A zeolite-based composite hemostatic agent and its preparation method

Abstract

The present invention relates to a zeolite-based composite hemostatic agent and a preparation method thereof. The zeolite-based composite hemostatic agent comprises: Ag-doped β-zeolite and a fibrin gel coated on the surface of the Ag-doped β-zeolite.

Description

Technical Field

[0001] The invention relates to a zeolite-based composite hemostatic agent and a preparation method thereof, and belongs to the field of hemostatic material preparation. Background Art

[0002] Postoperative bleeding and infection are major causes of death and pose a serious threat to life. Currently, commercial hemostatic agents, represented by zeolites, have been developed to address these issues. Their fundamental hemostatic mechanism lies in the heat released by the zeolite, which triggers microporous zeolite-mediated platelet adhesion, fibrinogen adhesion, and protein coagulation. However, the heat generated by the zeolite inevitably damages adjacent tissues. The efficacy of currently commercialized zeolite-based hemostatic agents is unsatisfactory. Therefore, current research focuses on mitigating the heat release of zeolite-based hemostatic agents. On the other hand, with the development of interdisciplinary research, research on other physical sealants or hemostats to inhibit blood rupture has become a key focus. Significant progress has been made in the development of new hemostatic agents, with various agents employing different hemostatic mechanisms other than thermal effects. Generally, direct hemostatic sealing through physical adhesion or specific binding between the hemostatic agent and tissue or protein has gained greater attention and widespread acceptance to address the primary challenge in hemostatic development (high adhesion to wet and moving tissue). In addition, changes in activated platelets and fibrinogen and adhesion, as well as water absorption-enhanced thrombin concentration, are also considered to design hemostatic agents to terminate hemorrhage. Although satisfactory hemostatic effects have been achieved, the biosafety issues of these new hemostatic agents have not yet been resolved based on clinical translation. At the same time, some carriers or dressings (such as bandages) are also needed to support the active ingredients to avoid their direct toxicity. However, this limits the application scenarios. More importantly, important issues such as actual operation, anti-infection, and whether healing occurs in hemostasis should also be reasonably addressed, but these issues have not received enough attention. Summary of the Invention

[0003] In view of the above problems, the present invention provides a zeolite-based composite hemostatic agent and a preparation method thereof.

[0004] In one aspect, the present invention provides a zeolite-based composite hemostatic agent, comprising: Ag-doped β-zeolite and a fibrin gel coated on the surface of the Ag-doped β-zeolite.

[0005] In this disclosure, fibrin gel acts as a physical barrier covering the Ag-βZ, not only promoting coagulation but also protecting the Ag-βZ from water, reducing solvent heat release, lowering the temperature, and preventing high-temperature damage to surrounding tissues. Furthermore, the doping of Ag ions reduces the exotherm of the zeolite, and the ROS generated by it can kill bacteria, alleviate bacterial infections, promote cell differentiation and proliferation, and accelerate wound healing.

[0006] Preferably, the Ag doping content in the Ag-doped β-zeolite is 0.5 to 4 at%, preferably 1 to 2 at%; the particle size of the Ag-doped β-zeolite is 200 nm to 1000 nm, preferably 200 nm to 500 nm.

[0007] Preferably, the pore size distribution of the Ag-doped β-zeolite is 3 nm to 30 nm; the specific surface area of ​​the Ag-doped β-zeolite is 0.1 to 0.3 cm 2 / g.

[0008] Preferably, the content of the fibrin gel is 2-40 wt%, preferably 10-30 wt%, and more preferably 12-29 wt%.

[0009] In another aspect, the present invention provides a method for preparing a zeolite-based composite hemostat, comprising: mixing Ag-doped β-zeolite and a solution containing fibrinogen and thrombin, and then centrifuging and drying to obtain the zeolite-based composite hemostat.

[0010] In the present invention, the coupling of Ag-doped β-zeolite (Ag-βZ) with fibrinogen (F) / thrombin (T) converts fibrinogen into a fibrin gel. The resulting fibrin gel acts as a physical barrier over the Ag-βZ, not only promoting coagulation but also protecting the Ag-βZ from water, reducing solvent heat release, lowering the temperature, and preventing damage to surrounding tissues caused by high temperatures.

