WO2018177554A1

WO2018177554A1 - Stimuli-responsive hydrogel and method for a piercing intervention into a mammalian eye

Info

Publication number: WO2018177554A1
Application number: PCT/EP2017/057772
Authority: WO
Inventors: Stephan Michels; Matthias Becker; Bradley Nelson; Franziska Ullrich; Hen-Wei Huang
Original assignee: Ophthorobotics Ag
Priority date: 2017-03-31
Filing date: 2017-03-31
Publication date: 2018-10-04

Abstract

The invention relates to a stimuli-responsive hydrogel (1) having hydrophilic properties for use as an injection site and/or as a piercing site on a mammalian eye (E) during an intraocular piercing intervention, the stimuli-responsive hydrogel (1) forming an interface between the mammalian eye (E) and the stimuli-responsive hydrogel (1), wherein under influence of at least one external stimulus the stimuli-responsive hydrogel (1) changes its hydrophilic properties to being hydrophobic at least along a section of the interface between the mammalian eye (E) and the stimuli-responsive hydrogel (1). Furthermore, the invention relates to a method for an intraocular injection of a substance into a mammalian eye (E) and/or for drawing a fluid from inner parts of a mammalian eye (E).

Description

Stimuli-responsive hydrogel and method for a piercing intervention into a mammalian eye

The invention relates to a stimuli-responsive hydrogel and a method for an intraocular injection of a substance into a mammalian eye and/or for drawing a fluid from inner parts of a mammalian eye (E). Such intraocular piercing interventions have to be made precisely in order to avoid a damage of eye parts. Usually, medical doctors perform piercing interventions being for example intraocular injections by inserting a needle of a syringe filled with a substance such as a drug at a suitable location and up to a suitable depth into the patient's eye, injecting the substance into the eye and withdrawing the needle from the eye. If the piercing intervention is done in order to draw a fluid from the eye a syringe is piercing the eye ball at a piercing site and afterwards a liquid is drawn from the eye. However, before performing such piercing interventions, due care must be given to pre-intervention preparation steps. Important pre-intervention steps comprise attaching a speculum to the eye globe, disinfecting the eye and usually administering local anesthesia to the eye. Usually, prior to a piercing intervention into an eye globe, there is a need to sufficiently rinse the accessible portions of the eye globe by a disinfectant such as povidone-iodine. Due to the high level of microbial activity in particular in the area of the eye lid, the step of disinfecting the accessible portions of the eye globe cannot provide a 100% success rate. This is because iodine concentration and exposition time may not be increased indefinitely due to discomforting side effects for the patients. Therefore, with regards to a sterile piercing intervention scenario there is a first trade-off to be met.

It is an objective of the invention to provide systems and a method for piercing interventions such as an intraocular injection of a substance into a mammalian eye and/or for drawing a fluid from inner parts of a mammalian eye (E) incurring less risk when performing intraocular piercing interventions.

Especially occurrence of an inflammation after the piercing intervention shall be prevented or at least be significantly reduced.

The objective is solved by a stimuli-responsive hydrogel having the features according to claim 1 , a kit of parts having the features of claim 15 and a method having the features of claim 20. The invention relates to a stimuli-responsive hydrogel having hydrophilic properties for use as an injection site and/or as a piercing site on a mammalian eye during an intraocular piercing intervention, the stimuli-responsive hydrogel (1 ) forming an interface between the mammalian eye and the stimuli- responsive hydrogel, wherein under influence of at least one external stimulus the stimuli-responsive hydrogel changes its hydrophilic properties to being hydrophobic at least along a section of the interface between the mammalian eye and the stimuli-responsive hydrogel. The intrinsically hydrophilic property of a hydrogel provides excellent adhesion on a mammalian especially a human eye. The use of a stimuli responsive hydrogel enables switching between hydrophilic and hydrophobic surface by externally controlled stimuli. The hydrogel has a cross-linked hydrophilic water-insoluble polymer structure that imbibes large quantities of water and optionally suitable solvents or biological fluids. The polymer structure is swellable by housing water and optionally suitable solvents or biological fluids. It can absorb from 10 to 20% up to thousands of times their dry weight. Preferably, they can contain 75 to over 90%, preferably 80 to 90%, of water and optionally suitable solvents or biological fluids. The polymer structure is a three-dimensional material with the ability to maintain its dimensional stability while absorbing large amounts of water and suitable solvents or biological fluids. The three dimensional integrity of the hydrogel in its swollen state can be maintained by physical or chemical crosslinking. Chemically crosslinked networks have permanent junctions, while physical networks have transient junctions that arise from either polymer chain entanglement or physical interaction such as ionic interaction, hydrogen bond, or hydrophobic interaction. A stimuli-responsive hydrogel shows stimuli-responsive changes in its three dimensional network. It undergoes reversible volume phase transitions or sol- gel phase transitions upon minute changes in the environmental condition as a response to at least one stimulus. A stimuli-responsive hydrogel is also called smart hydrogel because it has the ability to react to selective gradients of physical environment factors by remarkable volume changing. According to preferred embodiments, the stimuli-responsive hydrogel is sensitive to at least one of temperature, pH value, ions or substance concentration. In response to at least one of the stimuli, water and optionally suitable solvent or biological fluid is urged into the hydrogel or out of the hydrogel and thus, the hydrogel is deformed. This deformation is measurable and can be detected in a

