Water-cooling induced two-phase separated polyurethane ureteral stent and preparation method thereof

Abstract

The invention discloses a water-cooling induced biphase separated polyurethane ureteral stent and a preparation method thereof.The method comprises the steps that amphiphilic polyurethane containing a hydrophilic section and a hydrophobic section at the same time is obtained to serve as a forming raw material, thermoplastic extrusion forming is conducted, and a hollow tubular catheter is obtained in combination with water cooling treatment; cutting the catheter into a proper length, and performing secondary forming at one end or two ends to form a curled fixed structure so as to obtain the ureteral stent; according to the method, through formation of a water-cooling induced double-phase separation structure, on the premise that the chemical composition of polyurethane is not changed, the ureteral stent has high radial support in the initial stage to ensure that the ureter is smooth, and meanwhile the radial support force can be gradually reduced after the ureteral stent is implanted into a human body, so that foreign body sensation and stent related pain of a patient are relieved; the stent can be temporarily implanted into the ureter to treat ureteral stenosis and the like, and has a good application prospect.

Description

Technical Field

[0001] This invention relates to the field of polyurethane ureteral stent technology, specifically to a water-cooled induced biphasic separation polyurethane ureteral stent and its preparation method. Background Technology

[0002] A ureteral stent is an implantable medical device placed in the ureter between the bladder and kidney, primarily used for urine drainage, relieving ureteral stricture, and assisting in ureteral repair. These devices are widely used clinically for kidney stones, ureteral stricture, and intraoperative or postoperative support. As an implant, a ureteral stent must possess good flexibility, biocompatibility, and sufficient mechanical strength to maintain function in the body for several days to months. In practical applications, the ureteral stent needs to provide sufficient radial support in the initial implantation stage to maintain ureteral patency and prevent ureteral wall collapse. However, numerous clinical studies have shown that stent implantation is often accompanied by significant discomfort, with approximately 80% of patients experiencing "stent-related pain," severely impacting their quality of life. The exact pathological mechanism is not yet clear, but it is generally believed to be related to factors such as stent distal stimulation of the bladder mucosa, smooth muscle spasm, and inflammatory response. Therefore, the stent's material composition, surface coating, and flexibility have a significant impact on alleviating this side effect. Clinical evidence suggests that using a more rigid stent significantly increases the incidence of "stent pain."

[0003] Ureteral stents used to prevent ureteral stricture after stone surgery are typically left in place for 10-14 days. An ideal ureteral stent should have high strength and radial support in the initial implantation stage to ensure urinary tract patency; while the support should be gradually reduced in the later stages to minimize patient discomfort and improve clinical comfort. Current techniques for improving stent mechanical strength commonly involve adjusting the hard segment ratio of polyurethane or adding modifiers. However, while these methods improve mechanical properties, they also increase the overall rigidity of the stent, and its decay over time is difficult to control, making it difficult to simultaneously meet the performance requirements of "high initial support – later compliance." Furthermore, the phase structure of traditional polyurethane materials is relatively stable, lacking a controllable microstructural evolution process, resulting in limited room for mechanical property regulation. Therefore, a new technical approach is urgently needed to achieve a balance between high initial strength and controllable radial support decay by controlling the microstructure of the material without altering the chemical composition of polyurethane, thus meeting the comprehensive clinical needs for the mechanical properties of ureteral stents. Summary of the Invention

[0004] The purpose of this invention is to overcome the following disadvantages of the prior art: (1) Existing ureteral stents with strong radial support are often quite rigid overall. After implantation, they lack the controllability of gradually decreasing over time, which leads to increased foreign body sensation in patients and significantly increases adverse reactions such as "stent pain". (2) Traditional methods of improving mechanical strength (such as increasing the proportion of polyurethane hard segments) usually involve an increase in the overall rigidity of the material, which makes it difficult to meet the dual requirements of high support in the early stage and flexibility in the later stage of stent application in clinical applications, thus affecting the patient's implantation comfort.

