Preparation method of conductive thermal response drug release suture line

Abstract

The invention discloses a preparation method of a conductive thermal response drug release suture line, the obtained suture line has an inner conductive sensing functional coating and an outer thermal response drug-loading temperature-sensitive hydrogel functional coating, the inner coating has conductivity, heating property and wound sensing function, and the outer coating has thermal response drug-loading temperature-sensitive hydrogel functional coating. The outer coating has the functions of adhesion, drug carrying and thermal response drug release, the suture line is simple in process and convenient to operate, drug release can be regulated and controlled according to conductive thermal response, and the requirements of postoperative wound monitoring and on-demand treatment can be met.

Description

Technical Field

[0001] The invention belongs to the technical field of biomedical materials and relates to a method for preparing a conductive thermal response drug releasing suture. Background Art

[0002] Medical sutures are classified as absorbable or non-absorbable according to their sources, including natural materials (such as cotton, linen, silk, gut and collagen), synthetic materials (such as polyethylene terephthalate (EHIBOND), high molecular weight polyethylene (ORTHCORD), polyol-co-lactic acid (VICRYL), polydioxanone (STRATAFIX)) and metals (such as stainless steel and titanium alloy), and are designed in the form of monofilament, multifilament, braided or barbed. Conventional surgical sutures have excellent mechanical properties and biocompatibility and are widely used to close wounds such as skin, tendons, ligaments and provide physical support. Sutures are directly exposed to the wound site, and contact with infectious contaminants and microorganisms can cause surgical site infection. On the other hand, sutures carry tissue loads, and postoperative drag and friction may cause mechanical mismatch, causing wound damage and complications. Many other types of medical wound repair materials such as films, hydrogels, patches or biological glues are used for wound closure, but due to their weak mechanical properties, they are only used for low-stress soft tissues or to supplement postoperative leakage. Sutures provide mechanical support to the wound and are the “gold standard” for wound closure.

[0003] In order to prevent surgical site infection, antibacterial substances such as antibiotics and antimicrobial agents are added to sutures. For example: CN118087084A discloses a bacterial cellulose antibacterial suture carrying graphene oxide. However, due to the limitation of the initial drug dose, low concentration of drug release will lead to poor antibacterial efficiency, while high concentration will cause side effects to the human body and cause the emergence of drug-resistant strains. For example, CN113730644A discloses a suture with a gel coating to load drugs for slow release. However, when emergency or clinical needs arise, it is difficult to provide additional doses of drug treatment in time. Smart wearable technology is used to sense and respond to physiological characteristics of wounds, such as body temperature, bleeding, biological fluid exudation, bacterial infection, wound site dehiscence and suture breakage. For example: CN118234520A discloses a suture with a coating for monitoring tissue infection. The suture is coated with a sensing coating for monitoring biomarkers. CN115136500A discloses a conductive coated suture for in vivo implantation, which can be used to monitor pathological and physiological conditions. However, the commercialization process of these bioelectronic sensor devices for health monitoring is not yet mature, and large-scale production and functional applications are still challenging. In addition, the mechanical properties of the simple conductive functional coating used for suture coatings are poor, and it is easy for particles to break or fall off the suture, resulting in discontinuity in the electrical signal transmission path, which can easily lead to electronic failures and severe inflammation. In addition, because the treatment measures are limited and rely on medical intervention, they cannot be corrected in time before complications occur or even become serious, and cannot meet the complex environment and on-demand treatment requirements of wound suturing.

[0004] Environmentally responsive materials can change according to temperature, light, pH, ultraviolet light, electricity, and magnetism, and control drug release in hydrogels. For example: CN114177159A discloses a collagen hydrogel loaded with paclitaxel metal organic framework (ZIF-8), which can achieve pH and photothermal responsive drug release. However, these hydrogels usually have poor mechanical properties and adhesion. Biopolysaccharides are used in hydrogels to form a blended network to achieve recoverable tensile deformation and customized mechanical properties. For example: CN112999412A discloses a poly-N-isopropylacrylamide, polymethacrylic acid and gelatin composite hydrogel with temperature-responsive shrinkage properties. Although the hydrogel network has been verified, there is still work to be done in combining it with other technologies such as wound monitoring and on-demand local drug delivery. Existing conductive sutures show significant advantages in postoperative monitoring, but precision treatment is limited by functionality and it is difficult to effectively deal with the risk of long-term infection after surgery. Traditional drug-loaded sutures still have limitations. They may cause bacterial resistance due to too rapid release, or be difficult to effectively inhibit bacterial growth due to too short a drug effect. They are also unable to accurately control drug release and provide wound monitoring needs.

[0005] Therefore, it is of great significance to develop a conductive thermal responsive drug-releasing suture. Summary of the invention

[0006] The purpose of the present invention is to provide a method for preparing a conductive thermal responsive drug-releasing suture, so as to solve the problems that the existing suture cannot provide treatment on demand during actual use and the postoperative wound cannot be monitored in real time.

