Excessive adhesion prevention reagent, anti-adhesion medical instrument and application of anti-adhesion medical instrument

Abstract

The invention provides an anti-excessive adhesion reagent, an anti-adhesion medical instrument and application thereof, belongs to the field of new medical materials, and provides a treatment method for preventing excessive adhesion of silk fibroin-polyphenol adhesive gel. The silk fibroin-polyphenol adhesive gel is hydrogel formed by non-covalent crosslinking of silk fibroin and polyphenol compounds, and the treatment method comprises the following steps: after the silk fibroin-polyphenol adhesive gel is adhered to a tissue wound surface, applying an anti-excessive adhesion reagent to the exposed surface of the silk fibroin-polyphenol adhesive gel, and therefore, unexpected adhesion is prevented. The invention overcomes the defect that the existing silk fibroin-polyphenol adhesive gel may cause secondary adhesion due to lasting viscosity after being used for tissue repair, provides a simple and effective method, and endows the silk fibroin-polyphenol adhesive gel with an active anti-adhesion function in the later stage while retaining the initial adhesion advantage.

Description

Technical Field

[0001] This invention belongs to the field of medical new materials technology, and more specifically, relates to an anti-excessive adhesion reagent, an anti-adhesion medical device, and their applications. Background Technology

[0002] Silk fibroin and polyphenolic compounds (such as tannic acid) can form biocompatible hydrogels with good wet adhesion through non-covalent cross-linking, especially injectable gels with shear-thinning properties. These have been reported as surgical adhesives for wound closure (e.g., the applicant's prior patent ZL201810669143.X). While these adhesive gels provide excellent immediate hemostasis and closure, their durable and strong adhesive properties can become a clinical drawback in the later stages of repair: the exposed gel surface may unnecessarily adhere to adjacent moving tissues or organs, thus becoming a new risk factor for postoperative tissue adhesion. Currently, there is no effective method to actively and controllably eliminate the surface stickiness of such strongly adhesive gels to meet the requirements for anti-adhesion. Summary of the Invention

[0003] One of the objectives of this invention is to overcome the shortcomings of the prior art and to overcome the defect that existing silk fibroin-polyphenol adhesive gels may cause secondary adhesion due to their persistent adhesiveness after being used for tissue repair. This invention provides a simple and effective method that retains its initial adhesive advantages while giving it the function of actively preventing adhesion in the later stages.

[0004] One aspect of the present invention provides a treatment method for preventing excessive adhesion of silk fibroin-polyphenol adhesive gel, wherein the silk fibroin-polyphenol adhesive gel is a hydrogel formed by non-covalent crosslinking of silk fibroin and polyphenolic compounds, and the treatment method includes: after the silk fibroin-polyphenol adhesive gel adheres to a tissue wound, applying an anti-over-adhesion agent to the exposed surface of the silk fibroin-polyphenol adhesive gel to prevent unintended adhesion.

[0005] In this embodiment, the anti-over-adhesion agent may be a protein denaturant.

[0006] In the embodiments, the protein denaturant is one or more of ethanol, isopropanol, and acetone.

[0007] In the embodiments, the application of the anti-over-adhesion agent is carried out by one or more of wiping, spraying, and irrigation.

[0008] In an embodiment, the anti-over-adhesion agent is applied to the exposed surface of the silk fibroin-polyphenol adhesive gel within 24 hours to 14 days after the silk fibroin-polyphenol adhesive gel adheres to the tissue wound.

[0009] In the embodiments, the polyphenolic compound is one or more of tannic acid, gallic acid, and catechin.

[0010] According to another aspect of the present invention, an anti-over-adhesion reagent is provided for use in the processing method described above, wherein the anti-over-adhesion reagent is a protein denaturant, and the protein denaturant is one or more of ethanol, isopropanol, and acetone.

[0011] According to another aspect of the present invention, an anti-adhesion medical device for preventing excessive adhesion of silk fibroin-polyphenol adhesive gel is provided. The anti-adhesion medical device includes a reservoir unit and a quantitative application unit. The reservoir unit is used to store an anti-adhesion reagent, which is a protein denaturant selected from one or more of ethanol, isopropanol, and acetone. The quantitative application unit is connected to the reservoir unit and is used to quantitatively apply the anti-adhesion reagent to the exposed surface of the silk fibroin-polyphenol adhesive gel after wound closure.

