FR3112935A1 - IMAGEABLE AND RESORBABLE MEDICAL DEVICE AND USES THEREOF - Google Patents

Abstract

The invention relates to an imageable and resorbable medical device, comprising at least one tubular part (1) formed from a physical hydrogel of polysaccharides, suitable for insertion into the urethra of a subject, for various medical and/or surgical applications . Fig.1

Description

IMAGEABLE AND RESORBABLE MEDICAL DEVICE AND USES THEREOF

The present invention relates to the field of medical devices intended to be inserted into the urethra of a subject. More specifically, the invention relates to an imageable and resorbable medical device, comprising at least one tubular part formed from a physical hydrogel of polysaccharides, suitable for insertion into the urethra of a subject, for various medical and/or surgical applications. .

This disclosure relates to the field of medical devices intended for insertion into a subject's urethra.

Various medical devices, capable of being inserted into the urethra of a subject, are available in the prior art. Such devices are intended in particular to avoid stenosis of the urethra, in cases of urinary dysfunction, for example caused by inflammation or damage to the urethra or neighboring tissues. Such dysfunctions may, in particular, be due to surgery or treatment for prostate cancer. Prostate cancer is the most common cancer in men and the third deadliest cancer for men behind lung cancer and colorectal cancer. Radiation therapy is an effective and widespread method of treating prostate cancer. It consists in eliminating the cancerous cells, by irradiating them using a radioactive source internal or external to the body of the subject to be treated. Nevertheless, some side effects may occur. In particular, irradiation may, in some cases, cause inflammation of the prostate, resulting in urethral stricture and possibly leading to inability to urinate requiring rapid intervention to preserve the patient's life.

In order to overcome these problems, medical devices have been developed, in particular urinary catheters or intra-urethral devices, in particular in the form of stents, making it possible to maintain a sufficient diameter for the flow of liquids through the urethra, the time for the inflammation to subside. To date, the majority of stents used in urology are made from metal alloys, which can be coated with polymer membranes or with non-bioresorbable polymers such as silicones, polyurethane, PTFE. In addition, the companies Boston Scientific®, BARD®, UROVISION® and Optimed® offer polymer devices, which are rather proposed to fight against ureteral stenosis.

The use of a non-bioresorbable device requires two operations: one for its insertion and the other for its removal. Different forms of devices have been studied to facilitate their removal, such as The Spanner® device marketed by SRS Medical® or the prostate stents from Allium Medical®: Round Posterior Stent (RPS) and Triangular Prostatic Stent (TPS) (described in particular in application US2004/0167635). However, these solutions are not exempt from the intervention of a specialist to remove them.

In addition, it has been observed in use that certain metal stents can cause irritation and discomfort when they come into contact with tissues, due to the rigidity of the alloys. Their major drawback is that they disturb the dose of irradiation delivered to the patient in radiotherapy, due to their metallic structure which absorbs part of the radiation, and especially because they constitute sources of secondary electrons.

Application EP 0 634 152 proposes medical devices in the form of a tube made of a biodegradable polymer. Their polymeric composition gives them, compared to metallic devices, a lower rigidity and therefore a softer contact with the interior of the urethra, limiting irritation of the channel and providing better comfort for the patient. Their biodegradable nature eliminates the need for a double intervention, removal by a specialist being unnecessary. The polymers envisaged in this document are polyglycolides (PGA), polylactides (PLA), mixtures of glycolide/lactide, glycolide/trimethylene carbonate polymers, polydioxanones, polyhydroxybutyrates, polyhydroxypropionates, and mixtures thereof, copolymers of these polymers, chitins, polyester amides and glycolesters. Openings are made in the tube, so as to allow the tissues destroyed during a laser treatment to be evacuated with the urine which will flow on the walls of the tube (see column 3 lines 12-19). In this document, it is planned to implant the device in the subject, after treatment with laser irradiation. It is understood that the laser irradiation would damage the implanted device. Furthermore, the tubes proposed in application EP 0 634 152 due to the polymers used are still quite rigid, or in the case of structures in perforated form, allow direct contact between the urine and the urethra, which leads to inflammation issues.

Summary

In the context of the invention, it is proposed to use a device which is both resorbable and resistant to irradiation similar to the radiotherapies used in the treatment of prostate cancer, and which has a composition and a geometry adapted to limit inflammation problems. In addition, an imageable device is proposed, in particular by magnetic resonance imaging, thus making it possible to verify its positioning, to evaluate the state of resorption by urine over time, and/or to position the patient before a therapeutic irradiation.

Thus, the invention relates to a medical device formed from a hydrogel of polysaccharides, the polysaccharides being carefully selected to obtain advantageous physico-chemical and mechanical properties, and comprising at least one tubular part capable of being inserted into the urethra of a subject, for its use in the treatment or prevention of urinary disorders.

After insertion into the urethra of a subject, the tubular part formed of a hydrogel of polysaccharides ensures guidance of the urinary flow inside the urethra. It is thus possible to limit urinary disorders, or even avoid or remedy urinary disorders. In particular, the use according to the invention of such a medical device consists in avoiding urethral stenosis or, at the very least, fighting against urethral stenosis.

Furthermore, such a device has many advantages, due to its composition in a biodegradable polymer:

Since the device used in the context of the invention is resorbable, a single operation is required for its installation. The intervention to remove it is no longer necessary since it will be degraded after a certain time, following the flow of urine through the tube. Indeed, the polysaccharide hydrogel will gradually degrade in the implantation medium, with an acid pH.

It does not disturb the control of the dose of irradiation in radiotherapy, causing no absorption of the irradiation.

It generates little or no secondary electron radiation emissions potentially harmful to the patient.

Due to its composition in a hydrogel of chitosan and modified chitosan, it has sufficient flexibility not to constitute a hindrance in the body. It also does not generate inflammation once applied.

The tubular part formed from a polysaccharide hydrogel used in the context of the invention is open at both ends and preferably has solid walls as shown , that is to say non-perforated, acting as a barrier on a macroscopic scale between the wall of the urethra, at the level of which it is positioned, and the urinary flow. It is a question of solid or non-perforated walls and of a barrier on a macroscopic scale, because no opening or opening is visible to the naked eye, which nevertheless does not exclude a passage of urine, due to the fact the porosity of the tube and/or an at least partial exchange between the initial water of the hydrogel and the urine. Due to its solid walls, the polysaccharide hydrogel tube used in the context of the invention makes it possible to channel the flow of urine and ensure its circulation at a distance from the internal walls of the urethra. By thus limiting the contact between the flow of urine and the internal walls of the urethra, the problems of inflammation, even irritation, are thus reduced.

In the context of its use according to the invention, the medical device is inserted into the urethra of a patient, as for example illustrated in the and 3 in the case of human subject, male and female, respectively.

Such a device is used in the context of the invention to prevent urinary disorders that could be caused in particular by external radiotherapy or brachytherapy, treatment by focused ultrasound, cryotherapy, or any other physical treatment for prostate cancer, or even to remedy urinary dysfunction due to the presence of a fistula.

The invention proposes, in particular, a medical device defined in the context of the invention, for its use to prevent stenosis of the urethra.

The interest of guiding the urinary flow inside the urethra and/or of fighting against the stenosis of the urethra, can intervene in particular during different treatments.

The invention proposes, in particular, a medical device defined in the context of the invention, for its use to limit the side effects of external radiotherapy or brachytherapy, in particular in the context of the treatment of prostate cancer. In this case, advantageously, the medical device is inserted into the urethra of the subject to be treated, before the external radiotherapy or during the brachytherapy procedure. In addition, and because of its imageable properties, the device can serve as a reference for the positioning of the patient before irradiation for radiotherapy.