[0007] The technical solution of the present invention is:

[0008] A method for preparing a conductive thermal responsive drug-releasing suture comprises the following steps:

[0009] (1) Pretreatment of silk suture: soaking the silk suture in a cross-linking agent and drying;

[0010] (2) functionalizing the pretreated silk suture: immersing the pretreated silk suture in a conductive material solution, taking it out, washing it to remove excess conductive material on the surface of the silk fiber, and after drying, placing the silk suture coated with the conductive material in a container containing a reducing agent solution for reduction, repeating this step multiple times to obtain a conductive material coated suture;

[0011] (3) Preparation of a hydrogel coating drug sustained-release system: weigh natural polysaccharide powder, add water and antibacterial drugs, stir for the first time in a water bath to form a colorless, transparent, viscous solution, cool, and then add hydrogel material and N-isopropylacrylamide to the viscous solution in an ice bath, continue stirring for the second time, add N,N'-methylenebisacrylamide and initiator, stir slowly for the third time, eliminate bubbles in the solution by vacuuming, and finally add tetramethylethylenediamine and stir thoroughly to obtain a hydrogel coating drug sustained-release system;

[0012] (4) Immersing the conductive material coated suture thread into the hydrogel coating drug sustained release system to form a uniform gel coating on the surface of the conductive material coated suture thread to obtain a suture thread with a gel coating, leaving the suture thread with the gel coating to stand overnight, and then immersing it in a calcium chloride solution to form a thermally responsive coating layer adhered to the surface of the silk fiber, thereby obtaining a conductive thermally responsive drug releasing suture thread.

[0013] Furthermore, in step (1), the silk suture thread has a diameter ranging from 0.001 to 1.199 mm and a length of 20 to 30 cm.

[0014] Furthermore, in step (1), the crosslinking agent is selected from any one of polydopamine, a silane coupling agent, and glutaraldehyde. When the crosslinking agent is γ-glycidyloxypropyltrimethoxysilane, the mass percentage of the γ-glycidyloxypropyltrimethoxysilane solution is 1%-5%, and the pH value is 4.4-4.5.

[0015] Furthermore, in step (2), the conductive material is selected from any one of a conductive carbon-based material, a conductive polymer or a conductive metal material, and the reducing agent is selected from any one or more of phosphoric acid, hydrogen sulfide, glucose and ascorbic acid.

[0016] Furthermore, in step (2), when the conductive material solution is a graphene oxide solution, the concentration of the graphene oxide solution is 5-10 mg / mL, and the mass ratio of the reducing agent to the graphene oxide is 1-10:1.

[0017] Furthermore, in step (2), the immersion time is 1-15 min, the reduction temperature is 80-100° C., the reduction time is 1-8 h, and the step is repeated 1-8 times.

[0018] Furthermore, in step (3), the natural polysaccharide is selected from any one of sodium alginate, chitosan, and dextran, the mass fraction of the antibacterial drug is 1-10 mg / mL, and the antibacterial drug is selected from any one or more of berberine, gentamicin, silver nanoparticles, ciprofloxacin, and mupirocin.

[0019] Furthermore, in step (3), the hydrogel material is selected from any one of acrylamide, polyvinyl alcohol, and polyethylene glycol, the initiator is selected from any one of ammonium persulfate, potassium persulfate, and sodium persulfate, the concentration of N-isopropylacrylamide is 1-10 mg / mL, the mass percentage of N,N'-methylenebisacrylamide is 0.01-0.05%, and the mass percentage of tetramethylethylenediamine is 0.01-0.46%. When the hydrogel material is acrylamide and the initiator is ammonium persulfate, the concentration of acrylamide is 1-10 mg / mL, and the mass percentage of ammonium persulfate is 0.01-0.03%.

[0020] Furthermore, in step (3), the temperature of the water bath is 60-80° C., the first stirring time is 1-12 h, the second stirring time is 1-30 min, and the third slow stirring time is 1-2 h.

[0021] Furthermore, in step (4), the concentration of the calcium chloride solution is 0.01-0.1 M, and the soaking time is 1-5 min.

[0022] The present invention provides a method for preparing a conductive thermal responsive drug-releasing suture, which has the following advantages:

[0023] (1) Sutures are coated with a conductive layer and a thermally responsive drug coating, which can achieve controlled release of antimicrobial drugs within a specific temperature range by adjusting the temperature, effectively inhibiting bacterial infection, and are particularly suitable for surgical sites with high infection risks;

[0024] (2) The suture has built-in conductive material, which can monitor the strain changes of the suture in real time, providing a conductive strain monitoring function. It is suitable for real-time monitoring of the suture and healing process of abdominal surgery and deep wounds, which helps doctors evaluate the condition and formulate subsequent treatment plans;

