Biotransplantation polymer material having bleeding-inhibiting function, and preparation method therefor

Abstract

The present invention relates to a biotransplantation polymer material having a bleeding-inhibiting function, and a preparation method therefor. Disclosed are a biotransplantation polymer material and a preparation method therefor, the polymer material having an excellent bleeding-inhibiting function and excellent biodegradability so as to be suitable for inhibiting bleeding at a surgical site, and having an antithrombotic function through additional plasma surface treatment.

Description

Hemorrhage-inhibiting functional polymer material for biotransplantation and its manufacturing method

[0001] The technical idea of ​​the present disclosure relates to a polymer material for biotransplantation with a bleeding-inhibiting function and a method for producing the same, and more particularly, to a polymer material for biotransplantation with an excellent bleeding-inhibiting function and excellent biodegradability, which is suitable for use in suppressing bleeding at a surgical site, and which has an antithrombotic function through additional plasma surface treatment, and a method for producing the same.

[0002] Bone is a vital organ and tissue of the human body, composed of various tissue types, including bone marrow, endosteal membrane, periosteum, blood vessels, epithelium, nerves, cartilage, and mineralized bone tissue. Bone cutting or fracture can cause bleeding during surgery, obstructing the surgeon's vision during surgery and increasing the risk of postoperative complications.

[0003] In particular, during sternotomy or facial contouring surgery, a large amount of bleeding may occur, and during various surgical procedures such as heart surgery, spinal surgery, and artificial joint insertion, bleeding obstructs the medical staff's view of the surgical site, preventing precise surgery, and has a significant negative impact on the prognosis after surgery.

[0004] Various methods have been attempted to control this type of bleeding, but conventional methods include simply applying a hemostatic agent or, in cases of severe bleeding, using electrocautery. However, these methods do not sufficiently prevent the various negative effects of bleeding, and even if bleeding is controlled, other side effects may occur, leading to many problems.

[0005] In particular, non-degradable materials that do not decompose are known to be effective in controlling bleeding during surgery, but there are problems in that a series of side effects have been reported after use, such as infection, inflammatory reaction, delayed bone union, granuloma formation, nerve compression, osteophyte, venous sinus thrombosis, and soft tissue sarcoma. In the case of facial contouring surgery, if non-degradable materials are used, bleeding can be suppressed to some extent, which can contribute to securing a field of vision during surgery, but pain, fever, and inflammatory reaction may occur after surgery, and as a result, the material may remain in the treatment area even after one year after surgery, hindering normal bone regeneration, and there is a major disadvantage in that cortical bone is not formed in the resected area of ​​the mandible and remains in a pitted shape, requiring a second surgery to remove the wax.

[0006] Against this backdrop, there is an urgent need for a new material and method for manufacturing the same as a functional polymer material for biotransplantation that can effectively control bleeding, maintain stable hemostasis, and have minimal side effects during the post-surgical recovery process.

[0007] The technical idea of ​​the present disclosure is to provide a polymer material for a biotransplant with excellent hemorrhage suppression function and excellent biodegradability, and a method for manufacturing the same.

[0008] In addition, another problem that the technical idea of ​​the present disclosure seeks to solve is to provide a hemorrhage-inhibiting functional biotransplant polymer material having an additional antithrombotic function through surface treatment with plasma, and a method for manufacturing the same.

[0009] In order to achieve the above purpose, a functional biotransplantable polymer material with bleeding inhibition according to one aspect of the technical idea of ​​the present disclosure is provided.

[0010] It may be a functional biotransplantable polymer material having hemorrhage suppression, which includes L-lactic acid, poly(ethyleneglycol) (PEG), poly(ethylene glycol-ran-propylene glycol) (PEG-RAN-PPG), and magnesium hydroxide.

[0011] For example, the L-lactic acid may include OLLA (Oligomeric L-Lactide).

[0012] For example, when the L-lactic acid contains OLLA, the weight average molecular weight of the OLLA may be 2,000 to 4,000.

[0013] For example, the L-lactic acid may be included in an amount of 40 to 60 parts by weight based on 100 parts by weight of the total polymer material.

[0014] For example, the poly(ethylene glycol) may be included in an amount of 10 to 20 parts by weight based on 100 parts by weight of the total polymer material.

[0015] For example, the poly(ethylene glycol-lan propylene glycol) may be included in an amount of 30 to 40 parts by weight based on 100 parts by weight of the total polymer material.

[0016] For example, the magnesium hydroxide may be included in an amount of 2 to 4 phr based on the entire polymer material.

[0017] For example, the pH of the polymer material may be 6.5 to 7.5.