quantitative manner. Many physical and chemical stimuli can be applied to induce various responses of a stimuli-responsive hydrogel. The physical stimuli can include heat, electromagnetic radiation in particular light, solvent composition, mechanical pressure, sound and/or electro-magnetic fields, whereas the chemical or biochemical stimuli can include pH value, ions, substance concentration and/or specific molecular recognition events.

According to the present invention, the term "stimuli-responsive hydrogel" is to be understood that the hydrogel is responsive to at least one stimulus. The wording "external stimulus" means that the stimulus being applied to the hydrogel stems from a source being located external with respect to the stimuli-responsive hydrogel. Preferably, an external stimulus for the stimuli- responsive hydrogel can be a change in temperature caused in particular by heat radiation or heat convection and/or pH value. In a more preferred embodiment, the stimuli-responsive hydrogel is temperature-responsive. That means, the external stimulus is heat, thereby the stimuli-responsive hydrogel is having thermosensitive properties. For example, when the stimuli-responsive hydrogel having a temperature below the temperature of a living human body is attached on an eye of a living human being, the temperature of the eye itself can represent a stimulus for the stimuli-responsive hydrogel to change its hydrophilic properties to being hydrophobic.

Especially, a physically crosslinked temperature-responsive hydrogel may undergo sol-gel phase transitions instead of volume changing at a critical solution temperature. A positive temperature-responsive hydrogel shows phase transition at a critical temperature which is also called the upper critical solution temperature (UCST). A hydrogel made by polymer with UCST shrink when cooled below their UCST. A negative temperature-responsive hydrogel has a lower critical solution temperature (LCST). Such a hydrogel shrinks upon heating at a temperature higher than its LCST. A chemically crosslinked temperature-responsive hydrogel undergoes volume changing rather than sol- gel transitions. The stimuli-responsive hydrogel can have the physical form of a solid molded form, a membrane, a sheet, or a liquid having different levels of viscosity that forms the gel upon heating or cooling. Preferably, the stimuli-responsive hydrogel is a patch in the form of a membrane or a sheet.

The stimuli-responsive hydrogel can be a homo-polymer hydrogel, i.e. , it is composed of one type of hydrophilic monomer. Furthermore, the stimuli- responsive hydrogel can be a copolymer hydrogel, i.e. it comprises at least two co-monomer species, wherein at least one of the monomers is hydrophilic. Furthermore, the stimuli -responsive hydrogel can be an interpenetrating polymer network, i.e. it is made up of two polymers that are formed without covalent bond but are cross-linked among similar molecule so that two meshes with different chemistry integrate to each other. The polymer structure of the hydrogel can be based on polyacrylate such as N- iso-propylacrylamide (NIPAAm) (co)polymers, polyester such as polyethylene glycol (PEG)/poly(£-caprolactone) (PCL), and PEG/poly(£-caprolactone-co- lactide) (PCLA) block copolymers, poly(ester urethane) and/or natural polymer or its derivatives such as chitosan-g-PEG (PEG-g-CS).

Preferably, the stimuli-responsive hydrogel comprises a constituent having a hydrophilic characteristic and a constituent having hydrophobic characteristic. For example, the stimuli-responsive hydrogel can have one or more hydrophobic groups. Examples of hydrophobic groups are methyl, ethyl, and propyl.

In a preferred embodiment the stimuli-responsive hydrogel comprises an A-B-A type block copolymer, with A = a polymer and B = another polymer different from A. An example for a A-B-A type block copolymer is poly(ethylene glycol)- poly(£-caprolactone)-poly(ethylene glycol) (PEG-PCL-PEG), or alternatively poly(s-caprolactone-co-lactide)-b-poly(ethyleneglycol)-b-poly(s-caprolactone- co-lactide) (PCI_A-PEG-PCI_A). They are amphiphilic because PCL and PCLA are hydrophobic, whereas PEG is hydrophilic.

