Suture comprising special function and method for manufacturing same

Abstract

The present invention relates to a heparin-immobilized suture and a method for manufacturing same, and relates to a technology for immobilizing a heparin material having antithrombotic, antibacterial, anticancer, scar reduction, anti-inflammatory, and immunosuppressive functions onto various sutures by performing an atmospheric pressure plasma treatment process on the surface of an existing suture using an automatic winding machine to form a carboxyl group (- COOH), which is a functional group acting as a seed layer upon immobilization of heparin onto the suture, and covalently bonding an amine group-containing molecule acting as an intermediate layer thereto.

Description

Suture containing special functions and method of manufacturing the same

[0001] The present invention relates to a heparin-fixed suture and a method for manufacturing the same.

[0002] Medical sutures, used in various wound treatments, are essential medical devices that have been used for a long time and play a crucial role in suturing damaged tissues and organs and aiding wound healing after surgery. In recent years, advancements in materials science, engineering technology, and biomedicine have led to innovative changes in suture design and processing. Among these, material selection is a critical factor that significantly influences suture performance, and advancements in polymer engineering and technology have provided a wide range of options, from naturally derived materials to artificially synthesized ones. In particular, compared to conventional non-absorbable sutures, absorbable sutures have the advantage of naturally degrading within the body, eliminating the need for additional suture removal after surgery and thus preventing secondary trauma to the patient.

[0003] However, sutures currently widely used in the medical device field have disadvantages such as bacterial infection, inflammatory response, foreign body reaction, and excessive fibrosis occurring at the wound site after surgery, which delay the wound healing process. Consequently, there is a need to develop sutures that possess special healing-promoting functions, such as antibacterial properties, inflammation control, and scar reduction, as an active rather than passive healing method.

[0004] Meanwhile, research is currently being conducted on coating methods that impart special antimicrobial functions to sutures using binders such as PVP and PVA to apply drugs with antimicrobial properties, such as chlorhexidine, to sutures. However, while commercially available sutures with antimicrobial functions may be relatively simple and highly productive due to the use of a dip coating method, a significant drawback is that, as a simplified physical coating method, the duration of drug release is currently limited to within 7 to 10 days. This makes them insufficient as sutures to provide special functions with long-term effects, and they may not be suitable, particularly when long-term effects are required after surgery. Therefore, there is a need for the development of sutures capable of possessing special functions (antithrombotic, antimicrobial, anticancer, scar reduction, anti-inflammatory, immunosuppressive functions, etc.) through chemical bonding.

[0005] Meanwhile, although surface-mounted heparin materials are traditionally well known as anticoagulants, recent research results highlight them as multifunctional substances that can be utilized in the treatment of various diseases through their diverse biological functions. For example, in addition to its anticoagulant action, heparin possesses anti-inflammatory, anti-tumor, antiviral, anti-angiogenic, and anti-metastasis effects, which are expressed through various physiological mechanisms. First, heparin can alleviate post-surgical inflammatory responses through its anti-inflammatory effects. Heparin suppresses inflammatory responses by interacting with inflammation-related cytokines such as NF-κIL-6 and IL-8, and reduces inflammation by decreasing the permeability of vascular endothelial cells. Furthermore, it can reduce cellular damage at the site of inflammation by inhibiting the action of inflammatory mediators such as histamine and hindering the migration of leukocytes. Second, heparin also possesses anti-tumor effects. Heparin plays a role in preventing tumor metastasis by inhibiting the proliferation of tumor cells and regulating intracellular signaling pathways. Furthermore, it hinders tumor growth by inhibiting the formation of new blood vessels around the tumor through its anti-angiogenic effects. Thirdly, heparin also exhibits antiviral effects. Because heparin has a structure similar to heparin sulfate on the cell surface, it can interfere with viruses attaching to cells. Recent studies suggest that heparin has the potential to contribute to blocking infection by inhibiting the entry of viruses, such as SARS-CoV-2, into cells. Fourthly, research results indicate that heparin is effective in reducing scarring at wound sites. Heparin possesses the ability to inhibit scar formation by influencing the proliferation of skin fibroblasts and collagen production. According to current research, heparin binds to growth factors, stabilizes them, and delays their release, thereby promoting the wound healing process. This can reduce scar formation and accelerate the regeneration of the wound site.