[0012] In an embodiment, the metering unit may be one or more of a spray assembly, a pouring assembly, and a brush assembly.

[0013] According to another aspect of the invention, the anti-over-adhesion reagent as described above or the anti-adhesion medical device as described above is provided for use in preventing unintended adhesion when silk fibroin-polyphenol adhesive gel is used as a medical adhesive.

[0014] Compared with the prior art, the beneficial effects of the present invention are: 1. Functional sequential innovation: For the first time, the late-stage function of a known high-performance adhesive gel has been modified, giving it both "early strong adhesion" and "late-stage anti-adhesion" sequential intelligent functions, thus expanding the clinical application scenarios of the material.

[0015] 2. Simple and controllable method: The surface properties can be precisely and controllably transformed through a simple surface treatment step, which is easy to operate in clinical practice.

[0016] 3. Significant effect: Experiments show that after treatment with ethanol and other substances, the adhesion of the gel surface to moist tissues decreased by more than 90%, and it showed a significant anti-adhesion effect in multiple animal models, which was better than that of untreated gels of the same type and some commercial anti-adhesion products.

[0017] 4. High safety: The treatment is limited to the surface of the gel and does not affect its overall biocompatibility, degradability, or the normal healing process of the bonded wound. Attached Figure Description

[0018] The accompanying drawings illustrate exemplary embodiments of the inventive concept and, together with the description, serve to explain the principles of the inventive concept. The drawings are included to provide a further understanding of the inventive concept and are incorporated in and form a part of this specification.

[0019] Figure 1 This is a schematic diagram of a treatment method for preventing excessive adhesion of silk fibroin-polyphenol adhesive gel according to an embodiment of the present invention: wherein, Figure 1 (A) shows a gel-bonded structure, (B) shows the denaturing treatment of the exposed surface, and (C) shows the formation of a smooth barrier after the surface loses its adhesiveness. Detailed Implementation

[0020] The endpoints and any values ​​of the ranges disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.

[0021] The applicant discovered that silk fibroin and polyphenolic compounds (such as tannic acid and gallic acid) can form hydrogels with good biocompatibility and excellent wet adhesion properties under mild conditions through multiple non-covalent interactions. In particular, these gels often exhibit shear-thinning and self-healing properties, making them suitable as injectable surgical adhesives for rapid intraoperative hemostasis and wound closure (e.g., see prior art ZL201810669143.X). However, this durable and strong adhesive property may raise new clinical problems in the later stages of wound repair: 1. Risk of internal adhesions: When used in the abdominal cavity, tendons, or other areas, the exposed surface of the gel may adhere unnecessarily to adjacent moving tissues or organs, becoming a new source of risk for postoperative internal tissue adhesions.

[0022] 2. External Adhesion and Contamination: When applied to skin or other surface wounds, the stickiness of the exposed gel surface can easily cause it to adhere severely to the covering gauze, dressings, or clothing, resulting in secondary damage, pain, and bleeding during dressing changes. Simultaneously, the sticky surface readily attracts environmental contaminants such as dust and microorganisms, increasing the risk of wound infection.

[0023] Currently, there is a lack of effective methods to actively and controllably eliminate the surface stickiness of such gels after utilizing their immediate adhesive advantages, in order to solve the aforementioned adhesion and contamination problems encountered in the later stages of repair, thereby expanding their application in the field of anti-adhesion.

[0024] This invention first provides a method for surface de-adhesion and anti-adhesion treatment of silk fibroin-polyphenol adhesive gel, comprising the following steps: contacting the exposed surface of the silk fibroin-polyphenol adhesive gel, which has been formed and adhered to a tissue wound, with a protein denaturing agent to perform de-adhesion treatment, thereby causing the exposed surface to lose its adhesiveness. The core of this invention lies in discovering a subsequent method for surface de-adhesion treatment of silk fibroin-polyphenol adhesive gel already applied to a wound. This method, by treating the exposed surface of the gel with a protein denaturing agent (such as ethanol) at a specific time, can directionally and permanently eliminate the adhesiveness of the surface, without significantly affecting the structure of the gel itself or its fixing effect on the initial adhesive surface. Through this treatment, the gel is intelligently transformed from an "adhesive" into an "anti-adhesion isolation layer," thus resolving the contradiction of the same material in the context of timely medical needs.

