ES2812678T3 - Urethral stent, methods and uses of it - Google Patents

Abstract

Stent comprising a polymeric substrate wherein the polymeric substrate comprises 10-50% (w / w) alginate and 45-85% (w / w) gelatin; and a polymeric biodegradable resin to coat said polymeric substrate.

Description

DESCRIPTION

Urethral stent, methods and uses of it

Technical domain

The present disclosure relates to urethral stents, in particular to a composition for urethral stents that are used to guarantee the patency of a canal, in particular the ureter, which can be compromised, for example, by a urinary stone, neoplasm or a surgical procedure.

Background

A first generation of biodegradable urethral stents based on polymers of natural origin developed in the state of the art (described in the document by Barros AA, Rita A, Duarte C, Pires RA, Sampaio-Marques B, Ludovico P, Lima E, Mano JF, Reis RL. 2015. Bioresorbable urethral stents from natural origin polymers; J Biomed Mater Res, Part B 2015: 103B: 608-617) has proven to be an interesting alternative to conventional stents, but has nevertheless proven to fail in the first In vivo validation in a porcine model.

In the first generation of biodegradable urethral stents, these were produced using alginate, gellan gum and a mixture of these with gelatin (described in Barros AA, Rita A, Duarte C, Pires RA, Sampaio-Marques B, Ludovico P, Lima E, Mano JF, Reis RL. 2015. Bioresorbable urethral stents from natural origin polymers; J Biomed Mater Res Part B 2015: 103B: 608-617). Gram-positive and Gram-negative bacterial adhesion was evaluated and compared with a commercial stent (Biosoft® duo, Porges, Coloplast) and showed a decrease in adhesion. The biodegradation profile was found to be highly dependent on the composition of the stent, with complete dissolution of alginate-based stents for 14 days and gellan-gum-based stents for up to 60 days [16]. A first generation of biodegradable urethral stents based on naturally occurring polymers developed earlier has proven to be an interesting alternative, but has failed in the first in vivo validation due to poor mechanical properties (Figure 6D).

The most common adverse events reported by patients undergoing urethral stenting are pain and urinary tract difficulties [1]. These problems can significantly affect the quality of life of the patient with lost days of work, urinary leaks and sexual difficulties [2]. In recent years, new urethral stent designs with novel polymers, coatings, and the incorporation of active compounds have been tested in an attempt to significantly reduce the most common problems such as bacterial infection and encrustation [2-4]. Lange et al [1] in a recent review concluded that the stent of the future will be degradable, in a controlled manner, and able to coat or elute active compounds. No biodegradable urethral stent is currently available on the market, although in the last year there has been a growing interest in this field [1]. Polymers such as polylactic acid, polyglycolic acid, poly (lactic-co-glycolic acid), and alginate-based materials have been used to develop biodegradable urethral stents [5-9]. Lumiaho, J. et al reported in vivo studies in a porcine model using stents based on polylactic acid and poly (lactic-co-glycolic acid) that have shown good properties such as antireflux properties and favorable drainage, but biocompatibility and degradation profile they were shown to be insufficient for clinical use [5,10,11]. The same urethral stents showed a different behavior in a canine model, presenting good biocompatibility and degradation that occurred in 12 weeks [12]. Other studies using urethral stents based on poly (lactic-co-glycolic acid) reported favorable radiopaque and drainage properties, but biocompatibility was compromised, as reported in the literature [5,13-15]. The degradation of urethral stents must be uniform and homogeneous, avoiding the formation of fragments during the degradation process that can block the ureter [1,6,16]. An Uriprene stent (Poly-Med, USA), a radiopaque stent based on glycolic-lactic acid, has been designed to degrade in the direction of the bladder coil to the renal coil avoiding secondary urethral obstruction for the degradation of fragments of stent [1]. In vivo porcine model studies of Uriprene reported good stability and biocompatibility, with predictable degradation over 2-4 weeks maintaining drainage. In previous studies, a urethral stent produced with naturally-based polymers processed by critical point drying with carbon dioxide was reported [16]. However, this study was not the first in the literature to report on alginate polymer-based temporary urethral stents. Lingeman and colleagues [9,17] showed in phase I and phase II clinical trials that these urethral stents were designed to be intact for at least 48 h before degradation with facilitated urinary drainage, favorable tolerability, and safety profiles. The problem with these alginate-based stents is the fact that they presented an inhomogeneous dissolution profile and fragmentation that resulted in the need for secondary procedures to remove fragments in some patients.

General description

The urethral stent of the present disclosure overcomes the poor mechanical performance found in the prior art. Surprisingly, a specific concentration of gelatin and alginate as a substrate together with a polymeric biodegradable resin coating of said polymeric substrate, results in a stent with higher mechanical properties. These new urethral stent compositions surprisingly do not fail in the in vivo treatment of mammals (see Figures 6D, 7 and 8), and at the same time allow the formation of new tissue and avoid a second surgical intervention.

In one embodiment, the biodegradable urethral stents of the present disclosure were coated with a polymeric biodegradable resin. The morphological analysis of the surface of the stents was carried out by means of scanning electron microscopy. X-ray scanning demonstrated the radiocapacity of the biodegradable stents of the present disclosure. The degradation of biodegradable urethral stents was evaluated in artificial urine solution and it was observed that the degradation of the materials occurs in vitro between 9 and 15 days. The degradation was followed by the loss of weight of the samples and by the chemical analysis of the solutions by both induction coupled plasma (ICP) and gel permeation chromatography (GPC). The formulation with a higher amount of gelatin has shown good mechanical performance in terms of tensile properties compared to the commercial stent (Biosoft® duo, Porges, Coloplast), and the crosslinking concentration has shown not to have a great influence on the behavior. mechanical stent.