In another preferred embodiment the stimuli-responsive hydrogel comprises poly(N-iso-propylacrylamide) (PNIPAAm). PNIPAAm is a temperature-responsive polymer. It is advantageous because its LCST is close to human body

temperature, e.g. near in vivo temperature. The LCST of pure PNIPAAm is about 32°C. However, copolymers of N-iso-propylacrylamide (NIPAAm) can also be made using one or more other monomers or polymers to alter the LCST to be closer to or away from human body temperature. NIPAAm itself contains a hydrophilic amide group and a hydrophopic isopropyl pendant group. So, the afore-mentioned other monomer(s) or polymer(s) can be hydrophilic or hydrophobic.

For example, PNIPAAm forms a three-dimensional hydrogel when cross-linked with acrylamide (Aam), Λ/,Λ/'-methylene-bis-acrylamide (MBAm), Ν,Ν'- cystamine-bis-acrylamide (CBAm), acrylic acid (AAc), N, N-dimethylacrylamide (DMAAm), alkyl methacrylate comonomers, butyl methacrylate (BMA), hexyl methacrylate (HMA) or lauryl methacrylate (LMA). A PNIPAAm hydrogel can change from transparent to opaque after temperature changing. This has the advantage that a person who is willing to remove the hydrogel after a piercing intervention can see if the hydrogel has peeled off from the eye at least in part along the interface between the eye and the hydrogel or not. Furthermore, PNIPAAm hydrogel may undergo pressure-induced volume phase transition. It is collapsed at low pressure but expands at higher pressure. Preferably, a

PNIPAAm-based hydrogel contains NIPAAm and Aam. In another preferred embodiment the stimuli-responsive hydrogel comprises polyvinyl methyl ether) (PVME). A PVME hydrogel can be a homogenous, transparent and dense gel. More preferably, the PVME hydrogel is in the form of a heterogeneous, porous and opaque gel. A pure PVME hydrogel, i.e. a hydrogel consisting of PVME, has a LCST of about 40° C, i.e. a LCST near to body temperature.

In another preferred embodiment the stimuli-responsive hydrogel comprises poly(N,N-diethylacrylamide) (PDEAAm). Preferably, the hydrogel consists of PDEAAm. However, it can contain further hydrophobic or hydrophilic

comonomers such as acrylic acid (AAc) or methyl methacrlyate (MAA) or copolymers such as chitosan.

In another preferred embodiment the stimuli-responsive hydrogel comprises poly(N-vinylisobutyramide) (PNVIBA). A pure PNVIBA hydrogel shows a LCST of about 32° C. Also, crosslinked copolymers of NVIBA and N-vinylacetamide (NVA) can be used as PNVI BA-based hydrogel. In another preferred embodiment the stimuli-responsive hydrogel comprises Ethyl(hydroxyethyl)cellulose (EHEC). Ethyl(hydroxyethyl) cellulose is known to form hydrogels in the presence of an ionic surfactant such sodium dodecyl sulfate (SDS) or cetyltrimethylammonium bromide (CTAB). Preferably, the ionic surfactant is an amino acid based surfactant in order to show biocompatibility. For example, the amino acid can be lysine or arginine.

In another preferred embodiment the stimuli-responsive hydrogel comprises N-Trimethyl chitosan chloride (TMC). TMC is a quaternized chitosan derivative with improved aqueous solubility compared to native chitosan. However, TMC can have different degrees of quaternization.

In another preferred embodiment the stimuli-responsive hydrogel comprises poly(ethylene glycol) and glycerophosphate (poly(ethylene glycol)-grafted- chitosan (PEG-g-CS)).

In a preferred embodiment, the stimuli-responsive hydrogel comprises a constituent selected from the group consisting of poly(ethylene glycol)-poly(£- caprolactone)-poly(ethylene glycol) (PEG-PCL-PEG), poly(N-iso- propylacrylamide) (PNIPAAm), polyvinyl methyl ether) (PVME), poly(N,N- diethylacrylamide) (PDEAAm), poly(N-vinylisobutyramide) (PNVIBA),

Ethyl(hydroxyethyl)cellulose, N-Trimethyl chitosan chloride, poly(ethylene glycol) and glycerophosphate (poly(ethylene glycol)-grafted-chitosan (PEG-g- CS)), and poly(s-caprolactone-co-lactide)-b-poly(ethyleneglycol)-b-poly(s- caprolactone-co-lactide) (PCLA-PEG-PCLA).