[0018] For example, the compressive strength of the polymer material at 20 to 30 degrees Celsius may be 11 N or more.

[0019] For example, the solubility of the polymer material at 30 to 40 degrees Celsius may be such that 2.5 g of the polymer material is completely dissolved in 100 ml of PBS solution within 36 hours.

[0020] For example, the polymer material may additionally contain calcium phosphate tribasic.

[0021] For example, the polymer material may additionally include hydroxyapatite.

[0022] For example, the polymer material may additionally contain vitamin K2 (Menaquinone).

[0023] For example, the polymer material may additionally contain isoamyl acetate.

[0024] In order to achieve the above purpose, a method for manufacturing a functional biotransplantable polymer material with bleeding inhibition according to one aspect of the technical idea of ​​the present disclosure is provided.

[0025] A step of mixing L-lactic acid, poly(ethylene glycol), and poly(ethylene glycol-ran-propylene glycol) at 100 to 120 degrees Celsius, stirring at 40 to 60 RPM, degassing, and forming a polymer mixture;

[0026] A step of adding magnesium hydroxide to the polymer mixture and stirring at 100 to 200 RPM to completely disperse the magnesium hydroxide within the polymer mixture to form a polymer dough; and

[0027] It may include a step of putting the above-formed polymer dough into a mold to give it a shape and then rapidly cooling it with liquid nitrogen to manufacture a polymer material for biotransplantation with bleeding inhibition functionality.

[0028] For example, the method for manufacturing the above-mentioned bleeding-inhibiting functional bio-implantable polymer material may further include a step of plasma surface treatment of the formed bleeding-inhibiting functional bio-implantable polymer material, and the plasma surface treatment may be performed for 2 minutes under conditions of a power of 100 W, a pressure of 100 mTorr, and a flow rate of O2100 sccm.

[0029] For example, the L-lactic acid may include OLLA (Oligomeric L-Lactide).

[0030] For example, when the L-lactic acid contains OLLA, the weight average molecular weight of the OLLA may be 2,000 to 4,000.

[0031] For example, the L-lactic acid may be included in an amount of 40 to 60 parts by weight based on 100 parts by weight of the total polymer material.

[0032] For example, the poly(ethylene glycol) may be included in an amount of 10 to 20 parts by weight based on 100 parts by weight of the total polymer material.

[0033] For example, the poly(ethylene glycol-lan propylene glycol) may be included in an amount of 30 to 40 parts by weight based on 100 parts by weight of the total polymer material.

[0034] For example, the magnesium hydroxide may be included in an amount of 2 to 4 phr based on the entire polymer material.

[0035] For example, the polymer material may additionally contain calcium phosphate tribasic.

[0036] For example, the polymer material may additionally include hydroxyapatite.

[0037] For example, the polymer material may additionally contain vitamin K2 (Menaquinone).

[0038] For example, the polymer material may additionally contain isoamyl acetate.

[0039] A functional polymer material for biotransplantation with hemorrhage suppression according to the technical idea of ​​the present disclosure can be provided as a functional polymer material having excellent hemorrhage suppression function and excellent biodegradability.

[0040] In addition, the method for manufacturing a functional polymer material for biotransplantation with hemorrhage suppression according to the technical idea of ​​the present disclosure can be provided as a method for manufacturing a functional polymer material having excellent hemorrhage suppression function and excellent biodegradability.

[0041] In addition, the polymer material for biotransplantation with bleeding inhibition function according to the technical idea of ​​the present disclosure can be provided as a polymer material having additional antithrombotic function through surface treatment with plasma.

[0042] In addition, the method for manufacturing a polymer material for biotransplantation with hemorrhage suppression functionality according to the technical idea of ​​the present disclosure can be provided as a method for manufacturing a polymer material having additional antithrombotic functionality through surface treatment with plasma.

[0043] FIG. 1 is a flowchart schematically illustrating a method for manufacturing a hemorrhage-inhibiting functional biotransplantable polymer material according to an exemplary embodiment of the present disclosure.

[0044] FIG. 2 is a diagram showing a compressive strength test process of a hemorrhage-inhibiting functional biotransplant polymer material manufactured according to an exemplary embodiment of the present disclosure.

[0045] FIG. 3 is a diagram showing the results of a compressive strength test of a hemorrhage-inhibiting functional biotransplantable polymer material manufactured according to an exemplary embodiment of the present disclosure.

[0046] FIG. 4 and FIG. 5 are diagrams showing a process for evaluating the hemostatic properties and adhesiveness of a hemorrhage-inhibiting functional bio-implant polymer material manufactured according to an exemplary embodiment of the present disclosure.

