CN109789241A - The hydrogel of tunable optical and biosimulation intraocular lens - Google Patents

Abstract

A kind of biosimulation is implantable crystalline lens (" BIOL "), after natural lens NCL is removed and BIOL implantation camera oculi posterior is placed into the pouch that NCL is vacateed, can substitute every basic function of natural lens (NCL).Lenticular at least rear surface has convex shape and is made of transparent flexible hydrogel material.At least preceding optical surface and rear optical surface are to be limited by one or more conic sections along primary optical axis rotation, and included the plane perpendicular to axis and passed through axisymmetric conical surface by rotating the surface that limits.A kind of implantable crystalline lens of hydrogel, optical parameter can be optimized and/or be customized by control absorption of electromagnetic radiation, to change the infractive index of the hydrogel through irradiating.

Description

The hydrogel of tunable optical and biosimulation intraocular lens

Cross reference to related applications

This application claims the priority for the U.S. Application No. 15/190715 submitted on June 23rd, 2016, this application be in (it is in the international application submitted on December 12nd, 2013 to the Application U.S. Serial No 14/760868 that on July 14th, 2015 submits The American National stage of number PCT/IB2013/060869, it is desirable that in the U.S. Provisional Application No. 61/ that on January 15th, 2013 submits 752685 benefit of priority) part continuation application.The full content of all above-mentioned applications passes through reference herein and is integrally incorporated Herein.

Technical field

The present invention relates to a kind of hydrogel implantable ophthalmic crystalline lens, optical parameter can absorb electromagnetism spoke by control It penetrates to optimize and/or customize, such as the laser emission in visible light and/or near infrared region, it is more specifically more shorter than 1 nanosecond The radiation that pulse (referred to as femtosecond laser, FSL) issues changes so as to cause the infractive index of the hydrogel through irradiating.

Background technique

Intraocular lens (IOL) are the crystalline lens of implantation of can performing the operation, the optical function of substituted or supplemented NCL.White interior In the case where barrier, or recently in the case where farsightedness, so-called " posterior chamber intraocular lenss " or PC IOL pass through so-called " transparent crystal replacement operation " or CLE substitute NCL.Other implantable crystalline lenses be put into camera oculi anterior (AC IOL), cornea (cornea or Matrix implant) or be put between NCL and iris (so-called " implantable contact lenses " or ICL).Up to the present, greatly These IOL of majority are only designed for the basic optical function of substituted or supplemented NCL.It should be understood that describe as shown in figure 1, in human eye NCL be the labyrinth with multiple function.Main eye position include cornea 101, iris 102, NCL103, rear capsule 104, Ciliary muscle 105, small band 106, vitreum 107 and retina 108.

The basic optical function of NCL103 includes that cornea 101 is helped to focus incident light, and the object of distant place is projected On retina 108.Another important optical function is to adjust --- lenticular optical function is adjusted, so that different distance Object can project on retina 108.There are many theoretical explanation adjustment mechanisms.See, for example, L.Werner etc., Physiology of Accommodation and Presbyopia,ARQ.BRAS.OFTALMOL.63(6),DEZEMBRO/ 2000-503。

Most firm theory is von Helmholtz theoretical, is thought, referring to Fig.1, the ciliary muscle 105 loosened causes small Band 106 is tensioned, and 103 periphery of crystalline lens is pulled outwardly so that NCL103 keeps it to deform (flat) shape, to provide suitable remote Depending on low refractive power.Focusing near objects is to make the relaxation of small band 106 caused by being tensioned by ciliary muscle 105 and obtain NCL103 Its " natural " configuration (in front with all there is smaller diameter on back, bigger center thickness and smaller curvature are partly Diameter).Which increase the refractive power of NCL and the image of near objects is allowed to be incident upon on retina 108.

The spherical surface of most of common intraocular lens can be manufactured comparatively easy.For a period of time, always Think that NCL103 is substantially spherical surface.However, spherical surface crystalline lens is not completely monofocal, so-called " ball is shown Surface aberration ", wherein being bent to a focus, light of the focus than passing through the incidence of crystalline lens periphery by the light of center incident Linear distance crystalline lens is slightly farther.Therefore, the lenticular periphery of spherical surface is slightly more reflected than its center.This variation is continuous : such crystalline lens does not have single focus, but the short distance interval (focal range) between longest and shortest focal length It is interior that there are many focuses.In other words, spherical surface crystalline lens is negative multifocal (its focal length reduces from center to periphery).Ellipse and Aspherical crystalline lens (such as solidifying the surface generated by static meniscus) has even more obvious spherical aberration, because This, than spherical surface crystalline lens or even more negative multifocal.

Some artificial intraocular lens include hyperboloid and other second-order surfaces, such as with negative multifocal and non- The spherical surface of often opposite optical effect or even oval face.Importantly, the prior art usually by second order (or circular cone cut Face) surface with the not yet clearly defined only approximate second-order surface with spherical aberration,positive (although not with hyperbolic aberration Surface) crescent surface combination.

For example, Wichterle is claimed in U.S. Patent number 4,971,732 is similar to the crescent of oval in plan Surface, and Stoy thinks crescent surface almost spherical surface in U.S. Patent number No.5,674,283, the two all has negative Multifocal.Have the advantages that the surface combination of positive and negative multifocal reduces or counteracts the former.

In addition, Wichterle ' 732 describes the manufacturing method of intraocular lens a kind of, wherein solidifying in open mold Monomer, lenticular (rear) side have mold cavity shape, and leading flank have solidification meniscus shape (it is assumed that It is similar to the oval in plan with negative multifocal, between pure spherical and pure oblong surface).Mold cavity has second order The shape on surface (may include hyperboloid).It is noted that each optical surface can manufacture in different ways --- pass through polymerization on one side Object precursor solidifies in the surface of solids, and another side on liquid-gas interface by solidifying.It is known to those skilled in the art that in this way The surface quality of two optical surfaces formed under different situations may all have very big difference in terms of optics and biology.

Wichterle describes the manufacturing method of another intraocular lens in U.S. Patent number 4,846,832, wherein Lenticular trailing flank, which has, to be solidified meniscus shape (it is assumed that being similar to the oval in plan with negative multifocal), and Leading flank is formed as the marking that second-order surface (may imply including hyperboloid) solid mould of shape.Equally, it was noted that Each optical surface can manufacture in different ways --- on one side by polymer precursor the surface of solids solidify, another side by Solidify on liquid-gas interface.

Stoy ' 283 is disclosed using method described in two parts die improvement Wichterle ' 732, and a part is similar to Wichterle mold, and improvement of the another part for forming small diameter on crystalline body front surface is crescent.This is crescent The crescent feature having the same that optical surface and Wichterle ' 732 are generated, although diameter is smaller, it is thus possible to than ellipse Surface is closer to spherical surface.Under any circumstance, such surface all has negative multifocal.Trailing flank is formed as second-order surface The marking of the solid mould of (may include hyperboloid) shape, and another optical surface passes through liquid polymer precursor in liquid-gas Solidification is on body interface to form.

Michalek and Vacik is described in PCT/CZ2005/000093 uses rotational casting in open mold IOL manufacturing method.Mold filled with monomer mixture is rotated along its vertical axis, while being polymerize.One of optics Face is manufactured to the marking on solid mould surface, and another optical surface is rotated by mold and formed.The imprinted surface, which has, to be passed through Conic section is rotated along vertical axis and the shape (may include double-curved shapes) of formation.Another surface is formed as passing through centrifugation Power (some Liquid precursors are transferred to periphery from center by it) is improved crescent.In the case where convex meniscus, centrifugal force will So that center is flattened and generate steeper curvature on periphery, that is, improves the spherical aberration on surface.In the case where convex new lunar surface, centrifugation Power, which will generate, to be had smaller center radius crescent and improves surface with certain between almost spherical and parabolic shape Shape.Under any circumstance, for convex crescent surface or recessed crescent surface, it all can not achieve hyperbolic aberration.

Sulc etc. discloses a kind of intraocular lens, front surface in U.S. Patent number 4,994,083 and 4,955,903 Protrude forward so as to the iris permanent contact that makes crystalline lens centering.Rear surface and front surface may have by around optical axis Rotating cone section and the shape (spherical surface, parabola, hyperbola, ellipse) obtained.Lenticular iris contact portion is tool There is the inherently flexible and deformable hydrogel of very high water content (at least 70%, the water advantageously more than 90%).Therefore, The optical surface deformed and contacting with iris cannot accurately be conic section shape, but the surface with shape-variable, This depends on pupil diameter, may be close to the sphere with smaller center radius in a way.That is, such case is similar to The crystalline lens of another bibliography, by will be pressed in iris shape artificial element through deformable gel-filled crystalline lens The reduction (Nun, U.S. Patent number 7,220,279) of central diameter is realized on the hole of pupil shape.Nun ' 279 is not referred to or is implied To employ doubly curved optical surface.Cummings discloses a kind of liquid in U.S. Patent number 2007/0129800 and 2008/0269887 Pressure adjusts IOL, and wherein liquid is acted on by ciliary body organ is forced into internal IOL chamber, so as to cause optical surface variation And adjusting.

Hong etc. discloses a kind of non-in U.S. Patent number 7,350,916 and U.S. Patent Publication No. 2006/0244904 Spherical surface intraocular lens, optical surface at least one with spherical aberration is to compensate the spherical aberration,positive of cornea. Negative spherical aberration is realized by the hyperbolic shape of optical surface.

Hong etc. disclosed in U.S. Patent Publication No. 2006/0227286 a kind of best IOL shape for human eye because Son, and limit by -0.5 to+4 " form factor " optimal crystalline lens (form factor is the preceding curvature that is defined by Hong The ratio between with rear curvature summation and its difference), and at least one optical surface is advantageously aspherical, conic constants be -76 to - 27。

Hong etc. describes a kind of IOL in U.S. Patent number 7,350,916, has at least one in entire pressure model Enclose the optical surface that interior negative spherical aberration is about -0.202 micron to about -0.190 micron.

Summary of the invention

At at least one aspect, the present invention provides a kind of for substituting the people of the implantable human eye back room of natural lens Crystalline lens is made, with primary optical axis 1A, central optic portion 2 and peripheral support part 3；The global shape of implantation material is by its preceding table Transitional surface 6 between the coboundary of the front surface 7A and rear surface 7B in face 4, rear surface 5 and implantation material limits；With boundary 9A With optical surface 8B and preceding periphery branch behind optical surface 8A, the center with boundary 9B and rear vertex 10B before the center of preceding vertex 10A Hold surface 11A and rear perimeter edge support surface 11B (with reference to Fig. 3).

For substitute natural lens implantable human eye back room artificial lens as close possible to simulation NCL shape Shape, size, optical characteristics and material property, while considering the needs that operation implantation is carried out by small notch.

The artificial lens of at least one embodiment according to the present invention at least have close to natural lens rear surface Shape and size rear surface, with realize substantially completely contacted with capsule after eye.As defined herein, term " substantially " It can mean that at least about 90% rear surface BAIOL is contacted with rear capsule, or at least about 75% rear capsule (has a diameter larger than crystalline Body) it is contacted with crystalline lens rear surface.The part that artificial lens according to the present invention at least contact with rear capsule is by transparent flexible Made of hydrogel material, which nearly forms the optical of the tissue of natural lens, hydrophily and electrochemical properties.Before Side is designed to avoid and iris permanent contact.

In at least one embodiment, it is concave surface that front surface, which is shaped as preceding periphery support surface 11A, to avoid with The permanent contact of iris.

In at least one embodiment, artificial lens according to the present invention at least have its front surface and rear surface Major part, including two optical surfaces, as defined in one or more conic sections of optical axis rotation and passing through liquid State polymer precursor contacts solidification with the solid wall of mold (preferably hydrophobic plastic mold) and is formed.

One aspect of the present invention is intended to a kind of hydrogel, it includes the absorbing inclusion agent part UV and at physiological ph with negative The activator moiety of charge causes hydrogel wherein fully hydrated hydrogel, which is exposed to electromagnetic radiation, leads to two-photon absorption One or more structure changes and infractive index variation.In one embodiment, hydrogel is the water of covalent cross-linking Gel.In one embodiment, after the liquid medium around it is with crystalline lens reaches balance, structure change is realized and base The volume of processed hydrogel segment is not changed in sheet.A kind of short-cut method of determining volume change may include following step It is rapid: multiple equivalent regions (for example, 50 × 50 microns) in processing hydrogel to be set with different laser, with real in the different areas Existing different phase shift.After process sufficiently achieves the time of balance, the linear dimension and original area ruler in processed region It is very little to be no more than 20% compared to variation, for most said conditions change in size less than 10%.Due to processed region depth without Method easily or directly measures, it is therefore assumed that the variation of volume be it is isotropic, the variation of volume is due to all after processing The identical relative expansion of dimension or contraction.The hydrogel of one embodiment include containing (methyl) acrylic acid derivative and/or The polymer of the monomeric unit of (methyl) acrylic acid.In an embodiment of hydrogel, dopant part and activator portion The side group being divided on polyacrylate or polymethacrylate polymer.In one embodiment, dopant part is not The UV absorption compound of the strong light for absorbing about 400nm wavelength.In one embodiment, dopant part is selected from Luo Dan Bright, benzophenone, cumarin, fluorescein, benzotriazole and its derivative compound.In one embodiment, UV absorbs Agent part contain the carbonyl in conjunction with aromatic system, the phenolic hydroxyl group in conjunction with aromatic system or advantageously with aromatic system In conjunction with carbonyl and both phenolic hydroxyl groups.In one embodiment, activator moiety be comprising carboxylate radical, sulfonate radical, sulfate radical, The compound of carbolate group or phosphate radical.In an embodiment of hydrogel, one or more structure changes include water The part depolymerization of gel.In one embodiment, part depolymerization forms the gap of aqueous filling in hydrogel.In hydrogel An embodiment in, the variation of infractive index is negative variation.In one embodiment, the depth of the part depolymerization of hydrogel Degree depends on the cumlative energy that the given position in hydrogel absorbs.In one embodiment, hydrogel includes containing choosing From the polymer of following monomeric unit: acrylic acid derivative, methacrylic acid derivative, acrylic acid, methacrylic acid and its two The mixture of kind or more.

Another aspect of the present invention is intended to the ophthalmic implant comprising above-mentioned hydrogel.

