Biological glue

Abstract

The invention relates to the technical field of high polymer materials, in particular to biological glue applied to fixation of an esophageal hiatus hernia patch. The biological glue comprises 40 to 60 wt% of fibrinogen, 30 to 50 wt% of a polyethylene glycol polymer, 2 to 8 wt% of an amino-containing small molecule compound, 0.2 to 0.8 wt% of a growth factor and 1 to 3 wt% of glutaraldehyde. The biological glue provided by the embodiment of the invention has excellent mechanical properties and good histocompatibility, and can realize a better patch fixing effect in a hiatus hernia operation, so that postoperative recovery of a patient is guaranteed.

Description

Technical Field

[0001] The invention relates to the technical field of polymer materials, and in particular to a biological glue used for fixing a hiatal hernia patch. Background Art

[0002] During hiatal hernia surgery, commonly used patch fixation methods include suture needles and staplers. However, these traditional fixation methods still have obvious defects. The firmness of the suture method is affected by the surgical operation technique. If the suture is not firm, the patch effect cannot be fully exerted, which may lead to postoperative complications. Although the stapler can provide a strong fixation force, there is a risk of damaging large blood vessels and causing massive bleeding during its use, and foreign objects such as metal nails may be left after the operation, increasing the patient's recovery risk and postoperative complications.

[0003] Although some tissue adhesives, such as fibrin glue and cyanoacrylate medical glue, have been used in related surgeries, they also have certain limitations. Although fibrin glue has good tissue compatibility and is widely used in cardiac surgery and general surgery, its bonding strength is limited and it is difficult to play a good role in areas that need to withstand greater tension. Cyanoacrylate medical glue has the advantage of rapid solidification and can form a strong bond in a short time, but its potential toxicity and irritation, especially when used in internal surgery, may have adverse effects on patient tissues.

[0004] Therefore, it is urgent to develop a safer, stronger and more tissue-compatible biological glue to fill the gap in existing technology, especially in hiatal hernia surgery, to achieve better patch fixation effect and ensure the patient's postoperative recovery. Summary of the invention

[0005] The present invention solves one of the problems of the related art from at least the following aspects.

[0006] The present invention provides a biological glue, which comprises 40-60wt% of fibrinogen, 30-50wt% of polyethylene glycol polymer, 2-8wt% of small molecule compound containing amino group, 0.2-0.8wt% of growth factor and 1-3wt% of glutaraldehyde.

[0007] In some embodiments, the biological glue comprises: 50 wt % fibrinogen, 40 wt % polyethylene glycol polymer, 5 wt % small molecule compound containing amino group, 0.5 wt % growth factor and 2 wt % glutaraldehyde.

[0008] In some embodiments, the small molecule compound containing an amino group is glycine.

[0009] In some embodiments, the polyethylene glycol polymer is selected from one or more of the following: PEG400, PEG600, PEG1000, PEG2000, PEG8000, PEG10000, and PEG20000.

[0010] In some embodiments, the growth factor is epidermal growth factor.

[0011] In some embodiments, the bioglue further comprises 1-3 wt % buffer.

[0012] In some embodiments, the buffer is a phosphate buffer.

[0013] In some embodiments, the bioglue further comprises 0.2-0.8 wt % of a preservative.

[0014] In some embodiments, the preservative is benzyl alcohol.

[0015] Compared with the related art, the embodiments of the present application achieve at least the following beneficial effects:

[0016] 1. Simplify the surgical procedure

[0017] Reduce suturing steps: In operations such as hiatal hernia repair, traditional suturing methods require high surgical skills and a long time. The use of biological glue can directly bond the repair material to the tissue, replacing part or all of the suturing process. For example, for some smaller hernia defects, the use of biological glue can quickly fix the repair material and greatly shorten the operation time. For patients, this can reduce anesthesia time and reduce anesthesia risks, while also reducing the burden of postoperative recovery for patients.

