EP2726035A1 - Implantable small diameter drainage conduit - Google Patents

Abstract

An implantable drainage conduit of a small diameter, and methods of its implantation and of its production, are provided for repair and replacement of drainage systems such as the lacrimal, biliar and lymph drainage systems and capillary beds. In particular embodiments implantable drainage conduits produced from POSS- modified polyurethanes are provided.

Description

IMPLANTABLE SMALL DIAMETER DRAINAGE CONDUIT

FIELD OF THE INVENTION

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. In particular 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.

BACKGROUND OF THE INVENTION

In the prior art only very limited techniques are available for the repair or replacement of missing, damaged or obstructed drainage conduit systems, such as the lacrimal and biliar canaliculi, the lymphoid drainage system and the blood capillary beds because the small diameter of the lumen of these drainage passages which is generally less than 2 mm and often less than 1 mm renders the manufacture of suitable implants very difficult. Major difficulties which have been encountered include immune reactions to the previously considered polymers (e.g. plasticised PVC). Immune reactions with concomitant inflammation and scaring often cause obstruction of the implanted conduit. Furthermore, often the luminal surface of conduits produced from previously considered polymers were of insufficient hydrophilicity and therefore could not support adequate capillary action to promote flow through conduits of such small diameters. A further problem which was encountered in particular with implants made of silicone polymers was a lack of strength and tear resistance. Such thin-walled small diameter conduit implants would fail when sutured to connect to the physiological tissue. Further problems arising with conduit implants made of previously considered polymers include insufficient flexibility and elasticity, which limited the manufacture of conduits according to anatomical structure. Another common problem is insufficient resistance to collapsing of conduits manufactured from previously considered polymers.

Therefore above mentioned disadvantages severely limited the treatment of damaged or missing drainage systems such as the lacrimal duct system which is responsible for draining the tear fluid from the eye. Obstruction or lack of lacrimal ducts can lead to constant tearing (watery eyes) resulting in irritation of the eye region, disturbed vision and therefore serious reduction of life comfort. In the absence of suitable implantable small diameter drainage conduits for replacement of the anatomical structures of a healthy individual, Lester Jones tubes made of glass or acrylic tubes of 3 to 4 mm in diameter were implanted and used to bypass presaccal lacrimal duct obstructions. This method is still in use, however, it does not reconstruct the physiological anatomy and patients have to accept major surgery and multiple side effects including displacement or loss of the tube, foreign body sensation of the eye and regular need of tube syringing (Jones L. Trans Am Acad Ophthalmol Otolarynol 1962; 66:506-524). Small and soft silicon coated polyurethane stent implantations into the lacrimal drainage system were introduced, allowing minor surgery and less discomfort to patients (Song HY Radiology 1996; 199(l):280-282). In 2003 the same group tried to improve the stent using nitinol (Ko GY, Radiology 2003; 227(1 ):270- 276). After an initial improvement of epiphora (watery eye) the procedure failed in the long (5 -year trial) term. Different factors cause re-obstruction, such as foreign body reaction and inflammation to the material, mechanical factors, stent design and surface structure, hence regularly the stents have to be taken out (Bertelmann E, Rieck P.Graefes Archive for Clinical and Experimental Ophthalmology 2006; 244(6):677-682.1).

In WO2005/070988 copolymers including polyurethane copolymers such as POSS- modified polyurethane polymer, e.g. oligomeric silsesquioxanes (POSS) and poly (carbonate-urea)ur ethane (PCU) copolymers abbreviated as POSS-PCU copolymers, have been described for use as implantable devices. In particular, 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. However, POSS-PCU copolymers have previously not been suggested or adapted to manufacture small diameter conduits.

One exemplary application of the implantable drainage conduit of a small diameter includes the lacrimal drainage system. As background information its anatomy and physiology are outlined below in some detail, also by referring to Fig. 1. 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). Regarding the production of tears, 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. Once missing or obstructed, 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. However, 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.