[0011] Preferably, the concentration of fibrinogen in the solution containing fibrinogen and thrombin is 5 to 10 mg / mL, preferably 8 mg / mL;

[0012] The solvent in the solution containing fibrinogen and thrombin is selected from 0.9% physiological saline or deionized water.

[0013] Preferably, the concentration of thrombin in the solution containing fibrinogen and thrombin is 40-60u / mL, preferably 50u / mL; the mixing temperature is 20-40°C, preferably 37°C, and the mixing time is 40-80 minutes, preferably 60 minutes.

[0014] Preferably, the mass ratio of the fibrinogen to Ag β-zeolite is 400 mg: (1-10) g, more preferably 400 mg: (1-3) g.

[0015] Preferably, the washing method is water washing; and the drying method is vacuum drying.

[0016] Preferably, the preparation method of the Ag-doped β-zeolite comprises: mixing β-zeolite powder, silver nitrate and a solvent, and irradiating the mixture with an ultraviolet lamp under stirring to obtain the Ag-doped β-zeolite;

[0017] Preferably, the solvent is at least one of water, methanol, and 0.9% saline;

[0018] Preferably, the ratio of the β-zeolite powder to the solvent is (3-4 g):1 mL; preferably, the mass ratio of the β-zeolite powder to silver nitrate is (25-35):1, preferably 31:1;

[0019] Preferably, the power of the ultraviolet lamp is 200-400W, preferably 300W, and the irradiation time is no more than 50 minutes, preferably no more than 30 minutes.

[0020] Beneficial effects of the present invention:

[0021] (1) The present invention develops a composite hemostatic spray based on Ag doped βZ and F / T to seal postoperative hemorrhage, achieving rapid hemostasis while avoiding thermal damage to surrounding tissues. Simultaneously, the in situ loaded Ag generates ROS in the composite hemostatic agent, achieving antibacterial and anti-infective properties during the hemostasis process.

[0022] (2) Compared with traditional hemostatic agents, Ag-βZ-F / T has the characteristics of simple preparation, low cost, convenient spraying, good effect, good biocompatibility, and strong antibacterial effect, which determines that this high-efficiency composite hemostatic agent has high clinical translation potential. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 TEM (a), SEM (b), and bright field (BF) images (c) of Ag-βZ, as well as merged atomic mapping (d) and detailed atomic mapping (e) of Ag-βZ nanoparticles;

[0024] Figure 2 The pore size distribution of βZ and Ag-βZ nanoparticles (f) and the X-ray photoelectron spectroscopy (XPS) of Ag-βZ nanoparticles (g);

[0025] Figure 3 Low-magnification (upper) and high-magnification scanning electron microscopy images (lower) of Ag-βZ-F / T, in which the Ag-βZ-F / T composite hemostatic agent exhibits a flocculent and interconnected structure;

[0026] Figure 4 A fatal femoral arteriovenous rupture model was established in New Zealand rabbits. The experimental group (N=3) was treated with medical gauze, rapid coagulant, β-zeolite, and composite zeolite, respectively, while the control group received no intervention.

[0027] Figure 5 The histopathology and HE staining of wound tissues in the control group, zeolite group and composite zeolite group, including muscle, blood vessels and nerve tissues;

[0028] Figure 6 The immunohistochemical results of heat shock protein (HSP70) in the control group, β-zeolite group and composite zeolite group;

[0029] Figure 7 In vitro plate antibacterial experiment, there is an obvious antibacterial ring around the composite zeolite group (lower right), but no obvious antibacterial ring around the PBS control group (upper) and the β-zeolite group (lower left);

[0030] Figure 8 The wound healing status was shown in the control group, with obvious redness and swelling on the wound surface, while no abscess was observed on the wound surface in the Ag-βZ-F / T group;

[0031] Figure 9 Pathology and HE staining of wound tissue;

[0032] Figure 10 These are optical microscope images of rabbit injured tissues after CD34 immunohistochemical staining in the control group and the Ag-βZ-F / T group at 3d, 7d, and 14d, respectively;

[0033] Figure 11 Figure 1 shows the coagulation effects of Ag-βZ-F / T, βZ-F / T, Ag-βZ, βZ, and F / T as hemostatic agents in Example 1;

[0034] Figure 12 This is a diagram showing the coagulation effect of the composite hemostatic agent in Examples 1-3. DETAILED DESCRIPTION

[0035] The present invention is further described below through the following embodiments. It should be understood that the following embodiments are only used to illustrate the present invention, rather than to limit the present invention.

