Shape memory polymers containing compounds with 6-arm structures and their uses

Abstract

The present invention relates to a shape-memory polymer having a 6-arm structure and its use. The shape-memory polymer according to the present invention exhibits shape-memory properties through crosslinking, and the shape recovery temperature can be adjusted by adjusting the monomer. As a biocompatible material, it can be developed into a medical material such as a support for the outer wall of blood vessels.

Description

[Technical Field]

[0001] The present invention relates to a shape memory polymer containing a compound with a 6-arm structure and uses thereof, and more particularly to a shape memory polymer containing a compound with a 6-arm structure that exhibits shape memory properties through crosslinking and whose shape recovery temperature can be adjusted by adjusting the monomer, and uses thereof. [Background technology]

[0002] Chronic renal failure is a disease in which the kidney's ability to remove waste products declines and cannot be restored to normal, and treatment methods vary depending on the degree of decline in kidney function. In particular, when kidney failure progresses to a severe stage, alternative treatments such as dialysis to remove waste products accumulated in the blood or kidney transplantation are necessary. As a result, the number of patients with chronic renal failure has been increasing recently, and the number of hemodialysis patients is also steadily increasing.

[0003] Hemodialysis involves the process of blood passing through a dialysis membrane at a rate of 200–500 mL per minute and then returning to the patient's blood vessels. The problem is that a large amount of blood cannot be transported and dialyzed through peripheral blood vessels. Depending on the patient's vascular condition, a dialysis pathway may be created using an artificial blood vessel (arteriovenous graft, AVG) using ultrasound at the time of surgery. However, hemodialysis is generally performed using an arteriovenous fistula (AVF), which connects an artery and a vein. An arteriovenous fistula is usually created in the wrist or proximal upper limb. When an arteriovenous fistula is created using autologous veins, the venous diameter increases due to arterial pressure, causing the vein to mature. This remodeling allows for continuous dialysis. Patients with chronic renal failure who do not undergo kidney transplantation must undergo continuous hemodialysis through an arteriovenous fistula for the rest of their lives. Therefore, vascular management is essential for long-term use of the fistula. Inappropriate vascular management can lead to complications, such as stenosis, thrombosis, infection, pseudoaneurysm, bleeding, increased venous pressure, congestive heart failure, steal syndrome, and ischemic monolimb neuropathy. Frequent complications can lead to reoperation or increased hospitalizations, resulting in a decline in the patient's quality of life and increased medical expenses. In particular, when using autologous veins for arteriovenous fistula creation, the difference in the physical properties of the artery and vein and the strong arterial blood flow can generate vortices at the junction between the artery and vein, leading to thrombus formation and ultimately to stenosis and edema. Therefore, a method and device for preventing complications during dialysis is needed to extend the use of an arteriovenous fistula. Korean Patent Registration Nos. 10-1906472 and 10-2208921 disclose shape-memory polymers, their manufacturing methods, and their use as medical materials, but there is no disclosure at all about how the shape recovery temperature can be adjusted by adjusting the monomer, or how they can be used as medical materials particularly suited for arteriovenous fistula formation.

[0004] Therefore, the inventors have focused on the problems of the prior art and have made efforts to improve the conventional shape memory polymers into materials that are particularly suitable for vascular management. As a result, when a compound with a 6-arm structure is synthesized as in the present invention, it is possible to control the shape recovery temperature by adjusting the monomer as well as the shape memory property by crosslinking. When such a shape memory polymer is used as a medical material, it is possible to manufacture a support for the outer wall of blood vessels that can prevent blood vessel clogging from a physical and biological perspective by wrapping the blood vessels from the outside. This confirmed the present invention. Summary of the Invention [Problem to be solved by the invention]

[0005] The object of the present invention is to provide a novel compound having a 6-arm structure, a method for producing the same and its use. The purpose is to provide [Means for solving the problem]