In another preferred embodiment, the stimuli-responsive hydrogel consists of a constituent selected from the group consisting of poly(ethylene glycol)-poly(£- caprolactone)-poly(ethylene glycol) (PEG-PCL-PEG), poly(N-iso- propylacrylamide) (PNIPAAm), polyvinyl methyl ether) (PVME), poly(N,N- diethylacrylamide) (PDEAAm), poly(N-vinylisobutyramide) (PNVIBA),

In a preferred embodiment, the stimuli-responsive hydrogel comprises a temperature-controlling constituent. More preferably, the temperature- controlling constituent is a nanoparticle adapted to absorb near infrared light and/or is a magnetic nanoparticle. The control of temperature can be achieved by embedding nanoparticles in the hydrogel which are adapted to absorb for example near infrared electromagnetic radiation and alternating magnetic fields transforming the generated heat energy into a temperature elevation of the hydrogel. Nanoparticles are smaller than 1 micrometer in diameter, typically 5-500 nanometers. Near infrared electromagnetic radiation has wavelengths in the range of 800 and 1200 nm. Nanoparticles which heat up when they absorb near-infrared light are also referred to as plasmonic particles. Nanoparticles adapted to absorb near infrared light comprise noble metal such as gold or palladium or inorganic nanoparticles such as carbon nanoparticles, preferably molded into rod or shell structure. They can be surface-coated, e.g. by PEG or silica. Magnetic nanoparticles (MNPs) are a class of nanoparticles that can be manipulated using magnetic fields. Such particles can comprise two components, a magnetic material and a chemical component that have certain functionalities. Preferably, the magnetic material is selected from the group consisting of iron oxide, manganese iron oxide, iron nickel oxide or iron. The surface of the magnetic material can be modified or coated, e.g., by silica, carbon, or polymer such as PEG or polyvinylpyrrolidone (PVP).

Preferably, the stimuli-responsive hydrogel comprises a marker. More preferably, the marker is selected from the group of embedded magnetic nanoparticles, graphene oxide and/or embedded dyes. The embedded magnetic nanoparticles are the same as described above. Preferably, the dyes are embedded into selectively patterned areas of the hydrogel.

The stimuli-responsive hydrogel can have a polymer structure based on natural or synthetic origin. Preferably, the stimuli-responsive hydrogel has a polymer structure based on synthetic origin. Preferably, the polymer is prepared using chemical polymerization methods. Preferably, the stimuli-responsive hydrogel is prepared using at least one monomer or polymer constituent, a cross-linker, an initiator and a solvent. The monomer or polymer constituent is described above. Cross-linkers and initiators to produce the hydrogel from the monomer or polymer constituent are known. Solvent is only used to dissolve monomers, cross-linker and initiator.

In a preferred embodiment, the stimuli-responsive hydrogel is obtained by preparing a 3D mold and polymerizing a pre-gel solution inside the 3D mold. More preferably, the pre-gel solution contains at least one monomer and/or at least one polymer, a cross-linker, an initiator and a solvent. The modal can be a 3D printed mold. The mold serves to define the hydrogel shape. The pre-gel solution polymerizes inside the 3D mold to attain the stimuli-responsive hydrogel preferably in form of a patch. Preferably, the polymerization is incurred by radiation cross-linking. Especially, fast-response, temperature- sensitive PVME and PNIPAAm hydrogels can be prepared by irradiation using gamma radiation. For example, the structure of PVME hydrogels is dependent on the intensity of the gamma radiation and the temperature during

irradiation. When the radiation intensity is high, e.g. 9,8 kGy h^"1, the

temperature of the PVME pre-gel solution is increased so that an opaque gel with a heterogeneous and microporous structure is formed. Such a hydrogel has a large surface area for its volume, and swells and shrinks very quickly as a response to a change of temperature.

