Patent Application
20250084212
The present invention relates to a shape-memory polymer including a 6-arm structure compound and use thereof, and more specifically to a shape-memory polymer including a 6-arm structure compound that exhibits shape-memory properties by cross-linking and is controllable in shape restoration temperature through monomer control, and use thereof.
Chronic renal failure is a disease in which the function of the kidneys to remove waste products is reduced and cannot be restored to normal, and treatment methods vary depending on the degree of decline in kidney function. In particular, when the stage of renal failure is severe, it is necessary to remove waste products accumulated in the blood through dialysis as an alternative therapy or to transplant a kidney. Therefore, as the number of chronic renal failure patients increases, the number of hemodialysis patients continues to increase.
Hemodialysis is a process in which blood passes through a dialysis membrane at a rate of 200 to 500 mL per minute and then returns to the patient's blood vessels, and there is a problem in that since much blood cannot be moved through peripheral blood vessels and dialysis is impossible, a dialysis channel may be formed by using artificial blood vessels using ultrasound (arteriovenous graft, AVG) depending on the patient's vascular condition at the time of surgery, but generally, hemodialysis is performed by using an arteriovenous fistula (AVF), which connects an artery and a vein. Arteriovenous fistulas usually form in the wrist or proximal upper limbs, and when arteriovenous fistula formation is performed by using autologous veins, the diameter of the veins increases due to arterial pressure, thereby causing the veins to mature, and through this, the veins are remodeled, thereby making continuous dialysis possible.
If a patient with chronic renal failure does not undergo a kidney transplant, hemodialysis through an arteriovenous fistula must be continuously performed throughout the life of the patient, and thus, blood vessel management is required for the long-term use of an arteriovenous fistula. In this case, if blood vessels are not managed properly, arteriovenous fistula complications (stenosis, thrombosis, infection, pseudoaneurysm, hemorrhage, venous pressure increase, congestive heart failure, arrhythmia syndrome, ischemic simple neuropathy, etc.) may appear, and when the complications of arteriovenous fistula frequently occur, reoperation is inevitable or the number of hospitalizations increases, resulting in a decrease in the patient's quality of life and an increase in medical expenses. Particularly, in the case of an arteriovenous fistula using an autologous vein, eddy currents are generated at the junction of the artery and vein due to the difference in physical properties between the artery and the vein and strong arterial blood, which causes the formation of a thrombus, and eventually, it causes stenosis and edema. Therefore, there is a need for a method and apparatus for preventing complications for prolonging the use of an arteriovenous fistula during dialysis.
Korean Registered Patent Nos. 10-1906472 and 10-2208921 disclose a shape-memory polymer, a preparation method thereof and the use thereof as a medical material, but there is no disclosure at all about a utilization method as a medical material that can restore shape and control temperature through monomer control and is particularly suitable for arteriovenous fistula formation.
Accordingly, the inventors of the present invention focus on these problems of the related art and made diligent efforts to improve the existing shape-memory polymer into a material that is particularly suitable for blood vessel management, and as a result, when synthesizing a compound with a 6-arm structure as in the present invention, it is possible to control the shape restoration temperature by controlling the monomer in addition to shape-memory properties due to cross-linking. In addition, when such a shape-memory polymer is utilized as a medical material, the present invention was completed by confirming that it is possible to fabricate a vascular outer wall support that can prevent blood vessels from clogging physically and biologically by wrapping blood vessels on the outside.
An object of the present invention is to provide a novel compound having a 6-arm structure, a method for preparing the same and a use thereof.
In order to achieve the above object, the present invention provides a compound represented by Chemical Formula (1) below:
In the present invention, the compound may have shape-memory properties by cross-linking.
In the present invention, the compound may have an average shape restoration ability of 90% or more at a temperature of 35 to 58° C. after cross-linking.
In addition, the present invention provides a method for preparing the compound of claim 1, including the step of reacting dipentaerythritol, caprolactone and glycidyl methacrylate.
In the present invention, the reaction may be a ring-opening polymerization reaction.
In the present invention, the reaction may be reacted under the presence of a catalyst selected from the group consisting of 1,5,7-triazabicyclo(4.4.0)dec-5-ene, tin (II) (2-ethylhexanoate), trimethylopropane tris(3-mercaptopropionate) and zinc succinate.