In one embodiment, the in vivo performance of urethral stents of the present disclosure was validated herein. Biodegradable urethral stents were placed in the ureters of a female pig, following the normal surgical procedure. The animals remained asymptomatic, with normal urine flow, the stents remained intact for the first 3 days and after 10 days the urethral stents of the present disclosure were totally degraded. This new formulation combined with a new production process overcomes the problems verified with the first generation of natural-based biodegradable stents (described in Barros AA, Rita A, Duarte C, Pires RA, Sampaio-Marques B, Ludovico P, Lima E, Mano JF, Reis RL. 2015. Bioresorbable urethral stents from natural origin polymers; J Biomed Mater Res Part B 2015: 103B: 608-617).

The solution disclosed now relates to a composition for biodegradable stents, in particular urethral stents. This disclosure overcomes the problems found in available stents, in particular urethral stents, since in particular:

avoids the need for a second surgery to remove the stent;

reduces morbidity in patients undergoing a surgical procedure;

decreases or eliminates the risk of infection after urethral stent implantation.

The problems mentioned in the prior art are surprisingly solved by the composition of the present subject matter that a stent provides:

that is not rejected by the mammalian body,

This stent has improved mechanical properties and allows in vivo implantation of the device in the mammalian animal model.

was removed by the mammalian patient undergoing a surgical procedure, and

that it is in the body long enough to recover from the surgical procedure performed.

Furthermore, the composition of the present subject matter may further comprise local release active / therapeutic agent, in particular anti-inflammatory, antimicrobial, an anticancer agent, or mixtures thereof. Surprisingly results were achieved where the therapeutic drug is incorporated into the polymeric substrate. The present disclosure relates, in particular, to a new composition and a new injection molding and drying method for manufacturing stents, in particular urethral stents. Additionally, degradable urethral stents were coated with a biodegradable polymer. In particular, this disclosure makes degradable urethral stents made from naturally occurring polymers a success in vivo, four formulations were tested with different concentrations of gelatin and alginate and different concentrations of crosslinking agent to obtain higher mechanical properties.

The composition of the present subject matter is degradable by the mammalian organism and the combination with the method of obtaining said stent avoids the obstruction of the stent by itself when it is in contact with a fluid, specifically in the mammalian organism.

The present disclosure refers to a stent, specifically a urethral stent, comprising a polymeric substrate in which the polymeric substrate comprises 10-50% (w / w) alginate and 45-85% (w / w) gelatin; and a polymeric biodegradable resin to coat said polymeric substrate.

In one embodiment, for best results, the polymeric substrate may comprise 20-40% (w / w) alginate and 55-70% (w / w) gelatin.

In one embodiment, for best results, a 3-50% (w / v) solution of resin is added to said stent; preferably a 5-20% (w / v) solution of resin is added to said stent, more preferably a 5-10% (w / v) solution of resin is added to said stent.

In one embodiment, for best results, the stent may further comprise a contrast agent, particularly an X-ray contrast agent. In one embodiment, bismuth was added to impart radiopaque properties to the stent.

In one embodiment, for best results, the disclosed stent may now comprise:

2-5% (w / w) of the contrast agent, preferably 5% (w / w) of the contrast agent, specifically bismuth (III) carbonate;

the polymeric substrate can comprise 20-40% (w / w) of alginate and 55-70% (w / w) of gelatin, preferably the polymeric substrate can comprise 30% (w / w) of alginate and 65 % (w / w) gelatin.

In one embodiment, for best results, the polymeric biodegradable resin to coat the polymeric substrate can be selected from the following list: polycaprolactone resin, polyglycolide and its copolymers: poly (lactic-co-glycolic acid with lactic acid), poly (glycolide -co-caprolactone) with ^g -caprolactone and poly (glycolide-co-trimethylene carbonate) with trimethylene carbonate, or mixtures thereof.

In one embodiment, for best results, the contrast agent can be selected from the following list: barium salts, bismuth salts, spinel pigments or mixtures thereof, in particular bismuth (III) carbonate.

In one embodiment, for best results, the stent may further comprise a crosslinking agent, wherein said crosslinking agent is a chemical crosslinking element comprising a functional group capable of reacting with gelatin amines, preferably the crosslinking agent is select from the following list: ionic crosslinking agents include monovalent or divalent ions, of which the cation is calcium, magnesium, barium, strontium, boron, beryllium, aluminum, iron, copper, cobalt, lead or silver; the anion is selected from the group consisting of chloride, nitrate, phosphate, citrate, borate, succinate, maleate, or oxalate, or mixtures thereof.

In one embodiment, for best results, the crosslinking agent can be selected from a group consisting of calcium chloride, genipin, glutaraldehyde, carbodiimides, and mixtures thereof.

In one embodiment, for best results, the stent may further comprise a therapeutic agent, specifically, an anti-inflammatory agent, an antimicrobial agent, an anticancer agent, an antiviral agent, or mixtures thereof.

In one embodiment, for best results, the stent may further comprise an anti-inflammatory agent selected from the following list: prednisolone, methylprednisolone, fluorometholone, dexamethasone, betamethasone, hydrocortisone, medrisone ,lotprednol, rimexolone, triamcinolone, diclofenac, indurbiporolac, flomethasone suprofen, ibuprofen, ketorolac tromethamine, emedastine, levocabastine, azelastine, olopatadine, ketotifen, ketoprofen, cromolyn, iodoxamide, or mixtures thereof.

