WO2009016503A2

WO2009016503A2 - Development of improved smooth and textured mammary prostheses coated with highly biocompatible materials

Info

Publication number: WO2009016503A2
Application number: PCT/IB2008/002105
Authority: WO
Inventors: Paolo Giusti
Original assignee: Tecnologie Biomediche Srl
Priority date: 2007-08-01
Filing date: 2008-07-31
Publication date: 2009-02-05
Also published as: WO2009016503A3; ITPI20070089A1

Abstract

The present invention concerns the development of a mammary implant having a shell and a filler. The shell can be formed of any thermoplastic elastomer having good impermeability or a mixture thereof with silicone elastomers. In a preferred embodiment the shell is obtained using a fluorinated thermoplastic elastomer of the ABA type, wherein A is 1, 1-difluoroethylene and B is a difluoroethylene/perfluoromethylvinylether/tetrafluoroethylene terpolymer. In order to texturise the shell, the base polymer can be mixed with a biodegradable or bioresorbable polymer. A second mean for texturising the shell is the use of a hydrosoluble polymer in combination with the base material from which the shell is obtained. Among the biodegradable polymers, block copolymers of polyethylene glycol with lactic and/or glycolic acid or with epsilon-caprolactone were considered. Biocompatible hydrogel were used as filling materials. In a preferred embodiments gellan hydrogel was used as a filler. Among the synthetic hydrogels usable as fillers, poly(vinyl alcohol) was considered. In another embodiment, a mixture of PNIPAAM/ alginate/ gelatin was used as a filler. Pyrolitic carbon coatings were applied to the shell in order to increase the biocompatibility thereof.

Description

"Development of improved smooth and textured mammary prostheses coated with highly biocompatible materials" State of the art relative to the present invention

The present invention concerns the realisation of prototypes of innovative permanent impermeable, smooth and textured, mammary prostheses coated with biocompatible materials. Such mammary implants are used in reconstructive plastic surgery for the substitution of the breast or for increasing breast volume in additive plastic surgery, have shells made with silicon elastomers filled with highly cohesive silicon gel and have their surfaces texturised by means of inorganic materials. In recent years attempts to coat the shells with a thin film of highly biocompatible materials appeared in the literature. The mammary prosthesis market is in expansion due to an ever increasing request for reconstructions consequent to mastectomy surgery and an ever more diffuse aesthetic demand. This phenomenon is associated to the request for safer and safer prostheses in the long term. The enormous importance given by the mass media to the severity of the phenomena associated with the use of polymeric prostheses (polyurethanes and silicons) for plastic and aesthetic surgery and the attention that the health authorities (mainly in the USA) have paid to such materials, have led to suspension of the employment of nome prostheses in use.

In spite of notable progress in the choice of materials and their surface treatment, still today, in the application of long term prostheses, as in the case of mammary prostheses, the interaction phenomena between the surface of the device and the biological tissues with which it is in contact are critical. The formation of a periprosthetic capsule of fibrous tissue as a consequence of the inflammatory process (reaction to a foreign body) is a typical reaction mechanism of the biological tissue in contact with the prosthetics that may first create a situation of discomfort and then even pain to the point of obliging the removal of the prosthesis itself and of the fibrotic capsule.

Surface treatments to improve the interface between prosthesis and biological tissue, coatings with biocompatible materials preventing long term contact of biological tissues with silicon, fillings constituted by substances that are highly tolerable by the organism in case of leakage or breakage of the shell, are the scientific and technological aspects that the present invention faced with the aim of realising, by means of a pilot scale process suitable for being transferred to an industrial scale, a prototypical series of permanent, impermeable, texturised mammary prostheses coated with highly biocompatible material. Detailed description of the invention The present invention concerns in total or in part the following phases of the production process of mammary prosthesis prototypes.

1. Development and characterisation of impermeable prosthesis shells Realisation of shells impermeable to silicon gels alternative to those currently employed.

