P.J. Flori, J. Am. Chem. Soc., 1952, 74, 2718, and H. Frey et al., Chem. Eur. J., 2000, 6, No. 14, 2499.In the present embodiment, the high-polymer monomer group A) therefore has a polyamine functionality, which provides a correspondingly large number of points of attack for the tissue adhesive and enables a correspondingly strong, multicovalent bond between the tissue adhesive and the implant.

[0017] Alternatively or additionally, it is provided that the monomer group A) is selected from aminoalkyl(meth)acrylate, (aminoalkoxy)alkyl(meth)acrylate, N-(aminoalkyl)-N-benzyl(meth)acrylamide, N,N-bis-(aminoalkyl)(meth)acrylamide, N-(aminoalkyl)(meth)acrylamide hydrochloride, aminoalkyl(meth)acrylate hydrochloride, aminobenzyl(meth)acrylate, and mixtures thereof, wherein the alkyl groups are each independently selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, and octyl. Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl are particularly preferred within the scope of this disclosure. Furthermore, salts, especially hydrochlorides, as well as enantiomers and positional isomers of all the aforementioned compounds are generally to be considered included, insofar as this is structurally possible.The monomer group A) may preferably be 2-aminoethyl(meth)acrylate, 2-(aminomethoxy)ethyl(meth)acrylate, 2-(aminoethoxy)ethyl(meth)acrylate, 2-(aminoethoxy)methyl(meth)acrylate, N-(2-aminoethyl)-N-benzyl(meth)acrylamide, N-(2-aminomethyl)-N-benzylmethacrylamide, N,N-bis-(2-aminoethyl)methacrylamide, N-(3-aminopropyl)methacrylamide hydrochloride, 2-aminoethylmethacrylate hydrochloride, o-aminobenzylmethacrylate, m-aminobenzylmethacrylate, p-aminobenzylmethacrylate or any mixture thereof.

[0018] In a further advantageous embodiment of the invention, the ophthalmic implant comprises at least one further monomer group B) without amino groups, which is preferably selected from hydroxyalkyl(meth)acrylate, alkoxyalkyl(meth)acrylate, N-benzyl-N-isopropylacrylamide, N-benzyl-N-hydroxyalkyl(meth)acrylamide, N-(hydroxyalkyl)(meth)acrylamide, (alkylamino)alkyl(meth)acrylate, and mixtures thereof, wherein the alkyl groups are each independently selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, and octyl. Particularly preferred within the scope of the present disclosure are also, in general, methyl, ethyl, and / or propyl with respect to monomer group B) (or copolymer group B)).The monomer group B) can therefore be, in particular, 2-hydroxyethyl(meth)acrylate, 2-(hydroxymethoxy)ethyl(meth)acrylate, 2-(hydroxyethoxy)ethyl(meth)acrylate, 2-(hydroxyethoxy)methyl(meth)acrylate, N-(2-hydroxyethyl)-N-benzyl(meth)acrylamide, N-(2-hydroxymethyl)-N-benzylmethacrylamide, N-(2-hydroxypropyl)methacrylamide, 2-(tert-butylamino)ethylmethacrylate, or any mixture thereof. The compounds of monomer group B) preferably contain at least one secondary or tertiary amino group and / or one hydroxy group as functional group(s).

[0019] In a further advantageous embodiment of the invention, the proportion of monomer group A) in the total weight of the base body is between 0.5 wt.% and 50 wt.%, particularly between 2 wt.% and 10 wt.%. In other words, the base body consists not only of monomer group A), but of at least one further (co)monomer group (e.g., monomer group B)), wherein monomer group A) constitutes at most 50 wt.% of the total weight of the base body. Proportions between approximately 2 wt.% and 10 wt.% are particularly preferred. This can be achieved, for example, by replacing a corresponding proportion of a hydroxy monomer with a corresponding amino monomer.