In one embodiment, for best results, the stent may further comprise an antimicrobial agent selected from the following list: amoxicillin, dicloxacillin, augmentin, cephalosporins, gentamicin, tobramycin, neomycin, erythromycin, azithromycin, clarithromycin, ofloxacin, ciprofloxacin, levofloxacin, or levofloxacin mixtures thereof.

In one embodiment, for best results, the stent may further comprise an anticancer agent selected from the following list: methotrexate, vinblastine, doxorubicin, cisplatin, granulocyte colony stimulating factor, gemcitabine, carboplatin, 5-fluorouracil, ifosfamide, pemetrexed, paclitaxel , epirubicin, mitomycin C, capecitabine, Bacillus Calmette-Guerin (BCG), or mixtures thereof.

In one embodiment, for best results, the stent may further comprise an antiviral agent selected from the following list: acyclovir, valacyclovir, famciclovir, or mixtures thereof.

In one embodiment, for best results, the therapeutic agent can be incorporated into the polymeric substrate.

In one embodiment, for best results, the therapeutic agent can be incorporated into the polymeric substrate coating.

In one embodiment, for best results, the stent can now be for use in human or veterinary medicine, in particular, the stent can be for use in regenerative medicine or tissue engineering.

In one embodiment, for best results, the stent may be for use in the prevention or treatment of urological diseases.

In one embodiment, for best results, the stent now disclosed may be a urethral stent.

The present disclosure also refers to a method of producing a stent, in particular a urethral stent, which comprises the following steps:

dissolve alginate, gelatin in water at 40-90 ° C, preferably 70 ° C;

stir at 300-1500 rpm, for 30 minutes-3 hours, preferably at 600 rpm and for 1 hour to obtain a polymeric substrate;

optionally adding a chemical crosslinking element to the polymeric substrate;

injecting the polymeric substrate into a mold to obtain a stent;

placing the stent in an alcohol solution for 30 minutes-3 hours, preferably for 1 hour; placing the stent in a 0.05-2 M crosslinking agent solution under constant stirring for 1-24 hours, preferably 2 hours, at 20-25 ° C;

placing the stent in an alcohol solution;

drying the stent in a high pressure container with a supercritical fluid, in particular carbon dioxide, at 35-60 ° C, 71-200 bar and 60-360 minutes, in continuous mode;

immerse the stent in water for 15-90 minutes, preferably 30 minutes;

immersing the stent in ethanol for 1-5 hours, preferably 1 hour;

dry the stent at 20-25 ° C for 1 day;

immersing the stent in a 5-20% resin solution, preferably 10% polycaprolactone for 5-30 seconds, preferably 10 seconds;

dry at 15-35 ° C, preferably 20 ° C and for 12-24 hours, preferably 15 hours.

In one embodiment, for best results, the step of dissolving alginate and gelatin may further comprise dissolving bismuth (III) carbonate.

In one embodiment, for best results, the step of adding the crosslinking agent can be done by impregnation of supercritical fluid at 35-50 ° C, 100 bar and for 2 hours or by adding the therapeutic agent to the polymeric substrate.

In one embodiment, for best results, the concentration of the crosslinking agent, preferably an ionic crosslinking agent, can be between 5-50 mM, preferably 5-20 mM.

In one embodiment, for best results, the concentration of the crosslinking agent solution may be 0.24M, 0.48M, 1M.

In one embodiment, for best results, the drying step in the high pressure vessel with carbon dioxide can be carried out at 40 ° C, 100 bar and 90 minutes.

The present disclosure also refers to a composition for use in a method of prevention or treatment of urological diseases comprising alginate, gelatin and a polymeric biodegradable resin,

wherein said composition is delivered in a biodegradable stent,

wherein said stent comprises 10-50% (w / w) of alginate and 45-85% (w / w) of gelatin, as substrate, and the polymeric biodegradable resin as substrate coating.

Throughout the description and claims the word "understand" and variations of the word are not intended to exclude other technical features, additives, components or steps. Additional objects, advantages, and features of the invention will become apparent to those skilled in the art upon examination of the description or may be learned by practice of the invention.

Brief description of the drawings

The following figures provide preferred embodiments for the present disclosure and should not be construed as limiting the scope of the disclosure.

Figure 1. SEM micrographs of the biodegradable urethral stent (6 Fr, formulation 2, 0.48 M) a) before coating, b) after coating, c) greater amplification of a hydrogel layer d) greater amplification of two layers coating and hydrogel.

Figure 2. Radiography in abdomen mode of a) commercial urethral stent (Biosoft® duo, Porges, Coloplast) and b) developed biodegradable urethral stent (formulation 2, 0.48 M)

Figure 3. Weight loss of biodegradable urethral stents developed a) Different formulation tests and b) Formulation 2 with different crosslinking concentration.

Figure 4. GPC chromatograms of stent raw materials (alginate and gelatin) and leachables at 1, 3, 6, and 9 day time points.

Figure 5. Cytotoxicity study by cell viability measured after 72 h.

Figure 6. Mechanical properties of biodegradable stents (0.48M crosslinking concentration) before and after PCL coating in terms of aa) maximum load (N) b) maximum tensile strain (%) and c) Young's modulus (MPa ). d) Images of biodegradable stents before and after coating in the dry state and in immersion in the wet state in AUS (scale bar of 2 mm). Control - (Biosoft® duo, Porges, Coloplast). Values are represented as mean ± SD, n = 3. Statistical differences (* p <0.05, ** p <0.01) using one-way ANOVA followed by a post-Tukey test.

