Absorbable gastrointestinal tract tissue sealants and methods of use thereof

Abstract

The invention relates to an absorbable gastrointestinal tract tissue sealant. The absorbable gastrointestinal tract tissue sealant comprises a first component and a second component, wherein the second composition and the first component are mixed to react to form hydrogel; the first component is a mixed solution and comprises a colloidal substance, a biological adhesion material, an ion-sensitive gel material and the balance of a buffer solution; the second component is a water-soluble calcium solution, and the PH of the water-soluble calcium solution is adjusted to 1.8-2.2 with hydrochloric acid; the application method comprises the following steps: S1, uniformly spraying the first component on a target tissue; s2, immediately spraying a second component after the spraying of the first component is finished, spraying the second component and covering the first component, and enabling the first component and the second component to generate a cross-linking reaction to form flaky hydrogel; the invention has the following beneficial effects: the biodegradable material has good degradability, is safe and harmless to human body, can bear corrosion of acidic fluid, is soft and smooth enough, can be matched with tissues, and does not interfere with normal physiological functions of intestines and stomach.

Description

Technical Field

[0001] The present invention relates to the field of biomaterials, in particular to an absorbable gastrointestinal tissue sealant and a use method thereof. Background Art

[0002] Gastrointestinal surgery is a common surgical procedure, with approximately 14 million people undergoing it each year worldwide. These surgeries involve the removal of abnormal or unwanted tissue and the reconnection of healthy remaining tissue, usually secured with sutures or staples. However, there is the most feared complication - postoperative anastomotic leakage. In the days following a successful operation, digestive juices or microbiologically active fluids may leak from the site that was reconnected with sutures or staples, leading to infection and other complications. Anastomotic leakage may delay the patient's recovery process. When digestive juices or microbiologically active fluids leak into the abdominal cavity, it can cause an inflammatory response and infection, increasing the risk of postoperative complications. Patients may require additional treatments such as antibiotic therapy, drainage tube insertion or even reoperation to repair the leak, which can prolong hospital stay and recovery.

[0003] Gastrointestinal complications, such as bleeding and perforation, can occur naturally, as in the case of advanced ulcers, or as a result of lesions caused by interventional procedures such as polyp or tumor removal. The current solution to control these postoperative complications is closure via metal clips, which were developed in 1975 and are challenging, expensive, time-consuming, and rarely prevent postoperative bleeding. Currently, there is no material-based solution that can prevent postoperative complications, as the best alternatives achieve mucosal adhesion only during active bleeding or for only less than 1-2 days.

[0004] In order to reduce the occurrence of anastomotic leakage, surgeons use the most advanced techniques and equipment to ensure the stability of the anastomosis during surgery. Hydrogel tissue sealants are widely considered for covering and repairing damaged suture areas. Compared with conventional methods, tissue sealants are easy to apply and minimally invasive, which can reduce surgical time and procedures, improve patient safety and achieve rapid recovery, and have become a research hotspot in recent years.

[0005] Since gastrointestinal motility is one of the important functions of the digestive system, restoring motility after surgery is crucial for the patient's recovery. Existing hydrogel tissue sealants will affect the function of gastrointestinal motility while achieving sealing. Some hydrogel tissue sealants have poor degradation ability, which has a certain impact on the later recovery of the human body. It is necessary to consider developing a gastrointestinal tissue sealant that does not affect the function of gastrointestinal motility and is also degradable. Summary of the invention

[0006] The purpose of the present invention is to provide an absorbable gastrointestinal tissue sealant and a method of using the same. In addition to having good degradability, being safe and harmless to the human body, and being able to withstand corrosion from acidic fluids, the absorbable gastrointestinal tissue sealant is also soft and compliant enough to match the tissue and prevent stenosis or lumen occlusion. The components of the tissue sealant will not interfere with the normal physiological function of the gastrointestinal tract in the human body, will not hinder gastrointestinal peristalsis, and can effectively prevent intestinal anastomotic leakage and ensure tissue wound healing.