[0005] This invention fabricates a ureteral stent using a specific amphiphilic polyurethane material through extrusion molding. During the molding stage, a water-cooling induction treatment within a specific temperature range is introduced. The rapid heat exchange during water cooling induces biphasic separation of the soft segments within the polyurethane material, forming a wall layer with a specific microstructure. This structure maintains high tensile strength and radial support in the initial implantation stage while moderately attenuating the radial support over time in the body fluid environment, thus effectively balancing support performance and long-term comfort.

[0006] To achieve the above technical effects, the following technical solution is adopted: A method for fabricating a water-cooled induced biphasic separation polyurethane ureteral stent, specifically comprising: Step S1: Obtain amphiphilic polyurethane as a molding raw material. The amphiphilic polyurethane contains both hydrophilic and hydrophobic segments to form a two-phase separation structure in the subsequent molding process. Step S2: The amphiphilic polyurethane particles from step S1 are thermoplastically extruded and then subjected to water cooling to obtain a catheter with a hollow tubular structure, which is a water-cooled induced biphasic separation polyurethane ureteral stent.

[0007] Furthermore, in step S1, the amphiphilic polyurethane is a polyurethane composed of polycaprolactone and polyethylene glycol, wherein the mass ratio of polycaprolactone to polyethylene glycol is 1:3-3:1, and the synthesis method is not limited, as long as it meets the biocompatibility and molding and processing performance requirements of medical polyurethane ureteral stents. Furthermore, in step S2, the specific method for thermoplastic extrusion molding is as follows: Amphiphilic polyurethane particles are thermoplastically extruded at 60-130°C and an extrusion pressure of 5-10 MPa.

[0008] Furthermore, in step S2, the outer diameter of the catheter is 1 to 3 mm.

[0009] Furthermore, in step S2, the inner contour of the radial cross-section of the conduit is circular, and the outer contour is circular or triangular.

[0010] Furthermore, in step S2, the water cooling temperature is 0 ~ 10 ℃.

[0011] Furthermore, in step S2, the water cooling temperature is 0 ~ 5 ℃.

[0012] A water-cooled induced biphasic separation polyurethane ureteral stent is prepared by any of the above-described preparation methods.

[0013] A water-cooled induced biphasic separation polyurethane ureteral stent is provided by secondary molding of the polyurethane ureteral stent prepared above. The ureteral stent is cut to the required length and then secondary molded at one or both ends to form a coiled fixing structure. The fixing structure is a hollow circle, which can be any of the overlapping or non-overlapping coiled shapes of half a circle, one circle, or two circles, used to prevent stent slippage.

[0014] Furthermore, the length of the stent is 220 to 300 mm; the stent tube wall is provided with several drainage holes with a diameter of 0.5 to 1 mm, and the number, shape and spacing of the drainage holes are set according to the clinical drainage effect.

[0015] The beneficial effects of this invention are as follows: This invention provides a water-cooled induced biphasic separation polyurethane ureteral stent and its preparation method. The method includes: obtaining amphiphilic polyurethane containing both hydrophilic and hydrophobic segments as a molding raw material, thermoplastic extrusion molding, and combined with water cooling to obtain a hollow tubular catheter; then cutting the catheter to a suitable length and performing secondary molding at one or both ends to form a coiled fixing structure to obtain the ureteral stent. This method, through the formation of a water-cooled induced biphasic separation structure, forms a wall layer with a specific microstructure without changing the chemical composition of the polyurethane. This achieves high radial support in the initial stage of the ureteral stent to ensure ureteral patency, while its radial support force gradually decreases after implantation, thereby reducing the patient's foreign body sensation and stent-related pain; thus effectively balancing support performance and long-term comfort. This stent can be used for temporary implantation in the ureter to treat ureteral strictures, etc., and has good application prospects. Attached Figure Description

[0016] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. The drawings described below are only embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on the provided drawings without creative effort.