[0006] To achieve the above object, the present invention provides a compound represented by the following chemical formula (1): [ka] In the chemical formula (1), x and y are each independently an integer from 1 to 20; m and n represent the mole percent of repeat units; m+n is 100, and m may be 70-99. In the present invention, the compound is characterized by having shape memory properties due to crosslinking. In the present invention, the compound is characterized in that it has an average shape recovery ability of 90% or more at a temperature of 35 to 58°C. The present invention also provides a method for preparing the compound, which comprises reacting dipentaerythritol, caprolactone, and glycidyl methacrylate. In the present invention, the reaction is characterized by being a ring-opening polymerization reaction. In the present invention, the reaction is carried out by 1,5,7-triazabicyclo(4.4.0)deca-5 -ene (1,5,7-Triazabicyclo(4.4.0)dec-5-ene), tin(II)(2-ethylhexanoate), trimethylolpropane tris(3-mercaptopropionate) a catalyst selected from the group consisting of thylolpropane tris(3-mercaptopropionate) and zinc succinate The reaction is carried out in the presence of In the present invention, the production method is characterized in that dipentaerythritol, caprolactone, and glycidyl methacrylate are reacted at 80 to 140°C. The present invention also provides a shape-memory polymer in which the compound is crosslinked. The present invention also provides a method for preparing a shape memory polymer, which further comprises the step of inducing a crosslinking reaction of the compound prepared by the above method. In the present invention, the crosslinking reaction is characterized by being a photocrosslinking reaction or a thermal crosslinking reaction. The present invention also provides a medical material containing the compound. In the present invention, the medical material is characterized in that it is a support for vascular grafting or a stent for vascular grafting. In the present invention, the vascular graft support is characterized in that it is a vascular outer wall support that is arranged to surround the transplanted autologous vein and artery in a side-to-end model during arteriovenous fistula formation surgery. In the present invention, the vascular outer wall support is a U-shaped anastomosis instrument. In the present invention, the vascular outer wall support includes an artery supporting portion and a graft vein supporting portion, and the angle of the tangent to the arteriovenous anastomosis site is 30° to 90°. [Effects of the Invention]

[0007] The 6-arm compound of the present invention can be manufactured into a temperature-based shape-memory polymer that exhibits shape-memory properties through crosslinking, and the shape recovery temperature can be controlled by adjusting the monomer. It is biocompatible and can be developed into a medical material. In particular, crosslinking the compound of the present invention can be used to fabricate a vascular outer wall support that can promote the maturation of autologous veins transplanted during arteriovenous fistula formation, minimize the occurrence of abnormal blood flow, and facilitate smooth blood flow. [Brief explanation of the drawings]

[0008] [Figure 1] FIG. 1 is a diagram illustrating the synthesis mechanism of compounds having a 6-arm structure according to some embodiments of the present invention. [Figure 2] FIG. 2 shows the 1H-NMR results for the structural analysis of compounds having a 6-arm structure according to some embodiments of the present invention. [Figure 3] FIG. 3 is a GPC graph for molecular weight analysis of a compound having a 6-arm structure according to some embodiments of the present invention. [Figure 4] FIG. 4 is a DSC measurement graph showing the melting temperature (a) and crystallization temperature (b) of a compound having a 6-arm structure according to some embodiments of the present invention before crosslinking into a shape memory polymer. [Figure 5] FIG. 5 is a DSC measurement graph showing the melting temperature (a) and crystallization temperature (b) of a compound having a 6-arm structure according to some embodiments of the present invention after crosslinking to a shape memory polymer. [Figure 6] FIG. 6 is a graph showing the results of analyzing the mechanical properties of shape memory polymers after crosslinking according to some embodiments of the present invention through UTM measurement. [Figure 7] FIG. 7 shows the results of analyzing the shape memory properties of the shape memory polymers after crosslinking according to some embodiments of the present invention through DMA measurement. [Figure 8] FIG. 8 is a photograph showing the shape memory properties of shape memory polymers according to some embodiments of the present invention after crosslinking. [Figure 9] FIG. 9 is a schematic diagram of a shape-memory blood vessel outer wall support mechanism and the arrangement of arteries and veins. [Figure 10] FIG. 10 shows the results of analyzing the change in blood flow depending on the angle of the venous anastomosis. FIG. 10a shows the results of analyzing the toe, heel, and floor areas of an arteriovenous fistula model, and FIG. 10b shows the results of analyzing the blood flow in a U-shaped model. [Figure 11] Figure 11 is a schematic diagram of a vascular outer wall support according to some embodiments of the present invention, where Figure 11a shows the vascular outer wall support as viewed from the side, and Figure 11b shows the vascular outer wall support as viewed from the underside. [Figure 12] FIG. 12 illustrates an outer vascular wall support fabricated from a shape memory polymer according to some embodiments of the present invention. [Figure 13] FIG. 13 shows the results of comparing the circumferential tensile strength of a vascular outer wall support made of a shape memory polymer according to some embodiments of the present invention with the circumferential tensile strength of a vascular outer wall support made of a shape memory polymer cross-linked with a compound having a 4-arm structure. [Figure 14] FIG. 14 shows (a) a measuring device for measuring burst strength, and (b) the results of comparing the burst strength of a vascular outer wall support made of a shape-memory polymer according to some embodiments of the present invention with the burst strength of a vascular outer wall support made of a shape-memory polymer cross-linked with a compound having a 4-arm structure. [Figure 15] FIG. 15 is a computer modeling result showing the structural changes of a vein when the vessel wall is wrapped with an outer vessel wall support made of a shape memory polymer according to some embodiments of the present invention. [Figure 16] FIG. 16 shows an animal model of an arteriovenous fistula created through end-to-side anastomosis of the femoral artery and femoral vein in a dog. [Figure 17] FIG. 17 shows the results of Doppler ultrasound examination of the patency and blood flow pattern in the presence or absence of a vascular outer wall support made of a shape memory polymer according to some embodiments of the present invention, 3 months and 6 months after vascular anastomosis. [Figure 18] FIG. 18 shows the results of angiography performed 6 months after vascular anastomosis to confirm the anastomosis form and patency with and without a vascular outer wall support made of a shape-memory polymer according to some embodiments of the present invention. [Figure 19] 19 shows the results of histopathological analysis of veins at the anastomosis site six months after vascular anastomosis, with and without a vascular outer wall support made of a shape-memory polymer according to some embodiments of the present invention. Black - elastic fiber and nuclei, yellow - collagen, light blue - mucin, red - muscle. DETAILED DESCRIPTION OF THE INVENTION