[0036] In the present disclosure, the zeolite-based composite hemostatic agent is composed of a mixture of Ag-doped β-zeolite (βZ) and fibrinogen (F) / thrombin (T). All components in this composite Ag-βZ-F / T hemostatic agent have been approved for clinical use and are biosafe.

[0037] In an optional embodiment, Ag-doped β-zeolite (Ag-βZ nanozeolite) is negatively charged (e.g., -33.9 mV, -35.2 mV, and -38.4 mV) at different pH values ​​(pH = 5, 7, and 9), respectively. The negatively charged surface maintains a high colloidal stability and is also conducive to the stimulation, aggregation, and concentration of blood components, such as thrombin and fibrinogen.

[0038] The following is an exemplary description of the preparation method of the zeolite-based composite hemostatic agent.

[0039] Pure white zeolite (βZ) powder is obtained by high temperature calcination.

[0040] Ag was in situ doped into the zeolite by irradiation with a 300W ultraviolet lamp to obtain Ag-doped β-zeolite.

[0041] By coupling Ag-βZ (e.g., 0.1-0.3 g) with fibrinogen (F) / thrombin (T) (e.g., mixing a solution (5 mL) containing fibrinogen (8 mg / mL, F) and thrombin (50 u / mL, T)), a flocculent and interconnected structure is obtained to obtain a composite hemostatic agent (e.g., 12-29 wt%).

[0042] Compared with commercial zeolite-type hemostatic agents, the composite Ag-βZ-F / T hemostatic agent has the advantages of rapid termination of postoperative blood burst, reduced thermal effect, high antibacterial activity and good wound healing effect.

[0043] The following examples are further given to illustrate the present invention in detail. It should also be understood that the following examples are only used to further illustrate the present invention and cannot be understood as limiting the scope of protection of the present invention. Some non-essential improvements and adjustments made by those skilled in the art based on the above content of the present invention all fall within the scope of protection of the present invention. The specific process parameters and the like in the following examples are only examples within a suitable range, that is, those skilled in the art can make selections within a suitable range through the description herein, and are not limited to the specific numerical values ​​exemplified below.

[0044] Example 1

[0045] (1) Synthesis of βZ. After complete dissolution, a mixture containing Na2CO3 (0.14 g), KCl (0.14 g), H2O (9 g) and TeOH (tetraethylammonium hydroxide, 25 wt%, 15 g) was obtained, 5.85 g of silicic acid (H2SiO3) was added, and the mixture was stirred at 40°C for 4 h. Deionized water (3 g) and Na2CO3 (3 g) were then added, and the mixture was stirred at 40°C for another 4 h. The sample was then collected, rinsed twice with water, and then freeze-dried in a vacuum. The dried βZ was placed in a crucible, calcined in an air atmosphere in a muffle furnace at 550°C, and cooled to room temperature to obtain β-zeolite, which was recorded as βZ;

[0046] (2) Synthesis of Ag-βZ. 40 g of βZ was dispersed in a water / methanol mixed solvent of water (1.25 mL) and methanol (10 mL), and then AgNO3 (1.29 g) was dissolved in the dispersion. After that, it was irradiated with a 300 W ultraviolet lamp for 30 min while continuously stirring. Further, it was centrifuged, washed with water and freeze-dried to obtain Ag-doped β-zeolite, which was recorded as Ag-βZ; the Ag doping content in the Ag-doped β-zeolite was 1-2 at%; the particle size of the Ag-doped β-zeolite was 200-1000 nm; the pore size distribution of the Ag-doped β-zeolite was 3 nm to 30 nm; the specific surface area of ​​the Ag-doped β-zeolite was 0.1-0.3 cm 2 / g;

[0047] (3) Synthesis of Ag-βZ-F / T: Ag-βZ (0.1 g) was mixed with a solution (5 mL) containing fibrinogen (8 mg / mL, F) and thrombin (50 u / mL, T). The mixture was centrifuged and vacuum-dried to prepare a zeolite-based composite hemostatic agent, designated Ag-βZ-F / T. The fibrin gel content was 29 wt%.