[0020] In a further advantageous embodiment of the invention, the ophthalmic implant is designed as an intraocular lens, in particular as an accommodating intraocular lens, as a capsular tension ring, or as an artificial capsular bag. Monofocal intraocular lenses (IOLs) have a regular radius of curvature over their entire surface and consequently have the same refractive power at all points. They are considered the standard treatment in cataract surgery, i.e., the treatment of cataracts, so that the advantages of the implant or implantation system according to the invention can be realized in a particularly large number of patients. However, the ophthalmic implant can also be designed as an aspheric intraocular lens, a multifocal intraocular lens, a toric intraocular lens, a phakic intraocular lens, or an accommodating intraocular lens.Accommodating intraocular lenses (AIOLs) can additionally change their refractive power and, through this accommodative ability, at least substantially compensate for the loss of function of the natural lens. Without the implantation of an IOL into the empty capsular bag, the risk of posterior capsule opacification (PCO) is even increased, since in this case unimpeded cell migration to the posterior surface of the capsular bag is possible. Within the scope of this disclosure, the terms IOL and AIOL are used synonymously for a lens implant. An IOL according to the invention can be glued completely or only partially into the capsular bag in the peripheral region using tissue adhesive in order to form a tight rim around the optical part and to keep the posterior capsular bag free of cells. An embodiment as a capsular tension ring is suitable for stabilizing the capsular bag in cases of weakened or damaged zonular fibers.A design as an artificial capsular bag also allows for support and stabilization of an artificial lens if required.

[0021] Further features of the invention are evident from the claims, the figures, and the description of the figures. The features and combinations of features mentioned above in the description, as well as those subsequently mentioned in the description of the figures and / or shown in the figures alone, are not only usable in the combinations specified, but also in other combinations without departing from the scope of the invention. Thus, embodiments that are not explicitly shown and explained in the figures, but which can be derived and generated from the explained embodiments by separate combinations of features, are also to be considered as encompassed and disclosed by the invention. Embodiments and combinations of features that do not exhibit all the features of an originally formulated independent claim are also to be considered disclosed.Furthermore, embodiments and combinations of features, in particular those set out above, are to be considered disclosed which go beyond or deviate from the combinations of features set out in the cross-references of the claims. This shows: Fig. 1 a schematic representation of an ophthalmic implantation system according to the invention; Fig. 2 a cross-linking reaction of GelMA and modified hyaluronic acid (HA-NB) to produce a first network; and Fig. 3 a second network of a fabric adhesive produced by cross-linking the first network. Preferred embodiment of the invention

[0022] Fig. Figure 1 shows a schematic diagram of an ophthalmic implantation system 10 according to the invention. The ophthalmic implantation system 10 comprises an ophthalmic implant 12, which in this case is configured as an intraocular lens and consists of a base body 14 that forms an optical component. The ophthalmic implant 12 is packaged in an optional packaging 16. Furthermore, the ophthalmic implantation system 10 comprises a tissue adhesive 18, which is stored in an optional applicator 20. All of the aforementioned elements are in turn packaged in a common, also optional, outer packaging 22.

[0023] According to an embodiment of an ophthalmic implant 12 according to the invention, a mixture of a monomer group A) and a monomer group B) is produced and polymerized to form a lens blank in a manner known per se. The monomer group A) is selected from the following compounds with at least one primary amino group or is a mixture of the aforementioned compounds, which are suitable for the formation of Schiff bases:

[0024] Although essentially only methacrylates are shown, the present disclosure may generally include methacrylates, acrylates, or mixtures thereof. Therefore, these compounds and mixtures are also subsumed under the term "(meth)acrylates." The same applies to all disclosed acrylamides and methacrylamides, which are also subsumed under the term "(meth)acrylamides."

[0025] The length of the alkyl groups in the aforementioned compounds can also deviate from n=2 (ethyl) to fine-tune the properties. For example, a portion of N-benzyl-N-aminomethyl(meth)acrylamide (n=1), N-benzyl-N-aminopropyl(meth)acrylamide (n=3), N-benzyl-N-aminobutyl(meth)acrylamide (n=4), etc., could also be used, encompassing all possible positional isomers such as isopropyl, sec-butyl, and isobutyl. The same applies to the other amino(meth)acrylates mentioned.