In the present invention, the method may react dipentaerythritol, caprolactone and glycidyl methacrylate at 80 to 140° C.
In addition, the present invention provides a shape-memory polymer in which the compound is cross-linked.
In addition, the present invention provides a method for preparing a shape-memory polymer, further including the step of inducing a cross-linking reaction in the compound prepared by the method.
In the present invention, the cross-linking reaction may be a photo-cross-linking or thermal cross-linking reaction.
In addition, the present invention provides a medical material, including the compound.
In the present invention, the medical material may be a support for vascular transplantation or a stent for vascular transplantation.
In the present invention, the support for vascular transplantation may be a vascular outer wall support which is provided to surround transplanted autologous veins and arteries as a side-to-end model during arteriovenous fistula formation.
In the present invention, the vascular outer wall support may be a U-shaped anastomosis device.
In the present invention, the vascular outer wall support may include an artery support and a graft vein support, and the angle of a tangent at the anastomosis site between an artery and a vein may be 30° to 90°.
The 6-arm type compound according to the present invention can be prepared into a temperature-based shape-memory polymer that exhibits shape-memory properties by cross-linking, can adjust the temperature for shape restoration through monomer control, and can be developed as a medical material with biocompatibility. In particular, by cross-linking the compound of the present invention, it is possible to fabricate a vascular outer wall support which is capable of minimizing the occurrence of abnormal blood flow and smoothing the flow of blood by helping the transplanted autologous vein to mature during arteriovenous fistula formation.
Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which the present invention pertains. In general, the nomenclature used herein and the experimental methods described below are those that are well-known and commonly used in the art.
As used herein, the term “shape-memory polymer (SMP)” refers to a polymer that when an object is made to have a certain shape under specific conditions, even if the shape is changed by external impact thereafter, the polymer has the property of returning to the original shape when the object is kept under the same conditions as the first time (temperature, light, pH, humidity, etc.).
In the present invention, terms such as “include” or “have” are intended to designate that there is a feature, number, step, operation, component, part or combination thereof described in the specification, but it should be understood that it does not exclude in advance the possibility of the presence or addition of one or more other features, numbers, steps, operations, components, parts or combinations thereof.
In the present invention, when ε-caprolactone (ε-CL) and glycidyl methacrylate (GMA) are reacted together with dipentaerythritol, a novel polycaprolactone-based compound could be synthesized, and it was confirmed that excellent shape-memory properties were imparted when a network was formed between polymer chains of the compound through cross-linking, and it was possible to control the shape restoration temperature when controlling the monomers.
Accordingly, in one aspect, the present invention relates to a compound represented by Chemical Formula (1):
The shape restoration temperature of the compound of the present invention may be controlled according to the amounts of ε-caprolactone monomer and glycidyl methacrylate monomer constituting the compound.
More specifically, in Chemical Formula (1), x and y may be each independently integers of 1 to 20, which can be controlled by the carbon numbers of a lactone-based monomer and an initiator in the step of synthesizing the compound of Chemical Formula (1).
For example, x may be 3 when ε-caprolactone (ε-CL) is used, and y may be 1 when dipentaerythritol is used. In addition, the number of x may be adjusted by using monomers such as α-acetolactone, β-propiolactone, γ-butyrolactone and δ-valerolactone by replacing ε-caprolactone (ε-CL), and the number of y may be adjusted by using an initiator such as 6 arm PEG in place of dipentaerythritol. In the present invention, x and y may be easily adjusted by a person skilled in the art.
In addition, in Chemical Formula (1), m and n may represent mol % of the repeating unit, m+n may be 100, and x may be 70 to 99, or 88 to 96, or 92 to 96, or 94 to 96.
Herein, the mol % means the ratio of m and n repeating units, and it may specifically mean the mole fraction (ratio). For example, in PCL-co-PGMA, it may mean the mole fraction of repeating units of PCL and PGMA.
In the present invention, the compound may be characterized in that it has shape-memory properties by cross-linking.
In the present invention, after cross-linking, the compound may have an average shape restoration ability of at least 90%, such as 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., such as 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 the present invention is not limited thereto.
The compound of the present invention may be prepared by reacting α-acetolactone, β-propiolactone, γ-butyrolactone, δ-valerolactone or ε-caprolactone monomer together with an acrylic monomer including a glycidyl group and an initiator.