2. Development of texturisation processes

Realisation of texturisation with techniques that differ from those described in the literature. 3. Development of filling materials

Realisation of filling materials with cohesive characteristics

4. Development and characterisation of highly biocompatible coatings Realisation of coatings that improve the surface compatibility of the prosthetics and consequent reduction in the thickness and consistency of the periprosthetic capsule 1. Development and characterisation of impermeable prosthesis shells

In the currently commercially available mammary prostheses, constituted of a silicon shell and filled with silicon gel, the inconvenience of leakage of the silicon gel from the prostheses often occurs with consequent side effects (inflammation, mutagenesis). In this invention polymers of elastomeric nature were identified, with different physicochemical characteristics, more suited to the realisation of a highly impermeable multilayered shell.

Initially various silicon-based materials were selected, and then new polymeric materials belonging to the class of thermoplastic elastomers, possibly containing fluorine, never before tested in this sector were examined. The thermoplastic elastomers constitute a class of polymeric materials characterised by an elastomeric mechanical behaviour analogous to that of chemically vulcanised elastomers. They are constituted of multiple alternating of blocks (at least two) of A plastomer nature with blocks of B elastomer nature (at least one) . The simplest example being the SBS rubber where S is styrene and B is butadiene. The vulcanisation process present in these elastomers is physical in nature and therefore no low molecular weight substances are present that could interact with the tissues, leading to problems of toxicity or even carcinogenicity. Thermoplastic elastomers can be used for the production of mammary prostheses that guarantee a high level of safety.

2. Development: of texturisation processes The surface penetration of fibrohistocytes and fibroblasts that induce the optimal growth of collagen fibres for the development of a thin soft capsule around the prosthesis can be obtained by creating an interface between the prosthesis itself and the body. Such interface can be obtained through the process of surface texturisation of the silicon-based prosthesis consisting in the formation of small pores with a depth of approximately 0.1 mm distributed uniformly on the surface. Various methods exist for performing the texturisation process, but at present none is capable of performing an ideal texturisation process that is perfectly reproducible.

In this invention new texturisation methods have been studied that are capable of overcoming the critical aspects of the processes currently on the market.

The texturisation process should resolve the problem of periprosthetic capsule but could cause greater difficulty in positioning due to the higher coefficient of friction, and a more extensive area of contact between the silicon material and the body. The texturised prosthetics were coated with highly biocompatible materials with the aim of finding an optimal solution to this problem as is described in the following. In the present invention two completely innovative processes for realising texturisation in vivo are described. The first process involves the use of biodegradable and bioabsorbable polymers that are miscible with the base polymers with which the shell is made; the second process involves water-soluble polymers that are also miscible with the base polymers of the shell.

Among the biodegradable and bioabsorbable polymers three-block copolymers of polyethylene glycol with lactic acid and/or glycolic acid or with e-caprolactone were considered. The last dipping is to be carried out with a mixture of these copolymers and silicon, after which the process continues as usual. In vivo this type of shell slowly looses the biodegradable polymer from the outer layer. Thus voids very similar to texturisation will be created. As water-soluble polymers those with proven biocompatibility such as for example poly (N vinyl pyrrolidone) were considered. The texturisation process will occur due to the dissolving of these polymers in water, which can be carried out either in vitro before implantation or in vivo if the polymer is perfectly biocompatible. 3. Development of innovative shell filling material In the present invention new highly biocompatible filling materials were identified that are suitable for giving the prosthesis the necessary characteristics of flexibility, consistency and adaptability. Currently, approximately 50% of commercially available prostheses are filled with saline solution and the remaining 50% with silicon gel. Polysaccharides or other experimental materials are used in a small percentage.

Synthetic, natural and bioartificial hydrogels have been proposed as innovative polymeric filling materials. From a physical and mechanical point of view the hydrogels are very similar to biological tissues due to their agueous phase, their high level of permeability to small molecules and their favourable mechanical properties. Generally they are produced through chemical or physical crosslinking starting from synthetic or biological polymers.