[0018] Flexible application scenarios: Bioglue has advantages in bonding irregularly shaped repair materials and complex anatomical structures. Compared with sutures, it is not limited by the angle of the suture needle and the length of the thread, and can better fit the tissue around the esophageal hiatus and the hernia repair material. For example, when the esophageal hiatus is irregular in shape or the hernia repair material needs to be bonded to the curved diaphragm surface, the bioglue can be evenly applied to the contact surface to ensure that all parts of the repair material can be well fixed.

[0019] 2. Improve the quality of tissue repair

[0020] Promote tissue healing: Some biological glues contain ingredients that promote tissue growth, such as growth factors. These ingredients can stimulate the proliferation and migration of surrounding tissue cells and accelerate the wound healing process. In hiatal hernia surgery, the glue-bonded area can form new tissue faster, allowing the repair material to better integrate with the surrounding tissue. For example, the fibrin in fibrin glue can provide a scaffold for cell adhesion, guide cells such as fibroblasts to grow on its surface, and promote tissue regeneration and repair.

[0021] Reduce tissue damage: Compared with traditional suturing or stapling methods, the use of biological glue avoids puncture and extrusion of tissues. Suture needles and staples may cause complications such as local ischemia of tissues and nerve damage. However, biological glue can fix the repair material while reducing tissue trauma through gentle adhesion, which is beneficial to maintaining tissue integrity and physiological function. For the more fragile tissues around the esophageal hiatus, such as the esophageal mucosa and nerves, this gentle fixation method can reduce the incidence of postoperative complications.

[0022] 3. Reduce the risk of hernia recurrence

[0023] Good bonding effect: If the biological glue can firmly bond the repair material to the tissue, it can effectively prevent the displacement of the repair material after surgery. An important reason for hernia recurrence is that the repair material is displaced after surgery due to various reasons (such as increased abdominal pressure, tissue peristalsis, etc.), causing the hernia defect to reappear. Biological glue can provide uniform adhesion, so that the repair material can be stably fixed at the esophageal hiatus in the long term, thereby reducing the possibility of hernia recurrence.

[0024] Dynamic adaptation to tissue changes: During the postoperative recovery process, the tissue will undergo some physiological changes, such as swelling and contraction. Due to its elasticity and plasticity, biological glue can dynamically adapt to these tissue changes to a certain extent. For example, in the early postoperative period, when the tissue swells due to inflammatory response, the glue can stretch accordingly, and will not tear the tissue or loosen the repair material as easily as rigid suture fixation, thereby maintaining the stability of the bond. DETAILED DESCRIPTION

[0025] The present invention is further described in detail below in conjunction with specific embodiments. The examples provided are only for illustrating the present invention and are not intended to limit the scope of the present invention. The examples provided below can be used as a guide for further improvements by those of ordinary skill in the art and are not intended to limit the present invention in any way.

[0026] In the present invention, the term "comprising" is an open expression, that is, including the contents specified in the present invention, but not excluding other contents.

[0027] The embodiment of the present invention provides a biological glue, which is made based on the following understandings of the inventors:

[0028] The biological glue provided by the embodiment of the present invention can simulate the extracellular matrix components of the human body, and is more likely to be recognized as "self-substance" by the human immune system, thereby reducing inflammatory reactions and rejection phenomena.

[0029] The biological glue provided by the embodiment of the present invention can achieve rapid solidification through a reasonable chemical formula design. For example, some glues containing thrombin or other procoagulant components can rapidly undergo a cross-linking reaction after contacting the tissue surface due to the activation of certain components in the tissue (such as calcium ions, etc.), thereby solidifying in a short time (several seconds to several minutes). This is very important for rapid bonding during surgery, which can reduce operation time and postoperative complications.

[0030] The biological glue provided in the embodiment of the present invention can form a firm connection between the glue and the tissue and the repair material by optimizing the composition and bonding mechanism of the glue. For example, the biological glue forms a covalent bond with the protein or cell components on the surface of the tissue, and combines with the repair material (such as the polyester fiber of the hernia repair patch) through physical adsorption or chemical cross-linking, thereby ensuring that the repair material can be stably fixed to the hernia defect site after surgery.

