WO2024062020A1 - Matériau structuré biocompatible et ses utilisations - Google Patents

Matériau structuré biocompatible et ses utilisations Download PDF

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Publication number
WO2024062020A1
WO2024062020A1 PCT/EP2023/076043 EP2023076043W WO2024062020A1 WO 2024062020 A1 WO2024062020 A1 WO 2024062020A1 EP 2023076043 W EP2023076043 W EP 2023076043W WO 2024062020 A1 WO2024062020 A1 WO 2024062020A1
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WIPO (PCT)
Prior art keywords
zno
implant
biocompatible
drainage
microparticles
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PCT/EP2023/076043
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English (en)
Inventor
Anna Gapeeva
Rainer Adelung
Sören KAPS
Jörg BAHR
Leonard SIEBERT
Hartmut SCHMIDT-NIEPENBERG
Ala Cojocaru
Salvatore Grisanti
Ayseguel TURA
Judith Sewing
Stefanie GNIESMER
Swaantje GRISANTI
Svenja Rebecca SONNTAG
Original Assignee
Universität Zu Lübeck
Christian-Albrechts-Universität Zu Kiel
Phi-Stone Ag
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Application filed by Universität Zu Lübeck, Christian-Albrechts-Universität Zu Kiel, Phi-Stone Ag filed Critical Universität Zu Lübeck
Publication of WO2024062020A1 publication Critical patent/WO2024062020A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
    • A61L27/446—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with other specific inorganic fillers other than those covered by A61L27/443 or A61L27/46
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/56—Porous materials, e.g. foams or sponges
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/16—Materials or treatment for tissue regeneration for reconstruction of eye parts, e.g. intraocular lens, cornea

Definitions

  • the present invention relates to a biocompatible, antifibrotic structured material for implantable devices, especially for drainage implants in glaucoma surgery.
  • the invention further relates to glaucoma drainage implants comprising said material, and to their preparation and use.
  • Glaucoma describes a group of disorders associated with the damage of the optic nerve usually caused be an elevated intraocular pressure (IOP). Glaucoma leads to visual field deterioration and eventually to permanent vision loss, as there is currently no treatment to restore the optic nerve damage. Being the second leading cause of blindness after cataracts and the largest cause of irreversible blindness worldwide, glaucoma poses a significant threat to public health and the quality of life. It has been estimated that the total number of glaucoma cases for people aged 40-80 years will increase from 76.0 million in 2020 to 111.8 million in 2040 due to population ageing.
  • IOP intraocular pressure
  • glaucoma The main risk factor for the development of glaucoma is elevated intraocular pressure, which occurs due to a slowdown in the removal of the eye fluid (aqueous humor).
  • glaucoma can be divided into open-angle glaucoma (GAG) and angle-closure glaucoma (ACG), with the first type being the most common one.
  • GAG open-angle glaucoma
  • ACG angle-closure glaucoma
  • the first type being the most common one.
  • the angle between the iris and the cornea is open and wide, allowing the aqueous humor to flow its natural path around the lens and iris.
  • the drainage channels trabecular meshwork and Schlemm’s canal
  • the outflow of the aqueous humor is hindered, resulting in raised IOP and subsequent degeneration of the optic nerve.
  • First-line treatments include non-invasive medical therapy (in form of eye drops) and laser treatments, while invasive incisional surgery such as trabeculectomy or implantation of tube shunts is performed in more severe cases or when target IOP level could not be reached by other means.
  • these standard techniques suffer from several drawbacks.
  • the effectiveness of topical medications is limited by patient adherence to the medication regimen and by intolerance due to side effects such as ocular surface irritations and allergy.
  • IOP reduction up to 35.9%, the effect of laser treatments was found to decrease over time, requiring further medications or surgical intervention after 5 years.
  • Incisional surgeries provide the highest efficiency in lowering IOP to nearly 50% but are associated with a more than 30% postoperative complications rate (e.g., hypotony, bleb leak, or endophthalmitis) and with approximately 20% reoperation rate.
  • MIGS minimally invasive glaucoma surgery
  • MIGS devices Regardless of the placement, major challenges for MIGS devices are excessive wound healing (fibrotic scarring) and foreign body reaction processes as a response of the vascularized living tissue to injury and implant, causing restriction or complete blockage of the aqueous humor flow and resulting in an increase in IOP.
  • wound healing fibrotic scarring
  • foreign body reaction processes as a response of the vascularized living tissue to injury and implant, causing restriction or complete blockage of the aqueous humor flow and resulting in an increase in IOP.
  • As the success of glaucoma filtering surgeries are limited by postoperative encapsulation, introduction of MIGS has not reduced postoperative fibrosis, and five years after implanting of glaucoma drainage devices the success rate is only 40 to 50%.
  • adjunctive antiproliferative drugs such as mitomycin-C and 5-fluorouracil are used.
  • Inflammatory wound healing mechanisms caused both by surgery and the introduced materials are major determinant of success or failure in MIGS.
  • modern devices consisting of glutaraldehyde cross-linked porcine gelatin (XENTM) or polystyrene-b-isobutylene-b-styrene (PreserfloTM) appear to reduce the fibrotic reaction, antifibrotics are still needed also with these devices.
  • the invention provides biocompatible structured materials and implantable devices comprising such biocompatible structured materials.
  • a biocompatible structured material comprising a polymerized matrix and tetrapodal ZnO microparticles (t-ZnO) and/or fragments thereof, which are embedded in the polymerized matrix, and/or which are partially protruding from the matrix on the surface of the biocompatible structured material.
  • t-ZnO tetrapodal ZnO microparticles
  • the polymerized matrix of the biocompatible structured material comprises an elastomer, such as poly- and/or oligo-siloxanes, and more preferably it comprises polydimethylsiloxane (PDMS).
  • an elastomer such as poly- and/or oligo-siloxanes, and more preferably it comprises polydimethylsiloxane (PDMS).
  • PDMS polydimethylsiloxane
  • a biocompatible structured material comprising a polymerized matrix having substantially interconnected tunnel-shaped micropores, which is obtainable by partially or totally removing the substantially interconnected network structure of t-ZnO microparticles and/or fragments thereof from the polymerized matrix by acid hydrolysis.