[0009] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one skilled in the art to which this invention belongs. Generally, the nomenclature used herein and the experimental methods described below are those well known and commonly used in the art. In the present invention, the term "shape memory polymer (SMP)" refers to a polymer that has the property of returning to the original shape when an object is made to have a certain shape under specific conditions, even if the shape is subsequently changed by an external impact, by returning the object to the same conditions (temperature, light, pH, humidity, etc.) as when it was first made. In the present invention, the terms "comprise" or "have" and the like are intended to specify the presence of features, numbers, steps, operations, components, parts, or combinations thereof described in the specification, and should be understood as not precluding the presence or possible addition of one or more other features, numbers, steps, operations, components, parts, or combinations thereof.

[0010] In the present invention, epsilon-caprolactone (ε-CL) and glycidyl methacrylate (GMA) are reacted together with dipentaerythritol. It has been confirmed that by crosslinking, a new polycaprolactone-based compound can be synthesized, and by forming a network between the polymer chains of the compound through crosslinking, excellent shape memory properties are imparted, and by adjusting the monomer, it is also possible to adjust the shape recovery temperature. Thus, in one aspect, the present invention relates to a compound represented by the following chemical formula (1): [ka] In the chemical formula (1), x and y are each independently an integer from 1 to 20; m and n represent the mole percent of repeat units; m+n is 100, and m is 70 to 99. The shape recovery temperature of the compound of the present invention can be adjusted by adjusting the amounts of the ε-caprolactone monomer and glycidyl methacrylate monomer that constitute the compound. More specifically, in the formula (1), x and y are each independently an integer of 1 to 20, which can be adjusted depending on the carbon numbers of the lactone monomer and initiator in the step of synthesizing the compound of the formula (1). For example, when epsilon-caprolactone (ε-CL) is used, x may be 3, and when dipentaerythritol is used, y may be 1. Also, when epsilon-caprolactone (ε-CL) is used, α The value of x can be adjusted using monomers such as β-acetolactone, β-propiolactone, γ-butyrolactone, and δ-valerolactone, and the value of y can be adjusted using an initiator such as 6-arm PEG instead of dipentaerythritol. In the present invention, x and y can be easily adjusted by a person skilled in the art. In the chemical formula (1), m and n represent the mole percentage of the repeating unit, m+n is 100, and x may be 70-99, or 88-96, or 92-96, or 94-96. Here, mol % refers to the ratio of repeating units m and n, specifically, the molar fraction (e.g., the molar fraction of repeating units PCL and PGMA in PCL-co-PGMA). In the present invention, the compound is characterized by having shape memory properties due to crosslinking. In the present invention, the compound is characterized in that after crosslinking, the average shape recovery ability is 90% or more, for example, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%, at a temperature of 35 to 58°C, or any range of 35 to 58°C, or any temperature of 35 to 58°C, for example, about 35°C, about 36°C, about 37°C, about 38°C, about 39°C, about 40°C, about 41°C, about 42°C, about 43°C, about 44°C, about 45°C, about 46°C, about 47°C, about 48°C, about 49°C, about 50°C, about 51°C, about 52°C, about 53°C, about 54°C, about 55°C, about 56°C, about 57°C, or about 58°C, but is not limited thereto.

[0011] The compounds of the present invention can be prepared by reacting α-acetolactone, β-propiolactone, γ-butyrolactone, δ-valerolactone or ε-caprolactone monomers with an acrylic monomer containing a glycidyl group and an initiator. For example, the compound of the present invention can be produced by ring-opening polymerization of dipentaerythritol, caprolactone, and glycidyl methacrylate. In this case, the reactivity can be improved by adding a catalyst or adding a polymerization inhibitor together with or simultaneously with the initiator during the initial reaction when the polymerization conversion rate is almost zero, thereby suppressing the reaction between temperature-sensitive glycidyl methacrylate groups. Thus, in yet another aspect, the present invention relates to a method for preparing the compound, comprising the step of reacting dipentaerythritol, caprolactone, and glycidyl methacrylate.