[0031] The base material is one of the key factors that determine the degree of adhesive strength of the glue. The bioglue provided by the embodiment of the present invention, the fibrin-based glue can well simulate the fibrin clot in the natural coagulation process of the human body and has good affinity with the tissue. In some embodiments, the adhesive strength can be improved by modifying the fibrin, such as adding special chemical groups to enhance its interaction with the tissue and the surface of the repair material.

[0032] Furthermore, some natural or synthetic polymers with high viscosity, such as hyaluronic acid derivatives or polyethylene glycol (PEG) polymers, are used to compound with fibrin. Hyaluronic acid itself is an important component of the extracellular matrix, and its adhesion can be enhanced after chemical modification.

[0033] Adhesion promoter: Adding adhesion promoter to glue can significantly improve the bonding effect. For example, adding some small molecule compounds containing active functional groups such as amino, carboxyl or thiol. These functional groups can form chemical bonds, such as covalent bonds or ionic bonds, with components such as proteins and polysaccharides on the surface of tissues and chemical groups on the surface of repair materials. For example, adding compounds containing amino groups to the glue formula can form amide bonds with carboxyl groups on the surface of tissues, thereby enhancing adhesion. Some bioactive molecules, such as growth factors, can also be added, which can promote cell adhesion, proliferation and migration during tissue repair, and improve the bonding strength of glue from a biological perspective.

[0034] Controlling the cross-linking density of glue: Appropriate cross-linking can increase the cohesion of glue and adhesion to tissue. The cross-linking density of glue can be controlled by adjusting the amount of chemical cross-linking agent used in glue and the cross-linking reaction conditions. For example, for some polymer-based glues, chemical cross-linking agents such as glutaraldehyde (while ensuring a safe dose) or photoinitiators are used for cross-linking. If the cross-linking density is too low, the glue may be too soft and the bonding strength is insufficient; while if the cross-linking density is too high, the glue may become brittle and easy to break, which is not conducive to cell adhesion and tissue healing.

[0035] An embodiment of the present invention provides a biological glue, comprising 40-60wt% (for example, 41wt%, 42wt%, 43wt%, 44wt%, 45wt%, 46wt%, 47wt%, 48wt%, 49wt%, 50wt%, 51wt%, 52wt%, 53wt%, 54wt%, 55wt%, 56wt%, 57wt%, 58wt%, 59wt%) of fibrinogen, 30-50wt% (for example, 31wt%, 32wt%, 33wt%, 34wt%, 35wt%, 36wt%, 37wt%, 38wt%, 39wt%, 40wt%, 41wt%, 42wt%, 43wt%, 44wt%, 45wt%, 46wt%, 47wt%, 48wt%, 49wt%, 50wt%, 51wt%, 52wt%, 53wt%, 54wt%, 55wt%, 56wt%, 57wt%, 58wt%, 59wt%) of fibrinogen, wt%, 44wt%, 45wt%, 46wt%, 47wt%, 48wt%, 49wt%) polyethylene glycol polymers, 2-8wt% (e.g. 2.5wt%, 3wt%, 3.5wt%, 4wt%, 4.5wt%, 5wt%, 5.5wt%, 6wt%, 6.5wt%, 7wt%, 7.5wt%, 8wt%) of small molecule compounds containing amino groups, 0.2-0.8wt% (e.g. 0.3wt%, 0.4wt%, 0.5wt%, 0.6wt%, 0.7wt%, 0.8wt%) of growth factors and 1-3wt% (e.g. 1.5wt%, 2wt%, 2.5wt%) of glutaraldehyde.

[0036] In the embodiment of the present invention, fibrinogen is used as the main component to simulate the natural coagulation process of the human body, forming a fibrin clot, providing a basic bonding framework for the glue, having good affinity with the tissue, guiding cell adhesion and growth, and promoting tissue repair. Polyethylene glycol (PEG) polymers have good biocompatibility and viscosity, can enhance the overall adhesion performance of the glue, help the repair material to better fit the tissue, and its chemical properties are stable, which helps to control the physical properties of the glue. The amino group of the small molecule compound containing amino groups (such as glycine) forms chemical bonds such as amide bonds with functional groups such as carboxyl groups on the surface of the tissue, enhancing the bonding effect of the glue and the tissue, ensuring that the repair material can also be firmly attached under complex physiological environments. Growth factors (such as epidermal growth factor) promote cell adhesion, proliferation and migration during tissue repair, improve the long-term firmness of glue bonding from a biological perspective, and help wound healing and the fusion of repair materials and tissues. Glutaraldehyde reacts with the active groups in the glue components to promote cross-linking formation, control the hardness and elasticity of the glue, and ensure that good bonding effects can be maintained under different tissue states.