[0048] Example 2

[0049] The preparation process for the zeolite-based composite hemostatic agent in Example 2 was similar to that of Example 1, with the following differences: Ag-βZ (0.4 g) was mixed with a 5 ml solution containing fibrinogen (8 mg / mL, F) and thrombin (50 u / mL, T). The mixture was centrifuged and vacuum-dried to produce a zeolite-based composite hemostatic agent, designated Ag-βZ-F / T. The fibrin gel content was 9 wt%.

[0050] Example 3

[0051] The preparation process for the zeolite-based composite hemostatic agent in Example 3 was similar to that in Example 1, with the following differences: 1.0 g of Ag-βZ was mixed with 5 mL of a solution containing fibrinogen (8 mg / mL, F) and thrombin (50 u / mL, T). The mixture was centrifuged and vacuum-dried to produce a zeolite-based composite hemostatic agent, designated Ag-βZ-F / T. The fibrin gel content was 3.8 wt%.

[0052] Comparative Example 1

[0053] The Ag-βZ prepared in Example 1 was selected as a comparative sample.

[0054] Comparative Example 2

[0055] The βZ prepared in Example 1 was selected as a comparative sample.

[0056] Comparative Example 3

[0057] The preparation process for the zeolite-based composite hemostatic agent in Comparative Example 3 was similar to that in Example 1, with the following differences: βZ (0.1 g) was mixed with a 5 mL solution containing fibrinogen (8 mg / mL, F) and thrombin (50 u / mL, T). The mixture was centrifuged and vacuum-dried to produce the zeolite-based composite hemostatic agent, designated βZ-F / T. The fibrin gel content was 29 wt%.

[0058] Comparative Example 4

[0059] A solution (5 mL) containing fibrinogen (8 mg / mL, F) and thrombin (50 u / mL, T) was mixed, centrifuged, and vacuum-dried to prepare a fibrin gel, which was recorded as F / T.

[0060] Example 4

[0061] In vitro hemostasis assay: Fresh blood was collected from the ear vein of New Zealand rabbits (2.12 ± 0.23 kg) using blood collection tubes. The control group received no treatment, while the experimental groups received Ag-βZ and Ag-βZ-vc-egf-f / T (10%), respectively. Blood clotting time (CT), prothrombin time (PT), and activated partial thromboplastin time (APTT) were monitored, and Na + , K + 、Cl - and Ca 2+ Ion concentration. It is known that decreased PT (prothrombin time) and APTT (activated partial thromboplastin time) are both seen in a hypercoagulable state.

[0062] The results are as follows:

[0063] The PT and APTT of untreated blood were 8.2±1.2s and 67.9±10.3s, respectively. The PT and APTT of blood treated with Ag-βZ and Ag-βZ-F / T (10%) were significantly shorter than those in the control group (6.8±0.7s and 43.3±5.4s in the Ag-βZ group, and 6.7±0.6s and 19.8±2.5s in the Ag-βZ group). Calcium, as a coagulation factor, promotes the activation of prothrombin and participates in coagulation. 2+ The concentration decreased in both the Ag-βZ group and the Ag-βZ-F / T group (1.52±0.4mmol / L and 1.23±0.6mmol / L, respectively, and the control group was 2.48±0.3mmol / L), with the composite zeolite group showing a more significant decrease. + , K + 、Cl - No significant changes were observed in each group. This indicates that β-zeolite has a certain promoting effect on in vitro blood coagulation, and the promoting effect of Ag-βZ-F / T on in vitro blood coagulation is significantly stronger than that of Ag-βZ.

[0064] Example 5

[0065] In vivo hemostasis experiment: New Zealand rabbits were adaptively fed for 1 week before the experiment. All rabbits were nested for 12 hours and fasted for 6 hours before surgery. Rabbits were anesthetized by intravenous injection of 1% sodium pentobarbital (3 mL / kg) into the ear, and the skin around the right thigh and groin was depilated. Iodine was used to disinfect the skin. The skin was incised sequentially with a scalpel, and the fascia and muscle layers were directly separated to expose and isolate the unilateral femoral vein. The isolated blood vessels were cut to establish a fatal femoral artery and vein separation model. The control group received no intervention. The experimental group was divided into four groups (n=3): medical gauze group, Quikclot group, Ag-βZ group, and Ag-βZ-vc-egf-f / T group. In both the Ag-βZ and Ag-βZ-vc-egf-f / T groups, gauze was applied to stop bleeding after spraying. In each experimental group, gauze was repeatedly removed every 30 seconds after spraying to quickly observe bleeding, monitor wound temperature, and record the hemostasis process, duration, bleeding volume, and fever. Histopathological analysis was then performed to observe the vascular and neural status of blood vessels and muscle tissue, and to analyze inflammatory cell infiltration and thrombosis in the hemostatic wound site.

