Biodegradable stent and method for manufacturing the same

Abstract

The present invention relates to a method for manufacturing a biodegradable stent and a biodegradable stent manufactured therefrom, comprising: (a) a step of preparing a biodegradable polymer tube; (b) a step of performing a cutting process on the biodegradable polymer tube using a femtosecond laser; (c) a step of sterilizing the biodegradable polymer tube on which the cutting process has been performed; and (d) a step of performing a process of applying a temperature change to the sterilized polymer tube.

Description

Technology Field

[0001] The present invention relates to a biodegradable stent that completely decomposes after a certain period of time and a method for manufacturing the same. Background Technology

[0003] Coronary artery disease is one of the leading causes of death worldwide, and stent implantation is widely used as a treatment method. A stent is a medical device implanted into narrowed or blocked coronary arteries to expand blood vessels and facilitate smooth blood flow. To date, metal materials have been used as the primary components of stents and have dominated the market due to their high mechanical strength and flexibility.

[0004] However, metal stents present a problem in that they are difficult to remove from the body once the healing and regeneration of blood vessels are complete. Consequently, metal stents remain permanently within the blood vessels, causing persistent foreign body reactions and potentially leading to the development of neoatherosclerosis in the long term. Due to these issues, there is a growing need for research and development of next-generation material-based stents to replace metal stents.

[0005] Accordingly, the development of stents utilizing biodegradable materials that naturally decompose within the body after a certain period has been actively underway recently. Biodegradable stents gradually decompose within the body and can disappear without a trace once the blood vessel has healed, thereby resolving the problem of long-lasting foreign body reactions.

[0006] Therefore, biodegradable stents are attracting attention as a technology capable of overcoming the limitations of metal stents, and new manufacturing methods are required to implement them. The problem to be solved

[0008] The present invention relates to a biodegradable stent that completely decomposes after a certain period of time and a method for manufacturing the same.

[0010] The problems that the present invention aims to solve are not limited to the problem(s) mentioned above, and other unmentioned problems will be clearly understood by those skilled in the art from the description below. means of solving the problem

[0012] To achieve the above objective, the present invention provides a method for manufacturing a biodegradable stent comprising: (a) preparing a biodegradable polymer tube; (b) performing a cutting process on the biodegradable polymer tube using a femtosecond laser; (c) sterilizing the biodegradable polymer tube on which the cutting process has been performed; and (d) performing a process of applying a temperature change to the sterilized polymer tube.

[0013] The above biodegradable polymer may include at least one selected from the group consisting of poly(L-lactic acid, PLLA), polyglycolide, poly p-dioxanone, polycaprolactone, trimethylene carbonate, polyhydroxyalkanoates, polypropylene fumarate, polyortho esters, other polyesters, polyanhydride, polyphosphazenes, polyalkyl cyanoacrylates, poloxamers, polyamino L-tyrosine, modified polysaccharides, oxidized cellulose, gelatin, collagen, and combinations thereof.

[0014] In step (a) above, the IV (Inherent Viscosity) of the biodegradable polymer tube may be 2.2 dl / g or more and 3.6 dl / g or less.

[0015] In step (a) above, the weight-average molecular weight of the biodegradable polymer tube may be 250,000 or more and 530,000 g / mol or less.

[0016] In step (b) above, the femtosecond laser cutting process may involve irradiating the biodegradable polymer tube with a second harmonic laser having a wavelength of 470 nm or more and 776 nm or less.

[0017] The sterilization treatment in step (c) above may be irradiating the biodegradable polymer tube on which the cutting process has been performed with an electron beam (E-beam) at a rate of 15 kGy or more and 25 kGy or less.

[0018] The process of changing the temperature in step (d) above may be performed at a temperature of 20°C or higher and 80°C or lower.

[0019] The process of changing the temperature in step (d) above may include sequentially performing at least once the following steps: (d-1) raising the temperature from 25°C to 54°C; (d-2) maintaining the temperature at 54°C for 10 minutes or more and 30 minutes or less; (d-3) lowering the temperature from 54°C to 25°C; and (d-4) maintaining the temperature at 25°C for 10 minutes or more and 30 minutes or less.

[0020] The above biodegradable stent may have a change rate of the polydispersity index (PDI), represented by Formula 1 below, of 20% or less:

[0021] [Equation 1]

[0022] Change rate of polyvariance index (%) = (BA / A) x 100

[0023] In the above Equation 1,

[0024] A is the polydispersity index of the biodegradable polymer tube before performing the cutting process using a femtosecond laser, and

[0025] B is the polydispersity index of the biodegradable polymer tube after performing a cutting process using a femtosecond laser.