[0012] In the present invention, the reaction is characterized by being a ring-opening polymerization reaction. In the present invention, the reaction is carried out using 1,5,7-triazabicyclo(4.4.0)dec-5-ene, tin(II)(2-ethylhexanoate), trimethylolpropane tris(3-mercaptopropionate), and The reaction is carried out in the presence of a catalyst selected from the group consisting of, but not limited to, ethylolpropane tris(3-mercaptopropionate) and zinc succinate. In particular, it is preferable to use 1,5,7-triazabicyclo(4.4.0)dec-5-ene as a catalyst to induce the simultaneous ring-opening polymerization of the two monomers (CL and GMA), which can shorten the synthesis time of the compound.

[0013] In the present invention, an initiator and / or a polymerization inhibitor can be added during the initial reaction, i.e., before adding glycidyl methacrylate, to inhibit the reaction between methacrylate groups. In addition, the polymerization inhibitor serves to suppress the exothermic reaction that occurs locally in the latter half of the polymerization and to remove unreacted residual radicals to terminate the reaction. When the initiator and polymerization inhibitor are reacted with the monomers caprolactone and glycidyl methacrylate at about 110°C for about 6 hours, the ring structure in the monomer opens, synthesizing a six-armed polycaprolactone-polyglycidyl methacrylate (6-arm PCL-PGMA) copolymer. In the present invention, the initiator is dipentaerythritol, and specifically, the present invention is characterized in that a 6-arm polycaprolactone-polyglycidyl methacrylate (6-arm PCL-PGMA) copolymer is synthesized by initially adding the initiator. In the present invention, the polymerization inhibitor may be at least one selected from the group consisting of hydroquinone, hydroquinone monomethyl ether, p-benzoquinone, and phenothiazine, but is not limited thereto. Preferably, the polymerization inhibitor may be hydroquinone. In the present invention, the production method is characterized in that dipentaerythritol, caprolactone, and glycidyl methacrylate are reacted at 80 to 140°C, preferably 100 to 130°C, for example, at about 110°C. In this case, if the synthesis of the compound of the present invention is carried out at a temperature below 100°C, the catalytic reaction may not proceed, and if the synthesis of the compound of the present invention is carried out at a temperature above 130°C, the catalytic reaction rate may decrease. In a preferred embodiment, the polymerization mechanism of the compound of the present invention can be expressed as follows.

[0014] [ka] In the present invention, the crosslinking reaction is characterized by being a photocrosslinking or thermal crosslinking reaction, but is not limited thereto. The compound of the present invention is a polymer of an ε-caprolactone monomer and an acrylic monomer containing a glycidyl group. For example, the compound may have a copolymer structure obtained by polymerizing ε-caprolactone (CL) and glycidyl methacrylate (GMA) monomers [PCL-co-PGMA]. In the compound of the present invention, the ε-caprolactone monomer and the glycidyl methacrylate monomer are not particularly limited in arrangement order, and may be arranged alternately, randomly or in blocks. The copolymer may have a terminal group bonded to a hydroxy group, etc. A copolymer having a terminal group bonded to a hydroxy group can be produced by polymerization using an initiator having a terminal group bonded to a hydroxy group, etc. The glycidyl group contained in the glycidyl methacrylate monomer may be a crosslinkable functional group, a photocrosslinkable functional group, or a thermally crosslinkable functional group. Furthermore, the copolymer can have shape-memory properties due to crosslinking. Therefore, in yet another aspect, the present invention relates to a shape memory polymer in which the compound is crosslinked.

[0015] In yet another aspect, the present invention relates to a method for producing a shape memory polymer, further comprising the step of inducing a crosslinking reaction in the compound. In the present invention, the crosslinking agent for the crosslinking reaction may be one or more selected from the group consisting of potassium persulfate, ammonium persulfate, benzoyl peroxide, dilauroyl peroxide, dicumyl peroxide, hydrogen peroxide, azobisisobutyronitrile, Irgacure, Darocure, LAP (lithium phenyl-2,4,6-trim ethylbenzoylphosphinate), TPO (diphenyl(2,4,6-trimethylbenzoyl)phosphine), and TPO-L (ethyl(2,4,6-trimethylbenzoyl)phenylphosphinate). For example, the crosslinking agent that initiates the crosslinking reaction may be, but is not limited to, a peroxide crosslinking agent (such as benzoyl peroxide, dicumyl peroxide), Irgacure 2959, Irgacure 784, Irgacure 819, Darocur 1173, or Darocur 4265.