The invention also proposes a medical device defined within the framework of the invention, for its use, in order to limit the side effects of treatment by focused ultrasound, cryotherapy, or any other physical treatment for prostate cancer. In this case, advantageously, the medical device is inserted into the urethra of the subject to be treated, before the treatment by focused ultrasound, cryotherapy, or the other physical treatment applied. The subject of the invention is therefore a device according to the invention for its use in the treatment of prostate cancer. In such a treatment, the device will be inserted into the urethra of the subject and the physical treatment adapted to prostate cancer will then be carried out, and in particular, one or more irradiations for a radiotherapy treatment.

More generally, the subject of the invention is therefore a tube formed from a physical hydrogel of polysaccharides, capable of being inserted into the urethra of a subject for its use in the treatment or prevention of urinary disorders.

The invention also proposes a medical device defined in the context of the invention, for its use to limit urinary disorders, and in particular consecutive to a prostatic adenoma, a cancerous lesion, a fistula at the level of the urethra, a inflammation or surgery on the urethra.

The invention proposes, in particular, a medical device defined within the scope of the invention, for its use to isolate the interior of the urethra, in the event of a fistula, from a part of the body to which it should not be connected. In particular, the medical device defined in the context of the invention may be inserted into the urethra to isolate the interior of the urethra from the rectum, in the event of a fistula between the rectum and the urethra. In this case, the medical device defined in the context of the invention may also be used as an aid in the resorption of the fistula.

One of the advantages of the device of the invention is to be imageable, in particular by magnetic resonance imaging due to the presence of gadolinium cations.

The invention also proposes the use of a medical device defined in the context of the invention in a method of magnetic resonance imaging (MRI) on a subject in whom the device has been implanted, in particular to evaluate the state of resorption of the device, the bio-distribution of the resorption products and/or verifying its positioning in said subject to position the subject with a view to therapeutic irradiation.

Other characteristics, details and advantages will appear on reading the detailed description below, and on analyzing the appended drawings, in which:

Fig. 1

is a schematic view of a tube used in the context of the invention.

Fig. 2

is a schematic view of a medical device in the form of a tube inserted into the body of a male subject inside the urethra, according to one use of the invention.

Fig. 3

is a schematic view of a medical device in the form of a tube inserted into the organism of a female subject inside the urethra, according to one use of the invention.

Fig. 4

is a schematic view showing the section of a medical device that can be used in the context of the invention.

Fig. 5

shows the evolution of the wall thickness of the tube of physical hydrogel of chitosan, obtained, as a function of coagulation time, in the case of an aqueous solution of chitosan concentrated at 7.5% and coagulated in a bath of soda at 7 mol/L.

Fig. 6

represents the charge-discharge cycles obtained in the examples for a chitosan tube whose geometry is as follows: Length 30 mm, diameter 8 mm and thickness 1.7 mm .

Fig. 7

is a compression curve obtained for tubes used in the context of the invention and commercial tubes

Fig. 8

is a compression curve obtained for tubes used in the context of the invention and commercial tubes

Fig. 9

is a schematic view of a variant of the device comprising a tubular part 1 and a flared part 2 and its positioning in the urethra of a male subject.

Fig. 10

is an exploded view of the extrusion molding device for obtaining a device comprising a tubular part and a flared part.

Fig. 11

There is a photograph of devices as made with the extrusion-molding device shown in .

Fig. 12

There is an MRI image showing in cross section the inner and outer diameters of the devices.

The drawings and the description below contain, for the most part, certain elements. They may therefore not only serve to better understand this disclosure, but also contribute to its definition, where applicable.

In the description of the invention, it is possible to consider using instead of "for its use in" by "for its use""in order to" or "for", "for the manufacture of a medicament intended for or “intended for”.
Form and mechanical properties of the medical device

The device used in the invention comprises at least one tubular part 1 intended, after implantation, in a subject, to cover the wall of the urethra and thus limit the contact of the internal wall of the urethra with the urinary flow. The tubular part 1 used also exerts sufficient pressure on the walls of the urethra to ensure maintenance of the urinary flow in situations of stenosis (inflammatory or other) or of need to maintain a sufficient urinary flow to ensure urination of the subject. The mechanical characteristics of the tubular part 1 will be chosen accordingly and, in particular, the tubular part formed from polysaccharide hydrogel used in the context of the invention has the mechanical characteristics as defined below.

The device may be implanted in an animal or, preferably human, male or female subject, in particular male in the case of applications in the context of prostate cancer.

The device has dimensions, which must be adapted, allowing it to be inserted into the anatomical conduits, in particular the urethra of a male or female human subject or of an animal. In particular, the tubular part 1 has an internal diameter of 0.5 mm to 7.5 mm, preferably 4 mm to 6 mm and/or an external diameter of 3 mm to 10 mm, preferably 6 mm to 8 mm and / or a length of 1 cm to 8 cm, preferably 3 cm to 6 cm, in particular to cover the prostatic portion of the urethra. The length of the tubular part 1 is in particular less than that of the urethra in which it must be placed, so that the device can be completely inserted into the urethra. The length of the tubular part 1 will also be adjusted according to the female or male sex of the subject.

The outer section of the tubular part 1 used is generally annular in shape. The internal section of the tubular part 1 can, for its part, be annular, as illustrated or have any other shape, in particular in the shape of a cloverleaf as illustrated . Such clover-like shapes and their advantages are, in particular, described, for example in US Pat. No. 6,730,105.

In one embodiment shown in Figures 1 to 3, the device is a tube, that is to say it consists essentially of the tubular part 1. In another embodiment, the device further comprises at the one of the ends of the tubular part 1, a pavilion-shaped part 2 being able to be placed at the neck of the bladder to maintain the positioning of the tubular part 1 of the device in the urethra. Indeed, the flared shape at one of the ends of the device allows the device to be held in place in the urethra by placing the flared part in the bladder. In a preferred embodiment, the tubular part 1 and pavilion part 2 assembly consists of a polysaccharide hydrogel as described below. A diagram of this embodiment is shown in .

Advantageously, the tubular part of polysaccharide hydrogel used as a medical device of the invention has a linear force at stenosis measured in lateral compression of the tube greater than 0.5 N/mm, preferably greater than 1, 5N/mm. Such a linear force at the stenosis will preferably be measured according to the method described in the examples.

The polysaccharide hydrogel tubular part according to the invention has an elastic behavior, giving the device the ability to reduce its diameter when it is stretched and to regain its original size when it is at rest, facilitating placement with an ancillary. The polysaccharide hydrogel tubular part is resistant in lateral compression to avoid stenosis. These elasticity and mechanical strength properties will be adjusted by those skilled in the art, by choosing the characteristics of the polysaccharide hydrogel and the thickness of the tubular part, in particular.
Macromolecular structure of the polysaccharide hydrogel and physico-chemical properties of the device

The device comprises at least one tubular part formed from polysaccharide hydrogel.

By “hydrogel”, is meant a viscoelastic material comprising at least 60% by mass of water, and preferably at least 85% by mass of water. The hydrogel contains, in general, from 0.1% to 40% and preferably from 0.5 to 15% by mass of polysaccharides. In particular, the medical devices used in the invention consist of more than 98% by mass of hydrogel(s) of polysaccharides, or even exclusively consist of water and polysaccharides.

The polysaccharides used for the device are a mixture of chitosan A, where appropriate of chitosan B and of polysaccharide C consisting of a chitosan chemically modified via the grafting of chelating groups complexed with metal cations, preferably gadolinium cations.