Another aspect of the present invention is intended to a kind of hydrogel eye surgical implant that can be adjusted in situ, it includes acrylate or Methacrylate copolymer hydrogel, wherein the copolymer includes at least four comonomers: a) containing at least one hydroxyl The acrylate or methacrylate of side group；B) polyalcohol acrylate or polyalcohol methacrylate or amide, In each polyol ester or amide there is at least two acrylate or methacrylate group；C) there is at least one carboxyl The derivative of the acrylic or methacrylic acid of side group；D) vinyl, acrylic acid or the methyl-prop of group side group are absorbed with UV Acrylic monomer；Wherein the ametropia characteristic of implantation material absorbs the control of target electromagnetic radiation by hydrogel to adjust, to lead Cause the infractive index variation of the selected location of implantation material.In one embodiment, the ester of component a) band in the alcohol part of ester There is at least one pendant hydroxyl groups.In one embodiment, copolymer is covalent cross-linking.In one embodiment, it is implanted into Object has preceding refractive surface and rear refractive surface, forms the crystalline lens with positive or negative refractive power.In one embodiment, crystalline lens For Medium Culture crystalline lens.In another embodiment, crystalline lens is anterior lens.In yet another embodiment, crystalline Body is the Phakic crystalline lens between iris and natural lens.In another embodiment, crystalline lens is to use In the posterior chamber phakic at least partly substituting natural lens.In an embodiment of hydrogel eye surgical implant, until A few dioptric surface is the aspheric surface with negative spherical aberration.In another embodiment of hydrogel eye surgical implant In, the monomer of oxatyl-containing lateral group is neutralized or through partially neutralizing methacrylic acid.In one embodiment, based on copolymerization The monomer of all monomeric units of object, oxatyl-containing lateral group exists with the concentration of 0.1 mole of % to 5 moles of %.In another implementation In scheme, the monomer of all monomeric units based on copolymer, oxatyl-containing lateral group is deposited with the concentration of 0.5 mole of % to 2 moles of % ?.In one embodiment, all monomeric units based on copolymer, the monomer for absorbing group side group containing UV rub with 0.1 The concentration of your % to 5 moles of % exists.In another embodiment, all monomeric units based on copolymer are absorbed containing UV The monomer of group side group exists with the concentration of 0.2 mole of % to 2.5 moles of %.In an embodiment party of hydrogel eye surgical implant In case, UV absorbs group side group and contains the carbonyl in conjunction with aromatic group；In one embodiment, the institute based on copolymer There is monomeric unit, absorbs the monomer of group side group containing UV and exist with the concentration of 0.1 mole of % to 5 moles of %.In hydrogel ophthalmology In one embodiment of implantation material, UV absorbs derivative, the benzo three that at least one of group side group is selected from benzophenone The derivative of the derivative of azoles, the derivative of cumarin and fluorescein.In one embodiment, carboxyl side group and UV absorb base Group's side group exists with about 0.25 to 5 molar ratio；In another embodiment, UV absorbs group side group with about 0.5 to about 3.5 Molar ratio exist.In an embodiment of hydrogel eye surgical implant, copolymer includes to absorb group containing different UV At least two different copolymer monomers；In one embodiment, it is benzophenone that UV, which absorbs at least one of group,.

In an embodiment of ophthalmic lens, side chain carboxyl group is the carboxyl side group for ionizing, and ionizing The molar ratio that group side group is absorbed with UV is about 0.5 to about 3.5.In another embodiment of ophthalmic lens, at least water The major part of gelatin polymer is the derivative of methacrylic acid；In one embodiment, at least methacrylic acid is derivative The major part of object is the hydrophilic derivant of methacrylic acid.In one embodiment, hydrophily methacrylic acid derivative For the diol ester of methacrylic acid.In an embodiment of ophthalmic lens, the hydrogel of covalent cross-linking is in physiology of balance Under the conditions of containing having more than the liquid of 30 weight %.In one embodiment, the hydrogel of covalent cross-linking is in physiology of balance condition The lower liquid containing less than 55 weight %.In another embodiment, the hydrogel of covalent cross-linking is under the conditions of physiology of balance Contain 35 weight % to the liquid of 47.5 weight %.In an embodiment of ophthalmic lens, at least rear optical surface contribution Dioptric with negative spherical aberration.In another embodiment, it is -0.1 micron to -2 that rear optical surface, which contributes negative spherical aberration, The dioptric of micron.In another embodiment, negative spherical aberration is -0.5 micron to -1.5 microns.Alternatively, negative spherical aberration It is -0.75 micron to -1.25 microns.The ophthalmic lens of one embodiment include containing the carbonyl in conjunction with aromatic system UV absorbs group side group and the UV of the structure containing benzotriazole absorbs group.In one embodiment, contain and aromatic system In conjunction with the UV of carbonyl absorb the UV of group side group and the structure containing benzotriazole and absorb group and be located at the separated layer of ophthalmic lens In.In one embodiment, in ophthalmic lens implantation cornea.In another embodiment, lens implanting cornea and In camera oculi anterior between iris.In another embodiment, crystalline lens is to be implanted between iris and natural lens to have crystalline substance Shape body crystalline lens.In yet another embodiment, in lens implanting camera oculi posterior, natural lens are at least partly substituted.

Another aspect of the present invention is intended to a kind of side of ametropia characteristic for adjusting fully hydrated hydrogel of the invention Method, wherein method includes the following steps: with electromagnetic radiation focusing illumination hydrogel two-photon absorption occurs, and make water-setting The polymers compositions experience part depolymerization and/or decomposition of glue, to remove part polymer support effectively to generate gap.

A kind of method that another aspect of the present invention is intended to optical parameter in situ for adjusting hydrogel eye surgical implant, should Method is the following steps are included: a) provide the eye for containing hydrogel eye surgical implant according to claim 13；B) using winged Second laser irradiates a part of hydrogel eye surgical implant with electromagnetic radiation, thus the copolymer segment depolymerization of hydrogel and/or Ablation；Wherein adjust the optical parameter of implantation material.In an embodiment of this method, optical parameter includes infractive index. In an embodiment of this method, it is radiated in hydrogel eye surgical implant and generates elongated chamber or voxel.In some realities It applies in scheme, voxel depth is up to 20 microns to 30 microns or more.In one embodiment, increase voxel depth to increase Phase shift, and infractive index keeps approximately constant；In one embodiment, infractive index is >=1.3335.The one of this method In a little embodiments, phase shift up to 3 green wavelengths.In other embodiments of this method, by the solution for irradiating ablation Polymers matter includes low toxicity compounds that are solvable and being easy to spread.Since this method only releases very low concentration of de-polymerizing compound It is put into intraocular space, therefore the hypotoxicity of this method is also apparent.In an embodiment of this method, by water The pattern that the elongated voxel of different depth is formed in gel makes improved infractive index that approximately constant be kept to provide improvement simultaneously Optical characteristics.In an embodiment of this method, by changing voxel depth rather than by changing its infractive index To control phase shift.

Detailed description of the invention

Attached drawing is incorporated herein and forms part of this specification, and it illustrates currently preferred embodiment party Case, and the feature for explaining the present invention together with summary of the invention given above and detailed description of the invention described below.Attached In figure:

Fig. 1 shows the internal structure of eye, and primary structure includes cornea, sclera, iris, NCL, vitreum, retina With lenticular suspention tissue (lens capsule, small band and ciliary muscle)

Fig. 2 shows the distributions with a bi-curved lenticular refractive power.

Fig. 3 A is the sectional view of the biosimulation intraocular lens of an exemplary implementation scheme according to the present invention.

Fig. 3 B is the lenticular top view of Fig. 3 A.

Fig. 4 A is the top view of lenticular another exemplary embodiment, which has circular optical part and ellipse Round support part.

Fig. 4 B is the top view of lenticular another exemplary embodiment, which has by single longitudinal sectional truncation Round support part.

Fig. 4 C is the top view of lenticular another exemplary embodiment, which has by two symmetrical crescents The round support part of shape section truncation.

Fig. 4 D is the top view of lenticular another exemplary embodiment, which has longitudinal sectional and two by one The round support part of crescent section truncation.

Fig. 4 E is the top view of lenticular another exemplary embodiment, which has by four symmetrical crescents The round support part of shape section truncation.

Fig. 4 F is the top view of lenticular another exemplary embodiment, which has by two straight parallel cut surfaces The round support part of truncation, and the cylindrical lens with the cylindrical shaft 1B at α angle with section direction.Wherein circular support Part is truncated by two straight parallel cuts, and the cylinder axis 1B of cylindrical lens is at an angle of α relative to cut direction.

Fig. 5 A, Fig. 5 B and Fig. 5 C show exemplary lenticular top view, and wherein optical surface is divided into two or more A optical region.

Fig. 6 A, Fig. 6 B and Fig. 6 C are the another kind lenticular section according to the present invention being made of two or more materials Face figure.

Fig. 7 A, Fig. 7 B and Fig. 7 C are to show the expanded view of the substitution shape of exemplary lenticular peripheral support part.

Fig. 8 show an exemplary implementation scheme according to the present invention for manufacturing the schematic of lenticular mold Arrangement.

Fig. 9 A show representative hydrogel of the invention using femtosecond laser two-photon absorption (TPA) before and it The comparison of Raman spectrum afterwards.

Fig. 9 B and Fig. 9 C show the figure of the relevant parameter of Raman spectrum.

Detailed description of the invention

For the purpose of the application, term " (methyl) acrylic acid " and " (methyl) acrylate " indicate acrylic acid/propylene Acid esters or methacrylic acid/methacrylate moieties.In some embodiments, polymer includes acrylic acid/esters Part.In other embodiments, polymer includes methacrylic acid/methacrylate moieties.In other embodiment party In case, polymer includes acrylic acid/esters and methacrylic acid/methacrylate moieties.In a preferred implementation In scheme, polymer includes methacrylic acid/methacrylate moieties..

Moreover, term " ablation " refers to a part of polymeric structural support of removal hydrogel for the purpose of the application, It is preferred that by making polymer resolve into diffusible low molecular weight fraction.Term " depolymerization " constitutes a kind of ablation of specific type, Wherein segment is monomer.

There are the implantable ophthalmic for eye different location (to back room from corneal stroma to anterior chamber) of many types is crystalline Body.Can plant a lenticular problem is correct ametropia characteristic (so-called bio-measurement) complexity of selection, and if raw The optical requirement of object measurement result mistake or eye changes over time, then is difficult to replace or correct.This excites the sector exploitation can It is implanted into lenticular effort, optical parameter can non-invasively Postoperative adjustment.The variation of the optical characteristics of artificial lens It can in the preoperative or the postoperative infractive index by changing crystalline lens material is realized.

In the prior art, it describes by can plant lenticular two-photon absorption (TPA) or Multiphoton Absorbtion (MPA) The variation for acting on infractive index, is positive for hydrophilic polymer, is negative for hydrophobic polymer.This and assume mechanism one It causing, crosslink density increases, then the water content of hydrophilic acrylate and hydrogel reduces, on the contrary, hydrophobic acrylic acid's ester Increased hydrophilicity.The hypothesis of these variations is the reason is that local temperature increases.

It also illustrates in many papers, patents and patent applications and is changed naturally by the infractive index for changing these materials The optical characteristics of (for example, people's cornea) or artificial lens, such as following: Phillips, A.J., System and Method For Treatment of Hyperopia and Myopia, 6,102,906, Bille J.F.:System of U.S. Patent number For Forming And Modifying Lenses And Lenses Formed Thereby, U.S. Patent number 8,292, 952；USP 8,920,690；9,192,292；Sahler；Ruth etc.: " Hydrophilicity alteration system and method"USP 9,023,257；9,186,242 and 9,107,746；Sahler, Ruth etc.: " intraocular lens (IOL) fabrication system and method " U.S. Patent Application Publication No. 20160074967；Smith, T. etc.: Optical Hydrogel Material With Photosensitizer And Method For Modifying The Refractive Index, U.S. Patent Application Publication No. 20130268072；20090287306 and U.S. Patent number 8,901, 190；Knox, Wayne H. etc.: Optical Material And Method For Modifying The Refractive Index, U.S. Patent number 8,932,352；8,337,553；7,789,910B2；Knox, Wayne H. etc.: Optical Material And Method For Modifying The Refractive Index, U.S. Patent Application Publication No. 20130138093；20130178934；20100298933；20080001320；20090143858；20090143858；Knox, Wayne H. etc.: Method For Modifying The Refractive Index Of An Optical Material And Resulting Optical Vision Component, U.S. Patent Application Publication No. 20120310340, Knox, Wayne H. etc.: Method For Modifying Refractive Index Of Ocular Tissues, U.S. Patent number 8,486,055；8,512,320；8,617,147 and U.S. Patent Application Publication No. 20110071509；20130226162 Hes 0140107632；Knox, Wayne H. etc.: Method For Modifying Refractive Index Of Ocular Tissues And Applications Thereof, U.S. Patent Application Publication No. 20120310223, each by reference It is incorporated herein.Machine of these prior art references all without proposing to adjust ablation or depolymerization as the optics of hydrogel System.

In the International Application Serial No. PCT/IB2016/052487 Method for applicant's co-pending that on May 2nd, 2016 submits and Device for Optimizing Vision Via Customization of SphericalAberration of Eye includes relevant disclosure.

The wavelength of laser beam is usually in the range of near-infrared radiation, about 800nm to 1300nm, or more typically about In the range of 660nm to the visible light of about 1100nm and near-infrared radiation.Due to safety concerns, it is usually preferred to use more long wave It is long.It can be real on a kind of methodological principle for the infractive index for changing crystalline lens material by femtosecond laser (referred to as " FSL method ") Existing many ametropia characteristic variations, such as sphere power, cylinder refractive power, spherical aberration etc..It is even crystalline in implantation in principle In body, which can also change to being repeatedly selected property any coefficient (" Zernike coefficient ") in Zernike multinomial. " the Femtosecond laser writing of freeform gradient such as Gustavo A.Gandara-Montano Index microlenses in hydrogel-based contact lenses ", 2015.10.1 | volume 5, the 10th phase | DOI:10.1364/OME.5.002257 | OPTICAL MATERIALS EXPRESS 2257 has confirmed that this point.Author It notices when being handled with the femtosecond laser of 800nm,The negative of contact lens hydrogels moves.However, this A little systems are not in clinical use, because among other reasons, compared to ophthalmic lens material is currently available that, using The infractive index variation of FSL method is smaller.

FSL method (is wherein usually reduced in hydrophily (wherein usually increasing infractive index RI) and hydrophobicity IOL material RI it can be carried out on).

FSL method can be carried out more advantageously in hydrogel ophthalmic lens, especially various types of implantable On crystalline lens, because even being currently available that refractive change of the refractive change also above hydrophobic material of hydrogel.In addition, for Hydrophobic acrylic acid's ester, at least theoretically, FSL method may cause so-called " flash of light " or other with dredge in water-based material Form hydrophily " permeabilized cells " related other problems.Therefore, test a variety of hydrogels as femtosecond laser it is miniature plus The matrix of work.The sensitivity of a variety of " dopants " increase hydrogel designed for response different wave length electromagnetic radiation can be passed through Property.Up to the present, dopant has been described in patent and scientific literature.All dopants being currently known are being capable of UV The single compound of absorption, but Single Photon Absorption can be carried out under the wavelength for FSL method without known dopant.

We have found that by adding specific TPA activator (for example, the comonomer containing negatively charged side group, special It is not organic carboxylate) dopant can be improved, improve and enhance in acrylic acid and metering system acid hydrogel to TPA and MPA Influence.Dopant and its activator can advantageously with polymer chain covalent bond, more advantageously with form hydrogel The chain covalent bond of polymer network.Dopant and its activator can be chained from same polymer chain or different polymer It closes.