[0026] Monomer group B) is selected from the compounds 2-hydroxyethyl(meth)acrylate (HEA / HEMA), 2-ethoxyethyl(meth)acrylate (EOEA / EOEMA), N-benzyl-N-isopropyl(meth)acrylamide (BIPA), N-benzyl-N-hydroxyethyl(meth)acrylamide (BHEA), N-(2-hydroxypropyl)(meth)acrylamide, 2-(tert-butylamino)ethyl methacrylate, or a mixture thereof, although other monomers may also be used. Some of the compounds mentioned are given as examples:

[0027] It can be seen that the preferred compounds have a secondary or tertiary amino group and / or a hydroxy group as functional groups.

[0028] In hydrophilic biomaterials, which currently consist of HEMA and optionally one or more comonomers such as EOEMA, structurally similar, amine-containing monomers A) such as AEMA and AOEMA are also preferably used. Known mixtures can be used as a starting point, in which a portion of the conventional monomers is then replaced by a structurally similar monomer from group A). ​​For example, a portion of HEMA can be replaced by AEMA and / or a portion of EOEMA by AOEMA. In this way, the respective amine-containing monomers can be added in desired quantities without significantly altering the other material properties, such as water absorption or refractive index.

[0029] Aromatic acrylamide monomers such as N-benzyl-N-isopropylacrylamide (BIPA) or N-benzyl-N-hydroxyethylacrylamide (BHEA) are frequently used in hydrophobic biomaterials. These monomers combine a high refractive index with excellent mechanical stability. To maintain the same performance in a hydrophobic material but improve the affinity for a tissue adhesive containing aldehyde and / or keto groups, these monomers can also be wholly or partially replaced by a corresponding, amino-group-bearing monomer of group A), for example, N-benzyl-N-aminoethylacrylamide (BAEA).

[0030] Due to their chemical properties and potential charge, the described amino monomers A) often cannot be used directly, depending on the polymerization method and conditions. To achieve a high polymerization rate and avoid interfering with other chemical manufacturing steps, the monomers of group A) can therefore be initially protected and, after polymerization, reactivated by deprotection, at least on the surface of the resulting lens blank or base body 14, in order to react with the tissue adhesive 18 as intended. Suitable protecting groups include, for example, 9-fluorenylmethylcarbamate (FMOC), t-butylcarbamate (Boc), benzylcarbamate (Cbz / Z), acetamide (Ac), trifluoroacetamide, phthalimide, benzylamine (Bn), triphenylmethylamine (tritylamine, Tr), benzylideneamine, p-toluenesulfonamide (tosylamide, Ts), or a mixture thereof.A release agent for deprotection may be included in the implantation system 10 if necessary.

[0031] In addition to monomer groups A) and B), a UV absorber known per se or a mixture of UV absorbers is preferably used, at least in the case of IOLs. Generally, a crosslinker is also preferably used, which crosslinks the starting monomers A) and B) (and optionally the UV absorber) in a manner also known per se, in order to combine the comonomers A) and B) into a three-dimensional network. Ethylene glycol dimethacrylate (EGDMA), for example, can be used as a crosslinker, but other crosslinkers are also conceivable. The proportion of crosslinker based on the total weight of the mixture to be polymerized is typically about 0.5 to 2.0 wt.%.

[0032] In conventional monomer mixtures for hydrophilic materials, the proportion of HEMA in the copolymer of the lens material or an optical lens component is usually between approximately 70 and approximately 95 wt.%. According to the invention, a portion of the HEMA is replaced, as described above, by an amine-containing monomer of group A) until a proportion of approximately 2 to 10 wt.% of monomer A) is obtained, based on the total weight of the lens material. In principle, however, higher or lower proportions of monomers of group A) can also be used, with a weight proportion of approximately 50% generally being sufficient.