[0047] FIG. 6 is a diagram illustrating a process for evaluating the solubility of a hemorrhage-inhibiting functional bio-implant polymer material manufactured according to an exemplary embodiment of the present disclosure.

[0048] FIGS. 7 to 10 are diagrams showing the results of observing changes in cell proliferation patterns over a cell culture period when a hemorrhage-inhibiting functional biotransplantable polymer material manufactured according to an exemplary embodiment of the present disclosure is subjected to plasma treatment.

[0049] FIG. 11 and FIG. 12 are diagrams showing the results of evaluating the platelet adhesion rate of a hemorrhage-inhibiting functional biotransplant polymer material manufactured according to an exemplary embodiment of the present disclosure.

[0050] The following description of the present invention with reference to the drawings is not limited to specific embodiments, and various modifications and embodiments may be made. Furthermore, the following description should be understood to encompass all modifications, equivalents, and alternatives within the spirit and technical scope of the present invention.

[0051] In the following description, terms such as "first," "second," etc. are used to describe various components, and are not intended to limit their meanings. They are used solely to distinguish one component from another. Furthermore, the same reference numbers used throughout this specification represent the same components.

[0052] Unless otherwise stated herein, certain steps or processes may be performed at room temperature. Room temperature may range from 15 to 30°C, and preferably from 20 to 25°C.

[0053] As used herein, singular expressions include plural expressions unless the context clearly dictates otherwise. In addition, terms such as "comprise," "include," or "have" used herein should be interpreted to indicate the presence of a feature, number, step, operation, component, part, or combination thereof described in the specification, and should be understood to not preclude the possibility of the presence or addition of one or more other features, numbers, steps, operations, components, parts, or combinations thereof.

[0054] According to one aspect of the present disclosure, a hemorrhage-inhibiting functional biotransplantable polymer material can be provided.

[0055] The above-mentioned bleeding-inhibiting functional bio-transplant polymer material may be a bleeding-inhibiting functional bio-transplant polymer material containing L-lactic acid, poly(ethyleneglycol) (PEG), poly(ethylene glycol-ran-propylene glycol) (PEG-RAN-PPG), and magnesium hydroxide.

[0056] The above-described hemorrhage-inhibiting functional polymer material for bio-implantation can have excellent biocompatibility and biodegradability by containing the above-described components. That is, when the above-described hemorrhage-inhibiting functional polymer material for bio-implantation is applied to a bleeding site, it can exhibit an excellent hemostatic effect while maximally suppressing negative effects, including inflammation, on living tissue, and since it is naturally biodegraded after a certain period of time, no separate removal procedure or treatment is required, thereby greatly improving patient convenience.

[0057] For example, the L-lactic acid may include OLLA (Oligomeric L-Lactide). L-lactic acid is an organic compound having both a carboxyl group and a hydroxyl group, and has the property of exhibiting acidity when dissolved in water. The pH of the entire polymer composition can be maintained in a neutral range by the magnesium hydroxide included in the biotransplantable polymer material according to the present disclosure. In addition, when the L-lactic acid includes OLLA, the weight average molecular weight of the OLLA may be 2,000 to 4,000.

[0058] For example, the L-lactic acid may be included in an amount of 40 to 60 parts by weight based on 100 parts by weight of the total polymer material.

[0059] For example, the poly(ethylene glycol) may be included in an amount of 10 to 20 parts by weight based on 100 parts by weight of the total polymer material. Poly(ethylene glycol) is a polymer of ethylene oxide and water, and is a component having excellent biocompatibility. When included in the polymer material according to the present disclosure, it can provide a certain level of strength and water impermeability while also providing biodegradability that allows it to be naturally decomposed in the body environment over time. The poly(ethylene glycol) may be one or more poly(ethylene glycol) selected from the group consisting of PEG-32, PEG-60, PEG-80, PEG-90, PEG-135, PEG-200, PEG-350, PEG-500, PEG-800, PEG-8000, PEG-2M, PEG-5M, PEG-20M, PEG-45M, and the like.

[0060] For example, the poly(ethylene glycol-ran-propylene glycol) may be included in an amount of 30 to 40 parts by weight based on 100 parts by weight of the total polymer material. The poly(ethylene glycol-ran-propylene glycol) is a component used for purposes such as heat transfer fluid, lubricant, solvent, plasticizer, and foam control agent, and has excellent lubricity even in high-load environments, non-corrosion to metals, a low pour point, and excellent thermal stability.

[0061] For example, the magnesium hydroxide may be included in an amount of 2 to 4 phr based on the entire polymer material. The magnesium hydroxide may suppress the negative effects caused when L-lactic acid included in the polymer material according to the present disclosure dissolves in moisture provided in the body environment and exhibits acidity.