One particularly interesting and new class of starting material considered is that of the ^Λbioartificial' polymers, constituted of mixtures of synthetic and natural polymers, and having overall characteristics resulting from the combination of the favourable mechanical properties and processability of synthetic polymers with the biocompatibility generally shown by the biological polymers. The hydrogels proposed as potential filling agents must demonstrated perfect biocompatibility and, when possible, a good biodegradability so to annul any biological damage caused by their leakage from rupture of the prosthesis. 4. Development and characterisation of highly biocompatible coatings

In order to improve prosthesis-biological tissue interactions, the prostheses have been coated with thin layers of biocompatible materials. The optimal parameters have been defined for the following coatings :

- sputter-coating with pyrolytic carbon

- depositing of biological materials after chemical modification of the shell surface by means of plasma - coatings with polymers capable of controlled release of drugs

Pyrolytic carbon is used for the realisation of implantable devices in critical positions and functions because it is highly chemically inalterable, has a high tensile strength combined with low density, good compatibility with cellular elements and provokes negligible protein alterations. It can be deposited as a thin film on the polymers by means of ^sputtering' , effecting a mass transfer from a pyrolytic carbon target under vacuum to the substrate obtaining high adhesion between film and substrate, the absence of chemical, thermal and mechanical alterations of the substrate and the maintenance of the biological properties of the pyrolytic carbon. In addition, the coefficient of friction of pyrolytic carbon is much lower than that of silicon and therefore a coated prosthesis would minimise the trauma to which tissues are subjected during insertion and positioning of a mammary prosthesis. The other technology intended to be used is that of plasma treatment of the silicon to functionalise the surface. The processes by plasma are performed dry and not in liquid phase, are rapid and can be effected continuously and in addition the treated material exits from the process in an already sterile form. The modifiable surface characteristics were examined wettability, reactivity, crosslinking and roughness) in order to deposit a thin layer of biological material (hyaluronic acid, alginin, etc.). Concerning the coatings with polymers capable of releasing drugs, polymers proven to be biocompatible, biodegradable and bioreabsorbable with elastomeric properties approximating those of the material with which the shell is made, such as, for example, several new polyurethane products from Tecnologie Biomediche srl, were chosen and loaded with drugs suitable for slowing the process of periprosthetic capsule formation (such as, for example, antineoplastic antibiotics) . Having identified the optimal parameters for sputter deposition and for plasma treatment, coatings were realised and their physicochemical, mechanical, adhesive, permeability properties and in vitro biocompatibility characterisations were performed. Examples of embodiments and of materials object of the invention 1 Impermeable prosthesis shells

1.1 Description of preferred embodiments

The method and materials most commonly used for realising shells will now be described. To them, reference will be made to the use of innovative materials .

After a preliminary evaluation of the silicon materials present on the market, a silicon elastomer having superior mechanical characteristics and being produced by Nusil Silicone Technology and mixtures thereof with various thermoplastic elastomers were identified as being suitable for the production of shells. The trials carried out and tests performed led to identification of the parameters that allow the realisation of a solution with the ideal viscosity and concentrations for the dipping of prosthesis moulds: 7.8% by volume solute in solvent (cyclohexane) , 12 hours of soaking, 2 hours homogenisation at 300 rpm, filtration to 150 mesh. Several of models of such moulds were realised both in steel and in solid Teflon or delrin. A workstation was assembled and used for the movement of the moulds on two shafts by means of a PLC controller controlling the velocity and with the possibility of programming the rotation times and the end of cycle signals.

The number of dippings of the mould into the solution required to reach a shell thickness between 0.55 and 0.75 mm was determined. This thickness is suitable to guarantee the elasticity and resistance characteristics of the shell as verified in the successive tests for mechanical characterisation. According to the volume of the mould used, from 20 to 24 dippings must be realised to yield the desired thickness. Next a thermal curing is essential for the mechanical-elastic characteristics. The process as set up provides for curing for 20 minutes in a ventilated oven at 15O⁰C (with an acceptable interval of 145°C - 155°C) and insertion into a hot oven and removal from a cooled oven; unmolding of the shells from the steel or Teflon mounds (using a solution of 50% isopropanol in water) and a post-cure period at 140°C for 3 hours in a ventilated oven with cold insertion and removal are next .

