DESCRIPTION

Field of the invention

The present invention relates to an artificial bladder implantable in a patient's body for collecting and discharging biological urinary fluids, in particular an artificial bladder with performance comparable to that of the natural organ in terms of volume changes, further provided with high resistance to urinary fluids and stability over the long term.

State of the art

The bladder is an elastic tissue having the function of collecting the urinary fluid that flows from the kidneys through the ureters. The accompanying figure 1 shows a schematic representation of the bladder and of the adjacent anatomical structures to which it is connected and with which it interacts. Following the influx of urine inside the bladder, this is deformed, thereby expanding its volume. As a result of the emptying, due to the opening of the urinary sphincter, the urinary fluid flows into the urethra. The emptying is supported by the contraction of the muscles surrounding the bladder bag in an action called "squeezing": as a result, the intravesical pressure decreases and the organ is again ready to accommodate new fluid.

Due to tumours or trauma, surgery to remove the bladder, called radical cystectomy, may be inevitable in some cases. The bladder cancer is the seventh type of cancer worldwide, with an estimated 260,000 new cases per year in men and 76,000 in women, while it is the sixth leading cause of death in the western part of the globe. In Italy alone, more than 9,000 oral radical cystectomy surgeries per year are carried out. This so high incidence makes cystectomy a procedure anything but rare.

Once this bladder removal operation has been carried out, there is clearly the need to restore the function performed previously by the organ removed, which is the function that allows the urinary fluid to accumulate and then flow and be discharged at regular intervals outside the body. In order to do so, the implant of an appropriate natural bladder replacement structure, which at least partially replicates the functionality thereof, is necessary. In such cases, the most common operation, usually carried out on older patients, is ureterocutaneostomy, an operation in which the two ureters are subjected to anastomosis directly to the skin or to a properly isolated intestinal loop and, through this, to the skin. The urinary fluid is then collected in two external bags attached to the patient's abdomen. It is clear that for most patients, this solution can be psychologically frustrating: the two bags often come off, are smelly and can therefore easily compromise a normal social life. This solution is therefore generally considered not acceptable and socially disabling.

A second solution after bladder removal is to reconstruct the natural organ using an autologous intestinal segment; this is referred to as "orthotopic bladder". The operation involves generally taking about 30 cm of the patient's intestine at the ileus and subjecting the latter to a number of operations to transform the original tubular shape in a substantially spherical shape of about 7-8 cm in diameter; subsequently, this spherical bag is implanted in the patient at the natural position of the bladder. Finally, ureters and urethra are subjected to anastomosis to the new bladder. Also this type of surgery involves many problems. First, there is a high degree of difficulty inherent in the operation itself, which makes it effectively possible only in a few highly specialized centres; also, this is an operation that has a high morbidity with subsequent complications and a non-negligible mortality rate. Complications have been specifically detected over the years in patients who had undergone such surgery, related to hepatic metabolism and medications, vitamin deficiency, electrolyte disturbances, bone diseases, cancers, and problems related to the presence of ostomy such as bleeding, stenosis and hernia. Finally, in almost all cases there have been serious problems of incontinence, with the patient forced to wear diapers for incontinent adults and thus face even in this case the resulting physical and psychological discomfort.

There are also other types of so-called heterotopic neobladders, such as intestinal neobladder connected to navel, emptied by the patient through a catheter. This type of neobladder also exhibits drawbacks related to the difficulty of implantation and to the infections that can lead to kidney failure.

At the moment, therefore, patients who undergo removal of the bladder have the prospect of a quality of life totally unsatisfactory, which implies more significant economic cost for the health system; all the external urinary branches, such as bags, and also the internal ones, such as neobladders, imply substantial costs for periodic checks and replacement, specialised personnel in charge of such checks, ultrasound, blood tests, etc.; this must be added to the costs incurred by the patient for diapers for urinary incontinence.