[0062] For example, the pH of the polymer material may be 6.5 to 7.5.

[0063] For example, the compressive strength of the polymer material at 20 to 30 degrees Celsius may be 11 N or more. Since the polymer material must maintain its shape during storage, it is required to have a compressive strength within the above numerical range at room temperature.

[0064] For example, the solubility of the polymer material at 30 to 40 degrees Celsius may be such that 2.5 g of the polymer material is completely dissolved in 100 ml of PBS solution within 36 hours. Since the polymer material should decompose after a certain period of time in an environment within the temperature range of the human body, the objective of the present disclosure can be achieved when the polymer material has solubility defined in the above manner.

[0065] For example, the polymer material may further comprise calcium phosphate tribasic. When calcium phosphate tribasic is added to the polymer material according to the present disclosure, it can impart a bone regeneration effect while maintaining strength and water impermeability, and in particular, when the polymer material according to the present disclosure is applied to a bone hemorrhage site, it can provide an excellent bone regeneration effect, thereby providing a useful effect for post-surgical recovery.

[0066] For example, the polymer material may further comprise hydroxyapatite. When hydroxyapatite is added to the polymer material according to the present disclosure, it can impart a bone regeneration effect while maintaining strength and water impermeability. In particular, when the polymer material according to the present disclosure is applied to a bone hemorrhage site, it can provide an excellent bone regeneration effect, thereby providing a useful effect for post-surgical recovery.

[0067] For example, the polymer material may further comprise vitamin K2 (Menaquinone). When vitamin K2 is added to the polymer material according to the present disclosure, it can provide an improved hemorrhage suppression effect while maintaining strength and water impermeability, and in particular, it can provide a damage recovery effect on hemorrhagic tissue even after the polymer material according to the present disclosure is biodegraded. Vitamin K2 can be included in an amount of 1 to 3 parts by weight based on 100 parts by weight of the total polymer material, and when included within the corresponding numerical range, it can exhibit the useful effects described above.

[0068] For example, the polymer material may further comprise isoamyl acetate. When isoamyl acetate is included in the polymer material according to the present disclosure, it can provide an improved hemorrhage-inhibiting effect while maintaining strength and water impermeability, and in particular, it can maximally suppress the phenomenon of the hemorrhage-inhibiting effect decreasing over time. Isoamyl acetate may be included in an amount of 0.5 to 1.5 parts by weight based on 100 parts by weight of the total polymer material, and when included within the said numerical range, it can exhibit the useful effects described above.

[0069] In order to achieve the above purpose, a method for manufacturing a functional biotransplantable polymer material with bleeding inhibition according to one aspect of the technical idea of ​​the present disclosure is provided.

[0070] A step of mixing L-lactic acid, poly(ethylene glycol), and poly(ethylene glycol-ran-propylene glycol) at 100 to 120 degrees Celsius, stirring at 40 to 60 RPM, degassing, and forming a polymer mixture;

[0071] A step of adding magnesium hydroxide to the polymer mixture and stirring at 100 to 200 RPM to completely disperse the magnesium hydroxide within the polymer mixture to form a polymer dough; and

[0072] It may include a step of putting the above-formed polymer dough into a mold to give it a shape and then rapidly cooling it with liquid nitrogen to manufacture a polymer material for biotransplantation with bleeding inhibition functionality.

[0073] For example, the method for manufacturing the above-mentioned bleeding-inhibiting functional bio-implantable polymer material may further include a step of plasma surface treatment of the formed bleeding-inhibiting functional bio-implantable polymer material, and the plasma surface treatment may be performed for 2 minutes under conditions of a power of 100 W, a pressure of 100 mTorr, and a flow rate of O2100 sccm.

[0074] For example, the L-lactic acid may include OLLA (Oligomeric L-Lactide). L-lactic acid is an organic compound having both a carboxyl group and a hydroxyl group, and has the property of exhibiting acidity when dissolved in water. The pH of the entire polymer composition can be maintained in a neutral range by the magnesium hydroxide included in the biotransplantable polymer material according to the present disclosure. In addition, when the L-lactic acid includes OLLA, the weight average molecular weight of the OLLA may be 2,000 to 4,000.

[0075] For example, the L-lactic acid may be included in an amount of 40 to 60 parts by weight based on 100 parts by weight of the total polymer material.

[0076] For example, the poly(ethylene glycol) may be included in an amount of 10 to 20 parts by weight based on 100 parts by weight of the total polymer material.

[0077] For example, the poly(ethylene glycol-lan propylene glycol) may be included in an amount of 30 to 40 parts by weight based on 100 parts by weight of the total polymer material.