There are numerous problems with the currently available treatments: In the 1960s Lester Jones developed a big and rigid glass/acrylic tube (3-4mm in diameter and 14- 18mm length) to by-pass presaccal obstructions. This method is still in use but patients have to accept major surgery and multiple side effects including displacement or loss of the tube, foreign body sensation of the eye and regular need of tube syringing. It does by pass the whole lacrimal system without respecting or sparing the physiological part of it. Vessels were also tried similarly to bypass the system, mostly failed due to obstructions. Balloon dilatation minimizes treatment to the area affected, however can treat only minor incomplete obstructions and can't reconstruct a fully blocked or partially or fully destroyed canaliculus. Stents are subject to fail due to the small diameter of the canaliculi. Finally, in singles cases replacement of the injured inferior canaliculus by the superior canaliculus (same or contrary side)was tried, however, this techniques even destroyed part of the healthy lacrimal system and is ethically doubtful. 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. In particular it is an object of the current invention to provide a small diameter implantable conduit made of a suitable polymer and to provide a new implantation method for repair and replacement drainage systems. In particular 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.

SUMMARY OF THE INVENTION

According to a first aspect of the invention an implantable drainage conduit comprising a conduit wall and a conduit lumen with a diameter d is provided. Accordingly 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.

The term "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. This means that 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. Such 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).

The term "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.

An essential property rendering 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. This means that 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. They therefore support a long time repair or replacement of a damaged or missing physiological drainage system. 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. For example, 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. Furthermore, they exhibit a superb a tear resistance as measured in tear strength tests over 50, 60, 70, 80 or 90 N/mm according to the ISO 34 norm and also as measured as suture strength according to the international standard BS ISO 7198: 1998 section 8.8 (Karla Chaloupka, PhD thesis, 2011, p.172).

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.

Preferably, 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. Preferably 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. Preferably, 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. Typically, when 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. Examples of suitable aliphatic groups A include butylene, 2-methylpentylene, hexylene, octylene and methylene- biscyclohexylene moieties, in particular methylene-biscyclohexylene.

Typically, when 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.

In a preferred embodiment of the invention, the POSS segments in the copolymer are derived from using a compound of the following structure:

wherein R is preferably a phenyl group, a C1-C6 acylic aliphatic group, or a C3- C6cylcoalkyl group, preferably a C1-C6 alkyl group. Typically R is isobutyl.

The POSS segment in the copolymer for use in the invention is preferably chain terminating in the copolymer.

In some embodiments further 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. Thus, in monolayer conduits the wall consists substantially of POSS-modified polyurethanes. In dual layer and multilayer conduits the wall comprises at least two layers. In some embodiments of dual or multilayer conduits one and in other embodiments more than one or even all layers of the conduit consist substantially of POSS-modified polyurethanes. In some embodiments 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. Furthermore, in some embodiments 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.

In some embodiments of the implantable drainage conduit 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.

In other embodiments of the implantable drainage conduit at least the inner luminal layer is designed to exhibit hydrophobic properties as measured by a contact angle of 90° or 100° or more. Such embodiments with 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. In further embodiments 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.

Furthermore, embodiments of 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. Accordingly, 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. For example, in some embodiments 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. Preferably such 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. Furthermore 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.

In some embodiments 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.

In some embodiments according to the first aspect of the invention the implantable drainage conduit has a simple shape of an elongated tube. In some further embodiments drainage conduits are provided with branched tubes or multiply branched drainage conduits. In yet further embodiments 2D or 3D networks of branched drainage conduits thus forming a reticular structure are provided. In such branched and reticular implantable conduits the diameter of the conduit may vary within the branched or reticular drainage conduit system. Similarly the diameter of an unbranched tube does not necessarily exhibit the same luminal diameter over its entire length. In yet further embodiments according to the first aspect of the invention 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.

An enhanced 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.

In some embodiments 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. sodium bicarbonate in different amounts which changes porosity of the implant and changing therefore its flexibility) or the production of the implant (e.g. changing temperature in the coagulation procedure or doubling layers changes rigidity of the implant). Due to the nanocomposites in the material it holds a wide variability of options.

In some embodiments 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.

Applications of the implantable drainage conduits are widespread including the medical fields of surgery, trauma, radiotherapy as well as the treatment of 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. in some embodiments 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.

In another embodiment the implantable drainage conduit of the invention is a glaucoma filtration tube for use in a glaucoma drainage device. In this embodiment 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. Typically 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.