Figure 7. Mechanical properties of biodegradable stents prepared with formulation 2 with different concentrations of crosslinking agent before and after PCL coating in terms of aa) maximum load (N), b) maximum tensile strain (%), c) Young's modulus (MPa) and d) maximum tensile strain (%) of urethral stent formulation 2 during degradation time. Values are represented as mean ± SD, n = 3. Statistical differences (* p <0.05, ** p <0.01) using one-way ANOVA followed by a post-Tukey test.

Figure 8. Conventional ureteroscopy of the ureter with an in vivo stent in a porcine model: a) placement of a biodegradable urethral stent b) biodegradable urethral stent within the right-hole pig ureter at the time of placement c) biodegradable urethral stent after 3 days at the entrance of the right hole pig ureter d) after 3 days with the biodegradable urethral stent e) after 10 days with the biodegradable urethral stent f) right hole pig ureter after degradation on day 10.

Figure 9. Genipin-cross-linked biodegradable urethral stent inside the right-nosed pig ureter after 4 days after placement.

Materials and methods

Materials - In one embodiment, sodium salt of alginic acid, gelatin, urea, Canavalia ensiformis (Jack Bean) type IX urease, calcium chloride, chloroform, ethanol, basic bismuth (III) carbonate were obtained from Sigma-Aldrich (Germany). , dibasic sodium phosphate and sodium azide. Potassium dihydrogen orthophosphate and magnesium chloride hexahydrate were obtained from Riedel-de Haen (Germany).

The bismuth standard for ICP was obtained from Sigma-Aldrich (Germany). PCL 787 polycaprolactone resin, commercially available as TONE ™ polymer, was obtained from Union Carbide Chemicals and Plastics Division, Bound Brook, NJ. Carbon dioxide (99.998 mol%) was supplied by Air Liquide (Portugal). All reagents were used as received without any further purification.

Second generation preparation of biodegradable urethral stents- In one embodiment, the polymers were dissolved in hot distilled water (70 ° C) at different concentrations, as described in Table 1. The solutions were stirred for 1 hour and the polymeric solution it was injected into a mold to obtain a tubular structure. After 1 hour the piece was removed from the mold and placed in alcohol solution (100% ethanol) for 1 hour. The stents were then transferred to a calcium chloride (CaCh) crosslinking solution, with different concentrations (table 1) at room temperature. After crosslinking, the stents were relocated in an alcoholic solution (100% ethanol) to obtain an alcohol gel that can be dried in a high pressure vessel with supercritical carbon dioxide (scCO ² ) at controlled pressure (100 bar) and temperature (40 ° C) and a continuous flow of scCO ² for 90 minutes. Finally, the dried stents were immersed in distilled water for 30 min and in 100% ethanol for 1 hour to remove the template. The stents were finally dried at room temperature, for 1 day. The stents were coated by immersion in 10% polycaprolactone resin (PCL) 787 dissolved. in chloroform. The stents were dried under ambient conditions overnight. Also shown are commercial Biosoft® duo, Porges, Coloplast used as controls in this study.

Table 1. Summary of formulations tested to prepare the different biodegradable urethral stents.

Material concentration: (% by weight) Concentration of agent of Formulation 1 2 3 eticulation crosslinking (M) Alginate 10 30 45 0.24 Gelatin 85 65 50 CaCl2 0.48 Carbonate of 1

bismuth (III) 5 5 5

basic

Coating 10% PCL 787 resin

Scanning Electron Microscopy - In one embodiment, the morphology of biodegradable stents was analyzed in a JEOl SEM, model JSM-6010LV. The samples were fixed with mutual conductive adhesive tape on aluminum sample holders and plated with gold / palladium using a spray coating element.

Postoperative X-rays - In one embodiment, the radiopaque characteristics of the biodegradable urethral stent developed were evaluated in a postoperative X-ray machine located in the Imaging Department of the Braga hospital, Portugal. Radiographs were taken in abdomen mode with 0.27x magnification.

Degradation Study - In one embodiment, degradation of biodegradable stents was measured as a function of weight loss of the samples. The samples (10 mg) were immersed in artificial urine solution (AUS) prepared according to Khandwekar et al [18] with the composition presented in table 2. The submerged samples were dried and weighed to determine weight loss, which was calculated according to the following equation:

% weight loss = ( Wf -W ¡) / W * 100 (1)

Where Wf is the final weight of the sample (dried after immersion) and Wi is the initial weight of the sample. Each formulation was tested in triplicate.

Table 2. Composition of artificial urine solution (AUS).

Gel Permeation Chromatography (GPC) - In one embodiment, 5 mg of alginate, gelatin, and bismuth were dissolved in 5 ml of a 0.01 M aqueous solution of dibasic sodium phosphate containing 0.1 M sodium azide (pH 6 , 6) and were used as controls, while the dip solutions obtained by stent formulation 2 degradation test at a specific time point (1, 3, 6 and 9 days) were lyophilized and then dissolved in 5 ml of the same eluent. The solutions were filtered through a 0.22 µm filter and analyzed on a gel permeation chromatograph (Malvern, Viscotek TDA 305) with refractometer, right angle light scattering and viscometer detectors in a set of four. columns: 5 | im 8 x 50 S / N 3111265 guard column, 30 A 5 | im 8 x 300 S / N 3112751, 1000 A 5 pm supreme 8 x 300 S / N 3112851 PL and Aquagel- OH MIXED 8 pm 7.5 x 300 S / N 8M-AOHMIX-46-51, with refractive index detection (iR 8110 Detector, Bischoff). Elution was performed at 30 ° C using a flow rate of 1 ml min-1. Elution times and IR detector signal were calibrated with a commercial Varian calibration polysaccharide set containing 10 Pullulan calibrants with narrow polydispersity and Mw (molecular mass at maximum peak) ranging from 180 Da to 708 kDa.