[0017] Figure 1 This is a photograph of the polyurethane ureteral stent prepared in an embodiment of the present invention. Figure 2 Optical images of the polyurethane ureteral stents prepared in Examples 1, 2 and Comparative Examples 1 and 3 of the present invention under a polarizing microscope; Figure 3This is a Raman spectral image of the polycaprolactone distribution on the surface of the polyurethane ureteral stent prepared in Example 1 of the present invention; Figure 4 The tensile cycle curve of the polyurethane ureteral stent prepared in Example 1 of the present invention; Figure 5 The graph shows a comparison of the maximum tensile load after incubation at 37 °C for different times in Example 1, Comparative Example 1, and Comparative Example 3 of the present invention. Figure 6 The graph shows a comparison of Young's modulus bars after incubation at 37 °C for different times in Example 1, Comparative Example 1, and Comparative Example 3 of the present invention. Figure 7 This is a bar graph comparing the maximum radial load of Embodiment 1 and Comparative Examples 1-3 after incubation at 37 °C for different times. Detailed Implementation

[0018] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0019] It should be noted that the following detailed descriptions are exemplary and intended to provide further illustration of the invention. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0020] It should be noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the exemplary embodiments of the present invention. As used herein, the singular form is intended to include the plural form as well, unless the context clearly indicates otherwise. Furthermore, it should be understood that when the terms "comprising" and / or "including" are used in this specification, they indicate the presence of features, steps, operations, and / or combinations thereof.

[0021] In the following examples, unless otherwise specified, all reagents and consumables were purchased from conventional reagent manufacturers in the art; unless otherwise specified, the experimental methods and techniques used are conventional methods and techniques in the art.

[0022] The amphiphilic polyurethane and its preparation method provided by the present invention will be described below with reference to the embodiments. The scope of protection of the present invention is not limited by the following embodiments.

[0023] The manufacturers, models, specifications, or preparation methods of the reagents involved in the following examples are as follows: PEG (Mn = 2000, polyethylene glycol), polycaprolactone PCL and stannous octoate were purchased from Sigma and were chemically pure. Hexamethylene diisocyanate (HDI) was purchased from Huaxia Reagent Equipment Co., Ltd., with a purity of 99%. The preparation method of amphiphilic polyurethane raw material (PCEU) is as follows: 500 g of PEG and 500 g of PCL are added to a reaction vessel and mixed evenly. 169 g of hexamethylene diisocyanate (HDI) and 4 g of stannous octoate are added and mixed evenly. After the air in the reaction vessel is purged, nitrogen is introduced and the reaction is carried out at 120 °C for 24 h to obtain amphiphilic polyurethane.

[0024] Example 1: A polyurethane ureteral stent with improved mechanical properties through a biphasic separation structure and its preparation method, the method comprising: (1) Using amphiphilic polyurethane PCEU as raw material.

[0025] (2) The amphiphilic polyurethane PCEU was thermoplastically extruded at 90 ℃ and 9.8 MPa and then water-cooled at 4 ℃ to obtain a conduit with a radial cross-section and an inner and outer contour that are both circular and with an outer diameter of 1.27 mm.

[0026] (3) The catheter obtained in step (2) is subjected to secondary shaping processing. After the catheter is cut to a length of 260 mm, a circular coiled structure with an overlapping ring is formed at both ends as a fixing structure, such as Figure 1 As shown.

[0027] Example 2 A polyurethane ureteral stent with improved mechanical properties through a biphasic separation structure and its preparation method are basically the same as those in Example 1, except that: In step (2), the extrusion conditions are adjusted to 130 ℃, 6 MPa, and the water cooling temperature is adjusted to 0 ℃.

[0028] Comparative Example 1 A polyurethane ureteral stent with improved mechanical properties through a biphasic separation structure and its preparation method are basically the same as those in Example 1, except that: In step (2), the water cooling at 4 ℃ is changed to air cooling at 4 ℃.

[0029] Comparative Example 2 A commercial ureteral stent (Cook Medical; model: USI-526-B) was used as a comparison sample.

[0030] Comparative Example 3 A polyurethane ureteral stent with improved mechanical properties through a biphasic separation structure and its preparation method are basically the same as those in Example 1, except that: In step (2), the water cooling temperature of 4 ℃ is changed to water cooling temperature of 15 ℃.

[0031] Structural evaluation results: 1. Microstructural characterization of ureteral stent The microstructure of the ureteral stents prepared in Examples 1, 2, 1, and 3 was examined. The specific method was as follows: the ureteral stent was cut along the axis, spread on a glass slide and fixed, and then flattened with a weight. Optical observation was performed using an Axio Lab A1 upright polarizing microscope from Carl Zeiss.