[0006] However, since long-term use of heparin can cause side effects such as bleeding, bruising, and thrombocytopenia, various conjugation methods have been developed to compensate for these drawbacks. In particular, using a surface immobilization method is more effective in resolving these issues than a method of releasing heparin into the body. Surface immobilization allows heparin to act locally, thereby minimizing systemic side effects; furthermore, the immobilized heparin continuously exerts anticoagulant and anti-inflammatory effects on the surface while reducing side effects caused by absorption into the body. This can significantly lower the risks associated with the long-term use of heparin.

[0007] Despite the various advantages of heparin, immobilizing it onto sutures remains a challenge to date. In particular, the long reaction times of covalent coupling agents, such as EDC / NHS, used to stably immobilize heparin onto sutures currently used in various medical devices, act as a major obstacle. This process is highly sophisticated and complex, making it difficult to maintain consistent quality during mass production; furthermore, it slows down production speed, thereby reducing economic viability. Additionally, surface modification is essential for immobilizing heparin onto sutures, requiring additional processes such as plasma treatment. Since these surface modification devices are not roll-to-roll suitable for sutures, continuous processing is impossible, which lowers productivity. Moreover, plasma treatment requires vacuum-forming equipment such as vacuum pumps and vacuum gauges.

[0008] Accordingly, there is a need to develop a method to immobilize heparin on the surface of the suture.

[0009] [Prior Art Literature]

[0010] (Non-patent Document 1) Ryan A. Hoshi, Biomaterials Volume 34, Issue 1, January 2013, Pages 30-41

[0011] (Non-patent Literature 2) Hamzeh Mohammadi Sardo, Canon Journal of Medicine, Volume 4, Issue 4, December 2023, Pages 97-99

[0012] (Non-patent Document 3) Hatice Ferda Ozguzar, Biomaterials, Volume10, Issue6, February 23, 2023

[0013] The present invention was devised to solve the above-mentioned problems, and the inventors have diligently researched a method to fix heparin material to a suture. As a result, the present invention was completed by properly fixing the heparin material by treating the suture with a plasma surface treatment winding machine.

[0014] Accordingly, the objective of the present invention is to provide a method for manufacturing a suture with heparin fixed to its surface.

[0015] Another objective of the present invention is to provide a medical suture having heparin fixed to its surface according to the manufacturing method of the present invention.

[0016] Another objective of the present invention is to provide a method for inhibiting or treating thrombosis or inflammation in a subject, comprising the step of applying a medical suture with heparin fixed to the surface of a target area of ​​the subject.

[0017] To achieve the above objective, the inventors fixed heparin to the surface of a suture by treating the suture with atmospheric pressure plasma through the following embodiment.

[0018] The configuration of the present invention will be described in detail below.

[0019] One aspect of the present invention is a method for manufacturing a suture with heparin fixed to its surface.

[0020] In the present invention, the method for manufacturing a suture comprises the following methods:

[0021] Step 1: Passing the suture through the inside of an automatic winding machine to treat it with atmospheric pressure plasma;

[0022] Step 2, combining the suture with an alkyldiamine derivative after atmospheric pressure plasma treatment in Step 1 above; and

[0023] Step 3: Treating the suture immobilized with the alkyldiamine derivative of Step 2 above in a heparin mixture.

[0024] As used herein, the term "suture" refers to a thread used to suture damaged tissue caused by injury or surgery.

[0025] In the present invention, the suture may be an absorbable or non-absorbable suture yarn, but is not limited thereto.

[0026] The term "absorbable suture yarn" in this specification refers to a biodegradable suture that is naturally absorbed into tissue without the need for separate removal after the wound is sutured, making it suitable for suturing deep structures such as the dermis and fascia inside the skin. Initially, catgut made from the intestines or tendons of cattle, sheep, pigs, and horses was used, and chemically synthesized materials such as Vicryl and Dexon are being used.

