WO1994013234A1 - Implant device and method for treatment of glaucoma - Google Patents

Implant device and method for treatment of glaucoma Download PDF

Info

Publication number
WO1994013234A1
WO1994013234A1 PCT/AU1993/000656 AU9300656W WO9413234A1 WO 1994013234 A1 WO1994013234 A1 WO 1994013234A1 AU 9300656 W AU9300656 W AU 9300656W WO 9413234 A1 WO9413234 A1 WO 9413234A1
Authority
WO
WIPO (PCT)
Prior art keywords
fibre
implant device
eye
glaucoma
anterior chamber
Prior art date
Application number
PCT/AU1993/000656
Other languages
French (fr)
Inventor
Michael Andrew Coote
Original Assignee
Michael Andrew Coote
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Michael Andrew Coote filed Critical Michael Andrew Coote
Priority to AU66531/94A priority Critical patent/AU6653194A/en
Publication of WO1994013234A1 publication Critical patent/WO1994013234A1/en

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14Macromolecular materials
    • A61L27/22Polypeptides or derivatives thereof, e.g. degradation products
    • A61L27/222Gelatin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F9/00Methods or devices for treatment of the eyes; Devices for putting-in contact lenses; Devices to correct squinting; Apparatus to guide the blind; Protective devices for the eyes, carried on the body or in the hand
    • A61F9/0008Introducing ophthalmic products into the ocular cavity or retaining products therein
    • A61F9/0017Introducing ophthalmic products into the ocular cavity or retaining products therein implantable in, or in contact with, the eye, e.g. ocular inserts
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F9/00Methods or devices for treatment of the eyes; Devices for putting-in contact lenses; Devices to correct squinting; Apparatus to guide the blind; Protective devices for the eyes, carried on the body or in the hand
    • A61F9/007Methods or devices for eye surgery
    • A61F9/00781Apparatus for modifying intraocular pressure, e.g. for glaucoma treatment
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14Macromolecular materials
    • A61L27/16Macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14Macromolecular materials
    • A61L27/18Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2310/00Prostheses classified in A61F2/28 or A61F2/30 - A61F2/44 being constructed from or coated with a particular material
    • A61F2310/00005The prosthesis being constructed from a particular material
    • A61F2310/00365Proteins; Polypeptides; Degradation products thereof
    • A61F2310/00383Gelatin

Definitions

  • This invention relates to the treatment of glaucoma or intraocular pressure, and in particular it relates to an implant device and method for carrying out this treatment.
  • IOP intraocular pressure
  • Raised intraocular pressure is currently treated pharmacologically and surgically.
  • IOP is determined by the rate of production in the eye and the rate of outflow from the eye of an optically transparent nutrient fluid called aqueous.
  • Aqueous is a nutrient fluid of extraordinarily optical properties which contains, amongst others, 25 times the serum concentration of ascorbic acid, 3 times the serum concentration of lactate, as well as glucose, oxygen and a unique spectrum of amino acid concentrations (3). Because of this unique nature of aqueous, the preferred method of effecting change in the hypertensive eye is to increase the outflow of aqueous rather than reducing the rate of renewal.
  • POAG primary open angle glaucoma
  • Topical medications have a number of disadvantages. They may not be available to many patients (worldwide) due to expense or availability, and when prescribed there is a reported up to 30% compliance failure rate. The medications have significant short and long term side effects on the eyes and tend to have reducing efficacy over time. In addition some patients may experience significant systemic side effects from the medication. Topical medication may not be as effective as preventing glaucoma damage as surgery (3).
  • Laser surgery has limited application in some types of glaucoma, but its wide application has given disappointing results.
  • Surgical intervention to increase the facility of outflow of aqueous is achieved by creating an alternate pathway from the anterior chamber to the periocular tissues.
  • Various surgical strategies over 80 years led to the development of the current trabeculectomy operation, which Sugar first described in 1961 (4). Despite it's long incubation period, the current operation is imperfect and is not frequently adopted as first line therapy.
  • trabeculectomy has a high rate of post ⁇ operative complications: in one prospective study up to 40% of treated eyes suffered one of the following complications: hyphaema, transient flat anterior chamber, choroidal detachment or ulceris with synechiae formation (5). This study also found that some 40% of eyes post-trabeculectomy developed significant changes in the lens, and 3/4 eyes suffering from prolonged hypotony developed cataract. These results compare to previous retrospective studies (6).
  • Implant is a comparatively large and complicated silicone structure (8). Particular skill is required for its successful implantation and it is responsible for a number of unwanted side-effects.
  • an implant device for use in the treatment of glaucoma or intraocular pressure in an eye of a patient, which comprises a hollow fibre, preferably of a biologically inert material, said fibre being microperforated in the walls thereof and being adapted on implantation into the eye of a patient to extend between the anterior chamber of the eye and the periocular tissues, particularly the subconjunctival space of the eye.
  • a hollow fibre preferably of a biologically inert material
  • said fibre being microperforated in the walls thereof and being adapted on implantation into the eye of a patient to extend between the anterior chamber of the eye and the periocular tissues, particularly the subconjunctival space of the eye.
  • the implant device of this invention is implanted into the eye so as to provide a direct path into the eye with one end of the fibre located in the anterior chamber.
  • the end of the fibre which is to extend into the anterior chamber may be provided with anchoring means, such as a flange, T-shaped fitting of the microperforated tubing, silicon tubing or the like, to hold that end of the fibre in place in the anterior chamber.
  • anchoring means such as a flange, T-shaped fitting of the microperforated tubing, silicon tubing or the like
  • the other end of the fibre which is to extend into the subconjunctival space or other periocular tissues may also be provided with similar anchoring means to hold that end in the subconjunctival tissues.
  • the device may be implanted as a suture, with the fibre forming a loop in the anterior chamber and the two free ends located beneath the conjunctiva of the eye.
  • the surface of the microperforated device of this invention is modified, in particular by treatment with heparin, in order to increase its biocompatibility, in particular to reduce fibroblast proliferation.
  • heparin a treatment process, including covalent binding of heparin to solid surfaces, are well known in the art.
  • Suitable hollow fibres for use as an implant device in accordance with this invention are, for example, fibres having an external diameter of about 500-600 ⁇ m and an internal diameter of about 200-350 ⁇ m.
  • the fibres suitably have a pore size larger than 0.2 ⁇ m, and preferably the pore size is 0.4 - 0.6 ⁇ m or larger.
  • the hollow fibres may, for example, be made of polypropylene or a similar biologically inert material.
  • Particularly preferred microperforated hollow fibres are polypropylene fibres having an average pore size of 0.4 ⁇ m.
  • the lumen of the hollow fibre of the implant device may be at least partially occluded with a biodegradable material, such as a biodegradable polymer.
  • a biodegradable material such as a biodegradable polymer.
  • Suitable biodegradable polymers include those that will degrade rapidly and produce little reactive (scarring) byproducts. They include, for example, the polyglycolic and polylactic acid polymers and mixtures thereof (such as 50:50 mixtures) which already have intraocular use, as well as gelatin, or polyanhydrides or polyphosphates, (although these latter varieties may be too slow in degradation).
  • Such occlusion may be achieved by coating the inside walls of the fibre, or in fact filling the lumen of the fibre, with the biodegradable material.
  • the biodegradable material may be coated on the outside of the fibre.
  • the biodegradable material may also include pharmacologically active agents, such as drugs for reducing scarring, steroids such as dexamethasone or hydrophobic forms thereof, non-steroidal anti-inflammatory agents, or antimetabolite agents such as mitomycin C 5-fluorouracil or adriamycin.
  • pharmacologically active agents such as drugs for reducing scarring, steroids such as dexamethasone or hydrophobic forms thereof, non-steroidal anti-inflammatory agents, or antimetabolite agents such as mitomycin C 5-fluorouracil or adriamycin.
  • Such an occluded fibre may be used to prevent the eye becoming too soft immediately after implantation, and to act as a slow release reservoir of the pharmacologically active compounds.
  • the present invention provides a method for treatment of glaucoma or intraocular pressure in an eye of a patient, which comprises the step of implantation into said eye of an implant device as broadly described above, said device on implantation extending between the anterior chamber of the eye and the periocular tissues, particularly the subconjunctival space of the eye.
  • the patient may be either a human or animal.
  • the second mechanism that of wound healing and fibrosis, is of vital importance, and it is this which is the primary determinant of the long term success of the operation.
  • Many methods of reducing or retarding the fibrosis have been tried, however they all rely of creating a large wound, and hence a large biological stimulus to healing and fibrosis.
  • the essence of the present invention is to minimise the trauma, use an implant made of a biologically inert material, and preferably to coat the surface of the implant in heparin, a molecule that is found lining the surface of all blood vessels, so that the implant disrupts the tissues minimally, and is so designed and treated that any subsequent fibrotic reaction is minimalised.
  • Microperforated fibres are currently used in a great variety of applications and hence are readily available.
  • such fibres are used in plasmapherisis filters for use in human blood filtration where they are used grouped together in bundles of 2000. They provide a very high surface area to volume ratio for diffusion of fluids through their walls, and are biologically inert. Suitable fibres may however be available from other sources, or they may be made especially for the implant device of this invention.
  • the implant of this invention is designed to be simple, quick to place under local anaesthesia, and have minimal post-operative care. These are advantages in any community, but are necessities in the third world where glaucoma remains essentially untreated. 1. Ease of Placement:
  • the implant device of this invention is placed with one end of the fibre in the anterior chamber of the eye and the other outside the eye in the sub ⁇ conjunctival space.
  • the fibre is implanted as a sheath around a stilette-type needle, and the needle then withdrawn leaving the fibre in place with one end anchored in the anterior chamber and providing a water tight seal around the outside of the fibre where it passes through the wall of the eye.
  • the conjunctiva is lifted forward with atraumatic tissue forceps and the free end of the fibre located in the sub-conjunctival space before the conjunctiva is allowed to return to its normal anatomy leaving the free end buried beneath the conjunctiva.
  • the device may be placed from the inside of the anterior chamber, so that the fibre enters the subconjunctival space after being passed through the wall of the eye.
  • the device may be implanted as a suture.
  • the fibre will be swaged to a cutting needle of approximately 8-10 mm diameter.
  • the fibre will be introduced to the anterior chamber as a suture and passed through the limbal tissue.
  • Conjunctiva will be grasped some 15 mm posterior to the limbus and brought forward with atraumatic tissue forceps.
  • the tented conjunctiva will be perforated by the needle as it enters the eye.
  • the tip of the needle is delivered the fibre is pulled through, such that the middle of the fibre remains in the anterior chamber.
  • the needle can then be cut off, the conjunctiva relaxed, and the two free ends can be sutured to the sclera 15 mm posterior to the limbus.
  • the fibre now lies with a loop in the anterior chamber and two free ends buried beneath the conjunctiva with minimal trauma to the periocular tissues.
  • aqueous is known to obstruct microporous filters of pore diameter 0.2 ⁇ m (14).
  • the reason for this action of aqueous is unclear, and has only recently been demonstrated. The action is due to the combined actions of a protein and non-protein components of the aqueous, and is not due to fibrin /fibrinogen (15).
  • Fibre pore diameter would need to be larger than 0.2 ⁇ m to assure to continued patency of the intraocular portion of the fibre.
  • Fibres obtained for the initial study have a pore size of 0.5-0.6 ⁇ m (gambro PF2000, plasmapheresis fibres). If studies show blockage, then fibres can b especially made with pore sizes larger.
  • Fibrin /fibrinogen has been identified in the subconjunctival tissue of non- human primates 2-7 days post-trabeculectomy (19). Leakage of plasma from damaged blood vessels causes the formation of an extravascular clot consisting of fibrin, fibrinogen, fibronectin and platelets (20). This serves as a scaffold for the migration of inflammatory cells. Experiments suggest that the quantity of fibrin scaffold present in a wound determines the amount of scar tissue that ultimatel develops (21). Furthermore, aqueous has been shown to accelerate clotting time as a result of a procoagulant action (22).
  • Heparin is well known for its actions in prevention of the clotting cascade, however it has also been demonstrated to have an action directly against fibroblas proliferation, and specifically against sclera fibroblasts (23). It has also been demonstrated that heparin bound to polymer surfaces prevents the normal adherence and proliferation of human sclera fibroblasts over that surface (24). 3. Regulation of Outflow:
  • the size of the sclerostomy required can be calculated from Poiseuille's equation as the fluid flow is known (2.5 ⁇ i/min), the path length is normally under 2 mm, and the driving pressure needs to be as low as possible (under 2 mm/Hg). From this it can be ascertained that the sclerostomy diameter need only be greater than 200 ⁇ m diameter to not impede fluid flow from the eye.
  • the longer path length required in the use of the implant device of the present invention may necessitate the use of a fibre of larger diameter, for example, up to 350 ⁇ m.
  • the small size of the fibre lumen should be adequate to handle a proportion of aqueous outflow, the rest being catered for by uveoscleral and remaining flow through the trabecular meshwork.
  • Aqueous production has been determined at 2.5 ⁇ l/min (25).
  • Microperforated tubes offer the advantage that the whole of the wall of the tube acts as a diffusion surface. Given a subconjunctival length of 10mm, and hence a total length of 20 mm, the surface area of a tube of outside diameter is approximately 20 mm 2 . This is comparable to the original plate surface area as specified by Molteno (8).
  • Aqueous normally flows from the eye through dedicated channels. Surgical procedures allow aqueous to be absorbed as tissue oedema (the "bleb). Aqueous is virtually protein free (in the non-inflamed eye) and is thus drawn across the capillary walls by oncotic pressure. Scarring of the subconjunctival space, reduction in volume or capillarity of the absorptive tissue, or changes in the characteristics of aqueous will all jeopardise or prevent absorption.
  • Resistance to flow across the wall of the implant device of this invention adds another dimension to the regulation of the outflow of aqueous from the eye.
  • the fibres used in the initial trial were microperforated polypropylene fibre, manufactured by Gambro having an average pore size 0.4 ⁇ m, with a surface modification in which the fibres were coated with heparin according to a protocol described by Larm et al (26).
  • the preferred animal model is the rabbit and has been used in many animal trials of glaucoma implants (27,28). It has a relatively large eye, docile personality, and reacts well to anaesthesia. It has ocular anatomy not dissimilar to the human, and an IOP in the same range, although it should be noted that the rabbit is well known to have a high propensity to scarring in the subconjunctival space.
  • Fibres were implanted under general anaesthesia using a stilette-type needle as previously described. Fibres were passed from the conjunctival space through the limbal sclera such that the end remained buried under the conjunctiva and the anterior end was located in the anterior chamber in the angle. No sutures or glue were used on the conjunctiva.
  • Figure 1 B is a summary of the Schiotz pressure difference between the treated and untreated eyes as shown in Figure 1A.