[0032] like Figure 2 As shown, the ureteral stents prepared in Examples 1 and 2 exhibited obvious interference fringes under a polarizing microscope, and crystalline structures of varying sizes and regular arrangements could be observed. In contrast, the stents in Comparative Examples 1 and 3 did not show interference fringes, only uniformly sized crystalline structures. In Comparative Example 1, due to the good compatibility between PCL and PEG segments, no obvious phase separation structure was formed under air-cooling conditions. In Comparative Example 3, although water cooling at 15°C was used, the limited cooling efficiency resulted in more complete PCL crystal development and a more uniform crystalline phase, thus failing to induce an obvious two-phase separation structure. These results indicate that a water cooling process of 0–5°C can effectively induce the formation of a two-phase separation structure in amphiphilic polyurethane during extrusion molding, thus distinguishing it from Comparative Example 1 (which did not use water cooling) and Comparative Example 3 (which used water cooling at a higher temperature).

[0033] 2. Characterization of the two-phase separated structure The biphasic structure of the ureteral stent prepared in Example 1 was tested. The specific method was as follows: the ureteral stent prepared in Example 1 was cut along the axis, spread on a glass slide and fixed, and then flattened with a weight. The Raman spectrum range was scanned using a LabRAM Soleil Raman spectrometer (manufactured by HORIBA FRANCE SAS) in Example 1.

[0034] like Figure 3 As shown, the test results indicate that the ureteral stent prepared in Example 1 of this invention exhibits a significant biphasic separation structure. One type of phase-separated structure has more PCL crystals, while the other type has more PEG components. This result further verifies that the polyurethane ureteral stent obtained by the present invention through extrusion combined with water cooling process possesses biphasic separation characteristics.

[0035] Performance evaluation results: 1. Tensile mechanical testing The tensile mechanical properties of Examples 1, 2 and Comparative Examples 1-3 were tested as follows: Samples of Examples 1, 2 and 3 with a length of 5 cm were made and subjected to uniaxial tensile tests on an Instron 68TM-10 electronic universal tensile testing machine to evaluate their tensile mechanical properties. The tensile rate was set to 100 mm / min and the test temperature was 25 ℃. The data are shown in Table 1.

[0036] Table 1 Tensile mechanical properties of Examples 1-2 and Comparative Examples 1-3

[0037] The results are shown in Table 1. As can be seen from Table 1, Examples 1 and 2 of the present invention exhibit superior mechanical properties compared to the comparative examples, especially in terms of significantly improved fracture strength. The fracture strengths of Examples 1 and 2 are approximately 2.78 times and 3.00 times that of Comparative Example 1, respectively. Furthermore, Examples 1 and 2 demonstrate that appropriately increasing the melting temperature and decreasing the water cooling temperature during extrusion promotes the formation of the biphasic separation structure more rapidly, further enhancing the mechanical properties of the material and resulting in higher fracture strength. Comparative Example 3, due to its larger crystal structure and lack of biphasic separation, exhibits the highest Young's modulus. This indicates that the larger and more complete crystal structure results in a ureteral stent with weaker deformation capacity and higher rigidity. Therefore, the biphasic separation structure can significantly improve the mechanical properties of the material, increasing both tensile strength and flexibility.

[0038] 2. Tensile fatigue resistance test The tensile fatigue test of Example 1 was conducted as follows: the sample of Example 1 was made into a sample with a length of 5 cm and subjected to cyclic tensile test on an Instron 68TM-10 electronic universal tensile testing machine. The tensile rate was set to 100 mm / min and the temperature was 25 ℃. When the strain reached 100%, the sample was stretched 10 times continuously.

[0039] like Figure 4 As shown, the sample in Example 1 recovered to its original length after 10 cycles of stretching, without significant plastic deformation. This indicates that the ureteral stent with a biphasic separation structure prepared in this invention possesses good elastic recovery ability and excellent fatigue resistance.

[0040] 3. Radial support performance test The radial support performance tests of Examples 1, 2, and Comparative Examples 1-3 were conducted as follows: Dry samples of Examples 1, 2, and 1-3 were cut into 1 cm long short tubes and placed on a stage. A compression test was performed using a 1 cm diameter presser foot at a compression rate of 1 mm / min, and the radial load was recorded when the sample was compressed to 50% of its original diameter.