For example, the compound of the present invention may be prepared by ring-opening polymerization of dipentaerythritol, caprolactone and glycidyl methacrylate.
In this case, the reaction between temperature-sensitive glycidyl methacrylate groups may be suppressed by adding a catalyst or adding a polymerization inhibitor together with or simultaneously with an initiator during the initial reaction with little polymerization conversion, thereby improving reactivity.
Accordingly, in another aspect, the present invention relates to a method for preparing the compound, including the step of reacting dipentaerythritol, caprolactone and glycidyl methacrylate.
In the present invention, the reaction may be characterized in that it is a ring-opening polymerization reaction.
In the present invention, the reaction may be reacted under the presence of a catalyst selected from the group consisting of 1,5,7-triazabicyclo(4.4.0)dec-5-ene, tin (II) (2-ethylhexanoate), trimethylopropane tris(3-mercaptopropionate) and zinc succinate, but the present invention is not limited thereto.
In particular, as a material for inducing the simultaneous ring-opening polymerization of two monomers (CL, GMA), it is preferable to use 1,5,7-triazabicyclo(4.4.0)dec-5-ene, which can shorten the synthesis time of the compound, as a catalyst.
In the present invention, the reaction between methacrylate groups may be suppressed by introducing an initiator and/or a polymerization inhibitor during the initial reaction, that is, before introducing glycidyl methacrylate.
In addition to the above, the polymerization inhibitor serves to terminate the reaction by suppressing the exothermic reaction locally occurring in the latter half of the polymerization and removing unreacted residual radicals.
In this way, when the initiator and the polymerization inhibitor are reacted with the monomers, such caprolactone and glycidyl methacrylate, at about 110° C. for about 6 hours, the ring structure in the monomer is opened, and a polycaprolactone-polyglycidyl methacrylate (6 arm PCL-PGMA) copolymer with 6 arms is synthesized.
In the present invention, the initiator may be characterized in that it is dipentaerythritol, and specifically, the present invention may be characterized in that a polycaprolactone-polyglycidyl methacrylate (6-arm PCL-PGMA) copolymer having 6 arms is synthesized by initial addition of the initiator.
In the present invention, for the polymerization inhibitor, at least one selected from the group consisting of hydroquinone, hydroquinone monomethyl ether, p-benzoquinone and phenothiazine may be used, but the present invention is not limited thereto. Preferably, the polymerization inhibitor may be hydroquinone.
In the present invention, the preparation method may react dipentaerythritol, caprolactone and glycidyl methacrylate at 80 to 140° C., and preferably, 100 to 130° C., such as at about 110° C.
In this case, when the synthesis of the compound of the present invention proceeds at a temperature lower than 100° C., the catalytic reaction may not proceed, and when the synthesis of the compound of the present invention proceeds at a temperature exceeding 130° C., there may be a problem in that the catalytic reaction rate decreases.
In a preferred aspect, the polymerization mechanism of the compound of the present invention may be expressed as follows.
In the present invention, the cross-linking reaction may be a photo-cross-linking or thermal cross-linking reaction, but the present invention is not limited thereto.
The compound of the present invention may have a copolymer structure in which a ε-caprolactone monomer and an acrylic monomer including a glycidyl group are polymerized. For example, the compound may have a structure of a copolymer [PCL-co-PGMA) obtained by polymerizing ε-caprolactone (CL) and glycidyl methacrylate (GMA) monomers.
In the compound of the present invention, the arrangement order of the ε-caprolactone monomer and the glycidyl methacrylate monomer is not particularly limited, and they may be arranged alternately, randomly or in blocks.
In addition, a hydroxyl group or the like may be bonded to the terminal of the copolymer. Such a copolymer having a hydroxyl group attached to the terminal may be prepared by polymerization using an initiator having a hydroxyl group attached to the terminal.
Meanwhile, the glycidyl group included in the glycidyl methacrylate monomer may be a cross-linkable functional group, a photo-cross-linkable functional group or a thermally cross-linkable functional group. In addition, the copolymer may have shape-memory properties by cross-linking.
Accordingly, in another aspect, the present invention relates to a shape-memory polymer which is cross-linked with the compound.
In another aspect, the present invention relates to a method for preparing a shape-memory polymer, further including the step of inducing a cross-linking reaction in the compound.
