EP2164384A2 - Hydrogel implant for sensing metabolites in body tissue - Google Patents

Hydrogel implant for sensing metabolites in body tissue

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Publication number
EP2164384A2
EP2164384A2 EP20080759965 EP08759965A EP2164384A2 EP 2164384 A2 EP2164384 A2 EP 2164384A2 EP 20080759965 EP20080759965 EP 20080759965 EP 08759965 A EP08759965 A EP 08759965A EP 2164384 A2 EP2164384 A2 EP 2164384A2
Authority
EP
Grant status
Application
Patent type
Prior art keywords
implant
hydrogel
preceding
according
sensor
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP20080759965
Other languages
German (de)
French (fr)
Inventor
Achim Müller
Peter Herbrechtsmeier
Monika Knuth
Katharina Nikolaus
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Eyesense AG
Original Assignee
Eyesense AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/145Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/1455Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using optical sensors, e.g. spectral photometrical oximeters
    • A61B5/1459Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using optical sensors, e.g. spectral photometrical oximeters invasive, e.g. introduced into the body by a catheter
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/145Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/14532Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue for measuring glucose, e.g. by tissue impedance measurement
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00Investigating or analysing materials by the use of optical means, i.e. using infra-red, visible or ultra-violet light
    • G01N21/75Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
    • G01N21/77Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00Investigating or analysing materials by the use of optical means, i.e. using infra-red, visible or ultra-violet light
    • G01N21/75Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
    • G01N21/77Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator
    • G01N21/7703Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator using reagent-clad optical fibres or optical waveguides
    • G01N2021/7706Reagent provision
    • G01N2021/773Porous polymer jacket; Polymer matrix with indicator
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00Investigating or analysing materials by the use of optical means, i.e. using infra-red, visible or ultra-violet light
    • G01N21/75Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
    • G01N21/77Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator
    • G01N2021/7769Measurement method of reaction-produced change in sensor
    • G01N2021/7786Fluorescence

Abstract

An implant (110) is disclosed for detecting at least one analyte (126) in a body fluid, particularly eye water. Said implant (110) is designed to be implanted into a tissue layer and/or an eye chamber of a patient and comprises a hydrogel matrix (110) containing at least one hydrogel (114). The implant further comprises sensor particles (116) which are dispersed in the hydrogel matrix (110). The sensor particles (116) have at least one sensor matrix (120) with a sensor matrix material (122) as well as at least one sensor material (124).

Description

Hydrogel implant for sensors of metabolites in body tissues

Field of the Invention

The invention relates to hydraulic he gelformkörp which are constructed such that a can freely diffuse into the aqueous phase of a hydrogel network analyte to be determined, the chemical or biochemical sensor components are immobilized but the network. The outer shape and the mechanical properties of the shaped hydrogel article is optimized for the implantation and the implantation. Such hydrogel article may for example be used to detect analytes, in particular certain metabolites in a body tissue, in particular a body fluid. In particular, it may be in the body tissue to a body tissue of an eye and an eye fluid in the body fluid (eg, aqueous humor, lacrimal fluid, or interstitial fluid). but also for other tissue types and / or kinds of body fluids proposed hydrogel article is used in principle.

De detection of at least one analyte to be determined can range from a purely qualitative detection to a quantitative detection. can drive such detection processes for example to determine a glucose concentration in the body tissue, for example in the eye fluid, is used. then in particular the glucose can be made of this analyte or glucose concentration then by reference to known correlations for example to a concentration of the analyte to be closed in other body fluids, for example in blood. In addition to glucose, the present invention, alternatively or additionally, to other types of analytes applicable. State of the art

Conventional systems for determining analyte or metabolite concentrations, particularly in blood glucose concentration, usually based on the patient or a doctor, for example by means of a suitable lancing system, a skin area perforated and thereby generating a blood sample. This sample is then analyzed for analyte content by means of suitable measuring methods, such as optical and / or electro-chemical measurement methods. In addition to a detection in the blood can also evidence in other body fluids, take place such as in urine.

In order to reduce the costs associated with frequent generation of blood samples of patients inconvenience, various non-invasive or minimally invasive technologies to measure analyte concentrations were developed. In the following this the invention will be discussed in the determination of blood glucose concentrations without limiting the scope, whereby of course also other types of analytes or metabolites are detectable Israel.

