Colloidal gel material with hemostasis and wet tissue adhesion functions as well as preparation method and application of colloidal gel material
Through colloidal gel materials composed of gelatin microgel particles, negatively charged polymer particles and inorganic nanoparticles, the problems of difficulty in hemostasis and poor adhesion of wet tissue are solved, rapid hemostasis, strong adhesion and good biocompatibility are achieved, and surgical risks and complications are reduced.
Patent Information
- Application Number
- CN202510384281.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-03-28
- Publication Date
- 2025-08-01
AI Technical Summary
The existing hemostasis and tissue adhesion materials have problems such as difficulty in hemostasis, poor adhesion effect in wet tissue environments, and insufficient biocompatibility in surgical and trauma treatment, resulting in high surgical risks and many postoperative complications.
Colloidal gel material composed of gelatin microgel particles, negatively charged polymer particles and inorganic nanoparticles is used to enhance hemostatic and adhesion properties through electrostatic interactions and network structures, and bioactive molecules are added to promote tissue repair.
It achieves rapid hemostasis, strong adhesion on the surface of wet tissue, good biocompatibility and degradability, reduces surgical risks and postoperative complications, and improves treatment effect and safety.
Smart Images
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Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of biomedical materials, and particularly relates to a colloidal gel material with hemostatic and wet tissue adhesion functions and a preparation method thereof. In many medical fields such as surgical operations, wound repair, and tissue engineering, the present invention can quickly and effectively stop bleeding and achieve reliable tissue adhesion. Background Art
[0002] In the field of modern medicine, the problems of hemostasis and tissue adhesion during surgical operations and trauma treatments have always been key challenges in clinical practice, which are directly related to the treatment effect and recovery process of patients. As the core means to solve these problems, the performance of biomedical materials has a decisive impact on the medical quality.
[0003] Surgical operation, as an important means to treat various diseases, is widely carried out in each department. In cardiac surgery, the delicate operation of cardiac blood vessels is extremely likely to cause bleeding. Due to the beating of the heart and the continuous flow of blood, it is extremely difficult to stop bleeding. Once the bleeding cannot be controlled in time, it will not only interfere with the surgical operation, make the surgical field of vision blurred, increase the operation time and risk, but also may cause serious complications such as myocardial ischemia, arrhythmia, and even cardiac arrest, posing a great threat to the life of the patient. In liver surgery, the liver tissue is fragile and has rich blood supply. Conventional hemostatic methods, such as compression with hemostatic gauze, often cannot quickly stop a large amount of bleeding, and may cause secondary damage when the gauze is removed due to adhesion to the tissue. According to statistics, the surgical risk caused by bleeding in liver surgery increases by about 30%, and the incidence of postoperative complications also increases significantly.
[0004] In terms of trauma treatment, whether it is accidental trauma in daily life or severe trauma on the battlefield, timely and effective hemostasis and wound closure are the keys to preventing infection and promoting healing. For example, in traumas caused by traffic accidents or natural disasters, the injured may have multiple open wounds and the bleeding situation is complex. Traditional hemostatic materials, such as ordinary bandages, have limited effects in the face of a large amount of bleeding and complex wound surfaces, cannot quickly stop bleeding and close the wound, are easy to cause wound infection, prolong the healing time, and may even cause serious consequences such as septicemia.
[0005] At the same time, achieving reliable tissue adhesion in a wet tissue environment is another difficult problem. In surgeries or traumas in parts such as the oral cavity, nasal cavity, and gastrointestinal tract, due to the wet surface of the tissue, conventional tissue adhesion materials are difficult to achieve good adhesion effects. For example, in oral surgery, the presence of saliva makes ordinary adhesives unable to firmly adhere to the tissue, affecting the healing and repair of the wound. In gastrointestinal surgery, the secretion of digestive juices will also interfere with the action of tissue adhesion materials, increasing the surgical difficulty and the risk of postoperative complications.