Induction Coupled Pasma (ICP) - In one embodiment, dip solutions from the Stent Degradation Test, Formulation 2, were filtered and analyzed by Induction Coupled Plasma (ICP) to follow the concentration of bismuth (Bi) during the different moments of degradation. Sample absorption was measured at specific wavelengths (k = 206.17 nm for Bi), and the bismuth concentration was determined using calibration curves previously obtained with the bismuth standard for ICP (Sigma) (R2 = 0, 96).

Cytotoxicity assessment of leachables - In one embodiment, cytotoxicity of leachables was accessed during urethral stent degradation in AUS according to ISO / 10993 standard [19]. The cytotoxicity of the samples was evaluated using an immortalized mouse lung fibroblast cell line (L929) purchased from the European Cell Culture Collection. First, the dip solutions obtained by degradation testing at a specific time point (1, 3, 6 and 9 days) of the stent formulation 2 were lyophilized. The leachables were dissolved in DMEM basal medium (Dulbecco's modified Eagle's medium; Sigma-Aldrich, Germany) 10% FBS (heat inactivated fetal calf serum, Biochrom AG, Germany) and 1% antifungal antibiotic (Gibco, UK ). The cells were grown in a humidified incubator at 37 ° C in a 5% ^{CO 2 atmosphere.} The effect of leachables on cell metabolism was performed using a standard MTS viability test (Cell Titer 96® Aqueous Solution Cell Proliferation Assay, Promega, USA). A latex rubber extract was used as a positive control for cell death; while the cell culture medium was used as a negative control that represents the ideal situation for cell proliferation. Cell viability was assessed by the MTS assay after 72 h. This was quantified by UV spectroscopy, reading the formazan absorbance at 490 nm in a microplate reader (Synergy HT, Bio-Tek Instruments, USA). Each sample formulation and the control were tested using 12 replicates.

Mechanical tensile analysis - In one embodiment, the mechanical tensile analysis of biodegradable stents was evaluated using an INSTRON 5540 (Instron Int. Ltd, High Wycombe, UK) universal testing machine with a 1 kN load cell. The wet samples were hydrated prior to testing in AUS for 4 hours. The dimensions of the samples used were 5 mm in length, 2 mm in width and 0.5 mm in thickness. The load was placed in the middle between the supports with a length (L) of 3 mm. The feed rate was 1: 5 mm min-1. For each condition, the samples were loaded until core failure. The results presented are the average of at least three samples and the results are presented as the average standard deviation 6.

Surgical procedure and in vivo degradation validation - In one embodiment, the preliminary in vivo validation study was carried out at the University of Miño, Braga, Portugal, after the formal approval of the institution's review committee and in accordance with its internal ethical protocol for animal experiments. Female domestic pigs weighing = 30 kg were used to validate the procedure and stent degradation. The pigs were not given food or water for 12 h before the procedure. All procedures were performed under general anesthesia and mechanical ventilation, as previously described in detail [20]. After emptying the bladder, a 7 Fr semi-rigid ureteroscope (Karl Storz, Tuttlingen, Germany) was inserted through the urethra and serum was infused. The entire procedure was according to the standard ureteroscopy technique. Then, an 88.9 10.2 mm (0.035 inch) flexible tip guidewire (AQUATRACK® Hydrophilic Nitinol, Cordis®, Johnson & Johnson) was inserted into the ureters. The biodegradable urethral stents were guided by the guide wire until it was placed in either the right or left ureter, one at a time. Finally, a conventional ureteroscopy was performed in order to verify the degradation and the presence of any fragments and the morphology of the ureters.

Statistic analysis. In one embodiment, all data values are presented as mean ± standard deviation (SD). Statistical analysis was performed using Graph Pad Prism 6.00 software (San Diego, USA). Statistical values (* p <0.05, ** p <0.01 and *** p <0.001) were determined using one-way analysis of variance (ANOVA) for an average of three to twelve replicates, followed by the a-test. Tukey posterior for all pairwise mean comparisons.

To prepare the second generation of biodegradable urethral stents made of polymers of natural origin, new formulations were tested and the injection molding and drying method was optimized. The idea of coating the hydrogel with another biodegradable material in order to improve the mechanical properties of the stent was also tested with a PCL 787 polycaprolactone resin. Polycaprolactone resin was chosen as it is a safe material and has a rapid degradation compared to other biodegradable polymers. Biodegradable urethral stents are prepared from an initial aqueous alginate-gelatin solution from which gelation is induced by lowering the temperature followed by ionic crosslinking with a CaCl ² solution. Gelatin and alginate were chosen due to their versatility to form gels and the results obtained in the previous study [16] combining gelatin with other polysaccharides, it is possible to induce changes in water uptake, degradation profile and particularly beneficial in terms of bacterial adhesion. In this disclosure, bismuth was added to the formulation. The use of bismuth in the new formulation provides radiopaque properties to the urethral stent due to the inherent radiopaque characteristics of this compound. This material has already been used and shown to be safe and is already FDA approved [21]. After crosslinking a combination of steps in ethanol and supercritical carbon dioxide were further used to dry the biodegradable urethral stents. The parameters of the supercritical drying procedure were maintained as in the first version of these stents, since it has already been optimized; the supercritical fluid drying procedure used is a process in which the matrices do not undergo any phase transition and therefore the integrity of the stent lumen is not compromised [22]. Different drying methods were tested, namely air drying, but the lumen integrity of the stents was compromised, unlike what was observed when using CO ² supercritical fluid.