A technology of blood glucose concentration determination is based on the measurement of glucose in body tissue and body fluids, especially in eye fluids such as tears, aqueous humor, or interstitial fluid. Thus, a ocular sensor for glucose is described for example in WO 01/13783, which is configured as a lens. The ocular sensor comprises a glucose receptor, which is labeled with a first fluorescent label and a glucose competitor, which with a second fluorescent label ( "donor") is selected. The two fluorescent labels are selected such that when the competitor is bound to the receptor the fluorescence of the second fluorescent labels due to a resonant fluorescence energy transfer is deleted (quenching). by monitoring the change in fluorescence intensity at a wavelength around the fluorescence maximum of the quenchable fluorescent label, the proportion of the fluorescent-labeled competitor can be measured, has been what displaced by glucose is. in this way, the glucose concentration may be determined in the eye fluid. this measurement can in turn be used to deduce the blood glucose concentration. other types of evidence are conceivable and known to the expert, such as a Fluore szenznachweis the first fluorescent labels. WO 02/087429 also describes a fluorescence photometer, by means of which blood glucose concentrations can be determined by measuring the glucose concentration in an ocular fluid. The illustrated apparatus is capable of simultaneously measuring two fluorescence intensities at two different wavelengths.

The cited references of the prior art represent only some embodiments of how the analyte can be detected by appropriate sensors in an implant, such as an eye implant, and determines their concentration. However, a key aspect in most cases is the design of the implant, in particular of ophthalmic implant itself, which must meet numerous requirements and constraints for the analysis. As a suitable matrix material for such implants is particularly hydrogels have been found. Hydrogels are water-containing, but at least substantially water-insoluble polymers, the molecules chemically, z. For example by covalent or ionic bonds, or physically, for example. B. are linked by entangling of the polymer chains into a three dimensional network. Hydrogels generally have to hydrophilic polymer components which cause the hydrogel to swell in water to a considerable increase in volume, but their cohesion of material is substantially retained at least. Hydrogels have a high biocompatibility and tissue usually have similar mechanical properties.

Hydrogel article with certain additives, which are embedded in the hydrogel network, are known from the prior art, wherein a water-containing network is understood to be a hydrogel network, which is composed of a polymer which is insoluble in water either by itself or by suitable measures was rendered water-insoluble. Such suitable measures, in particular the generation of covalent or ionic bonds between the polymer blocks of the network can include; and physical measures such as entanglement of polymer building blocks are known.

Among the Hydrogelformkörpern described in the prior art, such count. B. implants to the eye, the applied either externally on the surface of the eye (eg. B. contact lenses) or to a layer or chamber of the eye implanted (z. B. intraocular lenses) can be. Examples are the moldings described in the following patent documents. The ophthalmic implant for the control of cataracts from the US 5,127,901 is between the sclera (dermis) and the conjunctiva (conjunctivitis) were charged, and has a suitable therefor shape.

The implants of US 5,300,114 or US 5,476,511 open the possibility that beneath the conjunctiva medically active substances can be effective. Ethylene-vinyl acetate copolymers are considered to be particularly suitable polymer for the implant, which is also a suitable diffusion barrier for the targeted drug to be released, the z itself. B. located in an inner matrix of this polymer. Also, the matrix enveloping the active ingredient with the membrane is constructed from this polymer. In addition, these implants contain an additive that indicates the consumption of the drug. In addition, these implants may also have coatings or sections at certain points of the molding that are not being transparent - not even temporarily - to the active ingredient, if so desired at certain points of the eye.

The implants of the US 6,416,777 and US 6,986,900 are thus introduced in the eye, that the medicinally active ingredient above the macula (yellow spot of the retina) and the implant is located outside the sclera. Their geometries have F-, C- or L-shape. The interior containing the active ingredient may, for. have as tablet form, and the polymer may - depending on the application target - for the drug more or less permeable. The polymer should be biocompatible and non-biodegradable. Ac rylate and silicones are listed as preferred. In one variant, the active ingredient is dissolved in a liquid, must be so as to provide for targeted delivery of the implant.

But the demands placed on these moldings with a medically active ingredient are not transferable to form body to be penetrate the analyte and studied there. In the latter case in which by the hydrogel moldings analyte to be detected, even often diametrically entgegen- set requirements are to be compared to drug implants, since the materials or the sensor precisely only slightly or not to diffuse in the implant, are but localized in the implant remain. On the other hand, is to allow the analytes to diffuse almost freely and quickly to the place of proof in the implant so that the analyte can be detected promptly. This is essential to ensure that necessary medical durables can be taken countermeasures such as appropriate medication of insulin.

OBJECT OF THE INVENTION

Object of the present invention is, therefore, len a hydrogel article bereitzustel- which allows the detection of one or more analytes in a body fluid, such as an ocular fluid and which at least substantially avoids the disadvantages of known hydrogel article. In particular, a hydrogel article is to be provided, whose external shape and its further construction allow that, in addition to a hydrogel analyte to be determined (eg., Glucose), at least one sensor component and optionally are at least one reference component.

Description of the Invention

This object is achieved by the invention with the features of the independent claim. Advantageous developments of the invention are characterized in the subclaims. The wording of all claims is hereby incorporated by reference into this specification.