[0027] In addition, the present invention provides a biodegradable stent manufactured by the method for manufacturing the biodegradable stent described above.

[0028] The weight-average molecular weight of the above biodegradable stent may be 150,000 g / mol or more and 220,000 g / mol or less.

[0029] The IV (Inherent Viscosity) of the above biodegradable stent may be 1.4 dl / g or more and 1.8 dl / g or less. Effects of the invention

[0031] The biodegradable stent of the present invention can maintain strength and support the lumen of the blood vessel for healing and regeneration of the blood vessel for about 6 months after implantation of the biodegradable stent into the blood vessel, and after 3 years have passed since implantation, it can be completely hydrolyzed in the body and excreted from the body through metabolic processes.

[0032] In addition, the biodegradable stent of the present invention can achieve an optimal biodegradation period by controlling the molecular weight of the biodegradable material.

[0034] The effects of the present invention are not limited to the effects described above, and should be understood to include all effects that can be inferred from the configuration of the invention described in the detailed description of the invention or the claims. Brief explanation of the drawing

[0036] Figure 1 shows the results of confirming the change in mechanical strength of a PLLA stent according to the biodegradation period of a poly-L-lactic acid stent prepared according to Example 1. Figure 2 shows the change in molecular weight of a PLLA stent according to the biodegradation period of a poly-L-lactic acid stent prepared according to Example 1. Specific details for implementing the invention

[0037] It should be noted that in the following description, only the parts necessary for understanding the embodiments of the present invention are described, and the description of other parts may be omitted to the extent that it does not detract from the gist of the present invention.

[0038] The terms and words used in the specification and claims described below should not be interpreted as being limited to their ordinary or dictionary meanings, but should be interpreted in a meaning and concept consistent with the technical spirit of the invention, based on the principle that the inventor can appropriately define the concept of the terms to best describe his invention. Accordingly, the embodiments described in this specification and the configurations illustrated in the drawings are merely preferred embodiments of the invention and do not represent all aspects of the technical spirit of the invention; therefore, it should be understood that various equivalents and modifications capable of replacing them may exist at the time of filing this application.

[0040] The present invention provides a method for manufacturing a biodegradable stent comprising: (a) preparing a biodegradable polymer tube; (b) performing a cutting process on the biodegradable polymer tube using a femtosecond laser; (c) sterilizing the biodegradable polymer tube on which the cutting process has been performed; and (d) performing a process of applying a temperature change to the sterilized polymer tube.

[0041] The present invention will be described below based on the method for manufacturing a biodegradable stent of the present invention.

[0042] First, (a) prepare a biodegradable polymer tube.

[0043] The above step (a) may be a step of preparing a biodegradable polymer tube to be fed into a femtosecond laser cutting process in order to shape a stent having a mesh structure using the femtosecond laser cutting process described later.

[0044] In one embodiment, the biodegradable polymer tube may be manufactured into a tube shape by injection molding a biodegradable polymer (e.g., resin).

[0045] Specifically, the step of preparing the biodegradable polymer tube may include: a step of manufacturing a biodegradable polymer tube by injecting a molten biodegradable polymer; and a step of expanding the diameter of the injected biodegradable tube.

[0046] In one embodiment, the step of expanding the diameter of the biodegradable polymer tube may be a step of determining the diameter of the biodegradable polymer tube during pattern formation in the femtosecond laser cutting process step. The expanded diameter of the biodegradable polymer tube may be the same as the diameter of the biodegradable polymer tube prepared for the femtosecond laser cutting process step.

[0047] In the step of expanding the diameter of the above-mentioned biodegradable polymer tube, the outer diameter of the expanded biodegradable polymer tube may be equal to the inner diameter of the blood vessel or smaller than the inner diameter of the blood vessel.

[0048] The inner diameter of the above blood vessel may vary depending on the blood vessel into which the polymer stent is to be inserted. For example, if the blood vessel into which the polymer stent is to be inserted is a coronary artery, the diameter of the blood vessel may be 2.5 mm or more and 4.0 mm or less.

[0049] In one embodiment, the outer diameter of the expanded polylactic acid tube may be 0.3 times or more and 1 time or less than the inner diameter of the blood vessel. If necessary, it may be 0.4 times or more and 0.7 times or less than the inner diameter of the blood vessel.

