WO2005070998A1 - Polymer for use in conduits and medical devices - Google Patents

Abstract

A copolymer comprising (a) one or more polysiloxane-containing segments and (b) one or more polyol segments, each of said segments being linked to one or more further segments, which may be the saure or different, via urea or urethane linkages, wherein said polysiloxane-containing segment(s) are in the backbone of the copolymer. The copolymer is useful in the production of implantable devices such as vascular grafts.

Description

POLYMER FOR USE IN CONDUITS AND MEDICAL DEVICES

FIELD OF THE INVENTION

The present invention relates to siloxane-containing polyurethane copolymers and a process for their production. The copolymers are useful as implantable devices, in particular in medical applications, including coronary and vascular applications.

BACKGROUND OF THE INVENTION

Atherosclerotic vascular disease in the form of coronary artery and peripheral vascular disease is the largest cause of mortality in both the United States and Europe. Surgical mainstays of therapy for affected vessels include bypass grafting with autologous veins or arteries; however, adequate autologous vein is lacking in many patients. Prosthetic vascular grafts are therefore required.

Several materials are presently available for use as prosthetic vascular grafts and other surgical prostheses. These include polytetrafluoroethylene (PTFE) and Dacron. These two materials are rigid and when used as grafts create a compliance mismatch at the anastomosis. The primary patency rates of PTFE or Dacron grafts is 20 to 30% at 4 to 5 years. A further material which can be used as a vascular graft is polyurethane (PU). This material has the advantage that it is more elastic and therefore more similar to the blood vessel which it is to mimic. PU grafts are thus compliant grafts in the sense that they behave in a similar way to a natural blood vessel in the body. In particular, they flex more readily than PTFE or Dacron grafts when the site at which they are contained flexes.

Compliance is regarded by many as the key attribute required for matching cardiovascular prostheses to the arterial tree. The development of a compliant material is therefore thought to be an important step towards the improvement of clinical performance of small diameter grafts, particularly in low flow situations such as below knee arterial bypass. Obtaining long term compliance has been an elusive goal as currently used grafts rely on an overall external dilation to provide compliance. However, perivascular ingrowth prevents external dilation and thus compliance is lost after a relatively short period of time.

PU based grafts however achieve compliance via a different mechanism. Increases in volume are accommodated by a mechanism of wall compression without the need for external dilation. The use of compliant PU rather than a more rigid material has previously been found to increase the patency rate of the graft (Seifalian et al, Tissue Engineering of Vascular Prosthetic Grafts, 1999 R.G.Landes).

However, the use of any of these materials alone for the graft is problematic: as the blood flows through the graft, particles such as platelets tend to adhere to the surface of the graft or the blood may coagulate, in particular in the area of the anastomoses, in particular the distal anastomosis, but also along the luminal surface of the graft. This causes a narrowing (stenosis) in the inner diameter of the vessel, which is particularly problematic in the context of grafts of low diameter (for example 5mm or less) where there is little blood flow. The major area which is affected is the distal anastomosis, where the downstream end of the graft meets the blood vessel. This has mainly been attributed to the lack of coverage by endothelial cells, the natural lining of normal blood vessels. The endothelium has the potential to release anticoagulant and platelet active substances which facilitate normal blood flow.

In order to address this problem, seeding grafts with endothelial cells, both before and during surgery, has been attempted. Broadly, seeding is carried out by extracting endothelial cells from the patient's adipose tissue or a vein and using these cells to coat the inside of the graft, in order to mimic the natural endothelium. Although seeding the graft in this manner has been shown to increase the patency rate, seeded cells adhere very poorly to the graft surface, in particular to PTFE. Indeed, where cells are seeded directly onto the graft lumen, only 1 to 14% of cells remain attached following exposure to blood flow.

Of crucial importance therefore in endothelial seeding is the ability of the seeded cells to resist the shear stress caused by the flow of blood through the vessel. The pulsatile nature of the blood flow makes it particularly likely that the cells will be swept away if not firmly attached to the surface of the graft. Where endothelial seeding is more difficult, e.g. with PTFE, the effect of shear stress is vital, although it is very important when using any graft material.

Numerous techniques have been developed to aid attachment of endothelial cells to the polymer surface. For example, fibronectin glue enriched with RGD (Arg-Gly Asp) has been used to increase adherence of endothelial cells. Various alternative bonding chemistries have also be attempted to attach to the surface of the polymer moieties such as RGD and heparin that aid endothelium formation, as well as other anticoagulants. However, recent in vitro studies have shown that these bonding chemistries lead to alterations in the mechanical properties of the polymer. In vivo studies have also shown that the presence of the anticoagulants on the polymer surface can lead to alterations in the chemical behaviour of the polymer, resulting in aneurismal failure.

For surgical use, the acceptable scope for variation in the physical and chemical properties of the graft is small. The change brought about by bonding anticoagulants and other materials to the surface of the polymer may be sufficient to cause failure of the graft in vivo. A new approach is therefore required, by which biocompatibility of the polymer is improved without the need for such bonding steps.

A further problem associated with PUs is the possibility of degradation in vivo over long periods of time. Clinically, polyurethanes used for permanent implants have a very mixed record due to the variety of degradation mechanisms that come into play, especially in the case of their usage for vascular grafts for lower limb bypass. In such lower limb bypass grafts, the site of degradation has invariably been the amorphous or soft segment, typically an ester, ether or carbonate.

The resistance of hydrolysable polymer structures to hydrolysis can be improved by incorporation of hydrocarbons such as silicones, sulfones, halocarbons and/or isolated carbonyl-containing molecules (ketones) in the polymer structure. Recent work has produced a number of polyurethanes in which siloxane blocks have been incorporated into polyurethanes. However, these structures have been found to have poor mechanical properties, possibly due to the presence of crystalline areas in the polymer. The poor resistance of these types of polymer to tear, and their tendency to discolour, have been noted as particular problems.

Previously known siloxane polymers also have inferior biological properties, noted by their reduced ability to support the growth of endothelial cells used in seeding bypass grafts. An alternative polymer is therefore required which addresses these difficulties by providing improved mechanical properties, notably increased stiffness and lack of discolouration, as well as improved biological properties, including compatibility to blood and the ability to support endothelial cell growth.

SUMMARY OF THE INVENTION

The present inventors have developed a new siloxane-containing polymer which addresses the problems of the prior art and has improved mechanical and biological properties. The present invention therefore provides a copolymer comprising (a) one or more polysiloxane-containing segments and (b) one or more polyol segments, each of said segments being linked to one or more further segments, which may be the same or different, via urea or urethane linkages, wherein said polysiloxane- containing segment(s) are in the backbone of the copolymer.

The present inventors have determined that previous polysiloxane-containing copolymers in fact consist of a mixture of two polymers, one polyol polyurethane and one polysiloxane polyurethane. These polymers are made by polymerising a mixture of polysiloxane, polyol, and diisocyanate. However, the materials in this mixture remain phase separated during polymerisation so that two distinct phases, one polysiloxane phase and one polyol phase, exist. The presence of two phases is evidenced by a non-transparent immiscible layer. The mixture thus consists of one "mother of pearl" layer and one cloudy layer. The presence of two phases in the polymerisation mixture is thought, by the present inventors, to prevent the production of a single polymer containing polysiloxane in the backbone. Instead, the polymers produced comprise two distinct polymers, one formed in the polysiloxane phase and one formed in the polyol phase. These previously described siloxane-containing polymers are therefore a blend of two separate polymers.

In the present invention, the inventors used suitably adapted polymerisation techniques to develop a novel series of copolymers in which the polysiloxane is incorporated into the backbone of the polyol polyurethane. This new series of copolymers differs from the prior art in that a single polysiloxane/polyol copolymer is present, rather than a mixture of two distinct polymers.