A basic idea of ​​the present invention is to pre-immobilizing a sensor component in the implant through an encapsulation of the components in micro- or nanoparticles dispersed in a hydrogel matrix, in particular dispersed are. Particularly preferred is an at least substantially homogeneous distribution.

It is therefore an implant for detecting at least one analyte in a body fluid, especially an eye fluid proposed, which is adapted to be in a body tissue of a patient, especially a fabric layer and / or a chamber of an eye of the patient, implanted. The term of a patient generally comprises while living things, especially humans, the term does not necessarily imply a disease. Including, for example, measurements on healthy humans or animals can be made to measure litkonzentration Metabo to, where appropriate, to detect illnesses early. However, the term implant is intended to include the event that no implantation in the real sense is made, ie introduction into a tissue of a patient, but should also be a simple application include on such a fabric, ie one application, without the need for surgical intervention, thus, for example, a contact lens and / or an inlay, which can be placed for example under an eyelid of a patient.

The implant comprises a hydrogel matrix with at least one hydrogel, wherein the implant further comprises dispersed in the hydrogel matrix sensor particles, the sensor particles at least one sensor array comprising a sensor matrix material (122) and at least one sensor material have.

The sensor particles are preferably designed as micro- or nanoparticles, preferably with a particle diameter in the range of a few micrometers (for example, <100 micrometers, preferably <20 microns) to a few 100 nanometers.

The microparticles or nanoparticles are preferably permeable to the analyte, either due to their structure or due to a semipermeable shell. The interior of the particles is such that the sensor components have an optimal activity.

The sensor material is designed such that it is sensitive to the analyte to be detected. Preferably, this sensor property is specific to the nachzuwei- send analytes. In this case, different detection principles can as known from the above-described prior art are used. For example, the analyte may react chemically with the sensor material (for example, a covalent bond, a complex bond or a similar compound received), this binding, for example by changing the fluorescence properties of the analyte and / or the Sensormate- rials and / or of the sensor material analyte - connection can be established. Even looser ties are possible, such as physical bonds and / or approximations of sensor material and analyte which for example can be detected spectroscopically in turn. In any case, the sensor material, however, is configured such that at least one detectable physical and / or chemical property of the implant changes when the analyte concentration in the body fluid, in particular the eye fluid is changed, or when analyte is present in the body fluid.

A significant aspect and advantage of the invention is the fact that the properties of the hydrogel matrix and sensor particles can be optimized separately. Thus, one needs implants with good mechanical strength, which can be achieved by higher network density and relatively low water content hydrogels substantially.

But are now for the sensor material, for example relatively large biomolecules such as Con A (104 kD), glucose oxidase (63 kD), glucose dehydrogenase, hexokinase or GIu- cose galactose binding protein (GGBP) was used, the functionality of the presence of the native configuration as well as the mobility the biomolecules is dependent, so, however, low water content and dense networks have an unfavorable effect on the activity and mobility of the proteins. In the microparticles the envi- can conditions be optimized independently of the demands on the implant for such proteins and / or other sensor components. Furthermore, a protein and / or a functionally equivalent fragment may comprise the sensor material, derivatives mutants of hexokinase and / or GGBP and / or boric acid ester.

For example, hydrogels can also be used for the microparticles or sensor particles whose water content is over 90%. Since in such cases, the proteins could diffuse because of low network density in part of the particles out, the sensor particles are preferably coated with a semipermeable layer.

This can "classical" LBL ( "layer-by-layer") - its layers, but it can also be used cross-linked proteins, polysaccharides, or other polymers which form a second, denser hydrogel layer to the interior of the particle. The term LBL refers also to the successive deposition of oppositely charged polyelectrolyte. for example, can be coated with a negatively or positively charged polyelectrolyte and subsequently with a correspondingly oppositely charged polyelectrolytes a sensor particles are particles first. This process can be repeated until the desired layer thickness and permeability is obtained. There are also variants in which partially uncharged polymer layers between two sets counteracted charged layers are introduced. Alternatively, to build up the "LBL" layer not stepwise but by a step, by including in the coating solution complexes of two oppositely charged polyelectrolytes are formed which are deposited under certain conditions on the surface of the particles. If the sensor components very large or the microparticle enveloping Hydro gel matrix particularly dense, including microparticles can be used without the membrane.

Suitable solutions for such special sensor particles, in particular in the construction of the LBL layers are, for example, disclosed in the following patent documents: WO 2005/089727, WO 2004/014540, WO 02/017888, WO 00/077281, WO 00/003797, EP -A 1,116,516, WO 99/047252, WO 99/047253, US 6,451,871, US 6,896,926, US 7,022,379 and US 6,926,965.