[0050] In one embodiment, the biodegradable polymer may comprise at least one selected from the group consisting of poly(L-lactic acid, PLLA), polyglycolide, poly p-dioxanone, polycaprolactone, trimethylene carbonate, polyhydroxyalkanoates, polypropylene fumarate, polyortho esters, other polyesters, polyanhydride, polyphosphazenes, polyalkyl cyanoacrylates, poloxamers, polyamino L-tyrosine, modified polysaccharides, oxidized cellulose, gelatin, collagen, and combinations thereof. Specifically, the biodegradable The polymer may be poly-L-lactic acid (Poly(L-lactic acid, hereinafter also referred to as "PLLA").

[0051] In particular, the PLLA is biodegraded slowly over a period of about 2 to 5 years, so it is maintained for the time required for blood vessel regeneration before degrading. Compared to other biodegradable polymers (e.g., Poly(glycolide), Poly(lactide-co-glycolide, Polycaprolactone, etc.), it has high crystallinity and excellent strength, resulting in excellent blood vessel support function. In addition, the PLLA is L-type lactic acid present in the body, which is highly biocompatible and safe. It also has the advantage of being able to achieve desired physical properties by controlling its amorphous and crystallin properties.

[0052] In step (a) above, the Inherent Viscosity (IV) of the biodegradable polymer tube may be 2.2 dl / g or more and 3.6 dl / g or less. When the Inherent Viscosity (IV) of the biodegradable polymer tube satisfies the above range, the required radial force strength and biodegradation period can be achieved when the stent processing process, including laser cutting, is performed and post-sterilization treatment is carried out.

[0053] In step (a) above, the weight-average molecular weight of the biodegradable polymer tube may be 250,000 or more and 530,000 g / mol or less. When the weight-average molecular weight of the biodegradable polymer tube satisfies the above range, the required radial force strength and biodegradation period can be achieved when the stent processing process, including laser cutting, is performed and post-sterilization treatment is carried out.

[0055] Next, (b) the biodegradable polymer tube is cut using a femtosecond laser.

[0056] The above step (b) may be a step of irradiating a biodegradable polymer tube with a second harmonic generator laser to process the biodegradable polymer tube into a stent pattern in the visible light wavelength range, thereby minimizing changes in molecular weight of number average molecular weight or weight average molecular weight.

[0057] In one embodiment, the second harmonic laser may refer to a laser whose wavelength is divided in half using a second harmonic generator (SHG).

[0058] In one embodiment, the cutting may not be a simple cutting, but may refer to a process of forming a stent pattern.

[0059] Biodegradable polymers such as the aforementioned PLLA are sensitive to external environmental factors such as heat and humidity, and the degree of thermal decomposition varies depending on processing conditions, which significantly affects the key performance characteristics of the biodegradable stent after processing, such as molecular weight, duration of mechanical strength maintenance, and biodegradation rate.

[0060] Accordingly, to ensure the mechanical strength of biodegradable stents and optimize the biodegradation rate, it is necessary to control the molecular weight of the biodegradable polymer, and it is important to design the device to minimize the reduction in molecular weight of the biodegradable polymer during the laser cutting process.

[0061] For example, when using a long-pulse laser during the laser cutting process in the manufacturing of biodegradable stents, the heat generated melts the processed surface, forming a heat-affected zone (HAZ) and significantly reducing the molecular weight of the biodegradable polymer. Therefore, biodegradable stents must be processed using an ultra-short pulse laser.

[0062] Accordingly, the inventors studied the changes in molecular weight and mechanical strength of a biodegradable polymer stent according to changes in the wavelength of a microwave femtosecond laser.

[0063] In one embodiment, the femtosecond laser cutting process can form a pattern on a biodegradable polymer tube by irradiating the biodegradable polymer with a second harmonic laser having a wavelength range of 470 nm to 776 nm. When the second harmonic laser is irradiated in the wavelength range, there is an advantage of small thermal damage and molecular weight change of the biodegradable polymer at the laser contact surface and high mechanical strength.

[0065] Next, (c) the biodegradable polymer tube on which the above cutting process has been performed is sterilized.

[0066] The above step (c) may be a step of killing bacteria that may remain in the biodegradable polymer tube and significantly reducing the average molecular weight while minimizing changes in the molecular weight distribution to shorten the biodegradation period of the biodegradable stent.

[0067] In one embodiment, the sterilization treatment may be performed by irradiating the biodegradable polymer tube, on which the cutting process has been performed, with an electron beam (E-beam) at a rate of 15 kGy or more and 25 kGy or less. When an electron beam is irradiated within the above numerical range, the weight-average molecular weight of the biodegradable stent intended in the present invention can be controlled so that it can be completely biodegraded after 36 months of implantation in the body.