[0027] As used herein, the term "non-absorbable suture yarn" refers to a non-biodegradable suture that must be removed after tissue closure. It is primarily used for skin closure but can also be used for tendon or blood vessel closure where permanent support is required, even if the suture is located inside the skin. The materials used are diverse, including silk extracted from silkworms and chemically synthesized materials such as nylon and prolene.

[0028] In the present invention, the absorbable suture yarn may be one or more selected from the group consisting of polyglycolic acid (PGA), polyglactin (PGLA), polydioxanone (PDO), poly(glycolide-co-caprolactone) (PGCL), poly L-lactic acid (PLLA), polylactic acid (PLA), polycaprolactone (PL), hyaluronic acid (HA), gold weaving, and chitosan, but is not limited thereto.

[0029] In the present invention, the non-absorbable suture yarn is silk, nylon 6, nylon (nylon6,6), nylon 12, polypropylene, polyester, polytetrafluoroethylene (PTFE), polyvinylidenefluoride (PVDF), polyetheretherketone (PEEK), polyimide (PI), polyphenylene sulfide (PPS), stainless steel 316L alloy (STS316L), magnesium (Mg), gold (Au), silver (Ag), titanium aluminum vanadium alloy (Ti-6Al-4V), cobalt-chromium alloy (Co-Cr alloy L605), and silicon It may be one or more selected from the group consisting of (Silicon), but is not limited thereto.

[0030] In the present invention, the suture may have a diameter of about 20 to 400 μm, for example, about 150 to 300 μm, but is not limited thereto.

[0031] The diameter of the above suture can be expressed using a standard system representing the diameter of the suture according to quality standards under the USP (United States Pharmacopeia), i.e., the United States Pharmacopoeia, and the following range of suture diameters according to USP grades can be indicated:

[0032] USP 1: approx. 350 μm ~ 400 μm

[0033] USP 2: Approx. 300 μm ~ 350 μm

[0034] USP 3: Approx. 250 μm ~ 300 μm

[0035] USP 4: Approx. 200 μm ~ 250 μm

[0036] USP 5: Approx. 150 μm ~ 200 μm

[0037] USP 6: Approx. 100 μm ~ 150 μm

[0038] USP 7: approx. 50 μm ~ 100 μm

[0039] USP 8: approx. 40 μm ~ 50 μm

[0040] USP 9: Approx. 30 μm ~ 40 μm

[0041] USP 10: Approx. 25 μm ~ 30 μm

[0042] USP 11: approx. 20 μm ~ 25 μm

[0043] In the present invention, the suture may include a diameter of USP 11 to USP 1, and, for example, may include a diameter of USP 5 to USP 3, but is not limited thereto.

[0044] In this specification, "atmospheric pressure plasma" refers to plasma generated under atmospheric pressure. Plasma is an ionized gas containing electrons, ions, neutral atoms, and molecules. Atmospheric pressure plasma is generated in a general atmospheric pressure environment rather than a vacuum, and is used for surface treatment, thin film deposition, antibacterial removal, and surface modification of materials. Since plasma is formed under atmospheric pressure, it offers the advantages of fast process speeds and the ability to uniformly process large areas.

[0045] In the present invention, the first step of passing a suture through an automatic winding machine to treat atmospheric pressure plasma may include a process of winding the suture at a winding speed of 100 mm / min to 1000 mm / min, for example, 200 mm / min, for atmospheric pressure plasma treatment, but is not limited thereto.

[0046] In the present invention, the first step of passing a suture through an automatic winding machine to treat atmospheric pressure plasma may include, but is not limited to, a process of delivering energy to the suture using radio frequency power (RF power) at 40 W to 200 W, for example, 40 W to 140 W, preferably 100 W, for atmospheric pressure plasma treatment.

[0047] In the present invention, the first step of passing a suture through an automatic winding machine to treat atmospheric pressure plasma may involve supplying oxygen for atmospheric pressure plasma treatment at a pressure of 10 to 100 sccm (standard cubic centimeters per minute), 20 to 100 sccm, 30 to 100 sccm, 40 to 100 sccm, 20 to 90 sccm, 30 to 90 sccm, 40 to 90 sccm, 20 to 80 sccm, 30 to 80 sccm, 40 to 80 sccm, 20 to 70 sccm, 30 to 70 sccm, 40 to 70 sccm, for example, 40 sccm, but is not limited thereto.