Abstract

An implant device for use in the treatment of glaucoma or intraocular pressure in an eye of a patient, comprises a hollow fibre, preferably of a biologically inert material which is microperforated in the walls thereof. In use, the device is implanted into the eye so as to extend between the anterior chamber of the eye and the periocular tissues.

Description

IMPLANT DEVICE AND METHOD FOR TREATMENT OF GLAUCOMA
Field of the Invention
This invention relates to the treatment of glaucoma or intraocular pressure, and in particular it relates to an implant device and method for carrying out this treatment.
Background to the Invention
In the USA over two million people suffer from glaucoma. The disease is a major cause of blindness, with approximately 30% of patients having visual impairment and 3.5% classified as legally blind (1 ). In Australia it is estimated that 120,000 people suffer from glaucoma, and it represents the fourth leading cause of people registering for the blind pension (2). Current treatments are unsatisfactory: topical drug treatment is not without side effects and is required for life, and surgical intervention is frequently unsuccessful.
The most prominent aspect of glaucoma is raised pressure inside the eye which is associated with the loss of nerve fibres in the retina, and partial or total loss of vision is a consistent sequel to this primary pathology. The intraocular pressure (IOP) at which irreversible damage to the optic nerve occurs is quite variable between individuals, however the one common factor is that all patients with glaucoma benefit from reduction of their IOP. All current primary therapies are directed at reducing the intraocular pressure to below 15 mmHg, a level at which retinal damage is minimised.
Raised intraocular pressure is currently treated pharmacologically and surgically. IOP is determined by the rate of production in the eye and the rate of outflow from the eye of an optically transparent nutrient fluid called aqueous.
Therapy is aimed at either reducing aqueous production, or increasing the rate of outflow of aqueous from the eye. Aqueous is a nutrient fluid of exquisite optical properties which contains, amongst others, 25 times the serum concentration of ascorbic acid, 3 times the serum concentration of lactate, as well as glucose, oxygen and a unique spectrum of amino acid concentrations (3). Because of this unique nature of aqueous, the preferred method of effecting change in the hypertensive eye is to increase the outflow of aqueous rather than reducing the rate of renewal.
increasing the outflow of aqueous can be achieved pharmacologically with topical (or oral) agents that cause the ciliary muscle to increase tone causing the trabecular mesh to become more porous. These agents have many disadvantages, not the least of which is miosis which can be quite debilitating in patients with reduced retinal function. For this reason, and others, these agents are not the usual first line of therapy for primary open angle glaucoma (POAG).
Topical medications have a number of disadvantages. They may not be available to many patients (worldwide) due to expense or availability, and when prescribed there is a reported up to 30% compliance failure rate. The medications have significant short and long term side effects on the eyes and tend to have reducing efficacy over time. In addition some patients may experience significant systemic side effects from the medication. Topical medication may not be as effective as preventing glaucoma damage as surgery (3).
Laser surgery (Laser trabeculoplasty) has limited application in some types of glaucoma, but its wide application has given disappointing results.
Surgical intervention (trabeculectomy) to increase the facility of outflow of aqueous is achieved by creating an alternate pathway from the anterior chamber to the periocular tissues. Various surgical strategies over 80 years led to the development of the current trabeculectomy operation, which Sugar first described in 1961 (4). Despite it's long incubation period, the current operation is imperfect and is not frequently adopted as first line therapy. ln addition to surgical failures, trabeculectomy has a high rate of post¬ operative complications: in one prospective study up to 40% of treated eyes suffered one of the following complications: hyphaema, transient flat anterior chamber, choroidal detachment or iritis with synechiae formation (5). This study also found that some 40% of eyes post-trabeculectomy developed significant changes in the lens, and 3/4 eyes suffering from prolonged hypotony developed cataract. These results compare to previous retrospective studies (6).
Renewed interest in surgery as first line therapy has been encouraged by a recent publication from Glasgow in which 99 patients with Primary Open Angled Glaucoma (POAG) were prospectively randomised to receive either surgical or medical treatment. At five years, this study has provided the challenging observation that surgical intervention (trabeculectomy) provided more stable control and less field loss than medical therapy, even when combined with later trabeculectomy (7).
The concept of treating glaucoma with an implant arose from basic surgical principals of drainage of a cavity. The most popular recent implant, the Molteno
Implant, is a comparatively large and complicated silicone structure (8). Particular skill is required for its successful implantation and it is responsible for a number of unwanted side-effects.
In general, current implants are bulky, complicated to place satisfactorily, and have the risk of displacement and erosion (9,10,11). Reoperation is difficult. Post-operative hypotony and shallow anterior chamber are common in implant surgery (15-45%) and appear to be related to choroidal effusion (7,12). Recently the Molteno implant has been shown to cause declining endothelial counts with increased pleomorphism and polymegathism (13). Operative modifications intended to bypass some of these problems tend to be complicated and require further intervention postoperatively to implement free drainage of aqueous. Although surgery may be desirable as first line therapy two major problems exist with all current surgical treatments:
1. the outflow pathway scleroses, and the pathway may become non- patent, and
2. the quantity of outflow is not able to be regulated easily
The combination of prolonged antiglaucomatous medication and significant anterior segment operative trauma sabotages attempts at creating a permanent lowering of IOP. A single operation is preferable to lifelong administration of medication, even in countries where the latter is an option. Current trabeculectomy operations are unsatisfactory for third world environments as the amount of post-operative care required is prohibitive. Furthermore, certain racial groups have a higher rate of failure related to an increased propensity to scarring. Thus early surgery which maintains lowered IOP before prolonged medical therapy or visual loss, in which there is minimal disturbance of the anterior chamber and surrounding tissues, and which has low post-operative risk, is seen as a major goal in the treatment of glaucoma.
It is a primary object of the present invention to provide a method for the surgical treatment of glaucoma by reduction of intraocular pressure using a novel implant, which method is safe, reliable and simple.
Summary of the invention In accordance with the present invention there is provided an implant device for use in the treatment of glaucoma or intraocular pressure in an eye of a patient, which comprises a hollow fibre, preferably of a biologically inert material, said fibre being microperforated in the walls thereof and being adapted on implantation into the eye of a patient to extend between the anterior chamber of the eye and the periocular tissues, particularly the subconjunctival space of the eye. It is to be understood that whilst the device of the present method is principally intended for use in the treatment of a human patient, it is equally applicable for use in the treatment of non-human animals such as companion animals (dogs and cats), horses (particularly race horses), and the like.
Preferably, the implant device of this invention is implanted into the eye so as to provide a direct path into the eye with one end of the fibre located in the anterior chamber. In this preferred embodiment, the end of the fibre which is to extend into the anterior chamber may be provided with anchoring means, such as a flange, T-shaped fitting of the microperforated tubing, silicon tubing or the like, to hold that end of the fibre in place in the anterior chamber. If desired, the other end of the fibre which is to extend into the subconjunctival space or other periocular tissues may also be provided with similar anchoring means to hold that end in the subconjunctival tissues. In an alternative arrangement, however, the device may be implanted as a suture, with the fibre forming a loop in the anterior chamber and the two free ends located beneath the conjunctiva of the eye.
Preferably also, the surface of the microperforated device of this invention, is modified, in particular by treatment with heparin, in order to increase its biocompatibility, in particular to reduce fibroblast proliferation. Suitable treatment processes, including covalent binding of heparin to solid surfaces, are well known in the art.