[0025] (3) The conductive treatment and hydrogel coating strategies of suture materials are simple and efficient, have the function of temperature-controlled drug release, are simple in process, have low equipment requirements, are suitable for large-scale production and industrialization, and reduce production costs;

[0026] (4) The suture retains mechanical properties while providing reliable antibacterial function, wound monitoring and care capabilities, adapting to different postoperative needs and helping to improve the quality of postoperative recovery of patients;

[0027] (5) Sutures utilize electric current heating and thermally responsive hydrogel coatings to release intelligent drugs to effectively inhibit bacterial infection, and regulating the drug release rate helps reduce local toxicity and bacterial resistance. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 This is a schematic diagram of the conductive thermal responsive suture prepared in Example 1 of the method for preparing a conductive thermal responsive drug-releasing suture according to the present invention at different modification stages;

[0029] Figure 2 This is a synthesis mechanism diagram of the hydrogel coating drug sustained-release system prepared in Example 1 of the method for preparing a conductive thermal responsive drug-releasing suture thread of the present invention;

[0030] Figure 3 This is a schematic structural diagram of a conductive thermally responsive drug-releasing suture thread prepared in Example 1 according to a method for preparing a conductive thermally responsive drug-releasing suture thread of the present invention;

[0031] Figure 4 (a) is a diagram of an experimental scene in which the conductive thermally responsive drug-releasing suture prepared in Example 1 of the method for preparing a conductive thermally responsive drug-releasing suture according to the present invention is used as a conductor to connect a circuit and light up an LED lamp;

[0032] Figure 4 (b) is a graph showing the resistance change rate of the conductive thermal responsive drug-releasing suture prepared in Example 1 according to the method for preparing a conductive thermal responsive drug-releasing suture of the present invention under 3%, 5% and 7% strain;

[0033] Figure 5 This is a diagram showing the antibacterial effect of the conductive heat-responsive drug-releasing suture prepared in Example 1 of the method for preparing a conductive heat-responsive drug-releasing suture according to the present invention on Escherichia coli and Staphylococcus aureus;

[0034] Figure 6 (a) is a schematic diagram of temperature-responsive drug release of a conductive heat-responsive drug-releasing suture prepared in Example 1 according to a method for preparing a conductive heat-responsive drug-releasing suture of the present invention;

[0035] Figure 6 (b) is a drug sustained release curve diagram of the conductive heat-responsive drug-releasing suture prepared in Example 1 according to the method for preparing a conductive heat-responsive drug-releasing suture of the present invention at various temperatures;

[0036] Figure 7 This is a graph showing the live cell and dead cell staining experimental results of L929 cells after 1, 3, and 5 days for the conductive heat-responsive drug-releasing suture prepared in Example 1 according to the method for preparing a conductive heat-responsive drug-releasing suture of the present invention;

[0037] Figure 8 (a) is an experimental photograph of the conductive thermal responsive drug-releasing suture prepared in Example 1 of the method for preparing a conductive thermal responsive drug-releasing suture according to the present invention, and implanted subcutaneously;

[0038] Figure 8 (b) is a graph showing the H&E staining experimental results of subcutaneous specimens of the conductive thermal responsive drug-releasing suture prepared in Example 1 according to the preparation method of the conductive thermal responsive drug-releasing suture described in the present invention at 7, 14, and 28 days. DETAILED DESCRIPTION

[0039] The purpose of the present invention is to provide a method for preparing a conductive thermal responsive drug-releasing suture, which uses an inner layer of reduced graphene oxide as a conductive material and an outer layer of a thermosensitive hydrogel composite coating. With this structure, the suture can not only achieve precise sustained release of drugs through thermal effects, but also monitor the stretching state of the suture in real time, thereby effectively maintaining antibacterial activity during wound healing and providing real-time feedback on the progress of healing.

[0040] The above method comprises the following steps:

[0041] (1) Pretreatment of silk sutures.

[0042] The silk suture can be woven by a 16-spindle weaving machine, or directly purchased from products that meet the corresponding standards. The suture meets the requirements of the non-absorbable suture standard YY0167-2020, and its wire diameter ranges from 0.001 to 1.199 mm. The suture ensures reliability and applicability in clinical applications.

[0043] The silk sutures were immersed in a crosslinking agent overnight and then dried in a fume hood to enhance the adhesion of subsequent coatings and ensure that the suture substrate had a stable conductive coating foundation.

[0044] The above-mentioned suture thread uses natural fibers, synthetic fibers or metal fibers as the base material. The preferred base material is natural fibers such as silk, collagen, sheep intestine, cotton, cellulose, or medical synthetic fibers such as polyethylene glycol acid (PGA), polydioxanone (PDO), polyglycolic acid-lactic acid copolymer (PGLA), polyglycolide (PLA), polycaprolactone (PCL), or biocompatible metal material silk suture thread such as magnesium, titanium, stainless steel, etc. If silk is selected, silk fibers with a length of 20-30 cm can be used.

