Classifications

• • 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
  • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
  • A61L29/04—Macromolecular materials
  • A61L29/06—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61F—FILTERS 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
  • A61F9/00—Methods 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
  • A61F9/007—Methods or devices for eye surgery
  • A61F9/00772—Apparatus for restoration of tear ducts
• • 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
  • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
  • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
  • A61L29/16—Biologically active materials, e.g. therapeutic substances
• • 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
  • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
  • A61L2300/10—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
  • A61L2300/102—Metals or metal compounds, e.g. salts such as bicarbonates, carbonates, oxides, zeolites, silicates
  • A61L2300/104—Silver, e.g. silver sulfadiazine
• • 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
  • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
  • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
  • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
• • 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
  • A61L2400/00—Materials characterised by their function or physical properties
  • A61L2400/12—Nanosized materials, e.g. nanofibres, nanoparticles, nanowires, nanotubes; Nanostructured surfaces

Definitions

• the invention lies in the field of medicine and concerns an implantable drainage conduit of a small diameter made of a suitable polymer, a method of implanting the drainage conduit into a human or animal patient and a method of producing the drainage conduit.
• the invention concerns a canalicular duct conduit such as a lacrimal duct conduit (LDC) and a method of producing and implanting the canalicular duct conduit.
• LDC lacrimal duct conduit
• POSS- modified polyurethane polymer e.g. oligomeric silsesquioxanes (POSS) and poly (carbonate-urea)ur ethane (PCU) copolymers abbreviated as POSS-PCU copolymers
• POSS-PCU copolymers have been described for use as implantable devices.
• these and other polyurethane copolymers have been suggested for vascular and coronary applications such as vascular grafts, heart valves or stents and also including urological stents or conduits for use in repair of nerve damage or orthopedic joint replacement.
• POSS- PCU is a biocompatible copolymer and supports the lining with endothelial cells.
• POSS-PCU copolymers have previously not been suggested or adapted to manufacture small diameter conduits.
• the pre- saccal part comprises the superior and inferior puncta and ampulla (1), the superior and inferior canaliculus (2) and the common canaliculus (3).
• the saccal and post- saccal parts comprise the lacrimal sac (4), the nasolacrimal duct (5), the valve of Hasner (6), the middle nasal turbinate (7), the inferior nasal turbinate (8) and the lacrimal gland (palbebral part) (9).
• the orbital portion of the lacrimal gland is located in the supero temporal orbit and the palpebral portion of the lacrimal gland is located on the posterior surface of the supero temporal upper lid.
• the lacrimal gland produces the aqueous portion of the tear film. Ducts from the orbital portion of the lacrimal gland pass through the adjacent palpebral lacrimal gland to empty in the superior conjunctival cul-de-sac. Smaller accessory lacrimal glands in the upper and lower lids also contribute to tear production.
• the tears bathe the surface of the eye and then drain into the nose via the lacrimal drainage system.
• the lacrimal drainage system comprises a pair of small openings, namely the superior punctum and inferior punctum, are located on the medial upper and lower lids of the eye. Tears flow into these puncta which lead to two small diameter delicate tubes, namely, the superior canaliculus and the inferior canaliculus. The canaliculi join together as a short common canaliculus that enters into the larger lacrimal sac. The tears then flow from the lacrimal sac down the nasolacrimal duct and out an opening which empties into the nose on the lateral nasal wall and on to the nasal floor beneath the inferior turbinate. This space beneath the inferior turbinate is called the inferior meatus of the nasal cavity.
• the canaliculi can be underdeveloped or become obstructed on a congenital basis, or acquired as a result of some trauma such as lacerations, inflammation, side effects of drug (eg glaucoma treatment) or chemotherapy, such as taxotere or five- fluorouracil— or need to be excised in case of cancer - or the obstruction can be idiopathic.
• tears can no longer drain from the surface of the eye through the lacrimal drainage system into the nose. As a result tears well up in the eye, and run down the face. Excess tears blur the vision and the patient has to constantly dab the eye.
• Obstructions can be present in presaccal (localised at the canalicular level) and postsaccal lesions (localised at the nasolacrimal duct) (figure 1).
• the therapeutic options include basically perforation of the obstruction, dilatation of a narrowing (partial stenosis) or bypassing a total obstruction. All methods used risk generation of new scarring with consequent recurrence of symptoms.
• Particularly presaccal canalicular obstructions are difficult to treat due to small diameter of the canaliculi ( ⁇ lmm), hence probability of obstructions is much higher.
• Partial canalicular obstruction can be treated by perforation and/or dilated with Dacryocystoplstie (DCP) and placement of an intubation (e.g. Ritleng, Crawford, Minimonoca) in order to keep it open.
• DCP Dacryocystoplstie
• an intubation e.g. Ritleng, Crawford, Minimonoca
• the intubation needs to be taken off and often obtruction re-occurs. Larger obstruction can't be perforated, therefore placement of an intubation is not even possible. And a non existing canaliculus simply can not be reconstructed by these methods. In these cases, the obstruction respectively the missing lacrimal duct is bypassed.
• the object of the current invention is to provide an implantable drainage conduit of a small diameter, and methods of its implantation and of its production, which overcomes the deficiencies of implants available in the state of the art.
• embodiments of the instant invention shall provide devices and methods to treat major obstructions of the upper lacrimal drainage system or even a missing canalicular duct.
• an implantable drainage conduit comprising a conduit wall and a conduit lumen with a diameter d.
• the conduit has an outer wall surface and an inner or luminal wall surface.
• the wall of the conduit may comprise one layer forming a monolayer conduit or more than one layers forming a dual- or multilayer conduit.
• At least one layer of the wall substantially consists of a POSS-modified polyurethane. In some embodiments at least one layer consists entirely of POSS-modified polyurethanes.
• POSS-modified polyurethanes in the context of this invention refers to a biocompatible polymer which substantially consists of POSS-modified polyurethanes e.g. POSS-modified poly (carbonate-urea)urethanes (PCU) abbreviated POSS-PCU.
• PCU carbonate-urea
• POSS-PCU POSS-modified polyurethanes
• the POSS-modified polyurethanes may comprise additional components such as additives which do not compromise the biocompatibility or other functional requirements of the implantable drainage conduits.