In the present invention, the cross-linking agent for the cross-linking reaction may be at least one selected from the group consisting of potassium persulfate, ammonium persulfate, benzoyl peroxide, diauryl peroxide, dicumyl peroxide, hydrogen peroxide, azobisisobutuyronitrile, 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 cross-linking agent that initiates the cross-linking reaction may be a peroxide cross-linking agent (benzoyl peroxide, dicumyl peroxide, etc.), Irgacure2959, Irgacure784, Irgacure819, Darocur1173 or Darocur4265, but the present invention is not limited thereto.
Meanwhile, the compound of the present invention is a temperature-sensitive compound that has biocompatibility and is capable of adjusting the shape restoration temperature through monomer control, and when a compound with a 6-arm structure was cross-linked to fabricate a shape-memory polymer compared to a compound with a 4-arm structure, it was confirmed that the circumferential tensile strength and pressurized bursting strength were improved. Actually, as a result of performing arteriovenous fistula formation by fabricating a vascular outer wall support using the compound according to the present invention, it was confirmed that the vascular U shape was well maintained, eddy current formation was suppressed after blood vessel anastomosis, and arterial blood flow was smooth, resulting in excellent patency. In addition, through histological analysis, it was confirmed that vascular stenosis can be suppressed through the formation of new vascular intima.
Therefore, in still another aspect, the present invention relates to a medical material including the compound.
In the present invention, the medical material may be prepared by using a shape-memory polymer that is cross-linked with the compound.
In the present invention, the medical material may be a support for blood vessel transplantation or a stent for blood vessel transplantation, but the present invention is not limited thereto.
In the present invention, the support for blood vessel transplantation may be characterized in that it is a vascular outer wall support which is provided to surround and arrange an autologous vein and artery transplanted in a side-to-end model during arteriovenous fistula formation, but the present invention is not limited thereto.
Such a vascular outer wall support has the properties of helping mature the transplanted autologous vein to minimize the occurrence of abnormal blood flow and facilitating the flow of blood flow.
In the present invention, the vascular outer wall support may be characterized in that it is a U-shaped anastomosis device, but the present invention is not limited thereto.
The U-shaped anastomosis device according to the present invention has the advantage of minimizing the occurrence of abnormal blood flow in blood vessels flowing from arterial blood through anastomosis to venous blood and maintaining blood flow.
In the present invention, the vascular outer wall support may include an artery support and a transplanted vein support.
In the present invention, the angle of a tangent at the anastomosis site of an artery and a vein may be 30 to 90°, and preferably 30 to 60°, or any range of 30 to 60°, such as any value of 30 to 45°, or 30 to 60°, such as 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°.
Adjusting the tangent angle of the anastomosis site according to the present invention has the advantages of preventing neointimal formation and preventing vascular stenosis.
In the present invention, as the curvature is lower, the blood flow may become more stable, but considering the anatomical structure, the angle of a tangent at the anastomosis site of an artery and a vein may be most preferably 30 to 45°, but the present invention is not limited thereto.
Hereinafter, the present invention will be described in more detail through examples. These examples are only for illustrating the present invention, and it will be apparent to those skilled in the art that the scope of the present invention is not to be construed as being limited by these examples.
By varying the ratio of PCL and PGMA, the following 6-arm PCL-PGMA copolymer was synthesized.
After dipentaerythritol (initiator, Sigma Aldrich) and hydroquinone (HQ, inhibitor, Sigma Aldrich) were placed in a three-necked flask and vacuum dried for 10 minutes, nitrogen purging was performed at a rate of 50 cc/min. Purified ε-caprolactone (ε-CL, monomer, AVENTION) was additionally added and stirred at 110° C. for 10 minutes. Afterwards, glycidyl methacrylate (GMA, monomer, Sigma Aldrich) was added and stirred for 10 minutes, followed by injecting 1,5,7-triazabicyclo(4.4.0)dec-5-ene (TBD, catalyst, TCI) dissolved in acetonitrile (CAN, Sigma Aldrich) and reacting at 110° C. for 6 hours. After dissolving the final compound in chloroform (Daejung Chemicals & Metals CO., LTD.), it was precipitated in ethyl ether (Daejung Chemicals & Metals CO., LTD.) at 4° C., and vacuum dried after filtering.
The synthetic mechanism is as shown in
A 4-arm PCL-PGMA copolymer was synthesized as follows.