The copolymers of the invention show good mechanical and biological properties. The linear nature of the copolymers means that the beneficial mechanical properties of polyol polyurethanes are substantially retained. Thus, the copolymers of the invention are believed to have good tear resistance and stiffness.

In terms of biological properties, the copolymers are highly compatible with blood and also have an improved ability to allow cells to grow on the polymer surface. The presence of both hydrophobic polysiloxane and polyol in the same polymer is significant in this regard. The presence of siloxane groups on the surface of the polymer reduces biodegradation since the polysiloxane is generally less prone to biodegradation than the polyol segments. However, the presence of polyol segments ensures that cell growth on the polymer surface is not inhibited.

The copolymers of the invention are therefore useful for the production of implantable devices such as vascular grafts, dialysis shunts and heart valves. The polymers are highly biostable and show good stiffness and mechanical strength. Further, the copolymers can be directly seeded with endothelial cells without the need for separate attachment moieties. This therefore avoids the need for separate attachment steps which have the potential to alter the mechanical properties of the copolymer.

A further advantage of the copolymers of the invention is their high transparency and lack of discolouration over time. The copolymers are therefore useful in areas where visual properties are important, for example as ocular implants and contact lenses, or in non-biological applications such as transparent screens or coverings.

Particularly preferred copolymers of the invention have a small proportion of siloxane groups compared with the number of polyol groups. For example, the ratio of polysiloxane-containing segments: polyol segments is typically less than 1:10, preferably less than 1:25. An excess of polysiloxane groups leads to a polymer which is highly compatible with blood, but the ability of cells to grow on the copolymer surface may be reduced. In contrast, copolymers containing a small proportion of polysiloxane groups still have a significant presence of polysiloxane on the surface leading to good blood compatibility, but the siloxane group presence is not detrimental to the growth of cells on the copolymer surface.

In a preferred embodiment of the invention, the polysiloxane is a bridged polysiloxane. These polysiloxanes typically have a low molecular weight. Use of these polysiloxanes provides polymers having improved biocompatibility due to the presence of the siloxane groups, but yet having mechanical properties which are virtually as good as those of a polyurethane polymer. Thus, these polymers provide a combination of high strength, tear resistance and biocompatibility.

The present invention also provides a process for producing the copolymers of the invention, the process comprising polymerising

(i) a polysiloxane having at least one substituent selected from primary amine, hydroxyl and carboxylic acid groups;

(ii) a polyol; (iii) an aromatic compound having two or more isocyanate groups; and optionally

(iv) one or more chain extenders selected from amino acids, peptides, polypeptides and C!-C₆ aliphatic groups, each of which has at least one substituent selected from primary amine, hydroxyl and carboxylic acid groups, said process comprising combining, in any order, components (i) to (iii) and optionally (iv) to form a polymerisation mixture, wherein components (i) and (ii), or prepolymers thereof, are present in a single phase of the polymerisation mixture.

Effecting the polymerisation with components (i) and (ii), or prepolymers thereof, in a single phase ensures that the resulting copolymer contains both polyol segments and polysiloxane-containing segments in the backbone of the polymer.

In a preferred embodiment of the invention, the process comprises polymerising component (iii) with one of components (i) and (ii), subsequently adding the other of components (i) and (ii). The process of the invention is in this embodiment effected in a two-step, or optionally three-step, procedure in which a pre-polymer of either the polysiloxane or the polyol is first produced before polymerising with further components. The initial pre-polymerisation step helps to enhance the homogeneity of the polymerisation mixture and thereby to inhibit phase separation. The use of this improved process therefore helps to ensure that both polyol and polysiloxane are present in the backbone of the same polymer chain and thereby provides polymers having enhanced mechanical properties.

In a particularly preferred embodiment, the pre-polymerisation is carried out by combining the polyol with the isocyanate component and subsequently adding the polysiloxane. This embodiment provides significantly improved compatibility within the polymerisation mixture and further inhibits phase separation. Polymers produced by this process thus have particularly good mechanical properties. The invention also provides a process for lining the copolymers of the invention, the process comprising seeding endothelial cells onto the surface of a copolymer of the invention. Also provided are lined polymers obtained or obtainable by this process.

The invention also provides moulded articles, in particular implantable devices, typically for use in the replacement of a body part, comprising the copolymers or lined copolymers of the invention. An implantable device is a device suitable for implanting into, or surgically attaching to, a human or animal body. An implantable device is typically a prosthesis.

Finally, the invention provides a method of treating a human or animal patient in need of the replacement of a body part, said method comprising replacing said body part with an implantable device of the invention.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 depicts an ED AX spectrum carried out on a copolymer of the invention (Label A: 189-03 Polymer P3 G477-Q block 5). The lowest peak at approximately 2.0 represents CK; the second peak at approximately 2.9 represents SiK; and the third peak at approximately 8.0 represents CuK.

Figure 2 depicts Alamar blue™ readings for copolymers of the invention. The y-axis represents Abs (570nm-630nm); the x-axis represents the number of days post- seeding. The lowest line indicated by a solid line, and inverted triangles at each point, shows the unseeded polymer; the next line indicated by a line formed of dots and dashes, with squares at each point, shows the performance of the blank; the third line indicated by a dashed line, with diamond-shapes at each point, shows the seeded polymer; and the highest line indicated by a dotted line, with triangles at each point, shows the positive control. DETAILED DESCRIPTION OF THE INVENTION

The copolymers of the invention contain one or more polysiloxane-containing segment(s) in the backbone of the copolymer. Thus, the polysiloxane-containing segment is a part of the main chain of atoms in the copolymer. The term "in the backbone" does not encompass the situation in which the polysiloxane-containing segment is present on a side chain, nor does this term encompass the situation in which the polysiloxane-containing segment is simply blended with the polyol polyurethane. The term "in the backbone of the copolymer" includes the situation in which the polysiloxane-containing segment is at the end of the copolymer chain (a chain terminating group).

Typically, a polysiloxane-containing segment is bound to neighbouring segments at one or more, preferably both, ends of the polysiloxane-containing segment. Thus, the polysiloxane is incorporated into the copolymer in a linear fashion.

The polysiloxane-containing segment(s) typically comprise repeating units of the formula

wherein each R is the same or different and represents an aliphatic or aromatic group. Typically, each R is the same or different and represents an alkyl, alkenyl, alkynyl, cycloalkyl or aryl group. Preferably, each R represents an alkyl group or phenyl group, in particular an alkyl group.

Preferred alkyl groups are Cι-C₆, for example C₁-C₄, alkyl groups which may be straight or branched. Examples of suitable alkyl groups are methyl, ethyl, n-propyl, i-propyl, n-butyl and t-butyl, in particular methyl and ethyl, preferably methyl. Preferred alkenyl groups are C₂-C₆, for example C₂-C , alkenyl groups which may be straight or branched. Examples of suitable alkenyl groups are ethenyl, n-propenyl, i- propenyl and n-butenyl, in particular ethenyl and n-propenyl.

Preferred alkynyl groups are C2-C₆, for example C2-C , alkynyl groups which may be straight or branched. Examples of suitable alkynyl groups are ethynyl, propynyl and n-butynyl, in particular ethynyl and propynyl.

Preferred cycloalkyl groups are C₃-C₁₀ cycloalkyl groups including single ring and fused ring systems. Examples of suitable cycloalkyl groups are C₃-C₆ cycloalkyl groups, in particular cyclohexyl and cyclopentyl.

Preferred aryl groups are C6-C₁₀ aryl groups including single ring and fused ring systems. Examples of suitable aryl groups are phenyl and naphthyl.