• additives may be incorporated into the POSS-modified polyurethanes prior to the production of the conduit or they may be applied to the conduit after its formation as an additional layer or cover or impregnation or combined with connecting molecules (e.g. RGD in order to enhance desired cell growth).
• layer which substantially consists of POSS-modified polyurethanes in the context of this application means that in this layer of the conduit the POSS-modified polyurethanes dominates the chemical and biological properties due to its prevalence. Generally this means that the percentage by weight of the POSS-modified polyurethanes relative to the total polymer weight of this conduit layer (excluding luminal contents) is over 50%, more specifically at least 75 % or yet more specifically at least 90%. In some embodiments with two or more layers all of them substantially consist of POSS-modified polyurethanes. In some other embodiments one or more layers do not consist of POSS-modified polyurethanes. For examples in embodiments of implantable drainage conduits used as scaffolds cell cultured cells form a layer of the implanted conduit.
• POSS-modified polyurethanes suitable for implantable drainage conduits is their superb biocompatibility, which surpasses the biocompatibility of most other polyurethanes and at the same time retain the extraordinary mechanical properties of polyurethanes.
• implanted drainage conduits made of POSS-modified polyurethanes elicit essentially no immune reaction to the polymer material. This prevents the occurrence of the concomitant inflammatory reaction with invasion of fibroblasts causing scaring and obstruction of the implantable drainage conduit.
• Such superb biocompatibility has the effect that implanted drainage conduits made of POSS-modified polyurethanes remain open and functional for draining the drainage fluid rather than suffering from obstruction.
• Biocompatible in the context of this invention therefore refers to such a minimal immunogenic material property of POSS-modified polyurethanes the implantable drainage conduits are made of.
• the superb mechanical properties of the POSS-modified polyurethanes provide for the production of small diameter drainage conduits are documented in the PhD Thesis by Karla Chaloupka, University of London, 2011, which is incorporated here by reference.
• small diameter drainage conduits made of POSS- modified polyurethanes have been tested which exhibit a tensile strength over 35, 40, 45, 50 or 55 mega PA as measured in tensile tests according to the ISO 37 norm.
• the polyhedral oligomeric silsesquioxane (POSS) modified polyurethanes include various types, which are suitable for the current application, for example: POSS-PCU is POSS modified polycarbonate urea-ur ethane. It generally comprises as a hard segment urea and as a soft segment a segment which is derived from approx. 2000 mw polycarbonate diol and linked to the hard segment with urethane groups. Further examples include POSS modified polyester based polyurethanes e.g. with a soft segment derived from 1,4- butylenes adipate or caprolactone or POSS modified polyether based polyurethanes e.g. with a soft segment based on polytetramethylene ether glycol.
• the polyurethanes can be formulated from both aromatic and aliphatic diisocyanates.
• the implantable drainage conduit of the present invention comprises a copolymer, which copolymer comprises one or more segments comprising a POSS group and one or more polyol segments.
• the segments in the copolymer are linked by urea or urethane linkages, typically urethane linkages. It is preferred that there are more polyol groups than POSS groups (in terms of moles). More preferably the ratio of polyol groups to POSS groups is X: 1 wherein X is at least 2, at least 5, at least 10 or at least 20.
• the segments are linked by a group which has the following formula -X-C(0)- H-A- H-C(0)-X-, wherein each X is the same or different and is -O- or - H- and each A is an aromatic or aliphatic moiety.
• A is an aliphatic moiety it is an unsubstituted, straight or branched C1-C12, preferably C3- C8, alkylene moiety, a C3-C8cycloalkylene moiety or a group of formula -(C3- C8cycloalkyl)-(Cl-C2alkylene)-(C3-C8cycloalkyl)-.
• Preferred C3-C8cycloalkylene moieties include cyclohexylene and cyclopentylene.
• Preferred groups of formula - (C3-C8cycloalkyl)-(Cl-C2alkylene)-(C3-C8cycloalkyl)- include methylene- biscyclopentylene and methylene-biscyclohexylene.
• suitable aliphatic groups A include butylene, 2-methylpentylene, hexylene, octylene and methylene- biscyclohexylene moieties, in particular methylene-biscyclohexylene.
• A is an aromatic moiety, it is a phenylene, naphthylene or methylene-bisphenylene group, each of which is unsubstituted or substituted with 1, 2 or 3 substituents selected from halogen atoms, C1-C4 alkyl, C1-C4 alkoxy and Cl- C4 alkylthio groups and groups of formula - R1R2 wherein Rl and R2 are the same or different and are selected from hydrogen atoms and C1-C4 alkyl groups.
• Preferred substituents include methyl, ethyl, methoxy, methylthio, amino and dimethylamino groups, in particular methyl.
• A may be linked to the groups -N-C(0)-X- either via the aromatic ring or via a substituent.
• Preferred polyol segments are polycarbonate, polyether, polyester or polybutadiene polyols. Polycarbonate is most preferred.
• the POSS segments in the copolymer are derived from using a compound of the following structure:
• R is preferably a phenyl group, a C1-C6 acylic aliphatic group, or a C3- C6cylcoalkyl group, preferably a C1-C6 alkyl group.
• R is isobutyl.
• the POSS segment in the copolymer for use in the invention is preferably chain terminating in the copolymer.
• additives are included in the polymer to enhance favourable or add additional desired properties to the polymer, e.g. silver to confer antimicrobial properties or e.g. including additives to facilitate a particular production step, sodium bicarbonate to enhance the formation of pores.
• the wall of the conduit may comprise one layer forming a monolayer conduit or more than one layers forming a dual- or multilayer conduit.
• the wall consists substantially of POSS-modified polyurethanes.
• the wall comprises at least two layers.
• one and in other embodiments more than one or even all layers of the conduit consist substantially of POSS-modified polyurethanes.
• multi-layer embodiments one or more layers do not substantially consists of POSS-modified polyurethanes but are rather made of another material, for example of another polymer, or of a cell culture lining or of biocompatible metal.
• the conduit has an adjustable porosity depending on different methods of production and on the addition of particles (e.g. sodium bicarbonate) to prevent shrinkage as described further below.
• An example of an application for a monolayer drainage conduit is the implantation of a biliar duct conduit for repair or replacement of a biliar canaliculus.
• Other applications of monolayer drainage conduit include conduits used as scaffold, for cell culture. After the coating with a cell lining the monolayer conduit is transformed into a dual layer conduit with one layer substantially consisting of POSS-modified polyurethanes and one layer comprising the cell lining.