[0007] The present invention is implemented by the following technical scheme: an absorbable gastrointestinal tissue sealant comprises a first component and a second component; wherein the second component and the first component are mixed and reacted to form a hydrogel;

[0008] The first component is a mixed solution, including a colloidal substance, a bioadhesive material, an ion-sensitive gel material, and a residual buffer solution; the second component is a water-soluble calcium solution, the pH of the water-soluble calcium solution is adjusted with a hydrochloric acid solution, and the pH of the adjusted calcium chloride solution is between 1.8 and 2.2;

[0009] In terms of weight ratio, in the first component, 27-30 parts of colloidal substances, 0.75-2 parts of bioadhesive materials, and 0.75-3 parts of ion-sensitive gel materials are added to 150 parts of buffer solution; the remainder is buffer solution.

[0010] A method for using an absorbable gastrointestinal tissue sealant comprises the following steps

[0011] Step 1, spraying the first component evenly on the target tissue;

[0012] Step 2, spraying the second component immediately after the first component is sprayed, spraying the second component and covering the first component, so that the first component and the second component undergo a cross-linking reaction to form a sheet-like hydrogel, thereby preventing tissue fluid leakage;

[0013] The wound area is 1cm 2 For example, the first component is sprayed at a dose of 0.2-0.25 times the wound area, i.e., an area of ​​1 cm 2 Spray 0.2-0.25mL of the first component on the wound surface. Immediately after spraying the first component, spray the second component. Spray the second component in an amount of 0.3-0.5 times the wound surface area, i.e. 1cm 2 Spray 0.3-0.5mL of the second component on the wound surface.

[0014] Compared with the previous technology, the beneficial effects of the present invention are:

[0015] 1. They are all made of degradable materials, which can ensure that they will be degraded in the body in the later stage and reduce clinical risks.

[0016] 2. The method adopts a segmented approach. First, the first component is sprayed to make it adhere to the surface of the gastrointestinal tissue. Subsequently, the second component is sprayed to make the first and second components undergo a cross-linking reaction to form a sheet-like hydrogel, which plays a role in preventing tissue fluid leakage. Since the first component has completely penetrated the gastrointestinal tissue, it can effectively avoid the situation where gastrointestinal peristalsis causes loss of adhesion. DETAILED DESCRIPTION

[0017] The present invention is described in detail below:

[0018] An absorbable gastrointestinal tissue sealant comprises a first component and a second component; wherein the second component and the first component are mixed and reacted to form a hydrogel;

[0019] The first component is a mixed solution, including colloidal substances, bioadhesive materials, ion-sensitive gel materials, and the remainder buffer; the second component is a water-soluble calcium solution, the pH of the water-soluble calcium solution is adjusted with a 12.1 mol / L hydrochloric acid solution, and the pH of the adjusted calcium chloride solution is between 1.8 and 2.2.

[0020] Appropriate acidity reduces the degree of carboxyl group ionization, reduces the electrostatic repulsion between molecular chains, and makes the formed hydrogel more uniform in structure.

[0021] In terms of weight ratio, in the first component, 27-30 parts of colloidal substances, 0.75-2 parts of bioadhesive materials, and 0.75-3 parts of ion-sensitive gel materials are added to 150 parts of buffer solution; the remainder is buffer solution.

[0022] The colloidal substance is one or more of poloxamer, cellulose acetate phthalate, and acid-soluble collagen. The colloidal substance is preferably poloxamer, specifically poloxamer 407. Poloxamer has unique temperature sensitivity, and within a specific temperature range, poloxamer can promote the sol-gel transition of the hydrogel. This temperature sensitivity provides more flexibility and controllability for the application of the hydrogel.

[0023] The bioadhesive material is any one of carboxymethyl cellulose, carboxymethyl chitosan, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polylysine, mussel adhesive protein, and sodium hyaluronate. The bioadhesive material is preferably hydroxypropyl methyl cellulose. The viscosity of the hydrogel can be significantly increased, which helps the hydrogel to better maintain its shape during use, is not easy to flow or disperse, and ensures that it can stably stay at the application site.