[0016] Furthermore, the compound of the present invention is a temperature-sensitive compound that is biocompatible and whose shape recovery temperature can be adjusted by adjusting the monomer. It has been confirmed that when a shape-memory polymer is prepared by crosslinking a compound having a 6-arm structure compared to a compound having a 4-arm structure, the circumferential tensile strength and compressive burst strength are improved. In fact, when a vascular outer wall support is prepared using the compound of the present invention and an arteriovenous fistula formation is performed, it is confirmed that the vascular U-shape is well maintained, the formation of vortex flow after vascular anastomosis is suppressed, arterial blood flow is smooth, and excellent patency is achieved. Furthermore, histological analysis has confirmed that the compound can suppress vascular stenosis through the formation of a neovascular intima. Therefore, in yet another aspect, the present invention relates to a medical material containing the compound. In the present invention, the medical material may be produced using a shape-memory polymer obtained by crosslinking the compound. In the present invention, the medical material is characterized as being a vascular graft support or a vascular graft stent, but is not limited thereto. In the present invention, the vascular graft support is characterized as a vascular outer wall support that is arranged to surround the transplanted autologous vein and artery in a side-to-end model during arteriovenous fistula formation, but is not limited thereto. Such a vascular outer wall support has the characteristic of promoting the maturation of the transplanted autologous vein, minimizing the occurrence of abnormal blood flow, and smoothing the flow of blood. In the present invention, the vascular outer wall support is characterized by being a U-shaped anastomosis instrument, but is not limited to this. The U-shaped anastomosis device according to the present invention has the advantage of minimizing the occurrence of abnormal blood flow in the blood vessels where arterial blood flows into venous blood, and maintaining blood flow. In the present invention, the vascular outer wall support may include an artery support portion and a graft vein support portion.

[0017] In the present invention, the angle of the tangent to the arteriovenous anastomosis site may be 30 to 90°, preferably 30 to 60°, or any value within the range of 30 to 60°, for example, 30 to 45°, or any value within the range of 30 to 60°, for example, about 31°, about 32°, about 33°, about 34°, about 35°, about 36°, about 37°, about 38°, about 39°, about 40°, about 41°, about 42°, about 43°, about 44°, about 45°, about 46°, about 47°, about 48°, about 49°, about 50°, about 51°, about 52°, about 53°, about 54°, about 55°, about 56°, about 57°, about 58°, about 59°, or about 60°. By adjusting the angle of the tangent at the anastomosis site according to the present invention, it is possible to prevent the formation of neointima and thus vascular stenosis. In the present invention, the lower the curvature, the more stable the blood flow can be. However, taking into consideration the anatomical structure, it is most preferable that the angle of the tangent to the arteriovenous anastomosis site is 30 to 45°, but this is not limited to this. [Example]

[0018] The present invention will be described in more detail below with reference to examples. It will be obvious to those skilled in the art that these examples are merely for the purpose of illustrating the present invention and should not be construed as limiting the scope of the present invention. Example: 6-arm PCL-PGMA synthesis The following 6-arm PCL-PGMA copolymers were synthesized with different ratios of PCL and PGMA.

[0019] [Table 1] Dipentaerythritol (initiator, Sigma Aldrich) and hydroquinone (inhibitor, Sigma Aldrich) were placed in a three-neck flask, dried under vacuum for 10 minutes, and then purged with nitrogen at a rate of 50 cc / min. Purified epsilon-caprolactone (ε-CL, monomer, AVENTION) was added and stirred at 110°C for 10 minutes. Glycidyl methacrylate (GMA, monomer, Sigma Aldrich) was then added and stirred for 10 minutes. Then, 1,5,7-triazabicyclo(4.4.0)dec-5-ene (TBD, catalyst, TCI) dissolved in acetonitrile (ACN, Sigma Aldrich) was added and reacted at 110°C for 6 hours. The final product was dissolved in chloroform (Daejung Chemicals & Metals Co., Ltd.) and precipitated with ethyl ether (Daejung Chemicals & Metals Co., Ltd.) at 4°C. The precipitate was filtered and dried in vacuum. The synthesis mechanism is shown in Figure 1. The monomers are epsilon-caprolactone (ε-CL) and glycidyl methacrylate (GMA), the initiator is dipentaerythritol, and the inhibitor is hydroquinone (hydroq When polycaprolactone (PCL, HQ) is reacted at 110°C for 6 hours, the ring structure in the monomer opens, resulting in the synthesis of a six-armed polycaprolactone-polyglycidyl methacrylate (6-arm PCL-PGMA) copolymer. Comparative example: 4-arm 94% PCL-06% PGMA synthesis The 4-arm PCL-PGMA copolymer was synthesized as follows.