The groups R may be unsubstituted or substituted with one or more, for example 1, 2 or 3 substituents. Examples of suitable substituents include halogen atoms, Cj_.-C₄ alkyl, Cι_.-C₄ alkoxy and Cι.-C₄ alkylthio groups and groups of formula -NR^² wherein R and R are the same or different and are selected from -C₄ alkyl groups. Preferred substituents include methyl, ethyl, methoxy, methylthio and dimethylamino groups. Preferably R is unsubstituted.

In an alternative embodiment, the polysiloxane-containing segments comprise bridged siloxanes having optionally repeating units of the formula

R ,ι¹ R ,1¹ I I -Si— Bridge— Si— O- I R R wherein each R¹ is the same or different and represents an aliphatic or aromatic group. Typically, R¹ is as defined for R above or is an alkoxy group. Preferably R¹ is a C_1-8, for example C_1-4 alkoxy group.

Each Bridge group is the same or different and represents an arylene, alkylene, alkenylene, alkynylene, cycloalkylene, alkyl-arylene, aryl-alkylene, alkyl-aryl- alkylene, alkyl-cyloalkylene, cycloalkyl-alkylene or alkyl-cycloalkyl-alkylene group. Typically, Bridge represents an arylene, alkylene, cycloalkylene, alkyl-arylene, aryl- alkylene, alkyl-aryl-alkylene, alkyl-cyloalkylene, cycloalkyl-alkylene or alkyl- cycloalkyl-alkylene group.

Examples of arylene groups incude phenyl and naphthyl groups as well as heteroaryl groups. An example of a heteroaryl group is pyridyl. Phenyl is a preferred arylene group.

Examples of alkylene groups include Cj.-C₈, for example Ci-Cβ, alkylene groups which may be straight or branched. Examples of suitable alkylene groups are methylene, ethylene, n-propylene, i-propylene, n-butylene and t-butylene, in particular methylene and ethylene, preferably methylene.

Examples of alkenylene groups are C₂-C₈, for example C₂-C₆, alkenylene groups which may be straight or branched. Examples of suitable alkenylene groups are ethenylene, n-propenylene, i-propenylene and n-butenylene, in particular ethenylene and n-propenylene.

Examples of alkynylene groups are C2-C₈, for example C2-C₆, alkynylene groups which may be straight or branched. Examples of suitable alkynylene groups are ethynylene, propynylene and n-butynylene, in particular ethynylene and propynylene. Examples of cycloalkylene groups are C₃-C₁₀ cycloalkylene groups including single ring and fused ring systems. Examples of suitable cycloalkylene groups are C₃-C₆ cycloalkylene groups, in particular cyclohexylene and cyclopentylene.

The groups Bridge may be unsubstituted or substituted with one or more for example 1, 2 or 3 substituents. Examples of suitable substituents include halogen atoms, Ci_.- C₄ alkyl, -C₄ alkoxy and C₁-C4 alkylthio groups and groups of formula -NR^² wherein R¹ and R² are the same or different and are selected from C₁-C₄ alkyl groups. Preferred substituents include methyl, ethyl, methoxy, methylthio and dimethylamino groups. Preferably Bridge is unsubstituted.

Further, the groups Bridge may include one or more heteroatoms selected from N, O and S within the carbon chain. Typically, the groups Bridge contain 0, 1, 2 or 3 heteroatoms, preferably one heteroatom. N and O are preferred heteroatoms.

Bridge may optionally contain one or more functional groups within the carbon chain, the functional groups being selected from -NR³CO-, -CONR³-, -NR³CONR³-, -CO-, -OCO-, COO-, -OCOO-, -CN- and -NC-, wherein each R³ is the same or different and is selected from hydrogen and C_M alkyl, preferably hydrogen. Preferred functional groups are -NR³CO-, -CONR³-, -NR³CONR³-, -CN- and -NC-.

Preferred groups Bridge are alkylene groups optionally containing 1, 2 or 3 -NH- and/or -O- groups, alkylene groups optionally containing one functional group as defined above, C_M alkyl-aryl-Cι-4 alkylene and C_1-4 alkyl- C₃.₁₀ cycloalkyl- C_1-4 alkylene groups, each of which may optionally contain 1, 2 or 3 -NH- and/or -O- groups in the alkyl chain.

Preferred polysiloxane-containing segments have a molecular weight of up to 5000, preferably up to 2000, more preferably up to 1000. The present inventors have found that by reducing the molecular weight of the polysiloxane-containing segment, the ability of cells to adhere to the polymer surface is improved. This improvement is achieved whilst still retaining good compatibility with blood. Further, the lower molecular weight polysiloxanes are more easily incorporated into the backbone of the copolymer.

The polysiloxane-containing segment is typically a polysiloxane polymer having repeating units of the formula -S-R2O- or a bridged polysiloxane polymer having optionally repeating units of the formula -SiR^-Bridge-SiR^O- as described above. Alternatively, however, the polysiloxane-containing segment may comprise such a polysiloxane polymer bound to one or more further groups. Any such further groups should typically be biostable and therefore suitable for inclusion in a polymer to be used as an implantable device. Examples of further groups are polypeptides including anticoagulants, in particular RGD (Arg-Gly-Asp). The polypeptides used as further groups are typically as defined below for the polypeptides of the chain extender segments.

Where more than one polysiloxane-containing segment is present in a copolymer of the invention, each polysiloxane-containing segment is the same or different. The copolymer may, for example, contain a mixture of polysiloxanes having repeating units of formula -SiR₂O- and bridged polysiloxanes. The polysiloxane-containing segments having repeating units of formula -Si ϊO- typically each contain the same groups R. The bridged polysiloxane-containing segments typically each contain the same groups R¹. However, the lengths of each of the polysiloxane chains present in the copolymer are typically different from one another.

The copolymers of the invention comprise one or more polyol segments. Preferred polyol segments are polycarbonate, polyether, polyester or polybutadiene polyols. Polycarbonate segments are preferred for medical applications since they have a higher biocompatibility due to their decreased rate of degradation in vivo. Polyethers are particularly useful for non-medical applications. Suitable polyol segments are those known in the art for the production of non-siloxane containing polyurethanes for use as implantable devices, or other devices.

Each polyol segment typically has a molecular weight of from 1000 to 3000 Daltons, preferably from 1500 to 2500 Daltons. Molecular weights in the region of 2000 Daltons are preferred where the copolymer is to be used as an implantable device, although alternative molecular weights can be envisaged where the copolymer is to have a different end use.

Where more than one polyol segment is present in a copolymer of the invention, each such segment is the same or different. Typically, each polyol segment comprises only one type of polymer. Thus, the polymer typically comprises, for example only polycarbonate, or only polyether, segments. The lengths of each of the polyol segments present in a copolymer of the invention are typically different from one another.

Typically, the copolymers of the invention contain more polyol segments than polysiloxane-containing segments. Thus, the ratio of polysiloxane-containing segmen poryol segment is less than 1:1. Preferred copolymers have a ratio of polysiloxane-containing segmen polyol segment of 1:10 or less, more preferably 1 :25 or less, in particular a ratio of 1 :50 or less.

Each segment of the copolymer of the invention is linked to one or more neighbouring segments by urea or urethane linkages, which typically have the formula

wherein each X is the same or different and is a nitrogen or oxygen atom and each A is the same or different and is an aromatic or aliphatic moiety. Each N is bound to one further group in addition to the depicted -A- and -COX- groups. This further group is typically a hydrogen atom. Preferably, two or more different groups A are present. The group A is typically derived from a diisocyanate compound. Thus, preferred groups A are those which form readily available diisocyanate compounds when the groups -NC(O)-X- in the above formula are each replaced with an isocyanate group.