Suitable hollow fibres for use as an implant device in accordance with this invention are, for example, fibres having an external diameter of about 500-600 μm and an internal diameter of about 200-350 μm. The fibres suitably have a pore size larger than 0.2 μm, and preferably the pore size is 0.4 - 0.6μm or larger. The hollow fibres may, for example, be made of polypropylene or a similar biologically inert material. Particularly preferred microperforated hollow fibres are polypropylene fibres having an average pore size of 0.4 μm. ln a modification of the device of this invention as broadly described above, the lumen of the hollow fibre of the implant device may be at least partially occluded with a biodegradable material, such as a biodegradable polymer. Suitable biodegradable polymers include those that will degrade rapidly and produce little reactive (scarring) byproducts. They include, for example, the polyglycolic and polylactic acid polymers and mixtures thereof (such as 50:50 mixtures) which already have intraocular use, as well as gelatin, or polyanhydrides or polyphosphates, (although these latter varieties may be too slow in degradation). Such occlusion may be achieved by coating the inside walls of the fibre, or in fact filling the lumen of the fibre, with the biodegradable material. Alternatively, the biodegradable material may be coated on the outside of the fibre. If desired, the biodegradable material may also include pharmacologically active agents, such as drugs for reducing scarring, steroids such as dexamethasone or hydrophobic forms thereof, non-steroidal anti-inflammatory agents, or antimetabolite agents such as mitomycin C 5-fluorouracil or adriamycin. Such an occluded fibre may be used to prevent the eye becoming too soft immediately after implantation, and to act as a slow release reservoir of the pharmacologically active compounds.
In another aspect, the present invention provides a method for treatment of glaucoma or intraocular pressure in an eye of a patient, which comprises the step of implantation into said eye of an implant device as broadly described above, said device on implantation extending between the anterior chamber of the eye and the periocular tissues, particularly the subconjunctival space of the eye.
As described above, the patient may be either a human or animal.
Detailed Description of the Invention
One of the major difficulties experienced in treatment of glaucoma using implants has been the biological response of the tissues; in essence the eye is always trying to plug holes that are made in it. It can do this by one or both of two ways. The first is probably the method that causes the glaucoma in the first place (ie gradual obstruction of the outflow passages from the eye), and the second is the healing response.
The second mechanism, that of wound healing and fibrosis, is of vital importance, and it is this which is the primary determinant of the long term success of the operation. Many methods of reducing or retarding the fibrosis have been tried, however they all rely of creating a large wound, and hence a large biological stimulus to healing and fibrosis. The essence of the present invention is to minimise the trauma, use an implant made of a biologically inert material, and preferably to coat the surface of the implant in heparin, a molecule that is found lining the surface of all blood vessels, so that the implant disrupts the tissues minimally, and is so designed and treated that any subsequent fibrotic reaction is minimalised.
Microperforated fibres are currently used in a great variety of applications and hence are readily available. By way of example, such fibres are used in plasmapherisis filters for use in human blood filtration where they are used grouped together in bundles of 2000. They provide a very high surface area to volume ratio for diffusion of fluids through their walls, and are biologically inert. Suitable fibres may however be available from other sources, or they may be made especially for the implant device of this invention. By implanting one of these individual fibres through the wall of the eye in accordance with the present invention, there is provided a stable and permanent route for drainage of fluid from the eye.
The implant of this invention is designed to be simple, quick to place under local anaesthesia, and have minimal post-operative care. These are advantages in any community, but are necessities in the third world where glaucoma remains essentially untreated. 1. Ease of Placement:
Preferably, the implant device of this invention is placed with one end of the fibre in the anterior chamber of the eye and the other outside the eye in the sub¬ conjunctival space. The fibre is implanted as a sheath around a stilette-type needle, and the needle then withdrawn leaving the fibre in place with one end anchored in the anterior chamber and providing a water tight seal around the outside of the fibre where it passes through the wall of the eye. The conjunctiva is lifted forward with atraumatic tissue forceps and the free end of the fibre located in the sub-conjunctival space before the conjunctiva is allowed to return to its normal anatomy leaving the free end buried beneath the conjunctiva. Alternatively, the device may be placed from the inside of the anterior chamber, so that the fibre enters the subconjunctival space after being passed through the wall of the eye.
Alternatively, the device may be implanted as a suture. The fibre will be swaged to a cutting needle of approximately 8-10 mm diameter. The fibre will be introduced to the anterior chamber as a suture and passed through the limbal tissue. Conjunctiva will be grasped some 15 mm posterior to the limbus and brought forward with atraumatic tissue forceps. The tented conjunctiva will be perforated by the needle as it enters the eye. When the tip of the needle is delivered the fibre is pulled through, such that the middle of the fibre remains in the anterior chamber. The needle can then be cut off, the conjunctiva relaxed, and the two free ends can be sutured to the sclera 15 mm posterior to the limbus. The fibre now lies with a loop in the anterior chamber and two free ends buried beneath the conjunctiva with minimal trauma to the periocular tissues.
2. Blockage of the Implant:
(a) From within the anterior chambers: aqueous is known to obstruct microporous filters of pore diameter 0.2 μm (14). The reason for this action of aqueous is unclear, and has only recently been demonstrated. The action is due to the combined actions of a protein and non-protein components of the aqueous, and is not due to fibrin /fibrinogen (15). Fibre pore diameter would need to be larger than 0.2 μm to assure to continued patency of the intraocular portion of the fibre. Fibres obtained for the initial study have a pore size of 0.5-0.6 μm (gambro PF2000, plasmapheresis fibres). If studies show blockage, then fibres can b especially made with pore sizes larger.
(b) In the subconjunctival space: The clinical problem of fibrosis o outflow tracts led to the laboratory observation that aqueous from glaucomatou eyes supported proliferation of fibroblasts in culture, and that aqueous fro normotensive eyes did not. A similar aqueous state was induced in a normal ey by operation on the anterior segment. It is not possible to induce "nutrient aqueous with simple anterior chamber aspiration in monkeys, nor b subconjunctival biopsy, but trabeculectomy is sufficient to induce changes in the aqueous (16). Although it is difficult to prove a pathogenic role of aqueous in glaucoma, ft is likely to have a significant effect on the results of surgery (16,17). A later study has shown that long term topical antiglaucomatous medication results in significantly increased number of macrophages, lymphocytes, mast cells and fibroblasts in the conjunctiva and tenon's capsule of recipients (18).
Fibrin /fibrinogen has been identified in the subconjunctival tissue of non- human primates 2-7 days post-trabeculectomy (19). Leakage of plasma from damaged blood vessels causes the formation of an extravascular clot consisting of fibrin, fibrinogen, fibronectin and platelets (20). This serves as a scaffold for the migration of inflammatory cells. Experiments suggest that the quantity of fibrin scaffold present in a wound determines the amount of scar tissue that ultimatel develops (21). Furthermore, aqueous has been shown to accelerate clotting time as a result of a procoagulant action (22).
Heparin is well known for its actions in prevention of the clotting cascade, however it has also been demonstrated to have an action directly against fibroblas proliferation, and specifically against sclera fibroblasts (23). It has also been demonstrated that heparin bound to polymer surfaces prevents the normal adherence and proliferation of human sclera fibroblasts over that surface (24). 3. Regulation of Outflow:
Current surgical intervention in the treatment of glaucoma involves two parts: firstly, the creation of an outflow pathway (sclerostomy) from the eye; and secondly, the establishment of a tissue bed for the absorption of aqueous drained from the eye.
The size of the sclerostomy required can be calculated from Poiseuille's equation as the fluid flow is known (2.5 μi/min), the path length is normally under 2 mm, and the driving pressure needs to be as low as possible (under 2 mm/Hg). From this it can be ascertained that the sclerostomy diameter need only be greater than 200 μm diameter to not impede fluid flow from the eye. The longer path length required in the use of the implant device of the present invention may necessitate the use of a fibre of larger diameter, for example, up to 350 μm.