[0020] [Table 2] Pentaerythritol (pentaerythritol, initiator, Sigma Aldrich) and hydroquinone (hydroquinone, HQ, inhibitor, Sigma Aldrich) were placed in a three-neck flask, dried under vacuum for 10 minutes, and then purged with nitrogen at a rate of 50 cc / min. Purified epsilon-caprolactone (ε-caprolactone, ε-CL, monomer, AVENTION) was added and stirred at 110 °C for 10 minutes. Glycidyl methacrylate (GMA, monomer, Sigma Aldrich) was then added and stirred for 10 minutes. 1,5,7-Triazabicyclo(4.4.0)dec-5-ene (TBD, catalyst, TCI) dissolved in acetonitrile (ACN, Sigma Aldrich) was then added and reacted at 110 °C for 6 hours. The final compound was chloroform (Daejung Chemical The residue was dissolved in Daejung Chemicals & Metals Co., Ltd., and then precipitated with ethyl ether (Daejung Chemicals & Metals Co., Ltd.) at 4°C, filtered, and then vacuum dried.

[0021] <Experimental Example> Experimental Example 1: Crosslinking of copolymer compounds The synthesized copolymer compound was dissolved in N-methyl-2-pyrrolidone (NMP, Sigma Aldrich) at 100 w / v% and Irgacure 2959 (photoinitiator, Sigma Aldrich) at 1 w / v%. The resulting solution was processed into a film and then crosslinked using a UV lamp (365 nm / 200 s). Experimental Example 2: <Structural Analysis> 1The structure was analyzed using H-NMR (AVANCE III HD 400, Bruker Biospin, USA). The sample was prepared by mixing the copolymer compound synthesized in the previous example with chloroform-D (Sigma Aldrich) at a concentration of 10 mg / mL. The structural analysis results are shown in Figure 2. PCL peaks appeared at δ = 4.10 [m, -OCH2, (E)], 2.41 [m, -CH2, (A)], 1.74 [m, -CH2, (B and D)], and 1.45 [m, -CH2, (C)]. PGMA peaks appeared at δ = 6.13 [s, =CH2, (G2)], 5.58 [s, =CH2, (G1)], and 1.97 [s, ​​-CH3, (F)], confirming the synthesis of a compound with a 6-arm structure. The mole percentages of PCL and PGMA were calculated by comparing the areas of the PCL and PGMA peaks. Experimental Example 3: Molecular weight analysis (GPC) The molecular weights of the compounds synthesized in the examples were analyzed using GPC (1260 Infinity II, Agilent). Samples were prepared by mixing the synthesized compounds with tetrahydrofuran (THF, JT Baker) at a concentration of 5 mg / ml and filtering through a 0.45 μm syringe filter. The eluent was THF, the flow rate was 1 ml / min, and the column temperature was 40°C. A standard curve was generated using PS (polystyrene, Agilent). The GPC graph showing the molecular weights of the synthesized compounds is shown in Figure 3 and Table 3. The molecular weight of the 6-arm PCL-PGMA copolymer (Example) appears to be higher than that of the conventional 4-arm PCL-PGMA copolymer (Comparative Example), and it can be seen that the molecular weight of the 6-arm PCL-PGMA copolymer increases as the PCL content increases.

[0022] [Table 3] Experimental Example 4: Thermal Characterization (DSC) The thermal properties were analyzed using a DSC (DSC214, NETZSCH) in the heating-cooling-heating mode over a temperature range of -80°C to 150°C, with a heating and cooling rate of 10°C / min. The results of DSC measurement before crosslinking are shown in Figure 4 and Table 4. The comparative example is a conventional 4-arm structure 94% PCL-06% PGMA, and the example 2 is a 6-arm When comparing 94% PCL-06% PGMA, the melting temperature (Tm) and melting enthalpy (Δ m ) and crystallization enthalpy (Δ c ) was lower. This means that in the case of the 6-arm PCL-PGMA example, the number of arms is increased compared to the comparative example, which increases the number of end groups and the proportion of PGMA. The increased proportion of PGMA further hinders the crystallization of PCL, and therefore the example shows different thermal properties from the comparative example. In Examples 1, 2, and 3, it was confirmed that the melting temperature, melting enthalpy, and crystallization enthalpy increased as the proportion of PCL, a crystalline polymer, increased. This is also because the change in the proportion of PGMA affected the crystal formation of PCL.

[0023] [Table 4] After crosslinking, the DSC measurement results are shown in Figure 5 and Table 5. Crosslinking polymer compounds creates connections between polymer chains, which results in shape memory properties and affects the melting temperature (shape recovery temperature) after crosslinking. Furthermore, crosslinking the synthesized compound with a 6-arm structure reduces its crystallinity, resulting in a lower melting temperature than before crosslinking (compare Figures 4 and 5). In Example 1, the PGMA content participating in the crosslinking reaction was high, so the material became amorphous as it was crosslinked, and no melting or crystallization temperature was observed. In Examples 2 and 3, the crystallinity could be adjusted by adjusting the ratio of PCL to PGMA, and changes in crystallinity affect the melting temperature. Using these characteristics, the shape recovery temperature could be adjusted by adjusting the ratio of PCL to PGMA in the 6-arm PCL-PGMA copolymer synthesized.

