Rubidium salt hemostatic sponge and its use

Abstract

The present application provides a rubidium salt hemostatic sponge and application thereof, the rubidium salt hemostatic sponge comprises rubidium salt, collagen and plasticizer, and the mass ratio of the rubidium salt, collagen and plasticizer is (1-8) : 100 : (1-5). The rubidium salt hemostatic sponge provided by the present application can be used as a trauma first-aid hemostatic material, has good tissue adhesion, can quickly stop bleeding and promote tissue healing, has no immunogenicity, is sterile, non-toxic and non-irritating, has good biocompatibility and absorbable degradability, and has no side effects on the body. Meanwhile, the hemostatic wound bandage is simple to operate and convenient to use, is suitable for stopping bleeding of gun injuries and explosion injuries in chest, abdomen and other parts of the body, and can be conveniently used for stopping bleeding at the junction of limbs, such as special parts, such as neck, armpit, groin and the like.

Description

Technical Field

[0001] This invention relates to the field of medical materials technology, and in particular to a rubidium salt rapid hemostatic material and its application. Background Technology

[0002] Currently, trauma care relies heavily on traditional, simple hemostatic materials such as tourniquets and triangular bandages. Tourniquets are highly effective in controlling limb bleeding, reducing the rate of major limb bleeding in the US military in Afghanistan and Iraq to 2%–7%. However, non-compressible bleeding from wounds to the trunk and junctional areas, as well as chest and abdominal wounds, remains a major challenge. The US military currently uses CELOX hemostatic dressings made of chitosan, which have proven effective in controlling major bleeding caused by vascular trauma in Afghanistan and Iraq. A US company hopes to develop an X-STAT hemostatic device using biodegradable materials to create hemostatic sponges for controlling life-threatening bleeding from wounds at the groin or axillary junction, as well as bleeding from narrow entry wounds in the arms or legs. The company has submitted an application to the FDA for approval of the X-STAT hemostatic device. Once approved, it could become the preferred equipment for battlefield first aid. However, X-STAT has limitations and is contraindicated in the chest, mediastinum, abdomen, retroperitoneal space, sacroiliac space above the inguinal ligament, and above the clavicle.

[0003] Rubidium is an important rare metal, abundant in my country, and is one of the country's key strategic resources. It holds significant potential for applications in military and medical fields, but its use is not yet widespread. While the application of rubidium compounds in the medical field is receiving increasing attention, its procoagulant activity has not been reported.

[0004] Collagen, as a biomedical material, possesses low immunogenicity, good biocompatibility, biodegradability, and hemostatic properties, leading to its widespread use in tissue engineering, burn treatment, and cosmetic medicine. Collagen is a biopolymer and the most abundant and widely distributed functional protein in animals, accounting for 25%–30% of total protein. It is closely related to tissue formation and maturation, intercellular communication, joint lubrication, wound healing, calcification, blood clotting, and aging. Collagen is also one of the most crucial raw materials in the biotechnology industry, with wide applications in medical materials, cosmetics, and the food industry.

[0005] Collagen and chitosan can be mixed in a certain proportion to make a sponge for hemostasis. Chinese invention patent application CN1387922A discloses a fast-coagulating hemostatic sponge containing collagen and chitosan in a weight ratio of (1-4):(6-12). The collagen used is collagen prepared by enzymatic hydrolysis of bovine or porcine Achilles tendon, or collagen prepared by enzymatic hydrolysis of bovine hide. These are all terrestrial collagen sources from livestock, and their safety is being questioned. Furthermore, hemostatic materials composed of collagen and chitosan do not have a significant hemostatic effect and are not suitable for sudden, large-scale traumatic bleeding. Summary of the Invention

[0006] The first objective of this invention is to provide a rubidium salt hemostatic sponge.

[0007] The second objective of this invention is to provide a method for preparing rubidium salt hemostatic sponges.

[0008] The third objective of this invention is to provide a rubidium salt rapid hemostatic and wound-protecting bandage.

[0009] A fourth objective of this invention is to provide the application of rubidium salts in the preparation of hemostatic materials.

[0010] To achieve the first objective of this invention, this invention provides a rubidium salt hemostatic sponge, which comprises rubidium salt, collagen and plasticizer, wherein the mass ratio of rubidium salt, collagen and plasticizer is (1-8):100:(1-5).

[0011] As a preferred embodiment, the rubidium salt is rubidium tetrafluoroborate or rubidium nitrate.

[0012] As a preferred embodiment, the collagen is fish collagen, which is obtained from fish skin through defatting, decolorization, decellularization and cross-linking treatment, and has not undergone acid hydrolysis and enzymatic hydrolysis.

[0013] As a preferred embodiment, the plasticizer is propylene glycol or glycerol.