According to a second aspect of the present invention 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. 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.

In some embodiments of the production method POSS-modified polyurethanes are utilized which comprise silver nanoparticles (NS) to confer antimicrobial properties to the conduit. In some embodiments the NS-POSS-modified polyurethanes are produced by dispersing NS with the POSS-modified polyurethanes solution. In some embodiments 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

2. provision of a mandrel with a diameter d as a removable carrier

3. application of the POSS-modified polyurethane to the mandrel forming a coat substantially consisting of the POSS-modified polyurethane

4. letting set the POSS-modified polyurethane coat 5. removal of the mandrel from the POSS-modified polyurethane coat thereby forming a POSS-modified polyurethane conduit with a lumen.

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.

Therefore 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. For the production of diameter conduits using POSS-PCU with a small luminal diameter of less than 1 mm or less than 2 mm or ranging from 0.1 to 0.2 or to 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3 1.5 1.6, 1.8, 2.0, 2.2, 2.5 or 2.8 mm 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. The polymer solution in DMAC (N N'-dimethylacetamide= solvent) coats the mandrel smoothly and curved conduits can be easily achieved due to its optimised viscosity. Hence, a variety of designs can be incorporated by employing different manufacturing techniques. For example, 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. 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).

Advantageously, different structural properties of the POSS-modified polyurethanes conduits are obtained depending on some variability in the method. In particular 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. In some embodiments 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.

According to a fourth aspect 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.

Particularly its high biocompatibility renders it usable as an implant where foreign body reaction is not desired or even fatal for the function. Foreign body reactions cause inflammatory response resulting in hypertrophic cell formation and scar tissue. Small conduits will be blocked by minor scar tissue and loose its function. As 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.

According to a fifth aspect of the invention a method of implanting a drainage conduit is provided 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. In a further optional step 3 the drainage conduit may be adjusted in size. In many embodiments the adjustment in size comprises a reduction in the length of the conduit. However, in other embodiments such as in reticular embodiments of the implantable drainage conduit, the areal size may be adjusted.

And in an optional step 4 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. In some embodiments 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. In some embodiments 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. In some embodiments 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. In other embodiments 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. For example 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. In some embodiments according to method of implanting the drainage conduit in step 2 the placement of the conduit repairs or replaces a part of the drainage pathway by reconstructing the physiological anatomy of the patients drainage pathway. For example a part of or the entire lower lacrimal canaliculus is replaced. In some embodiments of implanting the drainage conduit, it bypasses at least a part of the physiological drainage pathway, for example analogous to the Lester Jones tube in the lacrimal drainage pathway. In further embodiments or the method of implanting the drainage conduit 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. BRIEF DESCRIPTION OF THE FIGURES

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.

Fig. 2. a) An exemplary Lester Jones tube of the state of the art.

b) The placement of the implanted Lester Jones tube ignores all anatomical structures. It bypasses the whole drainage system.

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

a) cast PCU polymer (scan size X,Y, and Z = 96μπι x 96μπι x 2.5μπι b) coagulated POSS-PCU (scan size X,Y, and Z = 24μιη x 24μιη x 1.07μιη)

c) cast POSS-PCU nanocomposite surfaces (scan size X,Y, and Z = 22μπι χ 22μιη χ 4.8μιη). The lighter areas are structures protruding from the surface and the darker features represent the base substrate. The nano-topographic pattern of the surface attributes to the presence of POSS molecules in the structure of the polymer.

Fig. 6. SEM images of small diameter conduits using different extrusion

techniques resulting in variable wall formations

a) ultrasonic atomised

b) EHDA (electrohydrodynamic atomisation) spray ed/spinned c) coagulated

d) autoclaved

e) cast

f) laminated cast-coagulated

Fig. 7. testing of compressibility (magnified): showing

a) the open LDC (dark lumen) placed on a holder (grey) and

b) LDC compressed by a load which is suspended from the white strip folding over the LDC and applying equal pressure over the whole LDC. 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. On the left side 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. Capillarity testing showing

