Absorbable gastrointestinal hemorrhage hemostasis tube

Abstract

The absorbable gastrointestinal hemorrhage hemostasis tube comprises a first composition and a second composition, the first composition comprises polypeptide capable of being self-assembled in a water phase, and the second composition comprises methacrylamide gelatin (GelMA) and a photoinitiator; the polypeptide comprises 1-2 fragments R1 and 2-4 fragments R2, wherein the fragment R1 is connected to the N end or the C end of the fragment R2 or between the two fragments R2 through an amido bond; wherein the amino acid sequence of the fragment R1 is FLIVGSII. By means of various digestive enzymes in the digestive tract, different pH value environments and the scouring effect of fluid, the hemostasis tube can keep stable and play a role in the environments. For example, the structures and properties of polypeptides and GelMA enable them to resist the decomposition of digestive juice, maintaining their structural integrity of hemostasis in a dynamic environment within the digestive tract until the hemostasis process is completed and absorbed.

Description

Technical Field

[0001] The present invention belongs to the technical field of digestive tract blood vessels, and specifically relates to an absorbable hemostatic vessel for digestive tract bleeding. Background Art

[0002] Massive hemorrhage of the digestive tract is a clinically extremely dangerous disease, which can be caused by various diseases. Upper gastrointestinal bleeding refers to the bleeding of the esophagus, stomach, duodenum, upper jejunum, and pancreatic and bile ducts above the duodenal suspensory ligament (Treitz ligament). The bleeding of the intestine below the duodenal suspensory ligament is collectively referred to as lower gastrointestinal bleeding.

[0003] The existing technologies mainly include endoscopic hemostasis, embolization of large blood vessels, and surgical treatment, but the mortality rate remains high. The reason is that for endoscopic upper vascular clips and tissue glue injection, the curative effect is not definite in most patients, and there is a time limit for repeated bleeding. Embolization can only be targeted at medium and large blood vessels, and surgical operations have large traumas. Therefore, it is urgent to seek a clinically simple and easy-to-use hemostatic device with a low threshold. Summary of the Invention

[0004] In view of the above situation, in order to overcome the defects of the existing technologies, the present invention provides an absorbable hemostatic vessel for digestive tract bleeding to at least partially solve the above technical problems.

[0005] The technical solution adopted by the present invention is as follows:

[0006] The present invention provides an absorbable hemostatic vessel for digestive tract bleeding, comprising: a first composition and a second composition. The first composition comprises a polypeptide capable of self-assembling in an aqueous phase, and the second composition comprises methacryloyl gelatin (GelMA) and a photoinitiator. The polypeptide comprises 1 to 2 fragments R1 and 2 to 4 fragments R2, wherein fragment R1 is connected to the N-terminus or C-terminus of fragment R2 or between two fragments R2 through an amide bond. The amino acid sequence of fragment R1 is FLIVGSII, and the amino acid sequence of fragment R2 is VPGXG or VAPGXG, and X is any other amino acid except proline.

[0007] In one embodiment of the present invention, the polypeptide comprises 1 fragment R1 and 3 continuously repeated fragments R2, and its structure is R1-(R2)3 or (R2)3-R1.

[0008] In one embodiment of the present invention, the polypeptide further comprises 1 to 2 amino acid residues at its N-terminus or C-terminus.

[0009] In one embodiment of the present invention, X in the amino acid sequence of fragment R2 is aspartic acid.

[0010] In one embodiment of the present invention, the first composition further comprises an organic solvent for dispersing the polypeptide, and the organic solvent is any one or a combination of at least two of DMSO, DMF or glycerol.

[0011] In one embodiment of the present invention, the degree of amino substitution of methacrylamide gelatin in the second composition is 30% - 90%, and the molecular weight is 50 - 200 kDa; the photoinitiator is 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone, or lithium phenyl(2,4,6-trimethylbenzoyl)phosphate, or a combination of triethanolamine, vitamin C and disodium tetrabromofluorescein.