[0066] The results show that:

[0067] (1) Hemostatic effect: Rabbits in the control group died after 15 minutes, with a bleeding volume of approximately 17.3±2.8 mL / kg. The medical gauze group stopped bleeding in 7 minutes, with a bleeding volume of approximately 4.91±1.2 mL / kg. The Quikclot group and the Ag-βZ group stopped bleeding in about 3 minutes, with bleeding volumes of approximately 1.6±0.8 mL / kg and 1.8±0.6 mL / kg, respectively. The Ag-βZ-F / T group stopped bleeding in about 2 minutes, with a bleeding volume of approximately 1.2±0.5 ml / kg, showing the fastest hemostasis speed and the least bleeding volume.

[0068] like Figure 4 As shown, the blood clot treated with gauze was unstable and soft, and even slight contact with the clot revealed significant bleeding. Zeolite was used to stop bleeding. After cleaning the zeolite, blood clots mixed with β-zeolite were visible in the wounds of the Ag-βZ group. The β-zeolite had a grainy feel and poor visual field. In contrast, the Ag-βZ-F / T group had a clear visual field. The composite zeolite had a gelatinous feel after contact with blood, and the broken ends of blood vessels were visible.

[0069] (2) Tissue thermal effect: The highest temperature in the control group was 40.1°C, the highest temperature in the gauze group was 40.2°C, the highest temperature in the Quikclot group was 45.1°C, and the highest temperature in the Ag-βZ group was about 54.5°C. The highest temperature in the Ag-βZ-F / T group was 43.4°C. Wound tissue pathology HE staining showed that the muscles of the wound surface in the control group were tight, the vascular cavity was congested, a small amount of inflammatory cell infiltration was visible, the nerve structure was normal, and no obvious degeneration was observed. However, the Ag-βZ group had severe heat production and obvious tissue thermal damage. The muscle gap was significantly widened, the vascular cavity was congested, a small amount of inflammatory cell infiltration was visible, the epineurium was thickened, and the fibers were deformed. In contrast, the Ag-βZ-F / T group showed a slight widening of the tissue muscle gap, congestion in the vascular cavity, a small amount of inflammatory cell infiltration was visible, the nerve structure was OK, and no obvious deformation was observed, which was consistent with the control group. Figure 5 shown.

[0070] (3) When an organism is exposed to high temperatures, heat stimulates the synthesis of heat shock proteins to protect the organism itself. Compared with the control group, the expression of HSP70 in the Ag-βZ group was significantly higher, while the expression of HSP70 in the Ag-βZ-F / T group was not significantly increased. Figure 6 shown.

[0071] The above results indicate that Ag-βZ-F / T has a highly effective hemostatic effect and has no obvious thermal damage effect on tissues.

[0072] Example 6

[0073] In vitro plate inhibition test: Candida albicans (fungus), Staphylococcus aureus (Gram-positive bacteria), Escherichia coli (Gram-negative bacteria), or Pseudomonas aeruginosa (Gram-negative bacteria) were inoculated overnight in purple sand medium, tryptic soy broth (TSB) medium, lysing broth (LB) medium, and TSB medium at 37°C. The next day, the optical density of the bacteria was adjusted to 1×10 8 cfu / mL. Evenly spread 0.1 mL of bacterial solution onto the surface of the solid culture substrate. Subsequently, use a sterile pipette tip to drill several wells in the solid culture substrate and add sterile PBS, Ag-βZ, and Ag-βZ-F / T dispersions to the wells. After incubation at 37°C for 24-48 hours, monitor colony growth and determine the zone of inhibition.

[0074] The results showed that no obvious antibacterial ring was observed around the PBS group and the Ag-βZ group, while an antibacterial ring was observed around each bacterial species in the Ag-βZ-F / T group. The widths of the antibacterial rings for Candida albicans, Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa were 1.7 mm ± 0.2 mm, 2.7 ± 0.4 mm, 3.1 ± 0.3 mm, and 2.5 mm ± 0.2 mm, respectively, indicating that the composite zeolite had a significant antibacterial effect on these fungi and Gram-negative and Gram-positive bacteria. Figure 7 shown.