[0025] In one exemplary embodiment, a treatment method is provided for preventing excessive adhesion of a silk fibroin-polyphenol adhesive gel, the silk fibroin-polyphenol adhesive gel being a hydrogel formed by non-covalent crosslinking of silk fibroin and polyphenolic compounds, the treatment method comprising: after the silk fibroin-polyphenol adhesive gel adheres to a tissue wound, applying an anti-over-adhesion agent to the exposed surface of the silk fibroin-polyphenol adhesive gel to prevent unintended adhesion.

[0026] The agent used to prevent excessive adhesion can be a protein denaturant. The protein denaturant can be one or more of ethanol, isopropanol, and acetone. The application method can be one or more of wiping, spraying, and irrigation. De-adhesion treatment is usually performed at a clinically appropriate time, 24 hours to 14 days after the gel adheres to the tissue wound.

[0027] Alternatively, the polyphenolic compound may be one or more of tannic acid, gallic acid, and catechin.

[0028] The present invention also provides an anti-over-adhesion reagent for use in the processing method described above. The anti-over-adhesion reagent may be a protein denaturant, which may be one or more of ethanol, isopropanol, and acetone.

[0029] The present invention also provides an anti-adhesion medical device for preventing excessive adhesion of silk fibroin-polyphenol adhesive gel. The anti-adhesion medical device includes a reservoir unit and a quantitative application unit. The reservoir unit is used to store an anti-adhesion reagent, which is a protein denaturant, and the protein denaturant is one or more of ethanol, isopropanol, and acetone. The quantitative application unit is connected to the reservoir unit and is used to quantitatively apply the anti-adhesion reagent to the exposed surface of the silk fibroin-polyphenol adhesive gel after wound closure.

[0030] Optionally, the metering unit may be one or more of a spray assembly, a pouring assembly, and a brush assembly.

[0031] In another aspect, the present invention also provides the application of the anti-over-adhesion reagent as described above or the anti-adhesion medical device as described above for preventing unintended adhesion when silk fibroin-polyphenol adhesive gel is used as a medical adhesive.

[0032] The present invention also provides a novel use of silk fibroin-polyphenol adhesive gel in the preparation of anti-adhesion medical devices, wherein after the gel is used and adhered to the tissue wound, its exposed surface is subjected to de-adhesion treatment by the above method.

[0033] Furthermore, the uses include two aspects: (a) Used to prevent postoperative adhesions between tissues in the body, such as adhesions between the peritoneum, tendons, nerves or pelvic organs; (b) When used on skin wounds, after exerting an adhesive effect, the exposed surface is de-adhesive and smooth, thereby preventing adhesion to external dressings or clothing and reducing the adhesion of environmental contaminants (such as dust and microorganisms), providing a physical protective barrier.

[0034] The silk fibroin-polyphenol adhesive gel is preferably formed by mixing a silk fibroin solution with one or more of the following: tannic acid, gallic acid and catechins. It can be an injectable gel with shear-thinning properties.

[0035] According to the present invention, the defects of existing silk fibroin-polyphenol adhesive gels, which may lead to secondary adhesion of internal tissues or adhesion and contamination of external dressings due to their persistent adhesiveness after being used for tissue repair, can be overcome. The present invention provides a simple and effective surface post-treatment method, enabling the gel to retain its excellent initial adhesive properties while acquiring the functions of active anti-adhesion and anti-contamination in the later stage, realizing a temporal functional transformation from "adhesive" to "intelligent protective barrier".

[0036] To better understand the exemplary embodiments of the present invention described above, further explanation is provided below with reference to specific examples and comparative examples.

[0037] Example 1: Quantitative verification of the surface de-adhesion treatment effect 1. Prepare silk fibroin-tannic acid injectable adhesive gel using conventional methods.