[0006] From a biocompatibility perspective, there are obvious deficiencies in some existing hemostatic and tissue adhesion materials. Some traditional materials may trigger immune responses in the body, leading to adverse reactions such as inflammation and allergies. For example, certain hemostatic materials containing chemical cross-linking agents may cause local tissue inflammation in the body, delaying the wound healing process and even potentially leading to long-term complications such as tissue fibrosis. According to clinical research reports, approximately 10%-15% of patients have experienced varying degrees of inflammatory reactions after using certain traditional hemostatic materials.
[0007] In addition, with the aggravation of the aging society and the improvement of people's requirements for quality of life, higher expectations are placed on the performance of biomedical materials. Patients hope to use safer and more effective materials to reduce pain and risks during the treatment process and accelerate the recovery process.
[0008] In summary, it is urgent to develop a colloidal gel material that can quickly stop bleeding, has strong adhesion on the surface of wet tissues, and has good biocompatibility. This not only helps to improve the success rate of surgery and reduce the incidence of postoperative complications, but also provides a more effective treatment method for trauma patients, with important clinical significance and social value. Summary of the Invention
[0009] The colloidal gel material of the present invention is mainly composed of gelatin microgel particles, negatively charged polymer particles (such as hyaluronic acid, alginic acid, etc.), inorganic nanoparticles (such as bioactive glass particles, hydroxyapatite nanoparticles), and optionally bioactive molecules. The gelatin microgel particles provide a basic gel framework and certain biocompatibility; the negatively charged polymer particles interact electrostatically with the gelatin microgel particles to enhance the stability and adhesion performance of the gel; the inorganic nanoparticles can further improve the mechanical properties and hemostatic effect of the gel; bioactive molecules (such as coagulation factors, growth factors, etc.) can promote tissue repair and healing.
[0010] The present invention is prepared in the following manner:
[0011] Preparation of gelatin microgel particles: Dissolve gelatin in deionized water, heat to 40-60°C, stir to completely dissolve it, and prepare a gelatin aqueous solution with a concentration of 3-8 w / v%. Adjust the pH value of the solution to 3-5 or 9-11, slowly add 3-5 times the volume of the solution of ethanol, continuously stir for 30-60 minutes to form a dispersion of gelatin microgel particles. Add the cross-linking agent glutaraldehyde to the dispersion, and the molar ratio of glutaraldehyde to the amino groups in gelatin is 0.5-2. Cross-link at room temperature for 6-10 hours. After the reaction, remove the unreacted substances by centrifugation (5000-8000 rpm, 15-30 minutes) and washing with deionized water multiple times to obtain gelatin microgel particles.
[0012] Preparation of negatively charged polymer particle dispersion: Dissolve negatively charged polymer particles such as hyaluronic acid particles or alginic acid particles in deionized water to prepare a solution with a concentration of 1-3 w / v%, and stir evenly for standby.
[0013] Preparation of inorganic nanoparticle dispersion: Disperse silica nanoparticles or hydroxyapatite nanoparticles in deionized water, and make them uniformly dispersed by ultrasonic treatment to form a dispersion with a concentration of 0.5-2 w / v%.
[0014] Preparation of colloidal gel: Mix the gelatin microgel particle dispersion, negatively charged polymer particle dispersion, and inorganic nanoparticle dispersion according to a volume ratio of (2-5):(1-3):(1-2), and stir evenly. Then add an appropriate amount of pH regulator (such as hydrochloric acid or sodium hydroxide) to adjust the pH value of the mixed solution to 7.0-7.4, and stir for 10-20 minutes to form a uniform colloidal gel. If a bioactive molecule needs to be added, it can be dissolved in an appropriate amount of buffer solution at this time, added to the above mixed solution, and continue to stir for 5-10 minutes.
[0015] Compared with the prior art, the present invention has the following excellent effects:
[0016] 1. The colloidal gel material of the present invention can rapidly promote blood coagulation. Its unique composition, such as gelatin microgel particles and inorganic nanoparticles, can provide abundant coagulation sites, accelerate platelet aggregation and activation of coagulation factors, so as to achieve hemostasis in a short time.