Specifically, the polysaccharide hydrogel includes:
(i) a mass fraction fA of chitosan A with a high mass-average molar mass Mw1 of between 250 kg/mol and 1000 kg/mol, preferably from 500 kg/mol to 700 kg/mol and with a preferably lower degree of acetylation to 40%, preferably less than 15%, for example between 0% and 15%, ,
(ii) where appropriate, a mass fraction fB of chitosan B of low mass-average molar mass Mw2 of between 15 g/mol and Mw1 kg/mol, preferably between 40 and 70 kg/mol, and with a degree of acetylation preferably less than 40%, preferably less than 15%, for example between 0% and 15%,
(iii) a mass fraction fC of polysaccharide C consisting of a chitosan chemically modified via the grafting of chelating groups, of the following formula (I):
Formula (I)
in which
- Rc is a group comprising a chelating agent,
- Z is a binder which may be a single bond or a hydrocarbon chain comprising between 1 and 12 carbon atoms, said chain possibly being linear or branched and possibly comprising one or more unsaturations and possibly comprising one or more heteroatoms, preferably chosen from nitrogen, oxygen, sulfur and atoms of the halogen family;
- y is between 0.005 and 0.95, for example between 0.85 and 0.95;
- x is between 0 and 0.4, and, for example between 0 and 0.1;
- at least part of the chelating groups, preferably at least 90%, is complexed with a metal cation, more preferably gadolinium.

Within the meaning of the present disclosure, by “chitosan” is meant a natural polymer of the co-polysaccharide type, consisting of a random distribution (random copolysaccharide) or not (block or block copolysaccharides) of D-glucosamine (GlcN) and of N-acetyl-D-glucosamine (GlcNAc), or even exclusively of D-glucosamine, linked by glycosidic bonds of the β(1->4) type. Chitosan is not very present in the native state in the biomass, it is mainly obtained by chemical modification of chitin, of which it is a derivative. Chitin has a structural role, it is mainly found in certain fungi of which it constitutes the wall (Basidiomycetes ex: agariscus campestris, agariscus bisporus, Ascomycetes, Zygomycetes, and Deuteromycetes), but it also forms the exoskeleton of arthropods (crustaceans, insects ) especially in shrimp or crab and the endoskeleton of cephalopods such as squid or cuttlefish. The transition from chitin to chitosan takes place by deacetylation, i.e. by alkaline hydrolysis of the acetyl groups to generate primary amine groups.

Chitosan is a biodegradable and biocompatible polymer, exhibiting bacteriostatic and fungistatic properties.

In the context of the invention, the hydrogel is said to be physical, because the interactions responsible for the inter-chain crosslinking giving the hydrogel its cohesion are of the physical type, and are in particular hydrogen bonds and/or hydrophobic interactions, as opposed to a so-called chemical hydrogel (also called crosslinked hydrogel), in which the inter-chain interactions are of the covalent bond type. No chemical crosslinking agent is present in a purely physical hydrogel. Advantageously, in the context of the invention, the physical hydrogels of polysaccharides consist exclusively of water and of polysaccharides A, B and C, and preferably contain more than 85% (m/m) of water. . In particular, such hydrogels contain neither collagen, nor polycaprolactone, nor toxic chemical cross-linking agent (of the glutaraldehyde, formaldehyde, epichlorohydrin, etc. type). According to a particular embodiment, the hydrogel does not contain glycerophosphate. The use of a device made of hydrogel offers flexibility properties, favoring the comfort of the subject in whose urethra the device is inserted. In addition, a chemical hydrogel is poorly resorbable due to the stability of the covalent bonds, whereas the physical hydrogel of chitosan and modified chitosan according to the present invention is resorbable in an acid medium.

According to a preferred variant, the constituent polysaccharides of the hydrogel, that is to say chitosan A and B and polysaccharide C, represent from 5% to 20% (m/m) of the hydrogel, (m/ m: mass of chitosan relative to the total mass of the hydrogel), preferably from 6% to 12% (m/m), and preferentially approximately 8%.

In the context of the invention, it is advantageous, for the constitution of the hydrogel, to choose a fraction fA of a high molar mass polysaccharide. In particular, a chitosan having a mass-average molar mass Mw1 of greater than 250 kg/mol may be used to promote the formation of a macromolecular network with a high density of entanglement nodes immobilized by other types of inter-knots. -chains made up of hydrogen bonds, hydrophobic interactions and crystalline domains as well as the formation at various scale levels of the morphology of the hydrogel and obtaining suitable mechanical properties.

In the context of the invention, the mass-average molar masses Mw of the polysaccharides A, B and C are determined by steric exclusion chromatography, the experimental conditions of which are described in the publication “Physico-chemical studies of the gelation of chitosan in a hydroalcoholic medium” A. MONTEMBAULT, C. VITON, A. DOMARD, Biomaterials, 26(8), 933-943, 2005.

The degree of acetylation (DA) is determined using the proton NMR technique, following Hirai's methodology (A. HIRAI, H ODANI, A. NAKAJIMA, Polymer Bulletin, 26 (1), 87-94, 1991).

The low DA chitosan and modified chitosan used in the context of the invention have fungistatic and bacteriostatic properties, and will therefore have an additional beneficial effect on the injured parts, after implantation. The hydrogels of chitosan and modified chitosan used in the context of the invention, due to the DA of chitosan and their high water content, generate little inflammatory response, and are therefore perfectly suited to the biomedical applications envisaged.

The hydrogel is formed in particular of a mixture of two DA chitosans from 0% to 40%, preferably from 0% to 15%, and whose mass-average molar mass Mw1 is greater than 250 kg/mol for the a (chitosan A), for example between 500 kg/mol and 700 kg/mol, and the mass-average molar mass Mw2 is between 15 kg/mol and Mw1, for example between 40 kg/mol and 70 kg/mol for the other (chitosan B). This mixture makes it possible to obtain a hydrogel with good mechanical properties thanks to the high molar mass chitosan while integrating shorter chains likely to be released to ensure a better fungistatic and bacteriostatic effect and to promote resorption by the urinary flow in a period of, for example, 3 to 4 months.

Polysaccharide C is a chitosan modified by grafting a chelating group complexed at least in part with the gadolinium cation. The presence of gadolinium cation gives the device imageable properties, i.e. detectable by magnetic resonance imaging (MRI) processes.

The polysaccharide C according to the invention is composed of 3 monomeric units, namely an N-acetylglucosamine type unit, a glucosamine type unit and a glucosamine type unit functionalized by a chelating agent (Rc) bound by a Z binder to the glucosamine nitrogen.

The polysaccharide according to the invention is a random polymer. In other words, the sequence of the different monomeric units is random.

The polysaccharide C according to the invention has a weight-average molar mass of between 100 kDa and 1600 kDa, advantageously, the weight-average molar mass of the polysaccharide C according to the invention is between 250 kDa and 1200 kDa, more advantageously between 400 kDa and 1000 kDa and even more advantageously between 600 kDa and 1000 kDa.

Thus, the person skilled in the art will be able to adjust the number of monomeric units comprising the Rc motif complexed with gadolinium with respect to the total dry mass of polysaccharides so that it is sufficient to allow detection of the device, or of its state of resorption, by magnetic resonance imaging. This number of monomer units complexed with gadolinium relative to the total dry mass of polysaccharide in the stent depends in particular on the mass fraction fC of polysaccharide C, of y representing the proportion of monomer units comprising the Rc unit in the polysaccharide C, and the proportion of Rc motifs complexed with the gadolinium cation.

In one embodiment, the molar concentration of monomeric unit comprising the Rc unit in total dry mass of polysaccharides is greater than 5×10 ⁻⁸ mol/g.

In a preferred embodiment, the product [ ^y *fC] is greater than 2.10 ^-5 , for example between 2.10 ^-5 and 2.10 ^-3 . In this specific embodiment, it is thus possible to produce in particular two particular sub-embodiments: In a first sub-mode, it is possible to choose a hydrogel with a low concentration of polysaccharide C, with a proportion y of units comprising the pattern High RC. Typically, in this embodiment, y is between 0.6 and 0.95 and fC is between 0.2 and 2%.