Typically, when A is an aliphatic moiety it is an unsubstituted, straight or branched Ci-Cι.₂, preferably C3-C₈, alkylene moiety, a C₃-C₈ cycloalkylene moiety or a group of formula -(C₃-C₈ cycloalkyl)-(Cι-C2 alkylene)-(C3-C₈ cycloalkyl)-. Preferred C₃- C₈ cycloalkyl moieties include cyclohexylene and cyclopentylene. Preferred groups of formula -(C₃-C₈ cycloalkyl)-(C₁-C2 alkylene)-(C3-C₈ cycloalkyl)- 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, -C₄ alkyl, C1_.-C₄ alkoxy and Ci- C alkylthio groups and groups of formula - R^² wherein R¹ and R² are the same or different and are selected from hydrogen atoms and Cι.-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(O)-X- either via the aromatic ring or via a substituent.

Preferably, when A is an aromatic moiety it is a phenylene, methylphenylene, dimethylphenylene, naphthylene, methylene-bisphenylene, l,3-bis-(l- methylethyl)benzene or dimethoxybenzidinyl moiety, in particular a methylphenylene, l,3-bis-(l-methylethyl)benzene or methylene-bisphenylene moiety.

Preferably A is an aromatic moiety, since the resulting copolymer is typically more resistant to oxidation and thus biodegradation than a copolymer containing aliphatic moieties at the corresponding positions. A particularly preferred group A is methylene-bisphenylene.

The urea or urethane groups may be attached to A in any desired orientation. For example, when A is a methylene bisphenylene group, the urea and urethane groups may be attached in a 2,4 or 4,4 orientation, or a mixture of these orientations.

The copolymers of the invention typically comprise one or more chain extender segments (c), each of said chain extender segments being linked to one or more further segments, which may be the same or different, via urethane or urea linkages, as described above. Thus, the chain extender segment(s) may be present either within the copolymer structure or at the end of the copolymer chain, depending on whether the chain extender segment in question is linked to either one or two further segments.

The chain extender segment(s) may be any commonly known chain extender used in the production of polyurethane groups. Thus, for example, the chain extenders may be simple alkylene groups such as ethylene groups. However, more complex chain extenders may also be used such as amino acids, peptides and polypeptides. The preferred chain extenders for use in the present invention are amino acids, peptides, polypeptides and C1.-C6 aliphatic moieties.

The use of amino acids, peptides and polypeptides, in particular polypeptides, as chain extender segments enables functionality to be introduced into the copolymer chain. For example, the polypeptide may be RGD (Arg-Gly-Asp), a polypeptide that enhances non-thrombogenicity. Introducing such a polypeptide into the copolymer chain provides a final polyurethane having inherently increased biocompatibility. This therefore removes the need to attach groups such as RGD to the polymer after its formation. Thus, a non-thrombogenic polymer can be produced without altering the mechanical properties of the copolymer.

Polypeptides that can be introduced into the copolymers of the invention in this way include anticoagulant peptides, growth peptides or chemotactic peptides, especially heparin and/or RGD (Arg-Gly-Asp). Examples of anticoagulant peptides which can be used include any blood compatible anticoagulant peptide known in the art. Examples of suitable anticoagulant peptides include RGD, lysine and multipeptides of lysine, for example polpypeptides containing up to 10, for example 3 lysine units. The KRAD-7 peptide (containing 7 KRAD units) can also be used.

The presence of anticoagulant peptides such as those mentioned above in the copolymers of the invention has the advantage that, when a prosthesis formed from such a polymer is inserted into a patient, the anticoagulant effect is immediate. This is in contrast with the lining of the polymer with seed cells, since it takes some time for a full endothelial layer to form from the relatively few endothelial cells that adhere to the polymer surface during seeding.

Examples of suitable growth peptides for use as chain extender segments include any peptides known in the art to encourage the growth of the endothelial layer. Typical growth peptides are Arg-Gly-Asp, fibronectin fragments 1371-1382 and 1377-1388, for example as described by Mohri,H et al (Peptides.1995, 16: page 263; the contents of which are incorporated herein), fibronectin adhesion promoting peptide, for example as described by Woods, A., et. al. (Mol. Biol. Cell, 1993; 4: page 605; the contents of which are incorporated herein), Gly- Arg-Gly-Asp, for example as described by Haverstick, DM. et. al. (Blood; 1985; 66: page 946; the contents of which are incorporated herein).

Examples of suitable chemotactic peptides are those which attract endothelial cells to the surface to which they are attached, in the case of vascular grafts, the lumen of the graft. N-Formyl peptides are suitable for these purposes as they secrete chemoattractants which direct the migration of cells to the chemoattractant source.

Fibronectin fragments and related peptides can also be used. These proteins promote adhesion of endothelial cells to the graft lumen and also to other cells. They also help to stabilise clot formation. Further details regarding chemotactic proteins can be found in Freer R. J., et al, 1979; Peptides, structure and biological function;

Proceedings of the sixth American peptide symposium; Gross,E and Meienhofer, M., eds.:749 and Procter, R,A; Rev. Infect. Dis. 1987; 9: page 317. The contents of each of these documents is incorporated herein.

NO releasing agents may also be incorporated into the polymer, for example as cross-linking segments (Zhang H et al, Biomaterials 2002 Mar; 23(6): 1485-94, incorporated herein by reference). Examples of NO releasing agents include the group of non-linear optic materials disperse red, disperse yellow and disperse orange. Particular examples are disperse red 1 and 19, disperse yellow 3 and 7 and disperse orange 13.

The copolymer of the invention may comprise one or more different types of chain extender segment. For example, the copolymer may contain one or more chain extenders which are Cι-C₆ aliphatic moieties, preferably ethylene, and one or more chain extender segment(s) which are amino acids, peptides or polypeptides, preferably polypeptides, such as those described above.

The copolymers of the invention typically comprise units derived from

(i) a polysiloxane having at least one substituent selected from primary amine, hydroxyl and carboxylic acid groups;

(ii) a polyol;

(iii) an aromatic or aliphatic compound having two or more isocyanate groups; and optionally

(iv) one or more chain extenders selected from amino acids, peptides, polypeptides and

aliphatic groups, each of which has at least one substituent selected from primary amine, hydroxyl and carboxylic acid groups.

Thus, the copolymers of the invention are typically produced by polymerising (i) a polysiloxane having at least one substituent selected from primary amine, hydroxyl and carboxylic acid groups; (ii) a polyol;

(iii) an aromatic or aliphatic compound having two or more isocyanate groups; and optionally (iv) one or more chain extenders selected from amino acids, peptides, polypeptides and Ci-Cβ aliphatic groups, each of which has at least one substituent selected from primary amine, hydroxyl and carboxylic acid groups,

the process comprising combining, in any order, components (i) to (iii) and optionally (iv) to form a polymerisation mixture, wherein components (i) and (ii), or prepolymers thereof, are present in a single phase of the polymerisation mixture.

During reaction of the components (i) to (iii) above, the number of urethane groups present gradually increases, thus increasing the polarity of the reaction mixture. As the reaction mixture polarity increases, the solubility characteristics of the mixture also change, causing phase separation of the polysiloxane material.

As discussed above, the present inventors believe that the presence of two phases in the reaction mixture in prior art processes leads to the formation of two separate polymers and prevents the incorporation of the polysiloxane into the backbone of the copolymer. In order to manufacture the copolymers of the invention, it is therefore necessary to ensure that the polysiloxane components and the polyol components, or prepolymers formed from either of these components, are present in the same phase of the polymerisation mixture.