[0033] The lens blank can then be produced in the usual manner. For this purpose, the comonomer mixture A) and B), optionally with crosslinker and / or UV absorber, is placed in a polymerization mold and subsequently polymerized. The polymer is removed from the mold, after which the individual lens blanks are cut and formed into the final ophthalmic implant 12, for example by turning. Since the entire polymer material contains amino groups, amino groups are inevitably exposed on the surface of the ophthalmic implant 12, and these may, as already mentioned, require further deprotection. The implant 12 can contain water or be stored in water. Functional groups of a tissue adhesive 18 can react with the amino groups of the material according to the invention to form covalent bonds.

[0034] Depending on the design, the base body 14 of the resulting ophthalmic implant 12 can have only an optical part, only a haptic part, or at least one optical part and at least one haptic part. In the latter case, the optical and haptic parts can be made of the same material or polymer, or of different materials or polymers. Preferably, at least one haptic part of the base body 14 has monomer blocks of group A) to ensure a stable bond with the adjacent tissue (lysine) via the tissue adhesive 18. An optical part may have monomers of group A), but this is not mandatory.

[0035] A suitable tissue adhesive 18 generally has aldehyde and / or keto groups which can form imines (Schiff bases) with the amino groups of the implant 12 through condensation. A hydrogel tissue adhesive 18 is known from 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)). This hydrogel tissue adhesive is similar in composition to the extracellular matrix of biological connective tissues and is suitable for use in a treatment procedure in which the lens of a human or animal patient is replaced by the ophthalmic implant 12 and the ophthalmic implant 12 is bonded to the patient's capsular bag using the tissue adhesive 18. The treatment procedure could, for example, be cataract surgery.This tissue adhesive 18 forms a hydrogel and consists of approximately 5% methacrylated gelatin (GelMA) and approximately 1.25% N-(2-Aminoethyl)-4-(4-(hydroxymethyl)-2-methoxy-5-nitrosophenoxy)butanamide (NB) linked to the glycosaminoglycan hyaluronic acid (HA) (HA-NB).

[0036] The following reaction equation (II) schematically shows a formation reaction of GelMA in which gelatin is mixed with methacrylic anhydride and, if necessary, kept at 50 °C in DPBS (Dulbecco's phosphate-buffered saline) for 48 hours while stirring.

[0037] NB is in turn bound to HA and crosslinked with GelMA to form an initial GelMA / HA-NB network. The crosslinking reaction is initiated by UV photoactivation of the polymerization initiator lithium phenyl 2,4,6-trimethylbenzoylphosphinate (LAP) (0.1%). The crosslinking reaction of GelMA and modified hyaluronic acid (HA-NB) to produce an initial network is shown schematically in Fig. 2 shown.

[0038] Upon UV irradiation, hydroxymethyl groups of NA are converted into keto groups, which react with free amino groups of GelMA to form Schiff bases, thereby creating a second network. The resulting second network is in Fig. Figure 3 is shown schematically. The resulting tissue adhesive 18 bonds strongly to moist biological tissue surfaces after UV photoactivation of the LAP as well as to the implant 12 according to the invention.

[0039] The parameter values ​​specified in the documents for defining process and measurement conditions for characterizing specific properties of the subject matter of the invention are also to be considered as included in the scope of the invention in the event of deviations - for example due to measurement errors, system errors, weighing errors and the like. Reference symbol list 10 ophthalmological implantation system 12 ophthalmic implant 14 basic shapes 16 Packaging 18 Fabric adhesives 20 Applicator 22 Outer packaging QUOTES INCLUDED IN THE DESCRIPTION

[0000] This list of documents cited by the applicant was automatically generated and is included solely for the reader's convenience. The list is not part of the German patent or utility model application. The DPMA accepts no liability for any errors or omissions. Cited non-patent literature

[0000] TW Green, PGM Wuts, Protective Groups in Organic Synthesis (Wiley-Interscience, New York, 1999, 503-507, 736-739

[0012] Annabi et al. (“Engineering a highly elastic human protein-based sealant for surgical applications”, Sci. Transl. Med. 9, eaai7466 (2017