[0078] For example, the magnesium hydroxide may be included in an amount of 2 to 4 phr based on the entire polymer material.

[0079] For example, the polymer material may further comprise vitamin K2 (Menaquinone). When vitamin K2 is added to the polymer material according to the present disclosure, it can provide an improved hemorrhage suppression effect while maintaining strength and water impermeability, and in particular, it can provide a damage recovery effect on hemorrhagic tissue even after the polymer material according to the present disclosure is biodegraded.

[0080] For example, the polymer material may further include isoamyl acetate. When isoamyl acetate is included in the polymer material according to the present disclosure, it can provide an improved hemorrhage-inhibiting effect while maintaining strength and water impermeability, and in particular, it can suppress to the greatest extent the phenomenon of the hemorrhage-inhibiting effect decreasing over time.

[0081] Hereinafter, preferred embodiments of the present invention will be described. However, the following examples are intended only to illustrate the present invention and are not intended to limit the scope of the present invention to the following examples.

[0082] Examples 1 to 10: Preparation of functional biotransplantable polymer materials

[0083] L-lactic acid, magnesium hydroxide (Mg(OH)2), poly(ethylene glycol) PEG-8000, poly(ethylene glycol-ran-propylene glycol) were prepared. These were charged into a jacketed reactor maintained at 110°C in the amounts shown in Table 1 below, stirred at 50 RPM for about 2 hours, mixed, and degassed. Then, magnesium hydroxide was charged in the amounts shown in Table 1 below, stirred at 150 RPM for about 1 hour to ensure complete dispersion of the magnesium hydroxide in the polymer mixture. Thereafter, the manufactured polymer materials were charged into implantable specimen molds and rapidly cooled with liquid nitrogen to prepare materials of Examples 1 to 10.

[0084] Example L-Lactide PEG PEG-RAN-PPGM g(OH) 2 Paste pH 150 50--102 250-50-12 350 35158 24 50 25257 2550 15355 26 50 54 5227 50 1535 155.28 50 1535 357.19 50 1535 56 8.5 10 50 1535 106 12.8 Existing non-degradable material 5 Neutral Existing degradable material 7 Neutral

[0085] Examples 11 and 12: Preparation of functional bio-implantable polymer materials treated with plasma The materials of Example 5 and Example 8 were subjected to a RIE (Reactive Ion Etching) process to perform plasma surface treatment. The RIE plasma treatment was performed under the following conditions: plasma power of 100 W, chamber pressure of 100 mTorr, etching gas (O2) flow rate of 100 sccm, and etching time of 2 minutes, and each was prepared as the materials of Example 11 and Example 12, respectively.

[0086] Examples 13 to 17: Preparation of polymer materials with added other components

[0087] A material of Example 13 was prepared in the same manner as the material of Example 8, except that calcium triphosphate was added and mixed simultaneously with magnesium hydroxide in an amount of 1 part by weight based on 100 parts by weight of the total polymer material.

[0088] A material of Example 14 was prepared in the same manner as the material of Example 8, except that hydroxyapatite was added and mixed simultaneously with magnesium hydroxide in an amount of 1 part by weight based on 100 parts by weight of the total polymer material.

[0089] A material of Example 15 was prepared in the same manner as the material of Example 8, except that calcium triphosphate was added and mixed simultaneously with magnesium hydroxide in an amount of 1 part by weight based on 100 parts by weight of the total polymer material, and hydroxyapatite was added and mixed simultaneously with magnesium hydroxide in an amount of 1 part by weight based on 100 parts by weight of the total polymer material.

[0090] The Example 16 material was prepared in the same manner as the Example 8 material, except that vitamin K2 was added and mixed simultaneously with magnesium hydroxide in an amount of 2 parts by weight based on 100 parts by weight of the total polymer material for the Example 15 material.

[0091] The Example 16 material was prepared in the same manner as the Example 8 material, except that isoamyl acetate was added and mixed simultaneously with magnesium hydroxide in an amount of 1 part by weight based on 100 parts by weight of the total polymer material for the Example 15 material.

[0092] A material for Example 17 was prepared in the same manner as the material for Example 8, except that vitamin K2 in an amount of 2 parts by weight based on 100 parts by weight of the entire polymer material and isoamyl acetate in an amount of 1 part by weight based on 100 parts by weight of the entire polymer material were added and mixed simultaneously with magnesium hydroxide.