[0024] The ion-sensitive gel material is one or more of sodium alginate, potassium alginate, amidated low-methoxy pectin, and deacetylated gellan gum. The ion-sensitive gel material is sodium alginate. Sodium alginate can undergo ion cross-linking reaction with divalent cations (such as calcium ions) to quickly form a hydrogel with a three-dimensional network structure. This gelation process makes the sodium alginate hydrogel have good stability and mechanical strength, and can maintain its shape and structure in different application scenarios.

[0025] The buffer solution is one of pure water, physiological saline and phosphate solution. The buffer solution is preferably physiological saline.

[0026] The water-soluble calcium solution is one of calcium chloride, calcium lactate and calcium gluconate. The water-soluble calcium solution is preferably calcium chloride solution. The concentration of the water-soluble calcium solution is 0.3%-5%. The water-soluble calcium solution is used to cross-link with the first component to form a sheet-like hydrogel, which plays a role in preventing tissue fluid leakage.

[0027] The first component also includes a reinforcing agent, which is polyethyleneimine, and its weight portion is 0.5-1. PEI reacts rapidly when it contacts with mucosal tissue to form a sticky tissue barrier.

[0028] A method for using an absorbable gastrointestinal tissue sealant comprises the following steps

[0029] Step 1, spraying the first component evenly on the target tissue;

[0030] Step 2, spraying the second component immediately after the first component is sprayed, spraying the second component and covering the first component, so that the first component and the second component undergo a cross-linking reaction to form a sheet-like hydrogel, thereby preventing tissue fluid leakage;

[0031] The wound area is 1cm 2 For example, the first component is sprayed at a dose of 0.2-0.25 times the wound area, i.e., an area of ​​1 cm 2 Spray 0.2-0.25mL of the first component on the wound surface. Immediately after spraying the first component, spray the second component. Spray the second component in an amount of 0.3-0.5 times the wound surface area, i.e. 1cm 2 Spray 0.3-0.5mL of the second component on the wound surface.

[0032] The effects of the present invention are described below in conjunction with specific embodiments.

[0033] Example 1

[0034] The colloidal substance in the first component is 27g of poloxamer, the bioadhesive material is 0.75g of hydroxypropyl methylcellulose, and the ion-sensitive gel material is 0.75g of potassium alginate, which is fixed to 150mL with buffer saline; the second component is calcium chloride solution, the concentration of calcium chloride solution is 2.8%, and the pH value is 2. The acidic environment may make the calcium ions in calcium chloride more easily released, thereby regulating the physiological function of cells.

[0035] Example 2

[0036] The colloidal substance in the first component is 27 g of poloxamer, the bioadhesive material is 1.5 g of hydroxypropyl methylcellulose, and the ion-sensitive gel material is 0.75 g of sodium alginate, and the volume is adjusted to 150 mL with buffer saline; the second component is calcium chloride solution, the concentration of calcium chloride solution is 0.46%, and the pH value is 2.

[0037] Example 3

[0038] The colloidal substance in the first component is 27 g of poloxamer, the bioadhesive material is 2 g of carboxymethyl chitosan, and the ion-sensitive gel material is 0.75 g of sodium alginate, and the volume is fixed to 150 mL with buffer saline; the second component is calcium chloride solution, the concentration of calcium chloride solution is 0.33%, and the pH value is 2.

[0039] Example 4

[0040] The colloidal substance in the first component is 27 g of poloxamer, the bioadhesive material is 2 g of hydroxypropyl methylcellulose, and the ion-sensitive gel material is 0.75 g of sodium alginate, and the volume is fixed to 150 mL with buffer saline; the second component is calcium chloride solution, the concentration of calcium chloride solution is 1.00%, and the pH value is 2.

[0041] Example 5

[0042] The colloidal substance in the first component is 27 g of acid-soluble collagen, the bioadhesive material is 0.75 g of carboxymethyl cellulose, and the ion-sensitive gel material is 3 g of sodium alginate, which are fixed to 150 mL with buffer saline; the second component is calcium chloride solution, the concentration of calcium chloride solution is 0.48%, and the pH value is 2.