More specifically, hydrogel of the invention includes combined dopants agent (its for absorbing side group structure as UV of fraction Visible light will not significantly be absorbed) and fraction activator and most methyl of the ionizable salts as side group containing acid (especially the glycol of methacrylic acid or glyceride and fraction has at least two quilts to acrylate neutral hydrophilic derivative The polyalcohol of the hydroxyl of acrylic or methacrylic acid esterification).These hydrogels are particularly suited for use in be absorbed by femtosecond pulse It can be seen that or near-infrared radiation (femtosecond laser (FSL) processing) adjust the material of infractive index.The absorption of electromagnetic energy causes this The controlled degradation and depolymerization of the polymers compositions of hydrogel, to form the structural domain with lower infractive index.Due to activation Agent, even if by using the femtosecond laser with relatively low energy pulse in very high " writing speed " or " scanning speed " Lower irradiation hydrogel, can also form such structural domain.

Disclosed herein is containing negatively charged group (particularly carboxylate group) and also containing with UV absorption group side The acrylic acid and methyl of the biological analog covalent cross-linking of the monomer (such as methacryloxy benzophenone (MOBP)) of base Acrylic hydrogel.There is disclosed herein a kind of methods of this polymer of depolymerization, can be planted by absorption of electromagnetic radiation with adjusting The optical characteristics for entering hydrogel carrys out depolymerization portion hydrogel using femtosecond laser and forms internal voids, this will form new bend Light component (such as double-curved surface crystalline lens).Implicit but for certain, the gap of this new formation in hydrogel matrix is necessarily full of Water or aqueous fluids (individually or also the residue of the degradation polymer component containing hydrogel) and therefore have and female water-setting The infractive index of glue material difference (particularly lower).Also disclose over the implant it is in situ carry out this crystalline lens adjusting can Energy property, because the product of this decomposition is water-soluble low toxicity compounds and can slowly be spread by hydrogel.

We have demonstrated that UV absorbent group used in hydrogel takes on " dopant " for improving depolymerization rate, and The effect of negatively charged group takes on " activator " of dopant, further improves dopant.In addition, being used as quencher Activator protection materials during each a certain amount of absorption energy from undesirable " charing " or " burning " (may occur). Energy total amount needed for this allows for certain refractive change reduce, therefore safely using higher energy visible light rather than The near-infrared (NIR) of more low energy radiates.

It is not intended to the scope of the present invention to be limited by any specific hypothesis or theory, the solution for passing through electromagnetic radiation to hydrogel Poly- phenomenon, proposition are explained as follows.The femtosecond laser of known focusing promote in its volume of focus two-photon absorption (TPA) (or Even Multiphoton Absorbtion (MPA))." volume pixel " or " voxel " is commonly known as by the volume of the TPA material influenced.Voxel Size depends on multiple parameters, and usually increases with the energy of absorption.The smallest possible voxel size corresponds to " focus Volume " or ellipsoidal volume are about cube of the optical maser wavelength absorbed.Due to laser beam in the case where TPA or MPA Self-focusing, the diameter of voxel is much smaller than its depth, and typically about 500nm.Voxel depth is bigger and with deposition Energy and increase.In the material being currently known, the maximum voxel depth of report is about 6 microns.

If absorbing the radiation of a certain wavelength by TPA or MPA, dopant cumulative excitation energy, be equivalent into The Single Photon Absorption of optical wavelength is penetrated divided by the quantity for absorbing photon.For example, dopant is corresponding by the 400nm laser that TPA absorbs In the 200nm light absorbed by SPA.The light of 200nm wavelength is hard UV light (UVC band), with enough energy with causing The fracture and depth structure for learning key are reset.Certainly, although unlikely than TPA, 3 photonic absorptions or 4 photonic absorptions can accumulate Higher energy concentration.Excitation state with high cumlative energy is of short duration, because energy is fast by one of a variety of possible approaches Speed dissipates, and is most commonly converted into thermal energy.The usual effect of femtosecond laser processing tissue or synthetic hydrogel is related to local temperature Degree increases, and following effect that this may cause --- amount of the energy depending on absorption ---: begins through the heating for being enough to carbonize Substance is set to be converted into plasma (for example, passing through laser ablation), to carrying out more delicate being additionally crosslinked (example by number of mechanisms Such as resterification, disproportionation or dehydration), form ehter bond.

The presence of (negatively charged side group, particularly carboxylate) changes the mechanism of the process however, activator.I It is thought that caused by certain cooperations as activator groups and dopant.In the cooperation, the activation of dopant is further It promotes the absorption of TPA and increases this effect.Activator (such as carboxylic acid group of methacrylic acid or its salt) obviously with Dopant interaction, because its variation that there is the UV/Vis spectrum for causing dopant is (that is, from UV to the micro- of visible light region Wonderful transformation).This can increase " cross section TPA " of dopant and increase the absorption efficiency of dopant.

However, the main function of activator may be by two (or for MPA, multiple) absorb photon absorption energy from Dopant is guided to host polymer chain, to cause the fracture of the covalent bond in main chain.From the general features and methyl-prop of this method For the known depolymerization dynamics of olefine acid ester polymer it will be appreciated that the cracking is monopole and generates free radicals, free radical is negative in band The activator (such as carboxylate) of charge nearby starts depolymehzation process.This free radical mechanism can greatly increase photodegradative Quantum yield, and facilitate explain why can cause relatively low concentration (in mol) dopant part form and The profound change of structure, and therefore lead to the significant changes of local infractive index.

In addition, activator groups help that the energy transfer absorbed from dopant is enable simultaneously " to consume " this so that excitation state is quenched Amount is to destroy covalent bond.This " energy conduit " effect of activator prevents excessive thermal accumlation near dopant part, To help " to recycle " dopant molecule and be preserved for following TPA circulation.It additionally aids protection polymer Structure is from burning and carbonizing, and the effect of help to improve entire absorption process.

In addition, the mechanism of the proposition can explain such a fact, i.e., in the case where no activator, contain only doping The TPA of the hydrogel of agent is carried out by different mechanisms and is obtained opposite result: there are activator, infractive index It reduces, and infractive index increases in the absence of its.The seemingly additional crosslinking of the increased possible cause of infractive index, leads Water content is caused to reduce, and therefore infractive index increases, this is because the infractive index of water is minimum in all Hydrogel Components.

It is related to another of the regulation mechanism of activator the result is that the volume change as caused by TPA process is reduced (or very To elimination).That is, water content reduces in the case where additional crosslinking, and the amount of polymers compositions keeps roughly the same.Therefore, must Must reduce the quality and volume of processed hydrogel volume, and to a variety of negative consequences of product (such as generate internal stress, Geometry changes and mechanical property changes).On the contrary, if polymer becomes more hydrophilic and attracts more water, polymer Volume that treated has to expansion (same, to have an adverse effect to the geometry of material, optics and stress).

Mechanism specified in the present invention includes that certain a part of polymer material is exchanged for water, and if any, Net volume variation is low.The depolymerization of hydrogel of the present invention generates hypotoxicity monomer and/or its segment, mainly metering system Sour 2- hydroxyl ethyl ester, methacrylic acid and ethylene glycol.Around all these decomposition products are all well soluble in water and can pass through Complete hydrogel network diffusion, is dissipated from implantation material with low-down concentration whithin a period of time.

The mechanism proposed can explain that hydrogel according to the present invention can realize very big phase shift.Phase shift is by dioptric The variation of index and the optical path length (in other words, voxel depth) by material changed as infractive index changes determine 's.The infractive index of hydrogel is actually not less than the infractive index of water, or about 1.3335, because being filled with waterborne liquid The minimum index being contemplated that may be implemented in gap.For certain Basic thermodynamics reasons, in hydrophilic polymer base Gap is unable to gassy, and without the mechanism for generating hydrophobicity gap in hydrogel that is known or being readily apparent that.

Therefore, big phase shift (being greater than a wavelength) needs to form the big voxel of depth.Usually assume that voxel depth is most It can achieve about 5 microns to 6 microns.However, elongated voxel serves as light guide if the infractive index in volume of focus reduces, Other light pulse is guided to be absorbed in voxel bottom.Therefore, the depth of voxel can with the increase of number of pulses and gradually Increase, even if infractive index keeps approximately constant and is equal to or higher than 1.3335, but phase shift is also such.Then, the mechanism Different from mechanism described so far, wherein voxel size keeps approximately constant but infractive index variation is with the increase for absorbing energy (for example, being realized by number of pulses) increases.The voxel for thinking that the mechanism proposed at present can be provided greater than 10 microns is deep Degree, and have been observed that the phase shift for corresponding to up to 25 or 30 microns of voxel depth.It mentions this and is not limited to this hair It is bright, but illustrate the fundamental difference of the present invention with the prior art.The actual result of this difference first is that: make in the prior art Material allows to generate certain refraction or diffraction structure by forming infractive index gradient (GRIN), and according to the present invention Hydrogel allows to be accomplished by the following way similar refraction or diffracting effect, that is, forms the pattern of different voxel depth while making Improved infractive index keeps approximately constant.Additionally it is believed that the infractive index value initially close to and be finally similar to isotonic saline solution The infractive index of solution.

As this new mechanism as a result, newly generated refraction or diffraction structure form the parallel waveguide with different length System (that is, infractive index be lower than surrounding hydrogel elongated voxel), from there through change voxel depth rather than its change Infractive index controls phase shift.

Another feature of the invention is the generation infractive index gradient near each voxel.It is released by depolymerization inside voxel The monomer put and other segments are by diffusing through the hydrogel of surrounding come radial migration.When temperature decreases below ceiling temperature When (in the case where methacrylate about 200 DEG C), the monomer and/or segment at least partly discharged can polymerize and generate again Infractive index finer and close network structure more higher than female hydrogel.There are two beneficial results for mechanism tool: first, it is reduced It is diffused into the amount for the compound outside implantation material and being metabolized, secondly, the infractive index gradient being consequently formed improves body The photoconductive property of element.

Therefore, hydrogel may not all be diffused out by the monomer that depolymerization discharges, but may near voxel portion Ground is divided to polymerize again.In this sense, the method for the present invention is somewhat similarly to FS laser ablation, because it can both remove some polymerizations Object substance simultaneously retains water, although term " ablation " usually indicates that (wherein polymer and water are converted into plasma (gas to decomposable process Body)).Method disclosed by the invention is milder, therefore polymer decomposition will not generate volatile bubble.

Although it is considered that the depolymerization of gel copolymer is main mechanism involved in published method of the present invention, but can lead to It crosses to form other decomposition reactions (such as the hydrolysis of (methyl) acrylate-based side group, or oxidation) of small water-soluble segment to mend It fills.

Concentration of dopant is about 0.05 mole of % to about 5 moles of % in hydrogel according to the present invention, is advantageously about 0.1 mole of % to about 2.5 moles of %.Alternatively, different optimum doping agent concentration can be used for different dopant, such as It is 0.25 to 0.55 mole of % for benzophenone derivates, or is 0.1 to 0.2 mole of % for benzotriazole derivatives.It is excellent The dopant of choosing is to visible light (wavelength for being greater than about 390nm) the low UV absorbent of absorptivity.The reality of suitable dopant Example is benzophenone, the vinyl of benzotriazole and cumarin, acrylate or methacrylate derivative, but this field Technical staff can of course determine other the suitable UV absorbents for being used as dopant in the sense of the present invention.

Activated group is deposited with about 0.25 mole of % to about 5 moles of %, the concentration of advantageously about 0.75 to about 3.5 mole of % ?.In some embodiments, the preferred molar concentration of methacrylic acid is 1 to 1.25 mole of %.Preferred activator groups For the derivative of the acrylic or methacrylic acid of side group containing acidic-group (including carboxylate radical, sulfate radical, sulfonate radical and phosphate radical) Object.These acidic-groups are preferably neutralized by suitable organic or inorganic cation.Mole of activator groups and dopant group Than should be about 0.75 to 10, it is advantageously about 1 to about 5.Alternatively, different activator/dopants is most for different dopant Good molar ratio is different.For example, being about 2 to 4 for the optimum ratio of benzophenone derivates, most for benzotriazole derivatives Good ratio is about 5 to about 7.

The preferred composition of hydrogel according to the present invention includes the first with neutral hydrophilic group side group of major part Base acrylate monomer." major part " means at least 50 moles of % of all monomeric units in hydrogel.In some embodiment party In case, the molar fraction of hydrophilic methacrylate monomer is 90 moles of % to 99.5 moles of %, and in many cases For 97.5 moles of % to 99 moles of %.This hydrophilic methacrylate monomer can be the ester of polyol resin compounds of group, Such as glycol, glycol ethers, glycerol and sugar.Most familiar of is 2-hydroxyethyl methacrylate (2-HEMA).The substitution of above-mentioned ester Monomer includes the amide of methacrylic acid, such as Methacrylamide, N- isopropyl acrylamide or N- (2- ethoxy) Methacrylamide.The aquogel polymer of the major part also may include the mixture of these hydrophilic monomers.Alternatively, can To replace the methacrylate monomers (but being no more than 25 moles of %) of fraction with similar acrylic acid derivative.In some realities It applies in scheme, can replace the acrylate monomer of 0.5 mole of % to 5 moles of %.

The monomeric unit of fraction is formed by the above-mentioned activator monomer with negatively charged group side group, and another is small Part is formed by above-mentioned dopant monomers.

Polymer advantageously covalent cross-linking.Crosslinking can be real by any method known to those skilled in the art It is existing, such as crosslinking with radiation, it is crosslinked etc. by forming ehter bond between OH base side group.Preferred cross-linking method is and fraction Crosslinking polyalcohol diester or three esters methacrylate or acrylic ester copolymer, such as triethylene glycol dimethacrylate Ester.

The infractive index of hydrogel according to the present invention is about 1.38 to about 1.48, preferably from about 1.40 to about 1.45.? In some embodiments, RI is about 1.40, or about 1.41, or about 1.42, or about 1.43, or about 1.44, or about 1.45.

Preferred hydrogel according to the present invention contains the about 25 weight % with ocular environment balance living to about 85 weight %'s Liquid.For supplementing or substituting the intraocular lens of natural lens, more favorable balancing liquid concentration is 35 weight % to 50 Weight %, particularly 40 weight % to 47 weight %.In some embodiments, equilibrium water content is 41 ± 0.75 weight %, Or 42.5 ± 1 weight % or 44.5 ± 1 weight %.It will be appreciated by those skilled in the art that the balancing liquid content in hydrogel is by perhaps Multivariable influences, such as body temperature, body fluid composition or the pressure applied by surrounding tissue or body structure.Moreover, small hydrogel is planted The measurement for entering content liquid in object may be by the influence of certain measurement error, therefore these values are illustrative.Since band is negative The activator groups of charge tend to the infractive index for increasing balancing liquid content and therefore reducing hydrogel, therefore can pass through (it reduces water content and improves infractive index to ophthalmic implant and sets for the following hydrophobic acrylic acid's ester of addition or methacrylate The expected range of meter) compensate the activator of higher concentration, such as methyl methacrylate, ethyl methacrylate, methyl-prop Olefin(e) acid benzyl ester, isobornyl methacrylate or ethoxyethyl methacrylates.The methacrylate of this addition or third The typical concentration of olefin(e) acid ester up to about 40 moles of %.In some embodiments, the concentration of the hydrophobic monomer of addition is about 5 to rub You are % to 25 moles of %.