Morphology. Figure 1 presents the SEM images of the cross sections of the biodegradable urethral stent developed according to formulation 2. Figure 1a shows the uncoated stent and figure 1b the stent with PCL coating. Figures 1c and 1d are the magnifications of the stent wall. It is possible to distinguish the two layers, the outer PCL coating layer and the inner layer of the bismuth plus alginate-gelatin matrix. The internal diameter, that is, the lumen of the stent is 2 mm. The inner and outer diameter and length of the stents depend solely on the injection mold used to prepare the stents, and do not depend on the formulation under test. As in the first generation of biodegradable urethral stents, the surface area obtained without coating is similar [16].

X-ray validation. An important characteristic of urethral stents is their radiopacity. The possibility of evaluating postoperative X-rays, locating the stent in the body and following the degradation over time is of great importance and for this a standardized product is used, specifically basic bismuth (III) carbonate, however, they can be used others. In figure 2 it is possible to confirm the radiopacity, in a wet state, of the developed biodegradable urethral stent (figure 2b) in comparison with the commercial stent (figure 2a). In this disclosure, a lower concentration of this compound was used in the formulation, compared to Lingeman et al [21], unexpectedly demonstrating that low amounts are adequate to provide this characteristic to the stent.

In vitro degradation study - The in vitro degradation of biodegradable urethral stents was evaluated with the different formulations and different concentrations of crosslinking agent by measuring the weight loss of the samples. Weight loss, measured as the percentage of mass loss when immersed in AUS for a predetermined period of time, is presented in Figure 3. All conditions tested demonstrated in vitro that no degradation occurs during the first 3 days of immersion. After 9 days, the stents have shown complete degradation. Compared to the different formulations tested, the results suggest that a higher concentration of alginate (formulations 4 and 5, figure 3a) increases the degradation time. Compared with the different concentrations of crosslinking agent (Figure 3b), the results show that the stronger the crosslinking, the lower the degradation, even though it is not statistically significant. This can be justified due to the presence of more calcium cross-links with guluronic acid blocks (G), increasing its cross-linked network covalently [23]. The divalent cations of the ionic crosslinking agent bind exclusively to the G blocks of the adjacent alginate chains, since the L-guluronate structure offers greater flexibility than the D-mannuronate chains. By creating ionic bridges between chains, the divalent ions replace the hydrogen bonds between the carboxylic group of D-mannuronate and the 2-OH and 3-OH groups of the subsequent L-guluronate, causing the gelation of aqueous alginate solutions [ 24.25]. Block length G, polymer concentration and molecular weight are therefore critical factors affecting the physical properties of alginate and its consequent degradation. On the other hand, gelatin can form hydrogels by increasing and decreasing the temperature, which is simply a physical cross-linking phenomenon. The mechanism behind the crosslinking of gelatin molecules is a conformational change from a random spiral to a triple helix. Degradation then occurs because non-covalent associations are easily disrupted at temperatures above 30–35 ° C, therefore at body temperature [26]. This helps to understand that with higher amounts of gelatin in the formulation, faster degradation will occur. In our previous study, alginate-based urethral stents showed slower degradation compared to this work, for the same reason [16]. However, the mixture of the polymer with the alginate is unknown and therefore it is difficult to establish a working correlation compared to that of the now disclosed formulation.

Gel Permeation Chromatography (GPC) - Polymeric extractables from urethral stent degradation at 1, 3, 6, and 9 days were first lyophilized and then dissolved in an appropriate eluent for GPC analysis. As a control, alginate and gelatin raw materials were injected. The g Pc pattern of alginate and gelatin show an overlap of elution peaks between 18 ml and 21 ml of retention volume, so it is not easy to distinguish between the two. The extractable elements are essentially composed of the mixture of alginate and gelatin present in the biodegradable urethral stent formulation. The overlapping of raw materials makes it difficult to separately identify the presence of alginate and gelatin. However, it is possible to see the peaks of the elution curve with increasing intensity with degradation time. Taking into account the retention volume of the peaks in the different elution curves, a significant contribution of gelatin instead of alginate is observed. This was expected because this formulation (formulation 2) is composed of 65% gelatin and 30% alginate.

Induction Coupled Plasma (ICP) - ICP analysis of the concentration of bismuth in the dipping solutions from different time points starting from formulation 2 is present in table 3. The results show a gradual release of bismuth during the process degradation of the stent to artificial urine dissolution. According to the degradation profile (figure 3a) of urethral stents, formulation 2, and the bismuth measured in the immersion solutions, it is shown that the release of bismuth is associated with degradation and does not occur due to swelling of the stent or diffusion of the stent to the AUS. To support this observation and considering a homogeneous distribution of bismuth in the stent, it is expected that there will be a correlation between the degradation profile and the amount of bismuth in solution. On day 3, the urethral stent with formulation 2 shows a degradation of approximately 5%, which corresponds to the value of bismuth in solution is 0.271 g / l, that is, approximately 5% of the total bismuth present in the stent. The same is observed at the time point of day 6, in which the value of 1.285 g / l is 20% of the total bismuth and again approximates the value of the degradation observed in figure 3a.

Table 3. Bismuth concentration obtained by ICP, in immersion solution (AUS) during degradation.

Days Bismuth (g / l) Std Release (%)

1 0.0570 0.0058 -1%

3 0.271 0.0496 ~ 5%

6 1.285 0.06 -20%

9 5.953 0.1912 100%

Cytotoxicity of leachables - The cytotoxicity of leachables obtained from stent degradation was evaluated according to the protocol described in the ISO / EN 10.993 standard [19]. The viability of the cells grown in a tissue culture plate, in the presence of the leachables, was determined as a function of the cells grown in Dulbecco's Modified Eagle's Culture Medium (DMEM). Figure 5 shows the cell viability after 72 h in contact with the material dissolved in the culture medium. Significant differences were observed for cell viability in the presence of the leachables compared to latex, which was used as a positive control. The results demonstrate that there is no toxic interaction between the leachables from day 1 to day 9 and the L929 cells.