• Further embodiments include multilayer conduits with more than two layers, wherein at least one layer substantially consists of POSS-modified polyurethanes and at least one layer comprises a cell lining.
• At least a luminal layer of the conduit exhibits hydrophilic properties as measured by a contact angle of 90° or 80° or less In case of multilayered conduits such hydrophilic properties which enhance the capillary action in some embodiments are limited to the luminal layer.
• At least the inner luminal layer is designed to exhibit hydrophobic properties as measured by a contact angle of 90° or 100° or more.
• a hydrophobic luminal surface layer are preferably used as scaffold for epithelial cells supporting a cell lining of the luminal surface of the drainage conduit.
• the effect of such epithelial cell linig of the lumen is prevention of ingrowth of fibroblasts and formation of scaring tissue which would eventually lead to obstruction of the conduit.
• a hydrophobic outer wall surface is provided by the hydrophobic properties of the outer layer which promotes ingrowth of surrounding tissue into the implant surface resulting in anchoring of the implanted conduit in the tissue.
• implantable drainage with adjustable porosity in one or more wall layers are obtained depending on different methods of production and on the addition of particles (e.g. sodium bicarbonate) to prevent shrinkage.
• the porous structure and other properties of the conduit are selectable according to preferable quality characteristics required in particular for the innermost and the outermost layer providing the luminal conduit wall surface and the outer wall surface in various applications.
• the implantable drainage conduit comprises two layers: a luminal layer of the conduit wall of low porosity to exhibit a smooth surface to hinder the growth of cells potentially obstructing the conduit by scar tissue.
• luminal layer is also hydrophilic, to promote the drainage of fluids by capillary action.
• Such properties are obtained by using cast POSS-modified polyurethanes, e.g. cast POSS-PCU, for the inner wall as described in the second aspect of method of production of the implantable drainage conduit.
• the luminal layer can be thereafter covered with a coagulated layer of POSS-modified polyurethanes, e.g. POSS-PCU, which is porous and allows to suture the conduit e.g. to the residual parts of a lacrimal duct and prevent implant displacement and also promotes integration into the surrounding tissue by ingrowth of such tissue cells.
• ingrowth of physiological cells may include in-growth of nerves and blood vessels into the porous surface layer of the conduit wall.
• Such innervations and vascularisation allow a biofeedback as information can be transferred through the humoral and nerval feeback to the production line of tears (e.g. the glands produce more tears, when there is little tear flow through the canaliculus, when there is a swelling of the surrounding tissue or venous bed, or when toxic fluid is detected to flow through the drainage system in order to prevent further transportation of this damaging toxins.
• tears e.g. the glands produce more tears, when there is little tear flow through the canaliculus, when there is a swelling of the surrounding tissue or venous bed, or when toxic fluid is detected to flow through the drainage system in order to prevent further transportation of this damaging toxins.
• the implantable drainage conduit is used as a scaffold and the POSS-modified polyurethanes is selected to be biodegradable, and in others it is used as a permanent conduit with a POSS-modified polyurethanes selected to be nonbiodegradable, according the needed properties: a non biodegradable conduit is permanent and replaces or supports therefore at longterm the physiological structure. It can be also a permanent support for a cell layer.
• a degradable implant is used as a scaffold for cells which replace at long term the function of the non permanent implant, or leaves at long-term a desired gap or lumen in the drainage pathway to improve its function.
• the implantable drainage conduit has a small diameter where small diameter in this context refers to a diameter of less than 3.5 mm, in particular less than 1 mm, 1.5 mm, 2 mm, 2.5mm or 3.0 mm and more specifically a diameter in the order of 0.1 to 2.5 mm or yet more specifically in the order of between 0.3 mm and 0.8 mm or 1mm or 1.5 mm or 2 mm.
• the implantable drainage conduit has a simple shape of an elongated tube.
• drainage conduits are provided with branched tubes or multiply branched drainage conduits.
• 2D or 3D networks of branched drainage conduits thus forming a reticular structure are provided.
• the diameter of the conduit may vary within the branched or reticular drainage conduit system.
• the diameter of an unbranched tube does not necessarily exhibit the same luminal diameter over its entire length.
• the implantable drainage conduit is shaped according to the physiological anatomy of a particular drainage system such as the lacrimal drainage system or parts of it and in yet further embodiments artificial correlates performing the function of part of the lymphoid drainage system or a capillary bed are provided.
• kink resistance is needed for embodiments implanted in areas where the implanted drainage conduit is bound to be flexed.
• a further advantage of POSS- modified polyurethanes and POSS-PCU is that kink resistance is directly correlated to wall thickness. Accordingly, the implantable drainage conduits can be designed with variable wall thickness as necessitated by the implantation location. For example, lymph drainage systems and capillary vessels near a joint need a high kink resistance and therefore might need to have thickened walls, whereas further away from the joint the kink resistance is less important.
• the implantable drainage conduit is more flexible than in others.
• the flexibility is adjusted for different applications depending on placement and required length of the conduit: all conduits demand mainly an optimal balance between compressibility and kink resistance in order to allow the surrounding muscles to help the drainage process tough still keep the implant open in order to allow the flow drainage.
• High flexibility is demanded in implant under stress of flexion which occurs e.g. in the surrounding of joints (e.g. in some parts of the lymph- and capillary system) or where the implant is partially introduced into the residual lumen of the connecting drainage pathways (e.g. in the lacrimal or biliar system).
• the flexibility can be easily adapted by changing the material component (altering the hard and soft segments components or adding e.g.
• the implantable drainage conduit comprises silver nanoparticles which confers antimicrobial properties to the conduit. This is a particular advantage in applications of the lacrimal drainage system which is exposed to the microbial flora of the environment. It is also beneficial for the postoperative period to prevent postoperative infections. Additionally, silver nanoparticles reduce the inflammatory reaction and improve the healing process. Silver renders the materials also more hydrophilic and enhances capillarity which is desirable in some lumens as it improves drainage through capillary action.
• Implantable drainage conduits are widespread including the medical fields of surgery, trauma, radiotherapy as well as the treatment of diseases causing scaring.