Then the shells obtained as described above are characterised by physicochemical analyses (chemical elementary analysis, surface analysis with scanning electron microscopy SEM, DSC calorimetry, infrared (IR) and ultraviolet (UV) diffractometry, surface analysis by atomic force microscopy, mechanical analysis with DMTA using an Instrom instrument) , detecting the following average values:

Tensile Strength (Mpa) : 8.9; Tear Strength (kN/m): 36; Elongation (%) : 1200; Durometer Hardness: 35; Modulus 200% (Mpa) : 1.0. To guarantee the impermeability of these shells to silicon gel and to the other gels developed in the present invention the development of a multilayered shell was chosen in order to combine the characteristics of the chosen silicon elastomer (stability, resistance, elasticity, chemical and biological inertness) with those of another silicon having the chemical characteristics that provide a barrier effect to the molecules of the silicon used for filling the prosthesis. The material used was silicon from Nusil Silicone Technology with a formulation having diphenolic groups that allow the preset objective to be achieved and provide optimal binding to the silicon elastomer by means of mechanical characteristics very similar to the latter. After resolved the problems due to the different solvent in which the diphenolic silicon is provided, a 150 micron layer of this silicon was applied between two 250 micron layers of elastomeric silicon for a total thickness of 0.65 mm. The chemical, morphological and mechanical characterisations confirmed the results reported above and no modification of the described shell production procedure was necessary. Permeability to sample solutions with viscosities typical of silicon gels was null. Several examples will be described of shells realised with innovative materials with respect to those in silicon, and be described for the first time in this invention. Examples : Ex.l Shells for mammary prostheses were realised using fluorinated thermoplastic elastomers of the ABA type, where A is the segment of plastomeric nature and is constituted of 1, 1-Difluoroetilene (VF2) and B is the block of elastomeric nature and is constituted of a terpolymer: 1,1-

Difluoroetilene/perfluoromethylvinylether/tetrafluoroet hylene (VF2/PMVE/TFE) .

The dipping process is completely similar to that described for the silicon materials but notably simplified by the fact that the reticulation process is not necessary, being sufficient a thermal treatment to eliminate the solvent.

The mechanical properties are optimal. Modulus 100%: 8-10 (MPa); traction resistance: 10-12 (MPa); elongation to breakage (%): 200-600; Hydraulic permeability: zero; Permeability to gels: zero. Ex.2 All of the thermoplastic elastomers that are perfectly biocompatible and have suitable physicochemical properties can be used in a manner completely similar to the previous example. 2 Texturisation processes

2.1 Description of the preferred embodiment

In the present invention two completely innovative processes are described for realising in vivo texturisation. The first process involves the use of biodegradable and bioreabsorbable polymers, miscible with the base polymer with which the shell was realised; the second process involves the use of water- soluble polymers that are also miscible with the base polymers of the shell.

Among the biodegradable and bioreabsorbable polymers, three block copolymers of polyethylene glycol with lactic and/or glycolic acid or with e-caprolactone were considered. The last dipping is carried out with a mixture containing these copolymers and silicon, and then the process continues as usual. In vivo these types of shells slowly loose the biodegradable polymer from the outer layer. In this way, voids very similar to texturisation are created. As water-soluble polymers, those with proven biocompatibility, such as, for example poly (N vinyl pyrrolidone) were considered. The texturisation process occurs through the dissolving of these polymers in water, which can be carried out either before implantation in vitro or in vivo if the polymer is perfectly biocompatible.

3 Filling materials

3.1 Description of the preferred embodiment In the present invention the following hydrogels based on natural, synthetic and bioartificial polymers are proposed as innovative alternatives to the previously described silicon-based hydrogels. 3.1.1 Natural hydrogels Gellan hydrogels Gellan belongs to the family of polysaccharides classified as "gums" by virtue of the property of forming viscous solutions, dispersions or gels in hot or cold water. Hydrogels have found wide industrial use because of their suspension and stabilisation properties and for this are used as gelling agents, emulsifiers, adhesives, flocculants, binders and lubricants. Lowering the temperature of gellan solutions results in the rapid formation of a hydrogel.

The gelling temperature Tgel, depends on the concentration of the aqueous gellan solutions; around 30⁰C for concentrations of 0.5% by weight and around 45°C for 2% solutions. The transformation is thermoreversible and many authors agree that this is due to a conformational transition of the polymer. The gelling process is influenced by the molecular weight, the polymer concentration, the degree of deacetylation (if acetylated gelling does not occur) and the nature and concentration of added salts (the presence of salts improves the mechanical properties of the gel) .