[0017] 2. The present invention has excellent adhesion effect on the surface of wet tissues. The negatively charged polymer particles in the colloidal gel material can interact with components such as proteins and polysaccharides on the tissue surface to form physical and chemical adsorption, achieving strong adhesion. At the same time, the network structure of gelatin microgel particles can enhance the stability of adhesion.
[0018] 3. The main components such as gelatin and hyaluronic acid used in the present invention have good biocompatibility and will not cause obvious immune reactions. After cytotoxicity testing, the colloidal gel material has little effect on the cell survival rate, meeting the safety requirements of biomedical materials.
[0019] 4. The product of the present invention has excellent degradability. In the in vivo environment, the colloidal gel material can be gradually degraded, and its degradation products can be metabolized and absorbed by the human body without residue in the body. Through in vitro degradation experiments, it is determined that most of the material can be degraded within 2-4 weeks. Brief Description of the Drawings
[0020] In order to more clearly illustrate the embodiments of the present invention, the drawings related to the embodiments will be briefly introduced below.
[0021] Figure 1 It is a transmission electron microscope image of the gelatin nanoparticles prepared by the method of the present invention;
[0022] Figure 2 It is a transmission electron microscope image of the inorganic bioactive glass particles used in the composite process;
[0023] Figure 3 It is a transmission electron microscope image of the composite material of gelatin nanoparticles and inorganic bioactive glass particles with a mass ratio of 9:1;
[0024] Figure 4 It is the change process of the storage (G') and loss (G'') of the gelatin nanoparticle bulk gel over time;
[0025] Figure 5 The change of the storage (G') and loss (G'') of the colloidal gel composed of gelatin nanoparticles and inorganic materials with a mass ratio of 9:1 over time;
[0026] Figure 6 It is the shear-thinning property of the bioactive glass / gelatin composite colloidal gel prepared in Example 1 under the action of an external force;
[0027] Figure 7 It is the shear-thinning property of the bioactive glass / gelatin composite colloidal gel prepared in Example 2 under the action of an external force;
[0028] Figure 8 It is the injectability of the bioactive glass / gelatin composite colloidal gel prepared in Example 2;
[0029] Figure 9 It is the self-healing property of the bioactive glass / gelatin composite colloidal gel prepared in Example 2 Detailed implementation manners
[0030] The following will describe various embodiments and specific implementations in detail. These embodiments should not be construed as limiting the scope of the present patent application in any way, and changes and modifications can be made without departing from the essence and scope of the present invention. In addition, only some end uses are discussed herein, but end uses not specifically described herein are also included within the scope of this application. Therefore, the scope of this patent application should be determined by the claims.
[0031] Example 1
[0032] Dissolve 5 g of gelatin in 100 mL of deionized water, heat to 50 °C and stir until completely dissolved to prepare a 5 w / v% gelatin aqueous solution. Adjust the pH value to 4 with hydrochloric acid, slowly add 400 mL of ethanol, and continuously stir for 45 minutes. Add glutaraldehyde (25 wt% aqueous solution) so that the molar ratio of glutaraldehyde to amino groups in gelatin is 1, and carry out a cross-linking reaction at room temperature for 8 hours. Centrifuge (6000 rpm, 20 minutes) and wash multiple times to obtain gelatin microgel particles, as Figure 1 .
[0033] Dissolve 2 g of hyaluronic acid particles in 200 mL of deionized water, stir evenly to prepare a 1 w / v% hyaluronic acid solution.
[0034] Take 30 mL of the gelatin microgel particle dispersion, 20 mL of the hyaluronic acid dispersion and 15 mL of the bioactive glass nanoparticle dispersion, mix them and stir evenly. Adjust the pH value to 7.2 with sodium hydroxide and stir for 15 minutes to obtain a colloidal gel.