Typically, the polymerisation is carried out such that the polymerisation mixture forms substantially a single phase. This can be achieved, for example, by continuously stirring the reaction mixture, or by carrying out polymerization in a solvent in which components (i) and (ii), or prepolymers thereof, are both soluble.

The use of a polysiloxane-containing segment having a low molecular weight leads to a lower tendency for the polysiloxane component to separate out into a different phase from the polyol component. Thus, fewer difficulties are encountered in incorporating the polysiloxane into the backbone of the copolymer.

If very low molecular weight polysiloxanes are used, for example up to 1000 or even up to 500, the polysiloxane may not form a separate phase from the polyol component. Thus, in a preferred process of the invention, the polysiloxane component has a molecular weight of up to 2000, preferably up to 1000, more preferably up to 500, and the polymerisation is carried out optionally with stirring. In an alternative embodiment of the invention, the polysiloxane has a molecular weight of greater than 1000, such as greater than 2000, or greater than 5000 and the polymerisation is carried out (a) with stirring or (b) in solution.

In a further embodiment, a mixture of high molecular weight polysiloxanes having a molecular weight in excess of 1000, and low molecular weight polysiloxanes having a molecular weight of less than 1000, preferably less than 500, is used. In this embodiment phase separation of the polymerisation mixture is minimised.

The present inventors have found that phase separation of the polymerisation mixture can be further avoided by using a two-step procedure in which either the polyol or the polysiloxane is first pre-polymerised with isocyanate, and the other of the polyol and the polysiloxane is added in a subsequent step. Chain extenders can optionally be added in the subsequent step together with the polyol or polysiloxane. In a preferred embodiment, however, any chain extenders are added in a third separate step. The formation of a pre-polymer is thought to improve the compatibility of the reaction mixture so that phase separation is less likely. A more homogeneous polymerisation mixture is thus achieved compared with stirring or polymerising in solution alone. In a particularly preferred embodiment, polyol is pre-polymerised with isocyanate and polysiloxane is added subsequently.

Where the polysiloxane segment is intended to be present at the end of the copolymer chain, component (i) is a polysiloxane-containing group having one substituent selected from primary amine, hydroxyl and carboxylic acid groups. Where the polysiloxane segment is intended to be present other than at the end of the copolymer chain, component (i) is a polysiloxane-containing group having at least two substituents selected from primary amine, hydroxyl and carboxylic acid groups.

Similarly, where the chain extender segments are intended to be at the end of the copolymer chain, only one substituent selected from primary amine, hydroxyl and carboxylic acid groups is present on the chain extender component. Otherwise, where these segments are intended to be other than at the end of the copolymer chain, at least two substituents selected from primary amine, hydroxyl and carboxylic acid groups are present.

If it is desired to introduce cross-linking into the copolymer chain, the polysiloxane or other component may comprise three or more polymerisable groups (hydroxyl, primary amine or carboxylic acid groups). Similarly, cross-linking can be introduced by using an isocyanate component (iii) having three or more isocyanate groups.

Preferably, the polysiloxane is substituted with one or more primary amine groups since these provide improved reactivity. Similarly, preferred chain extenders contain primary amine groups to improve reactivity.

A polysiloxane component (i) is typically a polysiloxane-containing segment as described above wherein one or both of the ends of the polysiloxane segment are bonded to hydroxyl, primary amine or carboxylic acid groups. Alternatively, the polysiloxane component (i) comprises a polysiloxane chain linked to one or more further segments, each of which may be the same or different. Typically each of said segments within the unit are linked via urea or urethane groups. Thus, for example, the polysiloxane component (i) may comprise a series of different segments, at least one of said segments being a polysiloxane chain. Examples of such units include a polysiloxane chain linked to a chain extender, for instance a polysiloxane linked to a polypeptide; a polysiloxane chain linked to a further polysiloxane chain via a urethane or urea group, and a tri- or multi-block polymer having one or more polysiloxane-containing segments and one or more polypeptide segments.

A polyol component (ii) is typically a polyol segment as described above, and has at least two hydroxyl groups. Alternatively, the polyol component (ii) comprises a polyol chain linked to one or more further segments, each of which may be the same or different. Typically each of said segments are linked via urea or urethane groups.

A chain extender component (iv) is typically a chain extender segment as described above wherein one or both ends of the chain extender segment are bonded to hydroxyl, primary amine or carboxylic acid groups. Alternatively, the chain extender component (iv) comprises a chain extender segment linked to one or more further segments, each of which may be the same or different. Typically each of said segments are linked via urea or urethane groups.

The isocyanate component (iii) is typically a moiety A as described above which is bonded to two or more isocyanate groups. Typically, the isocyanate component (iii) has two isocyanate groups, i.e. it is a diisocyanate. Suitable diisocyanate compounds for use as the component (iii) are commercially available diisocyanates including those commonly used in the manufacture of polyurethanes. In a preferred embodiment, a mixture of 2,4- and 4,4-MDI is used.

The polymers of the invention are produced by polymerising components (i) to (iii) and optionally (iv) in any order. For example, components (ii) and (iii) can be polymerised first and subsequently component (i) added. Thus, a polyol polyurethane prepolymer is formed using standard polymerisation conditions. A solvent is then typically added to the prepolymer and the polysiloxane unit, optionally together with one or more chain extender units is added. The polysiloxane and chain extender units are typically also dissolved in a solvent. Following addition of the polysiloxane unit, the polymerisation mixture is typically mixed until a homogeneous solution of prepolymers and polysiloxane unit is achieved.

The polymerisation can be carried out as a bulk polymerisation or as a solution polymerisation. Effecting the polymerisation in a solution, using a solvent in which all of the components are soluble, aids the formation of a single polymer having polysiloxane in the backbone. This is because the use of such a solvent averts the formation of a two phase polymerisation mixture. The polysiloxane unit and polyol unit are therefore all present in the same solution phase and can become a part of the same final polymer.

Whether bulk or solution phase polymerisation is carried out, the reaction conditions used are typically those known in the art for producing polyurethanes, as long as the polymerisation mixture contains both the polysiloxane and polyol units, or prepolymers thereof, in the same phase. Thus, polymerisation is typically effected at elevated temperatures, for example from 50 to 100°C. Suitable polymerisation catalysts can be used if desired. If solution polymerisation is used, aprotic solvents are typically used, for example N,N-dimethylacetamide (DMAC) and tetrahydrofuran (THF) or mixtures thereof. To improve the homogeneity of the polymerisation mixture, THF is typically used for the pre-polymerisation stages, and DMAC is used during chain extension.

The starting materials for use in the process of the invention are typically commercially available or can be produced by known techniques. The bridged polysiloxanes can be produced, for example, by sol-gel polymerisation of a building block containing a Bridge group linked to two or more trialkoxysilyl groups. Such trialkoxysilyl groups linked to Bridge groups are commercially available or can be accessed via routine techniques. The polymers of the invention can, if desired, be lined with cells in order to increase their biocompatibility. The cells which can be used in the present invention include endothelial cells and microvascular cells, preferably endothelial cells. Examples of suitable cells include animal cells, such as animal endothelial cells, or cells which have been harvested from the human vein, typically the saphenous vein or the umbilical vein or from human adipose tissue. Cells are harvested using standard techniques such as those described by Jaffe et al (J. Clin. Invest. 1973; 52; 2745-56). Seeding such cells on the inside surface of a vascular graft is known to encourage the growth of the full endothelium. This provides a natural defence against particles adhering to the surface of the graft and increases the patency rate. Typically the cells used are derived from the patient's own tissue to avoid rejection.