[0069] Next, (d) a process of applying a temperature change to the above-mentioned sterilized polymer tube is performed.

[0070] The above step (d) may be a step of removing radicals in the sterilized biodegradable stent to satisfy the performance of the biodegradable stent within the shelf life.

[0071] In step (c) above, sterilizing the biodegradable polymer tube with an electron beam has many advantages regarding heat, humidity, product design, and packaging methods, but free radicals formed by radiation exposure can react with the biodegradable polymer chains. The free radicals generated by electron beam sterilization continue to react even after sterilization and pose a problem of promoting changes in the physical properties of the biodegradable polymer stent.

[0072] Therefore, by applying a post-sterilization process to remove free radicals generated in the biodegradable stent, changes in the physical properties of the biodegradable stent must be minimized and high mechanical strength can be maintained for a long period.

[0073] In one embodiment, the sterilization post-treatment process may refer to a process of applying a temperature change to a sterilized biodegradable polymer tube.

[0074] In one embodiment, the process of applying the temperature change may be performed at a temperature of 20°C or higher and 80°C or lower. When a post-sterilization process is performed within the above temperature range, free radicals generated in the biodegradable stent are removed, thereby minimizing changes in the physical properties of the biodegradable stent and maintaining high mechanical strength for a long period.

[0075] In one embodiment, the process of causing the temperature change may be performed using a constant temperature and humidity device.

[0076] Specifically, the process of introducing a temperature change in step (d) above is,

[0077] (d-1) a step of raising the temperature from 25℃ to 54℃; (d-2) a step of maintaining the temperature at 54℃ for 10 minutes or more and 30 minutes or less; (d-3) a step of lowering the temperature from 54℃ to 25℃; and (d-4) a step of maintaining the temperature at 25℃ for 10 minutes or more and 30 minutes or less; can be performed sequentially at least once, specifically 5 times.

[0078] In one embodiment, free radicals of a biodegradable stent can be removed by applying a specific temperature to a sterilized biodegradable polymer tube at periodic intervals.

[0080] In one embodiment, the biodegradable stent may have a change rate of the polydispersity index (PDI) represented by Formula 1 below of 20% or less, specifically 10% or less.

[0081] [Equation 1]

[0082] Change rate of polyvariance index (%) = (BA / A) x 100

[0083] In the above Equation 1,

[0084] A is the polydispersity index of the biodegradable polymer tube before performing the cutting process using a femtosecond laser, and

[0085] B is the polydispersity index of the biodegradable polymer tube after performing a cutting process using a femtosecond laser.

[0086] In one embodiment, the polydispersity index of the biodegradable stent may be 1 or more and 2 or less. Satisfying the polydispersity index of 1 or more and 2 or less means that the molecular weight of the biodegradable stent is controlled in the manufacturing process of the biodegradable stent according to the present invention.

[0087] Here, polydispersity index refers to the value obtained by dividing the mass-average molecular weight by the number-average molecular weight, and the closer the value is to 1, the narrower the distribution of molecular weights.

[0088] In one embodiment of the present invention, a biodegradable stent is provided that is manufactured by the method for manufacturing a biodegradable stent described above.

[0089] Content that overlaps with what was explained in the aforementioned method for manufacturing a biodegradable stent is omitted.

[0090] In one embodiment, the weight-average molecular weight of the biodegradable stent may be 150,000 g / mol or more and 220,000 g / mol or less. When the weight-average molecular weight of the biodegradable stent satisfies the above values, the biodegradable stent can maintain mechanical strength within the blood vessel for 6 months after implantation in the body and can be completely biodegraded at 36 months.

[0091] In one embodiment, the IV (Inherent Viscosity) of the biodegradable stent may be 1.4 dl / g or higher and 1.8 dl / g or lower. When the IV of the biodegradable stent satisfies the above values, the biodegradable stent can maintain mechanical strength within the blood vessel for 6 months after implantation in the body and can be completely biodegraded at 36 months.

[0093] The above description explains the technical concept of the present invention using one embodiment, and those skilled in the art to which the present invention pertains will be able to make various modifications and variations within the scope of the essential characteristics of the present invention. Accordingly, the embodiments described in this invention are intended to explain, not limit, the technical concept of the present invention, and the scope of the technical concept of the present invention is not limited by such embodiments. The scope of protection of the present invention shall be interpreted by the claims, and all technical concepts within an equivalent scope shall be interpreted as being included within the scope of rights of the present invention.