[0043] Example 6

[0044] The colloidal substance in the first component is 30 g of cellulose acetate phthalate, the bioadhesive material is 1.35 g of carboxymethyl chitosan, and the ion-sensitive gel material is 0.75 g of sodium alginate, and the volume is fixed to 150 mL with buffer saline; the second component is calcium chloride solution, the concentration of calcium chloride solution is 2.20%, and the pH value is 2.

[0045] Example 7

[0046] The colloidal substance in the first component is 30 g of poloxamer, the bioadhesive material is 1.35 g of carboxymethyl cellulose, the ion-sensitive gel material is 0.75 g of potassium alginate, the enhancer is 0.5 g of polyethyleneimine, and the volume is fixed to 150 mL with buffer saline; the second component is calcium chloride solution, the concentration of calcium chloride solution is 4.21%, and the pH value is 2.

[0047] Example 8

[0048] The colloidal substance in the first component is 30g of acid-soluble collagen, the bioadhesive material is 1.35g of carboxymethyl chitosan, the ion-sensitive gel material is 0.75g of deacetylated gellan gum, and the enhancer is 0.75g of polyethyleneimine, and the volume is fixed to 150mL with buffer saline; the second component is calcium lactate solution with a calcium lactate concentration of 3.20% and a pH value of 2.

[0049] Example 9

[0050] The colloidal substance in the first component is 30 g of cellulose acetate phthalate, the bioadhesive material is 1.35 g of hydroxypropyl methylcellulose, the ion-sensitive gel material is 0.75 g of sodium alginate, the enhancer is 1 g of polyethyleneimine, and the volume is adjusted to 150 mL with buffer saline; the second component is calcium chloride solution, the concentration of calcium chloride solution is 1.23%, and the pH value is 2.

[0051] Based on the above examples, the tissue adhesion, rupture strength and in vitro degradation time were tested:

[0052] The experiment of tissue adhesion (%) was as follows: New Zealand rabbits were fasted for 24 hours and anesthetized by intraperitoneal injection of 40 mg / kg sodium pentobarbital solution. Subsequently, the stomach was dissected and placed in 37°C saline. The inner wall of the stomach was thoroughly cleaned with saline to ensure that it was clean and free of residues and used within 2 hours. Then, a piece of gastric tissue with an area of ​​2 cm × 2 cm was cut from the stomach and fixed on a polyethylene film. 0.5 ml of protective glue was evenly applied on the wound surface of the gastric mucosa and the fixative was sprayed. Next, the treated gastric tissue was placed in a constant humidity sealed container with a relative humidity of 92.5% and allowed to stand for 20 minutes. The gastric tissue treated as above was fixed on the flushing chute, the angle of the chute was adjusted to 60 degrees, and the peristaltic pump flow rate was adjusted to 20 ml / min. The gastric tissue was flushed with a phosphate buffer of pH = 8.0 for 5 minutes, and the flushing solution was collected in a beaker of known weight. After that, it was dried at 70°C and weighed, and the adhesion percentage was used to express the adhesion of the tissue. Gastric tissue adhesion percentage (Bg / %) Bg / % = {[M-(Ggm)] / M} x 100%. M is the weight of the mucosal protective gel (0.5 ml dried under the same conditions); g is the weight of the empty beaker; G is the total weight of the beaker and the residue after drying; m is the amount of solid matter contained in the same volume of flushing solution (blank control).

[0053] The bursting strength (mmHg) experiment is as follows: The bursting strength reflects the mechanical properties of the hydrogel during use. The detection method is: a hole with a diameter of about 0.16 cm (+0.02 cm) is punched in a fresh pig casing, and the gel product of the present invention is applied to the hole to form a hydrogel of a specified thickness. A phosphate buffer solution with a pH of 7.4 is used to pressurize the bottom of the casing until the gel is broken, and the maximum pressure number is recorded by a digital readout connected to the sensor.

[0054] In vitro degradation period (d): The hydrogel was placed in phosphate buffer (pH 7.4) at 37±1°C and observed daily until it could no longer be seen. This was recorded as the in vitro degradation time of the gel.