[0014] To achieve the second objective of this invention, this invention provides a method for preparing a rubidium salt hemostatic sponge, characterized in that the preparation method includes the following steps:

[0015] (1) Emulsify collagen quickly and dissolve it in a 0.1M-0.5M acetic acid aqueous solution to prepare an aqueous solution with a mass concentration of 1-5%;

[0016] (2) Add rubidium salt and plasticizer according to the above ratio, homogenize at high speed until uniform, freeze dry to make a sponge-like hemostatic material with a thickness of 4-10mm.

[0017] The ratio refers to the mass ratio of rubidium salt, collagen and plasticizer as (1-8):100:(1-5).

[0018] To achieve the third objective of this invention, this invention provides a rubidium salt rapid hemostatic and wound-protecting bandage, characterized in that it is composed of the aforementioned rubidium salt hemostatic sponge and adhesive tape.

[0019] This invention provides the application of the above-mentioned rubidium salt hemostatic sponge in the preparation of hemostatic bandages.

[0020] To achieve the fourth objective of this invention, this invention provides the application of rubidium salts in the preparation of hemostatic materials, wherein the hemostatic materials refer to materials with hemostatic function.

[0021] As a preferred embodiment, the rubidium salt is rubidium tetrafluoroborate or rubidium nitrate.

[0022] Rubidium salts can significantly promote blood clotting and effectively improve the coagulation effect. Fish collagen carries both positive and negative charges, resulting in a significant hemostatic effect and good flexibility, but its water absorption rate is slow. Combining the characteristics of the above-mentioned raw materials, this invention integrates the advantages of the above-mentioned raw materials by adjusting different ratios of rubidium salts and fish collagen, and carrying out appropriate chemical cross-linking reactions under the action of plasticizers, thereby effectively improving the hemostatic effect.

[0023] The advantages of this invention are as follows: The rubidium salt hemostatic sponge provided by this invention can be used as a wound first aid hemostatic material. It has good tissue adhesion, can quickly stop bleeding and promote tissue healing, is non-immunogenic, sterile, non-toxic, and non-irritating, and has good biocompatibility and absorbability and biodegradability, with no side effects on the body. At the same time, the hemostatic wound dressing is simple to operate and convenient to use. It is suitable for hemostasis of gunshot wounds and blast wounds in the chest, abdomen and other parts of the body. It can also be conveniently used at the junction of limbs where tourniquets are difficult to use, such as the neck, armpits, groin and other special areas. It is an ideal individual rapid self-rescue hemostatic material, and can also be used for emergency hemostasis in sudden accidents such as earthquakes, car accidents and terrorist attacks. Detailed Implementation

[0024] The present invention will now be described in detail with reference to specific embodiments. It should be understood that the following specific embodiments are only for the purpose of helping those skilled in the art to understand the present invention, and are not intended to limit the present invention.

[0025] Example 1. Preparation of rubidium salt hemostatic sponge

[0026] The fabrication of rubidium salt hemostatic sponges requires a clean environment meeting the national GMP standard of Class 1,000,000, with a local clean bench meeting Class 100,000 standards. The specific fabrication method is as follows:

[0027] 1. Place 10 grams of fish skin collagen in a stainless steel container, add 600 ml of 0.5 M acetic acid solution, and homogenize using a homogenizer at high speed (10,000 rpm) for 10-20 minutes.

[0028] 2. Add 0.2 g of rubidium tetrafluoroborate and 2 g of glycerol, and homogenize for at least 10 minutes until the solution is completely homogeneous and becomes a translucent colloid.

[0029] 3. Spread the mixture on a tray and freeze-dry it until it becomes spongy.

[0030] 4. Slice the tissue, package it in a medical polyethylene box, and sterilize it with gamma ray irradiation.

[0031] Preparation of fish skin collagen: Fish skin is degreased, decolorized and decellularized by alkali and oxidant, and then thermally cross-linked. It is obtained without acid hydrolysis and enzymatic hydrolysis, thus maintaining the original chemical structure of collagen.

[0032] Example 2. Preparation of rubidium salt hemostatic sponge

[0033] 1. Place 100g of fish skin collagen in a stainless steel container, add 6000ml of 0.5M acetic acid solution, and homogenize at high speed using a homogenizer at 10000 rpm for 10-20 minutes.

[0034] 2. Add 2 grams of rubidium tetrafluoroborate and 40 grams of glycerol, and homogenize for at least 10 minutes until the solution is completely homogeneous and becomes a translucent colloid.

[0035] 3. Spread the mixture on a tray and freeze-dry it until it becomes spongy.

[0036] 4. Slice the tissue, package it in a medical polyethylene box, and sterilize it with gamma ray irradiation.