Suitable materials for sensor particles are, for example ionically crosslinked alginates and mixtures of alginates and polysaccharides or polysaccharide derivatives such as carboxy methyl cellulose or synthetic polymers or copolymers such as polyhydroxy xyethylmethacrylat (P-HEMA), polyacrylamides and copolymers of acrylic acid and / or acrylic acid and methacrylic acid derivatives such as dimethyl acrylamide, Hydroxyethyacrylat, methacrylic acid. In principle, all polymers are conceivable, which are water soluble and cross-linked or cross-linkable. It is also possible to use the same polymer as the hydrogel matrix for the sensor particles, generally, however, should distinguish the polymers in their degree of crosslinking. An example of this are polyvinyl alcohols with different amounts of functional, cross-linkable groups.

Suitable hydrogels for the sensor particles and / or for the hydrogel are such. As disclosed in the following patent documents: EP-B 0641806, EP-B 0790258, EP-B 0807265 and EP 0637490.

In addition to sensor particles of micro- or nanoparticles containing the sensor materials or sensor components, preferably, the implant further has at least one at least substantially analyte-invariant reference component. The reference component can in particular have at least one luminescent moiety, in particular a fluorescent component. The luminescence of luminszie- Governing component should be at least substantially analyte-invariant.

The reference component can in principle be introduced in various ways into the implant. For example, the reference component can be introduced in any manner in the hydrogel or matrix sensor, for example, dispersed in the matrix, dissolved, emulsified or suspended. Also a chemical bond such as a covalent bond, an ionic bond or a complex bond, to one or more components of the implant, for example, the hydrogel matrix is ​​possible.

In a particularly preferred embodiment, the at least one reference component is introduced by means of reference particles into the implant. As reference particles can be embedded in the hydrogel matrix containing one or more reference components. Further, a reference matrix material may be contained. Again, these reference particles preferably comprise microparticles or nanoparticles, preferably with a particle diameter in the range of a few micrometers (for example, <100 micrometers, preferably <10 microns) to a few 100 nanometers.

Basically, the above regarding the hydrogel matrix said can apply correspondingly to the reference matrix material. In particular, one or more of the above described materials may also be used for the reference matrix material. Also, the use of a shell around the reference particles is again possible, the materials and other properties of said can be made analogously with respect to also turn on the top to the shell of the sensor particles. The sensor and / or Referenzpar- Tikel should be relatively small relative to the thickness of the hydrogel article, so that a homogeneous distribution in the hydrogel or reference matrix material is possible. The diameter should preferably not be greater than about 10% of the thickness of the hydrogel and the hydrogel article.

The reference components for. be as fluorescent dyes or high molecular weight derivatives of fluorescent dyes or comprise that are chemically or physically bonded either on the surface of the hydrogel, the sensor particles and / or the reference particles or in the matrix (matrix material) of the reference or sensor particles.

Preferably, the reference components are at least substantially analyte-invariant, ie change its detectable physical and / or chemical properties (eg, in turn, fluorescence and / or luminescence) is substantially even in the presence of the analyte is not, or only slightly (eg, to no more than 5% , preferably less). For surface bonding of the dyes covalent bonds can be used or even strong complex bonds such as biotin-avidin. In these cases, functional groups on the surface of the particles with functional groups are reacted to the dye molecule. Corresponding synthetic procedures for coupling of, for example amino groups, thiol groups and carboxyl groups are known from the literature. Also, the dyes may be in LBL layers or other layers which are applied on inert particles embedded. In these cases, the dye can either be deposited along with the polyelectrolyte because of its properties such as charge or the dye is bonded directly to one of the polyelectrolytes covalently.

For binding in the particles, the reference components (hereinafter referred to without limitation of the general design possibilities simply "dye" or "dye molecule" or "dye moiety"), for example, directly polymerized with monomers, and are designed as a particle. In this case, the by polymerization of the monomers resulting network is preferably so closely that the dye molecule can not also diffuse. such physical immobilization may also be accomplished by swelling of particles in suitable solvents and incubation of the swollen particles in a dye solution. Use is made of the fact that the network is its pore large increases (water or physiological solution), the pore size is reduced again in the application solvent (eg polystyrene in toluene), and after diffusion of the dye molecules in good solvents. This is particularly b ei sensitive dyes advantageous since thus be avoided for the dye, the conditions of the polymerization.

Another variant is that the dye molecule itself contains polymerizable functional groups and copolymerized together with the monomer. The reference particles are characterized in that their measured parameter does not change, for example, fluorescence with the concentration of the analyte.