The small size of the fibre lumen should be adequate to handle a proportion of aqueous outflow, the rest being catered for by uveoscleral and remaining flow through the trabecular meshwork. Aqueous production has been determined at 2.5 μl/min (25).
Given that the diameter of the tube is not a limiting factor in the outflow, it is the resistance of the fluid entering the subconjunctival space that is important. Microperforated tubes offer the advantage that the whole of the wall of the tube acts as a diffusion surface. Given a subconjunctival length of 10mm, and hence a total length of 20 mm, the surface area of a tube of outside diameter is approximately 20 mm2. This is comparable to the original plate surface area as specified by Molteno (8).
Aqueous normally flows from the eye through dedicated channels. Surgical procedures allow aqueous to be absorbed as tissue oedema (the "bleb). Aqueous is virtually protein free (in the non-inflamed eye) and is thus drawn across the capillary walls by oncotic pressure. Scarring of the subconjunctival space, reduction in volume or capillarity of the absorptive tissue, or changes in the characteristics of aqueous will all jeopardise or prevent absorption.
Failure of aqueous to exit the eye ("failure of the sclerostomy") or to be absorbed at adequate rate from the subconjunctival tissue ("failure of the bleb") will result in failure of the operation to lower the pressure in the eye. Most operations for glaucoma fail because of scarring causing "failure of the bleb".
Optimally, drainage of aqueous is achieved atraumatically and is hydrodynamically stable early and in the long term. All current surgeries require extensive manipulation of ocular and periocular tissues and involve relatively prolonged periods of instability in the outflow dynamics. These are the major contributors to the high rate of side effects of the current procedures. Regulated outflow in accordance with the present invention reduces the risk of postoperative hypotony and it's associated complications.
Resistance to flow across the wall of the implant device of this invention adds another dimension to the regulation of the outflow of aqueous from the eye.
Further features of the implant device of the present invention and of its use in the treatment of glaucoma will be apparent from the following non-limiting Example.
EXAMPLE 1
The fibres used in the initial trial were microperforated polypropylene fibre, manufactured by Gambro having an average pore size 0.4 μm, with a surface modification in which the fibres were coated with heparin according to a protocol described by Larm et al (26).
The preferred animal model is the rabbit and has been used in many animal trials of glaucoma implants (27,28). It has a relatively large eye, docile personality, and reacts well to anaesthesia. It has ocular anatomy not dissimilar to the human, and an IOP in the same range, although it should be noted that the rabbit is well known to have a high propensity to scarring in the subconjunctival space.
As an initial trial ten animals were entered. The experiment was designed to run for three months from the time of implantation.
Measurements of intraocular pressure were made every week for the duration under topical anaesthesia using a Schiotz indentation tonometer with a 7.5 g weight. New Zealand white (NZW) rabbits are known to have an extensive diurnal fluctuation in IOP (29), and every effort was made to ensure consistency of testing procedure and time.
Fibres were implanted under general anaesthesia using a stilette-type needle as previously described. Fibres were passed from the conjunctival space through the limbal sclera such that the end remained buried under the conjunctiva and the anterior end was located in the anterior chamber in the angle. No sutures or glue were used on the conjunctiva.
The results are displayed in Figure 1A as the unadjusted Schiotz readings as no reliable conversion scale exists. The higher the reading the lower the intraocular pressure. Treated rabbit eyes are displayed with the unbroken lines, and the untreated eyes with hatched lines. The experiment was continued for 12 weeks.
The results indicate that a total of 10 NZW rabbits were entered. One treated eye failed after the first week. Clinically it was clear as to the reason, and in the context of this experiment should not be regarded as a failure. A significant difference in pressures was noted at the 12 week interval.
Figure 1 B is a summary of the Schiotz pressure difference between the treated and untreated eyes as shown in Figure 1A. EXAMPLE 2
In a second experiment 24 NZW rabbits were entered. One eye at random was selected for implantation with a heparin coated polypropylene hollow microperforated fibre of wall pore size average 0.4 μm manufactured by Memtec (Aust.). The experiment ran for three months and the IOP was measured weekly with a Tonopen®. Unlike the tonometer of Example 1 , this machine measures IOP, although the machine is calibrated for humans and the eye wall resistance of the rabbit is lower, and thus the machine might be expected to under-read.
The results are shown in Figures 2A and 2B, and it can be seen that a difference in pressure between the treated and untreated eyes exists to the termination of the experiment.
The above -Examples are included for the purposes only of illustration of the present invention. It will be appreciated that many variations may be made without departing from the spirit and scope of the invention as broadly described herein.
REFERENCES
1. Vision Research, A National Plan, 1983 Report of the National Advisory Ey Council, Vol I: 12-13.
2. Banks CN, Kratochvil R. Causes of blindness in Australia: Analysis o pensions granted by the department of Social Security on the ground o blindness for the year ending 30 June 1984. Aus N Z J Ophth 1986 14:263-268
3. Moses RA., Hart WM. (Eds) Adler's Physiology of the Eye. C.V. Mosby, Ed. 8, 1987; 212-16
4. Sugar HS. The filtering operations: an historical review. Glaucoma 1981 ; 3(2): 85-90
5. Bonomi L, Marchini G, de Franco I, Perfetti S. Prospective study of the lens changes after trabeculectomy. Dev Ophthalmol 1989; 17:97-100.
6. D'Ermo F, Bonomi L, Doro D. A critical analysis of the long-term results of trabeculectomy. Am J Ophthal 1979; 88:829-35.
7. Jay JL, Murray SB. Early trabeculectomy versus conventional management in primary open angle glaucoma. Br J Ophth, 1988, 72:881-889
8. Molteno ACB. New implant for drainage in glaucoma. Clinical trial. Brit J. Ophthal 1969; 53: 606-15
9. MacDonald RK., Pierce HF, Silicone Setons. Am J. Ophthal 1965; 59: 635- 46. 10. Newkirk JB Valve implants in filtering surgery. Am J. Ophthal 1976; 81 (2) 232-5
11. Stewart RH, Kimbrough RL, Okereke PC. Trabeculectomy with implantatio of the Mendez glaucoma seton: early results. Ophthal Surg 1986; 17(4) 221-6
12. Rose GE, Lawin MJ, Hitchings A. Silicone tubes in Glaucoma surgery: Th effect of technical modifications on early postoperative intraocular pressure and complications. Eye 1989; 3:553-61.
13. Tukel DB, Siegel MJ. The effect of Molteno implants on endothelial counts. Invest Ophthalmol Vis Sci, ARVO Conference proceedings, 1991 , 32(4):746.
14. Johnson M, Ethier CR, Kamm RD, Grant WM, Epstein DL, Gaasterland D. The flow of aqueous humour through micro-porous filters. Invest Ophthalmol Vis Sci 1986; 27:92-7
15. Ethier CR, Kamm RD, Johnson M, Pavao AF, Anderson PJ. Further studies on the flow of aqueous humour through micro-porous filters. Invest Ophthalmol Vis Sci 1989; 739-46
16. Herschler J., Claflin AJ., Fiorentino G. The effect of aqueous humour on the growth of subconjunctival fibroblasts in tissue culture and its implications for glaucoma surgery. Am J Ophthal 1980; 89:245-9.
17. Radius RL., Herschler J., Claflin A., Fiorentino G. Aqueous humour changes after experimental filtering surgery. Am J Ophthal 1980; 89: 250-4.
18. Sherwood MB, Grierson I, Millar L, Hitchings RA. Long-term morphological effects of antiglaucoma drugs on the conjunctiva and Tenon's capsule in glaucoma patients. Ophthalmology 1989, Mar; 96(3): 327-35. 19. Jampel HD, Morrson J, Vocci M, Quigley H. Identification Fibrin/Fibrinogen in glaucoma filtration wounds. Ophthalmic Surg 1988; 1 576-9.
20. Knighton DR, Hunt TK, Thakral KK, et al. Role of platelets and fibrin in th healing sequence: An in vivo study of angiogenesis and collagen synthesi Ann Surg 1982; 1996:379-87.
21. Dvorak HF. Tumours: Wounds that do not heal. Similarities betwee tumour stroma generation and wound healing. N Engl J Med 198 315:1650-59.
22. Hollinshead MB, Spillert CR, Lazaro EJ. Procoagulant effect of aqueou humour on in vitro clotting of blood and plasma. Curr Eye Res 1988 7(8):819-22.
23. Del Vecchio PJ, Bizios R, Holleran LA, Judge TK, Pinto GL. Inhibition o human scleral fibroblast proliferation with heparin. Inv Ophth Vis Sci 1988 229(8): 1272-6.
24. Larsson R. Biocompatible surfaces prepared by immobilised heparin o hyaluronate. Acta Otolaryngol Suppl (Stockh) 1987;442:44-9.
25. Moses RA., Hart WM. (Eds) Adler's Physiology of the Eye. C.C. Mosby, ed 8, 1987: 223.
26. Larm O, Larsson R, Olsson P. A new non-thrombogenic surface prepare by selective covalent binding of heparin via a reducing terminal residue. Biomat Med Devices Artif Organs 1983; 11 :161-74.
27. Molteno ACB. New implant for drainage in glaucoma. Animal trial. Brit J Ophthal 1969; 53: 161-8. 28. Dobrogowski MJ., Dolman PJ., Douglas GR. A new glaucoma filter implant Ophthalmic Surgery 1990; 21(7): 481-5.
29. Lee T, Kiuchi Y, Gregory DS. The effect of exposure to light during the dar phase of the circadian cycle on IOP and aqueous flow in NZW rabbits, Invest Ophthalmol Vis Sci, ARVO Conference Proceedings, 1991 , 32(4), 887.