[0093] Experimental Example 1: Compressive Strength Evaluation

[0094] Referring to Fig. 2, the process of evaluating the compressive strength of the material of Example 8 using a Shimadzu ASG-X model universal testing machine (UTM) can be confirmed. The compression speed was set to 100 μm / min, and the zero point of the universal testing machine equipment jig was set at 1 cm intervals. As a result of the experiment, it was confirmed that a break occurred at 12.9357 N, and a breaking stroke of 0.39193 was confirmed. The result of confirming the entire compressive strength evaluation process graphically is shown in Fig. 3, and the results of performing the same test on the materials of Examples 11 to 15 are shown in Table 2 below along with the results for Example 8. As a result, the material of Example 8 was evaluated to have a compressive strength value of 12.9 N, which is a compressive strength that can secure both shape retention and usability.

[0095] Example 8 Example 11 Example 12 Example 13 Example 14 Example 15 Compressive strength (N) 12.9 13.2 13.3 12.6 12.8 12.9

[0096] Experimental Example 2: Hemostasis Maintenance Test and Adhesion Evaluation With reference to FIGS. 4 and 5, the process of performing the hemostasis maintenance test and adhesive evaluation using the material of Example 8 can be confirmed. The polymer material according to the present disclosure should have a hemostatic effect confirmed immediately after application, and even when applied as a water-soluble formulation, considering the characteristic of dissolving after a certain period of time, the duration of hemostasis should be secured for at least 2 hours. The hemostasis maintenance test was performed at 23 degrees Celsius for 24 hours. Pig bones were coated with paraffin film, and then a certain area of ​​the coating was cut and removed. After that, each bone was prepared by soaking it in the same amount of dyeing reagent, and then 1 g of the material of Example 8 was applied without any gaps to the surface soaked in the reagent.

[0097] Afterwards, it was stirred in the same amount of physiological saline solution (200 ml) and the changes were observed over time. Referring to Fig. 5, it was confirmed that the polymer material according to the present disclosure had a hemostatic effect immediately upon application and maintained hemostatic performance and adhesiveness for up to 4 hours. In addition, the results of visual observation at each time point of 4 hours, 6 hours, and 8 hours were requested to a trained panel of 7 people, and the hemostatic performance and adhesiveness were evaluated as one of the integers between 0 and 5, with 0 being the worst and 5 being the best, and the results are shown in Table 2 below.

[0098] In addition, the hemostatic performance and adhesiveness were evaluated in the same manner as the material of Example 8 using the materials of Examples 11 to 17, and the scores were evaluated in the same manner as in Example 8, and the results are shown in Tables 3 and 4 below.

[0099] Example 8 Example 11 Example 12 Example 13 Hemostatic performance 4.8 / 3.6 / 3.1 4.8 / 3.9 / 3.7 4.7 / 4.1 / 3.5 4.9 / 4.6 / 3.8 Adhesiveness 4.6 / 4.1 / 2.3 4.7 / 4.2 / 3.3 4.6 / 4.1 / 3.8 4.7 / 4.2 / 4.1

[0100] Example 14 Example 15 Example 16 Example 17 Hemostatic performance 4.9 / 4.7 / 3.9 4.9 / 4.9 / 4.5 4.9 / 4.9 / 4.7 4.9 / 4.9 / 4.7 Adhesiveness 4.7 / 4.3 / 4.3 4.8 / 4.4 / 4.4 4.9 / 4.7 / 4.5 4.9 / 4.8 / 4.7

[0101] Referring to Tables 3 and 4 above, it was confirmed that the polymer material according to the present disclosure exhibited excellent hemostatic performance and adhesiveness even after 4 hours. Experimental Example 3: Solubility Evaluation

[0102] Referring to FIG. 6, the process and results of evaluating the solubility of the material of Example 8 can be confirmed. Since the polymer material according to the present disclosure should dissolve and decompose after a certain period of time at about 37 degrees Celsius, which is the temperature of the human body, the shape of the material of Example 8 should be maintained for at least 2 hours when left in a non-flowing aqueous solution. 2.5 g of the material of Example 8 was placed in a beaker of 100 ml of PBS solution, and the beaker was maintained in a water bath at 37 degrees Celsius so that it was approximately 70% submerged, and the degree of dissolution was confirmed over time. As a result, it was confirmed that the polymer material according to the present disclosure maintained its shape even after 4 hours, and was confirmed to be completely dissolved within 24 hours.

[0103] Experimental Example 4: Evaluation of Cell Proliferation Rate of Functional Biotransplantable Polymer Materials Treated with Plasma Surfaces

[0104] Referring to FIGS. 7 to 10, it can be confirmed that when the surface of a polymer material according to the present disclosure is treated with plasma, the cell proliferation rate is significantly reduced.