In a preferred embodiment the stimuli-responsive hydrogel comprises a stimuli- responsive hydrogel layer and a further layer. I.e., the hydrogel can have more than one layer. If it is multi-layered, it comprises a first layer having the features of the stimuli-responsive hydrogel as described above, forming the interface layer with the surface of the mammalian eye and at least one further layer. Also, this further layer can be a stimuli-responsive hydrogel layer, if necessary. Alternatively, the further layer is a layer that is insensitive to changes in temperature, e.g. polyethylenglycol diacrylate (PEGDA). Preferably, the stimuli-responsive hydrogel is adapted to receive fluid, more preferably a liquid. For example, it is adapted to be wetted, or, when attached on a mammalian eye to draw fluid from the eye's surface when an piercing intervention like an intraocular injection is performed. Preferably, the stimuli-responsive hydrogel is adapted to be wetted by a disinfectant. Preferably, the disinfectant is selected from the group consisting of povidone-iodine, chlorhexidine, ethanol, polyhexanide, octenidine

dihydrochloride, ozone and hydrogen peroxide. For example, povidone-iodine can be used in concentration of 1 -5%. When the disinfectant is ozone, it is preferably in the form of ozonated water and/or ozonized oil. An example for ozonized oil is sunflower ozonized oil. Alternatively or additionally, the stimuli-responsive hydrogel is adapted to be wetted by an anesthetic, especially a topical anesthetic. Preferably, the anesthetic is selected from the group consisting of benzocaine, butamben, dibucaine, lidocaine, oxybuprocaine, pramoxine, proparacaine,

proxymetacaine and/or tetracaine. Especially preferred, the anesthetic is oxybuprocaine.

Furthermore, the invention relates to a kit of parts comprising the stimuli- responsive hydrogel as described by one or more of the embodiments above and a disinfectant the disinfectant being structurally separated from the stimuli-responsive hydrogel. Preferably, the disinfectant is selected from the group consisting of povidone-iodine (PVP-I), chlorhexidine, ethanol,

polyhexanide, octenidine dihydrochloride, ozone, and hydrogen peroxide. The disinfectant can be provided in the kit of parts in the form of a liquid or a spraying device.

In a preferred embodiment the kit of parts further comprises an anesthetic. Preferably, the anesthetic is selected from the group consisting of benzocaine, butamben, dibucaine, lidocaine, oxybuprocaine, pramoxine, proparacaine, proxymetacaine and/or tetracaine. Especially preferred, the anesthetic is oxybuprocaine.

In a preferred embodiment the stimuli-responsive hydrogel and the

disinfectant are contained in a common packaging. More preferably, the stimuli-responsive hydrogel and the disinfectant are each in an individual compartment of the common packaging, the individual compartments being separated by a wall. Even more preferably, the wall is removable and/or breakable. By removing or breaking the wall the stimuli-responsive hydrogel is wetted by the disinfectant and is ready for use, i.e. ready to be attached onto a mammalian eye.

Additionally or alternatively, the anesthetic can be contained in a common packaging with the stimuli-responsive hydrogel, and optionally the

disinfectant. Thus, the anesthetic, the stimuli-responsive hydrogel, and optionally the disinfectant can each be provided in an individual compartment of the common packaging, the individual compartments being separated by one or several walls which are preferably adapted to be removable and/or breakable. Furthermore, the invention relates to a method for intraocular injection of a substance into a mammalian eye and/or for a piercing intervention to draw a fluid from inner parts of a mammalian eye (E), comprising the steps:

a) attaching a stimuli-responsive hydrogel having hydrophilic properties to a mammalian eye forming an interface between the mammalian eye and the stimuli -responsive hydrogel,

b) piercing a piercing member of an intraocular piercing intervention device through the stimuli-responsive hydrogel into an eye globe of the mammalian eye,

c) delivering a substance through the piercing member and/or drawing a fluid from the mammalian eye (E) through the piercing member, and

d) pulling the piercing member out of the eye globe and the stimuli-responsive hydrogel,

wherein under influence of at least one external stimulus the stimuli- responsive hydrogel changes its hydrophilic properties to being hydrophobic at least along a section of the interface between the mammalian eye and the stimuli-responsive hydrogel so that the stimuli-responsive hydrogel peels off at least partially by itself from the mammalian eye. Depending on the properties of the stimuli-responsive hydrogel this effect takes time. The time span may be several minutes and up to more than 60 minutes depending on the particulars of piercing intervention.

Preferably, the stimuli-responsive hydrogel is the stimuli-responsive hydrogel according to one or more embodiments described above. Features described above in respect to the stimuli-responsive hydrogel apply to the hydrogel used in the method. The delivered substance is preferably a drug.

Step a) may be made for example by use of forceps. An example for an intraocular piercing intervention device is a syringe having a needle as piercing member. The term "attaching" is to be understood that the stimuli-responsive hydrogel is applied on the eye. The attachment is done by the stimuli - responsive hydrogel itself by its intrinsically hydrophilic property providing excellent adhesion on a mammalian especially a human eye. Step c) is an injection and/or drawing a fluid from the mammalian eye through the piercing member. In a preferred embodiment, providing a piercing intervention as an intraocular injection step c) is performed by pushing a plunger of the syringe. If the piercing intervention is made to draw a liquid from the eye using a syringe the plunger of the syringe is drawn.