Dopant group and activated group can be located on same polymer chain, or positioned at the difference polymerization of close contact On object chain, for example, in blend polymer, or in two different fragments of polymer network.One or the other can be with In grafting or one can be upper in grafting and another can be on basic chain.Dopant group and activated group can be with It is present on individual molecule with suitable spatial relationship (allowing its interaction).Then, this " dopant-activator complexing Object " can perhaps be mixed into a part in polymer or as host polymer chain with polymer chain covalent bond.

For ophthalmic implant, negatively charged activator groups have the advantages that some other such as improved biologies Compatibility, resistance, the resistance to biofilm formation, the resistance to calcification and to cell adherence and diffusion to protein absorption Resistance (this be converted into rear capsule hardening resistance and to the resistance of post gelating time).

Hydrogel implant according to the present invention can be placed in intraocularly multiple positions along optical path.It can have " blank " Form or can have form (its optical characteristics of refraction or diffractive lens wherein generating refraction or diffractive lens It is improved by the change of infractive index at the selected location of implantation material).

Intraocular lens can partially or completely substitute natural lens.Intraocular hydrogel lenses, which have, is better than other Some advantages of IOL style, such as multiple types and relative manufacturing process are described in following patents and patent applications, Stoy, V. etc.: Bioanalogic Intraocular Lens, International Patent Application WO2014111769；Wichterle, O.:Method Of Molding An Intraocular Lens, U.S. Patent number 4846832；Wichterle,O.:Soft And Elastic Intracameral Lens And Method For Manufacturing Thereof, U.S. Patent number 4,846,832；Stoy,V.:Implantable Ophthalmic Lens, A Method Of Manufacturing Same And A Mold ForCarrying Out Said Method, beauty State's patent No. 5,674,283；Sulc, J. etc.: Soft Intracameral Lens, U.S. Patent number 4,994,083 and the U.S. The patent No. 4,955,903；And Michalek, J. etc.: Method Of Manufacturing An Implantable Intraocular Planar/Convex,Biconvex,Planar/Concave Or Convex/Concave Lens And A Lens Made Using This Method, U.S. Patent number 8409481 are each herein incorporated by reference.

Another type of implantable ophthalmic crystalline lens is referred to as " implantable contact lenses " (or ICL).ICL is placed in rainbow Phakic crystalline lens between film and natural lens.It is described in numerous patents, such as Fedorov etc. .Intraocular lens for correcting moderate to severe hypermetropia,US 5,766, 245；Feingold V.,Intraocular contact lens and method of implantation,UP 5,913, 898；Intraocular refractive correction lens,US6,106,553；It is each by being incorporated herein by reference In.

These implantable crystalline lenses are being incorporated to made of the hydrogel of biological components (in general, collagen).At more These so-called " Collamer ", such as Feingold etc., Biocompatible, optically are described in patent transparent,ultraviolet light absorbing,polymeric material based upon collagen and method of making,US 5,910,537；The Biocompatible such as Feingold optically transparent polymeric material based upon collagen and method of making,US 5, 654,349, US 5,654,388 and US 5,661,218；Fedorov etc., Biocompatible polymeric materials,methods of preparing such materials and uses thereof,US 5,993,796； Method of preparing a biological material for use in ophthalmology；It each leads to It crosses in being incorporated herein by reference.

Another method of correction of refractive errors is Medium Culture or cornea implant or insert, is described by following, example Such as, Miller, Aspherical corneal implant, US 7,776,086；Lang, Alan, Design of Inlays With Intrinsic Diopter Power,US 2007/0255401；Dishler；Jon etc., Small Diameter Inlays,US 2007/0203577；The Intracorneal such as Lang, Alan Inlays, US 2007/0129797；And The Method of using small diameter intracorneal inlays to treat such as Dishler visual impairment,US 8,057,541；Its each by being incorporated herein by reference in.

Some matrix implants are designed to carry out postoperative optical power adjusting by laser, such as Peyman, Gholam A., in intratrotromal corneal modification via laser, US2001/0027314；? In Adjustable ablatable inlay, US 2002/0138069 and 2002/0138070；Ablatable Intracorneal inlay with predetermined refractive properties, US 2003/0093066 with And in Bifocal implant and method for altering the refractive properties of the Described in eye, US 2005/0222679；It is each herein incorporated by reference.

There is also two concatenated intraocular implants of crystalline lens are used, with real when implantation material is by all parts assemble in situ Existing improved adaptability, design modularization or implantation incision size reduce.

All this ophthalmic lens types can be by manufacturing, then by using winged according to the hydrogel of present disclosure Second laser treatment is modified.

Equally, it is undesirable to be bound by any particular theory, the part depolymerization of method disclosed by the invention seemingly this hair The mechanism that the significant negative that hydrous gel is observed when being exposed to and focusing femto-second laser (FSL) moves.As described above, this method Seem to produce parallel longitudinal direction " voxel " system, which becomes more with the increase of the FSP number of pulses of absorption It is elongated.Voxel length control cannot be reduced to the RI value (i.e. 1.3335) of water for giving the achievable phase shift of infractive index Below.In addition, it is actually phase shift impacted in hydrogel disclosed by the invention and method, rather than infractive index sheet Body.The mechanism, which is different from any content disclosed in the prior art, (it is assumed that crosslinking causes water content to reduce, causes infractive index to increase Add, therefore generate corresponding positive phase shift).

With the prior art another difference is that, hydrogel disclosed by the invention and method replace portion with water or aqueous fluids Divide the copolymer for forming hydrogel, rather than reduces hydrogel by changing copolymer characteristic (such as passing through crosslinked polymer) Water content.

In the accompanying drawings, the similar element of similar digital representation in the text.Certain terms herein are only for convenience For the sake of, and should not be construed as limiting the invention.The preferred embodiment of the invention is illustrated below.However, should manage Solution, is based on the disclosure, and the present invention is not limited by preferred embodiment described herein.

NCL develops at any time has extremely complex structure.Its structure feature first is that the rear surface of NCL 103 and preceding table The asphericity in face.Such as the idea established in recent years, E.L.MARKWELL etc., MRI study of the change Incrystalline lens shape with accommodation and aging in humans, Journalof Vision(2011011(3)；19,1-16；M.Dubbelman etc., Change in shape of the aging Humancrystalline lens with accommodation, Vision Research45 (2005), 117-132； F.Manns etc., Radius of curvature and asphericity of the anterior and Posteriorsurface of human cadaver crystalline lens, Experimental Eye Research 78(2004),39-51；M.Dubbelman etc., The shape of the aging human lens:curvature, Equivalent refractive index and the lens paradox, Vision Research41 (2001) 1867- 1877, the lenticular front surface of young man and rear surface are all hyperbolas, and it is characterized in that equation:

Y-Yo=X^2/ { Ro* (1+1-h* (X/Ro) ^2) ^0.5 } ... ... ... equation 1

Wherein Y is the coordinate in the direction of primary optical axis 1A, and X is the distance to primary optical axis 1A, and Yo is on the top of primary optical axis 1A Point position, Ro are center of curvature radius, and h is circular cone coefficient (or form parameter).The description of equation 1 depends on form parameter h value Any conic section curve: being parabola when h=0；It is round when h=1；It is hyperbola when h < 0；When 0 < h < 1, It is the ellipse of prolate；It is oblate ellipse when h > 1.

It has been found that for usual young man NCL, front surface than rear surface be more it is hyp, the hyperbolic is with tune Section dramatically increases, and people's crystalline lens increases with the age, and its hyperbolicity reduces, so that the NCL of the elderly can become substantially For spherical shape.

The size of the typical NCL of selected demographic sample is depicted with reference to research.According to these bibliography, typical people Crystalline body front surface center radius range is about 5 to 13mm, and the circular cone parameter for the front surface that is averaged be about -4 (range be about - 22 to+6).Rear surface center radius range is about 4 to 8mm, and the circular cone parameter for the rear surface that is averaged be about -3 (range be about - 14 to+3).

The center thickness of the NCL of youth relaxation is typically about 3.2mm to about 4.2mm, adjusts with the age and/or with perifocus It increases to a thickness of about 3.5mm to about 5.4mm.The rear surface partial depth of NCL is generally identical, or than its front depth more Greatly.Therefore, the lenticular arrow of rear surface deep (sagittal depth) is typically about 1.75mm to about 2.75mm diameter under the line It is about 8.4mm to about 10mm.That define basic size of the Lens capsular under its " nature " state.

Although above-mentioned bibliography does not illustrate any specific connection between the geometrical property of NCL and optical characteristics, I Find that crystalline lens is become multifocal by hyperboloid by mathematical modeling, there is maximum optical power at center, and to week Gradually successively decrease on side.We are the lenticular big depths of focus from the desired direct result of such multifocal, this makes Near objects can be projected on retina, even if changing without any special lens shapes.Another shadow of modeling Sound is that lenticular mean power increases as aperture reduces.Therefore, we can inference, close focusing can pass through pupil Shrinking (so-called " pupillary reflex " or " neighbouring miosis ", can observe in actual clinical in nearly focusing) improves.Naturally Another of crystalline lens hyperbolicity is the result is that the mankind (especially young man) brain nerve accommodation image and is correctly explained naturally The ability of image, the image are projected on retina by hyperbola crystalline lens and are formed.

This adjustment mechanism using certain type of multifocal be worth deeper into explanation:

It is shown " hyperbola aberration " at least one bi-curved crystalline lens, it is opposite with spherical aberration: in The ray of heart incidence is curved to one close to lenticular focus, and from crystalline lens center to crystalline lens side with incident ray The distance of edge increases, and focus is gradually farther from crystalline lens.

Therefore, be positive multifocal with bi-curved crystalline lens: it has shortest focal length (that is, highest bend at center Luminous power), and increase (that is, refractive power reduction) from center to lens edge focal length.The lenticular focus of hyperbola can be with It is sizable and can be controlled by the so-called circular cone coefficient or form parameter for defining double-curved shapes.

The example of distribution with bi-curved lenticular refractive power is shown in Fig. 2, wherein the office indicated with diopter m-1 Portion's refractive power is directed to be drawn with the distance away from optical axis that mm is indicated.It should be understood that such optical curve (refractive power with Distance away from optic axis or with picture system aperture or pupil diameter and reduce) can reside in and be originally-implanted crystalline lens In or it can by being carried out with laser, hydrogel is modified to be generated after lens implanting.

According to our research, it should be understood that the positive multifocal promotes eye several with it in the change of natural lens Aspect is adjusted:

The image of all objects within the vision in all distances of lenticular focus covering simultaneously will be by It is projected on retina.This dramatically increases the depth of focus of eyes (being greater than 1 diopter), because all objects creation is good burnt Away from image (many non-focus images that can inhibit along with cerebrology).

Natural lens increase its hyperbolicity because of adjusting, and which in turns increases lenticular focuses, therefore, The depth of focus is further promoted.

Eye helps to focus near objects by reducing pupil.This so-called " pupillary reflex " or " nearby miosis " tool There are two types of consequences: firstly, it reduces aperture, and therefore increasing the depth of focus (reduced bore resistance of the eye as optical system It has filled in far from axis and has entered the light in eye with the sharp angle relative to axis)；And there is maximum bend by being used only The central part of luminous power increases lenticular mean power.

It is obviously found from our research, nearby miosis can only help (to have just multifocal with hyperbola aberration Point property) crystalline lens reach nearly focusing.It is lenticular on single-focusing parabola to influence less, and it is to negative multifocal Property crystalline lens generate adverse consequences: lentiglobus or oval crystalline lens (such as crescent crystalline lens) are because of nearby miosis change At the weaker crystalline lens with lower refractive power rather than the stronger crystalline lens that needs of nearly focusing.

Intraocular lens according to the present invention are for substituting can plant to the hydrogel of human eye back room of natural lens Device.It is designed to simulate or replicate the essential physiology and optical function of natural lens, without generating previously Trial can be led to the problem of in some cases.It should be understood that the combination of the Novel warp deep thinking of these features, can individually make With, or use in different combinations, this is being less susceptible to success in the past.Since the balance of its feature combines, rather than it is single Feature, natural lens also achieve its function.

Facilitate the feature of allomeric function, and assemblage characteristic of the present invention includes: the size and shape of implantation material；Material is special Property；Surface property；Optical characteristics；Method for implantation；And manufacturing method.We will be described hereinafter various features and provide individually special How sign interacts to provide the representative configuration of beneficial effect.It is important to recognize that implantation material can be retouched in conjunction with several The feature stated, to realize desired effects, still, the present invention is not limited to example described below constructions, and including feature Various combinations.

Referring to attached drawing 3A and 3B, implantation material has primary optical axis 1A and central optic portion 2 and peripheral support part 3.It plants Enter the overall shape of object by its front surface 4, rear surface 5 and transitional surface 6 (its coboundary 7A for being located at front surface and rear surface Between the 7B of coboundary) it is defined.Each face is by two or more surface compositions.Before center optical surface 8A have boundary 9A, and in Optical surface 8B has boundary 9B after the heart.Each surface can be divided into two or more areas, boundary between them ( Attached drawing 5A is indicated into 5C with 13A and 13B) it is round, straight line or otherwise determining shape.The top of optical surface before center The vertex 10B of optical surface is positioned on primary optical axis 1A behind point 10A and center.Preceding periphery support surface is 11A and rear perimeter edge branch Holding surface is 11B.

It include lenticular Fig. 6 A, 6B and the 6C of several different materials or layer with reference to description, it should be appreciated that any in optical path Layer or structure can be formed by hydrogel according to the present invention.Preferred layer can be the layer near cornea, that is, be formed crystalline The layer of the preceding optical surface of body.Refraction structure, diffraction structure can be by the optical texture that hydrogel optical modifier is formed, in Fig. 6 B The Fresnel lens shown, infractive index gradient lens etc..This structure can be formed in hydrogel or on the surface thereof, excellent It is formed on optical surface before being selected in.

Boundary 7A and 7B can be identified at the top of front surface 4 and rear surface 5 because of its discontinuity respectively.It is such not Continuity is located at surface in the inflection point of optical axis direction, or the discrete point of the second dervative on the surface of optical axis direction.Boundary It can be round and smooth and continuous, it is advantageous that it is formed by a sharp edges or sharp edge.The advantages of sharp edge, is embodied in shape At the obstacle of cell migration, such as the fibroblast (common cause of posterior capsule opacification) along lens capsule surface.