[0048] In the present invention, the first step of passing a suture through an automatic winding machine to treat atmospheric pressure plasma may involve supplying helium for atmospheric pressure plasma treatment at a pressure of 100 to 600 sccm (standard cubic centimeters per minute), 200 to 600 sccm, 300 to 600 sccm, for example, 400 sccm, but is not limited thereto.

[0049] In the second step of combining a suture with an alkyldiamine derivative after the first step of atmospheric pressure plasma treatment of the present invention, the alkyldiamine derivative may be one or more selected from the group consisting of hexamethylenediamine (HMDA), octamethylenediamine, and decamethylenediamine, for example, hexamethylenediamine, but is not limited thereto.

[0050] The above hexamethylenediamine may be diaminohexane (1,6-diaminohexane).

[0051] In the present invention, the second step of combining a suture with an alkyldiamine derivative after the first step of atmospheric pressure plasma treatment may additionally include a step of mixing the alkyldiamine derivative with an MES (2-(N-morpholino) ethanolsulfonic acid) buffer solution, but is not limited thereto.

[0052] In the above 2nd step, the MES (2-(N-morpholino) ethyl sulfonic acid) buffer solution may include EDC (N-3dimethylaminopropyl)-N'-ethylcarbodiimide) and NHS (N-hydroxysuccinimide) as catalysts, but is not limited thereto.

[0053] In the present invention, the second step of combining a suture with an alkyldiamine derivative after the first step of atmospheric pressure plasma treatment may include, but is not limited to, a process of combining the suture with an alkyldiamine derivative for 10 to 150 minutes, 10 to 100 minutes, 10 to 80 minutes, 10 to 60 minutes, 10 to 40 minutes, for example, 30 minutes after the first step of atmospheric pressure plasma treatment.

[0054] In the present invention, the third step of treating the suture immobilized with the alkyldiamine derivative of the second step in a heparin mixture may additionally include, but is not limited to, a process of preparing a heparin mixture by mixing heparin with EDC / NHS and MES buffer solutions.

[0055] In the above 3rd step, the MES (2-(N-morpholino) ethyl sulfonic acid) buffer solution may contain EDC (N-3dimethylaminopropyl)-N'-ethylcarbodiimide) and NHS (N-hydroxysuccinimide) as catalysts, but is not limited thereto.

[0056] In the present invention, the third step of treating the suture immobilized with the alkyldiamine derivative of the second step in a heparin mixture may include a process of reacting the suture immobilized with the alkyldiamine derivative in a heparin mixture for 10 to 150 minutes, 10 to 100 minutes, 10 to 80 minutes, 10 to 60 minutes, 10 to 40 minutes, for example, 30 minutes, but is not limited thereto.

[0057] In one embodiment of the present invention, since heparin is a compound containing sulfur (S) atoms, the amount and immobilization status of heparin attached to the fiber surface were evaluated through XPS (X-ray Photoelectron Spectroscopy) analysis. S2p atomic% represents the ratio of sulfur (S) atoms detected on the fiber surface, and when heparin is immobilized on the fiber surface, the sulfur atoms of heparin are measured together with other atoms on the fiber surface (e.g., carbon, oxygen, etc.), and it can be evaluated that the S2p atomic% increases. It was confirmed that high S2p atomic% were exhibited when the atmospheric pressure plasma treatment conditions were set to 100 W and the reaction time of the heparin mixture was adjusted to 30 minutes.

[0058] Another aspect of the present invention is a medical suture having heparin fixed to the surface of the suture according to the manufacturing method of the present invention.

[0059] In the present invention, the suture may be in the form of a monofilament suture, a braided suture, or a barbed suture, but is not limited thereto.

[0060] The monofilament suture described above is a suture composed of a single strand of fiber. It has a smooth and soft surface, resulting in minimal friction when passing through tissue, and can be made of absorbent or non-absorbent materials. Due to its smooth properties, it may have low knot retention, but it offers the advantages of a low risk of infection and resistance to foreign material accumulation. It is primarily used for clean surgical incisions or in areas requiring long-term tissue support; for example, it can be used for vascular or skin suturing.