[0105] First, the materials of Example 5 and Example 8 were designated as “P” and “PT”, respectively, the material of Example 11, which was obtained by plasma-treating the material of Example 5, was designated as “Pp”, and the material of Example 12, which was obtained by plasma-treating the material of Example 8, was designated as “PT-p”. The cell proliferation rate was evaluated by treating muscle cells on the surface of the plasma-treated material specimens according to the ISO10993 standard, and comparing the cell toxicity with the group that was not treated with plasma through XTT analysis on the measurement day.

[0106] First, 5 ml of a-MEM media (no FBS, 1% P / S) was filled into a 30 mm cell culture dish, and each sample was placed in the cell culture dish filled with the media. Afterwards, 1.8 ml of the culture medium was harvested on days 1, 4, and 7 while gently shaking each dish (at a clean bench). 0.2 ml of FBS was added to the harvested 1.8 ml of culture medium to make the FBS concentration 10%, and the cells were seeded into a 24-well cell culture dish at a concentration of 5 x 104 / well. Then, the dishes were cultured for 3 days in an environment of 37 °C and 5% CO2, and the WST-1 reagent was treated and the optical density at 450 nm was measured. This was repeated twice.

[0107] As a result, on the first day of cell culture, the cell proliferation patterns of all experimental groups were somewhat reduced compared to the control group, but it was confirmed that the results were not statistically significant. On the fourth day of cell culture, the cell proliferation patterns of the Pp (0.32±0.03) group compared to the control group P (0.41±0.03) and the PT-p (0.33±0.03) group compared to the control group PT (0.42±0.04) were confirmed to be statistically significantly reduced (P: Pp = 78.0%, PT: PT-p = 78.5%).

[0108] In addition, on the 7th day of cell culture, the cell proliferation patterns of the Pp (0.61±0.04) group compared to the control group P (0.60±0.02) and the PT-p (0.43±0.02) group compared to the control group PT (0.41±0.02) were confirmed to have statistically significantly decreased (P: Pp = 68.3%, PT: PT-p = 70.5%), and on the 14th day of cell culture, the cell proliferation patterns of all experimental groups were confirmed to have slightly decreased compared to the control group, but did not show statistically significant results.

[0109] The above experimental results suggest that the cell proliferation inhibition effect of plasma treatment can last for at least 7 days, and it is predicted that it becomes saturated before 14 days, and from that point onwards, the plasma treatment effect may not affect cell proliferation or the effect of plasma may be lost. In addition, it was confirmed that there was no statistically significant difference in cell proliferation between P and PT at all culture time points on days 1, 4, 7, and 14. These results were confirmed to be 78.5% on day 4 and 70.5% or less on day 7, which corresponds to the development target of 80% or less, and as a result, it was confirmed that the polymer material according to the present disclosure surface-treated with plasma exhibits an excellent cell proliferation inhibition effect.

[0110] Experimental Example 5: Evaluation of Platelet Adhesion Rate of Plasma-Surface-Treated Functional Biotransplantable Polymer Materials

[0111] Referring to FIGS. 11 and 12, it can be confirmed that when the surface of a polymer material according to the present disclosure is treated with plasma, the platelet adhesion rate is significantly reduced.

[0112] First, the materials of Example 5 and Example 8 were designated as “P” and “PT”, respectively, the material of Example 11, which was obtained by performing plasma treatment on the material of Example 5, was designated as “Pp”, and the material of Example 12, which was obtained by performing plasma treatment on the material of Example 8, was designated as “PT-p”. The plasma-treated material specimens were tested according to the ISO10993 standard. Fresh blood from animals was collected, centrifuged to separate only platelets, and applied to the surface of the plasma-treated material specimens. In addition, after 8 hours, the samples were fixed and dehydrated, and the number of platelets attached to the material surface was quantitatively evaluated and the shape of the platelets was qualitatively evaluated using a scanning electron microscope.

[0113] First, a centrifuge, optical microscope, SEM, CBC, hematology cytometer, incubator, 24-well culture dish, EtOH, SDW, sodium citrate, glutaraldehyde, PBS, pipettes (200p, 10p), and 50ml tubes were prepared. Blood was collected using an anticoagulant (3.2% Na citrate, Vacutainer (BD)), and the anticoagulant:blood ratio was prepared at 1:9.

[0114] Next, Cfg. supernatant (platelet rich plasma, PRP) was collected as 150g / 15min, then 500g / 20min: pellet (PRP), sup. (PPP), diluted 1 / 100 with PPP, and platelets were counted as 3Х108 platelets / ml using a hematological cytometer.