[0012] In one embodiment of the present invention, the second composition further comprises an aqueous solvent, and the aqueous solvent is any one of pure water, physiological saline or neutral phosphate buffer solution.

[0013] In one embodiment of the present invention, the gastrointestinal bleeding hemostatic tube is an overall tubular structure. The outer diameter of the tube body can be designed to be 0.5 - 5 mm according to different application scenarios, the inner diameter is 0.3 - 4.5 mm, and the length is 1 - 20 cm.

[0014] In one embodiment of the present invention, the inner layer of the tube body is an absorbable gel layer with good biocompatibility. The main components of the gel layer can be a composite of natural absorbable materials such as chitosan and gelatin, and the thickness of the gel layer is 0.1 - 0.5 mm.

[0015] In one embodiment of the present invention, the middle layer of the tube body is a high-strength absorbable fiber braided layer. The fiber can be selected as poly(lactic acid-co-glycolic acid) (PLGA) fiber, and the thickness of the middle layer is 0.2 - 1 mm; the outer layer of the tube body is a coating with hemostatic function, and the components of the coating include substances promoting blood coagulation such as thrombin and fibrinogen, and the thickness of the outer coating is 0.05 - 0.2 mm.

[0016] The beneficial effects of the technical solution of the present invention are as follows:

[0017] Due to the presence of various digestive enzymes, different pH value environments and the scouring action of fluids in the digestive tract, the hemostatic tube can remain stable and function in such an environment. For example, the structures and properties of the polypeptide and GelMA enable them to resist the decomposition by digestive juices and maintain their hemostatic structural integrity in the dynamic environment of the digestive tract until the hemostasis process is completed and absorbed.

[0018] Additional aspects and advantages of the present invention will be given in part in the following description, become apparent in part from the following description, or be understood through the practice of the present invention. Description of the Drawings

[0019] The above and / or additional aspects and advantages of the present invention will become apparent and be readily understood from the following description of embodiments in conjunction with the accompanying drawings, in which:

[0020] Figure 1 It is a schematic structural diagram of an absorbable hemostatic tube for gastrointestinal bleeding proposed in an embodiment of the present invention. Detailed implementation manners

[0021] Embodiments of the present invention will be described in detail below. Examples of the embodiments are shown in the accompanying drawings, in which the same or similar reference numerals denote the same or similar elements or elements having the same or similar functions throughout. The embodiments described below with reference to the accompanying drawings are exemplary and are intended to explain the present invention and should not be construed as limiting the present invention.

[0022] An absorbable hemostatic tube for gastrointestinal bleeding according to an embodiment of the present invention will be described below with reference to the accompanying drawings.

[0023] As Figure 1 shown, an absorbable hemostatic tube for gastrointestinal bleeding provided by an embodiment of the present invention includes: a first composition and a second composition. The first composition includes a polypeptide capable of self-assembling in an aqueous phase, and the second composition includes methacrylamide gelatin (GelMA) and a photoinitiator; the polypeptide includes 1 to 2 fragments R1 and 2 to 4 fragments R2, wherein the fragment R1 is connected to the N-terminus or C-terminus of the fragment R2 or between two fragments R2 through an amide bond; wherein the amino acid sequence of the fragment R1 is FLIVGSII, and the amino acid sequence of the fragment R2 is VPGXG or VAPGXG, and X is any other amino acid except proline.

[0024] In the specific application of the embodiment of the present invention, the polypeptide has the ability to self-assemble in an aqueous phase. In the aqueous environment of the digestive tract, this self-assembly property enables the polypeptide to form a specific structure. Due to its unique amino acid sequence composition, including 1-2 fragments R1 (amino acid sequence is FLIVGSII) and 2-4 fragments R2 (amino acid sequence is VPGXG or VAPGXG, and X is any other amino acid except proline), these fragments are connected by amide bonds. The self-assembly in the aqueous phase is based on the interactions between amino acid side chains, such as hydrophobic interactions, hydrogen bonds, etc.