[0061] The aforementioned composite suture is a suture formed by twisting and weaving multiple strands of fiber. Due to the interwoven structure, it offers good flexibility and facilitates the formation and maintenance of knots within tissues. However, because the strands are interwoven on the surface, friction within the tissue may be greater compared to monofilament sutures. Additionally, the somewhat rough surface increases the likelihood of bacteria or foreign substances accumulating on the suture, which may pose a risk of infection. It is available in absorbable and non-absorbable materials. It can be used in surgical sites where knot maintenance is critical or in surgeries requiring tissue support, and it can also be used for suturing muscles or connective tissues.

[0062] The aforementioned barbed suture features a small barb structure on its surface, which allows it to pass easily into tissue without being pulled in the opposite direction. Thanks to this barb structure, the suture can be secured within the tissue without the need for a separate knot. It enables reduced surgical time and can be used when tissue support is required or to avoid knot formation. Furthermore, the even distribution of tissue stress allows for effective tissue support across the entire area where the suture line is located. It offers strong fixation to the tissue, providing stability without knots, and has a low risk of unraveling. It can be used in laparoscopic surgery or surgeries requiring tension distribution.

[0063] Details regarding medical sutures in this specification that overlap with the method of manufacturing sutures are omitted.

[0064] Another aspect of the present invention provides a method for inhibiting or treating thrombosis or inflammation in a subject, comprising the step of applying a medical suture with heparin fixed to the surface of a target area of ​​the subject.

[0065] In the present invention, heparin may be immobilized in an amount effective for exhibiting an antithrombotic effect on the surface of the target site, but is not limited thereto.

[0066] The present invention relates to a heparin-fixed suture and a method for manufacturing the same. When the heparin-fixed suture of the present invention is used as a suture for vascular anastomosis, it can stop blood coagulation and prevent the formation of blood clots at the anastomosis site. When used as a suture in abdominal surgery or organ transplantation, it can suppress inflammation at the surgical site and reduce complications caused by inflammation. Furthermore, when the heparin-fixed suture is used for suturing areas with a high risk of infection, such as the skin or abdomen, it can prevent bacterial infection. When applied as a suture in skin reconstructive surgery or cosmetic surgery, it can regulate the proliferation of fibroblasts and collagen formation, thereby minimizing scar formation. Additionally, when the heparin-fixed suture is used after heart or major organ surgery, it promotes neovascularization, which has an excellent effect in accelerating tissue regeneration and wound healing, thus contributing to increasing the overall recovery speed of the patient.

[0067] Figure 1 is a figure showing a winding machine for plasma surface treatment.

[0068] Figure 2 is a figure showing an S2p mapping image of a manufactured nylon suture.

[0069] Figure 3 is a table showing the S2p atomic% according to the chemical reaction time of the heparin solution used in atmospheric pressure plasma treatment.

[0070] Figure 4 is a table showing the S2p atomic% according to the power conditions of the heparin solution used in atmospheric pressure plasma treatment.

[0071] Figure 5 is a figure showing the results of observing whether E. coli bacteria are attached using a fluorescence microscope.

[0072] Figure 6 is a figure showing the results of tissue collection and visual observation after inserting a suture into an animal model.

[0073] Hereinafter, embodiments of the present invention are described in detail so that those skilled in the art can easily implement the invention. However, the present invention may be embodied in various different forms and is not limited to the embodiments described herein. Since embodiments according to the concept of the present invention may be subject to various modifications and may take various forms, embodiments are illustrated in the drawings and described in detail in this specification. However, this is not intended to limit embodiments according to the concept of the present invention to a specific disclosed form, and includes modifications, equivalents, or substitutions that fall within the spirit and scope of the present invention.

[0074] Throughout this specification, when a part is described as 'comprising' a certain component, it means that, unless specifically stated otherwise, it does not exclude other components but may include additional components. Furthermore, throughout this specification, the singular form includes the plural form unless specifically stated otherwise.