In a second sub-embodiment, a hydrogel is chosen with a high concentration of polysaccharide C, but with a proportion y of units comprising the low Rc unit. Typically, in this embodiment, y is between 0.005 and 0.2 and fC is between 60% and 90%.

More generally, those skilled in the art will advantageously choose a hydrogel whose mass fraction of gadolinium cation relative to the total weight of hydrogel is between 0.1% and 10%, preferably between 0.5% and 2%.

In a more preferred embodiment, the fraction fC of polysaccharide C relative to the total dry mass of polysaccharides is between 0.2% and 10%. More preferably still, the hydrogel comprises, relative to the total dry mass of polysaccharides
i) a mass fraction fA of chitosan A of between 50 and 99%,
ii) a mass fraction fB of chitosan B between 0 and 50%,
iii) a mass fraction fC of polysaccharide C of between 0.1 and 10%.

By “chelating group” or “chelating agent”, within the meaning of the present disclosure, is meant an organic group or compound capable of complexing a metal cation. For example, in a specific embodiment, the chelating agent is selected from those whose log(KC1) complexation constant is greater than 15, preferably 20 with respect to the gadolinium cation.

Thus, the chelating agent has the function of complexing metallic elements (eg gadolinium cations) and reducing their release after implantation of the device in the patient.

Preferably, the chelating group Rc can be obtained by grafting (covalent bond) onto the chitosan of chelating agents consisting of polyamino polycarboxylic acids and their derivatives, and, more preferably macrocyclic agents.

The chelating agents may be chosen in particular from the following agents: DOTA (1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid), DTPA (diethylene triamine penta- acetic acid), NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid), DOTAGA (2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan- 1-yl)pentanedioic), and mixtures thereof.

The choice of binder Z in formula (I) essentially depends on the Rc group and on the metal to be chelated. Indeed, for steric reasons in particular, the Rc group can be more or less close to the 6-membered ring of unit C.

In formula (I), Z is a single bond or a hydrocarbon chain comprising between 1 and 12 carbon atoms, said chain possibly being linear or branched and possibly comprising one or more unsaturations and possibly comprising one or more heteroatoms, preferably chosen among nitrogen, oxygen, sulfur and atoms of the halogen family.

In a particular embodiment Z is an alkyl chain comprising between 1 and 12 carbon atoms.

In another particular embodiment, Z is a polyethylene glycol (PEG).

The polysaccharides used (chitosan A and B and modified chitosan C) have the advantage of solubilizing in an acidic aqueous medium, thanks to the protonation of the amine groups (–NH2 -> –NH3+) present in the GlcN units. The protonation of the amine groups will generate an accumulation of positive charges on the chains and create by electrostatic interactions a repulsion between them, while making them more hydrophilic. This capacity of chitosan to dissolve in an acid medium is particularly interesting since the urinary pH varies between 4.5 and 8.5 and more frequently between 5.5 and 6.5. With such a pH range, urine therefore has the ability to solubilize chitosan, allowing progressive resorption of the medical device by the single flow of the patient's urine in contact with the hydrogel.

In addition, the presence of Rc motif with a high complexation constant for gadolinium makes it possible to avoid the release of gadolinium in the body and its elimination in the urine by resorption.

Moreover, previous work had shown that the exposure of chitosan hydrogels to gamma or beta radiation drastically affected the molar mass Mw of the polymer for doses of 15 kGy (San Juan A., Montembault A., Gillet D. , Say JP, Rouif S., Bouet T., Royaud I. and David L. Degradation of chitosan-based materials after different sterilization treatments (IOP Conference Series: Materials Science and Engineering, 2012, 31, 012007). In the context of the invention, it has been demonstrated that the tube of physical hydrogel of chitosan used is stable when it is subjected to irradiation under gamma rays corresponding to a dose conventionally used in radiotherapy of prostate cancer, which are lower doses, in particular less than 100 Gy. In particular, the mechanical properties in tension and in compression and physicochemical properties (solubility, molar masses) are preserved after irradiation by X-rays (dose less than 100 Gy). The medical device envisaged within the framework of the invention, formed of hydrogel of chitosan and modified chitosan, is, for this reason, particularly suitable for the medical uses proposed within the framework of the invention.
Hydrogel Synthesis Process and Device Fabrication

A physical hydrogel of polysaccharides which can be used in the context of the invention can be obtained by coagulation of an aqueous or hydroalcoholic solution or neutralization of a hydroalcoholic gel of mixtures of polysaccharides A, B and C having the characteristic proportions selected as defined above.

Chitosan A and B can be obtained from a depolymerization of another chitosan of higher molar mass, according to the method described in the publication “Molecular-Weight Manipulation of Chitosan .1. Kinetics of Depolymerization by Nitrous-Acid, G.G. Allan, M. Peyron, Carbohydr. Res. 277 (1995) 257–272”.

If necessary, chitosan A, B and C can be reacetylated before their dissolution or their chemical modification according to the method described in the publication “Physico-chemical studies of the gelation of chitosan in a hydroalcoholic medium” A. Montembault, C. Viton, A. Domard, Biomaterials, 2005, 26(8), 933-943.

Chitosan C can be obtained by chemical modification, for example of chitosan A or B.

• Etape 1 : solubilisation d’un chitosane dans une solution acide à un pH compris entre 4 et 5 ;
• Etape 2 : acétylation partielle des fonctions amines du chitosane solubilisé en étape 1 (formation d'unités acétylées) ;
• Etape 3 : fonctionnalisation d’au moins une partie des fonctions amines toujours présentes à l’issu de l’étape 2 (formation des unités comprenant le groupement Rc).

In a particular embodiment, the process for obtaining the polysaccharide C which can be used according to the invention comprises at least the following three successive steps:

• Step 1: solubilization of a chitosan in an acid solution at a pH of between 4 and 5;
• Step 2: partial acetylation of the amine functions of the chitosan dissolved in step 1 (formation of acetylated units);
• Step 3: functionalization of at least some of the amine functions still present at the end of step 2 (formation of units comprising the Rc group).

Stage 3 can be subdivided into several sub-stages, in particular when the binder Z is a hydrocarbon chain as defined previously.

In the embodiments where the binder Z is a hydrocarbon chain as defined above, step 3 may comprise a sub-step 3-1 consisting in grafting said hydrocarbon chain onto at least some of the amine functions still present at the end of step 2, then a sub-step 3-2 consisting in the grafting of the Rc group onto said hydrocarbon chain. Alternatively, step 3 does not include a sub-step. In this alternative, said hydrocarbon chain is coupled with the Rc group prior to step 3, said step 3 is then carried out with a molecule comprising the Rc group and said hydrocarbon chain.

• Etape 1b : solubilisation d’un chitosane partiellement acétylé dans une solution acide à un pH compris entre 4 et 5 ;
• Etape 2b : fonctionnalisation d’au moins une partie des fonctions amines dudit chitosane partiellement acétylé solubilisé à l’étape 1b (formation des unités comprenant le groupement Rc).

Alternatively, the polysaccharide C which can be used according to the invention can be obtained from a chitosan having the desired acetylation rate, thus, in this embodiment, the acetylated units are already present and do not need to be be trained. In this embodiment, the process for obtaining the polysaccharide C which can be used according to the invention comprises at least the following two successive steps:

• Stage 1b: solubilization of a partially acetylated chitosan in an acid solution at a pH of between 4 and 5;
• Step 2b: functionalization of at least some of the amine functions of said partially acetylated chitosan dissolved in step 1b (formation of units comprising the Rc group).

In the same way as previously for said stage 3, said stage 2b can be subdivided into several sub-stages, in particular when the binder Z is a hydrocarbon chain as defined above.