[0025] The R1 fragment (FLIVGSII) plays a role in the recognition of other biomolecules or in the initial formation of the self-assembled structure. The specific amino acid composition in the R2 fragment (VPGXG or VAPGXG), especially when X is an amino acid other than proline, this variation regulates the properties of the polypeptide such as flexibility and hydrophilicity, thereby affecting the way of its self-assembly and the ability to interact with the surrounding environment.

[0026] GelMA is a material with good biocompatibility and processability. In the hemostatic vessel, it cooperates with polypeptides. On the one hand, GelMA itself can form a gel-like structure, which helps to form a physical barrier at the bleeding site to block the outflow of blood. On the other hand, GelMA can provide a supportive environment for the polypeptides, enabling the self-assembled structure of the polypeptides to function better. For example, it stabilizes the network structure formed by the self-assembly of polypeptides and prevents its premature disassembly.

[0027] The presence of the photoinitiator in this system is related to the cross-linking reaction of GelMA. Under the irradiation of light with a specific wavelength, the photoinitiator can initiate the cross-linking reaction between GelMA molecules. This cross-linking reaction can make the structure of GelMA more stable and firm, further enhancing its ability to form a physical barrier at the bleeding site and improving the overall hemostatic effect of the hemostatic vessel. At the same time, the cross-linked GelMA forms a closer interaction with the polypeptides and plays a synergistic hemostatic role.

[0028] In one embodiment, the polypeptide comprises 1 fragment R1 and 3 continuously repeated fragments R2, and its structure is R1-(R2)3 or (R2)3-R1. The polypeptide also comprises 1-2 amino acid residues at its N-terminus or C-terminus. In the amino acid sequence of fragment R2, X is aspartic acid.

[0029] In the specific application of the embodiments of the present invention, the polypeptide comprises 1 fragment R1 and 3 continuously repeated fragments R2, and its structure is R1-(R2)3 or (R2)3-R1. This unique structural pattern is crucial for the hemostatic function. Fragment R1 plays a role in recognizing specific targets at the bleeding site, such as certain receptors on the surface of vascular endothelial cells or special components in the extracellular matrix. The 3 continuously repeated fragments R2 enhance the binding ability with coagulation-related factors through their synergistic effects. When X is aspartic acid, the side chain of aspartic acid has special chemical properties, and it participates in forming hydrogen bonds or electrostatic interactions.

[0030] The polypeptide also comprises 1-2 amino acid residues at its N-terminus or C-terminus. Although the number of residues is small, they play a fine-tuning role in the overall function of the polypeptide. They affect the spatial conformation of the polypeptide, enabling the entire polypeptide to better match the microenvironment at the bleeding site. For example, these residues change the hydrophilicity and hydrophobicity of the polypeptide, thereby affecting its solubility and diffusibility in the blood, ensuring that the polypeptide can quickly reach the bleeding site and play a role.

[0031] During the coagulation process, normally multiple coagulation factors are involved. This polypeptide promotes coagulation by interacting with certain coagulation factors. For example, it binds to fibrinogen and promotes the formation of fibrin, and fibrin can form a network to block the bleeding opening.

[0032] In one embodiment, the first composition further comprises an organic solvent for dispersing the polypeptide, and the organic solvent is any one or a combination of at least two of DMSO, DMF or glycerol. The amino substitution degree of methacrylamide gelatin in the second composition is 30% - 90%, and the molecular weight is 50 - 200 kDa. The photoinitiator is 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone, or lithium phenyl(2,4,6-trimethylbenzoyl)phosphate, or a combination of triethanolamine, vitamin C and disodium tetrabromofluorescein. The second composition further comprises an aqueous solvent, and the aqueous solvent is any one of pure water, physiological saline or neutral phosphate buffer solution.