[0035] Measure the viscoelasticity change of its modulus with time through a rheometer, and the results are as Figure 4 shown. As the powder mass ratio in the prepared gel material increases, the storage modulus of the material gradually increases, indicating that the material has excellent properties with controllable modulus. Through Figure 6 shown, after the material passes through the shear thinning test, the viscosity of the material will decrease significantly, which proves that the gelatin colloidal gel material has good shear thinning effect and good injectability.
[0036] Example 2
[0037] Weigh 6 g of gelatin, add 120 mL of deionized water, heat and stir to dissolve at 45 °C to prepare a 5 w / v% gelatin aqueous solution. Adjust the pH value to 10 with sodium hydroxide, add 450 mL of ethanol, and stir for 50 minutes. Add glutaraldehyde (25 wt% aqueous solution) so that the molar ratio of glutaraldehyde to amino groups in gelatin is 1.5, and carry out a cross-linking reaction for 7 hours. Centrifuge (7000 rpm, 25 minutes) and wash to obtain gelatin microgel particles.
[0038] Dissolve 3 g of alginic acid particles in 300 mL of deionized water and stir to form a 1 w / v% alginic acid particle solution.
[0039] Disperse 1.5 g of bioactive glass nanoparticles in 150 mL of deionized water and ultrasonically disperse for 40 minutes to obtain a 1 w / v% bioactive glass particle dispersion, as Figure 2 .
[0040] Preparation of colloidal gel: Mix 40 mL of the gelatin microgel particle dispersion, 25 mL of the alginic acid particle dispersion and 20 mL of the bioactive glass nanoparticle dispersion, and stir evenly, asFigure 3 Adjust the pH value to 7.3 with hydrochloric acid and stir for 18 minutes to obtain a colloidal gel.
[0041] Measure the change of its modulus with time and the viscoelasticity change with time through a rheometer. The results are as Figure 5 shown. As the powder mass ratio in the prepared gel material increases, the storage modulus of the material gradually increases, indicating that the material has excellent properties with controllable modulus. Through Figure 7 as shown, after the material passes through the shear thinning test, the viscosity of the material will decrease significantly, which proves that the composite material also has good shear thinning effect and good injection performance. Through Figure 8 it can be clearly seen that the material can be extruded into filaments from the syringe needle, showing good extrudability. Figure 9 It can be seen that although the material is cut in half, it can also achieve good self-healing through dynamic intermolecular interactions.
[0042] Performance Test
[0043] Hemostasis performance test: Using a rat liver bleeding model, create a standardized wound on the liver surface, and use the colloidal gel materials prepared in Example 1 and Example 2 and traditional hemostatic gauze for hemostasis treatment respectively. Record the hemostasis time. The results show that the average hemostasis times of the colloidal gel materials in Example 1 and Example 2 are 5 - 8 minutes and 6 - 9 minutes respectively, while the average hemostasis time of the traditional hemostatic gauze is 12 - 15 minutes.
[0044] Wet tissue adhesion performance test: Select fresh pig liver tissue, apply the colloidal gel materials prepared in Example 1 and Example 2 and commercially available tissue adhesion materials on the tissue surface respectively, then stick the two pieces of tissue together, apply a certain pressure and maintain it for a period of time. Measure the adhesion strength through a tensile experiment. The adhesion strength of the colloidal gel material in Example 1 reaches 5 - 7 kPa, the adhesion strength of Example 2 is 6 - 8 kPa, while the adhesion strength of the commercially available tissue adhesion material is only 2 - 4 kPa.
[0045] Beneficial Effects
[0046] 1. The colloidal gel material of the present invention can stop bleeding quickly, effectively shorten the operation time, reduce the patient's blood loss, and reduce the operation risk.
[0047] 2. It has excellent adhesion performance on the wet tissue surface, which can ensure the stable adhesion of tissues during the operation, reduce the risk of tissue displacement and bleeding, and promote wound healing.
[0048] 3. Good biocompatibility and degradability reduce the risk of immune response and in - vivo residue, and improve the patient's safety and recovery effect.