(a) Lester Jones tube with medium hydrophilic character

(b) hydrophilic polymer tube (c) LDC produced by ultrasonic atomisation

(d) coagulated LDC

(e) cast LDC

(f) optimal capillarity shown by a standard capillary glass tube. (g-1) tube with increasing nanosilver concentration

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

Vicryl 6-0 suture indicating stability (circle) and excellent resistance to placement even of repetitive punctures when sutering (arrows) and b) mechanical testing for suture retention

Fig. 11. Suture technique showing the use of Vicryl 7-0 sutures in connecting the

LDC with the sheep lacrimal duct. Picture (a) shows the LDC from outside with sutures in place. Picture (b) shows the opened LDC, no sutures are visible on the inner wall as they are blind stitched. This prevents attraction of macrophages and inflammatory reaction and reduces the risk of obstruction. There is a similar approach in vivo: the ends of a traumatised canaliculus are approached by sutures of the surrounding tissue. Full penetration of the wall should be avoided. This is contrary to the sutures of an artery with an intima, where the whole wall has to be penetrated in order to prevent wall dissection. Fig 12. Anitmicrobial effect of silver nanoparticles mixed with the polymer, showing a MIC zone around polymer disc.

DETAILED DESCRIPTION OF THE INVENTION AND OF PREFERRED EMBODIMENTS

Here exemplary embodiments of implantable drainage conduit according to the first aspect of the invention are characterized in further detail. In particular embodiments wherein the POSS-modified polyurethanes is a POSS-PCU polymer and examples of unbranched conduits in particular of a lacrimal duct conduit (LDC) are presented. However, the invention is not limited to the embodiments described below.

1.1. Assessment and characterisation of POSS-PCU

1.1.1 Surface properties of POSS-PCU: Atomic force microscopy (AFM) analysis of surface topography

Surface topography was visualized by Atomic Force Microscopy (AFM) (Baguet J, et al. Biomaterials 1993; 14(4):279-284) and optical inspection of the LDC, using a small endoscope (retinoscope), was carried out for the presence of inclusions, irregularities and voids (Fig 3). Fourier Transform InfraRed (FTIR) was useful for analyzing whether POSS was on the surface of the polymer.

The 3D AFM images (Fig 5a-c) 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. However, due to excellent biocompatibility of POSS-PCU the inflammatory reaction and therefore scar formation is markedly reduces. (Baguet J et al, 1993; Kannan RY et al. Acc Chem Res 2005; 38(11):879-884; Kannan RY et al., Plastic and Reconstructive Surgery 2007; 119(6): 1653-1662).

Furthermore the porosity and therefore the surface structure can be adjusted using different extrusion techniques and addition of sodium bicarbonate.

1.1.2 FT-IR 4200 (Fourier transform infrared spectroscopy)

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)

1.1.3. Mechanical properties

The stress strain properties of each batch of POSS-PCU were tested before use and suggested that the mechanical properties are within the targeted specification for this product (measured tensile strength at break 55mPa minimum). This batch was therefore used to manufacture tubes by the various techniques. The control PCU without POSS had a lower modulus at higher elongations and much lower ultimate tensile strength. The high tensile strengths achieved by adding POSS to the PCU are important for our application as the LDC are thin walled cast or coagulated tubes and will require a high suture retention strength for surgery.

The coagulated POSS-PCU has stress strain properties that portray a material which is much softer then the cast sheet since the coagulation process produces a foam structure. Although the tensile strength at the breaking point is significantly lower than the cast (p=<0.0001; n=5), the strength is adequate for the intended application. 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 μπι 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).

1.1.4 Suture retention The 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).

1.2. Assessment and characterization of exemplary embodiments of lacrimal duct conduits (LDC)

Several characteristics of the different LDC types were analyzed and compared: LDC wall structure, wall thickness, inner/outer diameters, porosity, surface, contact angle, capillarity, and compressibility and kink resistance. Although capillarity was also measured directly, measurement of the contact angle also gave an insight into the effect of LDC hydrophobicity or hydrophilicity, respectively on its capillary action.

1.2.1. LDC wall structure, porosity, kink resistance and compressibility

Constant inner LDC diameters can be achieved regardless of the extrusion technique. However, the wall thickness and structure differs greatly in relation to the procedure. Particularly, the employment of EDHA (electrohydrodynamic atomisation) spraying technique to form a conduit is less efficient. When spraying onto a turning steel mandrel the constantly changing magnetic field required a continuous adjustment of the variables. In comparison to other techniques, which demanded an active time of a few minutes, 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. In this technique, however, 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.