[0055] Tissue adhesion (%) Bursting strength (mmHg) Degradation time (d) Example 1 94 225 10 Example 2 94 227 10 Example 3 94 237 10 Example 4 95 239 13 Example 5 95 249 13 Example 6 97 256 14 Example 7 98 291 16 Example 8 98 328 16 Example 9 99 337 19

[0056] Judging from the results, tissue adhesion is proportional to the content of hydroxypropyl methylcellulose in the adhesive material. Sodium alginate and calcium chloride are cross-linked to form a hydrogel with rupture strength, which means that when the molar ratio of the cross-linking functional groups of sodium alginate and calcium chloride reaches a certain proportion, the rupture strength is relatively stable, and is also affected by other components and has a floating threshold. Similarly, biodegradability is also affected by the composition of the components. The addition of polyethyleneimine prolongs the degradation time of the material. Therefore, the material not only implements effective blocking during the tissue healing period, but can also be absorbed and degraded after the tissue heals, reducing the impact on the human body.

[0057] Finally, it should be noted that the above is only a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the aforementioned embodiments, it is still possible for those skilled in the art to modify the technical solutions described in the aforementioned embodiments or to make equivalent substitutions for some of the technical features therein. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. An absorbable gastrointestinal tissue sealant, characterized in that: The method comprises a first component and a second component; wherein the second component and the first component are mixed and reacted to form a hydrogel; The first component is a mixed solution, including a colloidal substance, a bioadhesive material, an ion-sensitive gel material, and the balance is a buffer solution; the second component is a water-soluble calcium solution, the pH of the water-soluble calcium solution is adjusted with a hydrochloric acid solution, and the pH of the adjusted calcium chloride solution is between 1.8 and 2.2; In terms of weight ratio, in 150 parts of the mixed solution, the first component contains 27-30 parts of colloidal substances, 0.75-2 parts of bioadhesive materials, 0.75-3 parts of ion-sensitive gel materials, and the remainder is buffer solution.

2. The absorbable gastrointestinal tissue sealant according to claim 1, characterized in that: The colloidal substance is one or more of poloxamer, cellulose acetate phthalate, and acid-soluble collagen.

3. The absorbable gastrointestinal tissue sealant according to claim 2, characterized in that: The colloidal substance is preferably poloxamer, specifically poloxamer 407.

4. The absorbable gastrointestinal tissue sealant according to claim 1, characterized in that: The bioadhesive material is any one of carboxymethyl cellulose, carboxymethyl chitosan, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polylysine, mussel adhesive protein, and sodium hyaluronate.

5. The absorbable gastrointestinal tissue sealant according to claim 4, characterized in that: The bioadhesive material is preferably hydroxypropyl methylcellulose.

6. The absorbable gastrointestinal tissue sealant according to claim 1, characterized in that: The ion-sensitive gel material is one or more of sodium alginate, potassium alginate, amidated low-methoxyl pectin, and deacetylated gellan gum.

7. The absorbable gastrointestinal tissue sealant according to claim 6, characterized in that: The ion-sensitive gel material is preferably sodium alginate.

8. The absorbable gastrointestinal tissue sealant according to claim 1, characterized in that: The buffer solution is one of pure water, physiological saline and phosphate solution; wherein, when the buffer solution is phosphate solution, the pH value of the solution is 9.

0.

9. The absorbable gastrointestinal tissue sealant according to claim 1, characterized in that: The water-soluble calcium solution is one of calcium chloride, calcium lactate, and calcium gluconate, and the concentration of the water-soluble calcium solution is 0.3%-5%.

10. The absorbable gastrointestinal tissue sealant according to claim 1, characterized in that: The first component also includes a reinforcing agent, which is polyethyleneimine, and its weight proportion is 0.5-1 part.

11. The method for using the absorbable gastrointestinal tissue sealant according to any one of claims 1 to 10, characterized in that: The following steps are included Step 1, spraying the first component evenly on the target tissue; Step 2, spray the second component immediately after the first component is sprayed, spray the second component and cover the first component, so that the first component and the second component undergo a cross-linking reaction to form a sheet-like hydrogel, thereby preventing tissue fluid leakage.