Claims

CLAIMS:
1. An implant device for use in the treatment of glaucoma or intraocula pressure in an eye of a patient, which comprises a hollow fibre, said fibre bein microperforated in the walls thereof and being adapted on implantation into th eye of the patient to extend between the anterior chamber of the eye and th periocular tissues.
2. An implant device according to claim 1 , wherein said hollow fibre is of biologically inert material.
3. An implant device according to claim 1 or claim 2, wherein one end of th fibre extends into the anterior chamber of the eye and is provided with anchorin means to hold said one end of the fibre in place in the anterior chamber.
4. An implant device according to claim 3, wherein the other end of the fibr extends into the subconjunctival space of the eye and is provided with anchoring means to hold said other end of the fibre in place in the subconjunctival space.
5. An implant device according to claim 1 or claim 2, wherein said fibre forms a loop extending through the anterior chamber with the two ends of the fibre located in the subconjunctival space.
6. An implant device according to any of claims 1 to 5, wherein the surface of the fibre is modified to increase the biocompatibility thereof.
7. An implant device according to claim 6, wherein said surface modification comprises treatment with heparin.
8. An implant device according to any of claims 1 to 7, wherein said fibre is a microperforated, hollow polypropylene fibre.
9. An implant device according to claim 8, wherein said fibre has an externa diameter of about 500-600 μm, an internal diameter of about 200-350 μm, and pore size of at least 0.2 μm, preferably at least 0.4-0.6 μm.
10. An implant device according to any of claims 1 to 9 wherein the lumen o said hollow fibre is occluded with a biodegradable polymer or other biodegradabl material.
11. An implant device according to claim 10 or claim 11 , wherein said biodegradable polymer is selected from polyglycolic acid polymers, polylactic acid polymers, polyglycoiic/polylactic acid copolymers, and gelatin.
12. An implant device according to claim 10 or claim 11 , wherein said biodegradable material includes a pharmacologically active agent.
13. An implant device according to claim 12, wherein said pharmacologically active agent is selected from drugs for reducing scarring, steroidal or non-steroidal antiinflammatory agents and antimetabolic agents.
14. A method for the treatment of glaucoma or intraocular pressure in an eye of a patient, which comprises the step of implantation into said eye of an implant device according to any of claims 1 to 13, said device on implantation extending between the anterior chamber of the eye and the periocular tissues.
15. A method according to claim 14, wherein the patient is a human.
16. A method according to claim 14, wherein the patient is a non-human animal.
17. The use of an implant device according to any of claims 1 to 13 in the treatment of glaucoma or intraocular pressure in an eye of a patient.
PCT/AU1993/000656 1992-12-17 1993-12-17 Implant device and method for treatment of glaucoma WO1994013234A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU66531/94A AU6653194A (en) 1992-12-17 1993-12-17 Implant device and method for treatment of glaucoma

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AUPL6417 1992-12-17
AUPL641792 1992-12-17

Publications (1)

Publication Number Publication Date
WO1994013234A1 true WO1994013234A1 (en) 1994-06-23

Family

ID=3776605

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/AU1993/000656 WO1994013234A1 (en) 1992-12-17 1993-12-17 Implant device and method for treatment of glaucoma

Country Status (1)

Country Link
WO (1) WO1994013234A1 (en)