Tensile mechanical tests - The tensile mechanical properties such as maximum load (N), maximum tensile strain (%) and Young's modulus (MPa) of the developed biodegradable urethral stents are presented in Figure 6 and Figure 7. Figure 6 presents the results in dry and wet state of the four different stent formulations using a concentration of crosslinking agent 0.48 M. As a control, the traction results for the commercial stent (Biosoft® duo, Porges, Coloplast ). Comparing all the formulations studied, significant differences were observed before and after hydration and with and without coating, in terms of their mechanical properties. In all formulations and as expected from hydration in AUS (figure 6d) the tensile property values decrease in terms of Young's modulus but increase in terms of maximum tensile deformation. Furthermore, urethral stents after hydration become more elastic than in the dry state. The hydrated sample results are much more important for clinical purposes. Regarding the highest values, the maximum load was 78.7 N and in terms of Young's modulus it was 49.8 MPa after hydration for the coated stents of formulation 2. Compared with 41.2 N and 24.6 MPa, respectively, for the commercial stent. On the other hand, regarding the maximum tensile deformation (%) or elongation at break, the control presents values of approximately 736.5% compared to the 339.1% obtained for formulation 2. In general, the contribution of gelatin appears to increase the mechanical properties of biodegradable stents. The hydration of the stents also contributes to increasing the elasticity of the material. Analyzing the effect of the PCL coating also contributes to increasing the elasticity and ductility of the stents with significant differences. In order to study the influence of the concentration of calcium ions as a crosslinking agent, three different concentrations were tested with formulation 2. This formulation was selected according to the results obtained, due to the balance in terms of ductility and elasticity of the biodegradable urethral stent.

Figure 7 shows here the results of the urethral biodegradable stent with formulation 2, using different concentrations of crosslinking agent, specifically 0.24 M, 0.48 M and 1M. Compared with the different concentrations, the results suggest that the crosslinking concentration does not have a great impact on the final mechanical properties of the biodegradable urethral stent. Although a slight increase is observed by increasing the concentration of calcium ions. This is precisely reported in the literature, ions increase the bound network, but in the present disclosure the concentration tested does not greatly affect the mechanical properties of biodegradable urethral stents [27].

The mechanical properties were measured during the degradation process (figure 7d) and the results show a decrease in the mechanical properties during the degradation time. However, on day 6, before complete degradation, the urethral stent (formulation 2) shows an average maximum traction of about 200%. Although the mechanical properties decrease during the degradation process, the properties appear to be sufficient to maintain the function of the urethral stent before full degradation. These observations are extremely important when there is a clinical need to remove the stent without compromising the obstruction of the ureter by possible fragments left behind.

In the first generation of biodegradable urethral stents made by natural polymer, the values obtained were three times lower compared to the second generation [16]. Clearly, the increase in gelatin concentration, the modification of the manufacturing process and the incorporation of a new biodegradable coating allow the preparation of a biodegradable urethral stent capable of being used in vivo after conventional ureteroscopy.

An ideal urethral stent is expected to perform adequately in terms of mechanical properties. Compared to the maximum tensile strain results with resorbable urethral stents made of PGA and PLGA [15,28], the naturally occurring materials used herein exhibit higher elongation compared to synthetic materials. Regarding the overall mechanical performance obtained in this study proved to be similar to or better than the commercially available stent, Biosoft® duo, Porges, Coloplast.

In vivo study in a porcine model - In vivo validation of biodegradable urethral stents was performed in different female domestic pigs. Conventional ureteroscopy was used to implant the developed stents. The first stent to be tested in vivo was the first generation of biodegradable urethral stents based on naturally occurring polymers reported by Barros et al [20]. The first generation demonstrated in the surgical procedure that the stents glided perfectly into the cystoscope and the hydrophilic guide wire inside the bladder through the urethra. The developed urethral stent remains intact throughout the procedure and is not fragmented and has been shown to be easy to remove if necessary. However, it was not ductile enough to be able to position itself properly in the ureter. In contrast, this new second generation of biodegradable urethral stents was successfully implanted in vivo. The biodegradable urethral stents of this second generation in formulation 2 were placed in the right ureters without any complications and as a control, commercial stents (Biosoft® duo, Porges, Coloplast) were placed in the left ureters, following the conventional surgical procedure. In figure 8 it is possible to see the second generation of biodegradable stents placed in the ureters of the porcine model. During the experiments all the animals remained asymptomatic and with a normal urine flow. After 3 days, the animals were subjected to a ureteroscopy to assess the morphology of the ureters and stents. The biodegradable stent remains intact with great stability (figure 8c) and no unwanted side effects were observed in the ureters (figure 8d). On day 10, another ureteroscopy was performed and no biodegradable urethral stent fragments were found and the morphology of the ureters remains normal with no signs of inflammation or adverse reactions (Figures 8e and 8f). These biodegradable urethral stents prepared from formulation 2 were shown to be intact for the first 3 days and after 10 days they are completely degraded and no stent residues were observed in the urinary tract. This experiment was repeated three times and all procedures lead to the same observation.