[0033] In the specific application of the embodiments of the present invention, when an organic solvent (such as DMSO, DMF or glycerol) is present, the polypeptide is dispersed by the interaction with the polypeptide molecules. For example, the organic solvent molecules form weak interactions such as hydrogen bonds or van der Waals forces with the polypeptide molecules, reducing the aggregation between the polypeptide molecules, so that the polypeptide molecules are uniformly dispersed in the system. The uniformly dispersed polypeptide undergoes specific interactions with the components in the blood during the hemostasis process, such as interacting with platelets, coagulation factors, etc., to promote the coagulation process.

[0034] The amino substitution degree and molecular weight of acrylamide gelatin are within a specific range, which makes it have a suitable balance of hydrophilicity and hydrophobicity. When in contact with blood, it can absorb the water in the blood to form a gel-like substance, and its amino groups undergo chemical reactions with proteins or other components in the blood to promote hemostasis. For example, the amino groups interact with coagulation-related proteins such as fibrinogen to accelerate the formation of fibrin, and fibrin is a key component in the coagulation process and can form a network structure to block the damaged blood vessel.

[0035] If a photoinitiator such as 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone is used, under the irradiation of light with a specific wavelength, the photoinitiator molecules absorb photon energy and transition from the ground state to the excited state. The photoinitiator molecules in the excited state can initiate a series of chemical reactions, such as initiating the cross-linking reaction between methacrylamide gelatin molecules. This cross-linking reaction can make the structure of the hemostatic vessel more stable and enhance its physical support role in the hemostasis process.

[0036] For photoinitiators such as lithium phenyl(2,4,6-trimethylbenzoyl)phosphate, or a combination of triethanolamine, vitamin C and disodium tetrabromofluorescein, they also have a similar mechanism of action. Triggered by light or other conditions, they initiate chemical reactions to promote the curing or structural adjustment of the hemostatic vessel material to achieve a better hemostatic effect.

[0037] Pure water, normal saline or neutral phosphate buffer solution is used as the water-based solvent, which can ensure the uniform distribution of other components (such as acrylamide-based gelatin, photoinitiator, etc.) in the solution. Due to their similarity to the human physiological environment, normal saline and neutral phosphate buffer solution will not cause osmotic pressure changes or drastic fluctuations in pH value of cells when contacting with digestive tract tissues, thus reducing the damage to tissues and ensuring that the hemostatic vessel can perform its hemostatic function in a suitable physiological environment.

[0038] In one embodiment, the digestive tract hemostatic vessel is a tubular structure as a whole. The outer diameter of the tube body can be designed to be 0.5 - 5 mm according to different application scenarios, the inner diameter is 0.3 - 4.5 mm, and the length is 1 - 20 cm. The inner layer of the tube body is an absorbable gel layer with good biocompatibility. The main components of the gel layer can be a composite of natural absorbable materials such as chitosan and gelatin. The thickness of the gel layer is 0.1 - 0.5 mm. The middle layer of the tube body is a high-strength absorbable fiber woven layer. The fiber can be selected as poly(lactic acid-co-glycolic acid) (PLGA) fiber, and the thickness of the middle layer is 0.2 - 1 mm. The outer layer of the tube body is a coating with hemostatic function. The components of the coating include substances that promote blood coagulation such as thrombin and fibrinogen. The thickness of the outer coating is 0.05 - 0.2 mm.

[0039] In the specific application of the embodiment of the present invention, when the hemostatic vessel is placed at the digestive tract bleeding site, the outer hemostatic coating first contacts the blood. Components such as thrombin and fibrinogen quickly initiate the blood coagulation process. Fibrinogen forms fibrin clots under the action of thrombin. These clots will adhere around the bleeding point to form a preliminary seal, reducing the amount of blood outflow.