[0075] When a range of numerical values ​​is described in this specification, unless a specific range is otherwise described, the value has the precision of significant figures provided according to the standard rules in chemistry for significant figures. For example, 10 includes a range of 5.0 to 14.9, and the number 10.0 includes a range of 9.50 to 10.49.

[0076] A method for manufacturing a heparin-fixed suture according to one embodiment is described below.

[0077]

[0078] Preparation Example. Method for manufacturing a heparin-fixed suture

[0079] Figure 1 illustrates an automatic winder for plasma surface treatment. Inside the winder is a treatment unit that generates plasma, and a suture located in the center automatically passes through it. A mixture of helium and oxygen gas is injected through a nozzle, and when voltage is applied by an RF power generator, the inside of the nozzle becomes an atmospheric pressure plasma state. At this time, oxygen radicals are formed from the injected oxygen gas by the energy generated from the atmospheric pressure plasma, and carboxyl groups (-COOH) and hydroxyl groups (-OH) are formed on the surface of the suture by these reactive gases. Subsequently, after covalently bonding molecules containing amine groups that act as an intermediate layer, a heparin material is immobilized on the suture.

[0080] Specifically, non-absorbable nylon sutures 6,6 were used, and USP 6-0 (Braided, DEKATEL.INC, diameter 70 to 99 μm), USP 7-0 (Monofilament, SMENG, 50 to 69 μm), and PDO (Polydioxanone) (monofilament, METABIOMED, ​​150 to 199 μm) were ultrasonically cleaned in isopropyl alcohol (IPA) and ethanol for 10 minutes each. The nylon sutures were installed in a winding machine, and the surface of the sutures was treated with atmospheric pressure plasma under conditions of a winding speed of 200 mm / min, He 400 sccm, O 240 sccm, and RF power of 70 W. To covalently bond the suture to the diaminohexane (1,6-Diaminohexane) intermediate after atmospheric pressure plasma treatment, a 50 mM DH solution was prepared by mixing it with 0.1 M MES (2-(N-morpholino) ethanesulfonic acid) buffer (pH 5.5, containing 0.5 M NaCl) containing 300 mM EDC (N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide) and 150 mM NHS (N-hydroxysuccinimide) catalyst, and then reacted with the suture at room temperature for 30 minutes. Afterward, the suture was thoroughly rinsed with 2 M NaCl and deionized water to remove residual reagents. The DH-immobilized sutures were reacted with a heparin solution (5 mg / ml, heparin sodium salt isolated from porcine intestinal mucosa, molecular weight 15 kDa, 180 units / mg) in MES buffer containing 150 mM NHS and 300 mM EDC catalysts at room temperature for 30 hours to bind to the carboxylic acid groups of heparin. Residual reagents and non-covalently bound heparin were removed by thorough washing with 2 M NaCl solution and water.

[0081]

[0082] Example 1. Evaluation of Heparin Immobilization of Nylon Sutures

[0083] The S2p mapping image of the manufactured nylon suture is shown in Figure 2.

[0084] S2p mapping results confirmed that heparin was evenly immobilized on all nylon sutures USP 6-0 (Braided, DEKATEL.INC, diameter 70 to 99 µm), USP 7-0 (Monofilament, SMENG, 50 to 69 µm), and USP 5-0 (PDO monofilament, METABIOMED) (Fig. 2).

[0085]

[0086] Example 2. Evaluation of Heparin Immobilization According to Atmospheric Pressure Prisma Treatment Conditions

[0087] 2-1. Evaluation of Heparin Immobilization According to Time Conditions

[0088] Since heparin has sulfate (-SO3) groups in its molecular structure, the presence or absence of heparin immobilization on the surface of the USP 7-0 suture was determined by XPS surface analysis. Figure 3 shows the S2p atomic% according to the power used during atmospheric pressure plasma treatment and the chemical reaction time of the heparin solution.

[0089] Experimental results showed that the atmospheric pressure plasma treatment conditions of the sutures exhibited a distinct difference at 70W compared to 40W at a shorter treatment time (30 min). These results indirectly indicate that more activated reactive groups (-COOH) were formed on the surface at 70W. Additionally, when comparing the S2p atomic% after 30 minutes and 12 hours of treatment under 70W conditions, it was confirmed that the effect on the amount of immobilization due to the delay in time was not significant (Fig. 3).