[0041] Table 2 Comparison of radial load performance of different support samples (load values ​​when compressed to 50% of the tube diameter)

[0042] As shown in Table 2, Examples 1 and 2, which have a biphasic separation structure, both exhibited higher radial loads in the dry state, providing stronger tissue support compared to Comparative Example 2 (a clinically widely used flexible ureteral stent). Furthermore, Comparative Example 3, which has a larger crystalline structure and lacks a biphasic separation structure, showed the highest radial load in the test; however, excessively high radial stiffness often leads to more severe "stent pain" side effects in patients.

[0043] 4. Changes in the mechanical properties of stents under different environments The tensile properties and radial load of Example 1, Comparative Example 1, and Comparative Example 3 under different environments were tested. The specific method was as follows: Example 1, Comparative Example 1, and Comparative Example 3 were made into 5 cm long samples and placed in phosphate buffer solution (PBS) at 37 °C for 1 h. After 7 days and 14 days, uniaxial tensile tests were carried out on an Instron 68TM-10 electronic universal tensile testing machine to evaluate their tensile mechanical properties. The tensile rate was set to 100 mm / min and the test temperature was 25 °C.

[0044] like Figure 5 and Figure 6As shown, after 14 days of incubation, the maximum tensile load of Example 1 did not decrease significantly, indicating that the stent could maintain sufficient mechanical strength after implantation. Simultaneously, the test results also showed that the Young's modulus of Example 1 decreased with prolonged incubation time in a 37°C water environment, decreasing from 9.08 MPa in the dry state to 5.69 MPa (7 days) and 5.79 MPa (14 days). This indicates that the material gradually becomes softer and its deformation capacity increases with prolonged incubation time, thus better adapting to the physiological environment of the ureter. The results indicate that the ureteral stent with a biphasic separation structure described in this invention can gradually soften after implantation, maintaining necessary mechanical support in the initial stage while improving tissue compatibility in the later stage. After 1 hour of incubation in a 37°C water environment, the Young's modulus of Comparative Example 1 without the biphasic separation structure increased slightly and then remained stable; while the Young's modulus of Comparative Example 3 decreased slightly within 1 hour and then tended to stabilize. Comparative Examples 1 and 3 did not show significant mechanical changes over time, indicating a lack of dynamic adaptability.

[0045] 5. Variation of radial support performance of the support under different environments Example 1, Comparative Examples 1-3: Radial support performance variation test at different incubation times. The specific method was as follows: Example 1 samples were cut into 1 cm long short tubes and placed in a phosphate buffer solution at 37 ℃ for different incubation times. The samples were then removed and placed on a stage. A compression test was performed using a 1 cm diameter presser foot at a compression rate of 1 mm / min, and the radial load when compressed to 50% of the tube diameter was recorded.

[0046] like Figure 7As shown, the compressive load of the stent manufactured in Example 1 was 9.05 N in a dry state, which decreased to 5.63 N after soaking in PBS for 1 h. Further extending the incubation time to 7 days and 14 days, the required compressive force decreased to 2.51 N and 3.63 N, respectively, approaching the radial support force (2.12 N) of Comparative Example 2 (a widely used flexible ureteral stent). Comparative Examples 1 and 3, being made of amphiphilic polyurethane, experienced relaxation of the hydrophilic segments after PBS wetting, resulting in an initial decrease in radial support force. However, this decrease did not significantly reduce the radial support force with prolonged incubation. Example 1 exhibited significant dynamic mechanical regulation characteristics after implantation: initially possessing high radial support force, it provided sufficient expansion and support even with significant ureteral stenosis, edema, and inflammatory responses; as the implantation time increased, the material gradually softened in the body fluid environment, and the radial load decreased significantly over time, thereby enhancing its flexibility and effectively reducing the patient's foreign body sensation and "stent pain." Therefore, the ureteral stent of the present invention has the dynamic adaptation characteristics of both initial rigidity and later flexibility, which better meets the clinical needs in the recovery process of ureteral lesions, and is expected to improve the patient's implantation experience and improve the overall treatment effect.