[0040] The high-strength absorbable fiber woven layer in the middle layer plays a role in support and reinforcement. It can maintain the shape of the tube body, prevent deformation under pressure in the digestive tract (such as the pressure generated by digestive tract peristalsis), ensure that the outer hemostatic coating continuously contacts the bleeding site, and maintain the hemostatic effect. At the same time, the existence of the woven layer also provides certain structural support for the inner and outer layers, ensuring the integrity of the entire hemostatic vessel. As time goes by, the absorbable gel layer in the inner layer begins to be gradually absorbed. During this process, the gel layer will release some substances beneficial to tissue repair or provide a relatively mild microenvironment for the surrounding tissues to promote the self-repair of digestive tract tissues. The fiber woven layer in the middle layer and the coating in the outer layer are also continuously absorbed, and the entire hemostatic vessel gradually disappears, and the digestive tract tissues gradually return to their normal structure and function.

[0041] The outer coating of the tube body contains substances that promote blood coagulation, such as thrombin and fibrinogen. Thrombin can convert fibrinogen into fibrin, and the fibrin interweaves to form a reticular structure, thereby blocking the bleeding point and achieving the purpose of rapid hemostasis. The blood coagulation promotion mechanism at the bleeding site enables effective reduction of the blood loss in case of gastrointestinal bleeding, creating favorable conditions for the patient's recovery.

[0042] The overall tubular structure can adapt to the shape of the digestive tract, be directly inserted or placed at the bleeding site, and exert its hemostatic function through contact with the blood by the outer coating, fit with the digestive tract wall, prevent the blood from flowing out continuously, and improve the accuracy and effectiveness of hemostasis.

[0043] Example 1

[0044] Prepare a hemostatic tube:

[0045] Prepare a hemostatic tube with an inner diameter of 1 mm, an outer diameter of 1.5 mm, and a length of 5 cm according to the above method. Among them, the ratio of chitosan to gelatin in the gel layer is 2:1, and the thickness is 0.3 mm; the thickness of the middle layer of PLGA fiber braided layer is 0.5 mm; the concentrations of thrombin and fibrinogen in the outer coating are 1000 IU / ml and 50 mg / ml respectively, and the thickness is 0.1 mm.

[0046] Animal experiment:

[0047] Select experimental pigs as the animal model, and create a bleeding wound in the digestive tract (such as the duodenum) of the pigs through surgery.

[0048] Use an endoscope to place the prepared hemostatic tube at the bleeding site and observe the hemostasis time. The results show that after the hemostatic tube is placed, the average hemostasis time is 35 minutes, and the hemostasis effect is good.

[0049] In the subsequent observation, the hemostatic tube is gradually absorbed in the body, and no inflammatory reaction or other adverse reactions are found.

[0050] Example 2

[0051] Prepare a hemostatic tube:

[0052] Prepare a hemostatic tube with an inner diameter of 2 mm, an outer diameter of 2.5 mm, and a length of 10 cm. The ratio of chitosan to gelatin in the gel layer is 3:1, and the thickness is 0.4 mm; the thickness of the middle layer of PLGA fiber braided layer is 0.8 mm; the concentrations of thrombin and fibrinogen in the outer coating are 1500 IU / ml and 80 mg / ml respectively, and the thickness is 0.15 mm.

[0053] Clinical trial:

[0054] On the premise of obtaining the patient's consent and meeting the ethical norms, select patients with gastrointestinal bleeding for clinical trials.

[0055] Under endoscopy, the hemostatic vessel is placed at the bleeding site, and it is found that for gastrointestinal bleeding caused by various reasons (such as ulcers, vascular malformations, etc.), the hemostatic vessel has a good hemostatic effect. The hemostasis success rate reaches over 85%, and no complications occur in patients during the subsequent recovery process due to the presence of the hemostatic vessel. The hemostatic vessel is gradually absorbed in the body as expected.