In the light of the above, it is clear that the use of artificial bladder replacement prostheses made with suitable synthetic materials would have undoubted advantages. However, despite the efforts of research in this field, it has not so far succeeded in developing a device with satisfactory performance in the medium to long term. This is mainly due to the lack of a material that has appropriate features of deformability so as to expand when urine builds up as in the natural bladder, and at the same time that has a high resistance to urine in the long term by avoiding the deposits which would alter the chemical and mechanical properties of the material, and a high resistance to infection and the formation of bio-film. Urine, in fact, intended for continuous contact with the material inside the artificial bladder, is a fluid that tends to be acidic, which exposes all types of material, to a greater or lesser extent, to the risk of fouling.

To date, in particular, many elastomeric materials have been proposed that exhibit mechanical properties, both static and dynamic, suitable for use as a substitute for natural bladder tissue. None of these materials, however, has so far exhibited sufficient resistance to urine. It is for example the case of silicone that, due to its biocompatibility, had initially found the largest diffusion in the field of artificial bladders (see for example Bogash M. et al., Surg. Forum, 1960, 10:900-903; and Abbou C. et al., Trans Am. Soc. Artif. Intern Organs, 1977; 23:371-374). However, after the first studies on the use of silicone, the interest about it was immediately resized due to its poor resistance to infection and deposits compared to other materials, such as titanium or similar metal materials.

While on the one hand metals, particularly titanium and its alloys, have shown a very high biocompatibility and stability, on the other hand these materials, by their nature, are very rigid and absolutely unsuitable for the manufacture of a deformable bag that can expand to accumulate the urinary fluid and be "squeezed" to discharge the fluid and empty.

Recently, the possibility of regenerating a urothelium, which is the transitional epithelial tissue that comes into contact with urine and that lines the multilayer urinary tract, was also investigated (see for example, Omar M. Et al. Bladder reconstruction: The past, present and future (Review), Oncology Letters, 2015). These studies used regenerated tissues consisting of autologous cells of the patient, cultured in vitro, then seeded on media, such as made with collagen and polyglycolic acid, in order to give shape to the construct for the implantation. The first experimental results about using these regenerated tissues were certainly encouraging but before their extensive use clinically, progress and insights will be necessary, such as to optimize the regenerative materials to be used, the cellular phenotypes to be selected, the method of attachment and integration of devices within the organism, and so on.

US 4311659 discloses a process for manufacturing prosthesis of organs.

To the best knowledge of the Applicants, despite the efforts over the past two decades in the fields of tissue engineering, material sciences and regenerative medicine, to date a suitable material for the manufacture of an artificial bladder which meets the above said requirements, in particular that is biocompatible, deformable but also highly resistant to urine in the long run, has not yet been identified. Such material would clearly be suitable not only for use in the manufacture of artificial bladders, but also of any other implantable medical device that would benefit of the high flexibility and deformability features of the material, combined with high stability and resistance to urine.

The need for an artificial neobladder which meets the following requirements is therefore highly felt in the field: ease of implant into the patient's body; controlled emptying based operation; adequate stability and biocompatibility that allows long life of the implant; protection of renal function; cost-effectiveness. The need to have more generally implantable, biocompatible medical devices intended to come into contact with the urinary fluids, which are resistant to them and thus do not require replacement to avoid degradation due to fouling is also felt in the field.

Summary of the invention

The subject of the present invention therefore is to provide a prosthetic device, in particular an artificial bladder, useful for replacing the natural organ, for example as a result of its removal due to trauma, failure or cancer, made of a biocompatible material, highly resistant to urinary fluids and having variable geometrical shape and volume, thereby fully meeting the requirements highlighted above.

More specifically, the subject of the invention is to provide an artificial bladder, implantable in a patient's body for the collection and discharge of urinary fluids, being able to expand and collapse as needed, made of a biocompatible material and provided with a high resistance to urinary fluids and the formation of fouling.