Experimental data shows that a series of alginate and gelatin mixtures and different concentrations of crosslinking agent are used to obtain a biodegradable urethral stent from naturally occurring polymers that can be used for the treatment of urological disorders. In this second generation of stent, it is possible to see the radiopacity, in a wet state, of the developed biodegradable urethral stent. The in vitro study shows that a higher gelatin concentration in the biodegradable stent resulted in higher mechanical properties. Otherwise, the higher the alginate concentration, the slower in vitro degradation. The degradation products show not to be cytotoxic and their degradation showed to be homogeneous. The second generation of biodegradable urethral stents developed shown could be implanted following the surgical procedure performed daily in clinical practice. The urethral stent remains intact for the first 3 days and then begins to degrade. Complete degradation is achieved after 10 days, with no presence of the stent materials within the animal. The stents developed proved to be safe and fulfilled the function of maintaining the flow of urine from the kidney to the bladder while it was implanted in the ureter.

The present solution is obviously not limited in any way to the embodiments described in the present document and a person with average knowledge in the area can predict many possibilities of modification of the same solution and substitutions of technical characteristics by other equivalent ones, depending on the requirements of each situation, as defined in the appended claims.

The embodiments described above can be combined with each other. The following claims further define the preferred embodiments of the present solution.

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Claims (15)

i. Stent comprising a polymeric substrate wherein the polymeric substrate comprises 10-50% (w / w) alginate and 45-85% (w / w) gelatin; and a polymeric biodegradable resin to coat said polymeric substrate. Stent according to the preceding claim in which the polymeric substrate comprises 20-40% (w / w) of alginate and 55-70% (w / w) of gelatin. Stent according to any one of the preceding claims in which a solution of 3-50% (w / v) of polymeric biodegradable resin is added to said stent, preferably a solution of 5-20% (w / v) of polymeric biodegradable resin, more preferably 5-10% (w / v) of polymeric biodegradable resin. Stent according to any one of the preceding claims, further comprising a contrast agent, specifically an X-ray contrast agent, preferably the contrast agent is selected from the following list: barium salts, bismuth salts, pigments of spinel or mixtures thereof, in particular bismuth (III) carbonate. Stent according to any one of the preceding claims, comprising: 2-5% (w / w) of the contrast agent, specifically bismuth (III) carbonate; 20-40% (w / w) alginate and 55-70% (w / w) gelatin, preferably comprising 5% (w / w) of the contrast agent, specifically bismuth (III) carbonate; 30% (w / w) alginate and 65% (w / w) gelatin. Stent according to any one of the preceding claims, in which said resin is selected from the following list: polycaprolactone resin, polyglycolide and its copolymers: poly (lactic-co-glycolic acid with lactic acid), poly (glycolide-co- caprolactone) with ^g -caprolactone and poly (glycolide-co-trimethylene carbonate) with trimethylene carbonate, or mixtures thereof. Stent according to any one of the preceding claims, further comprising a crosslinking agent, preferably the crosslinking agent is a chemical crosslinking element comprising a functional group capable of reacting with gelatin amines. Stent according to the preceding claims wherein said crosslinking agent is selected from the following list: ionic crosslinking agents include monovalent or divalent ions, of which the cation is calcium, magnesium, barium, strontium, boron, beryllium, aluminum , iron, copper, cobalt, lead or silver; the anion is selected from the group consisting of chloride, nitrate, phosphate, citrate, borate, succinate, maleate, or oxalate, or mixtures thereof; preferably wherein the crosslinking agent is selected from a group consisting of calcium chloride, genipin, glutaraldehyde, carbodiimides, and mixtures thereof. Stent according to any one of the preceding claims, further comprising a therapeutic agent, specifically an anti-inflammatory agent, an antimicrobial agent, an anticancer agent, an antiviral agent or mixtures thereof. 10. Stent according to the preceding claim in which: the anti-inflammatory agent is selected from the following list: prednisolone, methylprednisolone, fluorometholone, dexamethasone, betamethasone, hydrocortisone, medrisone ,lotprednol, rimexolone, triamcinolone, diclofenac, ketorolac, flurbiprofen, indomethavocaine, trhemetamine, ibuprofen , olopatadine, ketotifen, ketoprofen, cromolyn, iodoxamide or mixtures thereof and / or; the antimicrobial agent is selected from the following list: amoxicillin, dicloxacillin, augmentin, cephalosporins, gentamicin, tobramycin, neomycin, erythromycin, azithromycin, clarithromycin, ofloxacin, ciprofloxacin, norfloxacin, levofloxacin or mixtures thereof and / or; the anticancer agent is selected from the following list: methotrexate, vinblastine, doxorubicin, cisplatin, granulocyte colony stimulating factor, gemcitabine, carboplatin, 5-fluorouracil, ifosfamide, pemetrexed, paclitaxel, epirubicin, mitomycin Calmette, Bacillusin C-capecitabine (BCG) or mixtures thereof; the antiviral agent is selected from the following list: acyclovir, valacyclovir, famciclovir or mixtures thereof and / or; wherein the antiviral agent is selected from the following list: acyclovir, valacyclovir, famciclovir, or mixtures thereof. Stent according to any one of claims 9-10, in which the therapeutic agent is incorporated into the polymeric substrate or is the coating of the polymeric substrate. Stent according to any one of the preceding claims for use in human or veterinary medicine. Stent according to any one of the preceding claims for use in regenerative medicine or tissue engineering, preferably for use in the prevention or treatment of urological diseases. Stent according to any one of the preceding claims, wherein the stent is a urethral stent. 15. Composition for use in a method of prevention or treatment of urological diseases comprising alginate, gelatin and a polymeric biodegradable resin, wherein said composition is delivered in a biodegradable stent, wherein said stent comprises 10-50% (w / w) of alginate and 45-85% (w / w) of gelatin, as substrate, and the polymeric biodegradable resin as substrate coating.