[0047] In summary, this invention discloses a water-cooled induced biphasic separation polyurethane ureteral stent and its preparation method. The method includes: obtaining amphiphilic polyurethane containing both hydrophilic and hydrophobic segments as a molding raw material, thermoplastic extrusion molding, and water-cooling treatment to obtain a hollow tubular catheter; then cutting the catheter to a suitable length and performing secondary molding at one or both ends to form a coiled fixing structure to obtain the ureteral stent. This method, through the formation of a water-cooled induced biphasic separation structure, achieves high radial support in the initial stage of the ureteral stent to ensure ureteral patency without changing the chemical composition of the polyurethane, while its radial support force gradually decreases after implantation, thereby reducing the patient's foreign body sensation and stent-related pain. This stent can be temporarily implanted in the ureter to treat ureteral strictures, etc., and has good application prospects.

[0048] Therefore, those skilled in the art will recognize that although embodiments of the present invention have been shown and described in detail herein, many other variations or modifications conforming to the principles of the present invention can be directly determined or derived from the disclosure of the present invention without departing from the spirit and scope of the invention. Therefore, the scope of the present invention should be understood and recognized as covering all such other variations or modifications.

Claims

1. A method for fabricating a water-cooled induced biphasic separation polyurethane ureteral stent, characterized in that, The preparation method is as follows: Step S1: Obtain amphiphilic polyurethane as a molding raw material. The amphiphilic polyurethane contains both hydrophilic and hydrophobic segments to form a two-phase separation structure in the subsequent molding process. Step S2: The amphiphilic polyurethane particles from step S1 are thermoplastically extruded and then subjected to water cooling to obtain a catheter with a hollow tubular structure, which is a water-cooled induced biphasic separation polyurethane ureteral stent.

2. The method for fabricating a water-cooled induced biphasic separation polyurethane ureteral stent as described in claim 1, characterized in that, In step S1, the amphiphilic polyurethane is a polyurethane composed of polycaprolactone and polyethylene glycol, wherein the mass ratio of polycaprolactone to polyethylene glycol is 1:3-3:1, and the synthesis method is not limited, as long as it meets the biocompatibility and molding and processing performance requirements of medical polyurethane ureteral stents.

3. The method for fabricating a water-cooled induced biphasic separation polyurethane ureteral stent as described in claim 1, characterized in that, In step S2, the specific method for thermoplastic extrusion molding is as follows: Amphiphilic polyurethane particles are thermoplastically extruded at 60-130°C and an extrusion pressure of 5-10 MPa.

4. The method for fabricating a water-cooled induced biphasic separation polyurethane ureteral stent as described in claim 1, characterized in that, In step S2, the outer diameter of the catheter is 1 to 3 mm.

5. The method for fabricating a water-cooled induced biphasic separation polyurethane ureteral stent as described in claim 1, characterized in that, In step S2, the inner contour of the radial cross-section of the conduit is circular, and the outer contour is circular or triangular.

6. The method for fabricating a water-cooled induced biphasic separation polyurethane ureteral stent as described in claim 1, characterized in that, In step S2, the water cooling temperature is 0 ~ 10 ℃.

7. The method for fabricating a water-cooled induced biphasic separation polyurethane ureteral stent as described in claim 1, characterized in that, In step S2, the water cooling temperature is 0 ~ 5 ℃.

8. A water-cooled, induced biphasic separation polyurethane ureteral stent, characterized in that, It is prepared by the preparation method according to any one of claims 1-7.

9. A water-cooled, induced biphasic separation polyurethane ureteral stent, characterized in that, The polyurethane ureteral stent prepared in claim 8 is subjected to secondary molding. The ureteral stent is cut to the required length and then subjected to secondary molding at one or both ends to form a coiled fixing structure. The fixing structure is a hollow circle, which can be any one of overlapping or non-overlapping coiled shape of half a circle, one circle, or two circles, used to prevent the stent from slipping.

10. The water-cooled induced biphasic separation polyurethane ureteral stent as described in claim 9, characterized in that, The length of the stent is 220 to 300 mm; the stent tube wall is provided with a number of drainage holes with a diameter of 0.5 to 1 mm, and the number, shape and spacing of the drainage holes are set according to the clinical drainage effect.

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