In the embodiments where the binder Z is a hydrocarbon chain as defined above, step 2b may comprise a sub-step 2b-1 consisting in grafting said hydrocarbon chain onto at least some of the amine functions, then a sub-step 2b -2 consisting in the grafting of the Rc group on said hydrocarbon chain. Alternatively, step 2b does not include a sub-step. In this alternative, said hydrocarbon chain is coupled with the Rc group prior to step 2b, said step 2b is then carried out with a molecule comprising the Rc group and said hydrocarbon chain.

In the following text, to simplify the reading, we will speak of “chitosan” to designate the mixture of chitosan and modified chitosan consisting of polysaccharides A, B and C.

Preferably, an aqueous solution of chitosan is obtained by mixing water, chitosan A, B and C and an acid, preferably acetic acid. The acid is, in particular, introduced in a stoichiometric quantity with respect to the amine functions of the chitosan. In the case of a hydro-alcoholic solution, this will contain, for example, an alcohol which does not form an azeotrope with water and which has a boiling point above 150° C., is chosen in particular from the group: 1,2- and 1,3-propane-diol, 1,2-, 1,3- and 1,4-butane-diol and 1,2,3-propane-triol. The hydro-alcoholic chitosan solution can be made by dissolving the chitosan and modified chitosan in an aqueous acid solution, then adding the alcohol to this solution. In particular, a hydro-alcoholic solution will contain a water/alcohol mixture in a proportion of 50/50 to 30/70 by mass.

To obtain a hollow tube, spinning may be used comprising an extrusion step through a die, for example circular, of the polysaccharide solution. The extrudate obtained is then introduced into a coagulating bath (in particular an alkaline solution or alkaline vapours). This method comprises at least one cycle of partial coagulation during which the coagulation is interrupted. The coagulation cycle is carried out by introducing the acidic aqueous solution of coagulable chitosan extruded into a bath or a coagulation chamber, under conditions making it possible to obtain a fiber which, in cross section, has a partially coagulated section. The coagulation bath or chamber contains a coagulating agent such as an alkaline gas such as ammonia or an alkaline solution of soda, potassium hydroxide or ammonia, the diffusion of which in the solution allows it to locally change to a gel state. or clotted. Coagulation is stopped, in particular by removing the fiber formed from the bath or the coagulation chamber and by rinsing, in particular with water. The fact of stopping the coagulation of the chitosan fiber makes it possible, in particular, to form the central channel of the hollow fiber by stopping the coagulation before the hydrogel solidifies in the heart of the fiber, without the need to preform the cavity using a central element with a fixed diameter as in an annular die. This sequenced coagulation also makes it possible to control the thickness of the tube formed. For more details, reference may be made to patent FR 2 920 786. It is also possible to obtain the tubular shape directly by passing the chitosan solution through a die having a central core, and to proceed with the coagulation directly by die exit.

Coagulation, also called neutralization, can be carried out using a coagulation bath, corresponding in particular to an alkaline aqueous solution, for example containing soda, potassium hydroxide or ammonia, as an alkaline agent, at a concentration of 0.5 to 10M, preferably from 1M to 5M. The immersion time in the coagulation bath or chamber will determine the thickness of the tube obtained. An immersion time of 1 to 6 minutes may in particular be considered.

The neutralization/coagulation operation is generally followed by a washing operation, so as to eliminate the salts formed and the excess base.

In the case of a hydro-alcoholic solution or gel, the alcohol contained in the gelled extruded element is eliminated during the neutralization operation, when this occurs, by passing through a bath containing a solution, basic or acid as the case may be and also during the washing operation.

The process parameters will be adapted by those skilled in the art to obtain the linear force at the desired stenosis. In particular, those skilled in the art will adjust the concentration of alkaline agent and the duration of the coagulation step, to obtain the desired thickness. The chitosan concentration will be adjusted, depending on the thickness, to obtain the desired mechanical properties.

Of course, the chitosan hydrogel containing neither collagen, nor polycaprolactone, nor toxic chemical cross-linking agent (of the glutaraldehyde, formaldehyde, glyoxal, epichlorohydrin, etc. type), nor glycerophosphate, the process used for the preparation of the tubes will not put not implement such products.

The tubes of physical hydrogel of chitosan thus obtained will be subjected to a sterilization operation before their implantation in the body of a subject. Any sterilization technique well known to those skilled in the art may be used, in particular steam sterilization by autoclave, gamma or beta irradiation. The medical devices which are going to be inserted into the urethra of a subject can therefore be qualified as sterile, according to the criteria of the European Pharmacopoeia in particular.
Uses of the medical device according to the invention and methods

Due to its imageable properties, the invention also relates to the use of the medical device as described above in a method of magnetic resonance imaging (MRI), in particular to evaluate the state of resorption of the device, the bio- distribution of resorption products, and/or verifying its positioning in said subject, or to position the subject for therapeutic irradiation.

Thus the invention relates to a method for imaging a subject in whom the device has been implanted, said method comprising the acquisition of an image by MRI scanner of said subject, in particular an image of the implantation zone of the device. In particular, the image acquisition is intended to assess the state of resorption of the device, the biodistribution of the resorption products and/or to verify its positioning in said subject.

The invention also relates to a method for treating and/or preventing urinary disorders and/or for avoiding stenosis of the urethra in a subject, said method comprising the insertion of the device into the urethra of the subject.

In one embodiment, this method is intended to treat urinary disorders resulting from a prostatic adenoma, a cancerous lesion, a fistula at the level of the urethra or a surgical intervention on the urethra.

Also, in one embodiment of the methods described above, the subject is treated for prostate cancer by external beam radiation therapy or brachytherapy. Advantageously, the device makes it possible to serve as a benchmark for positioning the patient for therapeutic irradiation.

Variants of realization

According to a variant 1, the invention relates to a medical device formed from a hydrogel of polysaccharides, and comprising at least one tubular part (1), capable of being inserted into the urethra of a subject, characterized in that the polysaccharide hydrogel includes:
(i) a mass fraction fA of chitosan A with a high mass-average molar mass Mw1 of between 250 kg/mol and 1000 kg/mol, preferably from 500 kg/mol to 700 kg/mol and with a preferably lower degree of acetylation at 40%, preferably less than 15%, for example between 0% and 15%,
(ii) where appropriate, a mass fraction fB of chitosan B of low mass-average molar mass Mw2 of between 15 kg/mol and Mw1 kg/mol, preferably between 40 and 70 kg/mol, and with a degree of acetylation preferably less than 40%, preferably less than 15%, for example between 0% and 15%,
(iii) a mass fraction fC of polysaccharide C consisting of a chitosan chemically modified via the grafting of chelating agents, of the following formula (I):
Formula (I)
in which
- Rc is a group comprising a chelating agent,
- Z is a binder which may be a single bond or a hydrocarbon chain comprising between 1 and 12 carbon atoms, said chain possibly being linear or branched and possibly comprising one or more unsaturations and possibly comprising one or more heteroatoms, preferably chosen from nitrogen, oxygen, sulfur and atoms of the halogen family,
- y is between 0.005 and 0.95
- x is between 0 and 0.4, and,
- at least part of the chelating groups, preferably at least 90%, is complexed with a gadolinium cation.

Variant 2: Medical device according to variant 1, characterized in that the fraction fC of polysaccharide C is such that the molar concentration of monomeric unit comprising the unit Rc in total dry mass of polysaccharides is greater than 5.10 ^-8 mol/g.

Variant 3: Medical device according to variant 1 to 2, characterized in that the fraction fC of the polysaccharide C relative to the total dry mass of polysaccharides is between 0.2% and 10%, preferably between 0.5% and 2% .