[0045] The cross-linking agent is selected from polydopamine, silane coupling agent, glutaraldehyde, etc., preferably γ-glycidyloxypropyltrimethoxysilane (CA), which is combined with the suture surface and the conductive material through the interaction of functional groups to improve the adhesion and stability of the conductive layer. The hydroxyl group formed after the hydrolysis of γ-glycidyloxypropyltrimethoxysilane in an aqueous solution can hydrogen bond with the amino, hydroxyl, carboxyl and other functional groups in the reduced graphene oxide to enhance the adhesion. The mass concentration of the γ-glycidyloxypropyltrimethoxysilane solution is 1%-5%. The solution is prepared by mixing γ-glycidyloxypropyltrimethoxysilane with deionized water in a mass ratio of 1:1-1:15, with a configuration volume of 1-50mL, and hydrochloric acid is added to adjust the pH value to between 4.4-4.5. This pretreatment process significantly improves the adhesion performance of the coating and lays the foundation for subsequent functionalization treatment.

[0046] (2) Functionalizing the pretreated sutures.

[0047] In this process, the conductive material is selected from conductive carbon-based materials, conductive polymers or conductive metal materials, preferably graphene and its derivatives (such as graphene oxide and reduced graphene oxide), carbon nanotubes, polyaniline, etc. Such materials can impart conductivity to the suture and support temperature-controlled heating to achieve drug release. Specifically, it includes graphene oxide coating and ascorbic acid coating to obtain a conductive suture with good conductivity. The key parameters in the process include the regulation of graphene oxide concentration, number of coatings and reduction time. Graphene oxide is prepared by the Hummers method and ultrasonically treated for 5-10 minutes to achieve uniform dispersion. Subsequently, the pretreated silk suture is immersed in a graphene oxide solution for 1-15 minutes to ensure that the surface of the silk fiber is in full contact with the graphene oxide solution. After taking it out, it is washed with deionized water to remove the excess graphene oxide on the surface of the silk fiber. After drying, the silk suture coated with graphene oxide is placed in a beaker containing a reducing agent solution. The mass ratio of the reducing agent to graphene oxide is 1-10:1, and the concentration of the graphene oxide solution is 5-10 mg / mL. Phosphoric acid, hydrogen sulfide, glucose, and ascorbic acid can be used as any one or more combinations as reducing agents. It is reduced at 80-100 ° C, the reduction time is 1-8 hours, and the number of coatings is 1-8 layers, thereby forming a uniform reduced graphene oxide coating to obtain a conductive material coated suture. This method effectively improves the conductivity of the suture and expands its application potential in the biomedical field.

[0048] (3) Preparation of hydrogel coating drug sustained-release system.

[0049] The preparation of this layer requires thermosensitive gel material, natural polysaccharides and antibacterial drugs.

[0050] The thermosensitive gel material is preferably N-isopropyl acrylamide, which has phase change properties at a lower critical solution temperature such as 32-34°C, and is suitable for controlling drug release under body temperature conditions; natural polysaccharides are preferably sodium alginate, chitosan, dextran, etc. The composite thermosensitive hydrogel can be used for on-demand drug delivery in sutures through temperature control properties, and the mechanical properties matching the sutures make it stable and reliable in vivo. The hydrogel material includes monomers such as acrylamide, polyvinyl alcohol, and polyethylene glycol, the cross-linking agent includes N,N'-methylenebisacrylamide, the initiator includes ammonium persulfate, potassium persulfate, sodium persulfate, etc., and the catalyst is tetramethylethylenediamine, etc. The preparation of the hydrogel can be achieved by cross-linking methods such as reaction between functional groups, ultraviolet light irradiation, and radiation irradiation, providing mechanical support and making up for the mechanical deficiencies of the thermosensitive hydrogel. Antibacterial drugs are preferably berberine, chitosan, gentamicin, silver nanoparticles, etc., which give the sutures antibacterial functions. The drugs in the hydrogel can be activated and released by electrical heating of the conductive coating, thereby achieving on-demand treatment. The thermosensitive hydrogel coating of the suture not only facilitates the sustained release of antimicrobial drugs, but also provides an immediate therapeutic response when the wound is infected.

[0051] Specifically, first weigh a certain amount of sodium alginate powder, add an appropriate amount of water to a beaker, then add an antibacterial drug with a mass fraction of 1-10 mg / mL, and stir with a magnetic stirrer for 1-12 hours in a water bath at 60-80°C until a colorless, transparent, viscous solution is formed. After the solution is cooled, add 1-10 mg / mL of acrylamide and 1-10 mg / mL of N-isopropylacrylamide to the colorless, transparent, viscous solution in an ice bath, continue to stir with a magnetic stirrer for 1-30 minutes, then add N,N'-methylenebisacrylamide and ammonium persulfate, the mass fractions of which are 0.01-0.05% and 0.01-0.03%, respectively, and after slowly stirring for 1-2 hours, eliminate the bubbles in the solution by vacuuming. Finally, add 0.01-0.46% of tetramethylethylenediamine, stir thoroughly and place the resulting gel solution in a culture dish to obtain a thermosensitive hydrogel loaded with poly N-isopropylacrylamide, polyacrylamide and sodium alginate. The hydrogel has good thermal responsiveness and drug release properties and is suitable for drug delivery systems;