According to an embodiment of this invention, an artificial bladder is provided that is implantable in a patient's body for collecting and discharging biological urinary fluids, comprising a flexible hollow body, two flexible ducts upperly connected to said body and intended for putting in communication the interior of said body with two ureters in said patient's body, and a junction lowerly connected to said body for connection with said patient's urethra, said hollow body being formed by more contoured walls made of a flexible multi-layered membrane comprising at least two layers, an inner layer in a metallic material or in a biocompatible carbon-based material, intended for the contact with said urinary fluids, and an outer layer of biocompatible polymer material intended for the contact with adjacent organs in the patient's body, said contoured walls being joined together so as to form said hollow body and allow it to expand and contract with a variation of its inner volume under the pressure of said fluids by folding of at least one of said walls, without said inner layer being subject to stretching or deformation.

In a general meaning, the invention provides an artificial bladder implantable in the body of a patient for collecting and discharging the biological urinary fluids, comprising a flexible hollow body, two flexible ducts upperly connected to said body and intended for putting in communication the interior of said body with two ureters in the body of said patient, and a junction lowerly connected to said body for connection with the urethra of said patient, said hollow body being formed by more contoured walls made of a flexible multi-layered membrane comprising at least two layers, an inner layer in a metallic material or in a biocompatible carbon-based material, intended for the contact with said urinary fluids, and an outer layer of biocompatible polymer material intended for the contact with the adjacent organs in the body of the patient.

According to another general meaning, this invention provides an artificial bladder implantable in a patient's body for collecting and discharging biological urinary fluids, comprising a flexible hollow body, two flexible ducts upperly connected to said body and intended for putting in communication the interior of said body with the two ureters in the body of said patient, and a junction lowerly connected to said body for connection to the urethra of said patient, said hollow body being formed by more contoured walls made of a flexible multi-layered membrane comprising at least two layers, an inner layer made of a material intended for contacting said urinary fluids and resistant to the associated corrosion and fouling, and an outer layer made of a biocompatible polymer material intended for the contact with the adjacent organs in the patient's body.

In the above mentioned general meaning, preferably said contoured walls are joined together so as to allow said hollow body to expand and contract with a variation of its inner volume under the action of the pressure of said fluids. To this aim, advantageously, at least one of said contoured walls is able to reversibly fold under the action of the pressure of said fluids.

These and other subjects are achieved by the artificial bladder according to the present invention, whose essential features are defined in the first of the appended claims. Further important features are defined by the dependent claims.

Brief description of the drawings

The features and the advantages of the artificial bladder according to the present invention shall now be described in more detail with the following description of some embodiments thereof, made by way of a non-limiting example with reference to the accompanying drawings, in which:

Figure 1 shows a schematic representation of a natural bladder and the adjacent organs (prior art);

Figure 2 shows a prospective view of a device of the invention in an embodiment thereof, with a cutaway view of a wall of the device's body;

Figures 3a and 3b show respectively a sample of multilayer material for the manufacture of the body of the artificial bladder in Figure 2, and a section thereof along the axis A-A;

Figure 4 shows a cross section of a sample of multilayer material for the manufacture of the body of the artificial bladder in Figure 2 in a preferred embodiment thereof; Figure 5 shows the artificial bladder of Figure 2, in a contracted configuration, with a cutaway view of a detail in the device having such configuration;

Figure 6 shows the artificial bladder of Figure 2 in a configuration of semi- expansion;

- Figures 7a and 7b show magnifications of a part of the artificial bladder of the invention in a particular embodiment, wherein two adjacent contoured walls of the device are joined together by a particular mechanical constraint, respectively shown in a position of pre-assembling and post-assembling.

Detailed description of the invention

With reference to the above said Figures, and in particular to the Figure 2, it is illustrated an embodiment of an artificial bladder 1 according to the present invention, comprising a flexible hollow body 2 having variable geometrical shape, with shape and size comparable to those of the natural organ that, as this latter, may be lowerly connected to the urethra and upperly to the kidneys through the two ureters during implant, by using known connection elements that are easily identifiable by any person skilled in the art.