[0095] <Example>

[0096] Example 1

[0097] A heating block was mounted in the center of the balloon forming machine, and a middle mold was inserted into the heating block. The prepared pre-expansion PLLA tube was then positioned to penetrate the middle mold. To allow nitrogen to flow into the tube, one end of the tube was inserted into a gripper and connected to the nitrogen line. After performing the tube expansion process under the set temperature, pressure, and time conditions, the completion of the process was checked on a screen, and the gripper holding the tube was released. The expanded PLLA tube was pulled in one direction to separate it from the middle mold (at this time, the pre-expansion PLLA tube was manufactured according to a standard PLLA tube injection process using PLLA resin with a weight-average molecular weight of 809,819 g / mol and an IV of approximately 4.3 dl / g, and the separated PLLA tube has a weight-average molecular weight of 503,162 g / mol and an IV of approximately 3.13 dl / g). A cutting process was performed on the separated PLLA tube by forming a stent pattern using a femtosecond laser, changing the 1030 nm wavelength laser to a 515 nm second harmonic laser and irradiating it. Next, the PLLA tube with the stent pattern formed after the cutting process was completed was sterilized by irradiating it with an electron beam at 15 kGy for 3.8 seconds. Next, the sterilized PLLA tube was placed in a constant temperature and humidity chamber (TH-DG-400, JEIO TECH), the temperature was raised from 25 ℃ to 54 ℃ (time required: 28 minutes), and maintained at 54 ℃ for about 15 minutes. Subsequently, the temperature was lowered from 54 ℃ to 25 ℃ (time required: 23 minutes) and maintained at 25 ℃ for about 15 minutes, performing a temperature change process once. This process was repeated a total of 5 times to manufacture the PLLA stent.

[0099] Example 2

[0100] A heating block was mounted in the center of the balloon forming machine, and a middle mold was inserted into the heating block. The prepared pre-expansion PLLA tube was then positioned to penetrate the middle mold. To allow nitrogen to flow into the tube, one end of the tube was inserted into a gripper and connected to the nitrogen line. After performing the tube expansion process under the set temperature, pressure, and time conditions, the completion of the process was checked on a screen, and the gripper holding the tube was released. The expanded PLLA tube was pulled in one direction to separate it from the middle mold (at this time, the pre-expansion PLLA tube was manufactured according to a standard PLLA tube injection process using PLLA resin with a weight-average molecular weight of 531,018 g / mol and an IV of approximately 3.24 dl / g; the separated PLLA tube had a weight-average molecular weight of 328,964 g / mol and an IV of approximately 2.4 dl / g).

[0101] A cutting process was performed on the separated PLLA tube by forming a stent pattern using a femtosecond laser, changing the 1030 nm wavelength laser to a 515 nm second harmonic laser and irradiating it. Next, the PLLA tube with the stent pattern formed after the cutting process was completed was sterilized by irradiating it with an electron beam at 15 kGy for 3.8 seconds. Next, the sterilized PLLA tube was placed in a constant temperature and humidity chamber (TH-DG-400, JEIO TECH), the temperature was raised from 25 ℃ to 54 ℃ (time required: 28 minutes), and maintained at 54 ℃ for about 15 minutes. Subsequently, the temperature was lowered from 54 ℃ to 25 ℃ (time required: 23 minutes) and maintained at 25 ℃ for about 15 minutes, performing a temperature change process once. This process was repeated a total of 5 times to manufacture the PLLA stent.

[0103] <Comparative Example>

[0104] Comparative Example 1

[0105] A heating block was mounted in the center of the balloon forming machine, and a middle mold was inserted into the heating block. The prepared pre-expansion PLLA tube was then positioned to penetrate the middle mold. To allow nitrogen to flow into the tube, one end of the tube was inserted into a gripper and connected to the nitrogen line. After performing the tube expansion process under the set temperature, pressure, and time conditions, the completion of the process was checked on a screen, and the gripper holding the tube was released. The expanded PLLA tube was pulled in one direction to separate it from the middle mold (at this time, the pre-expansion PLLA tube was manufactured according to a standard PLLA tube injection process using PLLA resin with a weight-average molecular weight of 521,273 g / mol and an IV of approximately 3.2 dl / g; the separated PLLA tube had a weight-average molecular weight of 317,528 g / mol and an IV of approximately 2.3 dl / g).