[0052] (4) Immerse the conductive material coated suture in the gel solution for 1-20 seconds. After this step is completed, the suture is left to stand overnight to form a uniform gel coating on its surface. Finally, the gel-coated suture is immersed in a 0.01-0.1M calcium chloride solution for 1-5 minutes to further cross-link the sodium alginate to form a thermally responsive coating layer adhered to the fiber surface, thereby obtaining a conductive thermally responsive drug-releasing suture;

[0053] (5) Using electric current heating to promote drug release from conductive thermal responsive drug-releasing sutures: The conductive thermal responsive drug-releasing sutures are heated by electric current. The thermosensitive hydrogel wrapped in the sutures shows good stability at 37°C, but when the temperature rises to 40-42°C, the hydrogel can quickly release the loaded drug. The hydrogel coating can effectively realize drug release under higher temperature conditions while maintaining the mechanical strength and conductive properties of the sutures in a stress environment, thereby achieving controllable drug release function and prolonging the antibacterial effect.

[0054] It can be seen that the hydrogel and the conductive material form an inner conductive sensing functional coating and an outer thermosensitive hydrogel composite coating carrying drugs on the suture by a layer-by-layer coating method. The suture can be treated by surface treatment such as degumming, organic solution activation and plasma treatment to remove impurities and enhance surface activity. Subsequently, a conductive material layer such as reduced graphene oxide, carbon nanotubes or polyaniline is coated by the action of a crosslinking agent to stably adhere to the fiber surface. Then, a thermosensitive drug hydrogel layer is coated on the outside of the conductive coating. The conductive mode of the thermosensitive gel coating can release drugs by electrification, treat wound infection on demand, and continuously monitor the strain signal of the tissue around the wound, and finally form a multifunctional drug sustained-release suture. The development of this suture provides a new solution for postoperative care and complex wound healing. The preparation process is simple, the coating is uniform, and the thermal response characteristics are significant. It will significantly improve the effect of sutures in clinical treatment, especially in situations where drugs need to be released quickly to deal with infection or promote healing. It has important clinical application value.

[0055] In order to make the above-mentioned objects, features and advantages of the present invention more clearly understood, the technical solutions of the present invention are further described below in conjunction with specific embodiments. However, the present invention is not limited to the embodiments listed, and should also include any other known changes within the scope of the rights claimed by the present invention.

[0056] The term "one embodiment" or "embodiment" as used herein refers to a specific feature, structure, or characteristic that may be included in at least one implementation of the present invention. The term "in one embodiment" that appears in different places in this specification does not necessarily refer to the same embodiment, nor does it refer to a separate or selective embodiment that is mutually exclusive with other embodiments.

[0057] Example 1

[0058] The following example shows a method for preparing a conductive thermal responsive drug-releasing suture, and the specific steps are as follows:

[0059] Step 1: Select degummed silk fibers, cut them into 20 cm lengths, and immerse them in a 1:15 mass ratio γ-glycidyloxypropyltrimethoxysilane (CA) aqueous solution for pretreatment. Providing active functional groups for the silk thread is beneficial for the subsequent attachment of graphene oxide (GO), providing better adhesion and stability for the subsequent conductive layer coating.

[0060] Step 2: The pretreated silk thread was soaked in 8 mg / mL GO solution and 10:1 ascorbic acid (AA) solution, and reduced in a water bath at 80°C for 24 hours. This cycle was repeated 6 times to form a uniform reduced graphene oxide (rGO) conductive layer. Through multiple cycles of GO and AA soaking, a thick and stable rGO coating was formed, which improved the conductivity of the silk thread and enabled it to have the functions of temperature response and conductive heating.

[0061] Step 3: After stirring 5 mg / mL berberine (BB) and 6 mg / mL sodium alginate (SA) solution in a 60°C water bath for 12 hours, 10 mg / mL acrylamide (AM) and 6 mg / mL N-isopropylacrylamide (PNIPAM) were added, stirred in an ice bath for 30 minutes, and then 0.05 wt% N,N'-methylenebisacrylamide, 0.03 wt% ammonium persulfate and 0.46 wt% tetramethylethylenediamine were added and stirred for 2 hours to obtain a pre-gel solution.

[0062] Step 4: The silk thread coated with the rGO layer (CA-rGSFS) was immersed in the pre-gel solution for 20 seconds, left to stand overnight for uniform distribution, and then immersed in a 0.1 mol / L CaCl2 solution for 5 min to further cross-link the hydrogel coating to form the final multifunctional silk thread.