Always with particular reference to the Figure 2 here attached where it is illustrated a particular embodiment, the flexible hollow body 2 having a variable geometrical shape is formed by more contoured walls of a flexible multi-layered membrane, suitably joined to each other by thermal processes and/or mechanical couplings, in order to give to the body 2 the ability to expand and contract by changing its inner volume without the material constituting the membrane be subject to internal deformation under the action of the urinary fluids pressure. The present multi-layered membrane comprises at least two layers, an inner layer 3 in metallic material, intended for the contact with the urinary fluid and an outer layer 4 of polymer material intended for the contact with the adjacent organs in the body of the patient. The inner layer 3 is alternatively constituted by a biocompatible carbon-based material, such as for instance pyrolytic carbon.

Always with reference to the Figure 2, to the body 2 are upperly connected two flexible ducts 5 intended for putting in connection the inner of the body 2 with the two ureters in the patient's body by known connection elements and techniques and commonly used in the field; whereas lowerly the body 2 is provided with a junction 6 for analogous connection to the urethra of the patient.

With reference to the Figure 3a, the single contoured walls 21 ,22,23,24 of multi- layered membrane may be advantageously obtained by appropriate carving methods starting from a sole multi-layered membrane 20 prepared in a single piece, before being joined together resulting in the closed structure of the body 2. According to a particular embodiment of the present invention, illustrated for instance in Figure 3b, the hollow body 2 is formed by a bi-layered membrane consisting of an outer layer 4 of flexible polymer material and of an inner layer 3 of metallic material. The metallic material of the layer 3 may be replaced by a biocompatible carbon-based material, such as in particular pyrolytic carbon.

The present invention provides an outer layer 4 having a much greater thickness than the inner layer 3, for instance comprised between 100 μηι and 5 mm vs. an inner layer 3 of thickness of the order of the nanometre or of the micrometre, typically comprised between 5 nm and 5 μηι. More in general, while the outer layer 4 constitutes the bearing structure of the multi-layered material, which gives it shape, biocompatibility with the surrounding organs and functionality linked to its characteristic of being deformable, the inner layer 3 instead, thanks to its features of high resistance to urinary fluids, guarantees to the device the characteristic of resistance and stability over long time also in contact with urinary fluids.

Polymeric materials suitable for making the outer layer 4 are in particular those biocompatible and biostable polymeric materials and are selected, for example, from polyurethanes, silicone rubbers and polydimethylsiloxane (PDMS). Other elastomeric or otherwise highly flexible, non-biodegradable and biocompatible materials are available to any person skilled in the art who can easily select the material suitable for use in the present invention based on the description herein.

"Biocompatibility" of a material intended to interface with biological systems refers to the ability of the material to act by determining an appropriate response of the host biological system for a given application, without interfering or interacting in a harmful manner with the routine physiological activities of the organism. The compatibility between the device made of a certain material and the biological system or host organism also determines the concept of reliability of the implanted device. Biocompatible materials suitable for use in the present invention, moreover, are typically biostable, i.e. are materials that, once implanted, do not undergo substantial physical and/or chemical transformation over time.

The biocompatibility of the material of the outer layer of the present medical device causes the device, once implanted, to be able to interface with the surrounding organs by minimising the inflammatory response of the organism.

Metallic materials suitable for the manufacture of the inner layer 3 of the multilayer membrane described above are for example selected from titanium and its alloys, such as nitinol, a nickel and titanium alloy. Titanium, in fact, has recognised corrosion resistance properties due to formation of a very stable passive layer of dioxide; it is also inherently biocompatible and is very light. Nickel-titanium alloys, such as nitinol, also have good biocompatibility and corrosion resistance in vivo, as well as unique shape memory and superelasticity properties. Urine resistance is very high in these materials in the short, medium and long term. The long term stability of devices made with these materials is therefore guaranteed. It is also known that these properties of biocompatibility and corrosion resistance improve with the nano- structuring of the material surface which, even in the present invention, will therefore preferably a nanoscale structure. Further non-limiting examples of metals that can be used in the inner layer are selected from silver, gold, molybdenum and steel.