The process of lining the polymer with cells may be carried out by any technique known in the art. The cells are typically cultivated by any standard cultivation technique such as that described by Zilla et al (J. Vase. Surg. 1990; 12: pages 180-9). The cells are suspended in a medium which is typically a tissue culture medium. The concentration of cells in the tissue culture medium is preferably from 1 to 50x10⁵ cells/cm², preferably from 2 to 24x10⁵ cells/cm², more preferably from 2 to 16xl0⁵ cells/cm .

The medium comprising the cells suspended therein, is then contacted with the copolymer of the invention. Typically, the medium is either inserted into a chamber containing the copolymer and incubated for a period of 0.1 to 10 hours, preferably 0.5 to 6 hours, or the medium is pumped over the copolymer for a period of 0.05 to 10 hours, preferably 0.5 to 6 hours. When the copolymer is in a tubular shape whilst lining is carried out, it may be rotated during incubation or pumping in order to obtain a more even lining of the polymer. The incubation or pumping procedure may be repeated one or more times to improve the seeding efficiency of the cells. The process is preferably carried out at a temperature of about 37°C. In order to enhance the adhesion of cells to the copolymer, electrostatic charges may be applied to the copolymer or 0.5 Tesla Helmholz coils may be used, for example before or during the incubation or pumping process.

The copolymers of the invention have a variety of different uses. The copolymers are principally envisaged for use as implantable devices. However, alternative uses may be made of the copolymers, for instance the copolymers may be used as screens, contact lenses or ocular implants due to their good transparency and lack of discolouration.

The copolymers are typically processed into moulded articles using standard polymer processing techniques such as extrusion or moulding. Where implantable devices are required, these can be produced, for example, using the technique described by Edwards, A., et al (J. Biomat. App. 1995; 10: pages 171-187; the contents of which are incorporated herein). The lining of the copolymer with cells is typically carried out after the polymer has been processed into its desired shape.

Typically, the copolymers of the invention are used to form prostheses, or implantable devices, including vascular grafts, heart valves, stents, including urological stents, conduits for use in surgery to correct nerve damage and orthopaedic joint replacements. Preferred implantable devices are vascular grafts.

The copolymers of the invention may also be envisaged for use in surgical devices other than prostheses. Examples include catheters, plastic tubing through which blood is passed during by-pass operations and tubes used for injecting labelling substances such as In for use in X-ray diagnosis techniques.

The copolymers of the present invention, when in the form of an implantable device, may be used in the treatment of a human or animal subject in need of the replacement of a body part, said method comprising replacing said body part with an implantable device of the invention. Said method may be carried out using standard techniques known in the art of prosthetic surgery. For example, where the implantable device is a vascular graft, the graft may be anastomosed to the natural blood vessel in an end-to-end, end-to-side, or side-to-side manner. The anastomosis is typically carried out using sutures. Alternative methods such as the use of clips or laser techniques are also possible. An advantage of these latter techniques is that they help to retain some of the compliant nature of the graft at the anastomoses.

EXAMPLES

The present invention is further illustrated with reference to the following Examples.

Example 1

This example illustrates the preparation of a urethane/urea polymer using a bishydroxypropyl terminated, polydimethylsiloxane, polycarbonate polyol and a chain extender package using ethylene diamine and polypeptide.

A mixture of the bishydroxypropyl terminated polydimethyl siloxane having a molecular weight of 248.5 [20 g] and the polycarbonate polyol [200 g] were dehydrated by heating under vacuum (<1 mm H_g) at 90°C-110°C with stirring in a resin flask. The flask cover was equipped with a mechanical stirrer, stirrer gland, thermometer and an outlet adapter for connection to the vacuum system. The flask was contained in a heating mantle. After 2 hours the temperature was allowed to fall to 70°C. The system was flushed with dry nitrogen. The top was removed and 4,4"- diphenylmethane diisocyanate (MDI) (61 g) added to the mix in one go. The flask top was replaced and the system flushed with dry nitrogen, and stirring commenced. The temperature was maintained by an exotherm and occasional gentle heating between 80°C-85°C for 2 hours.

The isocyanate content was then determined by the standard dibutylamine hydrochloric acid titration. The determined isocyanate content was then used to determine the quantity of the extender package, including an allowance for the final protein/polypeptide. EDA [3.1 g] was dissolved in AMAC [200 g] along with an amine terminated polypeptide (500 mol.wt. 25.8). Anhydrous DMAC (800 g) was added to the prepolymer and the mixture stirred until homogeneous. The mixture was cooled to 5°C in an ice/water bath and a dropping funnel fixed to the flask cover. The extender solution was placed in the dropping funnel and added portion wise with vigorous stirring over a period of 1 hour. It was important at this stage to allow any reacted material to become dispersed through the reaction mixture. The reaction was followed by the observation of the isocyanate (NCO) band at 2260 cm^"1 on FTIR analysis, after the disappearance of the NCO band the reaction was allowed to stir for another 30 min. The reaction was then deemed complete.

Example 2

This illustrates the preparation of a urethane polymer containing PDMS, polycarbonate and a polypeptide unit which was placed strategically and predominantly adjacent to the siloxane grouping. This was achieved by preparing a prepolymer from a bis(hydroxyl alkyl) terminated PDMS and a polycarbonate diol. The final prepolymer contained a 2 molar excess of MDI. This prepolymer was reacted with 2 moles of bis(4 hydroxy butyl) tetramethyldisiloxane to form a further prepolymer, which was then extended and terminated with polypeptide.

A mixture of bishydroxy propyl terminated polydimethysiloxane [20 g] and polycarbonate polyol [200 g] were dehydrated as described in example 1. The polydimethyl siloxane component consisted of a 1 :1 mixture of a 248.5 molecular weight polymer and a 950 molecular weight polymer. The reaction vessel was as described in example 1. After 2 hours dehydration the flask was flushed with dry nitrogen and allowed to cool to 70°C. The flask cover was removed and a 4 molar excess of MDI [122 g] added in one go to the flask. The flask cover was replaced, flushed with dry nitrogen, and stirring commenced. The temperature was maintained by the reaction exotherm and occasional gentle heating between 80°C-85°C for 2 hours.

The Bis(4-hydroxy butyl)tetramethyldisiloxane [75.2 g] was dissolved in DMAC [50 g] and added to the reaction mixture from a dropping funnel over a period of approximately 10 mins. The temperature was maintained at 80°C-85°C for a further hour. The reaction mixture was sampled and the isocyanate content determined. If the value was theoretical or slightly less then the extender package was calculated and prepared. Further DMAC [750 g] was added to the reaction mixture Z-Lys-NCA [305 mw] [33.48 g] was dissolved in DMAC [200 g] along with an amine terminated RGD moiety [400 m.wt. 4.0 g]. The reaction mixture was cooled to 20°C and then the extender mixture added portion wise over 1 hour. The disappearance of the isocyanate band was monitored by FTIR. After the complete disappearance of the band the mixture was stirred for another 30 mins.

The polymer can be processed further to remove benzylcarbonyl groups in order to leave free amino groups, which may be used for covalent heparin attachment.

Example 3

This illustrates the preparation of an urethane/urea polymer based upon bisaminopropyl terminated PDMS, polycarbonate polyol, a diamino terminated polypeptide chain extender and diethylamine as a chain terminator/reaction moderator.