[0037] The rubidium salt hemostatic sponge is white, spongy, and elastic in sheet shape. The appropriate ratio of rubidium salt, fish collagen, and plasticizer is key to achieving the desired effect; an inappropriate ratio will prevent the preparation of a hemostatic material with good tissue adhesion and rapid hemostasis.

[0038] Example 3. In vitro coagulation test with rubidium salts

[0039] 1. Materials and Methods

[0040] 1.1 Experimental Materials:

[0041] 1.1.1 Laboratory animals: Rabbits

[0042] 1.1.2 Experimental apparatus: syringe, test tube, arterial clamp, arterial cannula, constant temperature water bath, stopwatch.

[0043] 1.1.3 Experimental reagents: rubidium tetrafluoroborate, rubidium nitrate, rubidium carbonate, rubidium sulfate.

[0044] 1.2 Experimental Methods

[0045] 1.2.1 Anesthetize rabbits by injecting 200 g / L ethyl carbamate (urethane) into the marginal ear vein at a dose of 5 ml / kg body weight, and fix the rabbits in a supine position on the rabbit operating table.

[0046] 1.2.2 After cutting open the skin of the neck (remove the rabbit hair from the neck first), separate the external jugular vein and collect 10ml of blood.

[0047] 1.2.3 Dissect one side of the common artery, ligate the head with suture, and clamp the arterial end with an arterial clamp. Use ophthalmic scissors to cut a small "V" shaped incision in the vessel wall near the ligation line, insert the arterial cannula in the centripetal direction, and secure it with suture. This is for blood sampling.

[0048] 1.2.4 Take 5 test tubes, add 8 ml of physiological saline and 2 ml of freshly collected rabbit blood to each tube, and shake well. Tube 1 serves as a blank control. Tubes 2, 3, 4, and 5 are respectively supplemented with 10 mg each of rubidium tetrafluoroborate, rubidium nitrate, rubidium carbonate, and rubidium sulfate, and shake well. Observe whether the blood coagulates and its color change. Record the time until the blood forms a gel-like precipitate.

[0049] 1.2.6 Record the clotting time of each tube.

[0050] 2. The experimental results are shown in Table 1.

[0051] Table 1. Results of coagulation test on samples

[0052]

[0053] The above experimental results show that rubidium tetrafluoroborate has a rapid hemostatic effect, and its color changes immediately from bright red to black upon addition of the reagent. Rubidium nitrate also has a good hemostatic effect. Both of these rubidium salts can be used as hemostatic materials.

[0054] Example 4. Hemostasis and in vivo absorption test of rabbit liver by hemostatic sponge.

[0055] Twelve New Zealand rabbits were used, with six in the experimental group and six in the control group. The rabbits' chest was shaved, disinfected, and then incised to expose the liver. A 1-2 cm incision was made in the liver to create a bleeding model. The rubidium salt hemostatic sponge of this invention was applied to the bleeding site for hemostasis testing, and the hemostasis time was recorded. For the control sample, commercially available absorbable collagen sponge (produced by Shanghai Qisheng Biological Reagent Co., Ltd.) was used, and the hemostasis time was also recorded. The thoracic cavity was then closed, sutured, disinfected, and observed for 20 days. Experimental results: The average hemostasis time of the rubidium salt hemostatic sponge of this invention was 38 seconds, while the hemostasis time of the control sample was 152 seconds. After 20 days, the abdominal cavity was incised, and the placed rubidium salt hemostatic sponge was completely absorbed, with no inflammation or connective tissue formation observed.

[0056] Table 2. Results of rabbit liver hemostasis test

[0057]

[0058] **:p<0.01.

[0059] The results show that the rubidium salt hemostatic sponge of the present invention has a significantly stronger hemostatic effect than existing gelatin hemostatic products, and can be completely absorbed by animals, making it an ideal hemostatic material.

[0060] Example 5. Experimental study on the hemostatic effect of hemostatic sponge on femoral artery trauma in Bama miniature pigs.

[0061] Eighteen Bama miniature pigs were randomly divided into three groups of six each. After one week of captivity, the experiment was conducted to establish a vascular trauma model. The animals were anesthetized via the marginal ear vein with sodium pentobarbital (30 mg / kg). They were fixed supine on the operating table. The femoral artery was disinfected, fully exposed, and dissected for approximately 5 cm. The proximal end of the femoral artery was clamped with an arterial clamp, and the other end was held with a string. A medical arterial catheter sheath (F6 model, 0.3 cm diameter) was used to puncture the exposed femoral artery at the middle of the femoral artery. After the model was established, blood gushed from the puncture site after the arterial clamp was released. Immediately, hemostatic sponges were applied to the bleeding wound. 40 g of the test material was used for each bleeding wound: starch for the negative control, CELOX (UK product) for the positive control, and rubidium salt hemostatic sponges for the experimental group. Hemostasis was achieved by applying pressure for 3–5 minutes, and the hemostatic effect of the wounds in each group was observed and recorded.