[0075] Example 7

[0076] In vivo antibacterial experiment: New Zealand rabbits were adaptively fed for one week before the experiment. All rabbits were nested for 12 hours and fasted for 6 hours before surgery. They were then randomly divided into two groups (n = 6): a control group (i.e., Ag-βZ) and an experimental group (i.e., Ag-βZ-F / T). Rabbits were anesthetized by intravenous injection of 1% sodium pentobarbital (3 ml / kg), and the skin on both sides of the dorsal spine was depilated. Povidone-iodine was used to disinfect the skin. Using a sterile scalpel, the skin was sequentially incised, followed by direct separation of the fascia and superficial muscle layers. Finally, the femoral vein was exposed and isolated unilaterally, and 0.1 mL of Staphylococcus aureus was sprayed onto the wound surface to establish a bacterial infection model. The control group received a spray of Ag-βZ dispersion, while the Ag-βZ-F / T group received a spray of Ag-βZ-F / T dispersion. After these procedures, the skin surrounding the wound was disinfected again and a sterile dressing was applied. The treated New Zealand rabbits were then kept warm on a thermostat until they recovered, after which they were returned to their cages. Food and water were restored. Three days later, the back wounds were observed and the blood was tested for inflammatory cells.

[0077] The results are as follows:

[0078] (1) In the control group, the wounds were obviously red and swollen, and pus was formed. In the Ag-βZ-F / T group, the wounds were dry, without redness or swelling, and no pus was formed. Figure 8 shown.

[0079] (2) The inflammatory cells in the blood were detected and the numbers of leukocytes, neutrophils and lymphocytes in the Ag-βZ-F / T group were 6.32±2.14×10 9 / L, 3.40±1.46×10 9 / L, 1.66±0.42×10 9 / L) was significantly lower than the corresponding cell number in the control group (16.79±4.21×10 9 / L, 12.02±2.84×10 9 / L, 4.33±1.35×10 9 / L. This suggests that Ag-βZ-F / T has a good antibacterial effect in vivo.

[0080] (3) Tissue H&E staining showed that the interstitial inflammatory cell infiltration was obvious in the control group, while the inflammatory cell infiltration in the Ag-βZ-F / T group was significantly reduced. Figure 9 shown.

[0081] Example 8

[0082] Tissue regeneration and repair assessment: A New Zealand rabbit model of femoral artery and vein separation was established. The experimental group sprayed the wound with Ag-βZ-F / T, while the control group simply covered the wound lightly with gauze, sutured the skin, and disinfected the rabbits. Six New Zealand rabbits from each group were sacrificed 3, 7, and 14 days later. Tissue from the femoral vein and artery in the freed area was obtained for H&E staining to assess endothelial repair.

[0083] The results show:

[0084] The increase of CD34 in the Ag-βZ-F / T group over time was more obvious, indicating that the tissue repair in the Ag-βZ-F / T group was more active, e.g. Figure 10 shown.

[0085] See also Figure 11 In groups AE, Ag-βZ-F / T, βZ-F / T, Ag-βZ, βZ, and F / T in Example 1 were used as hemostatic agents (0.25 ml of blood, 0.01 g of material in each group, and the amount of F / T in group E was equivalent to the doping amount in the materials of groups A and B):

[0086] Group A: Ag-βZ-F / T: The coagulation effect was obvious, the blood was obviously aggregated and coagulated, and there was little residual blood on the tube wall, which was second only to Group E;

[0087] Group B: βZ-F / T: The coagulation effect was good, with obvious blood clots visible. The blood clots were smaller than those in the Ag-βZ-F / T group, and less residual blood was visible on the tube wall.

[0088] Group C: Ag-βZ: The coagulation effect was acceptable, with small blood clots visible and residual blood visible on the tube wall;

[0089] Group D: βZ: The coagulation effect was poor, only very small blood clots were seen, and granular residual blood was visible on the tube wall;

[0090] Group E: F / T: The coagulation effect was obvious, with only a small amount of residual blood on the tube wall that did not flow to the tube opening;

[0091] Overall, Ag-βZ-F / T exhibits the best coagulation effect, approaching that of F / T. Furthermore, due to the Ag component, it also possesses anti-inflammatory and tissue repair abilities. While Ag-βZ also contains Ag, its coagulation properties are inferior. Therefore, Ag-βZ-F / T offers the best overall performance in wound hemostasis and anti-inflammatory applications.