• diseases causing scaring For example cancer, inflammations and infections can cause failure of perfusion and lymph drainage leading to swelling, problems in would healing, secondary infections and bad scaring and loss of function of organs or limbs. Reformation of lymph drainage and capillary perfusion takes several weeks up to several months and is not always possible. Treatment options are regular physiotherapy and lymph drainage, however, this only helps to overcome time whilst the wound is healing and permanently destroyed capillaries and lymph drainage can not be reconstructed with these methods. With some embodiments of the small diameter drainage conduits reconstruction of lost drainage systems is provided.
• the conduits e.g.
• reticular conduit systems in other embodiments branched or unbranched conduits are implanted at the time of primary surgery or shortly after occurring traumas causing drainage failure. In other embodiments the implantation is performed at a later stage, if needed endoscopically in order to reduce new traumatisation of the involved area. In some applications the implanted drainage conduit attaches spontaneously after simply placing the implant in a tissue pocket or in other applications the implanted drainage conduit is attached by suturing it or using tissue gel.
• the implantable drainage conduit of the invention is a glaucoma filtration tube for use in a glaucoma drainage device.
• the conduit preferably has a lumen size of 0.3 mm or less, more preferably 0.2 mm or less, more preferably still 0.1 mm or less.
• the conduit preferably has a lumen size of 0.02mm or more, preferably 0.03 mm or more.
• the lumen has a lumen size of around 0.05 mm.
• the outer diameter of the conduit is preferably around 0.3 to 0.5 mm, typically around 0.4 mm (obviously the outer diameter must be larger than the lumen).
• the glaucoma device itself typically further contains an end plate at the end of the filtration tube. The nature of the end plate will depend on whether the glaucoma drainage device is designed to have set, variable or no resistance.
• POSS-modified polyurethanes are used for producing implantable drainage conduit such as for producing lacrimal duct conduits or biliar duct conduits from poly (carbonate-urea)ur ethane (PCU), e.g. from oligomeric silsesquioxanes (POSS) and poly (carbonate-urea)ur ethane (PCU) copolymers.
• PCU poly (carbonate-urea)ur ethane
• PCU poly (carbonate-urea)ur ethane
• PCU poly (carbonate-urea)ur ethane
• POSS-modified polyurethanes The synthesis of POSS-modified polyurethanes has been described in WO2005/070988 and additionally an example 2.1 is provided in this application for illustration of an exemplary synthesis of oligomeric silsesquioxanes (POSS) and poly (carbonate-urea)ur ethane (PCU) copolymers.
• POSS oligomeric silsesquioxanes
• PCU poly (carbonate-urea)ur ethane
• POSS-modified polyurethanes are utilized which comprise silver nanoparticles (NS) to confer antimicrobial properties to the conduit.
• NS-POSS-modified polyurethanes are produced by dispersing NS with the POSS-modified polyurethanes solution.
• NS is incorporated into the POSS-modified polyurethanes during its synthesis, in particular embodiments it is dispersed into a solution of POSS-modified polycarbonate polyol prepolymers prior to the chain elongation step.
• the process of producing an implantable drainage conduit is sometimes referred to as extrusion of the POSS-modified polyurethanes, e.g. "extrusion of POSS-PCU to lacrimal duct conduit” on page 150 in Chaloupka, "Development of a small diameter conduit for upper lacrimal system disorders using a novel nanocomposite polymer", PhD Thesis University of London, 2011 which is incorporated in here by reference.
• the process of producing an implantable drainage conduit from a POSS-modified polyurethane comprises at least the following steps: 1. provision of a POSS-modified polyurethane
• the application of the POSS-modified polyurethane to the mandrel in step 3 in some embodiments involves a dipping into the polymer or a spraying of the polymer onto the mandrel.
• Such dipping and spraying methods require the selection of a polymer of an appropriate dynamic viscosity as measured by a viscosity coefficient in Pa s. For example, if the polymer is not viscous enough it slides off the mandrel, forming an undesirable thin coating. Conversely, if the polymer is too viscous, it tends to produce a thickened and irregular coating.
• the viscosity coefficient was used as a crucial control parameter to test if a polymer is suitable for the manufacturing techniques involved in forming conduits.
• a mandrel of the corresponding size is chosen and optimal values of the viscosity coefficient range from 3-6 Pa s. Viscosity coefficients of values between 0.5 to 10 and preferably from 1 to 8 Pa s are acceptable.
• POSS-modified polyurethanes have an adjustable viscosity.
• the flow characteristics of the POSS-modified polyurethanes have been shown to have superior coating characteristics compared to unmodified polyurethane.
• a variety of designs can be incorporated by employing different manufacturing techniques.
• a curved conduit can be easily achieved by casting, and coagulated tubes tend to have shape memory. Latter allows to form the inner wall of the lumen in specific ways.
• the covering polymer When the mandrel is having a driller like curved outer surface, the covering polymer will have a responding imprint on the inner surface. This allows to reconstruct any needed form of the implantable drainage conduit such as a lacrimal or a biliar duct conduit or a lymph or capillary drainage system (bed or net of multiple small diameter conduits).
• conduits obtained by production with a casting method exhibit conduit walls of low porosity.
• Conduits obtained by production with a coagulation method exhibit walls with a highly porous structure.
• the casting method involves drying in step 4 directly after the application of the polymer in step 3.
• the coagulation method involves a coagulation step after step 3 wherein the polymer which is applied to the mandrel is coagulated with water or another suitable solvent, prior to drying in step 4.
• either the casting method or the coagulation method or a combination of the two methods are applied according to the desired structural properties of the conduit.
• a third aspect of the invention concerns small diameter drainage conduits which are obtained by the method of production described in this application.
• a large number of embodiments is available by variation of the production method including besides variation of the polymer provided in step 1 also variations in shape and structure such as number of layers of the wall depending on the number of repetitions of steps 3 and 4, variations in the porosity depending on the performance of a coagulation step or not, unbranched, branched and 2D- or 3D reticular conduits depending on the mandrel provided in step 2, kink resistance depending on the wall thickness.
• Small diameter conduits are available for many variable embodiments and applications such as for example as single and double conduits or multiple parallel drainage nets or beds) by applying the dipping or the extrusion method with some steps performed only once or repetitively as described above, or in a combination of the above described methods.
• POSS-modified polyurethanes are provided for use as an implantable drainage conduit for repair or in replacement of one or more parts of a drainage system of a human or animal patient such as for repair or reconstruction of the lacrimal or a biliar or a lymph drainage system or for use of repair or in replacement of one or more parts of a capillary bed or for anyone of the implantation methods described in this patent application. Due to its nanocomponent nature POSS-modified polyurethanes have a wide spectrum regarding flexibility, porosity, etc and are easily adjustable.