After pentaerythritol (initiator, Sigma Aldrich) and hydroquinone (HQ, inhibitor, Sigma Aldrich) were placed in a three-necked flask and vacuum dried for 10 minutes, nitrogen purging was performed at a rate of 50 cc/min. Purified ε-caprolactone (ε-CL, monomer, AVENTION) was additionally added and stirred at 110° C. for 10 minutes. Afterwards, glycidyl methacrylate (GMA, monomer, Sigma Aldrich) was added and stirred for 10 minutes, followed by injecting 1,5,7-triazabicyclo(4.4.0)dec-5-ene (TBD, catalyst, TCI) dissolved in acetonitrile (CAN, Sigma Aldrich) and reacting at 110° C. for 6 hours. The final compound was dissolved in chloroform (Daejung Chemicals & Metals CO., LTD.), precipitated in ethyl ether at 4° C. (Daejung Chemicals & Metals CO., LTD.) and vacuum dried after filtering.
100 w/v % of the synthesized copolymer compound and Irgacure2959 (photoinitiator, Sigma Aldrich) were added at a ratio of 1 w/v % and dissolved in N-methyl-2-pyrrolidone (NMP, Sigma Aldrich). After fabricating the dissolved solution in the form of a film, it was cross-linked using a UV lamp (365 nm/200 s).
Structural analysis was performed using 1H-NMR (AVANCE III HD 400, Bruker Biospin, USA). Samples were prepared using the copolymer compound synthesized in the above example and chloroform-D (Sigma Aldrich) at a concentration of 10 mg/mL.
The structural analysis results are shown in
The molecular weight of the compounds synthesized in the examples was analyzed using GPC (1260 Infinity II, Agilent). Samples were prepared with the synthesized compound and tetrahydrofuran (tetrahydrofuran, THF, J.T. Baker) at a concentration of 5 mg/mL and filtered with a 0.45 μm syringe filter. THF was used as the eluent, the flow rate was 1 mL/min, and the column temperature was 40° C. The standard curve was prepared using PS (polystyrene, Agilent).
A GPC graph showing the molecular weight of the synthesized compound is shown in
Thermal properties were analyzed using DSC (DSC214, NETZSCH). It was measured in the temperature range of −80° C. to 150° C. in the heating-cooling-heating mode, and the heating and cooling rate was carried out at 10° C./min.
The results of measuring DSC before cross-linking are shown in
In the case of Examples 1, 2 and 3, it can be confirmed that the melting temperature, melting enthalpy and crystallization enthalpy increased as the proportion of PCL, which is a crystalline polymer, increased, and this is also because changes in the proportion of PGMA affected the crystal formation of PCL.
The results of measuring DSC after cross-linking are shown in
In the case of Example 1, since the content of PGMA participating in the cross-linking reaction was high, the melting temperature and crystallization temperature did not appear because it became amorphous while cross-linking. In the case of Examples 2 and 3, the degree of crystallinity could be controlled by adjusting the ratio of PCL and PGMA, and the change in crystallinity affected the melting temperature. The shape restoration temperature can be controlled by adjusting the ratio of PCL and PGMA in the 6-arm structured PCL-PGMA copolymer which is synthesized using these properties.
The mechanical properties of the shape-memory polymer of the present invention were analyzed using UTM (34SC-1, INSTRON). The samples were UV cross-linked to fabricate in the form of a film having a size of W 5 mm×L 5 mm×T 0.4 mm, and it was measured under the conditions of the initial length of 10 mm and the tensile speed of 10 mm/min at 37° C.
The mechanical properties through UTM measurement are shown in
Shape-memory properties were analyzed using DMA (Discovery DMA850, TA instrument). The sample was UV cross-linked to produce a film having a size of W 5 mm×L 5 mm×T 0.4 mm.
After maintaining at 55° C. for 10 minutes (original permanent shape, εp(0)), strain was applied to deform the sample by stretching to 78 kPa at a rate of 4 kPa/min. Afterwards, it was cooled at a rate of 2° C./min to 0° C., maintained at 0° C. for 10 minutes (maximum strain, ε1(N)), and then released at a rate of 4 kPa/min to 0 Pa (temporary shape, εu(N)), and then, the temperature was raised to 55° C. at a rate of 2° C./min (permanent shape, εp(N)). This process was repeated a total of 4 times as one cycle.