[0063] Step 5: Place the prepared suture sample in 37°C physiological saline, take samples regularly and measure the drug release by high performance liquid chromatography (HPLC). Record the drug release amount at different time points to evaluate its sustained release effect.

[0064] See also Figure 1 , Figure 1 Schematic diagram of the conductive thermal responsive suture prepared in Example 1 of the method for preparing a conductive thermal responsive drug-releasing suture according to the present invention at different modification stages. Figure 1 As shown, the stepwise modification process from ordinary silk sutures to conductive and thermally responsive multifunctional sutures is displayed in layers, revealing the structural evolution of each coating.

[0065] See also Figure 2 , Figure 2 This is a synthesis mechanism diagram of the hydrogel coating drug sustained release system prepared in Example 1 of the preparation method of a conductive thermal responsive drug releasing suture according to the present invention. Figure 2 As shown, the synthesis process of the hydrogel coating system with polyacrylamide (PAAm), sodium alginate (SA) and N-isopropylacrylamide (PNIPAm) as the main components. Through the steps of solution mixing, cross-linking polymerization reaction, etc., the system can form a thermosensitive gel layer uniformly coated on the surface of the suture, and the antibacterial drug berberine (BB) is encapsulated in the gel network to provide a temperature-responsive drug release effect.

[0066] See also Figure 3 , Figure 3 FIG. 1 is a schematic diagram of the structure of the conductive heat-responsive drug-releasing suture prepared in Example 1 according to the method for preparing a conductive heat-responsive drug-releasing suture of the present invention. Figure 3 As shown in Figure 2, this composite structure enables the multifunctional suture to not only release drugs in response to temperature, but also possess biosensing and antibacterial functions. The combination of conductivity and controlled drug release can provide a wider range of clinical uses in suture applications.

[0067] See also Figure 4 , Figure 4 (a) is a diagram of an experimental scene in which the conductive thermally responsive drug-releasing suture prepared in Example 1 of the method for preparing a conductive thermally responsive drug-releasing suture according to the present invention is used as a conductor to connect a circuit and light up an LED lamp; Figure 4 (b) is a graph showing the resistance change rate of the conductive thermal responsive drug-releasing suture prepared in Example 1 of the method for preparing a conductive thermal responsive drug-releasing suture according to the present invention under 3%, 5% and 7% strain. Figure 4 As shown in (a), it is proved that the conductive thermoresponsive drug release suture has good conductivity. Conductivity is the basis for achieving temperature-controlled drug release and sensing functions, and the rGO coating gives the suture stable electrical properties. Figure 4 As shown in (b), the dynamic stability of the conductive thermoresponsive drug-releasing suture was confirmed, and the good electrical signal output and reliable durability of the layered structure allowed almost unimpeded transmission of electrons, which can be used to monitor stretching, release, and wound movement.

[0068] See also Figure 5 , Figure 5 This is a diagram showing the antibacterial effect of the conductive heat-responsive drug-releasing suture prepared in Example 1 of the method for preparing a conductive heat-responsive drug-releasing suture according to the present invention on Escherichia coli and Staphylococcus aureus, as shown in FIG. Figure 5 As shown, the inhibition zone of the drug-loaded stapler is much larger than 1 mm, which is mainly attributed to the sustained release of berberine in the coating and the killing effect of the rGO layer on bacteria;

[0069] See also Figure 6 , Figure 6 (a) is a schematic diagram of temperature-responsive drug release of a conductive heat-responsive drug-releasing suture prepared in Example 1 according to a method for preparing a conductive heat-responsive drug-releasing suture of the present invention; Figure 6 (b) is a graph showing the drug sustained release curves of the conductive heat-responsive drug-releasing suture prepared in Example 1 according to the method for preparing a conductive heat-responsive drug-releasing suture of the present invention at various temperatures. Figure 6 As shown in (a), the system can dissolve in a non-crosslinked solution below its lower critical solution temperature (swollen state) and shrink above the critical solution temperature to accommodate and release the drug to achieve temperature-controlled drug release. Figure 6 As shown in (b), it is confirmed that the conductive thermal responsive multifunctional suture thread has achieved a good drug release effect within the temperature range that the human body can feel on a daily basis.

[0070] See also Figure 7 , Figure 7 The results of the live and dead cell staining experiment of L929 cells after 1, 3, and 5 days for the conductive heat-responsive drug-releasing suture prepared in Example 1 according to the method for preparing the conductive heat-responsive drug-releasing suture of the present invention. Figure 7 As shown, according to ISO 10993-5:2009, a concentration greater than 75% can be considered non-cytotoxic, and the conductive thermal responsive multifunctional suture meets the cell survival requirements, confirming its good biocompatibility.