[0049] 4. The preparation method is simple, easy to operate and control, suitable for large-scale production, providing a new type of highly efficient and safe biomedical material for clinical applications.
Claims
1. A colloidal gel material with both hemostatic and wet tissue adhesion functions, characterized in that, It mainly consists of gelatin microgel particles, negatively charged polymer particles, inorganic nanoparticles and bioactive molecules; the gelatin microgel particles provide a gel framework and certain biocompatibility, the negatively charged polymer particles enhance the gel stability and adhesion performance through electrostatic interaction with the gelatin microgel particles, the inorganic nanoparticles improve the gel mechanical properties and hemostatic effect, and the bioactive molecules promote tissue repair and healing; wherein, the negatively charged polymer particles are selected from one or more of hyaluronic acid and alginic acid, and the inorganic nanoparticles are selected from one or more of bioactive glass nanoparticles and hydroxyapatite nanoparticles.
2. The colloidal gel material according to claim 1, wherein The preparation method of the gelatin microgel particles includes: dissolving gelatin in deionized water, heating to 40 - 60 °C and stirring until completely dissolved to prepare a gelatin aqueous solution with a concentration of 3 - 8 w / v%; adjusting the pH value of the solution to 3 - 5 or 9 - 11, slowly adding ethanol with a volume 3 - 5 times that of the solution, and continuously stirring for 30 - 60 minutes to form a dispersion of gelatin microgel particles; adding a crosslinking agent glutaraldehyde to the dispersion, the molar ratio of glutaraldehyde to the amino groups in gelatin is 0.5 - 2, and carrying out a crosslinking reaction at room temperature for 6 - 10 hours; after the reaction is completed, removing the unreacted substances by centrifugation (5000 - 8000 rpm, 15 - 30 minutes) and washing with deionized water multiple times to obtain the gelatin microgel particles.
3. The colloidal gel material according to claim 1, characterized in that, The preparation method of the dispersion of the negatively charged polymer particles is: dissolving the negatively charged polymer in deionized water to prepare a solution with a concentration of 1 - 3 w / v%, and stirring evenly for standby.
4. The colloidal gel material according to claim 1, wherein, The preparation method of the dispersion of the inorganic nanoparticles is: dispersing the inorganic nanoparticles in deionized water and making them evenly dispersed by ultrasonic treatment to form a dispersion with a concentration of 0.5 - 2 w / v%.
5. The colloidal gel material according to claim 1, wherein The preparation method of the colloidal gel is: mixing the dispersion of gelatin microgel particles, the dispersion of negatively charged polymer particles and the dispersion of inorganic nanoparticles according to a volume ratio of (2 - 5):(1 - 3):(1 - 2), and stirring evenly; then adding an appropriate amount of pH regulator to adjust the pH value of the mixed solution to 7.0 - 7.4, and stirring for 10 - 20 minutes to form a uniform colloidal gel; if a bioactive molecule is added, it is dissolved in an appropriate amount of buffer solution and added to the above mixed solution, and stirring is continued for 5 - 10 minutes.
6. The colloidal gel material according to claim 1, wherein In the simulated surgical trauma experiment, its average hemostasis time is shortened by 30 - 50% compared with traditional hemostatic materials.
7. The colloidal gel material according to claim 1, characterized in that, In the adhesion experiment on wet liver tissue, its adhesion strength is increased by 2 - 3 times compared with the currently clinically commonly used tissue adhesion materials.
8. The colloidal gel material according to claim 1, characterized in that, After cytotoxicity testing, it has a very small impact on cell viability and meets the safety requirements of biomedical materials.
9. The colloidal gel material according to claim 1, characterized in that, In the in - vivo environment, it can be mostly degraded within 2 - 4 weeks, and the degradation products can be metabolized and absorbed by the human body without residue in the body.
10. Use of the colloidal gel material according to any one of claims 1 - 9 in the preparation of biomedical materials for surgical hemostasis, wound repair, promoting tissue adhesion and healing in tissue engineering.