[0106] In Example 1, a PLLA stent was manufactured in the same manner as in Example 1, except that the laser with a wavelength of 1030 nm was changed to a laser with a wavelength of 343 nm instead of a laser with a wavelength of 515 nm to form a pattern on the PLLA tube.

[0108] Comparative Example 2

[0109] A PLLA stent was manufactured in the same manner as in Example 1, except that the same PLLA tube (weight-average molecular weight: 317,300 g / mol) as in Comparative Example 1 was used, and a pattern was formed on the PLLA tube using a 1030 nm wavelength laser that does not use a second harmonic generating element, instead of changing the 1030 nm wavelength laser in Example 1 to a 515 nm second harmonic laser.

[0111] Comparative Example 3

[0112] In Example 1, a PLLA stent was prepared in the same manner as in Example 1, except that the PLLA tube with the formed stent pattern was sterilized by conventional EO (ethylene oxide) gas sterilization instead of being sterilized by irradiating it with an electron beam at 15 kGy for 3.8 seconds.

[0113] - EO gas sterilization conditions

[0114] A. Preheating: 50±10℃, 50±20%RH, 4 hours

[0115] B. Adjustment: 55±10℃, 50±20%RH, 30 minutes

[0116] C. EO Gas Injection: 55±10℃, 50±20%RH, 20 minutes

[0117] D. EO Gas Exposure: 55±10℃, 50±20%RH, 4 hours

[0118] E. The following flushing process is omitted as it is performed at room temperature.

[0120] <Experimental Example>

[0121] Experimental Example 1. Measurement of molecular weight at each manufacturing stage

[0122] Using gel permeation chromatography (GPC), the weight-average molecular weight (Mw) and polydispersity index (PDI, Mw / Mn) of the preparation steps of Example 1 above are shown in Table 1 below.

[0123] At this time, a PL-gel Mixed-B column (Agilent) was used for GPC measurements, and Chloroform (100%, HPLC grade) was used as the eluent. The migration speed of the eluent was set to 1.0 ml / min.

[0125] Example 1 IV Mw PDI PLLA tube (g / mol) 3.13 503,162 1.6 After femtosecond laser cutting (g / mol) 3.0 477,000 1.6 After temperature change process (g / mol) (finished product) 1.5 180,000 1.6

[0126] Referring to Table 1 above, when a biodegradable stent is manufactured using the method for manufacturing a biodegradable stent according to the present invention, it can be seen that the weight-average molecular weight decreases as the femtosecond laser cutting process, sterilization process, and post-sterilization process (i.e., process of changing the temperature) are performed, and it can be seen that the polydispersity index does not change.

[0127] In particular, when processing polylactic acid (PLLA) biodegradable polymer tubes into a stent pattern during the femtosecond laser cutting process, irradiating them with a second harmonic generator laser in the visible light wavelength range reduced the heat-affected zone (HAZ) formed by melting the processed surface due to heat generated when using a long-pulse laser, thereby minimizing molecular weight reduction and maintaining mechanical strength. Additionally, it was confirmed that the electron beam sterilization process allows for controlling the weight-average molecular weight of the finished product so that it takes 3 years for the biodegradable stent to completely biodegrade in the body. Furthermore, by reducing the molecular weight while maintaining a uniform polydispersity index, it was possible to control the biodegradation of the biodegradable polymer stent so that there is minimal variation in biodegradation among stent samples and that the degradation occurs uniformly.

[0129] Experimental Example 2. Measurement of molecular weight before and after laser cutting

[0130] Using gel permeation chromatography (GPC), the weight-average molecular weight (Mw), polydispersity index (PDI, Mw / Mn), the rate of change in polydispersity index (PDI) expressed by Formula 1 below, and the rate of change in weight-average molecular weight expressed by Formula 2 below were measured for PLLA tubes before and after laser cutting in Example 2, Comparative Example 1, and Comparative Example 2 above, and the results are shown in Table 2 below. At this time, the gel permeation chromatography experimental conditions were the same as those in Experimental Example 1 described above.

[0132] [Equation 1]

[0133] Change rate of polyvariance index (%) = (BA / A) x 100

[0134] In the above Equation 1,

[0135] A is the polydispersity index of the biodegradable polymer tube before performing the cutting process using a femtosecond laser, and

[0136] B is the polydispersity index of the biodegradable polymer tube after performing a cutting process using a femtosecond laser.