Variant 4: Medical device according to any one of variants 1 to 3, characterized in that it comprises, with respect to the total dry mass of polysaccharides
i) a mass fraction fA of chitosan A of between 50 and 99%,
ii) a mass fraction fB of chitosan B between 0 and 50%,
iii) a mass fraction fC of polysaccharide C of between 0.1 and 10%.

Variant 5: Medical device according to variant 1 to 4, characterized in that the mass fraction fC of polysaccharide and the molar concentration of monomeric units comprising the unit Rc complexed with gadolinium is sufficient to allow detection of the device by magnetic resonance imaging , preferably y*fC is greater than 2 10 ^-5 .

Variant 6: Medical device according to variant 5, characterized in that y is between 0.6 and 0.95 and fC is between 0.2% and 2%.

Variant 7: Medical device according to variant 5, characterized in that y is between 0.005 and 0.2 and fC is between 60% and 90%.

Variant 8: Medical device according to any one of variants 1 to 7, characterized in that the mass fraction of gadolinium cation relative to the total weight of hydrogel is between 0.1% and 10%, preferably between 0.5% and 2%.

Variant 9: Medical device according to any one of variants 1 to 8, characterized in that all of the polysaccharides A, B and C represent from 5% to 20% (m/m) of the hydrogel, (m/ m: mass of polysaccharides relative to the total mass of the hydrogel), preferably from 6% to 12% (m/m), and preferentially approximately 8% (m/m).

Variant 10: Medical device according to any one of variants 1 to 9, characterized in that the hydrogel does not contain glycerophosphate.

Variant 11: Medical device according to any one of variants 1 to 10, characterized in that the hydrogel consists of more than 95% by mass of water, of polysaccharides A, B and C, preferably it consists exclusively water, and polysaccharides A, B and C.

Variant 12: Medical device according to any one of variants 1 to 11, characterized in that the hydrogel contains more than 85% (m/m) of water.

Variant 13: Medical device according to any one of variants 1 to 12, characterized in that the chelating group is chosen from the group consisting of DOTA, DOTAGA, DTPA, preferably DOTAGA.

Variant 14: Medical device according to any one of variants 1 to 13, characterized in that x is between 0 and 0.1.

Variant 15: Medical device according to any one of variants 1 to 14, characterized in that y is between 0.85 and 0.95.

Variant 16: Medical device according to any one of variants 1 to 15, characterized in that said tubular part ( 1 ) has solid walls acting as a barrier on a macroscopic scale between the wall of the urethra, at the level of which it is positioned, and the urinary flow.

Variant 17: Medical device according to any one of variants 1 to 16, characterized in that said tubular part (1) has an internal diameter of 0.5 mm to 7.5 mm, preferably of 4 mm to 6 mm and /or an external diameter of 3 mm to 10 mm, preferably 6 mm to 8 mm and/or a length of 1 cm to 8 cm, preferably 3 cm to 6 cm in order to cover the prostatic portion of the urethra .

Variant 18: Medical device according to any one of variants 1 to 17, characterized in that it further comprises, at one of the ends of the tubular part, a pavilion-shaped part (2) which can be placed at the level of the bladder neck to maintain the positioning of the tubular part in the urethra.

Variant 19: Medical device according to any one of variants 1 to 18, characterized in that the tubular part (1) has a linear force at stenosis measured in lateral compression of the tube greater than 0.5 N/mm, preferably greater than 1.5 N/mm.

Use of the medical device according to one of the variants 1 to 19, in a method of magnetic resonance imaging (MRI), in particular for evaluating the state of resorption of the device, the bio-distribution of the resorption products, and/ or verify its positioning in said subject, or to position the subject for therapeutic irradiation.

The invention relates to a method for treating and/or preventing urinary disorders and/or for avoiding stenosis of the urethra in a subject, said method comprising the insertion of the device according to any one of the variants 1 to 19 into the subject's urethra.

The above method is useful in particular for treating urinary disorders resulting from a prostatic adenoma, a cancerous lesion, a fistula at the level of the urethra or a surgical intervention on the urethra.

In particular, in one embodiment of the above method, the subject is treated for prostate cancer by external radiation therapy or brachytherapy.

Examples

The examples below make it possible to illustrate the invention, but have no limiting character.
Example 1: Preparation of the solution of polysaccharides A, B and C

The solution of chitosans A, B and C is obtained by dissolving these polymers in an aqueous solution of acetic acid. Here are the masses of the compounds to obtain 50 g of concentrated solution at 7.5% (m/m):
- Chitosan A from squid endoskeletons (Mw = 590 kg/mol and DA = 2.2%): 3.19 g
- Chitosan B from shrimp exoskeletons (Mw = 63 kg/mol and DA = 0.5%): 0.825 g
- Modified chitosan C from squid endoskeletons (Mw = 590 kg/mol and DA = 2.2%): 107 mg
- Pure acetic acid: 1.37 g
- Deionized water: 44.5 g
the mass fractions of chitosan A, B and C are respectively fA=77%; fB=20% and fC=3%.

These calculations take into account the fact that chitosans contain approximately 10% m/m water when weighed in powder form.

The powdered chitosans are mixed with the acidic water in a closed reactor with blades. The whole was stirred for 12 hours to give the polymers time to dissolve and the solution to homogenize.

Chitosan B can be obtained from a depolymerization of another chitosan of higher molar mass, according to the method described in the publication “Molecular-Weight Manipulation of Chitosan .1. Kinetics of Depolymerization by Nitrous-Acid, G.G. Allan, M. Peyron, Carbohydr. Res. 277 (1995) 257–272”.

If necessary, chitosan A, B and C can be reacetylated before their dissolution or their chemical modification according to the method described in the publication “Physico-chemical studies of the gelation of chitosan in a hydroalcoholic medium” A. Montembault, C. Viton, A. Domard, Biomaterials, 2005, 26(8), 933-943.
Protocol for obtaining modified chitosan C

Chitosan C is obtained by chemical modification, for example of chitosan A.

1. Fonctionnalisation du chitosane par le DOTAGA anydride pour un taux de fonctionnalisation proche de 60 %
2. Le chitosane A est dissous en solution aqueuse acide. Un réacteur de 1 L est rempli avec 3 g de chitosane A, 150 mL d’eau ultra-pure et 2.1 mL d’acide acétique glacial. Le pH de la solution est de 4.5 ± 0.5 et l’ensemble est maintenu sous agitation pendant une durée de 16 heures.
3. Puis 150 mL de propane-1,2-diol sont ajoutés à la solution précédente et l’agitation est maintenue pendant 1 h. 11 g de DOTAGA anhydride sont ensuite ajoutés et l’agitation est maintenue pendant 16 h. A l’issue de cette réaction, la solution brune claire est diluée par 10 dans l’eau ultra-pure et purifiée par filtration tangentielle en utilisant une membrane de 100 kDa. Ce premier cycle de purification est suivi d’un second en utilisant l’eau ultra-pure pour une purification d’un facteur 50. Les filtrations suivantes sont effectuées dans HCl 0.01 M pour un facteur final de purification de 1250.
4. Ajout d'un sel de gadolinium pour l’obtention d’un polymère imageable en IRM

The preparation of chitosan C is done in 2 stages:

1. Functionalization of chitosan by DOTAGA anydride for a functionalization rate close to 60%
2. Chitosan A is dissolved in acidic aqueous solution. A 1 L reactor is filled with 3 g of chitosan A, 150 mL of ultra-pure water and 2.1 mL of glacial acetic acid. The pH of the solution is 4.5±0.5 and the whole is kept under stirring for a period of 16 hours.
3. Then 150 mL of propane-1,2-diol are added to the previous solution and stirring is maintained for 1 h. 11 g of DOTAGA anhydride are then added and stirring is maintained for 16 h. At the end of this reaction, the light brown solution is diluted by 10 in ultra-pure water and purified by tangential filtration using a 100 kDa membrane. This first purification cycle is followed by a second using ultra-pure water for a purification of a factor of 50. The following filtrations are carried out in 0.01 M HCl for a final purification factor of 1250.
4. Addition of a gadolinium salt to obtain an imageable polymer in MRI