[0062] After observation, the peritoneum, muscles, and skin were sutured layer by layer, and the suture surfaces were disinfected with iodine to prevent infection. Aseptic technique was maintained throughout the experiment. Experimental data were processed statistically; non-normally distributed count data were analyzed using the χ² method. 2 The results of the test are shown in Table 2.

[0063] Table 3. Effects on hemostasis of femoral artery trauma in Bama miniature pigs

[0064]

[0065] 1) P<0.05, 2) P<0.01 compared with the starch group.

[0066] Results: Both the rubidium salt hemostatic sponge group and the CELOX group showed significant hemostatic effects within 5 minutes. However, within 3 minutes, the effective rate of the rubidium salt hemostatic sponge group was 83.33%, while that of the CELOX group was 16.67%. The hemostatic effect of the rubidium salt hemostatic sponge group was significantly better than that of the CELOX group.

[0067] The experimental results provide evidence for the application of rapid rubidium salt hemostatic bandages in vascular trauma hemostasis. The bio-rubidium salt hemostatic material used exhibits rapid hemostatic effect, good biocompatibility, no immunogenicity, sterility, non-toxicity, non-irritation, and is absorbable in the body, demonstrating excellent safety. It can be used for emergency hemostasis in combat injuries causing massive bleeding due to vascular trauma, as well as in sudden accidents such as earthquakes, car accidents, and terrorist attacks.

[0068] The above description is only a preferred embodiment of the present invention. It should be noted that those skilled in the art can make several improvements and modifications without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A rubidium salt hemostatic sponge, characterized in that, The rubidium salt hemostatic sponge is composed of rubidium salt, collagen and plasticizer, with a mass ratio of rubidium salt, collagen and plasticizer of 0.2g:10g:2g; The rubidium salt is rubidium tetrafluoroborate, the collagen is fish skin collagen, and the plasticizer is glycerol; The rubidium tetrafluoroborate has a coagulation effect. When 8 mL of physiological saline and 2 mL of rabbit blood are added to a test tube, and 10 mg of the rubidium tetrafluoroborate is added, the coagulation time is 1 minute and 21 seconds. The method for preparing the rubidium salt hemostatic sponge includes: (1) Place 10 grams of fish skin collagen in a stainless steel container, add 600 ml of 0.5 M acetic acid solution, and homogenize at high speed using a homogenizer at 10,000 rpm for 10-20 minutes. (2) Add 0.2 g of the rubidium tetrafluoroborate and 2 g of the glycerol, homogenize for more than 10 minutes until the solution is completely homogeneous and becomes a semi-transparent colloid. (3) Spread the mixture on a tray and freeze-dry it into a sponge-like state; (4) Slice the material, package it in a medical polyethylene box, and sterilize it by gamma irradiation; The method for preparing fish skin collagen includes: treating fish skin with alkali and oxidant to degrease, decolorize and decellularize, and then subjecting it to thermal cross-linking treatment, without acid hydrolysis and enzymatic hydrolysis.

2. A rubidium salt hemostatic sponge, characterized in that, The rubidium salt hemostatic sponge comprises rubidium salt, collagen, and plasticizer, wherein the mass ratio of rubidium salt, collagen, and plasticizer is 2g:100g:40g. The rubidium salt is rubidium tetrafluoroborate, the collagen is fish skin collagen, and the plasticizer is glycerol; The method for preparing the rubidium salt hemostatic sponge includes: (1) Place 100g of fish skin collagen in a stainless steel container, add 6000ml of 0.5M acetic acid solution, and homogenize at high speed using a homogenizer at 10000 rpm for 10-20 minutes. (2) Add 2 grams of the rubidium tetrafluoroborate and 40 grams of the glycerol, homogenize for more than 10 minutes until the solution is completely homogeneous and becomes a semi-transparent colloid. (3) Spread the mixture on a tray and freeze-dry it into a sponge-like state; (4) Slice the material, package it in a medical polyethylene box, and sterilize it by gamma irradiation; The rubidium salt hemostatic sponge is white, spongy, and elastic in shape.

3. A rubidium salt rapid hemostatic and wound-protecting bandage, characterized in that, The rubidium salt rapid hemostatic wound dressing includes adhesive tape and the rubidium salt hemostatic sponge according to any one of claims 1 or 2.

4. The use of the rubidium salt hemostatic sponge according to claim 1 or 2 in the preparation of hemostatic bandages.

5. The application of rubidium salts in the preparation of hemostatic materials, characterized in that, The hemostatic material refers to a material with hemostatic function, and the rubidium salt is rubidium tetrafluoroborate, which has a coagulation effect.

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