  • the present invention provides an implantable device comprising the biocompatible structured material comprising a polymerized matrix and tetrapodal t-ZnO microparticles and/or fragments thereof, and/or comprising a polymerized matrix having substantially interconnected tunnel-shaped micropores obtainable by partially or totally removing the substantially interconnected network structure of t-ZnO microparticles and/or fragments thereof from the polymerized matrix.
  • the implantable device is a glaucoma drainage implant.
  • glaucoma drainage implant may have the shape of a substantially straight, flexible, elongated body with a circular or polygonal cross-section.
  • the body of the glaucoma drainage implant may additionally contain a lumen.
  • This invention also provides methods for reducing intraocular pressure in an eye of a mammalian subject in need thereof, by implanting one or more implantable devices according to the invention into the eye.
  • Figure 1 shows scanning electron microscopy images (SEM) of tetrapodal ZnO microparticles (t-ZnO) according to the invention.
  • the black line in the graphs has the length of 20 pm (A), 10 pm (B), 50 pm (C), 20 pm (D) and 2 pm (E).
  • Figure 2 shows the absorption spectra of t-ZnO suspensions in HTF (human Tenon’s fibroblast) culture medium at different concentrations (B - D).
  • Figure 3 shows MTT test results to determine t-ZnO toxicity in a HTF culture.
  • the half maximal inhibitory concentration (IC50) was 9.4 pg/mL (range: 8.7 to 10.3 pg/mL).
  • Figure 4 illustrates the effect of t-ZnO microparticles on HTF proliferation:
  • A The control (medium only) shows high Ki67 expression (grey dots represent nuclei of proliferating HTFs).
  • B - F Treatment with t-ZnO microparticles results in a reduction of KI67 expression in HTFs, indicating a reduction of cell proliferation.
  • G Statistical analysis shows a significant reduction of HTF proliferation with concentrations of 8 and 10 pg/mL t-ZnO microparticles in the medium compared to the control (p ⁇ 0.05 and ⁇ 0.001 , one way ANOVA, Dunn's multiple comparison Test).
  • Figure 5 illustrates the effect of t-ZnO microparticles on HTF contractility (a-SMA expression):
  • A HTFs of the control group (medium only) exhibited an intense fibrillar pattern of a-SMA- specific proteins.
  • B - D Treatment with t-ZnO microparticles results in a reduction of a-SMA expression in HTFs, indicating a reduction in cell contractility (A: 0 pg/mL, B: 5 pg/mL.
  • C 10 pg/mL, D: 20 pg/mL).
  • Figure 6 illustrates the effect of t-ZnO microparticles on HTF transdifferentiation (p-SMAD expression):
  • A HTFs of the control group (medium only) showed many p-SMAD-positive cells.
  • B-D Treatment of HTFs with t-ZnO microparticles results in a reduction of p-SMAD expression, indicating decreased cell transdifferentiation.
  • Figure 7 illustrates wound healing rates 24 and 48 hours after treatment with t-ZnO at different concentrations:
  • A The wound gap areas were calculated following 24- and 48-hours treatment. Wound gaps in untreated controls (0 pg/mL) and 1 pg/mL concentrations are almost closed at 48 hours. Concentrations of 5 pg/mL keep the wound gap open over 48 hours. Concentrations of 10 and 20 pg/mL led to a widened wound gap due to toxic effects.
  • Figure 8 shows cytokine levels in HTFs 24 hours (A-E) and 48 hours (F-J) after treatment with t-ZnO at different concentrations.
  • PT cytokine levels in HTFs before the t-ZnO treatment.
  • Figure 9 A is a schematic illustration of the custom-made extrusion device for drainage implant (stent) preparation.
  • the polymer I t-ZnO mixture was loaded into the extrusion device, conveyed inside the cylinder and pressed out of a nozzle. The pressure was generated with a piston.
  • Figure 9 B shows a photograph of ready to use drainage implants.
  • Figure 9 C shows a drainage implant after tensile test. The drainage implant was fixed on a 3D printed sample holder, which was cut in the middle after being mounted into the tensile test machine and before starting the tensile test.
  • Figure 9 D shows a sample for/n vitro testing. Drainage implants of the same material composition I variation were placed next to each other on a glass slide with a thin PDMS coating.
  • C is a SEM micrograph of a drainage implant according to the invention showing a magnified view of the implant’s surface, in which t-ZnO microparticles partially protruding from the polymerized matrix are visible.
  • Figure 11 presents SEM micrographs of drainage implants containing different amounts of t- ZnO microparticles. Drainage implants produced with a 400 pm nozzle are shown at a magnification of A 500x, and B 3500x (top view), and at a magnification of C 500x, and D 1500x (cross-section). Drainage implants produced with a 200 pm nozzle are shown at a magnification of E 500x (top view), and F 1500x (cross-section).
  • the black line in the graphs has the length of 100 pm (A), 10 pm (B), 100 pm (C), 20 pm (D) and 50 pm (E) and (F).
  • Figure 12 A is a SEM micrograph of a cross-section of a drainage implant with a lumen.
  • B is a magnified image of the indicated section of A.
  • C and D represent energy-dispersive X-ray spectroscopy (EDX)-analysis results illustrating the determined distribution of the elements in a material cross-section of the implant according to the invention.
  • EDX energy-dispersive X-ray spectroscopy
  • SEM/EDX-images were obtained with a Zeiss Ultra Plus (Carl Zeiss Microscopy GmbH, Jena, Germany) SEM with an EDX-unit (Oxford Instruments).
  • Figure 13 is a graph illustrating the mechanical properties of drainage implants derived from the tensile test. All results are represented by mean values and standard deviations of 5 measurements for each material composition I variation tested.
  • Figure 14 is a graph illustrating cell viability of rat embryonic fibroblasts on drainage implants in correlation with roughness (Rz) and released Zn ion concentration. All results are represented by mean values and standard deviations of three samples. The statistical analysis shows a significant reduction in cell viability on implants containing 60 wt% and 75 wt% (p ⁇ 0.001 , indicated by three asterisks) as well as on etched implants (p ⁇ 0.01 , indicated by two asterisks) compared to the control.
  • Figure 15 is a photograph of a water droplet (stained with methylene blue) placed on drainage implants containing 75 wt% t-ZnO.
  • the combination of the hydrophobic PDMS matrix and the roughness created by protruding t-ZnO particles makes the surface superhydrophobic so that the water droplet remains nearly spherical.
  • Figure 16 depicts the in vivo position of drainage implants according to the invention 2-3 mm into the anterior chamber and at the distal end under the conjunctiva in a rabbit eye.
  • Figure 17 shows the intraocular pressure (IOP) R/L ratio in the eyes of rabbits upon insertion of drainage implants according to the invention. IOP was measured as IOP ratio between experimental right (R) and control left (L) eye immediately before (day 0) as well as after surgery on days 1 , 3, 7, 10, and 14.
  • A G1 Implant with 200 pm outer diameter.
  • B G2 Implant with 400 pm diameter. Statistically significant values are marked with *.
  • Figure 18 shows IOP R/L ratio in the eyes of rabbits upon insertion of drainage implants according to the invention. IOP was measured as IOP ratio between experimental right (R) and control left (L) eye immediately before (day 0) as well as after surgery on days 1 , 3, 7, 10, 14, 17, 21 , 24, 28, 31, 35, 38 and 42. G3 Implant with 200 pm outer diameter. Statistically significant values are marked with *.
  • Figure 19 shows IOP R/L ratio in the eyes of rabbits upon insertion of drainage implants according to the invention. IOP was measured as IOP ratio between experimental right (R) and control left (L) eye immediately before (day 0) as well as after surgery on days 1 , 3, 7, 10, 14, 17, 21 , 24, 28, 31, 35, 38 and 42. G4 Implant with 400 pm outer diameter. Statistically significant values are marked with *.
  • Figure 20 depicts eyes of rabbits upon insertion of drainage implants according to the invention. After two (A) and after six (B) weeks, the clinical examination of the inserted implants showed neither toxic changes nor inflammatory reactions in the eyes.
  • Figure 21 depicts the histological analysis of the implantation sites.
  • A-D two weeks and E-H: six weeks after insertion of the drainage implant.
  • ZnO is widely used in pharmaceutical products (e.g., as an antibacterial and UV absorbing component in creams) and is actively investigated for use in various biomedical applications (e.g., cancer treatment, periodontal membrane, anti-biofilm materials, and antivirals).
  • biomedical applications e.g., cancer treatment, periodontal membrane, anti-biofilm materials, and antivirals.
  • the shape and the size of ZnO particles have been shown to influence their biological effects. It has been demonstrated that the incorporation of low amounts of tetrapodal shaped ZnO (t-ZnO) into 3D membranes supports the growth of eukaryotic cells and promotes osteogenesis, while increased t-ZnO concentrations may lead to cell inhibitory effects.
  • t-ZnO tetrapodal shaped ZnO
  • t-ZnO microparticles both in an intact state and as fragments resulting from the breaking of one or more arms of the tetrapodal structure, represent a biocompatible material, which, on the one hand, may inhibit cell proliferation, and, on the other hand, does not cause an unacceptable degree of damage to cells or tissues.
  • t-ZnO microparticles which can be varied depending on the synthesis parameters, e.g., temperature and duration, and/or on the growth technique), as well as their concentration and spatial distribution in relation to the cell material I tissue crucially determine the biological properties of the t-ZnO, as exemplified in Figures 3 to 8 and presented in the corresponding parts of the Examples section.
  • Combining t-ZnO microparticles with an inert support allows the production of structured materials with substantially defined amounts and substantially defined spatial distributions of t-ZnO.
  • Such materials make it possible to localize the application of the t-ZnO microparticles and to control their effects in a targeted manner, e.g., in a biological tissue or in an organ.
  • the overall structural features of the resulting biocompatible structured material may further influence the behavior of the biological tissue, leading to the desired antifibrotic properties.
  • Matrices comprising t-ZnO micropaticles have already been used, e.g., as an antifouling yarn (WO2021228322A1).
  • the invention provides a biocompatible structured material comprising a polymerized matrix and t-ZnO microparticles and/or fragments thereof.
  • the material of the invention comprises t- ZnO microparticles having a core and arms having an arm length of about 0.5 pm to about 100 pm, a diameter at the core of about 0.8 pm to about 5 pm, and a diameter at the tip of about 0.05 pm to at most the diameter at the core.
  • the arms meet.
  • the tetrapodal ZnO microparticles have a tetrahedron angle between their arms. Fragments of such microparticles typically result from the breaking of one or more arms of the tetrapodal structure.
  • the material comprises tetrapodal microparticles and, optionally, fragments thereof, typically, in a smaller fraction.
  • the weight fraction of the t-ZnO microparticles and/or fragments thereof in the biocompatible structured material is about 20 to about 90 weight percent. It may be, e.g., 30- 80 weight percent, 40-70 weight percent or 50-60 weight percent.
  • the t-ZnO microparticles and/or fragments thereof of the invention are embedded in the polymerized matrix and/or are partially protruding from the matrix on the surface of the biocompatible structured material. This is illustrated in Figures 10, 11 and 12 and described in more detail in the Examples section.
  • the microparticles and/or fragments typically form a substantially interconnected network structure embedded in the matrix.
  • structured means that the material is not homogenous but comprises, in addition to a matrix, the specific ZnO microparticles and/or specific micropores obtainable from removal of said ZnO microparticles. However, typically, the t-ZnO microparticles and/or fragments thereof are homogenously distributed in the matrix throughout the material. This also applies for the implantable devices of the invention.
  • Biocompatible means that the material is suitable as an implant, as further demonstrated hereon.
  • the polymerized matrix of the biocompatible structured material comprises an elastomer.
  • elastomer may be, e.g., a poly- and/or oligo-siloxane [SiR 2 O] n or a mixture thereof, preferably polydimethylsiloxane (PDMS).
  • the polymerized matrix of the biocompatible structured material may comprise any biocompatible polymer, such as synthetic polymers, naturally- occurring polymers, or mixtures thereof.
  • the polymerized matrix of the biocompatible structured material may also be a hydrogel.
  • the elastic module of the material and the implant of the invention is at least 0.4 MPa, more preferably, at least 3 MPa, at least 10 MPa, or at least 15 MPa, e.g., 3-50 MPa, 3- 21 or 15-21 MPa, e.g., as found when using poly- and/or oligo-siloxane [SiR2O] n polymers.
  • the biocompatible structured material of the invention may be subjected to acid hydrolysis (e.g., with acetic or hydrochloric acid), so as to partially (e.g., 10- 90%, 20-80%, 30-70% or 40-60% or about 50%) or totally remove the substantially interconnected network structure of t-ZnO microparticles or fragments thereof from the polymerized matrix (see Examples section).
  • acid hydrolysis e.g., with acetic or hydrochloric acid
  • partially e.g., 10- 90%, 20-80%, 30-70% or 40-60% or about 50%
  • the resulting biocompatible structured material thus comprises a polymerized matrix having substantially interconnected tunnel-shaped micropores, the majority of the tunnel-shaped micropores forming a tetrahedron angle at the micropore junctions.
  • a tetrahedron angle can also be formed by more than 60%, more than 70%, more than 80% or more than 90% of junctions.
  • the matrix has interconnected tunnel-shaped micropores having a three-dimensional configuration corresponding to an interconnected hollow tetrapod network.
  • Such tunnel-shaped micropores can have an average tunnel diameter from about 0.05 to about 5 pm and an average tunnel length from about 0.5 pm to about 100 pm.
  • the tunnel length is determined between the micropore junctions forming a tetrahedron angle.
  • the tunnel density of the polymerized matrix preferably ranges between about 4 and about 65 volume percent.
  • the matrix preferably comprises an elastomer.
  • Microporous hydrogels comprising interconnected tunnel-shaped micropores having a three- dimensional configuration corresponding to an interconnected hollow tetrapod network suitable for reducing or eliminating motile cells from a solution or an object in contact with a solution are also disclosed in WO2016/177872 A2.
  • further biologically active molecules may be introduced into the biocompatible structured material by forming the biocompatible structured material in the presence of such biologically active molecules, by allowing the biologically active molecules to diffuse into the biocompatible structured material, or by otherwise introducing the biologically active molecules into the biocompatible structured material.
  • the biocompatible structured material of the invention may also be coated with biologically active molecules.
  • an implantable device comprising the biocompatible structured material of the invention.
  • Said implantable device may be an orthopedic implant, a dental implant, a cardiovascular implant, a neurological implant, a neurovascular implant, a gastrointestinal implant, a muscular implant, or an ocular implant. It can be used to avoid, reduce or eliminate fibrotic and foreign body reaction processes in a tissue or an organ upon implantation.
  • the implantable device of the invention may be a glaucoma drainage implant.
  • glaucoma drainage implant may have the shape of a substantially straight, flexible, elongated body with a substantially circular or a polygonal cross-section.
  • the glaucoma drainage implant of the invention is composed of a substantially straight, flexible, generally cylindrical body having a length preferably between about 5 and about 20 mm, and an outer diameter of preferably between about 0.1 and about 5 mm.
  • Figures 10 to 12 show examples of such glaucoma drainage implants.
  • glaucoma drainage implant of the inventions such as a substantially cuboid, flexible body having a length preferably between about 5 and about 20 mm, a width preferably between about 3 and about 10 mm, and a thickness preferably between about 0.2 and about 0.5 mm.
  • the glaucoma drainage implant of the invention may additionally contain a lumen in the body of the implant.
  • a lumen is a substantially hollow channel running along the length and connecting the extremities of the body of the implant (exemplified in Figures 10 and 12). The position and the dimensions of such lumen can further influence the outflow of the aqueous humor beyond the effect of the outer shape of the glaucoma drainage implant itself.
  • the glaucoma drainage implants of the invention are easy and economical to produce and to sterilize by methods known from the art.
  • Dimensionally stable, but at the same time sufficiently flexible implants according to the invention in the desired dimensions and with variable lengths can be manufactured in a single step, for example by means of extrusion processes.
  • An example of an extrusion device for drainage implant preparation is presented in Figure 9 A.
  • variable geometries and sizes can be realized using other techniques known from the art (e.g., injection molding).
  • the invention also provides a method for preparing an implantable device of the invention.
  • Said method may comprise a) providing a homogenously mixed composition comprising monomeric components of the polymerized matrix and t-ZnO and/or fragments thereof, b) extruding said composition and letting it polymerize, and c) cutting the polymerized material to the desired length.
  • the manufacturing process of a glaucoma drainage implant may comprise the following steps: a. A homogeneously mixed polymer composition comprising t-ZnO and/or fragments thereof is provided (depending on the proportion of t-ZnO, the mixture becomes paste-like to powder- like). b. The polymer composition is taken into the extruder (e.g., a piston extruder). c. The polymer composition is conveyed through a cylinder (in the case a piston extruder is used, the pressure for conveying the mixture is generated with a piston). d. The polymer composition is forced out of a shaping nozzle. e. The semi-finished material (filamentary in the case of a cylindrical nozzle) may be suspended between two supports and dried, e.g., in an oven. f. After polymerization, the material is cut to the desired length.
  • a glaucoma drainage implant comprising the compact biocompatible structured material of the invention leads to reduced IOP in vivo, it may be advantageous to further modify the flow properties of the implant.
  • one or both of the following steps may be performed in the production of a glaucoma drainage implant according to the invention with the aim of modifying its flow properties and thus its effect on IOP: g.
  • a lumen may be generated by masking of a partial area during the extrusion process (e.g., using a polymer fiber or a metal wire), and by subsequently removing the masking material (e.g., by etching or mechanical extraction of the wire), so that a substantially hollow channel running along the length and connecting the extremities of the body of the implant is formed. h. Further hollow channels in the body of the implant can be created by partially or totally etching out the t-ZnO particles with an acidic solution (e.g., acetic or hydrochloric acid). Depending on the initial t-ZnO content in the material and/or on the etching parameters, a narrow- or a wide-mesh framework structure can be obtained.
  • an acidic solution e.g., acetic or hydrochloric acid
  • Variations of the amount of t-ZnO used in the biocompatible structured material of the invention can be used to adjust the mechanical properties of the material, such as the elastic modulus.
  • the relatively high weight fraction of t-ZnO used in the biocompatible structured material of the invention (20 - 90 wt%) favors the rheological properties necessary for extrusion, as well as the sliding of the implant in the inserter device for the eye, and also facilitates the anchoring at the implantation site due to the t-ZnO particles protruding from the polymerized matrix.
  • the implants of the invention typically do not comprise fibers e.g., constructed from organic polymers.
  • Glaucoma drainage implants comprising the biocompatible structured material of present invention are particularly suited for MIGS, since they are easy to implant, they easily adapt to the shape of the implantation site and ensure long-term position stability.
  • glaucoma drainage implants provide controlled, long-term stable aqueous humor outflow for significant, permanent reduction of IOP, hence reducing surgical complications and extending the implants’ functional timespan in situ.
  • Another aspect of the invention further relates to a method for reducing intraocular pressure in an eye of a mammalian subject in need thereof, the method comprising implanting one or more glaucoma drainage implants according to the invention into the eye.
  • a method may be used for treating a subject having glaucoma.
  • the method may include the steps of measuring a pre-operative IOP in an eye of the subject, implanting the glaucoma drainage implant(s) into the eye, and measuring a post-operative IOP to confirm treatment of the subject.
  • t-ZnO microparticles were produced at Phi-Stone AG (Kiel, Germany) in a simple and cost-effective one-step approach described elsewhere (Paulowicz et al. 2018. Zinc Oxide Nanotetrapods with Four Different Arm Morphologies for Versatile Nanosensors. Sensors and Actuators B: Chemical 262: 425 - 435). Medical grade polydimethylsiloxane (PDMS) MED-6820 (NuSil Technology LLC, Carpinteria, USA) with a viscosity of 66 Pa*s was used as a matrix polymer, which was provided by HumanOptics AG (Er Weg, Germany).
  • PDMS polydimethylsiloxane
  • the t-ZnO was dispersed into HTF culture medium at 1 mg/mL at the start of each experiment.
  • One reproducible standard batch of t-ZnO served as reference in all experiments and was set in relation to other samples.
  • the dispersion was vortexed before a serial dilution (1 to 5000 pg/mL) was prepared in culture medium.
  • a microplate spectrophotometer (SpectraMax M4, Molecular Devices, Sunnyvale, USA) was used to evaluate the absorption spectrum of the t-ZnO dispersions in HTF-medium at 570 nm. Concentrations of O, 0.1 , 1 , 10, 100 and 1000 pg/mL were tested.
  • the tissue was dissected into 1 to 2 mm cubes and maintained in HTF-medium: DMEM/F-12 (1 :1) medium supplemented with 10% heat-inactivated fetal calf serum (FCS, Invitrogen-Gibco Life Technologies, Düsseldorf, Germany), 2 mM L-glutamine, 100 U/rnL penicillin, and 100 pg/mL streptomycin (Biochrom, Berlin, Germany) in a 100 mm Petri dish at 37°C in a humidified atmosphere with 5% CO2.
  • FCS heat-inactivated fetal calf serum
  • FCS heat-inactivated fetal calf serum
  • streptomycin Biochrom, Berlin, Germany
  • the fibroblasts migrating from these tissues were harvested after approximately 3 weeks by incubation with 0.05% trypsin and 0.02% EDTA (Invitrogen), centrifuged at 300 g for 8 minutes, and seeded in fresh culture medium in 75 cm 2 flasks. The cells between the third and ninth passages were used for the experiments.
  • the t-ZnO stock solution was diluted in DMEM and added to the cell culture at different concentrations (0-15 pg/mL, 20-200 pg/mL and 1000-5000 pg/mL).
  • HTF (passage 8) were grown initially for 36 h.
  • the incubation period with t-ZnO was 48 h.
  • An MTT test was performed to assess the number of viable cells (see below) and the absorbance at 570 nm was measured using a microplate reader (Tecan Group Ltd, Maennedorf, Switzerland). The standard error of the mean of three independent tests was calculated.
  • HTFs were seeded in triplicates at a density of 3 x 10 4 cells on each side of an I bidi culture insert for live cell analysis (Ibidi, Kunststoff, Germany) with a 500 pM separation between each side of the well, and cells were allowed to grow for 24 h.
  • the cells were treated with different concentrations of t-ZnO (0, 2, 4, 6, 8 and 10 pg/mL). The treatment was ended after 6 hours when a complete culture medium exchange was done. 48 hours later, the cells were fixed in 2% paraformaldehyde (PFA) followed by 4% PFA for 10 minutes. Immunostaining was performed as described previously (Tura et al. 2007.
  • Rho-Kinase Inhibitor H-1152P Suppresses the Wound-Healing Activities of Human Tenon’s Capsule Fibroblasts In Vitro. Invest Ophthalmol Vis Sci. 48 (5):2152), using primary antibodies against Ki67 (dilution 1 :300, MAB4190, Millipore, Hessen, Germany), alpha smooth muscle actin (a-SMA) (dilution 1 :100, Ab7817, Abeam, Cambridge, UK) or pSMAD 2 and 3 (1 pg/mL, ab65847, Abeam, Cambridge, UK) followed by Alexa 488-conjugated anti-rabbit antibodies (diluted 1 :100 in blocking buffer; Jackson Immuno-Research, Hamburg, Germany; Molecular Probes, Darmstadt, Germany, respectively).
  • Nuclei were counterstained with DAPI (1 pg/mL in PBS) for 10 minutes. Stained HTFs were examined with an inverted microscope (Leica DMI 6000 B, Wetzlar, Germany). Photographs were captured using a DFC 290 compatible camera and the appropriate software (Leica Application Suite LAS Software, Wetzlar, Germany).
  • HTFs were seeded at a density of 3 x 10 4 cells on each side of an Ibidi culture insert for live cell analysis (Ibidi, Kunststoff, Germany), with a 500 pM separation between each side of the well and allowed to grow for 24 hours.
  • the cells were treated with different concentrations of t-ZnO (0, 1 , 5, 10 and 20 pg/mL). The treatment was ended after 6, 24 or 48 hours, when a complete culture medium exchange was done.
  • Rate of wound healing at 48h 1 - : - : - : - x 100
  • HTF culture supernatant samples were collected after incubation with t-ZnO (1 , 5, 10 and 20 pg/mL) for 24 or 48 hours.
  • the control group was incubated without t-ZnO.
  • Samples were aliquoted under sterile conditions at volumes of 50 pL, labeled and stored at - 80°C until further use.
  • cytokine in each sample binds to their distinct capture antibody spots and subsequently to cytokine-specific, horseradish peroxidase (HRP)-bound secondary antibodies.
  • Samples were tested using a high sensitivity protocol. Samples were diluted at 1 :2 and 1 :5 in Quansys human sample dilution buffer (Quansys Biosciences, Logan, UT, USA). Diluted standards and samples were added to wells containing 5-plex arrays and incubated on a plate shaker for 1 hour at room temperature. The wells were then washed 3 times with washing buffer, a detection mix was added and incubated on a plate shaker for 1 hour at room temperature.
  • Quansys human sample dilution buffer Quansys Biosciences, Logan, UT, USA
  • Drainage implants were prepared by extrusion using a custom-made device illustrated in Figure 9 A. All parts except for nozzles were made of stainless steel to withstand high pressure during extrusion of the highly viscous polymer I particle mixture. As nozzles, standard MK8 brass nozzles for 3D printers with bore diameters of 400 pm and 200 pm were used, resulting in drainage implants as exemplified in Figure 9 B.
  • PDMS premixture was prepared by manually mixing PDMS components A and B in 1 :1 ratio for at least 5 min. Next, t-ZnO microparticles were manually mixed into the PDMS premixture until a homogeneous paste- or powder-like (depending on the t-ZnO concentration) mixture was obtained. After extrusion, the drainage implants were suspended between two supports and dried in an atmospheric oven at 85 °C overnight. After curing, the drainage implants were cut to 1.5 cm in length using a sharp blade. A minimal concentration of 45 wt% t-ZnO particles was necessary to retain the cylindrical shape of the drainage implant after extrusion and during curing. Drainage implants with 45 wt%, 60 wt%, and 75 wt% t-ZnO were produced.
  • Etched drainage implants were prepared by acid hydrolysis placing 75 wt% t-ZnO drainage implants in a 60 % acetic acid solution for 2 days. To accelerate the etching (acid hydrolysis) process, the solution with drainage implants was placed on a heating plate at 50 °C. After etching, the drainage implants were thoroughly washed with ethanol and subsequently with water using an ultrasonic bath for 15 minutes.
  • the drainage implants were sputtered with a conductive layer of gold for 90 s at 30 mA using the BAL-TEC SCD 050 Sputter Coater (Bal-Tec AG, Pfaffikon, Switzerland).
  • a tensile test was conducted with drainage implants with a nominal diameter of 400 pm without a lumen.
  • the drainage implants were placed on 3D printed frames with outer dimensions of 40 x 8 x 0.5 mm (L x W x D) and a 10 x 5 mm (L x W) slot in the middle, similar to tabs used for tensile testing of single carbon or glass fibers.
  • the tensile test was performed with a BETA 5-5 I 6x10 tensile testing machine (Messphysik GmbH Furstenfeld, Germany) at a constant strain rate of 5 mm/min. A total of 5 drainage implants per material composition I variation was measured. Mechanical properties derived from stress-strain curves were calculated by MATLAB R2019b (The MathWorks Inc., Natick, USA). The cross-sectional area of the drainage implants for each material composition I variation was calculated using the corresponding mean diameter obtained by SEM (three drainage implants were measured for each material composition I variation, with each drainage implant measured at three different points).
  • rat embryonic fibroblasts 30.000 rat embryonic fibroblasts per well were seeded directly on the samples.
  • Dulbecco Modified Eagle Medium (DM EM) was used (PAN-Biotech GmbH, Aidenbach, Germany), supplemented with 10 % fetal bovine serum (PAN-Biotech GmbH) and 1 % Penicillin I Streptomycin (Sigma-Aldrich Chemie GmbH, Taufmün, Germany).
  • Negative control (cells + culture medium) and positive control (cells + culture medium + dimethyl sulfoxide (DMSO, Sigma-Aldrich Chemie GmbH, Taufmün, Germany) were prepared at the same time. The cells were grown to confluency for 48 hours.
  • MTT test was conducted. 1 mL of MTT dye (3-(4,5-dimethylthiazolyl-2)-2 ⁇ 5-diphenyltetrazolium bromide; Sigma-Aldrich Chemie GmbH; 1 mg/mL) was added to each well and incubated for 3 hours. After washing with PBS, the samples were transferred to a new 24-well plate, DMSO was added to each well and the well plate was placed on a shaker for 5 min to solubilize formed formazan crystals.
  • MTT dye 3-(4,5-dimethylthiazolyl-2)-2 ⁇ 5-diphenyltetrazolium bromide; Sigma-Aldrich Chemie GmbH; 1 mg/mL
  • the lysates were then transferred to a 96-well plate and the absorption was measured at 570 nm using a plate reader (Epoch2, BioTek Instruments, Winooski, Vermont, USA).
  • One-way ANOVA followed by Tukey test was performed using Origin (OriginLab Corporation, Northampton, USA).
  • the concentration of free Zn ions (Zn 2+ ) in the culture medium after the cell test was assessed by a spectrophotometric method, where Zincon monosodium salt (Sigma-Aldrich Chemie GmbH, Taufmün, Germany) was used as an indicator of Zn by turning the Zn ion containing solution blue at pH 9. The intensity of the blue color was measured at 620 nm using a plate reader (Tecan Group Ltd., Maennedorf, Switzerland). A set of samples with known Zn ion concentration was used to obtain a calibration curve for the determination of the Zn ion concentration in the cell culture medium samples.
  • the drainage implants used in these experiments were a composite of t-ZnO microparticles (75 wt%) and PDMS.
  • the implants used in the experimental groups differed in outer diameter (200 pm and 400 pm).
  • a disposable inserter device with a grip, a 27-gauge slotted needle, and a deployment slide were developed to facilitate insertion of the 200 pm sized implants.
  • the 400 pm sized implants could be easily implanted without insertion device.
  • a scleral tunnel was created with a paracentesis starting from 1.5 mm posterior to the limbus and directed to the anterior chamber.
  • the 200 pm drainage implants were preloaded into the inserter.
  • the preloaded inserter was then forwarded through the scleral tunnel. Once the implant was 2-3 mm into the anterior chamber, it was released from the inserter by retracting the inserter needle. The distal end was then placed under the conjunctiva ( Figure 16). The conjunctiva was closed in three cases at the opening site, because the implant appeared exposed.
  • IOP was measured without topical anesthesia in both operated and nonoperated eyes just before (day 0) in all groups and at 1 , 3, 7, 10 and 14 days after surgery in groups G1 - G2 and at 1 , 3, 7, 10, 14, 17, 21 , 24, 28, 31 , 35, 38 and 42 days after surgery in groups G3 - G4. Animals were examined under general anesthesia at day 14 in groups G1 - G2 and at day 42 in groups G3 - G4 after surgery. Statistical analysis of the IOP values was performed using SPSS 26 software (SPSS Inc., Chicago, USA). The Mann-Whitney-U-Test for independent samples was used to compare postoperative IOP ratios pairwise with the preoperative value. Levels of p ⁇ 0.05 were considered statistically significant.
  • the arms of the t-ZnO particles exhibit a hexagonal wurtzite crystal structure oriented along the c-axis with alternating Zn 2+ and O 2 ' stacking planes.
  • the t-ZnO microparticles have a tetrahedral geometry with 109.5u bond angles to each other.
  • the thicknesses of the arms of the t-ZnO microparticles varied from 0.05 pm to 5 pm. Their lengths ranged from 0.5 pm to 100 pm ( Figure 1).
  • the surface morphology of drainage implants with different amounts of t-ZnO microparticles is shown in Figure 11 . Homogeneously distributed protruding t-ZnO microparticles on the surfaces of unetched drainage implants and distinct pores on the surface of an etched drainage implant can be observed. While single tetrapod arms are exposed from the surfaces of drainage implants containing 45 wt% and 60 wt% t- ZnO, the surface morphology of the drainage implant with 75 wt% t-ZnO is completely modified by the particles.
  • the diameter of drainage implants was found to decrease with the decreasing concentration of t-ZnO particles, which can be attributed to different viscosity during extrusion.
  • Mean diameter values amounted to 394.5 pm ⁇ 0.4 pm, 374.8 pm ⁇ 0.4 pm, and 333.4 pm ⁇ 0.3 pm for drainage implants containing 75 wt%, 60 wt%, and 45 wt% t-ZnO, respectively.
  • the etched drainage implants exhibited the smallest diameter with 325.3 pm ⁇ 0.3 pm due to shrinkage after removal of the t-ZnO particles.
  • the feasibility of creating a lumen in the drainage implant by placing a metal wire inside the nozzle during extrusion is demonstrated in Figure 12.
  • liquid silicone rubbers are typically not suitable for extrusion.
  • the addition of a high amount of t-ZnO particles into liquid PDMS increases the viscosity of the PDMS I t-ZnO mixture to an extent that allows retaining the cylindrical shape in the uncured state after extrusion.
  • high internal frictional forces arising from the extremely high viscosity prevent particles from “filtering”, i.e., agglomeration of the particles in the nozzle upon pressure created by a piston, and thus, prevent clogging of the nozzle and allow a homogeneous distribution of particles throughout the drainage implant.
  • the decrease of the elastic modulus can be attributed to entrapped air during extrusion, since a high amount of incorporated t-ZnO led to a nearly powder-like mixture. Less pronounced, but the same trend was observed for the ultimate strength, while the elongation at break decreased with the increasing amount of incorporated t-ZnO. Etched drainage implants exhibited the lowest elastic modulus (0.42 MPa ⁇ 0.07 MPa) and the highest elongation at break (232 % ⁇ 43 %).
  • a drainage implant must provide sufficient stiffness to be inserted through an injector into the target tissue, maintain the drainage implant structure, and stay in situ for a long-term period.
  • a drainage implant should also be flexible enough to conform to the natural curvature of an eye. It has also been shown that mechanical flexibility reduces the foreign body reaction to an implant. The flexibility of an implant can be altered by its elastic modulus, cross- sectional area, and length.
  • drainage implants with highest amount of t-ZnO 60 wt% and 75 wt%) exhibit elastic modulus values of approximately 15-20 MPa, which is higher than that of pure PDMS, but lower than a large number of drainage implants that have been released for clinic use and have an elastic modulus in the range of 104-105 MPa.
  • cytotoxic potential of the t-ZnO microparticles was first investigated more closely using HTF cell cultures. To estimate the IC50, a 4 parameters logistic nonlinear regression model was used. Cell viability with the MTT test revealed an IC50 of 9.4 pg/mL (range 8,7 - 10,3 pg/mL; Figure 3).
  • pSMAD- positive cells as a marker for transdifferentiation were significantly reduced after treatment with 8 and 10 pg/mL t-ZnO compared to controls (p ⁇ 0.05, p ⁇ 0.01 , one-way ANOVA, Dunn's Multiple Comparison Test; Figure 6).
  • fibroblasts covered the scratched area within 24 hours in the performed wound healing assays.
  • Treatment with t-ZnO microparticles resulted in a concentration and time dependent inhibition of HTF migration and proliferation.
  • Both short (6 hours) and longterm (24 and 48 hours) treatments with t-ZnO inhibited growth and migration of the cells in a dose-dependent manner.
  • the presented experiments show that fibroblasts tolerate treatment with concentrations of t-ZnO as high as 10 pg/mL for 6 hours without toxic effects (Figure 3), while long-term exposure of the cells leads to significant decrease in cell count, even at the low concentration of 5 pg/mL.
  • IL-6 concentration was significantly reduced in culture supernatant treated with 10 and 20 pg/mL t-ZnO for 24 and 48 hours compared to pre-treatment. (p ⁇ 0.001 and ⁇ 0.05, respectively, Dunn's Multiple Comparison Test; Figure 8). There was no significant difference between the cytokine concentrations 24 and 48 hours following t-ZnO treatment (data not shown).
  • Figure 14 shows that the exposure of cells to drainage implants with different amounts of t- ZnO reduced cell viability in a concentration dependent manner.
  • the statistical analysis shows a significant reduction in cell viability on drainage implants containing 60 wt% and 75 wt% (p ⁇ 0.001 , indicated by three asterisks) as well as on etched drainage implants (p ⁇ 0.01 , indicated by two asterisks) compared to the control.
  • Drainage implants containing 45 wt%, 60 wt%, and 75 wt% t-ZnO inhibited cell viability to 77 % ⁇ 9 %, 57 % ⁇ 8 %, and 43 % ⁇ 3 %, respectively.
  • ionic Zn Being an essential trace element, the second most common metal in the body (after iron) and the most abundant in the mammalian retina, ionic Zn can nonetheless exert toxic effects when present at elevated levels. Toxic effects have been observed from a concentration of ZnO particles of 10 pg/mL and higher. However, the acute toxicity of ionic Zn from ZnO is usually associated with a cellular uptake of ZnO particles, resulting in elevated intracellular Zn ion concentrations and intracellular generation of ROS, which is not the case when embedded microparticles such t-ZnO investigated in this study are used.