The implant may in particular comprise a hydrogel article. The hydrogel moldings themselves is then preferably made of a water-soluble crosslinkable prepolymer and the sensor and reference particles. The particles are homogeneously dispersed in an aqueous solution of the prepolymer and the aqueous dispersion are then crosslinked (for example, free-radically or photochemically or thermally loaddition in 2 + 2 Cyc-). The shaped body preferably has a maximum diameter of 10 mm and a surface to volume ratio of at least. 8 This development of the invention causes the response speed of the implant to changes in Analytkon- concentration in the eye fluid typically has a value of a few minutes, preferably upstream of no more than 3-4 minutes, does not exceed. The molded body must be a round disc not inevitable. Rather, any shapes are possible, as long as the shape of the circumscribing circle is not greater than 10 mm.

The edge of the shaped body may be substantially rectangular, but where "substantially", deviations of up to 60 °, preferably, however, can be tolerated by not more than 20 ° and particularly of not more than 5 °. The thickness of the

Shaped body preferably decreases from the edge. The rim has a preferred angle of 0 ° to 60 °. The edges may be preferred rounded. The shaped body can be plastically nar or curved. The buckle preferably has a radius of curvature of 14 mm to 8 mm. The curvature radius of curvature should preferably not be less than 8 mm.

embodiments

Further details and features of the invention will become apparent from the following description of preferred embodiments in conjunction with the subclaims. The respective features on their own or in groups can be implemented in combination. The invention is not limited to the embodiments.

The embodiments are shown schematically in the figures. Like reference numerals in the various figures denote identical or functionally identical with respect to their functions corresponding elements.

Specifically:

Figure IA a hydrogel matrix of an implant with sensor particles having membrane;

Figure IB a hydrogel matrix of an implant with sensor particles without membrane;

2 shows a shape of an implant body in various views; Figure 3 is a sectional view of a first embodiment of a shaped body of an implant in a side view; and

Figure 4 is a sectional view of a second embodiment of a shaped body of an implant in a side view.

In the figures IA and IB are each a hydrogel matrix 110 of an implant 112 (the implant is shown only symbolically), respectively. The following specifically explains the application of the invention to an eye implant, but as stated above, the invention is in principle applicable for other types of body tissue on implants 112th The hydrogel matrix 110 of the implant 112 has in each case as a base component, a hydrogel 114. The water content, the network density and shape of the hydrogel 110 can each be optimized for the particular implant application.

In both cases, 110 sensor particles 116 are dispersed in the hydrogel matrix. The embodiments in Figures IA and IB are not different in that in figure IA, the sensor particles 116 having a membrane 118, in the embodiment in Figure IB, however. However, there are also conceivable embodiments in which both sensor particles 116 with diaphragm 118 and those without membrane coexist.

The sensor particles 116 each include a sensor array 120 with a sensor 122 and a matrix material included in the sensor matrix material sensor material 124th The sensor material 124 is sensitive to an analyte 126, which is designated symbolically in the Figures IA and IB, the reference numeral 126 and which can diffuse through the hydrogel matrix 110 and preferably also through the sensor matrix 120th

Furthermore, reference particles 128 are dispersed in the hydrogel matrix 110 in the illustrated embodiments. These have a reference matrix material 130, and a reference component 132, wherein the reference component is attached physically and / or chemically, in this embodiment on the surface and / or inside the reference matrix material 130 132nd For example, a copolymerized fluorescent Dyes: Coloring ff and / or mounted on the surface of the reference matrix material 130 and / or 128 of the reference particle fluorescence dye can be used as a reference component 132nd

2 shows an embodiment of a molded body 210 of an implant 112 is shown in various views. The upper view shows a plan view, the middle view is a sectional view from the side without curvature and the lower view is a sectional view from the side with a curvature. The diameter D is preferably not more than 10 mm, and the thickness d is preferably about 250 micrometers. The radius of curvature R (bottom view) is preferably between 8 mm and 14 mm.

Furthermore, 210 edge two possible shapes are shown superimposed in the bottom view of the mold body. While the edge shape 212 has a substantially rectangular edge showing how it can be generated for example by means of a mold, 214 shows the edge shape of a tapered shape. Here, preferably, the edges of the edge shape 214 perpendicular to a plane of the disc shaped body 210. Such an edge profile 214 may, for example, formed by a lithographic manufacturing process, wherein the curing of the molded body 210, an irradiation takes place vertically from above.

In the figures 3 and 4, further embodiments of the edge molding a molded body are shown 210th Thus, Figure 3 shows a partially inclined edge shape. The thickness of the molded body 210 decreases from the initial thickness d to the edge on the thickness d 'from. While the thickness d, for example, 250 micrometers may be, the edge thickness d ', for example, 15 micrometers to 250 micrometers may be. Thus, obtained, for example, a contact angle, designated in Figure 3 with α of 0 ° to 60 °.