Preferably, the stimuli-responsive hydrogel can draw fluid from the eye's surface while performing step c), i.e. the injection. According to step d) the piercing member is pulled out of the eye globe and the stimuli-responsive hydrogel. Steps b), c) and d) are preferably performed by a robotic system. Several embodiments of such a system are described in published international patent application WO2017/005277A1 belonging to the same assignee as this patent application. The disclosure of this published patent application is incorporated by reference into this new patent application. After the stimuli-responsive hydrogel has peeled off at least partially by itself from the mammalian eye under the influence of an external stimulus, the hydrogel can be removed for example by use of forceps or by rinsing the mammalian eye. Preferably, the external stimulus is a temperature change caused by the heat of the surface of a living mammalian eye. Therefore, the stimuli-responsive hydrogel is temperature-responsive and responds to the surface temperature of the mammalian eye. In a preferred embodiment after step a) the piercing member is fine positioned above a marker of the stimuli-responsive hydrogel before step b) is carried out. Preferably, the marker is the marker as described above.

Preferably, the stimuli-responsive hydrogel attached to the mammalian eye is exposed to near infrared light and/or magnetic field in order to peel off at least partially by itself from the mammalian eye. Then, the stimuli-responsive hydrogel comprises preferably a temperature-controlling constituent as described above. In a preferred embodiment prior to step a) the stimuli-responsive hydrogel is wetted by a disinfectant. So, risk of an internal eye infection incurred by the piercing intervention can be further reduced. Preferably, prior to step a) the stimuli-responsive hydrogel is additionally wetted by an anesthetic. So, patient's pain during steps b) to d) can be further reduced. Preferably, between step a) and step b) is a predetermined time period so that the disinfectant and/or anesthetic can take effect. Preferably, the predetermined time period between steps a) and b) is in the range of 5 s to 20 min, more preferably, 30 s to 7 min, even more preferably, 1 min to 4 min. All of the method steps or subgroups of it may be performed manually or automatically by use of one or several robotic systems. With regards to steps b) to d) examples of such robotic system are described in published international patent application WO2017/005277A1 .

In the following figures one exemplary embodiment of the invention is shown.

Figs. 1 to 7 show schematically a method sequence for a piercing intervention such as an intraocular injection of a substance into a mammalian eye;

Fig. 8 shows a kit- of parts according to the invention; and

Fig. 9 shows the kit-of parts shown in Fig. 8 ready for use.

Figs. 1 to 8 respectively show steps of a method for a piercing intervention to a mammalian eye E. In this specific case the piercing intervention is performed as an intraocular injection of a substance into a mammalian eye. It is shown in a purely schematic way. For sake of simplicity, only a mammalian eye E especially an eye globe of a living patient is shown in Figs. 1 to 7. In a first method step, as shown in Fig. 1 , a stimuli-responsive hydrogel 1 wetted by a disinfectant (not shown) and an anesthetic (not shown) is approximated to the mammalian eye E by means of forceps 2 and placed on the mammalian eye E, as shown in Fig. 2. This step may either be performed manually or in an automated way by a robotic system.

The stimuli-responsive hydrogel 1 is to be stuck on top of an intended injection site on the surface of the eye globe E and provides the disinfectant and anesthetic at least to interface between the stimuli-responsive hydrogel 1 and the eye globe E. If the piercing intervention would instead not be an injection but the opposite to draw a liquid from the eye the piercing site on the surface of the eye globe would be prepared in exactly the same way as the injection site. Furthermore, piercing interventions as an injection and as drawing a liquid from the eye could be combined as well. Continuing with the injection scenario, an intraocular piercing intervention device 3 in form of a syringe comprising a cylindrical syringe body 31 , a piercing member 32 as an injection needle and a plunger 33 is approximated to the mammalian eye E. The syringe body 31 contains a substance 4 being for example a drug. Then, the piercing member 32 is pierced through the stimuli- responsive hydrogel 1 , and the plunger 33 is brought down in order to deliver the substance 4 into the mammalian eye E, as shown in Fig. 3. The injection is finished, when the syringe body 31 is empty. If a liquid should be drawn from the eye through the piercing member 32 of a injection device 3 in form of a syringe the plunger 33 would be moved in the opposite direction.