[0038] 2. The gel was adhered to a moist, detached porcine skin wound, and its initial adhesion strength (peak force) was determined using a materials testing machine.

[0039] 3. Using 75% ethanol cotton pads, evenly wipe the exposed surface of the gel adhering to the pigskin for 60 seconds, and then dry at room temperature for 5 minutes.

[0040] 4. The adhesion strength of the treated gel surface to another piece of fresh, moist pigskin was measured again.

[0041] 5. Results: After treatment with ethanol, the adhesion strength of the gel surface decreased to 3.5% ± 1.2% of the initial value, confirming that the surface de-adhesion effect was extremely thorough.

[0042] Example 2: Evaluation of anti-adhesion effect in a rat peritoneal injury model 1. Experimental Group: A standardized bilateral peritoneal abrasion model was established in rats. Silk fibroin-tannic acid gel was applied to the right-sided wound. On the third postoperative day, the exposed gel surface was sprayed with 75% ethanol for 30 seconds after laparotomy.

[0043] 2. Gel control group: The same gel was applied to the left side of the wound, but without ethanol treatment.

[0044] 3. Commercial control group: Another group of animals were treated with commercially available hyaluronic acid anti-adhesion gel (manufacturer ANIKA Therapeutics, SRL, model Hyalobarrier Gel Endo) on the wound.

[0045] 4. An autopsy was performed 14 days postoperatively, and an uninformed observer scored the adhesions in a blinded manner (0-11 points) based on the area and strength of the adhesions.

[0046] 5. Results: The adhesion score of the experimental group (gel + ethanol treatment) was significantly lower than that of the gel control group (p<0.01) and the commercial control group (p<0.05), proving that the surface treatment method of the present invention can effectively transform the adhesive gel into a highly efficient in vivo anti-adhesion barrier.

[0047] Example 3: Evaluation of anti-adhesion and anti-contamination effects in skin wounds 1. In a rat model of full-thickness skin laceration, silk fibroin-gallic acid gel was used to adhere the wound.

[0048] 2. On the second postoperative day, it was observed that the gel surface adhered to the covering gauze. The exposed gel surface of the wound in the experimental group animals was gently wiped with 90% isopropanol for 45 seconds.

[0049] 3. Assessment of anti-dressing adhesion: Continue observation after changing to new gauze. By the 5th postoperative day, the gel in the untreated control group adhered tightly to the gauze, easily causing rebleeding of the wound during dressing changes; while in the experimental group treated with isopropanol, the gel surface was smooth, did not adhere to the gauze, and separated easily.

[0050] 4. Evaluation of anti-fouling adhesion: In a dust control chamber, quantitatively standardized microparticles (particle size ~10µm) were blown onto the surfaces of pre- and post-treatment samples and commercial dressings using an airflow. Untreated gel surfaces exhibited significant dust adhesion, while isopropyl alcohol-treated gel surfaces, similar to commercial silicone dressings, showed only minimal dust adhesion, demonstrating excellent anti-fouling properties.

[0051] 5. Histological analysis: Wound tissue was taken on the 7th day after surgery. H&E staining showed that the degree of wound inflammation in the experimental group after surface treatment was not significantly different from that in the control group, and the epithelialization process was normal, indicating that the treatment method was safe and did not interfere with healing.

[0052] Example 4: Examination of the timing and safety of the processing The effects of different treatment timings (1, 3, and 7 days post-surgery) were investigated in multiple animal models (skin and peritoneum). Results showed that treatment within 1–7 days post-surgery effectively achieved deadhesion. Histological and blood biochemical analyses confirmed that the surface treatment did not cause local or systemic toxicity or accelerate gel degradation, demonstrating the broad clinical application window and high safety of this method.

[0053] Figure 1 This is a schematic diagram of a treatment method for preventing excessive adhesion of silk fibroin-polyphenol adhesive gel according to Example 1 of the present invention: wherein, Figure 1 (A) shows a gel-bonded structure, (B) shows the denaturing treatment of the exposed surface, and (C) shows the formation of a smooth barrier after the surface loses its adhesiveness.