4 shows two possible edge patterns 410, 412 of a molding 210 in turn are superimposed, which may be employed in other embodiments. Here, denotes an edge geometry by the reference numeral 410, which (for example, circular arc-shaped or elliptical curve) has a rounded (e.g., by using an appropriate mold) has. The reference numeral 412 designates an edge geometry is having a curved path, for example by using a laser ablation method. This curved path 412 can be one-sided provided (solid line 412) or both sides (shown in phantom in Figure 4). The shape of the hydrogel article 210 may for example be defined by a corresponding casting mold. The mold is preferably made so that a shrinking or swelling in the curing of the initial formulation for the forming is taken into consideration. The mold can (translucent UV) consists wholly or partially of a plastic such as polypropylene (PP), polymethyl methacrylate (PMMA), polycarbonate (PC), polyoxymethylene (POM) or polyether ester ketone (PEEK) or glass. In the case of closed molds the edge geometry is defined by the closed mold. In the case of open molds (glass forms) of the edge can be photolithogra- phisch defined by UV cross-linking or by the surface tension between prepolymer and molding material.

Also in the case of open shapes or larger pieces of the edge shape can be defined by cutting. In a mechanical cutting a far-going results rectangular edge geometry. For a cutting means of a laser using a Gaussian intensity profile, a "rounded" edge can be obtained.

The preparation of a hydrogel article is exemplified.

Example 1 Preparation of Alginathydrogelpartikeln for the sensor components:

Alginic acid sodium salt is dissolved in deionized water at 55 0 C with stirring. The alginate solution is sprayed by means of a Zweistoffzerstäuberdüse (Spraying Systems Co.) in a filled with calcium chloride solution an ultrasonic bath, where the alginate droplets harden.

The cured alginate particles are filtered through a 30 micron filter cloth and the filtrate concentrated by settling in a separating funnel. Subsequently, the alginate can be autoclaved as a 10% solution. can be varied depending on the desired water content of the alginate natpartikel the concentration of the alginate solution between 0.2% and 10%. By appropriate selection of the alginate type (molecular weight ratio GuIu- ronsäure to mannuronic acid) is another fine tuning of the network density possible.

Example 2 Optional pre-coating of the alginate: The alginate particles are centrifuged off and the ratio 1: 1 (w / v) with polyallylamine hydrochloride in 10 mM acetate buffer, pH 5.5 mixed and incubated for 5 min. The mixture is centrifuged, the supernatant removed and the alginate twice in the ratio 1: 2 centrifuged (w / v) with 10 mM acetate buffer, pH 5.5 for 2 minutes each and washed off. This process is repeated with polystyrene sulfonate in 10 mM acetate buffer, pH 5.5 as a second layer. The process is repeated until the desired number of layers has been applied. The number of layers and the concentration of polyelectrolyte determines the density of the pre-coating. Typical concentrations are between 0.05% and 1%, typical layer numbers 1 to 6

Example 3 filling the pre-coated with alginate sensor components dextran and ConA:

The (optional precoated) alginate particles are centrifuged, washed once with deionised water and again centrifuged off.

The required amount of dextran is weighed and dissolved in water.

On 1 g of the Alginate spun down pellet 1 ml of the dextran solution is added, mixed by shaking, homogenized in an ultrasonic bath and incubated overnight at 2-8 0 C. The alginate spheres are centrifuged and separated from the supernatant. The absorbed amount of dextran is calculated by forming the difference of the specific absorptions of the supernatant before and after loading. Typical loadings are between 0.01 and 10 mg dextran per g of alginate.

ConA is dissolved in a concentration of 5-15 mg / ml in TRIS buffer, pH 7.4. The required amount of ConA is added to the dextran-filled alginate pellet, mixed by shaking, homogenized in an ultrasonic bath and incubated overnight at 2-8 0 C. The alginate spheres are centrifuged and separated from the supernatant. The amount ConA taken up is calculated by subtraction of the protein-specific absorptions of supernatant before and after loading.

Example 4 Coating of the Alginate

The loaded (optional precoated) alginate beads are in the ratio 1: 1 (w / v) with polystyrene sulfonate in 10 mM acetate buffer, pH 5.5 mixed and incubated for 5 min. The mixture is centrifuged, the supernatant removed and the alginate beads twice in the ratio 1: 2 (w / v) with 10 mM acetate buffer, pH 5.5 for 2 minutes each and washed by centrifugation. This process is derholt How-alternating with polyallylamine hydrochloride in 10 mM acetate buffer, pH 5.5, and polystyrene sulfonate in 10 mM acetate buffer, pH 5.5, until the desired number are applied layers. The number of layers and the concentration of polyelectrolyte determines the density of the pre-coating. Typical concentrations are between 0.05% and 1%, typical layer numbers between 10 and 60th

Ex. 5 Preparation of the formulation:

A 10% reference particle suspension is homogenized in an ultrasonic bath.