The gellan hydrogels were prepared as described in the following. The gellan used was from Sigma Aldrich, the quantity of salts was measured with a Plasma Emission Spectrometer 400 from Perkin Elmer, which yielded the following results : Na⁺ 16 mg/gr, K⁺ 10 mg/gr, Ca⁺⁺ 4 mg/gr, Mg⁺⁺ 1 mg/gr The pH of a 1% solution was found to be 7.76 and the gelling temperature was 35-40⁰C. The gellan solution at 1% was prepared by dissolving 1 gr of polysaccharide in 100 ml of distilled water at 90⁰C with continuous stirring. When completely dissolved, 10 ml of the solution were placed in a petri dish and allowed to cool to room temperature. After cooling, the formation of a transparent elastic gel was observed.

As was said the gelling process is influenced by the molecular weight, by polymer concentration, by degree of deacetylation, by the nature and concentration of added salts. By appropriately varying these parameters hydrogels with characteristics similar to those described for silicon gels can be obtained.

Preparation of gellan hydrogels in the form of microspheres

Gellan microspheres with diameters included between 10-

25 microns were obtained using the single water/oil emulsion technique.

The aqueous phase is constituted of a 1.5% gellan solution, the hydrophobic phase by a 2% solution of phosphatidylcholine (PC, surfactant agent) in dichloromethane .

The solution of PC in dichloromethane was heated to

50⁰C in a reaction flask, the hot gellan solution (50⁰C) was added slowly to the reaction flask with continuous stirring (800 rpm) and then stirred for an additional 30 minutes.

Next the flask was removed from the 50⁰C water bath and after 2 hours of stirring at the same velocity the vessel was cooled in an ice bath and the stirring velocity was reduced to 200 rpm to allow gelling of the microparticles of gellan.

After cooling, the content of the flask was placed in a refrigerator overnight. The next day the content of the flask was place in a separating funnel to allow recovery of the particles, after multiple washings with CaCl₂ the microspheres were dried and characterised.

The most interesting property of the gellan microspheres, discovered during characterisation, was their capacity to absorb water in function of the pH of the medium. The advantages deriving from the use of microspheres in the production of mammary prostheses are numerous, among others the ease of injection and improved hydration, which allows the use of smaller quantities of polymer for a given filling volume.

3.1.2 Synthetic hydrogels FVA hydrogels

Among the various techniques used to produce PVA hydrogels, the method described by Nambu [M. Nambu, European Pat. 0058497 Bl (1985)] is one of the most interesting. This method is based on a physical reticulation obtained through repeated freeze-thaw cycles of aqueous solutions of PVA. Such cycles lead to the formation of crystallites that act as reticulation centres between the chains of PVA and produce a hydrogel with high swelling capacity.

The spatial structure of the PVA hydrogels is stabilised by intra- and inter-molecular hydrogen bonds that form through the numerous hydroxyl groups situated on the polymer chain.

Various studies have determined that the properties of PVA hydrogels depend on: - molecular weight and degree of hydrolysis of the polymer; - concentration of the initial PVA solution; - nature of the solvent; - temperature and duration of freezing; - velocity of thawing; - number of cycles. Appropriately varying the previously-described parameters leads also in this case to obtaining hydrogels with optimal characteristics for use in mammary prostheses.

3.1.3 Bioartificial hydrogels

PNIPAAm/Alginate/Gelatin hydrogels . Alginate is a salt of alginic acid, a water-soluble polysaccharide of natural origin, mainly extracted from brown algae.

The presence of divalent cations, like alkaline-earth metals, permits the formation of ionic bridges between the various chains, thus creating a 3-dimensional gelled structure from the aqueous solution. Preparation of PNIPAAm/Alginate/Gelatin hydrogels. A solution of PNIPAAm (1% weight/volume), a solution of alginate (2%) and a solution of gelatine (2%) are respectively prepared.

The three solutions are mixed at room temperature so to avoid gelling of the synthetic polymer, obtaining a homogeneous solution with a weight ratio of PNIPAAm/Alginate/Gelatin of 1:2:2.

The solution is then poured into appropriate containers to which a few ml of a 2.5% CaCl₂ solution are added. After 5 minutes the partially gelled material is removed from the containers and placed in a solution of CaCl₂ for 20 minutes to complete the alginate gelling process .

The samples are then placed in a 0.5 M acetic acid solution for 16 hours to form ionic interactions between the gelatine and alginate, stabilising the protein molecule.

Then the samples are washed repeatedly in distilled water to remove the acetic acid and the hydrogels obtained are stored in the freezer at -18°C. 4 Coatings with high biocompatibility 4.1 Description of the preferred embodiment of the invention

4.1.1 Sputter deposited pyrolytic carbon coatings In the present invention several highly biocompatible coatings were evaluated that allow an improvement of the integration characteristics of the prostheses with the biological tissues. As illustrated in the preceding paragraphs, the first material considered was pyrolytic carbon in the specific physical state known as turbostratic, in which the atomic lattice is particularly compact and above all inert with respect to any chemical or biological interaction. Various basic research experiments showed an absence or drastic reduction of tissue reaction to contact with devices covered in turbostratic carbon, as well as the presence of a barrier effect to the diffusion of substances from substrate material into the biological tissue. On the basis of such premises smooth and texturised mammary prostheses were coated with pyrolytic carbon and the successive characterisation revealed the following aspects: an extremely thin (ca. 0.3-0.8 micron) coating is obtained and therefore one that does not alter the flexibility of the silicon shell, but the passage of organic molecules from the silicon toward the surrounding tissues is inhibited due to the compactness of the atomic lattice of the pyrolytic carbon.

- The very low friction coefficient of the pyrolytic carbon minimises resistance to insertion and sliding during positioning of the prosthesis, allowing the operation to proceed with minor trauma to the insertion zone.

The parameters defined for Carbofilm coating are: pressure 5 x 10^~3 mbar; voltage 75 V, arc current 7 A; time 2 hours; source temperature 140⁰C.

4.1.2 Deposition of biological material after chemical modification of the shell surface by plasma.

The second material class that was studied for the purpose of an innovative coating for mammary prostheses is that of polysaccharides, and in particular hyaluronic acid, a highly hydrophilic natural polysaccharide that is biodegradable and biocompatible and which has a determining role in many biological mechanisms that involve and promote cellular regeneration. The process for coating employs a first phase constituted of activation of the surfaces to be coated using a gas in the plasma state and to a successive phase involving the formation of a covalent chemical bond between the surface and the hyaluronic acid. Then, it was determined if the plasma activation and successive chemical coating reaction were effective for the purpose of improving surface properties, without affecting the bulk physicochemical characteristics. Samples of 2 x 2 cm were subjected to activation on both surfaces and parameters such as the following were evaluated: which gas to use, discharge time and power for the plasma phase, and reagent concentrations and reaction time for the coating phase. Air was used as the gas, having the same efficacy as nitrogen and being more economical and safe. A radiofrequency generator with a power between 30 and 50 W was used as the discharge system. In particular, at a power of 50 W reaction times included between 15 seconds and 2 minutes were tested. At the end of the treatment the samples were compared with untreated silicon shells, both in terms of morphology and of contact angle reduction due to the increase in surface hydrophilicity from the hyaluronic acid layer. The stability of the coating over the ensuing 24 hours was then tested on samples treated with plasma in air for 45 seconds by measuring the contact angle, revealing minimal variation between the measurement taken at 0 hours and the last one at 24 hours (from 55° to 59°), verifying that the hydrophilic layer of anionic molecules remains stably adherent to the surface in the 24 hours following treatment. Next, for the coating reaction the plasma-activated samples are immersed in a dilute solution of polyethylimine for ca . 90 minutes. After washing with water to neutral pH the samples are immersed in an aqueous solution of hyaluronic acid and then NHS and EDC are added at variable concentrations between 0.25 and 0.5% w/v.

After reacting for 16 hours the samples are washed with double distilled water and dried in a laminar flow hood. The samples were then characterised using the contact angle. The level of hydrophilicity conferred by hyaluronic acid (on a mean of 12 determinations) on 4 samples in three different zones, a mean contact angle of 35°, standard deviation 1° was verified, confirming the homogeneity of coating along the surface. A reduction in cellular adhesion was also verified using L929 fibroblasts in contact with the samples for 3 hours. Evaluation by optical microscopy demonstrated that in the presence of the HA coating no significant adhesion is observed with respect to untreated silicon shells and the reduction is estimated to be in the order of 90%. Bacterial adhesion was also tested using S. Epidermidis at the concentration of Ie9 cfu/cm² for 2 hours ot contact. After washing and sonicating, SEM analysis revealed a reduction from Ie6 to Ie3. Therefore, the following were verified: an increase in hydrophilic power; a reduction in unspecific cellular adhesion/activation; inhibition of bacterial adhesion. 4.1.3 Coating with polymers capable of controlled release of drugs

Biostable or biodegradable polymers capable of releasing drugs contained in them in a controlled manner were used in the outer layer of the prostheses for the controlled release of anti-inflammatory and anti-mitotic drugs. Among the best polymers used for this purpose the example of non-toxic biodegradable polyurethane elastomers produced in the present invention is given.

Polyurethanes represent an important subclass in the thermoplastic elastomer family. They contain a urethane bond analogous to the carbamate group and are constituted of chains of alternating soft (flexible) and hard (rigid) blocks. The development of polyurethanes that are degradable in a physiological environment is more recent. The principal obstacle, the fact that the diisocyanates commonly used as precursors yield toxic or cancerogenic degradation products, was overcome by using an alphatic diisocyanate derived from L-lysine (LDI), which has ethanol and L-lysine as degradation products in an aqueous environment, or 1, 4-butanediisocyanate (BDI) which produces putrescene that is a diamine involved in cellular proliferation processes. The synthesis, characterisation and functionalisation of biodegradable polyurethanes of applicative interest in the biomedical sector were carried out according to procedures described in the literature.

The functionalisation of the polyurethanes with peptide sequences of interest were carried out using structural units containing the peptide itself and the appropriate spacers as chain extenders. The structural units themselves were synthesised according to standard protocols for solid-phase peptide synthesis. The spacer serves to insure the conformational freedom necessary for an efficacious interaction with cellular receptors in a biological environment. The procedure for synthesis was reported in a dissertation.

Having thusly described the invention, it is evident that it can be modified in many ways. Such variations must not be considered departures from the spirit and scope of the invention, and, if they are obvious to one skilled in the art, must be considered included in the scopes of the following claims.

Claims

1 - A shell for mammary prostheses realised in polymeric material and constituted of any thermoplastic elastomer impermeable to the gel normally used as filler and having suitable physicochemical and mechanical properties.

2 - The shell as in claim 1 where the polymeric material is any mixture of thermoplastic elastomers.

3 - The shell as in claims 1-2 texturised in vivo with the method based on the use of an outer layer constituted of a mixture of the polymeric material used to realise the shell with a biodegradable or bioreabsorbable polymer, capable of releasing drugs.

4 - The shell as in claims 1-2 texturised in vivo with the method based on the use of an outer layer constituted of a mixture of the polymeric material used to realise the shell with a water-soluble polymer, capable of releasing drugs.

5 - Materials for filling shells for mammary prostheses constituted of reticulated natural polymers, such as, for example gellan.

6 - Materials for filling shells for mammary prostheses constituted of physically or chemically reticulated hydrophilic synthetic polymers, such as, for example PVA.

7 - Materials for filling shells for mammary prostheses constituted of bioartificial polymeric materials.

8 - The shell for mammary prostheses as in claims from 1 to 2, coated with carbofilm. 9 - The shell for mammary prostheses as in claims from 1 to 2, coated after treatment with plasma, with biological polymers having high biocompatibility, such as, for example hyaluronic acid. 10 - The shell for mammary prostheses as in claims from 1 to 4, coated with biodegradable synthetic polymers having high biocompatibility where the coating contains drugs and is capable of releasing them in a controlled manner .