• POSS- PCU has been proven to be highly biocompatible, it can be used for all sorts of conduit requiring small diameter lumen such as for example the lacrimal and biliar system as well the lymph system and the capillary bed.
• a method of implanting a drainage conduit in which as a first step a suitable drainage conduit is provided and in a second step it is placed into a human or animal patient as a part of a drainage pathway.
• the drainage conduit may be adjusted in size.
• the adjustment in size comprises a reduction in the length of the conduit.
• the areal size may be adjusted.
• the drainage conduit is fixed to at least one part of an anatomical structure of the patients.
• This anatomical structure in some embodiments is part of the drainage pathway such as for example it may be at the junction to a healthy intact part of a canalicular duct. In some embodiments it is fixed to an anatomical structure which is not part of the drainage system per se such as a adjacent muscle or for example to the eye lid.
• the method of fixing is by suturing, however the method also includes other techniques such as by using tissue glue or stabilization of the conduit by surrounding tissue.
• the method of implanting is not limited to a sequence of the steps in a temporal succession of step 1 before step 2, before step 3, before step 4.
• the temporal succession may be varied such that for example the size of the conduit in step 3 is adjusted prior to its placement in step 2 or after its fixation in step 4 etc.
• the implantable drainage conduit provided is selected from implantable drainage conduits produced from the chemical compounds and/or according to the methods described according to one of the aspects one to four according to this invention.
• the implantable drainage conduit provided is produced from another polymer with the required properties with respect to biocompatibility, tensile strength and tear resistance, and depending on the application also with respect to hydrophilicity, flexibility and kink resistance as measured and described in this application and in the PhD thesis by K. Chaloupka, 2011.
• Such polymers are available among elastomers including Polyurethanes, Natural Rubber, Synthetic Rubbers (Styrenics), Polysiloxanes (Silicone Polymers), Fluoroelastomers, Ethylene-propylene copolymers, Polyamides, Polyesters.
• silicone derivatives with the biocompatibility level of silicone and much better mechanical properties such as a tensile strength of over 40 or preferably over 50 mega Pa and a tear resistance with of over 70 or preferably of 80 to 90 N/mm are considered.
• the placement of the conduit repairs or replaces a part of the drainage pathway by reconstructing the physiological anatomy of the patients drainage pathway.
• a part of or the entire lower lacrimal canaliculus is replaced.
• it bypasses at least a part of the physiological drainage pathway, for example analogous to the Lester Jones tube in the lacrimal drainage pathway.
• the conduit is introduced at least partially into the lumen of a part of the drainage pathway as a stent for example a lacrimal duct conduit may be introduced into a lacrimal canaliculus.
• Fig. 1 The lacrimal drainage system is divided into the upper lacrimal duct system (pre-saccal) formed by an upper and inferior canaliculus (circle) and lower tear drainage part (saccal and post-saccal).
• Example of a canalicular obstruction grey area in 2 which is an exemplary targeted reconstruction area.
• a drainage conduit can replace specifically the non functional area.
• Endoscopic light source allowing the examination of the wall structure by illumination from the lumen using a small diameter endoscope (retinoscope).
• Fig. 4. shows the option to form different designs, a) showing a LDC with a cone for the replacement of the punctum. b) curved design.
• the viscosity is important to achieve an optimal lining of the mandrel.
• Fig. 5. shows AFM 3D pictures of
• the total area of LDC in contact with the strip has an area of 0.0054m2 (length 0.018m x width 0.003m).
• Fig. 8. showing increasing capillarity of the NS POSS-PCU LDC in relation to nanosilver concentration.
• the bright POSS-PCU LDCs without NS On the right side the POSS-PCU LDC with NS (darker). The water is coloured with ink to make the water level visible.
• the coagulated LDC showed an interesting additional capillary effect in its vastly porous wall resulting in an uneven level of the coloured ink as the fluid diffuses into the coagulated POSS-PCU.
• Fig. 10 Shows a) the way of tearing of POSS-PCU in a triangle shape with a
• FIG. 11 Suture technique showing the use of Vicryl 7-0 sutures in connecting the
• exemplary embodiments of implantable drainage conduit according to the first aspect of the invention are characterized in further detail.
• the POSS-modified polyurethanes is a POSS-PCU polymer and examples of unbranched conduits in particular of a lacrimal duct conduit (LDC) are presented.
• LDC lacrimal duct conduit
• FTIR Fourier Transform InfraRed
• the 3D AFM images show the very different topographies of the cast PCU control without POSS and the coagulated versus cast sheets of POSS-PCU revealing a highly irregular surface of the coagulated polymer.
• a smooth surface is less inviting for cell growth, reducing scar formation in this case.
• due to excellent biocompatibility of POSS-PCU the inflammatory reaction and therefore scar formation is markedly reduces.
• porosity and therefore the surface structure can be adjusted using different extrusion techniques and addition of sodium bicarbonate.
• the FT-IR spectra for cast and coagulated POSS-PCU, cast PCU control and the pure trans-cyclohexanechlorohydrinisobutyl-POSS are typical of PCU and are similar to each other, apart from the intense Si-O-Si absorption ( ⁇ 1098cm-l) of the cast POSS-PCU.
• the shift in the characteristic Si-O-Si-peak in POSS-PCU (1098cm- 1) from that observed in pure POSS (1089cm-l) is due to the chemical reaction between POSS and isocyanate. Changes between POSS-PCU and PCU are due to migration of the POSS motif to the surface of the polymer, which is responsible for the favourable biological properties of POSS-PCU.
• the coagulated POSS-PCU shows a weaker and slightly shifted Si-O-Si absorption owing to the extremely high surface area of the porous structure (K. Chaloupka, PhD thesis, p.182)
• the autoclaved POSS-PCU sheet showed a slightly lower modulus and ultimate tensile strength than the cast sheet. This indicates that it is only minimally coagulated and more solid than foam.
• An Instron-5565 tensile tester (Instron Ltd., Bucks, UK) equipped with a 500N load cell and pneumatic grips with IkN capacity and Bluehill software was used to test the tensile strengths of samples at room temperature.
• 150 ⁇ thick sheets of polymer were cast in glass dishes and the solvent dried off at 60°C for 24 hours in an air- circulating oven.