[0090] 2-2. Evaluation of Heparin Immobilization According to Power Conditions

[0091] Figure 4 shows the results of evaluating heparin immobilization according to power conditions. The presence or absence of heparin immobilization was determined after synthesis for 30 minutes on the surface of USP 7-0 sutures using the same method as in Example 2-1. The power conditions were adjusted to 70, 80, 100, and 120 W, and the S2p atomic% according to power was shown.

[0092] Experimental results showed the highest S2p atomic% at 100W, which is because the plasma energy created optimal conditions suitable for surface activation. At 100W, reactive groups (-COOH) were effectively formed on the surface, which contributed to increasing heparin binding efficiency. On the other hand, if the power exceeds 100W, excessive energy is supplied, which increases surface non-uniformity and the possibility of decomposition, potentially reducing immobilization efficiency.

[0093] This demonstrates that a power condition of 100W is suitable for optimizing the suture surface modification and heparin immobilization processes using atmospheric pressure plasma, and confirms that the biocompatibility and functionality of the suture can be maximized under these conditions.

[0094]

[0095] Example 3. Evaluation of the antibacterial properties of PDO (Polydioxanone) sutures

[0096] The antimicrobial activity of PDO (Polydioxanone) sutures was evaluated. Escherichia coli (E. coli) was used as the bacterium, and bacterial adhesion was confirmed using a fluorescent marker (SYTO9_green). A comparative experiment was conducted by dividing the PDO sutures into heparin-immobilized samples and a control group.

[0097] PDO sutures (USP 5-0, diameter 150–199 μm) were used in experiments under the following conditions.

[0098] Control group: PDO sutures.

[0099] Experimental group: Heparin-fixed PDO sutures.

[0100] Each sample was cultured in a culture medium containing E. coli in an incubator at 37 °C for 12 hours. After incubation, the samples were washed with sterile PBS, and the bacteria were stained using SYTO9 fluorescent dye. Then, the presence or absence of bacteria attached to the surface was checked using a fluorescence microscope.

[0101] Fluorescence microscopy analysis revealed that a large amount of E. coli was attached to the surface of the PDO suture in the control group, which was confirmed by the SYTO9 fluorescence signal. In contrast, almost no fluorescence signal was observed in the heparin-immobilized PDO suture, and no E. coli attachment was observed (Fig. 5).

[0102] This indicates that heparin immobilization treatment significantly improves the antibacterial properties of the PDO suture surface. Since heparin possesses antibacterial properties, it was confirmed that it played an effective role in inhibiting bacterial adhesion.

[0103] It was confirmed that immobilizing heparin on PDO sutures can inhibit bacterial adhesion and impart antimicrobial properties. These results suggest that heparin immobilization technology can be usefully applied to enhance the infection prevention efficacy of PDO sutures.

[0104]

[0105] Example 4. Evaluation of anti-inflammatory activity in an animal model (in vivo).

[0106] The anti-inflammatory effects of in vivo heparin-immobilized sutures were evaluated using an animal model. For the animal model, a variant of the hairless SKH1 mouse breed produced by Charles River Laboratories (CrlOri:SKH1-hr, hairless mouse) was used.

[0107] The procedure involved making an incision in the dorsal skin of an animal model, inserting sutures to close the incision, collecting tissue samples, and observing the inflammatory response. The experimental group was composed as follows:

[0108] - Bare suture group: Group using sutures without heparin immobilization

[0109] - Heparin-immobilized suture group: Group using sutures immobilized with heparin

[0110] - Sham group: A group that underwent the same surgical procedure (incision) without sutures.

[0111] - No Surgery Group: A control group that did not undergo surgical procedures, including incisions and suturing.

[0112] All surgical groups (Bare suture group, Heparin-fixed suture group, and Sham group) underwent dorsal skin incisions under identical anesthesia conditions and surgical settings, and the experiment was conducted by varying only whether sutures were applied.

[0113] Tissue samples were collected from the relevant site of each experimental group 24 hours after surgery. The collected specimens were visually inspected for the degree of inflammatory response, and some were subsequently used for further analysis.