After these purification steps, 4.9 g of gadolinium chloride hexahydrate are added to the solution, the pH is then adjusted to 5 and the solution is left under stirring at 80° C. for 48 hours. The pH is continuously adjusted to 5 with 0.5 M NaOH until it becomes stable, indicating that the DOTAGA units of chitosan C have complexed all the Gd ³⁺ ions.
The aqueous solution obtained is concentrated to 4 g/L in chitosan C and has a density of 0.9970 g/mL.
Example 2: Manufacture of tube of chitosan hydogel

Two tube manufacturing processes have been implemented:
- The first used an extrusion method followed by an interrupted neutralization. The chitosan solution was extruded using a syringe connected to a compressed air system and was immersed in a soda bath which will cause the collodion obtained to gel. The gelation was interrupted by immersing it in water and the interior of the still soluble collodion was removed manually (compressed air or water), resulting in a tube-shaped hydrogel.
- The second used extrusion at the outlet of the syringe, by passage through an annular die giving the collodion the desired shape, before being gelled in a soda bath.
Solubilization of chitosan

The tubes were made from an aqueous solution of mass concentration of chitosan from squid endoskeletons (Mw = 590 kg/mol and DA = 2%) at 7.5% by mass (m/m).

For 30g of aqueous solution with a mass concentration of 7.5%, were used:
- Chitosan: 30*0.075*1.1 = 2.475g (a factor of 1.1 is applied because it is estimated that chitosan contains 10% water)
- Pure acetic acid: 0.82g (0.782mL)
- Deionized water: 26.7g

Powdered chitosan was mixed with acidic water in a closed, bladed reactor. The whole was stirred for 12 hours to give the polymer time to dissolve and the solution to homogenize. The solution was then collected, stored in a syringe, and air bubbles removed by centrifuging the solution.
Tube manufacturing process
Extrusion and neutralization interrupted

This process consisted in extruding the solution coming from the syringe using a compressed air system whose pressure was fixed at 4 bars. The solution is extruded through an assembly of silicone tubes of increasing diameters inserted one on top of the other, positioned at the outlet of the syringe, which made it possible to give the desired shape to the collodion. The extrudate was then immersed in a 7M soda bath for several minutes, which started the gelation process. The hydrogel was removed from the soda and immersed in water before the end of gelation, in order to remove the still liquid interior to form a tube. The thickness of the tube wall was dependent on the contact time with the soda. For a 7.5% mass solution of chitosan, a contact time of 4 minutes made it possible to obtain a thickness of approximately 1.5 mm.

This method has the advantage of being able to easily modify the diameter of the tubes produced, by simply changing the number of silicone tubes at the syringe outlet.
Extrusion via an annular die

This technique consisted in connecting the syringe containing the chitosan solution, to an annular die, inside which was a core held by 6 screws positioned on two levels and offset. The chitosan solution was expelled from the syringe using a compressed air system (regulated at 5 bar). The collodion passed through the die thus adopting the desired shape. On leaving the die, the chitosan was immersed in a bath of concentrated sodium hydroxide (7M), thus making it possible to obtain rapid gelation of the tube.

The main advantage of this method is that it gives the tube a trefoil shaped section as shown , due to the presence of the screws inside the die. This section makes it possible to guarantee a light within the tube, whatever the compression exerted on it.

The wall thickness of the tubes can be changed by varying the size of the core used.
Tube geometry control

The geometry of the tubes was checked using a binocular loupe. This made it possible, among other things, to check that the thickness and diameter of the sections remain constant over the entire length of the tube.

The diameter mainly depends on the extrusion method and geometry. The tubes produced had an external diameter of between 4.5 mm and 10 mm. The thickness of the wall, in turn, is governed by the contact time with the soda in the case of interrupted neutralization. For a contact time of 4 to 5 min in 7M soda, a thickness ranging from 1400 μm to 1800 μm was obtained.

Binocular magnifying glass observations showed that wall thickness variations within a single section were less than 200 μm, as were wall thickness variations from one end of the tube to the other. The tubes produced therefore have a rather constant geometry.
Sterilization process

Sterilization is a mandatory step before inserting the device. The tube being destined to integrate the patient's urethra, it is important that it does not carry any pathogen.

The process that was used is steam sterilization by autoclave. The sterilization cycle used was cycle B at 121°C for 15 min, suitable for liquid media. This type of cycle is therefore well suited to the sterilizing treatment of chitosan hydrogels.

Three tubes prepared from the same 7.5% solution were sterilized by autoclave. The geometry of the tubes was measured before and after sterilization. The results are shown in Table 1 below.

Tube 1 Pipe 2 Pipe 3 Mean Standard Deviation Loss Length (%) 3.4 3.6 4.2 3.7 0.41 Thickness loss (%) 5.2 7.7 1.8 4.9 2.96 Diameter loss (%) 1.5 4.4 2.4 2.8 1.46

The results show a shrinkage of the geometry less than 5% on average. This shrinkage can be taken into account when designing the tubes, in order to manufacture a device with the right geometry.
Evaluation of chitosan tubes formed

Unless otherwise specified, the tubes subjected to the following evaluations are chitosan tubes with an external diameter of 8 mm and a thickness of 2 mm obtained by the interrupted neutralization extrusion technique previously described, having undergone a sterilization step.
Mechanical properties

The mechanical properties of the chitosan hydrogel tubes produced were evaluated using a Shimadzu AGS-X 10 kN tensile machine. The device has been tested in simple tension, in load and unload cycles as well as in compression. The tests carried out showed in particular:
- mechanical properties compatible with the use of the chitosan tubes produced, as medical devices at the level of the urethra,
- an ability to deform plastically,
- resistance to lateral compression similar to that of silicone urinary catheters.

The tubes were subjected to longitudinal tensile and lateral compression tests in order to characterize their mechanical properties. These tests were carried out using a Shimadzu AgX-10kN tensile machine, they also made it possible to determine the impact of irradiation and sterilization on the mechanical properties of the tubes. Three different methods were used (simple traction, cycle, compression), each providing additional information to characterize the tubes.
single pull

The sterilized tubes were subjected to tensile tests (Shimadzu traction machine, with the use of mandrels for fixing the tubes; stainless steel cylinders were inserted at each end of the tube to be tested so as to deform it as little as possible mandrels tightened) and the results compared with those of unsterilized tubes. 8 tubes from the same batch (initial tubes from the same solution, cut into 40 mm long segments) were subjected to simple tensile tests, 4 of them were sterilized beforehand. The means of the parameters obtained for the sterilized and non-sterilized tubes are presented in Table 2 below. E (MPa) fracture (MPa) ε rupture 1/√(1+εr)
Unsterilized tubes Mean 2.65 3.05 0.45 0.83 standard deviation 0.40 1.17 0.08 0.02 Sterilized tubes Mean 2.89 2.64 0.40 0.85 standard deviation 0.14 0.58 0.07 0.02

The results obtained are similar, although the sterilized samples have a slightly larger Young's modulus and a slightly lower stress and elongation at break, they do not show any major alteration of the mechanical properties due to the sterilization process. .
Example 3: Extrusion-molding process for the manufacture of a stent comprising at one end a shape of a pavilion.

An example of the implementation of stents of simple tubular form consists of an extrusion of a chitosan solution (with a total chitosan concentration of 7.5% m/m) containing the fractions fA=0.9, fB=0.095 and fC=0.005.