• Tensile stress-strain properties were assessed according to ISO 37 using dumbbell- shaped specimens type 3 (length 50mm), with a 16mm gauge length and 4mm width, at a displacement rate of 100mm min-1. Sheet thickness was measured using an electronic micrometer (RS Components UK). A minimum of 5 specimens were tested for each polymer. Tensile stress-strain graphs were plotted using the mean ⁇ SEM and are available on pages 187-190 (without silver) and 232-234 (with silver) in the PhD Thesis of K. Chaloupka, 2011 (which is incorporated here).
• Suture retention test determines the force necessary to pull a suture from the polymer or cause the polymer to fail by tearing. Suture retention was assessed according to the international standard (BS ISO 7198: 1998 section 8.8). Two different sutures (Vicryl 6-0 and 7-0) were tested penetrating in full thickness through the edge of the polymer at a distance of 2 mm from the border. The samples were positioned between the grips of the Instron-5565 tensile tester (Instron Ltd., Bucks, UK) and a force was applied at 50mm/min to determine the point of failure. The results are available on page 192 -198 in the PhD Thesis of K. Chaloupka, 201 1 (which is incorporated here).
• LDC wall structure LDC wall structure
• wall thickness inner/outer diameters
• porosity porosity
• surface contact angle
• capillarity compressibility and kink resistance
• Constant inner LDC diameters can be achieved regardless of the extrusion technique.
• the wall thickness and structure differs greatly in relation to the procedure.
• EDHA electrohydrodynamic atomisation
• spraying onto a turning steel mandrel the constantly changing magnetic field required a continuous adjustment of the variables.
• the EDHA procedure required 6 hours of spraying with constant supervision; after which, a relatively thin wall was acquired, hardly forming a conduit.
• LDC produced by employing different extrusion techniques resulted in varying degrees of porosity (Fig. 6).
• the internal, external diameter and wall thickness were calculated from their scanning electron microscopy (SEM) images. Compressibility is shown in Fig. 7 and is related to the wall thickness and extrusion procedure.
• Kink resistance is directly related to the wall thickness and not depending on extrusion technique.
• the cast conduit walls showed no porosity.
• the groves on the one layer cast conduit are artefacts caused by cutting the LDC for the SEM (scanning electro microscopy).
• the EHDA technique did not form a proper covering on the LDC due to the constant manual adjustment of the variables required by the procedure. Hence, the kink resistance and compressibility could not be performed.
• the autoclaved conduit wall showed less and uneven, non-confluent pores.
• the porosity varies with wall thickness: a thin coating produces a structure comparable to casting whereas a thick coating creates a more porous wall due to longer retention of DMAC forming a wall comparable to a coagulated conduit.
• the coagulated LDC wall had high porosity with connecting pores while the ultrasonic atomized conduit wall had medium, non-connected pores. Hence, the wall surface porosity of these conduits was compared to conclude that only the coagulated LDC has pores reaching the surface of the wall.
• the compressibility for the LDC produced by ultrasonic atomization was relatively high, whereas the single cast tube and the autoclaved LDC had low compressibility. This increase was not directly proportional to the thickness as illustrated in the three cast tubes.
• the coagulated LDC displayed a compressive strength in the middle of the two extremes, with the highest kink resistance.
• the hydrophilic polymer tube and the ultrasonic atomised LDC exhibited similar capillarity to the coagulated LDC.
• the hydrophilic polymer was not suitable for this application due to its ability to rapidly biodegrade.
• the tube had disintegrated in a couple of weeks.
• the ultrasonic atomised LDC was very rigid, which would have displacement issues similar to the Lester Jones tube.
• the hydrophobicity and the lack of pores in the cast LDC accounted to its low capillarity. Nonetheless, improvement of capillarity can be achieved by changing the inner tube diameter.
• Vicryl 7-0 is commonly used to connect the two separated ends of the canaliculus.
• the suture retention showed that POSS-PCU is stronger than Vicryl 7-0, making it a suitable conduit material.
• the optimised wall thickness allows the application of a blind stitching technique (Fig. 11), which inhibits attachment of bacteria and scar tissue formation.
• Non absorbable Silkam 7-0 sutures are beneficial for superficial skin stitches in cases where the lesion and therefore the LDC reach the skin surface.
• a mono layered conduit or a partially mono layered and partially multilayered structure can be envisaged in different conduits or in some parts of a conduit, when the requirement of drainage change along the pathway, (e.g. part of the drainage pathway might not need to be hydrophilic, or the required wall thickness for suturing is only needed at the connecting points of the implant to the residual original drainage system and therefore limited to this area of need).
• Flake 4,4'-Methylenebis(phenyl isocyanate) (MDI) was added to the polyol blend and then reacted with nitrogen at 75-85°C for 90 minutes to form a pre-polymer.
• Dimethylacetamide was added slowly to the pre- polymer to form a solution, which was cooled to 40°C.
• Chain extension of the pre- polymer by the dropwise addition of a mixture of Ethylenediamine and Diethylamine in ⁇ , ⁇ -dimethylacetamide (DMAC) formed a solution of POSS modified PCU in DMAC. All the chemicals except POSS were purchased from Sigma Aldrich Limited (Gillingham, United Kingdom).
• Dynamic Viscosity (viscosity coefficient in Pa s) is a crucial control parameter to verify if the polymer is suitable for the manufacturing techniques involved in forming conduits.
• the viscosity of POSS-PCU was measured with a rotational viscometer (Bohlin CVO 100 Rheometer, Malvern Instruments, UK;) and Bohlin software CVO 100. Viscosity and shear stress were measured over a shear range of 0 - 200s "1 at 25°C, with an upper plate diameter of 40mm at a gap of 150 ⁇ .
• a shear rate of 100 sec "1 was selected as a quality control point for viscosity, since this is approximately the amount of shear, which is expected in the current method of producing the implantable drainage conduits.
• an optimal viscosity coefficient was 3-6 Pa s, where the polymer exhibits shear thinning, the reduction in viscosity with increasing shear rate.
• the shear stress increased with escalating shear rate.
• a viscosity coefficient in the order of X-y Pa or preferably a-c gave generally still acceptable results.
• the viscosity of this starter batch polymer can then be further adapted in dependence of extrusion or coating processing or altered in dependence of biodegradability.