[0024] [Table 5] Experimental Example 5: Mechanical Property Analysis (UTM) The mechanical properties of the shape memory polymer of the present invention were analyzed using a UTM (34SC-1, INSTRON). The sample was UV crosslinked and fabricated into a film measuring 5 mm W x 5 mm L x 0.4 mm T. The sample was measured at 37°C with an initial length of 10 mm and a tensile speed of 10 mm / min. The mechanical properties measured by UTM are shown in Figure 6 and Table 6. Compared to the Comparative Example, the Young's modulus (E), stress at max (σ), and strain (ε) values ​​increased in the Examples. In particular, in the case of Example 2, compared to the Comparative Example, Young's modulus (E) increased by 812%, stress at max (σ) increased by 383%, and strain (ε) increased by 189%. This result is due to the fact that as the number of arms in the copolymer structure increases, chain entanglement increases, resulting in improved mechanical properties, and the increased PCL content increases crystallinity.

[0025] [Table 6] Experimental Example 6: Shape Memory Characterization (DMA) The shape memory properties were analyzed using DMA (Discovery DMA850, TA instrument). The samples were UV cross-linked and fabricated into films measuring 5 mm W x 5 mm L x 0.4 mm T. Maintain at 55°C for 10 minutes (original permanent shape, ε p After (0)), the sample was deformed by pulling it to 78 kPa at a rate of 4 kPa / min. Then, it was cooled to 0°C at a rate of 2°C / min and kept at 0°C for 10 minutes (maximum strain, ε1 (N)). Then, the force was released at a rate of 4 kPa / min to 0 Pa (temporary shape, ε u (N)), and then the temperature was increased to 55°C at a rate of 2°C / min (permanent shape, ε p (N)) This process constituted one cycle and was repeated a total of four times. Shape recovery rate (R r ) and shape fixity (R f ) was calculated using the following equations (1) and (2).

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[0026] [Table 7] R r ,shape recovery;R f ,shape fixity;%, strain relaxation ratio compared to original length. Experimental Example 7: Design and fabrication of a support for the outer wall of a blood vessel Due to the physical properties of the compound according to the present invention and the shape memory properties due to crosslinking, the shape memory polymer according to the present invention is a biocompatible material that can recover its shape by adjusting the temperature, and can be developed as a medical material such as a support for the outer wall of blood vessels. Therefore, a vascular outer wall support for manufacturing a shape-memory polymer according to the present invention was designed. In one embodiment, the vascular outer wall support may be placed to surround the transplanted autologous vein and artery in a side-to-end model during arteriovenous fistula formation. In this case, the vascular outer wall support can promote maturation of the transplanted autologous vein, minimize the occurrence of abnormal blood flow, and facilitate smooth blood flow. Therefore, the vascular outer wall support according to the present invention was designed to include an arterial support section and a graft vein support section. When the vascular outer wall support anastomoses the blood vessels, in order to minimize the occurrence of abnormal blood flow in the blood vessels where arterial blood flows into venous blood, a U-shaped anastomosis device was devised, and curvatures were presented and compared depending on the angle of the venous junction. During arteriovenous fistula formation, the areas where vascular stenosis often occurs are known to be the toe, heel, and floor area, based on the anastomosis site, and the analysis was conducted based on these. However, in the case of the floor area, the proximal area, based on the tangent line where the vein meets the artery, plays an important role in the blood flow of the arteriovenous fistula, so the proximal area of ​​the tangent line was considered to be the floor area. area and proceeded with the analysis. Analysis of changes in blood flow depending on the angle of the venous anastomosis revealed that blood flow can be maintained in a U-shape, which is expected to induce blood flow that is hemodynamically closer to laminar flow than conventional surgical methods for connecting blood vessels, preventing neointima formation and vascular stenosis. Results showed that the lower the curvature, the more stable the blood flow, but considering realistic anatomical structures, a curvature radius of 10-20 mm (approximately 30-40°) was deemed particularly preferable (Figures 9 and 10). Based on the above results, we designed and fabricated a vascular outer wall support including a graft venous support portion and an arterial support portion (Figs. 11 and 12). The circumferential tensile strength of the prepared vascular outer wall support was measured by stretching it in the circumferential direction using a UTM (34SC-1, INSTRON) at 37°C, an initial length of 3 mm, and a stretching speed of 10 mm / min.