990 mg coated sensor particles are combined with 8,415 g of a 20 to 40% by weight solution of Acrylamidoacetaldehydo-l ^ acetal of polyvinyl alcohol mixed by stirring. 495 .mu.l 10% reference particle suspension are added by pipette and the mixture homogenised in the ultrasound bath. After that, the formulation is rolled on a roller block about 3 hours.

. Example 6 Preparation of implants:

The formulation is filled in a syringe and into a shaped body by means of a compressed air-driven dosing unit (female side BK7 glass, quartz glass male side) dosed. The shaped body is closed and under UV light (Hamamatzu Mercury xenon lamp) was irradiated for about 5 sec. The crosslinked implant is removed from the mold body, air dried and packaged.

Implants with 2 and 4 mm in diameter and a thickness of about 140 to 250 microns are already prepared and implanted into the human eye. There are implants with radii of curvature of 12 mm, 8.6 mm and planar implants used. The edges are defined by punching or by a form fit.

There are also edges with phases inserted at the top and bottom. The cutting means of excimer laser is also performed. reference numeral

110 hydrogel

112 implant

114 hydrogel

116 sensor particles

118 membrane

120 sensor matrix

122 S ensor matrix material

124 sensor material

126 analyte

128 reference particles

130 reference matrix material

132 reference component

210 moldings

212 rectangular peripheral shape

214 tapered edge shape 10 round edge profile 12 curved edge profile

Claims

claims
1. An implant (110) for detecting at least one analyte (126) in a body fluid, in particular an ocular fluid, wherein the implant (110) is arranged in a body tissue of a patient, especially a fabric layer and / or a chamber of an eye of the patient to be implanted, wherein the implant (110) comprises a hydrogel matrix (110) with at least one hydrogel (114), wherein the implant (110) further in the hydrogel matrix (110) dispersible alloyed sensor particles (116), wherein the sensor particle (116) comprise at least one sensor array (120) with a sensor matrix material (122) and at least one sensor material (124).
2. The implant (110) according to the preceding claim, wherein the sensor material (124) comprises at least one of the following materials: concanavalin A; Gluco- seoxidase; glucose dehydrogenase; hexokinase; Glucose galactose binding protein; a protein and / or a functionally equivalent protein fragment; a mutant of hexokinase; a mutant of glucose galactose binding protein; a Borsäureesterderivat.
3. The implant (110) according to one of the two preceding claims, wherein the sensor particles (116) have a for the analyte (126) at least partially permeable sheath (118), in particular a membrane.
4. comprise implant (110) according to the preceding claim, wherein the sheath (118) onshemmende diffusion properties for the at least one sensor material (124), in particular for the at least one sensor material (124) is at least largely opaque.
5. The implant (110) according to one of the two preceding claims, wherein the sheath (118) has at least one of the following materials: a crosslinked protein; a polysaccharide; a cross-linked polysaccharide; a polymer, in particular a hydrogel with the density of the hydrogel of the hydrogel (110) exceeding density; a layer-by-layer lay ER.
6. The implant (110) according to any one of the preceding claims, wherein the sensor material (124) comprises at least one of the following materials: a molecule and / or a group containing at least changes in the presence of an analyte (126) a chemical or physical property, in particular a luminescence, in particular a fluorescence characteristic; a molecule and / or a group, wherein the analyte (126) upon approach and / or reaction with the molecule and / or the group is changed at least one chemical or physical property, in particular a luminescence, in particular a fluorescence characteristic; - a molecule and / or a group, wherein the analyte (126) is received with the molecule and / or the group of a chemical or physical bond which at least one chemical or physical property is detectable by change, in particular by change of a luminescence, in particular by change in a fluorescent property.
7. The implant (110) according to any one of the preceding claims, wherein the at least one sensor matrix material (122) and the hydrogel matrix (110) are configured such that the at least one sensor material (124) in the sensor matrix material (122) has a higher diffusion coefficient than in the hydrogel matrix (HO), in particular as in the at least one hydrogel (114) of the hydrogel matrix
(110).
8. The implant (110) according to the preceding claim, wherein the sensor matrix material (122) has a lower density than the hydrogel matrix (110), especially as the hydrogel (114) of the hydrogel (110).
9. Implant (1 10) according to one of the preceding claims, wherein the sensor matrix material (122) comprises a hydrogel having a water content that exceeds the water content of the hydrogel (114) of the hydrogel (110).
10. The implant (110) according to the preceding claim, wherein the hydrogel of the sensor matrix material (122) has a water content of at least 70 weight percent, preferably of at least 85 percent by weight.