[0115] Afterwards, 100 ul of platelets were applied to the disc and incubated at 37°C for 30 minutes and 3 hours, respectively. The solution was removed and washed with PBS (solution -> CBC, disc -> SEM). Next, the platelets were fixed with 2.5% glutaraldehyde for more than 2 hours, dehydrated (40, 60, 80, 90, and 100% EtOH for 10 minutes each) and dried. Afterwards, SEM was performed and CBC counting was performed. The use of glassware was avoided, and all procedures were performed at room temperature. As a result, 1.74 um - normal, single, 4.54 um - 2-3 complexes formed, 9.34 um - complexes formed, thrombosis was confirmed.

[0116] As a result of the experiment, it was confirmed that the number of platelets attached to the surface was significantly reduced in the Pp (1,608±821) group compared to the P group (3,613±411) (P: Pp = 44.50%). In addition, it was confirmed that the number of platelets attached to the surface was significantly reduced in the PT-p (784±821) group compared to the PT group (3,028±608) (PT: PT-p = 22.59%). These results were confirmed to be Pp (44.5%) PT-p (22.59%), which corresponds to the development target of 80% or less, and as a result, it was confirmed that the polymer material according to the present disclosure surface-treated with plasma exhibits an excellent platelet adhesion rate reduction effect.

[0117] In summary, it was confirmed that the hemorrhage-inhibiting functional biotransplant polymer material according to the technical idea of ​​the present disclosure has excellent hemorrhage-inhibiting function and excellent biodegradability, and it was confirmed that when such a polymer material is surface-treated with plasma, a polymer material having additional antithrombotic function can be provided.

[0118] As described above, exemplary embodiments have been disclosed in the drawings and specifications. While specific terminology has been used to describe embodiments herein, it is intended solely to illustrate the technical concept of the present disclosure and is not intended to limit the scope of the present disclosure as defined in the claims. Therefore, those skilled in the art will appreciate that various modifications and equivalent embodiments are possible. Therefore, the true technical protection scope of the present disclosure should be determined by the technical concept of the appended claims.

Claims

1. A functional biotransplant polymer material having hemorrhage suppression, comprising L-lactic acid, poly(ethyleneglycol) (PEG), poly(ethylene glycol-ran-propylene glycol) (PEG-RAN-PPG), and magnesium hydroxide.

2. A functional polymer material for biotransplantation with bleeding inhibition, wherein the L-lactic acid in the first paragraph is contained in an amount of 40 to 60 parts by weight based on 100 parts by weight of the total polymer material.

3. A functional polymer material for biotransplantation with bleeding inhibition, wherein the poly(ethylene glycol) is included in an amount of 10 to 20 parts by weight based on 100 parts by weight of the total polymer material in the first paragraph.

4. A functional biotransplant polymer material for hemorrhage suppression, wherein in the first paragraph, the poly(ethylene glycol-lan propylene glycol) is contained in an amount of 30 to 40 parts by weight based on 100 parts by weight of the total polymer material.

5. A functional biotransplant polymer material for hemorrhage suppression, wherein the magnesium hydroxide is contained in an amount of 2 to 4 phr based on the entire polymer material in the first paragraph.

6. A polymer material for biotransplantation with bleeding inhibition function, wherein the pH of the polymer material in the first paragraph is 6.5 to 7.

5.

7. A polymer material for biotransplantation with bleeding inhibition function, wherein the polymer material has a compressive strength of 11 N or more at 20 to 30 degrees Celsius in the first paragraph.

8. In the first paragraph, the solubility of the polymer material at 30 to 40 degrees Celsius is such that 2.5 g of the polymer material is completely dissolved in 100 ml of PBS solution within 36 hours, a polymer material for biotransplantation with bleeding inhibition function.

9. A method for manufacturing a polymer material for biotransplantation with bleeding suppression function: A step of mixing L-lactic acid, poly(ethylene glycol), and poly(ethylene glycol-ran-propylene glycol) at 100 to 120 degrees Celsius, stirring at 40 to 60 RPM, degassing, and forming a polymer mixture; A step of adding magnesium hydroxide to the polymer mixture and stirring at 100 to 200 RPM to completely disperse the magnesium hydroxide within the polymer mixture to form a polymer dough; and A method for manufacturing a polymer material for biotransplantation with bleeding inhibition, comprising the step of putting the formed polymer dough into a mold to give it a shape and then rapidly cooling it with liquid nitrogen to manufacture a polymer material for biotransplantation with bleeding inhibition functionality.

10. In the 9th paragraph, the method for manufacturing the hemorrhage-inhibiting functional polymer material for biotransplantation further includes a step of plasma surface treatment of the formed hemorrhage-inhibiting functional polymer material for biotransplantation, wherein the plasma surface treatment is performed for 2 minutes under the conditions of a power of 100 W, a pressure of 100 mTorr, and a flow rate of O2100 sccm.

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