1.2.2. Capillarity

Previous studies have proven that the conduit hydrophobicity respectively hydrophilicity has an effect on its capillary action. The glass Lester Jones tube (Fig. 8) was optimally hydrophilic; which improved tear drainage, but has the disadvantage of being rigid and easily displaced. POSS-modified polyurethanes are less hydrophilic, yet suitable in this application due to its other desirable properties. A contact angle (Young angle) smaller than 90° is suggestive of a hydrophilic surface while values greater than 90° indicate a hydrophobic surface (Riedel 2001). The equilibrium contact angle of 2% POSS-PCU nanocomposite is 80° in its coagulated form, and 100° in its cast form. Therefore, the contact angle values for POSS-PCU vary depending on the extrusion process. This suggests that the coagulated LDC having more capillarity. This result was confirmed by the uneven level of the coloured ink in the LDC (Fig. 9), which was also attributable to its high porosity.

The hydrophilic polymer tube and the ultrasonic atomised LDC exhibited similar capillarity to the coagulated LDC. However, 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.

1.2.3. Applicability for suturing technique

The ease of handling the LDC regarding suturing was tested with Vicryl 6-0 / 7-0 and Silkam 6-0 sutures. The LDC was connected to sheep canaliculi. Due to the porous but strong wall with a comparable structure to the canaliculus, it was easily possible to blind suture the two materials together without perforating into the lumen as this could cause the formation of scar tissue. Suture retention testing with Vicryl 6-0 revealed an isosceles triangular shaped tear formation on the POSS-PCU sheet (Fig. 10), which is typical of the Vicryl suture even when the strain stress is vertical. This is a consequence of the elastomeric properties of the polymer and its extremely high tear strength. The white portions in the figure (see white circle) are indications of crystallinity induced by extension of the polymer prior to propagation of tear.

In reconstructive surgery 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. Especially the viscoelastic nature and mechanical strength of the coagulated POSS-PCU lends itself to the easy insertion of sutures. In addition, 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.

The overall results suggest that a combined method of production yields embodiments of the drainage conduits which have cumulated advantages, which are particularly useful for some applications. Using cast POSS-PCU for the inner wall allows to prevent formation of scar tissue and better drainage. This layer can be thereafter covered with a coagulated layer allowing to sutures the conduit to the residual lacrimal duct and prevent implant displacement.

However, 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).

1.2.4 Enhanced antimicrobial properties of POSS-PCU by adding silver nanoparticles:

The advantage of silver nanoparticles (nanosilver=NS) in surgical implants as antibacterial and anti-inflammatory agents has been highlighted in reviews (see also Chaloupka K et al, 2010). This quality is also exploited for some embodiments of theiof lacrimal duct conduit (LDC). Different methods of producing silver nanoparticles and adding them to POSS-PU are adequate, including exemplary methods of adding silver nano particles to POSS-PU, in particular POSS-PCU which are described in Example 2.9 together with quality measurements.

Example 2.1: Synthesis of POSS-PCU Nanocomposites

Synthesis of the POSS-PCU nanocomposite has been previously described in detail e.g. in US 7' 820' 769. In brief, as an exemplary method Polycarbonate polyol (2000mwt) and trans-cyclohexanechloroydrinisobutyl-Silsesquioxane (Hybrid Plastics Inc) were placed in a 250ml reaction flask equipped with mechanical stirrer and nitrogen inlet. The mixture was heated to 135°C to dissolve the POSS cage into the polyol and then cooled to 70°C. 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 Ν,Ν-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).

Example 2.2: Viscosity Measurements of POSS-PCU Nanocomposites

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 150μπι. Generally, for the extrusion techniques, 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. For producing conduits size with a diameter of approx. 0.8 mm an optimal viscosity coefficient was 3-6 Pa s, where the polymer exhibits shear thinning, the reduction in viscosity with increasing shear rate. As expected 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.