[0037] In some embodiments, the bio-glue comprises: 50 wt % fibrinogen, 40 wt % polyethylene glycol polymer, 5 wt % small molecule compound containing amino group, 0.5 wt % growth factor and 2 wt % glutaraldehyde.

[0038] In some embodiments, the polyethylene glycol polymer is selected from one or more of the following: PEG400, PEG600, PEG1000, PEG2000, PEG8000, PEG10000, and PEG20000.

[0039] In some embodiments, the small molecule compound containing an amino group is selected from one or more of the following: glycine.

[0040] In some embodiments, the growth factor is selected from one or more of the following: epidermal growth factor.

[0041] In some embodiments, the bioglue further comprises 1-3 wt % (eg, 1.5 wt %, 2 wt %, 2.5 wt %) of a buffer.

[0042] In some embodiments, the buffer is a phosphate buffer.

[0043] In the embodiment of the present invention, the buffer (such as phosphate buffer) is 2% (adjusting the pH value of the glue to the physiologically suitable range, generally pH 7.0-7.4) Function: maintaining the stability of the glue, ensuring that it functions normally under the physiological environment, and avoiding the influence of pH changes on the activity of the components and the bonding effect.

[0044] In some embodiments, the bioglue further comprises 0.2-0.8 wt % (e.g., 0.3 wt %, 0.4 wt %, 0.5 wt %, 0.6 wt %, 0.7 wt %, 0.8 wt %) of a preservative.

[0045] In some embodiments, the preservative is benzyl alcohol.

[0046] In the embodiment of the present invention, the preservative (such as benzyl alcohol) is 0.5%. The function is to prevent the glue from being contaminated by microorganisms during storage and use, extend the shelf life of the product, and ensure safety in use.

[0047] The following examples are used to further illustrate the advantages and features of the present method, but are not intended to limit the present invention. The experimental methods in the following examples, unless otherwise specified, are conventional methods, and are performed according to the techniques or conditions described in the literature in the art or according to the product instructions.

[0048] The scheme of the present invention will be explained below in conjunction with the embodiments. It will be appreciated by those skilled in the art that the following embodiments are only used to illustrate the present invention and should not be considered as limiting the scope of the present invention. Where specific techniques or conditions are not indicated in the embodiments, the techniques or conditions described in the literature in this area or the product specifications are used. The reagents or instruments used are not indicated by the manufacturer and are all conventional products that can be obtained commercially.

[0049] Unless otherwise specified, the quantitative analysis experiments in the following examples were repeated three times and the results were averaged.

[0050] Example 1

[0051] The components were mixed according to the ratio in Table 1 to prepare bioglue 1-3 and comparative bioglue 1.

[0052] Table 1

[0053]

[0054] Application Example 1

[0055] The bio-glue 1-3 prepared in Example 1 and the comparative bio-glue 1 were respectively applied to fixation of hiatal hernia patches, and the bio-glue 1-3 showed significantly better adhesion and biocompatibility.

[0056] Preparation of the surgical site: Before applying glue, you must ensure that the surgical site is clean, dry, and free of excess blood and tissue fluid. Blood and tissue fluid will dilute the glue and reduce its bonding effect. During hiatal hernia surgery, a suction device can be used to absorb as much fluid as possible from the surgical site, or hemostatic materials can be used to control bleeding to provide a good bonding environment for the glue. In addition, the tissue surface should be properly treated, such as lightly polished or treated with chemical reagents (within a safe range) to increase the roughness of the tissue surface and the exposure of active groups, which is conducive to the adhesion of glue.