• Example 2.3 Methods of preparation of POSS-modified polyurethanes which comprise silver nanoparticles.
• the implantable drainage conduit is produced from POSS-modified polyurethanes comprising silver nanoparticles, which are added to confer antimicrobial properties to the polymer.
• silver nanoparticles NS were synthesized by the reduction of silver nitrate with dimethylformamide in the presence of an excess of fumed silica nanoparticles (Aerosil 200 from Degussa) to prevent aggregation of NS.
• Silver nitrate and fumed silica were mixed with dimethylformamide and sonicated for 10 minutes in a sonicating bath. The dispersion was then homogenised for 5 minutes using an Ultra- Turrax T25 at 10000 min-1.
• the NS dispersion as prepared above was dispersed into the POSS-PCU during its synthesis (2) and in particular it is dispersed into a solution of POSS-modified polycarbonate polyol prepolymers prior to the chain elongation step, which is termed below and in K. Chaloupka, PhD Thesis, 201 1, p.205 as POSS-PCU with incorporated nano silver particles (NS).
• Chain extension of the pre-polymer was carried out by the drop wise addition of a mixture of Ethylenediamine and Diethylamine in Dimethylacetamide to form a solution of POSS modified Polycarbonate urea-urethane in Dimethylacetamide.
• the resulting polymers were tested for the reduction of bacterial biofilm formation of Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) in dependence of the NS concentrations.
• Qualitative and quantitative methods including disc diffusion method, viable colony counting method, Alamar blue assay and SEM imaging were used to document and evaluate the antibacterial properties in relation to the different concentrations and synthesis.
• the mechanical properties of POSS-PCU were investigated to evaluate if the incorporation of NS altered its properties.
• the size of the NS was measured using transmission electron microscopy (TEM). The results are presented in K.Chaloupka, PhD thesis chapters 6.3 and 6.4
• Example 2.4 Methods of producing POSS-modified polyurethane conduits with variable pore size on the conduit outer surface.
• conduits the number and size of the pores on the outer surface of the conduit, in particular in the outer layer and/or on the surface of outer layer is increased. Increased porosity of the outer surface of the conduit improves incorporation of the implant into the surrounding tissue. In order to enhance porosity, sodium bicarbonate is added to the outer layer of the tube.
• the liquid POSS-modified polyurethane polymer is mixed with sodium bicarbonate (NaH03) at a concentration of approx. 40-60 vol% and with a surfactant e.g. Tween 20 at a concentration of approx. 1-5 vol%, e.g. 2 vol%.
• sodium bicarbonate is applied at a later stage when the polymer sets on a mandrel and starts to become compact by sprinkling sodium bicarbonate to the outer surface of a conduit while it is still mounted on the mandrel. After drying off, the sodium bicarbonate is dissolved and washed out together with the surfactant by washing with destilled sterile water.
• an inner and an outer layer are comprising different POSS-modified polyurethane.
• the inner layer is made of a POSS- modified polyurethane comprising nano silver whereas in other embodiments the inner layer comprises no nano silver particles.
• Either of these and other multi layered embodiments comprise an outer layer which is made of a POSS-modified polyurethane polymer without or with enhanced pores.
• enhanced pores are obtainable by a treatment of the polymer with sodium bicarbonate by either one of or by a combination of the methods described above.
• a POSS-modified polyurethane conduit comprising two layers, an inner layer comprising nano silver particles and an outer layer with enhanced porosity was produced according to the following protocol:
• the polymer was stored for at least overnight or longer, and used when the viscosity was convenient (which is changing over time depending on ambient temperature and humidity) for production of the inner layer by immersion of the mandrel into the polymer as described.
• the outer layer is added by dipping it into a freshly prepared POSS-modified polyurethane treated with sodium bicarbonate.
• POSS-PCU was mixed with 40g of NaH03 (TATA chemicals Europe 40microns or BM Brunner Mont PO Box 4 Mond house Northwich. Cheshire, CW84DT UK) 2g tween 20 (Sigma Lot75H003415/P-9416 and LotSZBB 1080V P-7949).
• mixing and degassing is achieved by a thinky apparatus e.g by mixing for 3 min at 2000 rpm followed by 2 min at 1000-1500 rpm for degassing.
• Sodium bicarbonate treated POSS-modified polyurethane has to be applied to the mandrel within approx 2 hours and preferably sooner, e.g. instantly after its preparation.
• Examples 2.5 to 2.10 show different embodiments of the method for producing an implantable drainage conduit.
• the wall thickness of the conduit is primarily determined by the type of polymer used, the number of layers and the method of application. In particular application by coagulation methods leads to a thicker more porous wall, while casting to a thinner wall without air entrapments.
• the invention is not limited to the particular exemplary embodiments listed here for illustrating the methods of production of the implantable drainage conduit and particularly also includes further variations and combinations thereof.
• an "Extrusion-Coagulation” method is used. This method has been previously described for the production of blood vessel conduits in Sarkar S, Burriesci G, Wojcik A, Aresti N, Hamilton G, Seifalian AM. Manufacture of small calibre quadruple lamina vascular bypass grafts using a novel automated extrusion- phase-inversion method and nanocomposite polymer. J Biomech 2009; 42(6): 722- 730. According to the first embodiment of the method of production this method is applied to produce conduits of a small diameter:
• the mandrels were dip-coated in the polymer solution before being coagulated in distilled water at 4°C for 2 hours. They were then air-dried for 24 hours at room temperature, then pulled off the mandrel. This prevented shrinking of the conduit.
• the temperature of the water may be varied within the range of 0 to 37°C more specifically within 1 to 10°C.
• the drying in air should be at least 30min, more specifically at least 6 hours or preferably over 12 hours.
• Automated versions of this first type of embodiment of the production method may also be achieved for example with an automated inversion extrusion device to manufacture the conduit.
• This particular device consisted of a polymer chamber held in an alignment device into which 3.0ml of polymer dissolved in DMAC (N N'- dimethylacetamide) was injected.
• a 1.2mm diameter stainless steel mandrel was passed vertically through the polymer chamber and cut through a 1.4mm exit aperture.
• the mandrel passed directly into a reservoir containing de-ionised water at 5°C. This ensured phase inversion of the polymer with exchange of solvent in the polymer for the water (coagulant).
• the mandrels were left undisturbed in the coagulant for 30 minutes before being transferred within the reservoir to a fridge at 4°C for 48 hours (Sarkar et al 2009).
• an "Extrusion-Coagulation" method is used.
• the conduit is formed by using high pressure coagulation by autoclaving:
• the mandrel was dipped in the polymer and pulled out at a speed of 4 mms "1 .
• the conduits were allowed to cool down at room temperature for 120 min before being removed off the mandrel.
• the speed of pulling out the mandrel may be varied within a range of approximately 1 mms "1 l to 10 mms “1 more specifically 2 mms “1 l to 8 mm s “1 or more specifically 3 mms "1 to 6 mm s “1 .
• the conditions for setting in step 4 may be varied within a temperature range from 0 to 60 °C, more specifically from 10 to 40 °C or yet more specifically from 15 to 30°C and a time range within 15 minutes to over 12 hours depending on the temperature and the type of POSS polymer which was used in step 3 for coating.
• the mandrel was dipped in the polymer and pulled out at a speed of 4 mms "1 . It was then placed vertically in an air circulating oven at 60°C for e.g. 120min to remove the DMAC solvent (N N'-dimethylacetamide). The resulting POSS-PCU conduit was allowed to cool down at room temperature for e.g. 120 min and then removed off the mandrel. Speed of pulling out the mandrel may be varied similarly as described for the example 1 time and temperature conditions in the circulating oven may be varied within the ranges of 30-70°C.
• multilayered conduits are produced using casting and extrusion coagulation extrusion method according to the third and the first embodiment in combination of consecutive application of the POSS nanocomposite polymer to the mandrel forming a multilayered coat made of the POSS nanocomposite polymer.
• the multilayered conduits are produced for which the properties of the individual layers is adaptable to qualities yield effect of producing a
• the mandrel was first treated according to the third embodiment, the casting method of production described above yielding a cast mandrel in step 3 of the method. Prior to the removal of the mandrel in step 4 another layer was placed above the cast mandrel by way of the method according to the first embodiment, extrusion coagulation. To prevent shrinkage of the coagulated outer layer after drying - which shrinkage is induced by its higher porosity - sodium bicarbonate was added to the polymer used for the outer layer resulting in the a uniformly flat double layered or multilayered wall. Either the casting step according to the first method or the
• ultrasonic atomisation spraying was used, which is a technique available in the prior art but has never been used for the production of a small diameter conduit.
• Sono- Tek ultrasonic atomiser (Sono-Tek Corp., New York, USA) converted POSS-PCU into ultra fine sprays without the use of air pressure.14-17
• the optimal ultrasonic power for efficient coating was 1.5W.
• the N2 focusing gas was set at 3 atm (optional 2-5 atm), reducing the effects of air humidity on the polymer.
• the flow rate of POSS-PCU was set at 2-15 ml/min.
• POSS PCU was diluted to 5% (optional 2-10%) with tetrahydrofuran (THF), a highly volatile solvent, as opposed to only with DMAC in other techniques.
• THF tetrahydrofuran
• the optimum distance of the nozzle to the mandrel was 5 cm (optional 2-8cm).
• the mandrel was rotating at a speed of 200 RPM (optional 100-300 RPM) and additional horizontal movements allowed even coverage.
• EHDA implantable drainage conduit electrohydrodynamic atomisation
• EHDA is a process in which an electric force is generated on the surface of the liquid by applying a potential difference of the order of kilovolts between the needle, which perfuses the liquid, and the collection electrode. The latter gathers the product droplets of a jet that forms due to the electric.
• the deposition of POSS-PCU on the mandrel was achieved using a combination of EHDA spraying and spinning in the stable cone-jet mode, at a voltage of 9-12kV (optional 5-20kV) and at an adjusted distance (+/- 30mm) on the turning mandrel.
• the tubes were then coagulated in water maintained at 4°C (optinal 2-25°C) and left to dry overnight at room temperature.
• the equipment used consisted of a stainless steel needle with an internal orifice diameter of 750 ⁇ . It was held in epoxy resin and a point-like electrode was held directly below the axis of the needle.
• the needle was connected to a high voltage power supply (Glassman Europe Ltd., Tadley, UK).
• the inlet of the needle was connected to a Harvard PHD 4400 programmable syringe pump (HARVARD Apparatus Ltd., Edenbridge, UK) using a silicone rubber tube, allowing the flow rate of liquid to the needle exit to be set to > 1 ⁇ /hour.
• Computer software CompuC AM and Motion Planner
• the POSS-PCU solutions were printed onto the rotating mandrel with an applied voltage of 4 to 15 kV. The distance between the needle exit and the wire was ⁇ 2mm.
• a drainage conduit is implanted.
• the placement of the conduit repairs or replaces a part of the drainage pathway by reconstructing the physiological anatomy of the patients drainage pathway, or in some the conduit bypasses at least a part of the physiological drainage pathway or in in some the conduit is introduced at least into the lumen of a part of the drainage pathway as a stent.
• the drainage conduit is a lacrimal duct conduit and/or in step 4 in step 4 the lacrimal duct conduit is fixed at its distal end to a canalicular duct and optionally also at its proximal end.
• endoscopy keyhole surgery
• additional instruments might be used such as radiological using imaging with or without contrast medium, or endoscopic procedures using a light source and endocopic trochars and instruments.
• anti-inflammatory drugs such as steroids contribute to the effort of minimizing the formation of scar tissue. This is important as scar tissue threatens to obstruct an implanted drainage conduit. Damage of the physiological epithelium or endothelium induces a cascade of reparative mechanisms to restore an intact surface. Often this reparative process involves the production of scar tissue. However, production of scar tissue in the narrow lumen of a implanted drainage conduit, may cause obstruction of the conduit and failure of its function as a drainage conduit. To interrupt this physiological repair mechanism and reduce scaring, anti-inflammatory drugs can be applied.
• cell culture medium developed for the support of epithelial or endothelial cell growth can be used to help the reparative mechanism and reduce development of scar tissue.
• cell culture medium is applied in form of eye drops into the eye and into lacrimal drainage area, respectively.
• a combination of anti-inflammatory drugs and cell culture medium are applied to the tissue integration of bioengineered conduits (when using biodegradable or non biodegradable conduits as a scaffold for epithelial or endothelial cell layers, or even in minor fresh injuries of the drainage system to help repairing the physiological surface without forming or reduce scar tissue to a minimum and therfore prevent obstruction of the lumen.

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