The multilayer membrane described above can be prepared by deposition of the metallic layer on the underlying layer, consisting of at least a polymeric layer. The process of deposition may be carried out by known techniques for the deposition of metal thin films on surfaces of various natures. Suitable deposition techniques according to the process of the invention are for instance selected from sputtering, chemical vapour deposition, atomic layer deposition and thermal evaporation. The nanometric or micrometric thickness of the metallic layer of the membrane described above makes the mechanical properties of the polymeric sheet, having much larger thickness, be perfectly maintained, and the composite structure obtained is still highly flexible and deformable, though the inner layer is metallic in nature. According to a wholly similar procedure, the multi-layered membrane wherein the inner layer consists of pyrolytic carbon or of other biocompatible carbon-based material, may be prepared.

Furthermore, thanks to the particular variable geometry structure of the body 2 clarified below and described in more details, the artificial bladder of the invention is able to expand and contract respectively following to the filling and the emptying of the body 2 with the urinary fluids, keeping always stable and without causing alterations on the multi-layered membrane, in particular deformations or stretching of the metallic layer 3 that, under the action of a possible mechanical stress of this type, would be subject to cracks loosing homogeneity in its resistance to urinary fluids, with a consequent rapid acceleration of the degradability of the device because of the direct contact of the urine with the polymer wall left exposed by the alterations in the metallic layer. Also an inner layer of a biocompatible carbon-based material such as the pyrolytic carbon may be subject to cracks if exposed to stretching and deformation. These drawbacks are instead prevented in the present prosthetic device, thanks to its particular variable geometry structure.

The body 2 of the present artificial bladder comprises in fact more contoured walls of flexible multi-layered membrane, appropriately joined between each other by means of thermal processes and/or mechanical couplings, in order to confer to the device the ability to expand and contract changing its volume without the material to be subject to internal deformation under the action of the pressure of said fluids.

According to a further embodiment of the invention, the multi-layered membrane constituting the body 2 of the present artificial bladder comprises an inner metallic layer 3 and an outer polymer layer 4 formed on its turn by more flexible polymer overlapping layers, equal or different among each other. Alternatively, the inner layer 3 is constituted by a biocompatible carbon-based material, such as in particular pyrolytic carbon. According to a particularly preferred embodiment of the invention, the flexible polymer overlapping layers are interspersed by layers of an inextensible material, preferably a mesh material, which provides to the membrane advantageous properties of non-deformability. Materials suitable for the manufacture of such layers of an inextensible material are for instance polymers such as polypropylene or metallic materials such as titanium. A sample of this embodiment of outer layer 4 is illustrated in cross section in the Figure 4, wherein are visible walls of a mesh layer 7. The structure described above allows that at least a part of the artificial bladder bends in a controlled way under action of the pressure of the urinary fluids collected therein, in order to allow the passage from a contracted configuration to an extended one, respectively illustrated in the Figures 5 and 6, and to return then to the contracted configuration after the discharge of the fluids to the outside, without similar repeated cycles of loading and unloading be the cause of damages to the present prosthetic device, in particular to the inner layer 3.

The artificial bladder implantable in a patient's body for collecting and discharging biological urinary fluids according to the invention comprises a flexible hollow body 2, two flexible ducts 5 upperly connected to the body 2 and intended for putting in connection its inner space with the two ureters in said patient's body, and a junction 6 lowerly connected to the body 2 for the connection to said patient's urethra, the hollow body 2 being formed by more contoured walls 21 ,22,23,24 made of a flexible multi- layered membrane comprising at least two layers, an inner layer 3 in metallic material, intended for the contact with said urinary fluid, and an outer layer 4 in a biocompatible polymer material intended for the contact with the adjacent organs in the patient's body, these contoured walls being joined to each other so as to allow the hollow body 2 to expand and contract varying its inner volume under action of the pressure of said fluids by folding of at least one of said walls, without being subject to stretching or deformation of the inner layer 3. The inner layer 3 of the present multi-layered membrane is alternatively constituted by a biocompatible carbon-based material, such as in particular pyrolytic carbon.

In other words, in the present artificial bladder, at least one of the contoured walls forming the hollow body 2 is able to fold reversibly by folding to achieve the contraction and expansion of the hollow body with the variation of the pressure of the biological urinary fluids contained therein in the phases of collection and of discharge.