According to some embodiments the implantable drainage conduit is produced from POSS-modified polyurethanes comprising silver nanoparticles, which are added to confer antimicrobial properties to the polymer. In one exemplary method 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.

Two exemplary methods of production of poly(carbonate-urea)urethane (POSS- PCU) solutions comprising silver nano particles (NS) are described: In the first technique, the NS as prepared above was dispersed with an 18% solution of POSS- PCU in DMAC (1), which is termed below and in K. Chaloupka, PhD Thesis, 2011, p.205 as POSS-PCU with silver nano particles (NS) mixed in. In the second technique, it was attempted to bind the NS more effectively into the polymer, 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).

For the preparation of POSS-PCU with silver nano particles (NS) mixed in POSS- PCU was synthesised by solution polymerisation (as described in chapter 5 of the PhD thesis by K. Chaloupka, 2011). Six different NS dispersions were prepared as described above and were dispersed into 18% solutions of POSS-PCU in DMAC by homogenising for 5 minutes using an Ultra- Turrax T25 at 10000 min-1 resulting in five different concentrations (0.19%, 0.38%, 0.75%, 1.5% and 3.00%) of NS in POSS-PCU. For the preparation of POSS-PCU incorporated silver nano particles (NS) at a concentration of 0.75% NS, Polycarbonate polyol (2000 mwt) and trans- cyclohexanediolisobutyl-Silsesquioxane were placed in a 250 ml reaction flask equipped with mechanical stirrer and nitrogen inlet. The mixture was heated to 135°C to dissolve the POSS cage into the polyol and then cooled to 70°C. Flake 4,4'- Methylenebis(phenyl isocyanate), (MDI), was added to the polyol blend and then reacted, under nitrogen, at 70°C - 80°C for 90 minutes to form a pre-polymer. A dispersion of NS, previously prepared in Dimethylformamide, was added to the prepolymer and maintained at 70°C - 80°C for a further 60 minutes. Dimethylacetamide was added slowly to the pre-polymer and the solution was cooled to 40°C. 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.

In some embodiments of production methods of POSS-modified polyurethanes 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.

In some embodiments 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%. Alternatively or additionally, 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.

In some embodiments of an implantable drainage conduits comprising multiple layers, an inner and an outer layer are comprising different POSS-modified polyurethane. For example, in some embodiments 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. In some of these embodiments 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.

In one exemplary method 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:

Production of the polymer for the inner layer: 64mg silver nitrate, 150mg fumed silica (aerosol 200) and 7.5mg Dimethylformamide (DMF )were mixed and sonicated with three of 5 to 30 sec, e.g. 20 sec bursts to yield nano silver particles which were then added 30g POSS-modified polyurethane, in particular POSS-PCU. Then another one or two bursts of 5 to 30 sec, e.g. 20 sec bursts of ultrasound were applied. Subsequently the mixture was stored rolling over night in the dark.

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.

After letting set and drying the polymer on the mandrel for at least 30 min, the outer layer is added by dipping it into a freshly prepared POSS-modified polyurethane treated with sodium bicarbonate. In one example 58g of 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). Optionally, 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. Then the polymer was applied on the mandrel and the sodium bicarbonate and surfactant were washed out with sterile distilled water. 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.

In all of the examples a conduit with an inner tube diameter of 0.8 mm was targeted. Thus, a 0.8mmx40mm length stainless steel mandrel was used. However, size can be adapted to the needed diameter. The examples listed here were performed with POSS- poly (carbonate-urea)urethane (PCU) PCU copolymers, however, the methods are adaptable to other POSS-modified polyurethanes.

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.

Example 2.5:

According to the first embodiment of the method of production of an implantable drainage conduit 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:

In one example of the first embodiment, 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. Thus coated with a uniform layer of polymer, 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). Example 2.6:

According to the second embodiment of the method of production of an implantable drainage conduit an "Extrusion-Coagulation" method is used. According to this newly developed embodiment the conduit is formed by using high pressure coagulation by autoclaving:

In one particular example of the second embodiment of the production method, the mandrel was dipped in the polymer and pulled out at a speed of 4 mms^"1. The coated mandrel was then placed vertically in a medical autoclave (e.g. a Prestige Medical, 2100 Classic) and subjected to steam pressure for 11 min at 126°C to remove the solvent (DMAC = N N'-dimethylacetamide) or another appropriate time and temperature, which removes the solvent according to the knowledge of a person skilled in the art. 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.