Cited By (65)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5702414A (en) * 1995-05-14 1997-12-30 Optonol Ltd Method of implanting an intraocular implant
WO1998023237A1 (en) * 1996-11-29 1998-06-04 The Lions Eye Institute Of Western Australia Incorporated Biological microfistula tube and implantation method and apparatus
WO1998035640A1 (en) * 1997-02-17 1998-08-20 Corneal Industrie Sclero-ceratectomy implant for descemet's membrane
WO1998035639A1 (en) * 1997-02-17 1998-08-20 Corneal Industrie Implant for deep sclerectomy
US5868697A (en) * 1995-05-14 1999-02-09 Optonol Ltd. Intraocular implant
US5968058A (en) * 1996-03-27 1999-10-19 Optonol Ltd. Device for and method of implanting an intraocular implant
WO2000033774A1 (en) * 1997-09-23 2000-06-15 Acoustic Technologies, Inc. Bioerodable myringotomy tube
AU721915B2 (en) * 1996-11-29 2000-07-20 Lions Eye Institute Limited Biological microfistula tube and implantation method and apparatus
US6379323B1 (en) 1997-05-09 2002-04-30 Acoustic Technologies, Inc. Bio erodable myringotomy tube
US6666841B2 (en) 2001-05-02 2003-12-23 Glaukos Corporation Bifurcatable trabecular shunt for glaucoma treatment
US6736791B1 (en) 2000-04-14 2004-05-18 Glaukos Corporation Glaucoma treatment device
US7094225B2 (en) 2001-05-03 2006-08-22 Glaukos Corporation Medical device and methods of use of glaucoma treatment
US7135009B2 (en) 2001-04-07 2006-11-14 Glaukos Corporation Glaucoma stent and methods thereof for glaucoma treatment
US7160264B2 (en) 2002-12-19 2007-01-09 Medtronic-Xomed, Inc. Article and method for ocular aqueous drainage
US7331984B2 (en) 2001-08-28 2008-02-19 Glaukos Corporation Glaucoma stent for treating glaucoma and methods of use
US8109896B2 (en) 2008-02-11 2012-02-07 Optonol Ltd. Devices and methods for opening fluid passageways
US8118768B2 (en) 2001-04-07 2012-02-21 Dose Medical Corporation Drug eluting ocular implant with anchor and methods thereof
US8142364B2 (en) 2001-05-02 2012-03-27 Dose Medical Corporation Method of monitoring intraocular pressure and treating an ocular disorder
US8348877B2 (en) 2000-04-14 2013-01-08 Dose Medical Corporation Ocular implant with therapeutic agents and methods thereof
US8486086B2 (en) 1997-11-20 2013-07-16 Optonol, Ltd Flow regulating implant, method of manufacture, and delivery device
US8506515B2 (en) 2006-11-10 2013-08-13 Glaukos Corporation Uveoscleral shunt and methods for implanting same
US8852256B2 (en) 2010-11-15 2014-10-07 Aquesys, Inc. Methods for intraocular shunt placement
US8852136B2 (en) 2011-12-08 2014-10-07 Aquesys, Inc. Methods for placing a shunt into the intra-scleral space
US8945038B2 (en) 2003-05-05 2015-02-03 Transcend Medical, Inc. Internal shunt and method for treating glaucoma
US8974511B2 (en) 2010-11-15 2015-03-10 Aquesys, Inc. Methods for treating closed angle glaucoma
US9017276B2 (en) 2010-11-15 2015-04-28 Aquesys, Inc. Shunt placement through the sclera
US9084662B2 (en) 2006-01-17 2015-07-21 Transcend Medical, Inc. Drug delivery treatment device
US9089392B2 (en) 2009-12-23 2015-07-28 Transcend Medical, Inc. Drug delivery devices and methods
US9095413B2 (en) 2011-12-08 2015-08-04 Aquesys, Inc. Intraocular shunt manufacture
US9095411B2 (en) 2010-11-15 2015-08-04 Aquesys, Inc. Devices for deploying intraocular shunts
US9125723B2 (en) 2013-02-19 2015-09-08 Aquesys, Inc. Adjustable glaucoma implant
US9155656B2 (en) 2012-04-24 2015-10-13 Transcend Medical, Inc. Delivery system for ocular implant
US9173774B2 (en) 2010-03-26 2015-11-03 Optonol Ltd. Fluid drainage device, delivery device, and associated methods of use and manufacture
US9192516B2 (en) 2010-11-15 2015-11-24 Aquesys, Inc. Intraocular shunt placement
US9220632B2 (en) 2002-03-07 2015-12-29 Glaukos Corporation Fluid infusion methods for ocular disorder treatment
US9283116B2 (en) 2010-11-15 2016-03-15 Aquesys, Inc. Intraocular shunt deployment device
US9301875B2 (en) 2002-04-08 2016-04-05 Glaukos Corporation Ocular disorder treatment implants with multiple opening
US9326891B2 (en) 2010-11-15 2016-05-03 Aquesys, Inc. Methods for deploying intraocular shunts
US9351873B2 (en) 2003-11-14 2016-05-31 Transcend Medical, Inc. Ocular pressure regulation
US9398977B2 (en) 2006-01-17 2016-07-26 Transcend Medical, Inc. Glaucoma treatment device
EP2260804B1 (en) 1999-04-26 2016-10-19 Glaukos Corporation Trabeculotomy device for treating glaucoma
US9480598B2 (en) 2012-09-17 2016-11-01 Novartis Ag Expanding ocular implant devices and methods
US9585790B2 (en) 2013-11-14 2017-03-07 Aquesys, Inc. Intraocular shunt inserter
US9585789B2 (en) 2007-07-17 2017-03-07 Novartis Ag Ocular implant with hydrogel expansion capabilities
US9592151B2 (en) 2013-03-15 2017-03-14 Glaukos Corporation Systems and methods for delivering an ocular implant to the suprachoroidal space within an eye
US9597230B2 (en) 2002-04-08 2017-03-21 Glaukos Corporation Devices and methods for glaucoma treatment
US9610195B2 (en) 2013-02-27 2017-04-04 Aquesys, Inc. Intraocular shunt implantation methods and devices
US9636254B2 (en) 2006-06-30 2017-05-02 Aquesys, Inc. Systems for reducing pressure in an organ
US9730638B2 (en) 2013-03-13 2017-08-15 Glaukos Corporation Intraocular physiological sensor
US9763828B2 (en) 2009-01-28 2017-09-19 Novartis Ag Ocular implant with stiffness qualities, methods of implantation and system
US9763829B2 (en) 2012-11-14 2017-09-19 Novartis Ag Flow promoting ocular implant
US9808373B2 (en) 2013-06-28 2017-11-07 Aquesys, Inc. Intraocular shunt implantation
US9987163B2 (en) 2013-04-16 2018-06-05 Novartis Ag Device for dispensing intraocular substances
US10016301B2 (en) 2008-06-25 2018-07-10 Novartis Ag Ocular implant with shape change capabilities
US10085633B2 (en) 2012-04-19 2018-10-02 Novartis Ag Direct visualization system for glaucoma treatment
US10085884B2 (en) 2006-06-30 2018-10-02 Aquesys, Inc. Intraocular devices
US10159600B2 (en) 2013-02-19 2018-12-25 Aquesys, Inc. Adjustable intraocular flow regulation
US10271989B2 (en) 2012-03-26 2019-04-30 Glaukos Corporation System and method for delivering multiple ocular implants
US10307292B2 (en) 2011-07-18 2019-06-04 Mor Research Applications Ltd Device for adjusting the intraocular pressure
US10517759B2 (en) 2013-03-15 2019-12-31 Glaukos Corporation Glaucoma stent and methods thereof for glaucoma treatment
US10959941B2 (en) 2014-05-29 2021-03-30 Glaukos Corporation Implants with controlled drug delivery features and methods of using same
US11116625B2 (en) 2017-09-28 2021-09-14 Glaukos Corporation Apparatus and method for controlling placement of intraocular implants
CN114129769A (en) * 2021-09-22 2022-03-04 海思盖德(苏州)生物医学科技有限公司 Artificial aqueous humor micro-drainage tube with drug slow-release function and preparation method thereof
US11363951B2 (en) 2011-09-13 2022-06-21 Glaukos Corporation Intraocular physiological sensor
US11925578B2 (en) 2016-09-01 2024-03-12 Glaukos Corporation Drug delivery implants with bi-directional delivery capacity

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4037604A (en) * 1976-01-05 1977-07-26 Newkirk John B Artifical biological drainage device
WO1983000420A1 (en) * 1981-07-29 1983-02-17 Mendez, Antonio, M., D. Implantable glaucoma treatment device
GB2156684A (en) * 1984-04-06 1985-10-16 Perry Scott Binder Seton for relief of intraocular pressure
AU6024886A (en) * 1985-07-16 1987-02-19 Terumo Kabushiki Kaisha Hollow fibre membrane, method of manufacture thereof, and artificial lung using said membrane
US4936825A (en) * 1988-04-11 1990-06-26 Ungerleider Bruce A Method for reducing intraocular pressure caused by glaucoma
WO1991007195A1 (en) * 1989-11-17 1991-05-30 Stewart Gregory Smith Pressure-relieving device and process for implanting
WO1991012046A1 (en) * 1990-02-12 1991-08-22 Atos Medical Ab Glaucoma valve

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4037604A (en) * 1976-01-05 1977-07-26 Newkirk John B Artifical biological drainage device
WO1983000420A1 (en) * 1981-07-29 1983-02-17 Mendez, Antonio, M., D. Implantable glaucoma treatment device
GB2156684A (en) * 1984-04-06 1985-10-16 Perry Scott Binder Seton for relief of intraocular pressure
AU6024886A (en) * 1985-07-16 1987-02-19 Terumo Kabushiki Kaisha Hollow fibre membrane, method of manufacture thereof, and artificial lung using said membrane
US4936825A (en) * 1988-04-11 1990-06-26 Ungerleider Bruce A Method for reducing intraocular pressure caused by glaucoma
WO1991007195A1 (en) * 1989-11-17 1991-05-30 Stewart Gregory Smith Pressure-relieving device and process for implanting
WO1991012046A1 (en) * 1990-02-12 1991-08-22 Atos Medical Ab Glaucoma valve