[0057] How to apply glue: The correct glue application method is essential for a strong bond. A precisely controlled application device, such as a syringe-type device with a fine nozzle, can be used to evenly apply glue to the repair material and tissue surface. Make sure that the thickness of the glue layer is uniform and moderate, and a thickness between 0.1-0.5 mm is generally appropriate. If the glue layer is too thick, the interior may not be fully cured, affecting the bonding strength; if it is too thin, it may not be able to completely cover the bonding interface, resulting in a weak bond. After applying the glue, appropriate pressure can be used to fit the repair material to the tissue. The pressure can be determined based on the tolerance of the tissue and the characteristics of the glue. It is generally between 0.1-0.3MPa and lasts for about 1-3 minutes to help the glue better fill the tiny gaps between the tissue and the repair material and promote bonding.

[0058] Control of curing conditions: Strictly control the curing conditions according to the type of glue. For some glues that require light curing, ensure that the surgical site can receive light of sufficient intensity and time. For example, use blue light of a specific wavelength (such as 400-500nm) for irradiation, and the irradiation time can be between 30-120 seconds according to the instructions of the glue. For chemically cured glues, pay attention to the effects of factors such as ambient temperature and humidity on the curing speed and quality. Generally speaking, the appropriate temperature range is between 20-37°C. This temperature range is close to human body temperature, which is conducive to the curing reaction of the glue and its bonding with tissues.

[0059] Postoperative Care and Monitoring

[0060] Limit local activities: Before the glue bonding site is completely healed after surgery, try to limit the patient's related activities to reduce the relative displacement between the repair material and the tissue. For patients after hiatal hernia surgery, they should be advised to avoid violent bending, coughing, forceful defecation and other actions that increase abdominal pressure to prevent the displacement of the repair material. It is generally recommended that patients maintain a relatively quiet rest state within 1-2 weeks after surgery, and then gradually increase the amount of activity according to the recovery situation.

[0061] Monitoring adhesion: The firmness of glue adhesion can be monitored through imaging examinations (such as ultrasound, CT, etc.) and clinical symptom observation. Ultrasound examination can observe the fit between the repair material and the tissue in the early postoperative period to check for signs of effusion, separation, etc. CT examination can more clearly show the position of the repair material and its relationship with the surrounding tissue in the later stage. At the same time, closely observe whether the patient has symptoms such as pain, swelling, and vomiting, which may indicate that the repair material is displaced or the adhesion fails. If signs of weak adhesion are found, timely measures should be taken, such as reoperation or the use of other auxiliary fixation methods.

[0062] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, without contradiction.

[0063] Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations of the present invention. A person skilled in the art may change, modify, replace and vary the above embodiments within the scope of the present invention.

Claims

1. A biological glue, characterized in that: The invention comprises 40-60 wt% of fibrinogen, 30-50 wt% of polyethylene glycol polymer, 2-8 wt% of small molecule compound containing amino group, 0.2-0.8 wt% of growth factor and 1-3 wt% of glutaraldehyde.

2. A biological glue according to claim 1, characterized in that: The invention comprises: 50 wt% of fibrinogen, 40 wt% of polyethylene glycol polymer, 5 wt% of small molecule compound containing amino group, 0.5 wt% of growth factor and 2 wt% of glutaraldehyde.

3. The biological glue according to claim 1, characterized in that The small molecule compound containing an amino group is glycine.

4. The biological glue according to claim 1, characterized in that The polyethylene glycol polymer is selected from one or more of the following: PEG400, PEG600, PEG1000, PEG2000, PEG8000, PEG10000, and PEG20000.

5. The biological glue according to claim 1, characterized in that The growth factor is epidermal growth factor.

6. The biological glue according to claim 1, characterized in that Also contains 1-3 wt% buffer.

7. The biological glue according to claim 6, characterized in that The buffer is a phosphate buffer.

8. The biological glue according to claim 1, characterized in that It also contains 0.2-0.8 wt% of a preservative.

9. The biological glue according to claim 8, characterized in that The preservative is benzyl alcohol.

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