Example 2.7:

According to the third embodiment of the method of production of an implantable drainage conduit a "Casting" method is used. Casting as a method for producing blood vessel conduits has been described before by Sarkar et al, 2009. According to the third embodiment this method is applied to the production of small diameter conduits and furthermore double and triple casting methods are described for the first time:

In one particular example of the third embodiment of the production method, 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.

In particular three different types of cast tubes were investigated for coating efficiency and elasticity: single, double and triple layered casting. The time interval between dip coatings for the double cast was 60min and the triple cast was 30 min, both at 60°C. Each was kept at 60°C for 120 min and then allowed to cool down at room temperature for another 120min. Removal of the formed tube from the mandrel was carried out shortly after washing it in distilled water. The conduit was gently loosened from the rod along its whole length with small circular and longitudinal stresses, after which the whole tube easily slid off without excessive strain (Sarkar et al 2009). The skilled person may wish to vary time (e.g. 30min-24h) and temperature (e.g. 30-70°C) conditions between successive coatings within reasonable values. Example 2.8:

According to the fourth embodiment of the method of production of an implantable drainage conduit 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. Depending on the application method used by varying the embodiment of 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

Example 2.9:

According to the fifth embodiment of the method of production of a implantable drainage conduit 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.) In one particular example of this fifth embodiment of the production method, 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. In order to reduce the risk of blockage and improve the setting of the polymer on the mandrel, 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 evaporates at room temperature and enables a more even wall formation, comparable to a cast conduit, and prevents POSS dripping off the mandrel before solidification. 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.

Example 2.10:

According to the sixth embodiment of the method of production of the implantable drainage conduit electrohydrodynamic atomisation (EHDA) spraying and spinning is used which is also a known technique, that is new the current application.

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 μπι. 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 μΐ/hour. Computer software (CompuC AM and Motion Planner) were used for controlling the process. 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.

According to the fifth aspect of the invention a drainage conduit is implanted. In exemplary embodiments according to the fifth aspect of the invention in step 2 eg. 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.

In exemplary applications within lacrimal drainage system e.g. in step 1 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. In further embodiments, in order to reduce trauma of implantation, endoscopy (keyhole surgery) may be applied. To help and visualize the correct placement of the implant in a visually not directly accessible area, 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.

In further embodiments of the method of implantation post-operational application of 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.

Further, 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. In some embodiments of methods of implanted drainage conduits into the eye, cell culture medium is applied in form of eye drops into the eye and into lacrimal drainage area, respectively.

In some embodiments 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.

Claims

WHAT IS CLAIMED IS:

1. Implantable drainage conduit with a wall surrounding a lumen with a diameter d characterized in that the wall comprises at least one layer which substantially consists of a POSS-modified polyurethane.

2. Implantable drainage conduit according to claims 1 wherein a conduit wall comprises two or multiple layers.

3. Implantable drainage conduit according to claims 1 or 2 characterized in that it has a lumen with a diameter d of less than 3.5 mm.

4. Implantable drainage conduit according to anyone of claims 1 to 3 wherein the conduit comprises branches, multiple branches or wherein it forms a 2D or a 3D reticular drainage conduit system.

5. Implantable drainage conduit according to anyone of claims 1 to 4 characterized in that a luminal layer of the conduit exhibits hydrophilic properties as measured by a contact angel of 90° or 80° or less.

6. Implantable drainage conduit according to anyone of claims 1 to 5 wherein the POSS-modified polyurethane comprises silver nanoparticles.

7. An implantable drainage conduit according to any one of claims 1 to 6 which is a lacrimal duct conduit, a biliar duct conduit, a lymph duct conduit, a blood capillary bed conduit or a glaucoma filtration tube conduit.

Method of producing an implantable drainage conduit from a POSS-modified polyurethane comprising at least the following steps:

provision of a POSS-modified polyurethane provision of a mandrel with a diameter d as a removable carrier application of the POSS-modified polyurethane to the mandrel forming a coat substantially consisting of the POSS-modified polyurethane letting set the POSS-modified polyurethane coat removal of the mandrel from the POSS-modified polyurethane coat thereby forming a POSS-modified polyurethane conduit with a lumen.