Cited By (123)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5868697A (en) * 1995-05-14 1999-02-09 Optonol Ltd. Intraocular implant
US5702414A (en) * 1995-05-14 1997-12-30 Optonol Ltd Method of implanting an intraocular implant
US5968058A (en) * 1996-03-27 1999-10-19 Optonol Ltd. Device for and method of implanting an intraocular implant
WO1998023237A1 (en) * 1996-11-29 1998-06-04 The Lions Eye Institute Of Western Australia Incorporated Biological microfistula tube and implantation method and apparatus
US6544249B1 (en) 1996-11-29 2003-04-08 The Lions Eye Institute Of Western Australia Incorporated Biological microfistula tube and implantation method and apparatus
AU721915B2 (en) * 1996-11-29 2000-07-20 Lions Eye Institute Limited Biological microfistula tube and implantation method and apparatus
US6383218B1 (en) 1997-02-17 2002-05-07 Corneal Industrie Sclero-ceratectomy implant for descemet's membrane
WO1998035640A1 (en) * 1997-02-17 1998-08-20 Corneal Industrie Sclero-ceratectomy implant for descemet's membrane
WO1998035639A1 (en) * 1997-02-17 1998-08-20 Corneal Industrie Implant for deep sclerectomy
FR2759576A1 (en) * 1997-02-17 1998-08-21 Corneal Ind PRE-DESCEMETIC SCLERO-KERATECTOMY IMPLANT
FR2759577A1 (en) * 1997-02-17 1998-08-21 Corneal Ind DEEP SCLERECTOMY IMPLANT
US6383219B1 (en) 1997-02-17 2002-05-07 Corneal Industrie Implant for deep sclerectomy
US6379323B1 (en) 1997-05-09 2002-04-30 Acoustic Technologies, Inc. Bio erodable myringotomy tube
WO2000033774A1 (en) * 1997-09-23 2000-06-15 Acoustic Technologies, Inc. Bioerodable myringotomy tube
US8486086B2 (en) 1997-11-20 2013-07-16 Optonol, Ltd Flow regulating implant, method of manufacture, and delivery device
US10568762B2 (en) 1999-04-26 2020-02-25 Glaukos Corporation Stent for treating ocular disorders
US10492950B2 (en) 1999-04-26 2019-12-03 Glaukos Corporation Shunt device and method for treating ocular disorders
EP2260804B2 (en) 1999-04-26 2022-03-02 Glaukos Corporation Trabeculotomy device for treating glaucoma
EP2260804B1 (en) 1999-04-26 2016-10-19 Glaukos Corporation Trabeculotomy device for treating glaucoma
US9827143B2 (en) 1999-04-26 2017-11-28 Glaukos Corporation Shunt device and method for treating ocular disorders
US9492320B2 (en) 1999-04-26 2016-11-15 Glaukos Corporation Shunt device and method for treating ocular disorders
US9993368B2 (en) 2000-04-14 2018-06-12 Glaukos Corporation System and method for treating an ocular disorder
US8348877B2 (en) 2000-04-14 2013-01-08 Dose Medical Corporation Ocular implant with therapeutic agents and methods thereof
US6736791B1 (en) 2000-04-14 2004-05-18 Glaukos Corporation Glaucoma treatment device
US9066782B2 (en) 2000-04-14 2015-06-30 Dose Medical Corporation Ocular implant with therapeutic agents and methods thereof
US9789001B2 (en) 2000-04-14 2017-10-17 Dose Medical Corporation Ocular implant with therapeutic agents and methods thereof
US10485702B2 (en) 2000-04-14 2019-11-26 Glaukos Corporation System and method for treating an ocular disorder
US8814820B2 (en) 2000-04-14 2014-08-26 Glaukos Corporation Ocular implant with therapeutic agent and methods thereof
US8118768B2 (en) 2001-04-07 2012-02-21 Dose Medical Corporation Drug eluting ocular implant with anchor and methods thereof
US9987472B2 (en) 2001-04-07 2018-06-05 Glaukos Corporation Ocular implant delivery systems
US10828473B2 (en) 2001-04-07 2020-11-10 Glaukos Corporation Ocular implant delivery system and methods thereof
US7135009B2 (en) 2001-04-07 2006-11-14 Glaukos Corporation Glaucoma stent and methods thereof for glaucoma treatment
US10406029B2 (en) 2001-04-07 2019-09-10 Glaukos Corporation Ocular system with anchoring implant and therapeutic agent
US7857782B2 (en) 2001-04-07 2010-12-28 Glaukos Corporation Ocular implant delivery system and method thereof
US9155654B2 (en) 2001-04-07 2015-10-13 Glaukos Corporation Ocular system with anchoring implant and therapeutic agent
US9572963B2 (en) 2001-04-07 2017-02-21 Glaukos Corporation Ocular disorder treatment methods and systems
US8075511B2 (en) 2001-04-07 2011-12-13 Glaukos Corporation System for treating ocular disorders and methods thereof
US8062244B2 (en) 2001-04-07 2011-11-22 Glaukos Corporation Self-trephining implant and methods thereof for treatment of ocular disorders
US8142364B2 (en) 2001-05-02 2012-03-27 Dose Medical Corporation Method of monitoring intraocular pressure and treating an ocular disorder
US6666841B2 (en) 2001-05-02 2003-12-23 Glaukos Corporation Bifurcatable trabecular shunt for glaucoma treatment
US7273475B2 (en) 2001-05-03 2007-09-25 Glaukos Corporation Medical device and methods of use for glaucoma treatment
US7094225B2 (en) 2001-05-03 2006-08-22 Glaukos Corporation Medical device and methods of use of glaucoma treatment
US9561131B2 (en) 2001-08-28 2017-02-07 Glaukos Corporation Implant delivery system and methods thereof for treating ocular disorders
US7879079B2 (en) 2001-08-28 2011-02-01 Glaukos Corporation Implant delivery system and methods thereof for treating ocular disorders
US10285856B2 (en) 2001-08-28 2019-05-14 Glaukos Corporation Implant delivery system and methods thereof for treating ocular disorders
US7331984B2 (en) 2001-08-28 2008-02-19 Glaukos Corporation Glaucoma stent for treating glaucoma and methods of use
US9220632B2 (en) 2002-03-07 2015-12-29 Glaukos Corporation Fluid infusion methods for ocular disorder treatment
US9597230B2 (en) 2002-04-08 2017-03-21 Glaukos Corporation Devices and methods for glaucoma treatment
US10485701B2 (en) 2002-04-08 2019-11-26 Glaukos Corporation Devices and methods for glaucoma treatment
US9301875B2 (en) 2002-04-08 2016-04-05 Glaukos Corporation Ocular disorder treatment implants with multiple opening
US7160264B2 (en) 2002-12-19 2007-01-09 Medtronic-Xomed, Inc. Article and method for ocular aqueous drainage
US8945038B2 (en) 2003-05-05 2015-02-03 Transcend Medical, Inc. Internal shunt and method for treating glaucoma
US9844462B2 (en) 2003-05-05 2017-12-19 Novartis Ag Internal shunt and method for treating glaucoma
US10226380B2 (en) 2003-11-14 2019-03-12 Novartis Ag Ocular pressure regulation
US9351873B2 (en) 2003-11-14 2016-05-31 Transcend Medical, Inc. Ocular pressure regulation
US9421130B2 (en) 2006-01-17 2016-08-23 Novartis Ag. Glaucoma treatment device
US9084662B2 (en) 2006-01-17 2015-07-21 Transcend Medical, Inc. Drug delivery treatment device
US10905590B2 (en) 2006-01-17 2021-02-02 Alcon Inc. Glaucoma treatment device
US9398977B2 (en) 2006-01-17 2016-07-26 Transcend Medical, Inc. Glaucoma treatment device
US9789000B2 (en) 2006-01-17 2017-10-17 Novartis Ag Glaucoma treatment device
US11786402B2 (en) 2006-01-17 2023-10-17 Alcon Inc. Glaucoma treatment device
US9668917B2 (en) 2006-01-17 2017-06-06 Novartis Ag Drug delivery treatment device
US10085884B2 (en) 2006-06-30 2018-10-02 Aquesys, Inc. Intraocular devices
US9636254B2 (en) 2006-06-30 2017-05-02 Aquesys, Inc. Systems for reducing pressure in an organ
US10828195B2 (en) 2006-11-10 2020-11-10 Glaukos Corporation Uveoscleral shunt and methods for implanting same
US8506515B2 (en) 2006-11-10 2013-08-13 Glaukos Corporation Uveoscleral shunt and methods for implanting same
US9962290B2 (en) 2006-11-10 2018-05-08 Glaukos Corporation Uveoscleral shunt and methods for implanting same
US9585789B2 (en) 2007-07-17 2017-03-07 Novartis Ag Ocular implant with hydrogel expansion capabilities
US8109896B2 (en) 2008-02-11 2012-02-07 Optonol Ltd. Devices and methods for opening fluid passageways
US10016301B2 (en) 2008-06-25 2018-07-10 Novartis Ag Ocular implant with shape change capabilities
US10531983B2 (en) 2009-01-28 2020-01-14 Novartis Ag Ocular implant with stiffness qualities, methods of implantation and system
US11344448B2 (en) 2009-01-28 2022-05-31 Alcon Inc. Ocular implant with stiffness qualities, methods of implantation and system
US9763828B2 (en) 2009-01-28 2017-09-19 Novartis Ag Ocular implant with stiffness qualities, methods of implantation and system
US11839571B2 (en) 2009-01-28 2023-12-12 Alcon Inc. Ocular implant with stiffness qualities, methods of implantation and system
US9549846B2 (en) 2009-12-23 2017-01-24 Novartis Ag Drug delivery devices and methods
US9089392B2 (en) 2009-12-23 2015-07-28 Transcend Medical, Inc. Drug delivery devices and methods
US9173774B2 (en) 2010-03-26 2015-11-03 Optonol Ltd. Fluid drainage device, delivery device, and associated methods of use and manufacture
US9192516B2 (en) 2010-11-15 2015-11-24 Aquesys, Inc. Intraocular shunt placement
US9326891B2 (en) 2010-11-15 2016-05-03 Aquesys, Inc. Methods for deploying intraocular shunts
US9693901B2 (en) 2010-11-15 2017-07-04 Aquesys, Inc. Shunt placement through the sclera
US8852256B2 (en) 2010-11-15 2014-10-07 Aquesys, Inc. Methods for intraocular shunt placement
US9877866B2 (en) 2010-11-15 2018-01-30 Aquesys, Inc. Intraocular shunt placement
US8974511B2 (en) 2010-11-15 2015-03-10 Aquesys, Inc. Methods for treating closed angle glaucoma
US9017276B2 (en) 2010-11-15 2015-04-28 Aquesys, Inc. Shunt placement through the sclera
US9283116B2 (en) 2010-11-15 2016-03-15 Aquesys, Inc. Intraocular shunt deployment device
US10004638B2 (en) 2010-11-15 2018-06-26 Aquesys, Inc. Intraocular shunt delivery
US9393153B2 (en) 2010-11-15 2016-07-19 Aquesys, Inc. Methods for intraocular shunt placement
US9095411B2 (en) 2010-11-15 2015-08-04 Aquesys, Inc. Devices for deploying intraocular shunts
US10307292B2 (en) 2011-07-18 2019-06-04 Mor Research Applications Ltd Device for adjusting the intraocular pressure
US11363951B2 (en) 2011-09-13 2022-06-21 Glaukos Corporation Intraocular physiological sensor
US8852136B2 (en) 2011-12-08 2014-10-07 Aquesys, Inc. Methods for placing a shunt into the intra-scleral space
US9095413B2 (en) 2011-12-08 2015-08-04 Aquesys, Inc. Intraocular shunt manufacture
US9113994B2 (en) 2011-12-08 2015-08-25 Aquesys, Inc. Intraocular shunt manufacture
US9271869B2 (en) 2011-12-08 2016-03-01 Aquesys, Inc. Intrascleral shunt placement
US9592154B2 (en) 2011-12-08 2017-03-14 Aquesys, Inc. Intraocular shunt manufacture
US11197780B2 (en) 2012-03-26 2021-12-14 Glaukos Corporation System and method for delivering multiple ocular implants
US10271989B2 (en) 2012-03-26 2019-04-30 Glaukos Corporation System and method for delivering multiple ocular implants
US10085633B2 (en) 2012-04-19 2018-10-02 Novartis Ag Direct visualization system for glaucoma treatment
US10912676B2 (en) 2012-04-24 2021-02-09 Alcon Inc. Delivery system for ocular implant
US9155656B2 (en) 2012-04-24 2015-10-13 Transcend Medical, Inc. Delivery system for ocular implant
US9907697B2 (en) 2012-04-24 2018-03-06 Novartis Ag Delivery system for ocular implant
US9241832B2 (en) 2012-04-24 2016-01-26 Transcend Medical, Inc. Delivery system for ocular implant
US9480598B2 (en) 2012-09-17 2016-11-01 Novartis Ag Expanding ocular implant devices and methods
US9763829B2 (en) 2012-11-14 2017-09-19 Novartis Ag Flow promoting ocular implant
US9125723B2 (en) 2013-02-19 2015-09-08 Aquesys, Inc. Adjustable glaucoma implant
US10159600B2 (en) 2013-02-19 2018-12-25 Aquesys, Inc. Adjustable intraocular flow regulation
US9610195B2 (en) 2013-02-27 2017-04-04 Aquesys, Inc. Intraocular shunt implantation methods and devices
US10849558B2 (en) 2013-03-13 2020-12-01 Glaukos Corporation Intraocular physiological sensor
US9730638B2 (en) 2013-03-13 2017-08-15 Glaukos Corporation Intraocular physiological sensor
US9592151B2 (en) 2013-03-15 2017-03-14 Glaukos Corporation Systems and methods for delivering an ocular implant to the suprachoroidal space within an eye
US11559430B2 (en) 2013-03-15 2023-01-24 Glaukos Corporation Glaucoma stent and methods thereof for glaucoma treatment
US10285853B2 (en) 2013-03-15 2019-05-14 Glaukos Corporation Systems and methods for delivering an ocular implant to the suprachoroidal space within an eye
US10517759B2 (en) 2013-03-15 2019-12-31 Glaukos Corporation Glaucoma stent and methods thereof for glaucoma treatment
US11523938B2 (en) 2013-03-15 2022-12-13 Glaukos Corporation Systems and methods for delivering an ocular implant to the suprachoroidal space within an eye
US10188551B2 (en) 2013-03-15 2019-01-29 Glaukos Corporation Systems and methods for delivering an ocular implant to the suprachoroidal space within an eye
US9987163B2 (en) 2013-04-16 2018-06-05 Novartis Ag Device for dispensing intraocular substances
US9808373B2 (en) 2013-06-28 2017-11-07 Aquesys, Inc. Intraocular shunt implantation
US9585790B2 (en) 2013-11-14 2017-03-07 Aquesys, Inc. Intraocular shunt inserter
US10959941B2 (en) 2014-05-29 2021-03-30 Glaukos Corporation Implants with controlled drug delivery features and methods of using same
US11925578B2 (en) 2016-09-01 2024-03-12 Glaukos Corporation Drug delivery implants with bi-directional delivery capacity
US11116625B2 (en) 2017-09-28 2021-09-14 Glaukos Corporation Apparatus and method for controlling placement of intraocular implants
CN114129769A (en) * 2021-09-22 2022-03-04 海思盖德(苏州)生物医学科技有限公司 Artificial aqueous humor micro-drainage tube with drug slow-release function and preparation method thereof
CN114129769B (en) * 2021-09-22 2022-08-05 海思盖德(苏州)生物医学科技有限公司 Artificial aqueous humor micro-drainage tube with drug slow-release function and preparation method thereof