11. The implant (110) according to any one of the preceding claims, wherein the sensor matrix material (122) comprises at least one of the following materials: an alginate, particularly an ionically crosslinked alginate; a polysaccharide; a Polysaccharidde- Rivat, in particular carboxymethyl cellulose; a synthetic lymer covalently or via hydrogen bonding or cross-linked ionically crosslinked polymer or Copo-, in particular polyvinyl alcohol and / or polyhydroxyethyl methacrylate; a polyacrylamide; an acrylic acid unit-containing copolymer; an acrylic acid derivative or a methacrylic acid derivative, in particular dimethylacrylamide, hydroxyethyl thyacrylat or methacrylic acid.
12. The implant (110) according to any one of the preceding claims, wherein the hydrogel matrix (110) and the sensor matrix material (122), a chemically identical hydrogel
(114) each having a different degree of crosslinking, in particular wherein the hydrogel (114) of the hydrogel matrix (110) has a higher degree of crosslinking than the hydrogel of the sensor matrix material (122).
13. The implant (110) according to any one of the preceding claims, wherein the implant (110) further comprises at least one at least substantially analyte-invariant reference component (132).
14. The implant (110) according to the preceding claim, wherein the Referenzkomponen- te (132) at least one luminescent moiety, in particular a fluorescent component, wherein the luminescence properties of the component are luminszieren- the at least substantially analyte-invariant.
comprises 15. The implant (110) according to one of the two preceding claims, wherein the implant (110) into the hydrogel matrix (110) implanted reference particles (128), wherein the reference particles (128), the (at least one at least substantially analyte-invariant reference component 132), wherein the reference particles (128) further comprises at least one reference matrix material (130), wherein the reference component (132) at the surface and / or inside the Referenzmat- rixmaterials (130) is physically and / or chemically bonded.
16. The implant (110) according to the preceding claim, wherein the physical and / or chemical bonding comprises at least one of the following relationships: a covalent bond; a complex bond; an ionic interaction and / or an ionic bond.
17. The implant (110) according to one of the two preceding claims, wherein the reference component (132) is at least partially connected by polymerization with the reference matrix material (130).
18. The implant (110) according to one of the three preceding claims, wherein the reference component (132) is immobilized at least largely physically in the reference matrix material (130), in particular by a swelling.
19. The implant (110) according to any one of the preceding claims, wherein the implant (HO) comprises a hydrogel article, wherein the shaped hydrogel article in a
having substantially flat, circular shape with the diameter of the hydrogel molding is not greater than 10 mm.
20. The implant (110) according to the preceding claim wherein the shaped hydrogel article having a surface-to-volume ratio of at least 5, preferably at least. 8
21. The implant (110) according to one of the two preceding claims, wherein the shaped body has a substantially rectangular border.
22. Implant (1 10) according to one of the three preceding claims, wherein the shaped body has a curvature with a radius of curvature between 5 mm and 20 mm, particularly preferably between 8 mm and 14 mm.
23. Implant (1 10) according to one of the preceding four claims, wherein the shaped body has a thickness of not more than 250 micrometers.
24. The implant (110) according to one of the preceding five claims, wherein the shaped body in the edge region a thickness of not more than 250 micrometers, vorzugswei- se has a thickness between 15 microns and 250 microns has.
25. Implant (1 10) according to one of the preceding six claims, wherein the shaped body has a rounded edge, in particular a rounded edge with a Gaußprofϊl.
26. The implant (110) according to one of the preceding claims, comprising a mold body, wherein the shaped body is made at least partially using a laser serablationsverfahrens and / or a lithographic process and / or a casting process.
EP20080759965 2007-05-24 2008-05-23 Hydrogel implant for sensing metabolites in body tissue Withdrawn EP2164384A2 (en)

Priority Applications (3)

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DE200710024642 DE102007024642A1 (en) 2007-05-24 2007-05-24 Hydrogel implant for sensors of metabolites on the eye
US92466907 true 2007-05-25 2007-05-25
PCT/EP2008/056364 WO2008142158A3 (en) 2007-05-24 2008-05-23 Hydrogel implant for sensing metabolites in body tissue

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EP20140186223 EP2842481B1 (en) 2007-05-24 2008-05-23 Hydrogel implant for sensors for metabolites in body tissue

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EP (2) EP2164384A2 (en)
KR (1) KR101510488B1 (en)
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CA2688011C (en) 2016-08-30 grant
EP2842481B1 (en) 2017-07-12 grant
ES2643055T3 (en) 2017-11-21 grant
WO2008142158A2 (en) 2008-11-27 application
CN101707931A (en) 2010-05-12 application
KR101510488B1 (en) 2015-04-08 grant
WO2008142158A3 (en) 2009-05-28 application
CA2688011A1 (en) 2008-11-27 application
EP2842481A1 (en) 2015-03-04 application
CN101707931B (en) 2012-12-05 grant
US8647271B2 (en) 2014-02-11 grant
KR20100033382A (en) 2010-03-29 application
US20100331634A1 (en) 2010-12-30 application

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