Method according to claim 8 wherin in step 1 a POSS-PCU polymer provided.

Method according to claim 8 or 9 wherein in step 2 the mandrel is made of stainless steel and /or has a diameter in a range between 0.1 mm and 4 mm, particular in a range between 0.3 and 0.8 mm.

Method according to anyone of claims 8 to 10 wherein between steps 3 and step 4 an additional coagulation step is performed. Method according to anyone of claims 8 to 11 wherein steps 3 and 4 and optionally one or more additional coagulation step are repeated to form implantable drainage conduits with a wall comprising more than layer of polymer.

Method according to anyone of claims 8 to 12, wherein in step 3 the POSS- modified polyurethanes are applied by at least one of a coagulation method, ί casting method or a combination of the coagulation and the casting method.

Method according to anyone of claims 8 to 13 wherein in step 1 a POSS- modified polyurethane is provided comprising nano silver particles and /or which POSS- modified polyurethane was treated with sodium bicarbonate.

15. Implantable drainage conduit obtainable by the method of anyone of claims 8 to 14.

Use of POSS-modified polyurethane drainage conduits according to anyone of claims 1 to 7 or 15 for implantation in a human or non-human animal.

POSS-modified polyurethane for use as in implantable conduits in repair of or for replacement of a drainage pathway, in particular of one or more parts of a lacrimal or a biliar or a lymph drainage system or of a capillary bed or for use as a glaucoma filtration tube conduit.

18. POSS-modified polyurethanes for use in any one of the methods according to claims 19 to 28.

Method of implanting a drainage conduit according to any of claims 1 to 7 or 15 comprising at least the steps of

- providing a drainage conduit and

- placing the drainage conduit into a human or animal patient as a part of a drainage pathway.

- and optionally adjust the size of the drainage conduit, in particular the length of the conduit

- and optionally fixing the drainage conduit to at least one part of a anatomical structure of the patient, wherein in particular this structure is part of the drainage pathway.

Method of implanting a drainage conduit according to claim 19 wherein the drainage conduits replaces or repairs at least part of a drainage pathway, in particular of a lacrimal drainage system, in particular a lacrimal canaliculus, of a biliar drainage system, in particular a biliar canaliculus, of a lymphoid drainage system or of a blood capillary bed, or wherein the drainage conduit is a glaucoma filtration tube conduit.

Method of implanting a lacrimal canicular drainage conduit comprising at least the steps of

- providing a drainage conduit and

- placing the drainage conduit into a human or animal patient as a part of a drainage pathway.

- and optionally adjust the size of the drainage conduit, in particular the length of the conduit - and optionally fixing the drainage conduit to at least one part of a anatomical structure of the patient, wherein in particular this structure is part of the drainage pathway.

Method of implanting a drainage conduit according to anyone of claims 19 to 21 wherein in step 2 the placement of the conduit repairs or replaces a part of the drainage pathway by reconstructing the physiological anatomy of the patients drainage pathway.

Method of implanting a drainage conduit according to anyone of claims 19 to 21, wherein the conduit bypasses at least a part of the physiological drainage pathway.

Method of implanting a drainage conduit according to anyone of claims 19 to 23, wherein the conduit is introduced at least into the lumen of a part of the drainage pathway as a stent.

Method of implanting a drainage conduit according to anyone of claims 19 to 24 wherein in step 1 the drainage conduit is placed as part of the lacrimal drainage system

26. Method of implanting a drainage conduit according to anyone of claims 19 to 25, wherein in step 1 the drainage conduit is a lacrimal duct conduit. Method of implanting a drainage conduit according to anyone of claims 19 to 26, wherein in step 4 the lacrimal duct conduit is fixed at its distal end to a canalicular duct and optionally also at its proximal end.

Method of implanting a drainage conduit according to anyone of claims 19 to 27, wherein for a correct placement additional instruments are provided such as radiological instruments using imaging with or without contract medium, or wherein endoscopic procedures using a light source and endocopic trochars and instruments are provided.