Similar Documents

Publication Publication Date Title
WO1994013234A1 (en) Implant device and method for treatment of glaucoma
US10285856B2 (en) Implant delivery system and methods thereof for treating ocular disorders
US9789001B2 (en) Ocular implant with therapeutic agents and methods thereof
US10238536B2 (en) Ocular filtration devices, systems and methods
US8333742B2 (en) Method of delivering an implant for treating an ocular disorder
US6533768B1 (en) Device for glaucoma treatment and methods thereof
US20150223981A1 (en) Combined treatment for cataract and glaucoma treatment
US20030088260A1 (en) Combined treatment for cataract and glaucoma treatment
JP2003180730A (en) Medicine releasing trabecular implant for treatment of glaucoma
WO2016168686A1 (en) Ocular filtration devices, systems and methods
US20180036173A1 (en) Ocular filtration devices, systems and methods
WO2008030951A2 (en) Glaucoma implant device
Pandya et al. Experimental evaluation of a hydroxylapatite reservoir tube shunt in rabbits
Kondo et al. Synthetic meshwork implant for glaucoma filtering surgery: effect of adjunct heparin and sodium hyaluronate in rabbits
Kivalo et al. A one-piece ocular drainage implant for glaucoma surgery: A preliminary report
Kivalo et al. Ett ögondränerings implant för glaukomkirurgi: En preliminär studie

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AT AU BB BG BR BY CA CH CZ DE DK ES FI GB HU JP KP KR KZ LK LU LV MG MN MW NL NO NZ PL PT RO RU SD SE SK UA US UZ VN

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA