WO2016071290A1

WO2016071290A1 - Process for obtaining a silicone patch having at least one surface coated with carbon applied by arc deposition for the replacement of a portion of bladder wall

Info

Publication number: WO2016071290A1
Application number: PCT/EP2015/075480
Authority: WO
Inventors: Antonio Sambusseti
Original assignee: Antonio Sambusseti
Priority date: 2014-11-05
Filing date: 2015-11-02
Publication date: 2016-05-12
Also published as: EP3215052A1; TN2017000172A1; CN107072768A; MA40896A

Abstract

A description is given of a process for coating the surface of a patch (1; 100; 200) for the replacement of a portion of bladder wall following partial cystectomy. The patch comprises a multilayered membrane (2) of soft silicone, with a thickness of approximately 600 microns so as to be sufficiently elastic in order to be able to withstand the dilations due to the expansion and to the deflation of the bladder, and a surface coating in carbon applied by means of arc deposition.

Description

PROCESS FOR OBTAINING A SILICONE PATCH HAVING AT LEAST ONE SURFACE COATED WITH CARBON APPLIED BY ARC DEPOSITION FOR THE REPLACEMENT OF A PORTION OF BLADDER WALL DESCRIPTION

The present invention relates to a process for obtaining a patch in silicone, coated with carbon applied by arc deposition, to be used for the replacement of a portion of bladder wall following partial cystectomy, and to the relative patch obtained therefrom.

As is known, when a portion of the bladder of a patient is affected by a serious pathology, such as partial neoplasia or bilharzia (schistosomiasis), this portion of bladder has to be removed to prevent the pathology from spreading to the entire bladder. The removal of this portion of bladder creates a hole in the bladder which is closed by using a patch which is sutured in the perimeter of the bladder wall which defines this hole.

The patches currently available for this surgery differ one from the other essentially through the type of material used: natural material, for example tissue deriving from the inside-out intestine of the patient; non-absorbable synthetic material, such as for example silicone, polypropylene and the like; absorbable synthetic material, such as for example polyglycolic acid (PGA).

Since synthetic materials offer higher mechanical performances such as, for example, elasticity and non-collapsibility under the weight of the growing tissue, they are particularly advantageous in the case of replacement of large portions of bladder. However their biocompatibility is not high so that they are normally covered with a layer of biocompatible material.

Currently, as biocompatible material for this type of synthetic patches, fatty acids of the omega-3 family or diamond-like carbon are used, which also exhibit a good resistance to urine.

However it is a constant need of this sector to have an increasingly high number of biocompatible materials, alternatives to those currently used, which are found to be suitable for being applied to synthetic patches and which have at the same time a good, if not improved, resistance to urine. Another biocompatible material suitable for covering the surface of synthetic patches is pyrolytic turbostratic carbon, which is applied in the form of a thin microfilm, with thickness from a hundred nanometres up to a few microns, using the technique of physical deposition known as sputtering, so as to obtain a coating with a very smooth surface.

This coating of pyrolytic turbostratic carbon has been found to be better with respect to texturised (rough) silicone, used in the prior art due to the performances of anti-adhesion with the internal body tissues. See, for example, what is stated in the application WO2009/033528 in the name of the Applicant.

However said technique of sputtering which is one of the known techniques of physical deposition in the vapour- phase (PVD, physical vapour deposition) requires long times of production, therefore causing low productivity of said coated patches, with consequent increase in production costs.

US2013/317622 describes a method for implanting a patch on a bladder in the surgical treatment of diseases of the bladder wherein the edge of the patch is interposed between the muscle tissue and the underlying portion of urothelial tissue, in replacement of the removed portion of the bladder so as to be sandwich-stitched between the muscle tissue and the urothelial tissue.

The object of the present invention is to eliminate the disadvantages of the prior art, providing a process for obtaining a biocompatible synthetic patch for the replacement of a portion of bladder wall, following partial cystectomy, which is fast, simple and having improved productivity so as to reduce the costs of production of the patch.

Another object is that of providing such a patch appropriately coated with a biocompatible material which has good performances of anti-adhesion with the internal body tissues, and which is also provided with a high resistance to urine and with a low tendency towards incrustation, following prolonged contact with the urine due to its content of sediments, in order to result in a patch for bladder which is reliable and durable. Yet another object of the present invention is to provide such a patch which is also practical for implanting for the surgeon and economical.

These objects are achieved by the process in accordance with the invention having the features listed in the appended independent claim 1.

Advantageous embodiments of the invention are disclosed by the dependent claims.

The object of the present invention is therefore a process for obtaining a patch in biocompatible silicone for the replacement of a portion of bladder wall following partial cystectomy, said process comprising the steps of

(A) preparing a membrane of soft silicone in the form of a planar patch of preset dimensions by dipping, optionally incorporating a synthetic mesh in said silicone;

(B) applying a layer or microfilm of carbon on at least one of the two surfaces of said patch by arc deposition, preferably at least on the surface intended to be turned towards the inside of said bladder.

In a particular embodiment it is possible to provide, after step A) but before step B), an optional step (Α') wherein at least one hole having a diameter greater than the diameter of a ureter or urethra is formed in said membrane, then closing said hole with a disk in silicone having greater diameter with respect to said hole, as will be explained in detail here below.

The patch for the replacement of a portion of bladder wall following partial cystectomy, according to the invention, comprises a multilayered membrane of soft silicone, with a thickness of approximately 600 microns.

In this way the patch is sufficiently elastic in order to be able to withstand the dilations due to the expansion and to the deflation of the bladder.

Moreover at least the surface of the patch intended to be turned towards the interior of the bladder is coated with an arc-deposited microfilm of cai'bon, while the surface of the patch intended to be turned towards the exterior of the bladder can be simply texturised or also coated with arc-deposited carbon.

The optional texturising takes place by sprinkling with cooking salt the final layer in silicone before the phase of vulcanization according to what is described, for example, in the application WO2007/039160 incorporated here in full for reference, repeating the phases of salting and vulcanization twice, then immersing the patch obtained in this way in water and brushing the final layer. Preferably both the surfaces of the patch are coated with arc-deposited carbon, preferably by means of cathodic vacuum arc, a technique widely used also to create films of diamond-like carbon.

Arc deposition is a process wherein the evaporation of the material to be deposited is produced by an electrical discharge (electrical arc) directed onto the material.

Said arc deposition process ehe takes place in a vacuum chamber and provides for the following steps:

1. evaporation: the material to be deposited is made to evaporate from a target source by means of a simple electrical discharge which is self-supporting in vacuum without the feeding into the chamber of an inert or reactive gas,

2. transport: the evaporated material is transported, in vapour form, through an environment in a vacuum, as far as the substrate to be coated,

3. condensation: the material coming from the target nucleates and grows on the substrate, forming the coating.

The evaporation of the coating material in said process of arc deposition takes place by means of an (arc) electrical discharge rather than by thermal evaporation (direct through the Joule effect, by means of the heating of a crucible containing the material to be evaporated), electrons beam evaporation (e-beam wherein a beam of electrons impacts on the material to be deposited, thus dissipating its kinetic energy in the material, causing the evaporation thereof) or other type of evaporation, for example by means of sputtering (the material is vaporised from a surface known as target via a physical sputtering, that is to say the surface atoms of the target are physically extracted from the solid surface thanks to the energy transfeiTed to them by a bombarding of ions created by plasma constituted by insert gas such as argon or by reactive gas such as nitrogen or oxygen).

Arc deposition uses therefore an electrode through which a current with high density and low potential difference is made to pass. The evaporation of the material to be deposited comes from the triggering of an electrical arc on the surface of the material to be evaporated: this arc "melts" the material which sublimates. The evaporated material is almost totally ionised and forms a plasma with high energy,

The substrate is placed under a bias voltage in order to be able in this way to attract the ions more easily.

This technique of arc deposition, although causing surface defects and irregularities in the coating caused by the melted drops which deposit on the substrate, since not all the material is perfectly vaporised, has the advantage of allowing greater speeds of deposition with respect to other processes of physical deposition such as for example that of sputtering used to make smooth coatings of pyrolytic turbostratic carbon.

By means of laboratory experimental tests and test bench tests with the scanning electron microscope performed on samples of strips of silicone coated with this arc-deposited carbon, the Applicant has found that, with the same thickness, an arc-deposited carbon coating shows the same resistance to urine as a coating in pyrolytic turbostratic carbon, although exhibiting a greater surface roughness with respect to said coating in pyrolytic turbostratic carbon: the samples were immersed in human urine for a week and subjected to stresses of torsion, flexure and bending for cycles of 10,000 times. The microscope scanning did not show any sign of deterioration due to the corrosive effect of the urine.

Additionally the Applicant has found that the greater surface roughness of the arc- deposited carbon with respect to the DLC carbon films and to the films of pyrolytic turbostratic carbon does not have a negative influence on the resistance to urine, the biocompatibility of the patch, the adhesion of the patch to the surrounding tissues, its population by cells.

"Rough surface" of the coating is intended here to identify a surface which has roughness or irregularities on the surface, which can be in the form of grooves or scratches, with variable shape, depth and direction.

The Applicant has also found that, with the same time and dimensions of the patch, arc deposition allows the production of a number of pieces at least 10 times greater with respect to the process of sputtering generally used to apply films of pyrolytic turbostratic carbon. The multilayered membrane of the patch can also incorporate in its thickness a reinforcement mesh in Dacron to facilitate the stitching of the patch to the bladder and avoid the tearing of said stitches. Further features of the patch of the invention will be made clearer by the following detailed description referred to some of its embodiments purely by way of a non-limiting example, illustrated in the accompanying drawings, in which:

Fig. 1 is a plan view of a patch according to a first preferred embodiment of the invention, shown from the side intended to be turned towards the exterior of the bladder;

Fig. 2 is a plan view of the patch of Fig. 1 , but shown from the side intended to be turned towards the interior of the bladder;

Fig. 3 is an enlarged view in cross section of a portion of the patch, wherein the section has been taken along plane III-III of Fig. 1 ;

Fig. 4 is a plan view, partially sectioned, of a patch according to a second prefeixed embodiment of the invention, shown from the side intended to be turned towards the exterior of the bladder;

Fig. 5 is a plan view of the patch of Fig. 4, but shown from the side intended to be turned towards the interior of the bladder;

Fig. 6 is an enlarged view in cross section of a portion of the patch, wherein the section has been taken along plane VI-VI of Fig. 4; and

Fig. 7 is a perspective view, illustrating schematically the application to a bladder of the patches according to the first and the second preferred embodiments of the invention;

Fig. 8 is a plan view of a patch of a third embodiment of the invention which incorporates internally a reinforcement mesh, shown with a removed surface portion;

Fig. 9 is an enlarged view in cross section of a portion of the patch, wherein the section has been taken along plane ΓΧ-ΙΧ of Fig. 8.

Referring to Figs. 1 - 3, a patch according to a first embodiment of the patch preferred in accordance with the invention is described, denoted overall by reference numeral 1 , where both the surfaces of the patch are coated with arc-deposited carbon.

The patch 1 is made with a membrane 2 (Fig. 3) of soft silicone, preferably multilayered, having a thickness of approximately 600 microns so as to be sufficiently elastic in order to be able to withstand the dilations due to the expansion and to the deflation of the bladder. The silicone used can consist, for example, of copolymers of dimethyl and methyl vinyl siloxane reinforced with silicon. A medical silicone is preferably used, such as for example a medical elastomeric silicone with high tensile strength such as the one known by the code MED 4735™ and marketed by the company Nusil Technology.

The membrane 2 of the patch 1 is preferably constituted by twenty layers of silicone, each one having a thickness of approximately 30 microns. The multilayered membrane 2 is obtained from raw material of silicone, by means of a processing procedure known as dipping where the layers of silicone are superimposed one on the other in the semi-fluid state.

This technique of multilayered dipping consists in forming the first layer, making it evaporate with cyclohexane for 10 minutes, superimposing the second layer, making it evaporate again with cyclohexane for 10 minutes and so on up to the final layer.

At this point the layered membrane 2 of silicone is in a semi-fluid state, and is then placed in the oven for vulcanization at a temperature of approximately 150°C and for a time varying from 30 min. to 1 h, on the basis of the size of the patch to be created. After the cycle of vulcanization the multilayered membrane 2 of silicone is in its consistency of optimal elasticity and softness and no longer in the semi-fluid state.

The surface of the patch 1 intended to be turned towards the interior of the bladder is then coated with a film 3 of a single layer of arc-deposited carbon, having a thickness of approximately 0.2 - 0.3 micron.

The surface of the patch 1 intended to be turned towards the exterior of the bladder is also preferably coated with a microfilm 3 of a single layer of arc-deposited carbon, having a thickness of approximately 0.2 - 0.3 micron.

Said coating of arc-deposited carbon, although having a surface roughness of the order of thousandths of a micron, was found to be however a material highly suitable to be used as coating for a patch in silicone so as to confer thereto biocompatibility and resistance to urine. More particularly it was found that the arc-deposited carbon is hydrophobic to such an extent as to guarantee a high flow of the urine and a smaller tendency of the latter to adhere to this material, showing a lack of incrustations. Moreover said arc-deposited carbon was found to be neutral when in contact with cells and micro-organisms: this entails a rapid population of the cells and accelerated assimilation of the device implanted. At the same time the adhesion to the surrounding tissues is reduced due to the reduced interaction between the arc-deposited carbon of the coated surface and the cells of these tissues.

The process of coating by means of arc deposition takes place according to the prior art as described above.

Should a more rigid patch be needed, it is also possible to use a patch 200 in silicone (Fig. 8) constituted by the same membrane 2 described above for the patch 1 but incorporating internally, in the thickness, a synthetic mesh 4 in Dacron or another similar material, as reinforcement to facilitate its stitching to the bladder.

The insertion of said mesh 4 is obtained by means of a known technique, for example moulding, dipping or similar techniques which allow said mesh 4 to be incorporated in a layer of silicone. Subsequently a layer 3 of arc-deposited carbon is applied on the surface of the membrane, similarly to the patch 1 without reinforcement mesh.

Referring to Figs. 4 - 6 a description is given of a patch 100 according to a second embodiment of the preferred patch in accordance with the invention, wherein identical elements or elements corresponding to those already described are denoted by the same reference numerals and their detailed description is omitted.

In this case the patch 100 provides for the multilayered membrane 2 of soft silicone to be provided with a hole 5 having a diameter greater respectively than the diameter of the ureters 20, 20' and of the urethra 21 (shown in Fig. 7). This hole 5 can have a diameter, for example, of 20 mm.

The hole 5 is formed with a special surgical instrument consisting of a handpiece or punch, with a square section tip of 3 cm in length, and final diameter comprised between 8 and 14 Charrier (Ch) or French (Fr) in accordance with the possible dimensions of the ureters 20, 20' or of the urethra 21.

The hole 5 is closed by a portion of membrane 6 with a substantially discoid shape of greater diameter with respect to the hole 5. The portion of membrane 6 is similar to the multilayered membrane 2 but can have the surface intended to be turned towards the exterior of the bladder not provided with the layer of arc-deposited carbon.

The portion of membrane 6 is applied on the side of the patch 100 intended to be turned towards the interior of the bladder by melting or heat sealing of the silicones of the membranes 6 and of the membrane 2 and subsequent vulcanization in the oven so as to obtain a single layer. Subsequently the inner and outer surface of the assembly constituted by the patch 100 and by the portion of membrane 6 are coated with the microfilm (layer) 3 of arc-deposited carbon.

The patches 1, 100 and 200 can be made in any shape and size. Preferably said patches have a rectangular shape 200 mm x 300 mm, or square shape with a side of 200 mm.

For all types of patches 1, 100 and 200 the manufacturing cycle is performed in a controlled environment, that is to say with controlled contamination, in a white room. Once processing has finished, the patches 1, 100 and 200 are placed in a double blister closed with a sheet of Tyvek to avoid contaminations, and sent to a cycle of sterilisation with a base of ETO (ethylene oxide). At this point the patches 1, 100 and 200 are ready for use in an operation.

Fig. 7 illustrates schematically a natural bladder 40 with the relative ureters 20, 20' and urethra 21. If the zone of the bladder 40 affected by neoplasia is distant from the ureters 20, 20' and urethra 21, the surgeon removes this affected zone and, in order to cover the removal hole, applies a patch 1 by means of stitches 7 which connect the perimeter of the patch 1 to the wall of the bladder 40 around the removal hole. Fig. 7 also illustrates the case wherein the zone of the bladder 40 affected by neoplasia is close to one 20 of the ureters. In this case the surgeon removes this affected area, detaching it from the relative ureter 20. Then the surgeon makes a hole 9 in the portion of membrane 6 of the patch 100. In order to perforate the portion of membrane 6 the surgeon can use the same handpiece or punch used to perforate the membrane 2 in the phase of making of the patch 100. The tip of the handpiece is chosen on the basis of the dimensions of the ureter 20 and the hole 9 is formed with the measurement in Ch or Fr which the surgeon considers appropriate on the basis of the dimensions of the ureter 20 in the operation.

The ureter 20 is inserted in the hole 9 of the patch 100 which, being elastic, tightens slightly around the tube of the ureter 20. Then the portion of membrane 6 of the patch 100 is attached to the ureter 20 by means of four stitches 11 arranged in a square, around the tube of the ureter 20 and passing through the portion of membrane 6 and through the tissue of the ureter 20.

Finally the perimeter of the patch 100 is attached, by means of stitches 10, to the wall of the bladder 40 around the ureter 20.

For example for the stitches 7, 11 and 10 a curved cylindrical needle has to be used and Monocryl Ethicon™ 4-0 and 5-0 yam can be used, produced by Johnson & Johnson and composed of poliglecaprone, i.e. a copolymer made by means of synthesis of glycolide (75%) and epsilon-caprolactone (25%). This yam is not coated, is monofilament and is not woven. The manufacturer indicates this yarn as the most suitable for stitches in general for soft tissues and blood vessels, including those to ureters and urethra.

There are however other suture yams which could conveniently suit the cases in question and the needs of the patches, and it remains the decision of the surgeon to choose that most congenial to him or her.

The holes of passage of the stitches 7, 1 1 and 10 in the ureter 20 and in the bladder 40 do not constitute a risk of leaks of liquid, in that in a few hours the tissue is reconstructed. To avoid leaks of urine (liquid), the holes of the stitches 7, 11 and 10 are sealed and closed with a cc (a drop) of surgical glue, such as for example Glubran 2™, nomially available commercially. The Monocryl™ yarn used for the stitches is reabsorbed in 90 - 120 days approximately but starts its downward curve of loss of tension at the 22nd day, concluding and losing 75% of the tensile strength on the 28th day. From the 28th day there is no longer tensile strength in the yarn, but on this date the ureter 20 and the patches 1, 100 and 200 are held fixed by the glue and above all by the formation of the fibrotic capsule which acts as sealing member of the ureter and of the patches 1, 100 and 200. It should be noted that the fibrotic or polyprotein capsule is formed in approximately 30 days. What is described above in relation to Fig. 7 can be applied also to the reinforced patch 200, without thereby departing from the scope of the present invention.

Numerous detailed modifications and changes, within the reach of a person skilled in the art, may be made to the present embodiments of the invention, in any case coming within the scope of the invention disclosed by the appended claims.

Claims

1. Process for preparing a patch (1; 100; 200) for replacement of a wall portion of a natural bladder having ureters (20, 20') and urethra (21), after partial cystectomy, comprising a planar membrane (2) of soft and elastic silicone able to withstand the dilations due to the expansion and to the deflation of the bladder, said patch having a first surface intended to be turned towards the outside of the bladder and a second surface intended to be turned towards the inside of the bladder,

said process comprising the step of

applying a microfilm or layer (3) of carbon on at least said surface of said membrane (2) intended to be turned towards the inside of the bladder by means of arc deposition.

2. Process according to claim 1, characterised in that said layer (3) of said patch (1 ; 100; 200) is a film having a thickness of approximately 0.2 - 0.3 micron.

3. Process according to claim 1 or 2, characterised in that said layer (3) of carbon applied by means of arc deposition is also on the surface of said patch (1; 100; 200) intended to be turned towards the outside of the bladder.

4. Process according to any one of the preceding claims, characterised in that said membrane (2) of said patch (1; 100; 200) is multilayered and comprises a plurality of superimposed and vulcanized layers of silicone.

5. Process according to any one of the preceding claims, characterised in that said membrane (2) of said patch (1 ; 100; 200) comprises twenty superimposed layers of silicone, wherein each layer has a thickness of approximately 30 microns.

6. Process according to any one of the preceding claims, characterised in that the silicone of the membrane (2) of said patch (1; 100; 200) consists of copolymers of dimethyl and methyl vinyl siloxane, reinforced with silicon.

7. Process according to claim 6, characterised in that said layers of silicone of the membrane (2) of said patch (1; 100; 200) comprise a silicone for medical use, such as medical elastomeric silicone with high tensile strength known commercially as MED 4735™ of the firm Nusil Technology.

8. Process according to any one of the preceding claims, characterised in that said patch (100) also comprises a hole (5) with a larger diameter than the diameter of the ureters (20, 20') and of the urethra (21), said hole (5) being covered by a portion of soft silicone membrane (6) heat sealed to said membrane (2).

9. Process according to claim 8, characterised in that said portion of membrane (6) of said patch (100) has the same structure and is made in the same material as the membrane (2) and is optionally not provided with the layer (3) of carbon coating applied by means of arc deposition.

10. Process according to any one of the preceding claims, characterised in that said membrane (2) of said patch (200) incorporates inside the thickness a reinforcing mesh (4) in Dacron or the like,

11. Patch ( 1 ; 100; 200) as defined in any one of the preceding claims, characterised in that the surface of said layer (3) of carbon applied by means of arc deposition has a surface roughness.