  • the highest detected amount of dissolved Zn ions in the culture medium after 48 h was 2.55 ⁇ 0.27 pg/mL for the glass slide samples, which were completely covered with 75 wt% t-ZnO drainage implants (as illustrated in Figure 9 C). Therefore, the amount of Zn ions released from a single drainage implant is negligibly small. Nevertheless, at low distance, the released Zn ions could also contribute to the cell inhibiting properties at the drainage implant surface as a secondary mechanism.
  • drainage implants exhibit elastic modulus values from 3.3 MPa ⁇ 0.5 MPa to 21.3 MPa ⁇ 2.7 MPa.
  • a lumen in a drainage implant can be created by placing a metal wire inside the nozzle during the extrusion and mechanically removing it after the curing process is completed.
  • the addition of t-ZnO microparticles resulted in an increase in roughness (RMS) up to 3.9 pm ⁇ 0.4 pm, leading to a superhydrophobic surface.
  • RMS roughness
  • the present invention provides a relatively simple and direct method for the fabrication of drainage implants with promising biological and mechanical properties, which have a great potential for application in MIGS.
  • t-ZnO microparticles were shown to effectively inhibit HTF proliferation, migration and transdifferentiation.
  • Antifibrotic and anti-inflammatory properties of t-ZnO were demonstrated as suppressed expression of Ki67, a-SMA and pSMAD, as well as reduced synthesis of the cytokines IL-6 and HGF.
  • Expression of Ki67, SMA and pSMAD was significantly downregulated in vitro following short-term treatment with t-ZnO for 6 hours, demonstrating the suppression of fibroblast proliferation, migration, and mesenchymal transformation functions. This might indicate a potential long antifibrotic effect without the need of repeated treatments.
  • a brief exposure of the scleral flap and conjunctiva to t-ZnO during glaucoma surgery may be a suitable option to deliver high concentrations of t-ZnO.
  • Extended-release systems or coated implants may be suitable to use lower concentrations of t-ZnO microparticles to suppress excessive wound healing.
  • Prolonged treatment with high concentrations of t-ZnO (10 and 20 pg/mL) was associated with morphological changes of the fibroblasts, like the loss of their spindle shape or the reduction of their cytoplasm. As cellular uptake of the tetrapodal particles can be excluded (Papavlassopoulos etal. 2014.
  • Toxicity of functional nano-micro zinc oxide tetrapods impact of cell culture conditions, cellular age and material properties. PloS one. 9 (1): e84983), it is possible that the observed toxicity occurs due to a disruption of the cell membrane by the tips of the t-ZnO microparticles.
  • IL-6 is a pleiotropic cytokine that is involved in growth and differentiation of numerous cell types.
  • t-ZnO treatment could suppress IL-6 production by HTF even at low concentrations of 1 pg/mL. This decrease in IL-6 may reflect the antiproliferative abilities of t-ZnO but may also be associated with its potential toxic effects at higher concentrations.
  • the low IL-6 concentration might also reflect a milder inflammatory response following treatment with t-ZnO compared to the untreated control.
  • t-ZnO is proposed as a new antiscarring agent with the potential to contribute to an effective wound modulation following glaucoma surgery.
  • ZnO nanoparticles are among the most widely used nanomaterials in biomedicine and were recently described as selective killers for rapidly proliferating cells, whereas differentiated cells were not affected. Therefore, HTFs, which are proliferating after glaucoma filtering surgery, might also be a target for ZnO nanoparticles.
  • ZnO nanoparticles might be also cytotoxic for the surrounding, non-proliferating tissue, which could cause a breakdown of the conjunctiva followed by postoperative hypotony.
  • tetrapodal ZnO structures are proposed by the inventors.
  • t-ZnO microparticles have less cytotoxic potential than spherical ZnO nanoparticles (Zarbin etal. 2010. Nanomedicine in ophthalmology: the new frontier. Am J Ophthalmol. 150 (2): 144-162. e2).
  • the tetrapodal structure of the t-ZnO microparticles used in this study consists of a ZnO core in a zinc blende structure from which four ZnO arms radiate out of the wurtzite structure ( Figure 1).
  • This relatively large, biologically active structure prevents cellular uptake and maintains the specific properties of the tetrapod tips (Papavlassopoulos et al. 2014. Toxicity of functional nano-micro zinc oxide tetrapods: impact of cell culture conditions, cellular age and material properties.
  • t-ZnO microparticles were shown to inhibit wound healing processes such as fibroblast proliferation, migration, transdifferentiation, as well as cytokine release.
  • t-ZnO microparticles represent an innovative approach both for wound healing modulation in ocular surgery and as material for ocular implants.
  • the drainage implants of the invention reduced the IOP in vivo for as long as 2 weeks.
  • a limitation of the present study is that drainage implants of the invention were not compared with other implants devoid of microparticles.
  • a previous study using the same model but different implants showed normal levels of the intraocular IOP within 1 week.
  • This study compared a poly(styrene-b-isobutylene-b-styrene) (SIBS) drainage implant with a silicone drainage implant, which had an outer diameter of 250 ⁇ 10 pm and 640 ⁇ 15 pm, respectively. Additionally, both the SIBS drainage implant and the silicone drainage implant had an inner lumen with 65 ⁇ 10 pm and 300 ⁇ 10 pm, respectively (Acosta et al. 2006.
  • a drainage implant design without a lumen was used.
  • the drainage implants currently in clinical use such as XEN TM or PreserfloTM, have a lumen. Implementation of a lumen should improve the outflow of the aqueous humor and further reduce the IOP.

Abstract

Un matériau structuré biocompatible comprend une matrice polymérisée et des microparticules de ZnO tétrapodal (t-ZnO) et/ou des fragments de celles-ci, les microparticules de t-ZnO ayant un noyau et des bras ayant une longueur de bras d'environ 0,5 µm à environ 100 µm, un diamètre au noyau d'environ 0,8 µm à environ 5 µm, et un diamètre à la pointe d'environ 0,05 µm à au plus le diamètre au niveau du noyau ; la fraction de poids des microparticules de t-ZnO et/ou des fragments de celles-ci est d'environ 20 à environ 90 pour cent en poids ; et les microparticules de t-ZnO et/ou des fragments de celles-ci sont incorporés dans la matrice polymérisée et/ou font partiellement saillie à partir de la matrice sur la surface du matériau structuré biocompatible.
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