[0138] [Equation 2]

[0139] Weight-average molecular weight change rate (%) = (DC / C) x 100

[0140] In the above Equation 2,

[0141] C is the weight-average molecular weight of the biodegradable polymer tube before performing the cutting process using a femtosecond laser, and

[0142] D is the weight-average molecular weight of the biodegradable polymer tube after performing a cutting process using a femtosecond laser.

[0144] Laser wavelength Example 2 (515 nm) Comparative Example 1 (343 nm) Comparative Example 2 (1030 nm) Weight-average molecular weight / PDI Mw PDI Mw PDI Mw PDI molecular weight of PLLA tubes before laser cutting 328,964 1.5 317,528 1.9 317,300 1.9 molecular weight of PLLA tubes after laser cutting 312,000 1.6 128,800 4.6 296,700 2.3 PDI Change Rate (%) 6.67% 142.11% 21.05% Mw change rate (%) 12.16% 83.23% 22.75%

[0145] Referring to Table 2 above, it was found that Example 2 showed almost no change in weight-average molecular weight after forming the pattern.

[0146] However, it was observed that in Comparative Example 1, the molecular weight decreased rapidly and the polydispersity index increased significantly after pattern formation. This is because the C=O bonds of PLLA have absorption bands at wavelengths of 280 nm and 190 nm, and the CC and CH bonds of PLLA absorb wavelengths shorter than 180 nm; therefore, when processed with ultraviolet light or a femtosecond laser with a wavelength shorter than ultraviolet light, PLLA undergoes photodegradation due to absorption. Accordingly, it was confirmed that ultraviolet light or a femtosecond laser with a wavelength shorter than ultraviolet light is not suitable for processing PLLA stents.

[0147] In addition, it can be seen that Comparative Example 2 did not show a relatively large change in molecular weight but a large rate of change in polydispersity index, which indicates that the distribution of molecular weight has widened.

[0149] Experimental Example 3. Measurement of Radial Force

[0150] In order to confirm the change in mechanical strength according to the biodegradation period of the PLLA stent prepared according to Example 1, the radical force of the PLLA stent prepared according to Example 1 was measured, and the results are shown in Table 3 and Figure 1.

[0151] 1) Measuring equipment

[0152] - Manufacturer: Blockwise

[0153] -model

[0154] : RJU62 (compression crimp station)

[0155] : TTR2 (Tensile test and temperature setting)

[0157] 2) Measurement conditions

[0158] - Temperature: 37±2 ℃

[0159] - Target compression diameter: 1.5 mm

[0160] -Compression speed: 0.05 mm / s

[0162] mechanical strength (radial force) Biodegradation period (months) 0 3 months 6 months 2069 mbar / mm 2566 mbar / mm 2410 mbar / mm

[0163] Referring to Table 3 and Figure 1, it was confirmed that the PLLA stent according to the present invention maintained its strength for 6 months.

[0165] Experimental Example 4. Measurement of Biodegradation Period

[0166] The number average molecular weight (Mn), weight average molecular weight (Mw), peak molecular weight (Mp), and polydispersity index (PDI, Mw / Mn) of the PLLA stent prepared according to Example 1 were measured in vivo and in vitro using gel permeation chromatography (GPC) to determine the biodegradation period, and the results are shown in Table 4 and Figure 2 below.

[0168] 1) in vivo

[0169] Four Yucatan mini-pigs were prepared, and one biodegradable polymer stent was implanted in each pig's LAD (left anterior descending artery), RCA (right coronary artery), and LCx (left circumflex artery), for a total of three stents per pig. Subsequently, at 6, 24, 30, and 36 months, the vessels implanted with the stents were excised from the pigs, and the molecular weight of the stents was measured.

[0170] Method (Using Polystyrene Standard)

[0171] Standard = EasiCal PS-1 (Agilent)

[0172] Column = PLgel Mixed-B 10μm 7.5 x 300 mm (Agilent)

[0173] Solvent = Chloroform 100% (HPLC grade)

[0174] Flow = 1.0 ml / min

[0175] Temperature = Ambient temperature

[0176] Injection volume = 10.0 μl

[0177] Detector = ELSD (N2, gas flow = 1.5 ml / min, temp. = 50℃)

[0179] 2) in vitro

[0180] One biodegradable polymer stent was placed in a vial and filled with 20 ml of PBS. In the same manner, a total of 23 vials were prepared by distributing 23 stents among them and filling them with PBS. The groups were divided into 3 months (n=5), 6 months (n=5), 24 months (n=5), 30 months (n=4), and 36 months (n=4). The stents contained in the vials were placed in a shaking bath, the temperature was set to 37 degrees, and the vial was rotated at 100 rpm for storage. (The pH of each vial was measured weekly using a pH meter, and if the pH value fell outside the range of 7.4 ± 0.2, the PBS solvent was replaced with fresh liquid.) At the 3, 6, 24, 30, and 36-month mark, the biodegradable stents from the respective groups were collected, dried in a vacuum chamber, and their molecular weight was measured using GPC.