After having finished the injection, the syringe 3 is removed from the mammalian eye by pulling the piercing member 32 out of the eye globe and the stimuli-responsive hydrogel 1 , as shown in Fig. 4.

The stimuli-responsive hydrogel 1 attached to the mammalian eye E can be exposed to near infrared light and/or an alternating magnetic field in order to produce or intensify an external stimulus which is provided for example in form of a temperature change. Under influence of external stimuli the stimuli- responsive hydrogel 1 changes its hydrophilic properties to being hydrophobic at least along a section of the interface between the mammalian eye E and the stimuli-responsive hydrogel 1 so that the stimuli-responsive hydrogel 1 peels off at least partially by itself from the mammalian eye E, as shown in Fig. 5, and forceps 2 are approximated to the stimuli-responsive hydrogel 1. The stimuli-responsive hydrogel 1 is grasped by the forceps 2, as shown in Fig. 6 and can be easily removed from the mammalian eye E by means of those forceps 2, as shown by Fig. 7.

Fig. 8 shows a kit- of parts according to the invention in a purely schematic way. The kit of parts comprises a stimuli-responsive hydrogel 1 and a disinfectant 6 the disinfectant 6 being structurally separated from the stimuli- responsive hydrogel 1. Both constituents are contained in a common packaging 5. The common packaging 5 has one compartment 51 and a further

compartment 52 which are separated by a wall 53. The compartment 51 contains the stimuli-responsive hydrogel 1. The further compartment 52 contains the disinfectant 6. Furthermore, the common packaging 5 comprises a lid 54 so that each of the stimuli-responsive hydrogel 1 and disinfectant 6 are contained in an individual cavity being both separated from each other and from the environment.

Fig. 9 shows the kit-of parts shown in Fig. 8 ready for use. The lid 54 is removed from the common packaging 5. For this purpose, the wall 53 is removable and/or breakable in order to overcome the structural separation of the stimuli-responsive hydrogel 1 and the disinfectant 6. Thereby, the stimuli- responsive hydrogel 1 is wet by the disinfectant 6. Although Fig. 8 and 9 show a disinfectant 6, the common packaging 5 can additionally comprise an anesthetic (not shown). Also, the common packaging 5 can comprise a further compartment (not shown) separated by a further wall (not shown) from the compartments 51 , 52. In the following the invention is described by a non-limiting example.

Example

3D mold is provided. A pre-gel solution comprising N-iso-propylacrylamide (NIPAAm) and acrylamide (Aam) as monomers, poly(ethylene glycol)diacrylate (PEGDA) as cross-linker, 2,2-Dimethoxy-2-phenylacetophenone (DMPA) as photoinitiator and arylamide as solvent is polymerized inside the 3D mold. The pre-gel solution polymerizes inside the 3D mold to attain the hydrogel in form of a patch. The polymerization is incurred by radiation cross-linking. Thereby, a stimuli-responsive hydrogel is obtained.

Reference numeral list:

E eye

1 stimuli responsive hydrogel

2 forceps

3 injection device

31 syringe body

32 piercing member

33 plunger

4 substance

5 packaging

51 compartment

52 compartment

53 wall

54 lid

6 disinfectant

Claims

Claims:

1. A stimuli-responsive hydrogel (1 ) having hydrophilic properties for use as an injection site and/or as a piercing site on a mammalian eye (E) during an intraocular piercing intervention, the stimuli-responsive hydrogel (1 ) forming an interface between the mammalian eye (E) and the stimuli-responsive hydrogel (1 ), wherein under influence of external stimuli the stimuli-responsive hydrogel (1 ) changes its hydrophilic properties to being hydrophobic at least along a section of the interface between the mammalian eye (E) and the stimuli-responsive hydrogel (1 ).

2. The stimuli-responsive hydrogel (1 ) according to claim 1 , characterized by being temperature-responsive.

3. The stimuli-responsive hydrogel (1 ) according to claim 1 or 2, comprising a constituent having a hydrophilic characteristic and a constituent having hydrophobic characteristic.

4. The stimuli-responsive hydrogel (1 ) according to preceding claims, comprising a constituent selected from the group consisting of poly(ethylene glycol)-poly (E-caprolactone)-poly(ethylene glycol) (PEG-PCL-PEG), poly(N-iso- propylacrylamide) (PNIPAAm), polyvinyl methyl ether) (PVME), poly(N,N- diethylacrylamide) (PDEAAm), poly(N-vinylisobutyramide) (PNVIBA),

5. The stimuli-responsive hydrogel (1 ) according to preceding claims, characterized by further comprising a temperature-controlling constituent.