Crystalline lens overall diameter is defined as the larger diameter of boundary 7A and 7B.Lens optical area diameter is defined as boundary The minimum diameter of 9A and 9B.Rear surface swears that depth is the vertical range between rear vertex 10B and the plane for limiting rear surface boundary 7B. Center thickness is the distance between vertex 10A and 10B.Preceding depth is between preceding vertex 10A and the plane for limiting front border 7A Vertical range.

It is defined in boundary 7A and 7B and boundary 9A and 9B by the circle in the plane perpendicular to optical axis, and if center Opticator 2 is symmetrical, and for example without any circular cylinder shaped portion in the case where, primary optical axis 1A can be symmetry axis.Have This implantation material of symmetrical circle footprint is shown in Fig. 3 B.However, edge and boundary may have different from circular footprint, example Ellipse footprint as shown in Figure 4 A, or 1,2,3 or 4 truncation section 12A to 12D is had into 4E with attached drawing 4B The footprint for cutting off round shape.The shape of these truncation footprints is used for several purposes:

In implantation process, they make it possible to preferably enter the space of crystalline lens rear surface.Importantly, in hand Before art cut closure, the space is cleaned well to remove any viscoelastic polymer or lubricant or other auxiliary agents.

After lens capsule is shunk around IOL, they can prevent lenticular rotation.This is for toric crystalline Body is especially important.

They promote to pass through the folding and insertion of small notch.

In the case where optical device has circular cylinder shaped portion, then cylindrical shaft 1B will be with determining direction positioning, the direction It is relevant to the asymmetry of outer rim, such as the angle [alpha] of section 12A and 12B are truncated shown in Fig. 4 F.Needless to say, section 12A is truncated It is not necessarily to 12D longitudinal sectional, and can also be properly formed for example crescent, and its quantity may be even higher than 4.Also, it cuts Disconnected section may not have identical length or be symmetrically positioned.It is appreciated that the footprint at the edge with truncation will promote to plant Enter object to fold and be inserted by a minor operation notch.In addition, once lens capsule, around its placement, asymmetrical edge footprint will Implantation material is prevented to rotate.This is especially heavy for the torus shape crystalline lens with circular cylinder shaped portion designed for complementary astigmatism phenomenon It wants.

The shape and size of rear surface 5 are to be similar to the shape and size of the rear surface of natural lens, and realize contact At least major part of eyes Lens capsular.This is critically important, the reason is as follows that:

It is its natural shape that implantation material, which will keep Lens capsular, without gauffer and smooth to obtain best optical property；

The close contact of lens capsule and the implantation material will prevent fibroblastic migration, this may cause Lens capsular Opacification；If rear surface is high degree of hydration and carries fixed negative electrical charge, this just becomes to be particularly effective.

The space that implantation material vacates the rear occupied by natural lens, and therefore prevent vitreum advance forward and because This prevents reduction of the vitreum to the pressure of retina (this can lead to detachment of retina and/or cystoid macular edema).

It should be noted that when implantation material contact surface be it is hydrophilic and carry fixed negative electrical charge with prevent cystic fibrosis and When by interference the stiff of implantation material function, opacification and contraction (or even dislocating), then between implantation material and Lens capsular Close contact is it is particularly advantageous that this will be described below.

In a preferred embodiment of the invention, the major part of at least rear surface 5 is by substantially smooth convex What shape surface was formed, which rotates to be formed or the combination on above-mentioned surface is formed by the conic section around optical axis.Periphery It point is preferably formed by conical surface or hyperbolic surface, and the preferred hyperboloid in central optical face, paraboloid or spherical surface (or its group It closes).The arrow of rear surface is deep, and (i.e. the boundary of rear surface central optical vertex of surface 10B and rear surface 7B measures on primary optical axis 1A Vertical range) it should be greater than 1.1mm so that crystalline physical efficiency well runs its function.To keep it good in the performance of entire range of refractive, Arrow is deep afterwards should be greater than 1.25mm, be advantageously greater than 1.75mm, and preferably greater than 2mm, but it is less than about 2.75mm under any circumstance.

The entire outer diameter (LOD) of implantation material is very heavy for its centricity, positional stability and lens capsule filling capacity It wants.The outer diameter of rear surface 5, the i.e. full-size of rear surface outer boundary 7B (in the plane perpendicular to main shaft 1A) should be big In 8.4mm, preferably at least 8.9mm and preferably at least 9.2mm.The maximum outside diameter of permission is about 11mm, but should preferably be lower than 10.75mm, preferably with smaller than

10.5mm.Sizable flexibility of external dimensions, is allowed by several factors --- lenticular flexibility, and it is outstanding It is the flexibility of periphery support part 3, and the latter is suitable for various lens capsule sizes and lens capsule is shunk, in making Heart opticator 2 deforms.

Central optical face can be made of one or more regions with different geometries.The region can be together The heart, in this case, the rear surface boundary 13B between the region in Fig. 5 A can be circle.It region can also be by straight Boundary demarcation, in this case, region can have crescent footprint or wedge-shaped footprint.Various embodiments are shown in Fig. 5 A extremely 5C.The region can be in preceding optical surface or rear optical surface.Fig. 5 A shows rear optical surface and is divided into two with one heart by boundary 13B Optics area --- central optical zone 8B1 and outer optics area 8B2.For example, the rear optical surface of central optical zone 8B1 can be and be used for The spherical surface area or paraboloid area of sharp near vision (sharp near vision), and hyperbola outskirt serve intermediate vision and Remote eyesight.Alternatively, the two regions can have hyperbolic surface with different center radius Ro and/or difference Circular cone coefficient.Each optical surface can also be divided into more than two region.Example shown in Fig. 5 B shows lenticular bow View, the lenticular preceding optical surface 8A are divided into Liang Ge optics the area 8A1 and 8A2 of area equation by straight boundary 13A.These regions Each of have with different optical parameters different shape.Example shown in Fig. 5 C shows lenticular top view, The lenticular preceding optical surface 8A is divided into four pairs of optics area 8A1 and 8A2 by two straight boundaries 13A and 13B, respectively has Different zones and different optical parameters.For example, 8A1 may have refractive power more higher than 8A2 and for closely focusing.These regions One of can have circular cylinder shaped portion.

Two optical surfaces (or their region or part) are by cone interface along the surface that optical axis rotation is formed, or The surface formed by their combination.One optical surface may include or two optical surfaces may include one or more spherical Optics area.Advantageous, at least one optical surface includes at least one hyperboloid, preferably in outer optics area.Preferably, two optics Face respectively includes at least one double-curved areas.Such hyperboloid similar to NCL surface and imitate it some beneficial optics it is special Property.It even further preferably, rear optical surface and preceding optical surface are hyperboloids, or is two or more concentric hyperbolical zones The combination in domain.Crystalline lens at least one hyperbolic surface has so-called hyperbola aberration, this with spherical, ellipse Or the lenticular spherical aberration on crescent surface is exactly the opposite.Crystalline lens with hyperbola aberration is bent at center with highest Luminous power, and (in the crystalline lens with spherical aberration, refractive power is between optical axis with being gradually reduced at a distance between optical axis Distance increase.).The hyperbola aberration facilitates eye and is adjusted by above-mentioned several mechanism.It should be understood that hyperbola aberration is not It can only be generated by the accurate hyperboloid on geometric meaning, and can be by surface steepness usually with the distance away from optical axis Reduced similar surfaces generate.Therefore, " hyperboloid " also means the other similar hyp surface close to this characteristic.

Measure spherical aberration as aperture (or pupil diameter) increases, the negative spherical aberration on hyperboloid shape surface it is absolute Value increases (that is, becoming more negative).Spherical aberration can be indicated with various alternatives, such as wavefront is inclined as unit of micron The difference steepness that perhaps localized optical power reduces from optical axis perhaps reduces refractive power with the increase of aperture or by corresponding to The constant of the cone of this optical curve or the value of form parameter.Those skilled in the art can be easily by one in these values Be converted to the respective value indicated in different ways.Implantation material according to the present invention initially can have any spherical aberration, because Its value can be used method of the invention and carry out postoperative adjustment.

Spherical aberration under final implanting state (that is, after carrying out hydrogel by laser and being modified) is in the hole 4.5mm - 0.1 micron to -2 microns is typically about on diameter.Preferably, final spherical aberration be on the aperture 4.5mm about -0.5 micron to - 1.5 microns, and even more desirably, spherical aberration is about -0.75 micron to -1.25 microns on the aperture 4.5mm.

In order to simulate the optical characteristics of NCL, the circular cone coefficient of preceding optical surface and rear optical surface need to be selected, so that The refractive power of central optic portion 2 is gradually lowered to from the peak on optical axis in the minimum of the periphery of central optic portion 2 Value.

Refractive power is as the steepness declined at a distance between optical axis is dependent on bi-curved form parameter (circular cone coefficient). It should select circular cone parameter that being averaged for refractive power is made to fall to -0.25Dpt/mm to -3Dpt/mm, be advantageously -0.5Dpt/mm Extremely -2.5Dpt/mm, and it is preferably from about -1Dpt/mm to -2Dpt/mm.

The rear surface center radius (in optical axis and rear vertex intersection) of curvature is advantageously 2.5 to 8mm, and preferably from about 3.0 to 5mm.For NCL, the circular cone coefficient of rear surface is advantageously selected from about+3 to about -14, and preferably from about -1 to -8.

The center radius Ro of preceding optical surface 8A is selected as greater than about+3mm, or is less than about -3mm, and is preferably greater than about+5mm Or it is less than -5mm.

For people NCL, the circular cone coefficient of preceding optical surface 8A is selected from+6 to -22, preferably from about -1 to -8mm.

Preceding optical surface 8A can partially or completely by spherical surface or paraboloidal at.In this case, optical surface behind center 8B should be preferably with the hyperboloid of certain circular cone coefficient, which is selected from so that entire crystalline lens has hyperbola aberration Range.

It is preferable, however, that the major part of optical surface 8A is hyperboloid, especially outer optics area before at least.With diameter It is about 1.5 between 4mm, the central optical zone of advantageously about 2 to 3.5mm preceding optical surface can be by paraboloid or spheric At to further increase nearly focusing resolution ratio.

Fig. 2 schematically shows an examples in the lenticular preferred optical cross-sectional of the present invention.It should be understood that different eyes It is required that the lenticular refractive power of implantation is different.

Most of current IOL are not biosimulations, because they are designed to only simulate the basic optical function of NCL It can, that is, basic refractive power needed for the object for focusing distant place on the retina is provided.According to specific eyes, basic refractive power Usually 15 to 30Dpt, in either side, there are some deviations.This requirement can by be located adjacent to NCL principal plane certain The rigid crystalline lens of (usually spherical in shape) of the substantially monofocal at place meets.It is located at because most detailed image is projected onto The relatively small part of retina (spot) on optical axis, and due to we it is many activity all ommatidium aperture (contraction Pupil) carry out, so most of IOL ratio NCL it is significant it is smaller (most of IOL are 4.5 to 6mm, relatively, NCL be 9.5 to 10.5mm).The small size of optical device is had a preference for by some IOL manufacturers, because such IOL is more easily adapted to conform to pass through small notch Implantation.For the same reason, most of IOL is made of soft elastic material, allows through small notch to deform Shape (fold, roll) implantation.However, this deformation is unrelated with optical function.

However, the small size of optical device also has its disadvantage.When (for example, during night running) big pupil opening, The edge IOL meeting reflection light, and cause glare, halation and adverse effect.In addition, small optical device cannot project it is all periphery and Off-axis ray, but NCL can be with especially when big pupil is opened.Finally, the optical device of small size interferes retinal periphery Clear vision power, which is required for diagnosing and treating.For these reasons, it is similar in size to The big optical device of NCL is preferred for for the smaller optical device used in most of current IOL. Importantly, entire big optics area must have the geometry well limited, this is optically useful.With crescent The crystalline lens of shape optical surface is difficult to define its shape, especially in neighboring area.This may result in unexpected and interference optics Phenomenon.

The IOL in some modern times, which is designed to the adjusting of the NCL simulated to a certain extent or quasi- adjust, (allows eyes same When focusing in remote object and nearly object).A variety of IOL realize this target using different means: some be using bifocus, Multifocal (multifocal) or multifocal (polyfocal) optical device；Other designs used allow, relative to eyeball, By IOL optical device front surface --- rear surface is mobile；Or allow by change two crystalline lenses between mutual alignment from And change luminous intensity.Certain crystalline lenses by the liquid in the pressure-actuated crystalline lens of ciliary muscle or vitreum even because moved It moves and changes refractive power, change head position, or crystalline lens is driven by micropump.

The sometimes considerably complicated setting of these designs, has very very much not in size, shape and material property with NCL Together.This makes them be easy to produce various problems, as lens capsule fibrosis or cell ingrowth or proteinosis On its surface, to influence its function.In addition, the design of its increased volume and complexity and all modern times IOL are planted by small notch The needs entered are inconsistent.This needs to design minor diameter optical device and using the material with high refractive index ratio, more than NCL With reflectivity, thus the problem of increasing dazzle and halation.

In most cases, these crystalline lenses use the optical device of minor diameter, and typically 4.5 to 6mm, have thin It is long, it is " tactile " flexible, to place optical device in the center of optical path.In addition, deformable material is used to lead to Small notch is crossed to be folded or rolled up for being implanted into.The surface nature of this IOL is sometimes through modifying, to reach better biocompatibility (for example, A.M Domschke, in U.S. Patent Publication No. 2012/0147323, J.Salamone etc. is in U.S. Patent Publication No. In 2008/0003259).

This universal design allows for folding intraocular implants when being implanted by relatively small notch (usually 2 to 3mm) Body.However, the shortcomings that small IOL size has its own:

If due to light it is bad under conditions of the eyelet diameter that (generates Night Glare, halation, limited peripheral visual acuity etc.) compared with It greatly, is 6mm small light below with diameter or if IOL becomes deviation center (leading to " sundown syndrome " or other problems) The crystalline lens of diameter 9 to 10.5mm may not be able to be substituted completely by learning device；

Small optical device cannot project all surrounding rays and off-axis ray, and NCL can be with, therefore reduces imaging performance, Especially when big pupil is opened (for for example, night peripheral vision)；

Small optical device can complicate or even prevent dynamic retinoscopy and treatment, and (this may be important, and especially exist In the case where diabetes).

In addition, small IOL size keeps the space initially occupied by larger NCL substantially vacant.Therefore, vitreum will be allowed Advance, and it mitigates the pressure portion of retina.This can cause the probability of the retinal detachment after cataract operation to increase, This is reported in J.A.Rowe, J.C.Erie, K.H.Baratz etc. (1999) " Retinal detachment in OlmstedCounty, Minnesota, 1976through1995 " .Ophthalmology 106 (1): 154 159.Similarly Effect can also cause or promote cystoid macular edema (CME).Referring to Steven R.Virata, The Retina Center, Lafayette, Indiana:Cystoid Macular Edema, webpage.

Small optical device and the tactile conventional IOL design of tool have another disadvantage that: using and pass through relatively fragile touching The method of feel be suspended in the optical device of opposite idle space IOL may vulnerable in the case of accidental impact (in smooth surface Slip, car crass, punched) damage and/or dislocation.