The shape recovery rate (Rr) and the shape fixation degree (Rf) were calculated according to Formulas (1) and (2) below.
The shape-memory properties of the copolymer-based shape-memory polymer of Example 2 through DMA measurement are shown in
According to the physical properties of the compound according to the present invention and the shape-memory properties by cross-linking, the shape-memory polymer according to the present invention is a biocompatible material which is capable of restoring the shape by temperature control, and it can be developed as a medical material such as a vascular outer wall support.
Accordingly, a vascular outer wall support prepared by the shape-memory polymer according to the present invention was designed. In an aspect, the vascular outer wall support may be provided to surround the implanted autologous veins and arteries as a side-to-end model during arteriovenous fistula formation, and in this case, the vascular outer wall support can help the maturation of transplanted autologous veins, minimize the occurrence of abnormal blood flow, and facilitate the flow of blood.
Therefore, the vascular outer wall support according to the present invention is designed to include an arterial support part and a transplanted vein support part, and in order to minimize the occurrence of abnormal blood flow of blood vessels flowing from arterial blood to venous blood when the vascular outer wall support anastomoses blood vessels, an anastomosis device was designed in a U shape, and the curvature was presented and compared according to the angle of the vein junction.
The areas where vascular stenosis is likely to occur during arteriovenous fistula formation are known as the toe, heel and floor areas based on the anastomosis, and the analysis was conducted based on these areas. However, in the case of the floor area, based on the tangent line where the vein contacts the artery, the proximal area mainly plays an important role in arteriovenous fistula blood flow, and thus, the analysis was conducted with the proximal area of the tangent line as the floor area.
As a result of analyzing a change in blood flow according to the angle of the vein anastomosis, it was possible to maintain blood flow in a U shape, which induces blood flow that is hemodynamically closer to laminar flow than connecting blood vessels with conventional surgical methods, and it was expected to prevent neointimal formation and be able to prevent vascular stenosis. As the curvature was lower, the results were obtained in which the blood flow, became stable, but realistically, when the anatomical structures were reflected, it was determined that it would be particularly desirable to form a radius of curvature of 10 to 20 mm (about 30 to) 40° (
Based on the above results, a vascular blood vessel support including a transplanted vein support part and an artery support part was designed and fabricated (
The vascular outer wall support fabricated as described above was stretched in the circumferential direction using a UTM (34SC-1, INSTRON) to measure the circumferential tensile strength. At 37° C., the initial length was 3 mm, and the tensile rate was measured at a rate of 10 mm/min.
As a result, compared to the vascular outer wall support fabricated by the shape-memory polymer based on Comparative Example (4 arm 94% PCL-06% PGMA), it was confirmed that the vascular outer wall support fabricated by the shape-memory polymer based on Example 2 (6 arm 94% PCL-06% PGMA) had a certain tendency and the circumferential tensile strength increased by about 7% on average (
Meanwhile, the pressurized bursting strength of the fabricated vascular outer wall support was measured using the pressurized bursting strength measuring device of
As a result, compared to the vascular outer wall support fabricated by the shape-memory polymer based on the comparative example (4 arm 94% PCL-06% PGMA), it was confirmed that the vascular outer wall support fabricated by the shape-memory polymer based on Example 2 (6 arm 94% PCL-06% PGMA) had a certain tendency and the pressurized bursting strength increased by about 39% on average (
In order to determine the effect of the vascular outer wall support according to the present invention, structural changes were determined through computer modeling, when veins were wrapped with the vascular outer wall support.
Vein is a biological tissue with hyperelastic properties, and since it does not follow the linear and nonlinear properties of other polymer materials, it recovers elastically and exhibits incompressible behavior even when considerable plastic deformation occurs.
In the present invention, parameters were calculated to simulate a homogeneous, isotropic and incompressible hyperelastic model for blood vessels.
The strain energy function (W) is expressed as a function of the elongation invariant and a function of the principal elongation, and is defined as Formula (3).
Since most elastic bodies are incompressible, 13=1, and Formula (3) can be derived as Formula (4).
I1 and I2 are defined as invariants of principal elongation (λ), and the 2-curve fitting analysis was performed for the rabbit inferior vena cava using the 2-parameter Mooney Rivlin model which is applied to the deformation analysis of incompressible elastic bodies.