6. The stimuli-responsive hydrogel (1 ) according to claim 5, characterized in that the temperature-controlling constituent is a nanoparticle adapted to absorb near infrared light and/or is a magnetic nanoparticle.

7. The stimuli-responsive hydrogel (1 ) according to preceding claims, characterized by comprising a marker.

8. The stimuli-responsive hydrogel (1 ) according to claim 7, characterized in that the marker is selected from the group of embedded magnetic

nanoparticles, graphene oxide and/or embedded dyes.

9. The stimuli-responsive hydrogel (1 ) according to preceding claims, obtained by preparing 3D mold and polymerizing a pre-gel solution inside the 3D mold.

10. The stimuli-responsive hydrogel (1 ) according to claim 9, characterized in that the pre-gel solution contains at least one monomer and/or at least one polymer, an initiator, a cross-linker, and a solvent.

1 1 . The stimuli-responsive hydrogel (1 ) according to claim 9 or 10,

characterized in that the polymerization is incurred by radiation cross-linking.

12. The stimuli-responsive hydrogel (1 ) according to at least one of the preceding claims, characterized by a stimuli-responsive hydrogel (1 ) layer and a further layer.

13. The stimuli-responsive hydrogel (1 ) according to at least one of the preceding claims, characterized by being adapted to be wetted by a

disinfectant.

14. The stimuli-responsive hydrogel (1 ) according to claim 13, characterized in that the disinfectant is selected from the group consisting of povidone-iodine, chlorhexidine, ethanol, polyhexanide, octenidine dihydrochloride, ozone, and hydrogen peroxide.

15. A kit of parts comprising the stimuli-responsive hydrogel (1 ) according to at least one of the preceding claims and a disinfectant (6) the disinfectant (6) being structurally separated from the stimuli-responsive hydrogel (1 ).

16. The kit of parts according to claim 1 5, characterized in that the

disinfectant (6) is selected from the group consisting of povidone-iodine, chlorhexidine, ethanol, polyhexanide, octenidine dihydrochloride, ozone, and hydrogen peroxide.

17. The kit of parts according to at least one of the preceding claims, characterized in that the stimuli-responsive hydrogel (1 ) and the disinfectant (6) are contained in a common packaging (5).

18. The kit of parts according to claim 17, characterized in that the stimuli- responsive hydrogel (1 ) and the disinfectant are each in an individual compartment (51 , 52) of the common packaging (5), the individual

compartments (51 , 52) being separated by a wall (53).

19. The kit of parts according to claim 18, characterized in that the wall (53) is removable and/or breakable.

20. A method for intraocular injection of a substance into a mammalian eye (E) and/or for a piercing intervention to draw a fluid from inner parts of a mammalian eye (E), comprising the steps:

a) attaching a stimuli-responsive hydrogel (1 ) having hydrophilic properties to a mammalian eye (E) forming an interface between the mammalian eye (E) and the stimuli-responsive hydrogel (1 ),

b) piercing a piercing member (32) of an intraocular piercing intervention device (3) through the stimuli-responsive hydrogel (1 ) into an eye globe of the mammalian eye (E),

c) delivering a substance (4) through the piercing member and/or drawing a fluid from the mammalian eye (E) through the piercing member, and

d) pulling the piercing member (32) out of the eye globe and the stimuli- responsive hydrogel (1 ),

wherein under influence of external stimuli the stimuli-responsive hydrogel (1 ) changes its hydrophilic properties to being hydrophobic at least along a section of the interface between the mammalian eye (E) and the stimuli-responsive hydrogel (1 ) so that the stimuli-responsive hydrogel (1 ) peels off at least partially by itself from the mammalian eye (E).

21 . The method according to claim 20, characterized in that the external stimulus is a temperature change caused by the heat of the surface of a living mammalian eye.

22. The method according to claim 20 or 21 , characterized in that after step a) the piercing member is fine positioned above a marker of the stimuli- responsive hydrogel (1 ) before step b) is carried out.

23. The method according to one of preceding claims 20 to 22, characterized in that the stimuli-responsive hydrogel (1 ) attached to the mammalian eye (E) is exposed to near infrared light and/or magnetic field in order to peel off at least partially by itself from the mammalian eye (E).

24. The method according to at least one of preceding claims 20 to 23, characterized in that prior to step a) the stimuli-responsive hydrogel (1 ) is wetted by a disinfectant.