[0054] Depend on Figure 1 It is understood that after treatment with the denaturing agent of this invention, the gel-bonded tissue surface loses adhesion and forms a smooth barrier. The loss of adhesion of the gel-bonded tissue surface is expected to reduce patient pain, reduce nursing difficulty and improve healing quality.

[0055] The advantages of this invention include, but are not limited to: (1) Pioneering new application of functional sequentialization: For the first time, a creative "postoperative treatment" was carried out on the known high-performance adhesive gel, endowing it with the sequential intelligent function of "early strong adhesion and later active anti-adhesion / anti-pollution", which solved the contradictory needs of the same material at different repair stages.

[0056] (2) Achieve dual protection inside and outside: The same treatment method can prevent harmful adhesion between organs / tissues in the body and solve the pain and infection risk of dressing changes on the body surface, greatly expanding the clinical application value of the material.

[0057] (3) The method is simple, safe and effective: with just one simple surface chemical treatment, the adhesion of the gel surface can be reduced by more than 90% in a targeted and permanent manner. Moreover, the treatment is limited to the surface layer and does not affect the stability of the gel body, biocompatibility and normal wound healing.

[0058] (4) Improve patient experience and prognosis: When used on the body surface, it can achieve painless dressing changes and keep the wound environment clean, which is expected to reduce patient pain, reduce nursing difficulty and improve healing quality.

[0059] The above description is merely a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.

Claims

1. A method for preventing excessive adhesion of silk fibroin-polyphenol adhesive gel, wherein the silk fibroin-polyphenol adhesive gel is a hydrogel formed by non-covalent crosslinking of silk fibroin and polyphenolic compounds, characterized in that... The treatment method includes applying an anti-over-adhesion agent to the exposed surface of the silk fibroin-polyphenol adhesive gel after the gel adheres to the tissue wound to prevent unintended adhesion.

2. The treatment method for preventing excessive adhesion of silk fibroin-polyphenol adhesive gel according to claim 1, characterized in that, The anti-excessive adhesion agent is a protein denaturant.

3. The treatment method for preventing excessive adhesion of silk fibroin-polyphenol adhesive gel according to claim 1, characterized in that, The protein denaturant is one or more of ethanol, isopropanol, and acetone.

4. The treatment method for preventing excessive adhesion of silk fibroin-polyphenol adhesive gel according to claim 1, characterized in that, The application method of the anti-excessive adhesion agent is one or more of wiping, spraying, and irrigation.

5. The treatment method for preventing excessive adhesion of silk fibroin-polyphenol adhesive gel according to claim 1, characterized in that, The timing for applying the anti-over-adhesion agent to the exposed surface of the silk fibroin-polyphenol adhesive gel is 24 hours to 14 days after the silk fibroin-polyphenol adhesive gel adheres to the tissue wound.

6. The treatment method for preventing excessive adhesion of silk fibroin-polyphenol adhesive gel according to claim 1, characterized in that, The polyphenolic compounds are one or more of tannic acid, gallic acid, and catechin.

7. An anti-excessive adhesion reagent, characterized in that, In the processing method according to any one of claims 1-6, the anti-excessive adhesion agent is a protein denaturant, and the protein denaturant is one or more of ethanol, isopropanol, and acetone.

8. A medical device for preventing excessive adhesion of silk fibroin-polyphenol adhesive gel, characterized in that, The anti-adhesion medical device includes a liquid storage unit and a quantitative application unit. The liquid storage unit is used to store an anti-adhesion reagent, which is a protein denaturant, and the protein denaturant is one or more of ethanol, isopropanol and acetone. The quantitative application unit is connected to the liquid storage unit and is used to quantitatively apply the anti-adhesion agent to the exposed surface of the silk fibroin-polyphenol adhesive gel after the wound closure is completed.

9. The anti-adhesion medical device for preventing excessive adhesion of silk fibroin-polyphenol adhesive gel according to claim 8, characterized in that, The quantitative application unit is one or more of a spray assembly, a pouring assembly, and a brush assembly.

10. The anti-over-adhesion reagent of claim 7 or the anti-adhesion medical device of claim 8 or 9 for use in preventing unintended adhesion when silk fibroin-polyphenol adhesive gel is used as a medical adhesive.

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