This solution is extruded into the alkaline coagulating bath consisting of a sodium hydroxide solution at a concentration of 4M. A first step is the centrifugation of the solution in a 30cc polyethylene syringe of the Nordson EDF brand. Then a plunger is placed over the solution and pressurized air extrudes the solution from the syringe, using an Optimus Nordson EDF dosing system. The end of the syringe is connected to a flexible PVC tube with an internal diameter of 8mm. The contact time with 4M sodium hydroxide allows the constitution of a gelled membrane of tubular shape with a thickness of about 1.7 mm after a coagulation time of 2 minutes. When this gelation time is reached, the partially gelled extrudate is extracted from the coagulation bath. The solution that remained in the central part of the formed tube is expelled with pressurized air. The tube formed is then washed in several water baths until the pH of the washing bath is close to 6.5.

Another embodiment leads to a pavilion-shaped stent at its end ( ). In this case, the mobile mold is used ( ) by connecting it to a Norson EDF syringe containing the chitosan solution at part 11 fitted with a Luer Lock connector. The body of the mold 11 contains in its center a core 12 immobilized using 6 screws, and allowing an annular extrusion between the core 12 and the body 11. The first phase of the implementation consists in filling the distal end of the mould, in the form of a pavilion. When the latter is full, the distal part 14 and 15 separates from the die comprising the parts 11, 12 and 13 which allows the extrusion of the tubular zone of the stent.

When the length of the desired tubular part is reached, the extrudate is cut and the assembly is immersed in the coagulation bath (4M NaOH) for 2 minutes. The distal part of the stent is demolded, thus forming the pavilion. Then, the solution residues are manually removed from the central part.

The die-mould therefore consists of a body with an external diameter of 15 mm and an internal diameter of 10 mm, in which is centered a core 12. The air gap between core and body constitutes a tubular space in which the chitosan solution can flow and be extruded in the form of a tube.

In the distal part, a pavilion-shaped mold makes it possible to give a flared shape to the extrudate. This part is filled when pressure is applied to the solution in the syringe. A tubular part is therefore formed by annular extrusion, secured to the filled pavilion mould. This assembly will be immersed in the 4M NaOH coagulation bath to induce gelation. The internal and external parts of the pavilion mold must be chemically inert, for example made of polytetrafluoroethylene (Teflon).

This molding-extrusion process therefore makes it possible to fill the body-core air gap, then the distal mold to obtain a pavilion shape. Then, the pavilion end of the mold is separated from the body, manually or by the effect of the thrust of the solution, which induces the annular extrusion and the formation of a liquid extrudate of tubular shape, always connected to the mold of pavilion form. After cutting on leaving the body, this assembly is neutralized in the coagulating bath, then unmolded to free the pavilion end, then the stent is washed to free it of the soda, and finally it can be sterilized by autoclave.

The method thus described makes it possible to obtain a device with a tubular shape 1 widened by a flag 2 at one end. It is possible to adapt the size of the body 11, of the core 12 or of the pavilion end to easily adapt the geometric characteristics of the device (internal and external diameter, size and shape of the pavilion).

The duration of the extrusion makes it possible to control the length of the stent in its tubular part.

There shows devices developed with the extrusion-molding device illustrated by the .
Example 4 : MRI Imaging of a Device According to the Invention and Measurement of Diameters

Devices according to the invention prepared according to examples 1 and 2 were included in a gelatin hydrogel and were studied with an MRI machine used in the clinic.

The total concentration of chitosan A+B+C was 7.5% m/m, the mass concentration of gadolinium in the dry mass of the hydrogel was 0.5%. For the production of the image, the sequence used is an Axial 3D T1 FastSat GD sequence. This is a gradient echo 3D MRI sequence (tilt angle at 10°), with fat saturation. It is used routinely at the Center Hospitalier Lyon Sud (France) for the acquisition of MRI images of the pelvis and prostate. The sequence was acquired on the Ingenia Elition X® machine (Philips) with a 3T magnetic field and a “pelvis” antenna. The slice thickness was 0.9 mm and the space between two slices was 0.45 mm. It is a fast sequence and sensitive to metal artifacts.

• Tube (1) diamètre externe : 6,4 mm, diamètre interne :2,0 mm ;
• Tube (2): diamètre externe : 6,6 mm, diamètre interne : 2,25mm ;
• Tube (3): diamètre externe : 6,3 mm, diamètre interne :1,7 mm.

The section of the tubes appears perfectly on a transverse (axial) section perpendicular to the axis of the devices ( ) and allows the measurement of the external and internal diameters of the tubes.

• Tube (1) outer diameter: 6.4mm, inner diameter: 2.0mm;
• Tube (2): outer diameter: 6.6mm, inner diameter: 2.25mm;
• Tube (3): external diameter: 6.3 mm, internal diameter: 1.7 mm.

Claims (9)

Medical device formed from a hydrogel of polysaccharides, and comprising at least one tubular part (1), capable of being inserted into the urethra of a subject, characterized in that the hydrogel of polysaccharides comprises:
(i) a mass fraction fA of chitosan A with a high mass-average molar mass Mw1 of between 250 kg/mol and 1000 kg/mol, preferably from 500 kg/mol to 700 kg/mol and with a preferably lower degree of acetylation at 40%, preferably less than 15%, for example between 0% and 15%,
(ii) where applicable, a mass fraction fB of chitosan B of low mass-average molar mass Mw2 of between 15 kg/mol and Mw1 kg/mol, preferably between 40 and 70 kg/mol, and with a degree of acetylation preferably less than 40%, preferably less than 15%, for example between 0% and 15%,
(iii) a mass fraction fC of polysaccharide C consisting of a chitosan chemically modified via the grafting of chelating agents, of the following formula (I):
Formula (I)
in which
- Rc is a group comprising a chelating agent,
- Z is a binder which may be a single bond or a hydrocarbon chain comprising between 1 and 12 carbon atoms, said chain possibly being linear or branched and possibly comprising one or more unsaturations and possibly comprising one or more heteroatoms, preferably chosen from nitrogen, oxygen, sulfur and atoms of the halogen family,
- y is between 0.005 and 0.95
- x is between 0 and 0.4, and,
- at least part of the chelating groups, preferably at least 90%, is complexed with a gadolinium cation. Medical device according to Claim 1, characterized in that the fraction fC of the polysaccharide C relative to the total dry mass of polysaccharides is between 0.2% and 10%, preferably between 0.5% and 2%. Medical device according to Claim 1, characterized in that it comprises, relative to the total dry mass of polysaccharides
i) a mass fraction fA of chitosan A of between 50 and 99%,
ii) a mass fraction fB of chitosan B between 0 and 50%,
iii) a mass fraction fC of polysaccharide C of between 0.1 and 10%. Medical device according to Claim 1, characterized in that

• y is between 0.6 and 0.95 and fC is between 0.2% and 2%, or
• y is between 0.005 and 0.2 and fC is between 60% and 90%.

Medical device according to any one of Claims 1 to 4, characterized in that the mass fraction of gadolinium cation relative to the total weight of hydrogel is between 0.1% and 10%, preferably between 0.5% and 2% . Medical device according to any one of Claims 1 to 5, characterized in that the hydrogel consists of more than 95% by mass of water, of polysaccharides A, B and C, preferably it consists exclusively of water , and polysaccharides A, B and C. Medical device according to any one of Claims 1 to 6, characterized in that the chelating group is chosen from the group consisting of DOTA, DOTAGA, DTPA, preferably DOTAGA. Medical device according to any one of Claims 1 to 7, characterized in that it also comprises, at one of the ends of the tubular part, a pavilion-shaped part (2) which can be placed at the neck of the the bladder for maintaining the positioning of the tubular part in the urethra. Use of the medical device according to one of Claims 1 to 8, in a method of magnetic resonance imaging (MRI), in particular for evaluating the state of resorption of the device, the bio-distribution of the resorption products, and/ or verify its positioning in said subject.