The Mooney-Rivlin 2 parameter model is defined as Formula (5).
In this case, the values of C10 and C01 are constant terms and are derived during curve fitting, and the values of C10=0.01 MPa and C01=0.0095 MPa were obtained using ANSYS Software. When the vascular outer wall support was applied to the artery-vein-artery straight model by applying the calculated physical properties, it was determined by modeling what changes occurred in the vascular outer wall support and the vessel wall.
After connecting the vein and artery, arterial pressure was applied to the vein, and the vein was deformed by the pressure. When the arterial pressure was 120 mmHg, which was the maximum systolic pressure, changes in the anatomical structure of the inner diameter of the vessel occurred. However, compared to a case where the blood vessel diameter increased nearly three times when only veins were present, it was confirmed that the vascular outer wall support prevents the rapid expansion of blood vessels, and the bridge structure can further alleviate the changes.
Animal experiments were conducted in compliance with the guidelines of IACUC (KBIO-IACUC-2021-174) of the Osong Advanced Medical Industry Promotion Foundation (KBIO Health). Zolazepam (5 mg/kg, Zoletil™, Virbac Korea) and xylazine (2 mg/kg, Rompun® Bayer Korea) were injected intramuscularly to 7 to 8 kg female beagles (Orient Bio) to anesthetize, and the anesthetized state was maintained during the surgical time by respiratory anesthesia (isoflurane, <2.5%, Piramal).
An arteriovenous fistula (AVF) animal model using a dog was prepared as follows (
A midline incision (about 5 cm) of the inner thigh of the right hindlimb of beagles (n=6/group) was made to locate the femoral artery and vein under the connective tissue. After tying the distal part of the femoral vein with 4-0 silk and cutting the blood vessel, blood flow was temporarily blocked using a vascular tournique in the proximal and distal parts of the femoral artery. A longitudinal incision of about 5 mm was made on the side surface of the femoral artery, and an end-to-side anastomosis was performed with the previously incised vein using 7-0 prolene. In the experimental group (w/vascular outer wall support) with the vessel outer wall support (fabricated by the shape-memory polymer cross-linked in Example 2) inserted, the anastomosis was performed after the vascular outer wall support was placed in the venous area before the vein and artery anastomosis, and the artery part was treated with saline solution in the body temperature range, and the support was fixed by surrounding the artery. Afterwards, the subcutaneous layer and skin were closed to complete model production. In the control group where no vascular outer wall support was added (w/o vascular outer wall support), all steps except the step of adding the vascular outer wall support were performed as is.
After 3 months and 6 months of arteriovenous fistula modeling, the blood flow pattern of the arteriovenous anastomosis site was determined using ultrasonography (EKO7, Samsung Medison). As a result, in the case of the anastomosis vessels of the control group without the vascular outer wall support, vortex formation intensified over time, whereas the vortex formation of the experimental group with the vascular outer wall support inserted was suppressed, and the flow of arterial blood (red arrow) appeared smoothly (
After 6 months of arteriovenous fistula modeling, the condition and patency of the arteriovenous anastomosis were determined by angiography. A catheter (6Fr) was placed in the iliac artery, and iohexol was injected to perform angiography using a C-arm. As a result, as shown in
Finally, after sacrificing the subject by the intravenous injection of potassium chloride under general anesthesia, the arteriovenous anastomosis site was collected to perform histopathology. The collected blood vessels were fixed by treatment with 4% paraformaldehyde for 24 hours, and then embedded in paraffin wax, and the arteriovenous anastomosis site was cross-sectioned to a thickness of 5 μm. As a result of pentachrome staining (Pentachrome staining, StatLab, item #: KTRMP) of the cut cross-section, it was confirmed that compared to the control group, the effect of inhibiting neointima formation was excellent in the experimental group where the vascular outer wall support according to the present invention was inserted (
Having described specific parts of the content of the present invention in detail above, it will be clear to those skilled in the art that these specific descriptions are only preferred exemplary embodiments, and the scope of the present invention is not limited thereto. Accordingly, the substantial scope of the present invention will be defined by the appended claims and their equivalents.
| Number | Date | Country | Kind |
|---|---|---|---|
| 10-2021-0162378 | Nov 2021 | KR | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/KR2022/018588 | 11/23/2022 | WO |