[0013] 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)) bekannt (vgl. Seite 7-9, Methods

[0013] PJ. Flori, J. Am. Chem. Soc, 1952, 74, 2718

[0016] H. Frey et al., Chem. Eur. J., 2000, 6, Nr. 14, 2499

[0016] 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

[0035]

Claims

[1] Ophthalmic implantation system (10), comprising an ophthalmic implant (12) for implantation into the eye of a human or animal patient and a tissue adhesive (18) by means of which the ophthalmic implant (12) is to be connected to the patient’s eye tissue after its implantation, characterized by , that the tissue adhesive (18) comprises aldehyde and / or keto groups which can form imines with amino groups by condensation, and that the ophthalmic implant (12) has a base body (14) which consists of at least one monomer group A) which has at least one amino group. [2] Ophthalmic implantation system (10) according to claim 1, characterized by, that the amino groups of monomer group A) are at least partially protected by at least one amino protecting group, wherein the amino protecting group is preferably selected from 9-fluorenylmethylcarbamate (FMOC), t-butylcarbamate (Boc), benzylcarbamate (Cbz / Z), acetamide (Ac), trifluoroacetamide, phthalimide, benzylamine (Bn), triphenylmethylamine (tritylamine, Tr), benzylideneamine, p-toluenesulfonamide (tosylamide, Ts) or a mixture thereof. [3] Ophthalmic implantation system (10) according to claim 2, characterized by that this further comprises cleaving agents for the partial or complete cleaving of at least one amino protecting group. [4] Ophthalmic implantation system (10) according to any one of claims 1 to 3, characterized by, that the tissue adhesive (18) comprises a MeTro (methacrylated recombinant tropoelastin) prepolymer and / or a GelMA (methacrylated gelatin) / NB (N-(2-aminoethyl)-4-(4-(hydroxymethyl)-2-methoxy-5-nitrosophenoxy)butanamide)-containing polymer, which is preferably combined with a biopolymer, in particular with hyaluronic acid (HA). [5] Ophthalmic implant (12) for an ophthalmic implantation system (10) according to one of claims 1 to 4, characterized by , that the ophthalmic implant (12) has a base body (14) which consists of at least one monomer group A) which has at least one amino group. [6] Ophthalmic implant (12) according to claim 5, characterized by , that the base body (14) consists at least predominantly or entirely of aliphatic and / or aromatic poly(meth)acrylate (co)monomers. [7] Ophthalmic implant (12) according to claim 5 or 6, characterized by, that the monomer group A) is a highly branched polymer with at least two amino groups and / or that the monomer group A) is selected from aminoalkyl(meth)acrylate, (aminoalkoxy)alkyl(meth)acrylate, N-(aminoalkyl)-N-benzyl(meth)acrylamide, N,N-bis-(aminoalkyl)(meth)acrylamide, N-(aminoalkyl)(meth)acrylamide hydrochloride, aminoalkyl(meth)acrylate hydrochloride, aminobenzyl(meth)acrylate and mixtures thereof, wherein alkyl groups are each independently selected from methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl and octyl. [8] Ophthalmic implant (12) according to any one of claims 5 to 7, characterized by, that this comprises at least one further monomer group B) without amino groups, which is preferably selected from hydroxyalkyl(meth)acrylate, alkoxyalkyl(meth)acrylate, N-benzyl-N-isopropylacrylamide, N-benzyl-N-hydroxyalkyl(meth)acrylamide, N-(hydroxyalkyl)(meth)acrylamide, (alkylamino)alkyl(meth)acrylate and mixtures thereof, wherein alkyl groups are each independently selected from methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl and octyl. [9] Ophthalmic implant (12) according to any one of claims 5 to 8, characterized by , that the proportion of the monomer group A) in the total weight of the base body (14) is between 0.5 wt.- and 50 wt.-, in particular between 2 wt.- and 10 wt.-. [10] Ophthalmic implant (12) according to any one of claims 5 to 9, characterized by that this is designed as an intraocular lens, as a capsular tension ring or as an artificial capsular bag.

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