Some problems derived from the IOL of small size and the optical device of minor diameter are designed by IOL and are solved, and IOL design exists The position that NCL is vacated is filled in smaller or bigger degree.There is several methods that reaching this purpose, each there is the excellent of oneself Point and disadvantage:

The curable lens capsule of liquid filling is transparent solid flexible such as silicone rubber.As long as filler have with The similar morphotropism of NCL, it is contemplated that this method will restore the adjusting of natural lens (for example, Gasser et al. is in United States Patent (USP) Number 5224957).However, the material being often used so far often results in the fibrosis and opacification of lens capsule.Further, it is difficult to control Make the shape and optical parameter of the IOL being formed in situ.

It is implanted into bulky IOL with the shape after high deformation, makes it through reasonable small notch implantation, and substantially Full of lens capsule.This method is attempted using hydrophobic memory polymer, which can be with the shape of high deformation by " freezing " To be used to be implanted into, and back to original shape, (Gupta is in U.S. Patent number 4,834,750 and the U.S. when being heated to body temperature Patent No. RE 36,150).However, the hydrophobicity memory polymer is very external material and causes and be used to fill crystalline substance Similar problem in material in shape somatocyst.

Similar method was also attempted with hydrogel.Very big IOL substantially imitates the size and shape of natural lens Shape is implanted to the lens capsule (for example, 732 patent of Wichterle ' and this 283 patent of Stoy ') vacated.These are special The problem of IOL is its unique optical device.These crystalline lenses have crescent preceding optical surface, deviate from the several of NCL strongly What shape.Crescent shape is formed by curing by the free surface of monomer mixture, and in the optical characteristics of such IOL There are problems in control.In addition, these crystalline lenses are often excessively heavy in being implanted by small notch.In addition, being used for this A little lenticular some hydrogels lack fixed negative charges, and calcification when such hydrogel has after the implantation some Tendency.The crystalline lens (' 083 and ' 903 of Sulc etc.) of some other filling lens capsules has the front for encountering iris convex It rises, and therefore stablizes crystalline lens in approximate centre position, but various problems can be caused, such as blocking liquid flow, lens optical Deformation and iris corrode.

Another method is the hollow crystalline lens (or crystalline body shell) of implantation, and after implantation, by it, liquid curing is filled out in situ Fill (for example, Nakada et al. is in U.S. Patent number 5,091,121 and 5,035,710).

Another method is that there are two lenticular double optics device IOL for implantation tool, one of them is contacted with anterior capsule, separately One contacts with Lens capsular, two crystalline lenses all by flexible member or connector be held apart at state (U.S. Patent number 4,946, 469；U.S. Patent number 4,963,148；U.S. Patent number 5,275,623；U.S. Patent number 6,423,094；U.S. Patent number 6, 488,708；U.S. Patent number 6,761,737；U.S. Patent number 6,764,511；U.S. Patent number 6,767,363；United States Patent (USP) Numbers 6,786,934；U.S. Patent number 6,818,158；U.S. Patent number 6,846,326；U.S. Patent number 6,858,040；The U.S. The patent No. 6,884,261).

Being substantially filled with such implantation material of the entire lens capsule of Phakic eye, there are also problems:

Unless being made of the extremely biocompatible materials with aquation similar with NCL and negative electrical charge, before IOL Surface may touch iris and cause erosion, colour fading, bleeding or inflammation.

Some materials are by being prepared into more bio-compatible with high equilibrium water content.However, this reduces refractive index Far below optimum value (value of young NCL).

It is important for IOL, it is not only shape and optical device type or its material.NCL is comprising water, salt and to gather The complicated natural hydrogel structure composition of polymer component, the component of polymer contain collagen, polysaccharide and proteoglycans.Weight It wants, the acid ion group of suitable concentration is contained in component of polymer, such as carboxylate radical or sulfate radical.These groups provide Crystalline lens material with fixed negative charge.Aquation and negative electrical charge influence the phase between protein and NCL in intraocular liquid Interaction.In addition, the interaction between its surface properties affect crystalline lens and cell.It is known that having containing surface The synthetic hydrogel of fixed negative charge does not attract protein and cell, and makes hydrogel more anticalcium (Karel Smetana Jr. Deng " Intraocular biocompatibility of Hydroxyethylmethacrylate and MethacrylicAcid Copolymer/Partially Hydrolyzed Poly(2-Hydroxyethyl Methacrylate),”Journal of Biomedical Materials Research(1987)vol.21pp.1247- 1253) foreign matter (Karel Smetana Jr. etc., " The Influence of, and are not considered by immune system Hydrogel FunctionalGroups on Cell Behavior”,Journal of Biomedical Materials Research (1990) volume 24, the 463-470 pages).Although many IOL manufacturers, based on carboxylate radical attract calcium ion and because This leads to the reason of calcification, avoids the material with carboxylate group, still has many bibliography to refer to containing carboxylic acid foundation Group hydrogel IOL (U.S. Patent number 5 of ' No. 732 patents, Sulc of Wichterle etc. ' 083 and ' No. 903 patent, Stoy, 939,208, No. 093 patent of Michalek and Vacik ').

Carboxylate radical can be generally uniformly dispersed in hydrogel, or be concentrated mainly on surface and formed expansion and charge density Gradient, such as be described in the U.S. Patent number 5,158,832 of ' No. 208 patents and Sulc of Stoy.Typically, NCL material is flat The weight containing water is about 66%.However, NCL has been configured to dense-core and more hydration collets, and the aquation of NCL with Change of age varies with each individual.It is thus impossible to the single water content value different from average value of specified NCL.

Similarly, each layer of NCL has different refractive index.Lenticular diopter from central core about 1.406 Drop to the 1.386 of lenticular low-density layer.For example, see Hecht, Eugene.Optics, 2nd ed. (1987), Addison Wesley, ISBN 0-201-11609-X. page 178.Therefore, optically significant equivalent refractive index, or ERI, the characteristic as NCL are presented.Refractive index and water content all change with the crystalline lens age.Average ERI=1.441- The 3.9x10^-4x age, thus from connatae about 1.441 reduce to 70 years old when about 1.414.Referring to M.Dubbelman etc. “TheShape Of The Aging Human Lens:Curvature,Equivalent Refractive Index And TheLens Paradox ", Vision Research 41 (2001) 1867-1877, Fig. 9.

In addition, ERI increases with adjusting, and about 0.0013-0,0015 every diopter.Referring to M.Dubbelman etc., “Change In Shape Of The Aging Human Crystalline Lens With Accommodation”, Vision Research45 (2005), the 127-128 pages of 117-132.People are it may be speculated that this variation of refractive index and water The variation (reduction) of content be it is relevant, this due in adjustment process crystalline lens deforming.Ignore these complex situations, we will Using average ERI=1.42, unless otherwise indicated.

It enjoyably finds, if finding has water content identical as NCL material and simultaneously the synthesis water-setting of identical refractive index Glue is also difficult if not impossible.Specifically, the synthetic hydrogel containing 66% water (weight) usually has about 1.395, rather than 1.42 refractive index, 1.42 refractive index are to be desired for the hydrogel containing the water close to 50%.

The Mean fluid content (very young average NCL) of ERI=1.441 is the water with 40%, and for ERI= It is about the hydrogel of 55% (by weight) that 1.414 (the average NCL of aging), which need water content,.Due to it is considered that for biology IOL material is simulated, simulation refractive index is more important than the water content for simulating NCL, we have selected exemplary embodiment party of the invention The expectation average water content range of the IOL of case, between 40% and 55% (by weight).Certainly, this is that average water contains Amount --- similar with NCL, crystalline lens can have a variety of layers with different water contents, for example, internal have higher dioptric Rate and outer layer have compared with low-refraction

Many existing technical literatures refer to the IOL from the hydrogel with high water content, however, they do not recognize Water content and refractive index value between relationship.For example, the specified desired refractive index value of ' 732 patents of Wichterle is 1.4 or so (broadly for 1.37 to 1.45, this be clearly be to the known synthetic hydrogel with specified water content impossible , the specified water content is at least 60% and preferred 65-70%, is converted into the refractive index that range is from 1.39 to 1.405). Embodiment shows the preparation with the low carboxylate group of content.

Sulc etc. is in patent ' 083 and ' discloses in 903 in the upper water content at least 70% in surface or part thereof and preferably extremely Few 90%, and mention the water content of the 55-70% in the IOL of the prior art.Refer to core with higher refractive index and have compared with The shell of low refractive index, and core can have the form of Fresnel lens.Aquation and the gradient of refractive index optionally pass through NaOH It handles and obtains, the recombination of hydrogel covalent networks is realized in the NaOH processing.The embodiment 1 of the bibliography shows IOL Water content be 88.5%, embodiment 2 show IOL water content be 81% and embodiment 4 show with water content 91% Crystalline lens.Embodiment 3 does not provide water content.

Charles Freeman describes water content lower than 55% and is bent in U.S. Patent Publication No. 2009/0023835 Light rate is greater than 1.41 hydrogel material, and sodium ion fluxes are about 16 to about 20micro.eq-mm/hr/cm², for crystalline Body back room IOL is particularly useful.Carboxylic group or acidic-group are not mentioned, it is known that although their presence, which increases, passes through hydrogel Ion diffusion flux.

The hydrogel character of NCL material has certainly possible, less obvious but has potential great influence: its water contains Amount is dependent on to lenticular pressure.Therefore, it is directed at the NCL of distant place, relative to the crystalline lens for the relaxation for being directed at nearly object, can be had Different water contents, and therefore there is different refractive indexs.Due to alignment distant place NCL pressure be not it is equally distributed, can Lead to the gradient of expansion and the gradient of refractive index.Other than the multifocal on the surface NCL, this will also generate the micro- of optical property Wonderful variation.These subtle variations may be important our eyesight, and it is difficult to be imitated, unless by using having The hydrogel of similar with NCL physicochemical properties and optical characteristics and similar geometry.In particular, NCL substitute Hydrogel should have similar refractive index and water content is changed by the external stress that can be acted on NCL with rational expectation Ability.Therefore, the hydrogel used in the IOL of biosimulation should have the ability to the turbulent flow of water.

Therefore, a part at least contacting the implantation material of Lens capsular is made of transparent flexible hydrogel material, close to shape It is carried out at optical characteristics, hydrophily and the electrochemical properties of natural lenticular tissue.

The front of IOL may interfere with or even prevent the flowing of vitreum body fluid, so that the increase of intraocular pressure is caused, And eventually lead to glaucoma.This design generally requires to carry out iridectomy first.

Unless prepared using the extremely biocompatible materials with aquation similar with NCL and negative electrical charge, it is crystalline Somatocyst and coming into contact in a large area between the artificial material that current IOL is used, cause lens capsule opacification, fiber sometimes Change etc..Biosimulation intraocular lens of the invention are solving these problems.

Central optic portion 2 by deformable elastic material, such as equilibrium water content about 35 to 65%, advantageously between (all % are weight percent, and equilibrium water content is intraocular liquid between about 38% to 55% and preferably about 40% to 50% Hydrogel water content when in equilibrium state, unless otherwise indicated) is made.

The deformability of optical component for by small notch carry out implantation and its regulatory function be all critically important.Optics Component may be structured to hydrogel shell, and the core constituted with liquid or soft gel, as shown in FIG.Fig. 6 A, which is shown, to be had The lenticular cross-sectional view of rear surface hydrogel collet 14, softer core 15 and front housing 16.Advantageously, rear surface hydrogel collet 14 with 3 groups of lenticular peripheral support part it is integral be advantageous, and 14 at least contain fixed negative charge on surface behind. Core 15 can be advantageously made by hydrophobic liquid (such as mineral oil or silicone oil), or be coagulated by soft silicone or acrylic acid are slightly cross-linked Glue is made, this easily can be designed and be created by those skilled in the art.Alternatively, core can be by hydrophylic fluids or soft water Gel is made.Front housing 16 can be made of the material identical or different with rear surface hydrogel collet 14.

In one embodiment, hydrogel collet and soft core 15 have essentially identical refractive index, so that the master of refraction Mian part distribution is raw on lenticular outer optical surface, rather than in its inner boundary.This can for example be achieved by the following way: by silicon Core made of ketone liquid or silicone gel (refractive index with about 1.42), and (water content is between about 41 to 45% by hydrogel Water) made of collet.By correctly preparing hydrogel, the adjustable water in the hydrogel of those skilled in the art Content is substantially matching with the refractive index that reaches.Alternatively, core and collet can have different refractive index, to make to reflect Part occur on inner boundary between the materials.

Fig. 6 B shows lenticular cross-sectional view, and the crystalline lens is in core 15 and to form compound lens (Fresnel lens) And there is internal interface between the adjacent optical media 16 shaped.The material of the core 15 and optical medium 16 has different Refractive index, and advantageously, one of them is the deformability that the two can be improved and the fluid of refraction.The benefit arranged in this way It is that possible be able to use the hydrogel with high water content and low-refraction to realize as basic structure material, and also, allows The lenticular relatively low center thickness being implanted by small notch.

Fig. 6 C shows lenticular alternate design comprising two different materials.Material at rear 14 is that have height Hydration rate and the hydrogel for containing negatively charged group.It is identical as opticator and support section.The front of core 15 Material is the material with low water content and high refractive index.Interface between two kinds of materials is refractive.

The diameter of optical surface 8B is all larger than about 5.6mm behind optical surface 8A and center before center, be advantageously greater than about 6.5mm and Preferably greater than about 7.2mm.Biggish one optimum diameter is greater than about 7.5mm in two optical surfaces, and advantageously about 8mm is with approximation The size of NCL optical system.Optical device big in this way is commonly available to convex-concave or plano-convex central optic portion 2.For Convexo-convex optical component, preceding optical diameter generally select smaller, are minimized the center thickness of optical component.Any In the case of, the diameter of the preceding optical surface 8A is advantageously not more than the diameter of optical surface 8B behind center.

Central optical face 8A and 8B is surrounded by boundary 9A and 9B (being not necessarily circle).Boundary 9A and/or 9B can also be with It is ellipse or with cutting off round shape, for the ease of being folded by small notch and implantation crystalline lens.Non-circular optical surface Particularly suitable for the crystalline lens with circular cylinder shaped portion.

Rear perimeter edge support surface 11B is formed by nonreentrant surface, and hyperboloid or conical surface are advantageously, have with The identical axis of primary optical axis 1A.This surface is highly hydrophilic and carries fixed negative electrical charge, this is attributed to acidic groups The content of group's (such as carboxylate group, sulfo group, sulfate groups or phosphate groups).Aquation and negative electrical charge it is this Combination can prevent from being permanently adhered on lens capsule, prevent cell (especially fibroblast) along crystalline lens and lens capsule Between interfacial migration, reduce irreversible protein adsorption, and hinder cystic fibrosis and opacification.Advantageously, rear circumferential surface by Sharp edge 7B limitation, further block cell are migrated to optical region.