[0056] It should be noted that in this text, relational terms such as first and second are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any actual relationship or order between these entities or operations. Moreover, the term "comprising", "including" or any other variant thereof is intended to cover non-exclusive inclusion, so that a process, method, article or device comprising a series of elements not only includes those elements, but also includes other elements not expressly listed, or further includes elements inherent to such process, method, article or device.

[0057] The above describes the present invention and its implementation manners. Such description is not restrictive. What is shown in the drawings is only one of the implementation manners of the present invention, and the actual structure is not limited thereto. Generally speaking, if those of ordinary skill in the art are inspired by it and design similar structural manners and embodiments without creative efforts without departing from the purpose of the present invention, they shall fall within the protection scope of the present invention.

Claims

1. An absorbable gastrointestinal bleeding vascular stop, characterized in that: include: A first composition and a second composition, wherein the first composition comprises a polypeptide capable of self-assembly in an aqueous phase, and the second composition comprises methacrylamide-based gelatin (GelMA) and a photoinitiator; The polypeptide comprises 1 to 2 fragments R1 and 2 to 4 fragments R2, wherein the fragment R1 is connected to the N-terminus or C-terminus of the fragment R2 or between two fragments R2 through an amide bond; The amino acid sequence of fragment R1 is FLIVGSII, the amino acid sequence of fragment R2 is VPGXG or VAPGXG, and X is any other amino acid except proline.

2. The absorbable gastrointestinal bleeding vascular stopper according to claim 1, characterized in that: The polypeptide comprises one fragment R1 and three consecutively repeated fragments R2, and its structure is R1-(R2)3 or (R2)3-R1.

3. The absorbable gastrointestinal bleeding vascular stopper according to claim 1, characterized in that: The polypeptide further comprises 1 to 2 amino acid residues at its N-terminus or C-terminus.

4. The absorbable gastrointestinal bleeding vascular stopper according to claim 1, characterized in that: In the amino acid sequence of the fragment R2, X is aspartic acid.

5. The absorbable gastrointestinal bleeding vascular stopper according to claim 1, characterized in that: The first composition further comprises an organic solvent for dispersing the polypeptide, and the organic solvent is any one of DMSO, DMF or glycerol, or a combination of at least two thereof.

6. The absorbable gastrointestinal bleeding vascular stopper according to claim 1, characterized in that: The amino substitution degree of the methacrylamide-based gelatin in the second composition is 30% to 90% and the molecular weight is 50-200 kDa; The photoinitiator is 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone, or phenyl (2,4,6-trimethylbenzoyl) phosphate lithium salt, or a combination of triethanolamine, vitamin C and tetrabromofluorescein disodium.

7. The absorbable gastrointestinal bleeding vascular stopper according to claim 1, characterized in that: The second composition further comprises a water-based solvent, and the water-based solvent is any one of pure water, physiological saline or neutral phosphate buffer.

8. The absorbable gastrointestinal bleeding vascular stopper according to claim 1, characterized in that: The gastrointestinal bleeding stop blood vessel is a tubular structure as a whole. The outer diameter of the tube body can be designed to be 0.5-5 mm, the inner diameter is 0.3-4.5 mm, and the length is 1-20 cm according to different application scenarios.

9. The absorbable gastrointestinal bleeding vascular stopper according to claim 1, characterized in that: The inner layer of the tube body is an absorbable gel layer with good biocompatibility. The main component of the gel layer can be a composite of natural absorbable materials such as chitosan and gelatin. The thickness of the gel layer is 0.1-0.5 mm.

10. The absorbable gastrointestinal bleeding vascular stopper according to claim 1, characterized in that: The middle layer of the tube body is a high-strength absorbable fiber braided layer, the fiber can be selected from polylactic acid-acetic acid copolymer (PLGA) fiber, and the thickness of the middle layer is 0.2-1 mm; The outer layer of the tube body is a coating with a hemostatic function. The coating contains thrombin, fibrinogen and other substances that promote blood coagulation. The thickness of the outer coating is 0.05-0.2 mm.

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