[0071] See also Figure 8 , Figure 8 (a) is an experimental photograph of the conductive thermal responsive drug-releasing suture prepared in Example 1 of the method for preparing a conductive thermal responsive drug-releasing suture according to the present invention, and implanted subcutaneously; Figure 8 (b) is a graph showing the H&E staining experimental results of subcutaneous specimens of the conductive heat-responsive drug-releasing suture prepared in Example 1 according to the method for preparing a conductive heat-responsive drug-releasing suture of the present invention at 7, 14, and 28 days. Figure 8 (b) It can be seen that multifunctional sutures have the potential to actively promote early healing.

[0072] Example 2

[0073] The following example shows a method for preparing a conductive thermal responsive drug-releasing suture, and the specific steps are as follows:

[0074] Step 1: 1 mg / mL carbon nanotubes and 0.1% (w / v) PVP were dispersed in a mixed solution of ethanol and deionized water in an equal volume ratio, and ultrasonically treated for 60 min to obtain a uniform carbon nanotube suspension.

[0075] Step 2: Fix the silk suture between the two poles, and electrophoresed the suture in the carbon nanotube suspension for 30 minutes through an electric field of 10V / cm to make the carbon nanotubes evenly embedded in the silk fibers. Through the action of the electric field, the carbon nanotubes are evenly embedded along the fiber direction to form a highly conductive sensing path, thereby improving the electrical heating capacity of the suture.

[0076] Step 3: Soak the silk suture embedded with carbon nanotubes in a gentamicin sulfate solution for 30 min to allow the drug molecules to adsorb on the surface of the suture, and then dry it in a vacuum drying oven at 50°C for 4 h.

[0077] Step 4: Immerse the suture in a 1% (w / v) chitosan solution for 10 seconds to form a polymer protective layer. Repeat the immersion and drying steps three times to eventually form a stable drug-loaded layer, which prolongs the duration of drug release of the suture in vivo.

[0078] Step 5: Place the prepared suture sample in 37°C physiological saline, take samples regularly and measure the drug release by high performance liquid chromatography (HPLC). Record the drug release amount at different time points to evaluate its sustained release effect.

[0079] Example 3

[0080] The following example shows a method for preparing a conductive thermal responsive drug-releasing suture, and the specific steps are as follows:

[0081] Step 1: Soak the silk fiber in 70% ethanol for 10 minutes to remove surface grease and impurities; then soak it in sodium citrate buffer at pH = 5 for 15 minutes for surface activation treatment to enhance the adhesion of subsequent coatings. After treatment, rinse with deionized water 3 times and dry naturally at room temperature.

[0082] Step 2: Place the treated silk suture in a pH 5-6 citric acid buffer, gradually add aniline (PANI) monomer and 0.05M ammonium oxalate, and slowly stir at room temperature for 2 hours to polymerize PANI on the fiber surface into a uniform conductive layer. This step can give the silk fiber a certain conductivity, which is convenient for subsequent heating response.

[0083] Step 3: Prepare a 5 mg / mL N-isopropylacrylamide (PNIPAM) solution, add 1 mg / mL berberine (BB), and mix thoroughly. Soak the suture with a conductive polymer layer in this thermosensitive drug solution for 15 minutes to allow PNIPAM and BB to evenly adhere to the fiber surface. Dry at room temperature after each soaking, and repeat the soaking and drying steps 3 times to ensure the formation of a stable drug loading layer.

[0084] Step 4: The drug-loaded suture was immersed in a 0.5% glutaraldehyde solution for cross-linking treatment for 10 minutes to improve the stability of the multilayer coating. After the treatment, it was rinsed with deionized water and dried at room temperature.

[0085] Step 5: Place the prepared suture sample in 37° C. physiological saline for drug release experiment. Take samples regularly, measure the drug release amount by high performance liquid chromatography (HPLC), and record the release data at each time point to evaluate the sustained release effect of the suture.

[0086] In summary, the preparation method of a conductive thermal responsive drug release suture described in the present invention adopts a "conductive-thermal responsive" composite structure design, combined with silk as a substrate and a functional coating of a conductive material, aiming to realize an intelligent drug release system. By considering silk as a "support skeleton" and the conductive coating as a "functional coating", the conductivity and thermal response characteristics of the suture are effectively improved, ensuring the controlled release of drugs at a specific temperature. The suture adopts a "shell-core" structure design, the core layer is responsible for conductivity, and the outer layer is responsible for drug storage. The drug release rate is adjusted by the thermal responsive material, and it can adapt to different physiological environments. While improving the controllable drug release performance of the suture, the silk is modified by a crosslinking agent pretreatment technology, retaining the excellent conductivity and sensing stability of reduced graphene oxide, ensuring that the monitoring and thermal conduction process of the material in the body is smooth and meets the needs of tissue healing. In addition, by adding antibacterial components and polysaccharides to the hydrogel coating, it can not only inhibit infection, but also have good adhesion and mechanical properties, providing precise treatment support. This innovative conductive thermal responsive drug-releasing suture has broad application prospects and is suitable for wound sutures in complex surgeries and high-risk infections, especially in the abdominal cavity, stomach, spleen and other fields, showing strong clinical value.