[0092] See also Figure 12 Figures A, B, and C represent the in vitro coagulation effects of the composite zeolite doped with 0.1g Ag-βZ in Example 1, 0.4g Ag-βZ in Example 2, and 1.0g Ag-βZ in Example 3, respectively (all based on 1ml of blood and 0.05g of material). At the same F / T ratio, the lower the amount of doped Ag-βZ and the higher the F / T per unit nanomaterial load, the better the coagulation effect.

Claims

1. A zeolite-based composite hemostatic agent, characterized in that: include: Ag-doped β-zeolite and fibrin gel coated on the surface of Ag-doped β-zeolite; The content of the fibrin gel is 29 wt%; The preparation method of the zeolite-based composite hemostatic agent comprises: mixing Ag-doped β-zeolite and a solution containing fibrinogen and thrombin, and then centrifuging and drying to obtain the zeolite-based composite hemostatic agent; the mass ratio of the fibrinogen to the Ag-doped β-zeolite is 400 mg: (1-3) g.

2. The zeolite-based composite hemostatic agent according to claim 1, characterized in that The Ag doping content in the Ag-doped β-zeolite is 0.5 to 4 at; and the particle size of the Ag-doped β-zeolite is 200 nm to 1000 nm.

3. The zeolite-based composite hemostatic agent according to claim 2, characterized in that The Ag doping content in the Ag-doped β-zeolite is 1 to 2 at %.

4. The zeolite-based composite hemostatic agent according to claim 1, characterized in that The pore size distribution of the Ag-doped β-zeolite is 3 nm to 30 nm; the specific surface area of ​​the Ag-doped β-zeolite is 0.1 to 0.3 cm 2 / g.

5. The zeolite-based composite hemostatic agent according to claim 1, characterized in that The concentration of fibrinogen in the solution containing fibrinogen and thrombin is 5-10 mg / mL.

6. The zeolite-based composite hemostatic agent according to claim 5, characterized in that The concentration of fibrinogen in the solution containing fibrinogen and thrombin is 8 mg / mL; The solvent in the solution containing fibrinogen and thrombin is selected from 0.9% physiological saline or deionized water.

7. The zeolite-based composite hemostatic agent according to claim 1, characterized in that The concentration of thrombin in the solution containing fibrinogen and thrombin is 40-60 u / mL; the mixing temperature is 20-40° C., and the mixing time is 40-80 minutes.

8. The zeolite-based composite hemostatic agent according to claim 7, characterized in that The concentration of thrombin in the solution containing fibrinogen and thrombin is 50 u / mL; the mixing temperature is 37° C., and the mixing time is 60 minutes.

9. The zeolite-based composite hemostatic agent according to claim 1, characterized in that The drying is vacuum drying.

10. The zeolite-based composite hemostatic agent according to claim 1, characterized in that The preparation method of the Ag-doped beta-zeolite comprises: mixing beta-zeolite powder, silver nitrate and a solvent, and irradiating the mixture with an ultraviolet lamp under stirring to obtain the Ag-doped beta-zeolite.

11. The zeolite-based composite hemostatic agent according to claim 10, characterized in that The solvent is at least one of water, methanol, and 0.9% saline.

12. The zeolite-based composite hemostatic agent according to claim 10, characterized in that The ratio of the β-zeolite powder to the solvent is (3-4 g):1 mL.

13. The zeolite-based composite hemostatic agent according to claim 10, characterized in that The mass ratio of the β-zeolite powder to silver nitrate is (25-35):

1.

14. The zeolite-based composite hemostatic agent according to claim 13, characterized in that The mass ratio of the β-zeolite powder to silver nitrate is 31:

1.

15. The zeolite-based composite hemostatic agent according to claim 10, characterized in that The power of the ultraviolet lamp is 200-400W, and the irradiation time does not exceed 50 minutes.

16. The zeolite-based composite hemostatic agent according to claim 10, characterized in that The power of the ultraviolet lamp is 300W, and the irradiation time does not exceed 30 minutes.

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