According to a particularly preferred embodiment of the artificial bladder of the invention, illustrated in the annexed Figures, the body 2 of this prosthetic device comprised two first walls 21 and 22 of flexible multi-layered membrane, facing one another and joined along the respective sides 25; and further comprises two second walls 23 and 24 of the same membrane, facing one another and joined to the respective sides 26 left free of the above said first walls 21 and 22, so as to form a hollow body 2 closed. In this embodiment the second walls 23 and 24 are joined to the walls 21 and 22 so as to fold inside said first walls 21 and 22 and have their own edges doubled in proximity of the joined ends. This is well visible in Figure 5, where the present artificial bladder is shown in a completely contracted configuration, and in particular in the magnification of the panel in Figure 5 where two parts of the wall 23 are visible, folded one over the other between the first walls 21 and 22; the dashed lines 29 and 30 respectively indicate the folds in the second walls 23 and 24, underlying the wall 21. In Figure 6, where the same device is represented in a semi- extended form, the fold 29 is visible, around which the wall 23 collapses when the artificial bladder contracts.

This embodiment allows the geometrical configuration of the artificial bladder to vary in a particularly efficacious and reproducible way when the contoured walls of the multi-layered membrane vary their profile according to the amount of urinary fluid collected therein. In the contracted configuration (Figure 5) the profiles of the first walls 23 and 24 present the folds 29 and 30 with a radius of curvature close to the thickness of the polymer layer 4 and the inner volume of the body 2 is reduced to the minimum of the collected fluid. When the artificial bladder returns to an extended or semi-extended configuration (respectively Figure 2 and Figure 6), the curvature radius of the same folds 29 and 30 increases and the inner volume available to the fluid to be collected enlarges.

It is to be understood that the present invention also comprises embodiments of the device wherein the contoured walls are joined together so as to form folds towards the outside of the body 2, for instance embodiments wherein the second walls 23 and 24 are joined to the first walls 21 and 22 so that they fold towards the outside of the body 2.

In Figure 7a and b a particular type of link between the two walls 21 and 22 of the body 2 is illustrated, respectively in a pre-assembling position and in a post-assembling position. As it can be seen in Figure 7 the link between the two walls is in this case achieved thanks to the presence of two complementary profiles 27 and 28 at the ends of the walls to be joined 21 and 22, which engage to each other by interlocking. Preferably the interlocking profiles are directly made by the polymer material of the multi-layered membrane, so as to guarantee a higher tightness of the device, and at the same time assemble the contoured walls in a simple and rapid way.

The implantable prosthetic devices according to the present invention can be used in a medical context, and particularly in the field of urology, in developing implantable artificial bladders able to maintain for long periods, potentially for the patient's lifetime, a functionality comparable to that of the natural organ in terms of accumulation and discharge of urinary body fluids, or in developing of artificial urinary sphincters, which do not require periodical replacement after implantation. The present devices are easy to be implanted in the patient's body and made of totally biocompatible materials.

The present, moreover, is a bladder completely artificial and stable over the long term, which does not require the removal of parts of the intestine or of other tissues of the patient, thus eliminating the risks, complications and loss of performance over time as shown by the two main strategies outlined above, currently used to restore the functionality of the bladder removed. Moreover, compared to the use of external pouches attached to the abdomen, the present artificial bladder would have definite advantages on the patient's quality of life by helping to eliminate those social problems related to the use of the external pouch.

A further advantage associated with the use of the present multilayer membrane for manufacturing an artificial bladder is represented by the fact that, once implanted in the patient, this device does not require special inspections, replacements and periodic checks as it happens with internal or external urinary branches, resulting in the reduction of discomfort for the patient and significant savings in health care costs.

Also the cost per se for the production and implantation of the present artificial devices is far less than the costs predictable for the development of the same organs obtained from regenerated tissues starting from autologous or heterologous cells.

The present invention has been described so far with reference to preferred embodiments thereof. It is understood that other embodiments may exist that relate to the same inventive scope, all falling within the scope of protection of the following claims.