Preceding periphery support surface 11A is concave surface, and vertex is located on optical axis, and it is preferably symmetrical along axis 1A.Advantageously, It is conical surface or hyperbolic surface, and its axis is overlapped with primary optical axis 1A.Advantageously, surface is highly hydrophilic and takes Band fixed negative charge, to prevent cell adherence and migration and preceding cystic fibrosis.Advantageously, preceding circumferential surface is limited by sharp edge 7A, Its further block cell migration.

Preceding periphery support surface 11A and rear perimeter edge support surface 11B and joint face 6 together define peripheral support part 3 Shape.The peripheral support part is convex surface at rear, is concave surface in front, the average distance between the two surfaces Range is about 0.05 to 1mm, is advantageously about 0.1 to 0.6mm, preferably from about 0.15 to 0.35mm.Optimum distance depends on material The rigidity (stiffness) of material, this depends on water content, negative charge density, crosslink density and other parameters.

If rear surface and front surface are formed by the surface (such as hyperbolic surface) of similar geometry, periphery branch Uniform thickness will be had by holding component 3.Arrangement shown in fig. 7 this have the advantage that easily deformable and according to lens capsule Different sizes be adjusted, and two sharp edges 7A and 7B prevent fibroblasts from migrating to optics area.

Peripheral support part 3 can also be made into more difficult change from the extrorse thickness in center by increaseing or decreasing it Component that is shape or more easily deforming, is shown in Fig. 7 B and 7C.These attached drawings also show a variety of substitutions of edge 7A and 7B Property arrangement.

The front surface 4 of implantation material is shaped, to avoid with iris it is any it is permanent contact, which may cause iris Erosion, pupillary block, iris pigment are transferred to implantation material and other problems.This contact may also interfere the flowing of intraocular liquid, So as to cause the undesirable change of intraocular pressure.It may also interfere pupil contraction, and to prevent so-called neighbouring miosis, neighbouring miosis is helped In the nearly focusing of natural lens and implantation material of the invention.Therefore, optical surface 8A component part sinks before center, this is because Preceding periphery support surface 11A recess portion and due to being positioned at boundary 9A under the plane limited by front border 7A.Center front surface 8A It is plane, convex surface or concave surface, preceding vertex 10A is more than that the limit of lenticular highest point (the higher person of 7A and 7B) is up to about 0.25mm is advantageously more than top edge, and preferably has preceding vertex 10A not at all, below the 7A of highest point at least 0.1mm。

At least major part (8A and 8B of face containing central optical) of front surface 4 and rear surface 5 is all to pass through one or more What conic section was defined around primary optical axis 1A rotation.Wherein term " conic section " includes the piece for the purpose line of the application Section.The surface as defined by rotation will include perpendicular to the plane of axis and along the symmetrical conical surface of primary optical axis 1A.Periphery branch It is convex surface that component, which is held, at rear, is concave surface in front, the average distance range between the two surfaces be about 0.05 to 1mm is advantageously about 0.1 to 0.6mm, preferably from about 0.15 to 0.35mm.

In at least one embodiment, crystalline lens of the invention is to solidify to manufacture by liquid polymer precursor. In preferred embodiments, solidification occurs in contacting with solid model, and especially the mold with hydrophobic plastic manufacture connects Touching.It is understood that the surface microstructure of polymer, which depends on it, solidifies the environment occurred.If solid-liquid circle occurs for solidification On face, occur with it in liquid-liquid or liquid-gas interface, surface micro-structure will be different.Preferably, at least all optical surfaces are It is formed by curing by precursor in solid interface.Even further preferably, the whole surface of implantation material is by liquid precursor in the surface of solids (especially hydrophobic plastic surface) is formed by curing.Preferred plastic mould is polyolefin, and especially preferred plastics are polypropylene. Polyolefin has low polarity, and has and be used as the highly polar monomer of hydrogel precursor with lower interaction.Similarly, The hydrogel being formed by curing by liquid precursor has a low-down adhesive attraction to die surface, and can be even without appointing What neatly removed in the case where microcosmic surface damage.This is for optical property and for the long-term biocompatibility of implantation material It is all important.

It is difficult by the crystalline lens that molding manufactures sizable accurate shape.Those skilled in the art is it is known that before liquid Any solidification of body is all with the volume contraction possibly even beyond 20%.In the closed mould of constant volume, such receipts Contracting can prevent the duplication on inner mould surface, and result in vacuole, bubble, surface deformation and other defect.Here it is be assorted The main reason for casting method of above-mentioned new lunar surface is molded for IOL.A kind of method and mould has been described in other inventors Tool design, allow excessive monomer can be transferred from adjacent by suction that volume contraction generates (Shepherd T., U.S. Patent number 4,815,690).But this method cannot be used for such situation, wherein due to cross-linked polymeric, before liquid Body is with low-conversion (for example, 5% to 10%) gelation (gellify).

We have discovered the distinct methods of volume contraction compensation, that is, due to the deformation of certain mold components, in reduction Portion's cavity volume.Mold shown in Fig. 8 is made of two component 18A and 18B, and 18A component is used for moulding front surface 4,18B component In molding rear surface 5.

The forming surface 19B of 18B component is with shape needed for forming lenticular rear optical surface 8B.The week of molded surface Enclosing component 22B, there is the diameter greater than lens diameter advantageously to have hyperboloid or cone.

18A component has forming surface 19A, and being divided into makes the lenticular molding central module 21A of preceding optical surface 8A, It is greater than the peripheral parts 22A of lens diameter with diameter.Advantageously, circumferential component 22A has hyperboloid or cone.Outer weekly form Face 22A is roughly parallel to the respective surfaces 22B of 18B component.

The diameter of the mold component 18A and 18B of molded item are generally bigger than lenticular diameter, and advantageously, they are phases With.One of surface of 22A or 22B is equipped with relatively thin and deformable barrier 20, with corresponding to lenticular table The inner surface of the geometry in face 6.The height of 20 components is typically between about 0.05mm to 1.3mm, and its thickness is than its height It is smaller.The section of component 20 is advantageously wedge-shaped or triangle.At least one its surface is desirably parallel to optical axis 1A.Barrier 20 It can be opened by component 18A and 18B points, but advantageously, barrier 20 is the component part of one of them.Advantageously, the component 20 Positioned at concave surface 22B.In the preference pattern of operation, liquid precursor is filled into female mold part 18B, it is slightly excessive to reach more than Then barrier 20 covers it with 18A component.Mold is built into such a mode, unique between component 18A and 18B Contact is by component 20.Precursor solidify generation shrink and the pressure in die cavity reduce therewith.In low-conversion, add Liquid precursor be drawn into die cavity.Once reaching gel point due to crosslinking, precursor can no longer flow.Reduced pressure will Cause component 20 to deform, and causes the distance of component 18A and 18B to reduce, and cavity volume is then reduced.IOL's of the invention Two parts mold is preferably by using polyolefin (advantageously using polypropylene) injection molding.

Currently preferred liquid precursor be acrylic monomers and/or methacrylic acid monomer and crosslinking agent, initiator and Well known to a person skilled in the art the mixtures of other compositions.Preferred precursor component includes acrylic monoester and/or methyl-prop The mixture of the monoesters and diester of olefin(e) acid and ethylene glycol, wherein monoesters is hydrophilic ingredient, and diester is crosslinking agent.Before preferred Body further includes acrylic acid and/or methacrylic acid or its salt.Advantageously, it further includes the ultraviolet radiation absorption with polymerizable double bond Molecule, such as methacrylyl oxygroup benzophenone (MOBP).Other possible derivatives or acrylic or methacrylic acid are them Ester, amide, amidine and salt.

In addition, the part of hydrogel structure is the ionogen with negative electrical charge, such as carboxylate radical side group, sulfate radical side Base, phosphate radical side group or sulfonate radical side group.They can by with it is suitable with these groups (such as methacrylic acid or acrylic acid) When monomer copolymerization and be introduced into.In this case, ionizable functional groups can be generally uniformly dispersed in hydrogel.Especially have Benefit is the hydrogel with ionogen, and wherein ionogen is concentrated mainly on the gradient with expansion and charge density Surface on.Such gradient can be created by moulding lenticular post-processing, such as the method described by Stoy ' 208 With Sulc etc. U.S. Patent number 5,080683 and 5,158,832 method.

Other methods include, such as include the monomer of ionogen in lens surface grafting.It should be understood that can only handle A part of lens surface, so that its ionogen for containing high concentration or the different parts on surface can be by different sides Method is handled.

Crystalline lens of the invention can be in deformation and the implantation of partially dehydrated state.It is controlled it is partially dehydrated can be by making crystalline lens With physiologically acceptable salt (such as chloride of magnesium chloride, magnesium sulfate or magnesium phosphate or monovalention, sulfate or phosphate, The monovalention such as sodium or potassium) appropriate hypertonic aqueous solution contact to realize.Adjustable salinity, to realize between about The aquation of 15% and 25% (liquid weight).Advantageously, the crystalline lens in hypertonic solution can be disappeared by high pressure sterilization Poison.

Another method for being prepared as the hydrogel lenses being implanted by the notch for reducing size is with such Hydrogel is plasticized by mode by the organic water-miscible solvent of non-toxic (such as glycerol or dimethyl sulfoxide), so that the plasticising The softening temperature of hydrogel is higher than room temperature but is lower than eye temperature.This component and method are described in the U.S. of such as Sulc et al. The patent No. 4,834,753 is incorporated herein by the bibliography herein.

The crystalline lens of at least one embodiment according to the present invention is advantageously to be planted with permeating nonequilibrium state Enter, to be temporarily attached to tissue.Infiltration nonequilibrium condition makes when lens capsule is shunk around it, by adhering to crystalline lens In on Lens capsular, making crystalline lens be located at center.Once crystalline lens is encapsulated by lens capsule, position is stablized.Permeate non-equilibrium energy It is accomplished in several ways: before being implanted into hypertonic salt solution, impregnating crystalline lens, hypertonic salt solution is for example between 10% To the solution of 22% (NaCl weight), advantageously 15% to 19% (weight)；Water is replaced by before being implanted into smaller dense The solvent miscible with water of degree, the solvent miscible with water such as glycerol or dimethyl sulfoxide；Or ionogen not (i.e. in and before acid state) implantation crystalline lens completely in the state of ionization, and by the cation of body fluid in situ from Hair is neutralized.After implantation, within a few hours to a couple of days, crystalline lens spontaneously realizes its osmotic equilibrium.

Lens shapes are preferably ester and salt by methacrylic acid and/or acrylic acid in two parts mold of closure It is formed by copolymerzation with cross-linking.

Lenticular shape can be adjusted after forming, this can by remove the lenticular mode in part, such as By cutting off a part of support part, by boring crystalline lens etc. outside optics area.Shape adjustment can be in hydrogel or or dry solidifying It is carried out under glue (i.e. non-hydrated) state.We have found that negatively charged hydrogel material even allow for using mainly for The method of living tissue (including NCR) exploitation, such as ultrasonic lens emulsification, burn or the method for femtosecond laser processing.These sides Method allows to adjust shape even if fully hydrated hydrogel state.It is crystalline that femtosecond laser even may be used to form hydrogel The internal cavities of body may be used to form crystalline intracorporal new refractive component, such as cylindric crystalline lens for dissipating Light compensation.It is water-soluble and substantially nontoxic situation in the substance removed by shape adjustment (for example, passing through laser treatment) Under, it is even contemplated that the adjusting of this optics can be realized in situ after surgery.Water in lenticular at least processed part Gel component should be beneficially based on the ester of polymethylacrylic acid.It is known that such polymer can be depolymerizated into theirs Parent monomers (such as 2-hydroxyethyl methacrylate or methacrylic acid), the parent monomers are that have good soluble, toxicity Low easy diffusion compound.Other polymers, such as polyacrylate, polyvinyl or polyurethanes do not have this The advantage of sample.

The present invention is further illustrated by the examples that follow, and is intended to provide the hair of the invention without limitation of additional information Bright range.

Embodiment 1:

Following monomer mixture is prepared as follows: 2-hydroxyethyl methacrylate (HEMA), 0.5 parts by weight of 98 parts by weight Triethylene glycol dimethacrylate (TEGDMA), the methacrylyl oxygroup benzophenone (MOBP) of 1 parts by weight, 1 weight The methacrylic acid, the camphorquinone (CQ) of 0.25 parts by weight and the triethanolamine (TEA) of 0.05 parts by weight of part.Mixture is used Carbon dioxide degasification is simultaneously filled into two parts plastic mould shown in Fig. 8, and wherein 18B is for moulding crystalline lens rear surface The component of mold, 18A are the components for the front on lenticular surface to be divided to molding mold.This two component is all made of poly- third Alkene (PP) injection molding.Component 18B forming surface 19B have by two concentric hyperboloids at shape.The center on surface Partial diameter is 3mm, and center radius is 3.25mm and circular cone coefficient is -3.76, and periphery is hyperboloid, and center radius is 3.25mm and circular cone coefficient are -6.26.Molded surface has symmetrical equipped with circular barrier 20 outstanding, diameter 8.5mm Triangular cross-section is highly 0.2mm.It is designed to form the joint face 6 in Fig. 3 A.

Component 18A has molded surface 19A, is divided into around the central part 21 and diameter 13mm of diameter 6.8mm Part 22A.The hyperboloid that the peripheral part by center radius is 3.25mm and circular cone coefficient is -6.26 at.Periphery hyperboloid It is parallel to the respective surfaces of component 18B.The center radius of the curvature of the central part of component 18A is 20mm and circular cone coefficient h= 1。

The monomer mixture of about 0.1ml is moved in component 18B, is then covered it with component 18A, component 18A quilt It is careful placed in the middle and gently pressed with small weight.Unique directly contact is barrier 20 and peripheral part of 22A between each section Between annular contact.Then mold blue light is irradiated 10 minutes in wavelength 471nm.The polymerization of light-initiated monomer, and companion With the gelling of volume contraction in relatively low conversion ratio and substantially proportional to conversion.The contraction of soft gel generates mild true Two parts of mold are pulled together by sky.Circular cone peripheral part 22A of mold 18A squeezes barrier 20, it is slightly distorted simultaneously Close to part 18B, to reduce the volume of die cavity.Which compensates the volume contractions that polymerization generates.Described mold design, especially Suitable for the IOL relatively large with the material production volume with high polymerization shrinkage, which assigns in relatively low conversion ratio To gel point.

Mold component is separated, and xerogel crystalline lens (exact duplicate of die cavity) sodium bicarbonate solution is neutralized simultaneously It is extracted with isotonic solution.Linear expansion coefficient between xerogel and hydrogel lenses is 1.17.After evaluating optical characteristics, Crystalline lens is immersed in sealing blister package in the NaCl aqueous solution of 18% (by weight) and passes through high pressure sterilization.