[0114] As a result of the experiment, when comparing the collected tissues, the group using heparin-immobilized sutures showed a lower intensity of visually observable inflammatory reactions (redness, swelling, etc.) compared to the group using bare sutures (Fig. 6). In addition, it was confirmed that the inflammatory reaction of the heparin-immobilized group was at a similar level when compared to the Sham group and the No Surgery group. In particular, it was confirmed that heparin immobilization treatment of PDO sutures effectively reduced the inflammatory reaction compared to bare sutures.

[0115] Through this, it was visually observed that heparin-immobilized sutures are effective in alleviating inflammatory responses, and it was confirmed that the anti-inflammatory properties of heparin were locally expressed on the surface of the sutures to suppress the inflammatory response.

Claims

1. A method for manufacturing a suture with heparin immobilized on the surface, comprising the following steps: Step 1: Passing the suture through the inside of an automatic winding machine to treat it with atmospheric pressure plasma; Step 2, combining the suture with an alkyldiamine derivative after atmospheric pressure plasma treatment in Step 1 above; and Step 3: Treating the suture immobilized with the alkyldiamine derivative of Step 2 above in a heparin mixture.

2. In Paragraph 1, A method of manufacturing in which the above suture is an absorbable or non-absorbable suture yarn.

3. In Paragraph 2, A method for manufacturing, wherein the absorbable suture yarn is one or more selected from the group consisting of polyglycolic acid (PGA), polyglactin (PGLA), polydioxanone (PDO), poly(glycolide-co-caprolactone) (PGCL), poly L-lactic acid (PLLA), polylactic acid (PLA), polycaprolactone (PL), hyaluronic acid (HA), gold weaving, and chitosan.

4. In Paragraph 2, The above-mentioned non-absorbable suture yarn is silk, nylon 6, nylon 6,6, nylon 12, polypropylene, polyester, polytetrafluoroethylene (PTFE), polyvinylidenefluoride (PVDF), polyetheretherketone (PEEK), polyimide (PI), polyphenylene sulfide (PPS), stainless steel 316L alloy (STS316L), magnesium (Mg), gold (Au), silver (Ag), titanium aluminum vanadium alloy (Ti-6Al-4V), cobalt-chromium alloy (Co-Cr alloy L605), and silicon A manufacturing method comprising one or more types selected from the group consisting of (Silicon).

5. In Paragraph 1, A manufacturing method wherein the above-mentioned first step includes a process of winding a suture at a winding speed of 100 mm / min to 1000 mm / min for atmospheric pressure plasma treatment.

6. In Paragraph 1, A manufacturing method wherein the first step above includes a process of delivering energy to a suture using radio frequency power (RF power) at 40 W to 200 W for atmospheric pressure plasma treatment.

7. In Paragraph 1, A manufacturing method in which the first step above involves supplying oxygen at a rate of 10 to 100 sccm (standard cubic centimeters per minute) for atmospheric pressure plasma treatment.

8. In Paragraph 1, A manufacturing method in which the above-mentioned first step involves supplying helium at a rate of 100 to 600 sccm (standard cubic centimeters per minute) for atmospheric pressure plasma treatment.

9. In Paragraph 1, A method for manufacturing, wherein the above alkyldiamine derivative is one or more selected from the group consisting of hexamethylenediamine (HMDA), octamethylenediamine, and decamethylenediamine.

10. In Paragraph 1, A manufacturing method wherein the above-mentioned second step includes a process of combining a suture with an alkyldiamine derivative for 10 to 150 minutes after atmospheric pressure plasma treatment.

11. In Paragraph 1, The above 3rd step further comprises the process of preparing a heparin mixture by mixing heparin with EDC / NHS and MES buffer solutions, a manufacturing method.

12. In Paragraph 1, The above third step comprises a process of reacting a suture immobilized with an alkyldiamine derivative in a heparin mixture for 10 to 150 minutes, a method of manufacturing.

13. A medical suture having heparin fixed to its surface according to the manufacturing method of any one of paragraphs 1 to 12.

14. In Paragraph 13, The above suture is a medical suture in the form of a monofilament suture, a braided suture, or a barbed suture.

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