A mixture of the bisaminopropyl terminated [20 g] PDMS and polycarbonate polyol [200 g] were dehydrated as described in example 1. The PDMS was a 1 :2 mixture of a 248.5 molecular weight polymer and a 950 molecular weight polymer. The reaction vessel and fittings were as described in example 1. After 2 hours dehydration the flask was flushed with dry nitrogen and allowed to cool to 70°C. The flask cover was removed and MDI [61 g] added in one go to the flask. The cover was replaced, flushed with dry nitrogen and stirring recommenced. The temperature was maintained by the exotherm and occasional gentle heating between 80°C-85°C for 2 hours. The isocyanate content of the pre-polymer was measured by the standard Di-N-Butylamine-hydrocaloric acid titration. The isocyanate content was used to calculate the extender package. DMAC [800 g] was added to the pre-polymer and the mixture stirred to ensure homogenecity. The extender package was prepared by dissolving polypeptide [500.0 mw.58 g] and diethylamine [0.3 g] in DMAC [200 g]. The mixture was stirred and transferred to the dropping funnel. The flask was cooled to 20°C and the extender package added portion wise over Vi hour. The reaction was followed by the disappearance of isocyanate band at 2260 cm^"1. After the disappearance of the band the reaction was stirred for a further 30 min. The reaction was then deemed complete.

Example 4

This illustrates the preparation of a urefhane/urea polymer in which the PDMS units have a larger molecular separation in the polymer than in the previous examples. The polymer will also have an alternating block structure PDMS-polycarbonate-PDMS- polycarbonate whereas the previous samples could be random. This was achieved by producing a pre-polymer, which was two polycarbonate units long and then extending separately with PDMS.

Polycarbonate polyol [200 g] was dehydrated as stated in the earlier examples. MDI [37.5 g] was added in the usual manner to form a pre-polymer. The mix was reacted for 2 hours at 80-85°C. The isocyanate content was measured by the standard technique and the amount of chain extender and termination calculated. In this case the chain extender was the bisaminopropyl PDMS and the chain terminator was an RGD moiety, which was amine terminated.

The bisaminopropyl PDMS [92 g] and the RGD [0.85 g] moiety were dissolved in DMAC [200 g]. DMAC [800 g] was also added to the pre-polymer mix and stirred until homogeneous. The prepolymer solution was cooled to 20°C and then the extender package added portion wise over a one-hour period. The reaction was followed by FTIR. On the disappearance of the NCD band at 2260 cm^"1 the reaction was stirred for a further 30mins and then deemed complete. Example 5

This illustrates the use of a PDMS containing urethane groups and being terminated with hydroxyl (primary) alkyl groups. This material was prepared by the reaction of ethylene carbonate with an amine terminated PDMS. The use of this material improves the compatibility problem of siloxane materials with urethanes by having some preformed urethane groups in the siloxane molecule. The preformed urethane groups in the PDMS help 'compatibilise' the material with the forming urethane groups.

The polycarbonate polyol [200 g] and the hydroxyl terminated urethane polydimethyl siloxane [200 g] were dehydrated in the manner described in example 1. The mixture was cooled to 70°C and the MDI [59 g] added to the flask as stated in example 1. The mixture was reacted for 2 hours at 80-86°C. The isocyanate value was determined and the extender package amounts were calculated. DMAC [800 g] was added to the pre-polymer and the mixture stirred for 30mins.

The extender package was weighed out as EDA [3.46 g], polypeptide [288 g] and diethylamine [0.2 g]. A mixture of these extenders was dissolved in DMAC [200 g] and added to the pre-polymer portion wise over 20mins. The pre-polymer solution had been cooled previously to 20°C. Addition took place over 20mins. The reaction was followed by monitoring the peak at 2260 cm^"1. The reaction was stirred for another 30mins after the disappearance of the peak.

Example 6

This illustrates the use of a polypeptide coupled to polydimethylsiloxane unit for use as a chain terminator surface modifying end group. An RGD - siloxane terminated polymer can be produced using this method. The use of this molecule ensures both the siloxane and the peptide are at the end of the polymer chain. Polycarbonate polyol [200 g] was dehydrated by the technique described in example 1 and then reacted with MDI [50 g] to form a pre-polymer as described in Example 4. Reaction was carried out for 2 hours at 80 - 85°C as in the previous examples, the isocyanate content was measured by the standard method and the extender package calculated. The extender package consists of the peptide - PDMS [1.8 g] and ethylene diamine [5.88 g]. DMAC [800 g] was added to the pre-polymer and the temperature was maintained at 60°C. The peptide - PDMS [1.8 g] was dissolved in DMAC [50 g] and then added with stirring to the pre-polymer solution. The temperature was maintained at 60°C for 1 hour. The reaction mixture was cooled to 20°C and the EDA [5.88 g] in DMAC [150 g] was added slowly over 30 mins allowing any reacted material to disperse. The mixture was stirred vigorously for another 30 mins after the completion of the EDA addition. A sample was taken for IR analysis to check for completion of reaction by the lack of a peak at 2260 cm^"1.

Example 7

This method illustrates the formation of the first stage pre-polymer using a solvent mixture.

A mixture of the bis(aminopropyl) PDMS [20 g] and polycarbonate polyol [200 g] were dehydrated as described in example 1. The mixture was cooled to 60°C and a reflux condenser fitted to the flask. A DMAC/THF solvent blend [80:20400 g] was added to the flask and the mixture stirred for 20mins. The MDI [61 g] was then added in one go. The reaction temperature was maintained at 70°C for 3 hours. After this period a sample was removed for isocyanate determination. If the value was theoretical or slightly below the first stage was deemed complete and the extender package calculated. The EDA [6.98 g] and amine terminated polypeptide [1.86 g] were weighed out and dissolved in DMAC [200 g]. The reaction mix was cooled to 20°C and further DMAC [600 g] added with stirring to achieve a homogeneous mixture.

The extender terminator package was now added over a period of 1 hour with vigorous stirring. The reaction was followed by the disappearance of the band at 2260 cm^'1. After the band had disappeared, the mixture was stirred for another 30mins and then reaction deemed complete.

Example 8

This illustrates the use of a polydimethylsiloxane polypeptide to form a tri-block material. The polypeptide PDMS was formed by the reaction of amine terminated PDMS and an N-carboxyanhydride monomer, in accordance with known techniques.

Di or mono functional amine terminated units can be prepared. In the mono functional case the material can be used as a chain terminator which acts as a surface modifying end group.

Polycarbonate polyol [200 g] was dehydrated as described previously and then reacted with MDI [50 g] for the standard 2 hours at 80-85°C. The mixture was diluted with DMAC [800 g] and stirred until homogeneous. The chain terminator, a monoamine terminated polypeptide PDMS [mol wt 1800 as determined by GPC; 3.6 g] was dissolved in DMAC [50 g]. The prepolymer solution was allowed to cool to 20°C. The PDMS -polypeptide solution was added over 30 mins and allowed to react for a further 30 mins. The reacted chain terminator molecules help moderate the reaction of the prepolymer with EDA. Since the PDMS - polypeptide was slower to react than EDA, this order of addition was found to be beneficial.

The EDA [5.88 g] was then dissolved in DMAC [150 g] and added portion wise to the mixture over a period of 40mins with vigorous stirring, allowing any reacted material to become dispersed. After the addition was completed the mixture was stirred for another 30mins. The reaction mix was checked for the disappearance of the isocyanate absorption peak at 2260 cm^'1 on FTIR. Then reaction was then deemed complete if this peak was absent. Example 9: physical properties of copolymer

A copolymer was produced by polymerising 8.8g MDI and 350g of a polycarbonate polyol. The temperature was maintained at approximately 60-70 °C and reaction continued for 1.5 hours. 20g THF were then added and the reaction mixture stirred to ensure proper mixing. PDMS (l.lg; 1:1 ratio of 950 MW and 248.5 MW) in lOg THF was added as a chain extender. DMAC was then added to the reaction mixture and the mixture stirred to ensure dissolution. EDA, DEA and 1,3CHD added as a chain extender/terminator package.