Embodiment 2:

Following monomer mixture is prepared as follows: 2-hydroxyethyl methacrylate (HEMA), 0.5 parts by weight of 94 parts by weight Triethylene glycol dimethacrylate (TEGDMA), 4.5 parts by weight methacrylyl oxygroup benzophenone (MOBP), 1 weight Measure the methacrylic acid of part and the dibenzoyl peroxide of 0.25 parts by weight.Mixture using the degasification of nitrogen carbon and is filled into Fig. 8 Shown in two parts plastic mould.The forming surface 19B of component 18B has the shape formed by two concentric surfaces.Surface Central part diameter be 3mm, center radius is 3.00mm and circular cone coefficient is 1, and peripheral portion is hyperboloid, center Radius is 3.25mm and circular cone coefficient is -6.26.Molded surface is equipped with circular barrier 20 outstanding, diameter 8.8mm, tool There is symmetrical triangle section, is highly 0.15mm.The inside of barrier 20 is designed to form the joint face 6 in Fig. 3 A.

Component 18A has molded surface 19A, is divided into around the central part 21 and diameter 13mm of diameter 7.1mm Part 22A.The hyperboloid that the peripheral part by center radius is 3.25mm and circular cone coefficient is -6.26 at.Periphery hyperboloid It is parallel to the respective surfaces of component 18B.The central part of component 18A is perpendicular to the plane of optical axis 1A.

The monomer mixture of about 0.1ml is moved in component 18B, is then covered it with component 18A, component 18A quilt It is careful placed in the middle and gently pressed with small weight.Unique directly contact is barrier 20 and peripheral part of 22A between each section Between annular contact.Then mold is heated 6 hours at 75 DEG C.

Mold component is separated, and xerogel crystalline lens (exact duplicate of die cavity) is neutralized with sodium bicarbonate solution, And extracted 3 times with ethyl alcohol, isotonic solution extracts 5 times.The crystalline lens is yellow, is absorbed and with to the whole of UV light to indigo plant Color visible light partially absorbs.Linear expansion coefficient between xerogel and hydrogel lenses is 1.13.It is special in evaluation optics Property after, sealing blister package in by crystalline lens immerse 15% (by weight) NaCl aqueous solution in and pass through high pressure sterilization.

Embodiment 3:

Following monomer mixture is prepared as follows: 2-hydroxyethyl methacrylate (HEMA), 0.5 weight of 94.5 parts by weight Part triethylene glycol dimethacrylate (TEGDMA), 5 parts by weight methacrylyl oxygroup benzophenone (MOBP) and The dibenzoyl peroxide of 0.25 parts by weight.Mixture using the degasification of nitrogen carbon and is filled into two parts the modern designs of plastics shown in Fig. 8 In tool.The forming surface 19B of component 18B has the shape formed by two concentric surfaces.The diameter of the central part on surface is 6.5mm, center radius is 4.5mm and circular cone coefficient is 0, and peripheral portion is hyperboloid, and center radius is 4.25mm and circle Boring coefficient is -8.For molded surface equipped with circular barrier 20 outstanding, diameter 9.3mm is high with symmetrical triangle section Degree is 0.35mm.The inside of barrier 20 is designed to form the joint face 6 in Fig. 3 A.

Component 18A has molded surface 19A, is divided into around the central part 21 and diameter 13mm of diameter 6.4mm Part 22A.The hyperboloid that the peripheral part by center radius is 4.25mm and circular cone coefficient is -8 at.Periphery hyperboloid is parallel In the respective surfaces of component 18B.The central part of component 18A is that diameter is 6.4mm, and center radius is -3.75mm and circular cone system The surface that number is -6.

The monomer mixture of about 0.1ml is moved in component 18B, is then covered it with component 18A, component 18A quilt It is careful placed in the middle and gently pressed with small weight.Unique directly contact is barrier 20 and peripheral part of 22A between each section Between annular contact.Then mold is heated 6 hours at 75 DEG C.

Mold component is separated, and takes out xerogel crystalline lens (exact duplicate of die cavity).Then crystalline lens is used into season Alkali process, this description is in bibliography Stoy ' 208.

By clear, Z crystalline lens made of the cross-linked hydrophilic polymer of electroneutral have by with hyperhydrated effect with The surface that the gradient layer of negative charge density is created.The crystalline lens is neutralized with sodium bicarbonate solution, and is extracted 3 times with ethyl alcohol, etc. Osmometer solution extracts 5 times.The crystalline lens is clear, the adjoint whole absorption to UV light.Xerogel and hydrogel lenses it Between linear expansion coefficient be about 1.12.After evaluating optical characteristics, crystalline lens is immersed into NaCl etc. in sealing blister package In isotonic aqueous and pass through high pressure sterilization.

Embodiment 4:

The Raman spectrum of hydrogel of the invention shows original hydrogel and the focus on light beam by being exposed to femtosecond laser The significant difference between same hydrogel handled through TPA.That is, corresponding to the 3420cm of water^-1The signal at place with correspond to polymerize The 2945cm of the CH2 group of owner's chain^-1There are significant difference for the ratio of the signal at place (referring to Fig. 9 A).Between the intensity at two peaks Ratio and modified and non-modified material between phase shift (number of wavelengths) of testing laser beam it is proportional (referring to Fig. 9 B). The Raman scanning of modification band in hydrogel shows that the water content in treated areas increases (referring to Fig. 9 C).Another party Face, 2000cm^-1The Raman spectrum of following region does not show new chemical group.This is incited somebody to action with by the mechanism (such as depolymerization) It is consistent that partial polymer substance is replaced into waterborne liquid.

According to aforementioned specification, these and other advantages of the invention are apparent to those skilled in the art 's.It therefore, can be to upper it will be appreciated by those skilled in the art that in the case where not departing from extensive inventive concept of the invention Embodiment is stated to modify or change.It will be understood, therefore, that the present invention is not limited to some special embodiments described herein, But it is intended to include all modifications in scope and spirit of the present invention defined in the claims and change.

Claims (55)

1. a kind of hydrogel of covalent cross-linking, it includes the lists containing (methyl) acrylic acid derivative and/or (methyl) acrylic acid The polymer of body unit and include the absorbing inclusion agent part UV and activator moiety negatively charged at physiological ph, wherein complete Full hydrated hydrogel, which is exposed to electromagnetic radiation, leads to two-photon absorption, cause hydrogel one or more structure changes and The negative variation of infractive index.

2. hydrogel according to claim 1, wherein the dopant part and the activator moiety are polyacrylic acid Side group on ester or polymethacrylate polymer.

3. hydrogel according to claim 1, wherein the dopant part is the light for not absorbing about 400nm wavelength strongly UV absorption compound.

4. hydrogel according to claim 1, wherein the dopant part is selected from rhodamine, benzophenone, tonka-bean Element, fluorescein, benzotriazole and its derivative compound.

5. hydrogel according to claim 1, wherein the activator moiety be containing carboxylate group, sulfonate group, The compound of sulfate groups or phosphate groups.

6. hydrogel according to claim 1, wherein one or more structure change includes the hydrogel Part depolymerization.

7. hydrogel according to claim 6, wherein the part depolymerization forms aqueous filling in the hydrogel Gap.

8. hydrogel according to claim 6, wherein the depth of the part depolymerization of the hydrogel is depended in institute State the cumlative energy that the given position of hydrogel absorbs.

9. a kind of ophthalmic implant, it includes hydrogels according to claim 1.

10. the cross-linked hydrogel ophthalmic implant that one kind can be adjusted in situ, it includes acrylate or methacrylate copolymers Object hydrogel, wherein the copolymer includes at least four comonomers:

A) acrylate or methacrylate containing at least one pendant hydroxyl groups；

B) polyalcohol acrylate or amide or polyalcohol methacrylate or amide, wherein each polyol ester or amide With at least two acrylate or methacrylate group；

C) derivative of the acrylic or methacrylic acid at least one carboxyl side group；With

D) vinyl, the acrylic or methacrylic acid monomer of group side group are absorbed with UV；

Wherein the ametropia characteristic of the implantation material controls target electromagnetic radiation by the hydrogel and absorbs to adjust, to lead Cause the negative variation of infractive index at the selection position of the implantation material.

11. hydrogel eye surgical implant according to claim 10, wherein the implantation material has preceding refractive surface and bends afterwards Smooth surface forms the crystalline lens with positive or negative refractive power.

12. hydrogel eye surgical implant according to claim 11, wherein the crystalline lens is Medium Culture crystalline lens.

13. hydrogel eye surgical implant according to claim 11, wherein the crystalline lens is anterior lens.

14. hydrogel eye surgical implant according to claim 11, wherein the crystalline lens is to be placed in iris and natural crystalline Phakic crystalline lens between shape body.

15. hydrogel eye surgical implant according to claim 11, wherein the crystalline lens is at least partly replacing For the posterior chamber phakic of natural lens.

16. hydrogel eye surgical implant according to claim 11, wherein at least one of described refractive surface be with The aspheric surface of negative spherical aberration.

17. hydrogel eye surgical implant according to claim 10, wherein the monomer of oxatyl-containing lateral group is neutralized or warp The methacrylic acid that part neutralizes.

18. hydrogel eye surgical implant according to claim 10, wherein all monomeric units based on copolymer, contain carboxylic The monomer of base side group exists with the concentration of 0.1 mole of % to 5 moles of %.

19. hydrogel eye surgical implant according to claim 18, wherein all monomeric units based on copolymer, contain carboxylic The monomer of base side group exists with the concentration of 0.5 mole of % to 2 moles of %.

20. hydrogel eye surgical implant according to claim 10, wherein all monomeric units based on copolymer, contain UV The monomer of group side group is absorbed to exist with the concentration of 0.1 mole of % to 5 moles of %.

21. hydrogel eye surgical implant according to claim 20, wherein all monomeric units based on copolymer, contain UV The monomer of group side group is absorbed to exist with the concentration of 0.2 mole of % to 2.5 moles of %.

22. hydrogel eye surgical implant according to claim 10 contains and fragrance wherein the UV absorbs group side group The phenolic hydroxyl group that race's group combines.

23. hydrogel eye surgical implant according to claim 22, wherein all monomeric units based on copolymer, contain UV The monomer of group side group is absorbed to exist with the concentration of 0.1 mole of % to 5 moles of %.

24. hydrogel eye surgical implant according to claim 10, wherein the UV absorbs at least one in group side group Kind is selected from the derivative of benzophenone, the derivative of benzotriazole, the derivative of cumarin and the derivative of fluorescein.

25. hydrogel eye surgical implant according to claim 10, wherein the carboxyl side group and the UV absorb group Side group exists with the molar ratio of about 0.25 to about 5.

26. hydrogel eye surgical implant according to claim 25, wherein the carboxyl side group and the UV absorb group Side group exists with the molar ratio of about 0.5 to about 3.5.

27. hydrogel eye surgical implant according to claim 10, wherein copolymer, which contains, absorbs group containing different UV At least two different copolymer monomers.

28. hydrogel eye surgical implant according to claim 27, wherein at least one of UV absorption group is Benzophenone or derivatives thereof.

29. ophthalmic lens according to claim 11, wherein the carboxyl side group is ionization, the carboxyl of ionization It is about 0.5 to about 3.5 that side group and UV, which absorb the molar ratio of group side group,.

30. ophthalmic lens according to claim 11, wherein at least most of polymer of the hydrogel is methyl The hydrophilic derivant of acrylic acid.

31. ophthalmic lens according to claim 30, wherein hydrophily methacrylic acid derivative is at least most of For the diol ester of methacrylic acid.

32. ophthalmic lens according to claim 11, wherein the hydrogel of the covalent cross-linking is in physiology of balance condition The lower liquid containing greater than 30 weight %.

33. ophthalmic lens according to claim 11, wherein the hydrogel of the covalent cross-linking is in physiology of balance condition The lower liquid containing less than 55 weight %.

34. ophthalmic lens according to claim 11, wherein the hydrogel of the covalent cross-linking is in physiology of balance condition Under contain 35 weight % to the liquid of 47.5 weight %.

35. ophthalmic lens according to claim 11, the wherein at least described rear optical surface helps have negative sphere mapping The dioptric of difference.

36. ophthalmic lens according to claim 11, wherein it is -0.1 that optical surface, which facilitates negative spherical aberration, after described The dioptric of micron to -2 microns.

37. ophthalmic lens according to claim 36, wherein the negative spherical aberration is -0.5 micron to -1.5 microns.

38. the ophthalmic lens according to claim 37, wherein on the aperture of > 4.5mm, the negative spherical aberration is- 0.75 micron to -1.25 microns.

39. ophthalmic lens according to claim 11 are absorbed comprising the UV containing the phenolic hydroxyl group in conjunction with aromatic system Property group side group and the UV of the structure containing benzotriazole absorb both groups.

40. ophthalmic lens according to claim 39, wherein the UV containing the phenolic hydroxyl group in conjunction with aromatic system The UV of absorbing group side group and the structure containing benzotriazole absorbs group and is located in the separated layer of the ophthalmic lens.

41. ophthalmic lens according to claim 11, wherein in the lens implanting cornea.

42. ophthalmic lens according to claim 11, wherein eye of the lens implanting between cornea and iris In anterior chamber.

43. ophthalmic lens according to claim 11, wherein the crystalline lens is to be implanted in iris and natural lens Between Phakic crystalline lens.

44. ophthalmic lens according to claim 11, wherein at least partly being replaced in the lens implanting camera oculi posterior For the natural lens.

45. a kind of method for the ametropia characteristic for adjusting fully hydrated hydrogel according to claim 1, the method packet Include following steps: the hydrogel described in electromagnetic radiation focusing illumination, so that two-photon absorption occurs, wherein the hydrogel is poly- Polymer component undergoes part depolymerization and/or decomposition.

46. a kind of method of the optical parameter in situ for adjusting hydrogel eye surgical implant, the described method comprises the following steps:

A) eye for containing hydrogel eye surgical implant according to claim 9 is provided；And

B) a part of the hydrogel eye surgical implant is irradiated with electromagnetic radiation using femto-second laser, thus the hydrogel Copolymer segment depolymerization and/or decomposition；

Wherein adjust the optical parameter of the implantation material.

47. according to the method for claim 46, wherein the optical parameter includes infractive index.

48. according to the method for claim 46, wherein it is described be radiated in the hydrogel eye surgical implant generate it is elongated Chamber or voxel (voxels).

49. according to the method for claim 48, wherein the voxel depth is greater than 10 microns.

50. according to the method for claim 48, wherein the depth for increasing the voxel increases phase shift, and infractive index is protected Hold approximately constant.

51. according to the method for claim 50, wherein the infractive index is greater than or equal to 1.3335.

52. according to the method for claim 50, wherein the phase shift is up to 30 microns.

53. according to the method for claim 46, wherein including solvable by the depolymerization substance of the irradiation ablation and easily spreading Low toxicity compounds.

54. according to the method for claim 46, wherein passing through the figure for the elongated voxel for forming different depth in the hydrogel Case, and improved infractive index approximately constant is kept to provide the improved optical characteristics.

55. according to the method for claim 50, wherein by changing voxel depth rather than by changing its infractive index To control the phase shift.