[0087] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present invention may be modified or replaced by equivalents without departing from the spirit and scope of the technical solutions of the present invention, which should all be included in the scope of the claims of the present invention.

Claims

1. A method for preparing a conductive thermal responsive drug-releasing suture, characterized in that: The following steps are involved: (1) Pretreatment of silk suture: soaking the silk suture in a cross-linking agent and drying; (2) functionalizing the pretreated silk suture: immersing the pretreated silk suture in a conductive material solution, taking it out, washing it to remove excess conductive material on the surface of the silk fiber, and after drying, placing the silk suture coated with the conductive material in a container containing a reducing agent solution for reduction, repeating this step multiple times to obtain a conductive material coated suture; (3) Preparation of a hydrogel coating drug sustained-release system: weigh natural polysaccharide powder, add water and antibacterial drugs, stir for the first time in a water bath to form a colorless, transparent, viscous solution, cool, and then add hydrogel material and N-isopropylacrylamide to the viscous solution in an ice bath, continue stirring for the second time, add N,N'-methylenebisacrylamide and initiator, stir slowly for the third time, eliminate bubbles in the solution by vacuuming, and finally add tetramethylethylenediamine and stir thoroughly to obtain a hydrogel coating drug sustained-release system; (4) Immersing the conductive material coated suture thread into the hydrogel coating drug sustained release system to form a uniform gel coating on the surface of the conductive material coated suture thread to obtain a suture thread with a gel coating, leaving the suture thread with the gel coating to stand overnight, and then immersing it in a calcium chloride solution to form a thermally responsive coating layer adhered to the surface of the silk fiber, thereby obtaining a conductive thermally responsive drug releasing suture thread.

2. The method for preparing a conductive thermal responsive drug-releasing suture according to claim 1, characterized in that: In step (1), the silk suture thread has a diameter ranging from 0.001 to 1.199 mm and a length of 20 to 30 cm.

3. The method for preparing a conductive thermal responsive drug-releasing suture according to claim 1, characterized in that: In step (1), the crosslinking agent is selected from any one of polydopamine, a silane coupling agent, and glutaraldehyde. When the crosslinking agent is γ-glycidyloxypropyltrimethoxysilane, the mass percentage of the γ-glycidyloxypropyltrimethoxysilane solution is 1%-5%, and the pH value is 4.4-4.

5.

4. The method for preparing a conductive thermal responsive drug-releasing suture according to claim 1, characterized in that: In step (2), the conductive material is selected from any one of a conductive carbon-based material, a conductive polymer or a conductive metal material, and the reducing agent is selected from any one or more of phosphoric acid, hydrogen sulfide, glucose, and ascorbic acid.

5. The method for preparing a conductive thermal responsive drug-releasing suture according to claim 4, characterized in that: In step (2), when the conductive material solution is a graphene oxide solution, the concentration of the graphene oxide solution is 5-10 mg / mL, and the mass ratio of the reducing agent to the graphene oxide is 1-10:

1.

6. The method for preparing a conductive thermal responsive drug-releasing suture according to claim 1, characterized in that: In step (2), the immersion time is 1-15 minutes, the reduction temperature is 80-100° C., the reduction time is 1-8 hours, and the step is repeated 1-8 times.

7. The method for preparing a conductive thermal responsive drug-releasing suture according to claim 1, characterized in that: In step (3), the natural polysaccharide is selected from any one of sodium alginate, chitosan, and dextran, the mass fraction of the antibacterial drug is 1-10 mg / mL, and the antibacterial drug is selected from any one or more of berberine, gentamicin, silver nanoparticles, ciprofloxacin, and mupirocin.

8. The method for preparing a conductive thermal responsive drug-releasing suture according to claim 1, characterized in that: In step (3), the hydrogel material is selected from any one of acrylamide, polyvinyl alcohol, and polyethylene glycol, the initiator is selected from any one of ammonium persulfate, potassium persulfate, and sodium persulfate, the concentration of N-isopropylacrylamide is 1-10 mg / mL, the mass percentage of N,N'-methylenebisacrylamide is 0.01-0.05%, and the mass percentage of tetramethylethylenediamine is 0.01-0.46%. When the hydrogel material is acrylamide and the initiator is ammonium persulfate, the concentration of acrylamide is 1-10 mg / mL, and the mass percentage of ammonium persulfate is 0.01-0.03%.

9. The method for preparing a conductive thermal responsive drug-releasing suture according to claim 1, characterized in that: In step (3), the temperature of the water bath is 60-80° C., the first stirring time is 1-12 h, the second stirring time is 1-30 min, and the third slow stirring time is 1-2 h.

10. The method for preparing a conductive thermal responsive drug-releasing suture according to claim 1, characterized in that: In step (4), the concentration of the calcium chloride solution is 0.01-0.1 M, and the soaking time is 1-5 min.

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