[0181] Method (Using Polystyrene Standard)

[0182] Standard = EasiCal PS-1 (Agilent)

[0183] Column = PLgel Mixed-B 10μm 7.5 x 300 mm (Agilent)

[0184] Solvent = Chloroform 100% (HPLC grade)

[0185] Flow = 1.0 ml / min

[0186] Temperature = Ambient temperature

[0187] Injection volume = 10.0 μl

[0188] Detector = ELSD (N2, gas flow = 1.5 ml / min, temp. = 50℃)

[0190]

[0191] Referring to Table 4 and Figure 2, it was confirmed that the PLLA stent according to the present invention was completely biodegraded at 36 months.

[0193] Although the present invention has been described above with reference to embodiments, the present invention is not limited by the embodiments disclosed in this specification, and it is obvious that various modifications can be made by a person skilled in the art within the scope of the technical concept of the present invention. Furthermore, even if the effects of the configuration of the present invention were not explicitly described while describing the embodiments of the present invention above, it is natural to acknowledge that the effects predictable by said configuration should also be recognized.

Claims

Claim 1 A method for manufacturing a biodegradable stent comprising: (a) preparing a biodegradable polymer tube comprising at least poly(L-lactic acid, PLLA); (b) performing a cutting process on the biodegradable polymer tube using a femtosecond laser; (c) sterilizing the biodegradable polymer tube on which the cutting process has been performed, including radiation exposure; and (d) performing a process of applying a temperature change to the sterilized polymer tube; wherein the process of applying a temperature change in step (d) is performed at a temperature of 20°C or higher and 80°C or lower, the weight-average molecular weight of the biodegradable polymer tube on which the cutting process has been performed is 250,000 g / mol or higher and 530,000 g / mol or lower, and the weight-average molecular weight of the biodegradable stent is 150,000 g / mol or higher and 220,000 g / mol or lower. Claim 2 A method for manufacturing a biodegradable stent according to claim 1, wherein the biodegradable polymer further comprises at least one selected from the group consisting of polyglycolide, poly p-dioxanone, polycaprolactone, trimethylene carbonate, polyhydroxyalkanoates, polypropylene fumarate, polyortho esters, other polyesters, polyanhydride, polyphosphazenes, polyalkyl cyanoacrylates, poloxamers, polyamino L-tyrosine, modified polysaccharides, oxidized cellulose, gelatin, collagen, and combinations thereof. Claim 3 delete Claim 4 delete Claim 5 A method for manufacturing a biodegradable stent according to claim 1, wherein the femtosecond laser cutting process in step (b) is irradiating the biodegradable polymer tube with a second harmonic laser having a wavelength of 470 nm or more and 776 nm or less. Claim 6 A method for manufacturing a biodegradable stent according to claim 1, wherein the sterilization treatment in step (c) is irradiating the biodegradable polymer tube on which the cutting process has been performed with an electron beam (E-beam) at a rate of 15 kGy or more and 25 kGy or less. Claim 7 delete Claim 8 A method for manufacturing a biodegradable stent according to claim 1, wherein the process of changing the temperature in step (d) comprises sequentially performing at least once the following steps: (d-1) raising the temperature from 25 ℃ to 54 ℃; (d-2) maintaining the temperature at 54 ℃ for 10 minutes or more and 30 minutes or less; (d-3) lowering the temperature from 54 ℃ to 25 ℃; and (d-4) maintaining the temperature at 25 ℃ for 10 minutes or more and 30 minutes or less. Claim 9 In claim 1, the method for manufacturing a biodegradable stent having a change rate of polydispersity index (PDI) of 20% or less, represented by the following Equation 1: [Equation 1] Change rate of polydispersity index (%) = (BA / A) x 100 In the above Equation 1, A is the polydispersity index of the biodegradable polymer tube before performing a cutting process using a femtosecond laser, and B is the polydispersity index of the biodegradable polymer tube after performing a cutting process using a femtosecond laser. Claim 10 A biodegradable stent manufactured by the method for manufacturing a biodegradable stent according to claim 1. Claim 11 delete Claim 12 delete

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