[0027] As a result, compared with the vascular outer wall support fabricated with a shape-memory polymer based on Comparative Example (4 arm 94% PCL-06% PGMA), It was confirmed that the vascular outer wall support fabricated from a PGMA-based shape memory polymer showed a certain tendency, with the circumferential tensile strength increasing by an average of about 7% (Figure 13). The burst strength of the prepared vascular outer wall support was measured using a burst strength measuring device as shown in Figure 14a. The burst strength measuring device is composed of a pressure gauge, a syringe pump, and a sample fixing device, and was designed to measure the pressure that the balloon could withstand when it was inserted into the sample and inflated by injecting water at a constant rate. The venous portion of the vascular outer wall support was attached to the burst strength measuring device, and the burst pressure when the inner tube was inflated was measured. Measurements were taken at 37°C with distilled water injected at a rate of 10cc / min. As a result, compared to the vascular outer wall support made with the shape-memory polymer of the Comparative Example (4 arm 94% PCL-06% PGMA), the vascular outer wall support made with the shape-memory polymer of Example 2 (6 arm 94% PCL-06% PGMA) showed a consistent tendency, and the burst strength increased by an average of about 39% (Figure 14). Experimental Example 8. Structural changes in venous vascular walls due to application of vascular outer wall support through computer modeling In order to confirm the effect of the vascular outer wall support according to the present invention, structural changes when a vein is wrapped with the vascular outer wall support were confirmed through computer modeling. Veins are biological tissues with hyperelastic properties, and do not follow the linear or nonlinear properties of other polymeric materials. Therefore, even if they undergo significant plastic deformation, they exhibit elastic recovery and incompressible behavior. In the present invention, parameters were calculated to simulate a homogeneous, isotropic, incompressible hyperelastic model for blood vessels. The strain energy function (W) is expressed as a function of the stretch rate invariant and the main stretch rate, and is defined as shown in equation (3).

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[0028] Six months after arteriovenous fistula modeling, angiography was performed to confirm the condition and patency of the arteriovenous anastomosis site. A 6Fr catheter was placed in the iliac artery, iohexol was injected, and angiography using a C-arm was performed. As shown in Figure 18, the experimental group with the vascular outer wall support inserted maintained a good U-shape of the arteriovenous anastomosis and demonstrated good patency compared to the control group (Figure 18). Finally, the animals were sacrificed under general anesthesia with intravenous potassium chloride injection, and then arteriovenous anastomosis was performed. The sections were harvested for histopathology. The harvested blood vessels were fixed in 4% paraformaldehyde for 24 hours, embedded in paraffin wax, and cross-sectioned at 5 μm thickness at the arteriovenous anastomosis site. Pentachrome staining (StatLab, item #: KTRMP) of the cut cross-sections confirmed that the experimental group, in which the vascular outer wall support of the present invention was inserted, had a superior effect of inhibiting neointima formation compared to the control group (FIG. 19).

[0029] While the present invention has been described in detail above, it will be apparent to those skilled in the art that these specific embodiments are merely preferred embodiments and are not intended to limit the scope of the present invention. Therefore, the true scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A compound represented by the following chemical formula (1): 【Chemical 1】 In the chemical formula (1), x and y are each independently an integer from 1 to 20; m and n represent the mole percentage of repeat units; m+n is 100, and m is 70 to 99.

2. The compound according to claim 1, characterized in that the compound has shape memory properties due to crosslinking.

3. 2. The compound according to claim 1, wherein the compound has an average shape recovery ability of 90% or more at a temperature of 35 to 58° C. after crosslinking.

4. 10. A method for preparing the compound of claim 1, comprising reacting dipentaerythritol, caprolactone, and glycidyl methacrylate.

5. 5. The method according to claim 4, wherein the reaction is a ring-opening polymerization reaction.

6. The reaction is 1,5,7-Triazabicyclo(4.4.0)dec-5-ene, tin(II) 2-ethylhexanoate, trimethylolpropane tris(3-mercaptopropionate), 5. The method according to claim 4, wherein the reaction is carried out in the presence of a catalyst selected from the group consisting of tris(3-mercaptopropionate) and zinc succinate.

7. The method according to claim 4, wherein the reaction is carried out at 80 to 140°C.

8. A shape memory polymer crosslinked with the compound according to claim 1.

9. A method for producing a shape memory polymer, further comprising the step of inducing a crosslinking reaction in the compound according to claim 1 produced by the method according to any one of claims 4 to 7.

10. The method according to claim 9, wherein the crosslinking reaction is a photocrosslinking reaction or a thermal crosslinking reaction.

11. A medical material comprising a compound according to any one of claims 1 to 3.

12. The medical material according to claim 11, wherein the medical material is a support for vascular grafting or a stent for vascular grafting.

13. The medical material according to claim 12, wherein the vascular graft support is a vascular outer wall support that is arranged to surround the transplanted autologous vein and artery in a side-to-end model during arteriovenous fistula formation.

14. 14. The medical material according to claim 13, wherein the vascular outer wall support is a U-shaped anastomosis instrument.

15. 14. The medical material according to claim 13, wherein the vascular outer wall support comprises an artery support portion and a graft vein support portion, and the angle of the tangent to the arteriovenous anastomosis site is 30° to 90°.

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