Figure 1 shows an ED AX spectrum carried out on the same copolymer. This spectrum confirms the presence of siloxane in the copolymer. The ED AX spectrum relates to an individual crystallite of the copolymer and thus confirms that the siloxane is present in the hard segment of the polymer.

Example 10: seeding of copolymer

This study was carried out to investigate any potential cytotoxicity of poly(carbonate- siloxane-urea) urethane (PCSU) to human umbilical endothelial vein cells (HUVEC).

Sections of PCSU graft material formed from the copolymer described in Example 9 were cut (160 mm discs, n=12) and placed into a 24-well plate. Six graft discs were seeded with HUVEC at 2x10⁵ cells/ml for 24 hours using standard seeding conditions.

As a positive control six wells were seeded with the same number of HUVEC in the same manner as above. Six wells containing discs of graft were left unseeded with only medium in them as a negative control. Alamar blue™ readings were taken at 1, 2, 3 and 4 days post initial seeding for all samples. Details regarding the Alamar blue technique can be found in Seifalian AM, Salacinski H J, Punshon G, Krijgsman B, Hamilton G: A new technique for measuring the cell growth and metabolism of endothelial cells seeded on vascular prostheses. J Biomed Mater Res. 2001;55:637- 44.

In a further experiment a sample of the graft was dismembrinated using a Micro- Dismembrator. Powder graft (10 mg) was added to each of six wells seeded with HUVEC as above. Cells were exposed to powder, graft for 48 hours following which an Alamar blue™ reading was taken.

Alamar Blue™ results showed viable cells present on all of the seeded graft segments 4 days post seeding, though at a lower level than the control cells (Fig. 2). Viable cells were still present 48 hours after exposure to dismembrinated graft, again at a lower level than for control cells (pO.OOl). The new polymer has improved compatibility to blood, but at the same time is found to optimally support the growth of endothelial cells as used in seeding of cardiovascular bypass graft and tissue engineering application.

Example 11: biocompatibility of copolymer

Flat sheets of the copolymer described in Example 9 were inserted into the backs of 4 sheep using standard surgical techniques. The polymers were monitored over a period of 6 months by monthly clinical examination and ultrasound scanning. No inflammation or any immunological reaction was visible.

Claims

1. A process for producing a copolymer comprising (a) one or more polysiloxane-containing segments and (b) one or more polyol segments, each of said segments being linked to one or more further segments, which may be the same or different, via urea or urethane linkages, wherein said polysiloxane-containing segment(s) are in the backbone of the copolymer, which process comprises polymerising (i) a polysiloxane having at least one substituent selected from primary amine, hydroxyl and carboxylic acid groups;

(ii) a polyol; (iii) an aromatic compound having two or more isocyanate groups; and optionally

(iv) one or more chain extenders selected from amino acids, peptides, polypeptides and C_!-C₆ aliphatic groups, each of which has at least one substituent selected from primary amine, hydroxyl and carboxylic acid groups,

said process comprising combining, in any order, components (i) to (iii) and optionally (iv) to form a polymerisation mixture, wherein components (i) and (ii), or prepolymers thereof, are present in a single phase of the polymerisation mixture.

2. A process according to claim 1, which process comprises polymerising component (iii) with one of components (i) and (ii), subsequently adding the other of components (i) and (ii).

3. A process according to claim 1 or 2, which process comprises polymerising components (ii) and (iii) and subsequently adding component (i).

4. A process according to claim 1 or 2, which process comprises polymerising components (i) and (iii) and subsequently adding component (ii).

5. A process according to any one of claims 1 to 4, wherein component (i) is a polysiloxane having at least two substituents selected from primary amine, hydroxyl and carboxylic acid groups.

6. A process according to any one of claims 1 to 5, wherein component (i) is a polysiloxane containing at least one urethane group.

7. A process according to any one of claims 1 to 5, wherein component (i) comprises at least one polysiloxane-containing segment and at least one polypeptide segment.

8. A process according to any one of claims 1 to 7, which process is carried out in an aprotic solvent.

9. A process according to any one of the preceding claims, wherein the polysiloxane comprises repeating units of the formula

wherein each R is the same or different and represents an aliphatic or aromatic group.

10. A process according to claim 9, wherein each R is the same or different and represents an alkyl, alkenyl, alkynyl, cycloalkyl or aryl group.

11. A process according to any one of the preceding claims, wherein the polysiloxane comprises optionally repeating units of the formula

R¹ R¹ I Si— Bridge— Si— O R¹ R^<

wherein each R¹ is the same or different and represents an aliphatic or aromatic group and each Bridge is the same or different and represents an arylene, alkylene, alkenylene, alkynylene, cycloalkylene, alkyl-arylene, aryl-alkylene, alkyl-aryl- alkylene, alkyl-cyloalkylene, cycloalkyl-alkylene or alkyl-cycloalkyl-alkylene group.

12. A process according to any one of the preceding claims, wherein one or more of said chain extenders is an anticoagulant.

13. A process according to any one of the preceding claims, wherein one or more of said chain extenders is RGD (Arg-Gly-Asp).

14. A process according to any one of the preceding claims, wherein the polyol is a polycarbonate polyol.

15. A process according to any one of the preceding claims, wherein the ratio of polysiloxane to polyol is 1:10 or less.

16. A process according to any one of the preceding claims, wherein the ratio of polysiloxane to polyol is 1 :25 or less.

17. A process according to any one of the preceding claims, wherein the polysiloxane has a molecular weight of up to 5000.

18. A copolymer obtained or obtainable by the process of any one of the preceding claims.

19. A copolymer comprising (a) one or more polysiloxane-containing segments and (b) one or more polyol segments, each of said segments being linked to one or more further segments, which may be the same or different, via urea or urethane linkages, wherein said polysiloxane-containing segment(s) are in the backbone of the copolymer.

20. A copolymer according to claim 19, further comprising (c) one or more chain extender segments, each of said chain extender segments being linked to one or more further segments, which may be the same or different, via urethane or urea linkages.

21. A copolymer according to claim 20, wherein said chain extender segments are selected from amino acids, peptides, polypeptides and Cι.-C₆ aliphatic moieties.

22. A copolymer according to any one of claims 19 to 21 wherein the polysiloxane, chain extender and polyol are as defined in any one of claims 9 to 14 or 17.

23. A copolymer according to any one of claims 19 to 22, wherein each segment is linked to one or more further segments by a group of formula

wherein each X is the same or different and is a nitrogen or oxygen atom and each A is the same or different and is an aromatic or aliphatic moiety.

24. A copolymer according to any one of claims 19 to 23, wherein the ratio of polysiloxane-containing segment(s) (a) to polyol segment(s) (b) is 1:10 or less.

25. A copolymer according to claim 24, wherein the ratio of polysiloxane- containing segment(s) (a) to polyol segment(s) (b) is 1 :25 or less.

26. A process for producing a lined copolymer, which process comprises seeding cells onto the surface of a copolymer as claimed in any one of claims 18 to 25.

27. A lined copolymer obtained or obtainable by the process of claim 26.

28. A moulded article comprising a copolymer as claimed in any one of claims 18 to 25 or a lined copolymer as claimed in claim 27.

29. An implantable device comprising a copolymer as claimed in any one of claims 18 to 25 or a lined copolymer as claimed in claim 27.

30. An implantable device according to claim 29 which is a vascular graft.

31. A method of treating a human or animal patient in need of the replacement of a body part, said method comprising replacing said body part with the implantable device of claim 29 or 30.

32. Use of a copolymer according to any one of claims 18 to 25 in the manufacture of an implantable device for the replacement of a body part.