CN117122725B - Biological hydrogel for umbilical vessel occlusion and preparation method thereof - Google Patents

Biological hydrogel for umbilical vessel occlusion and preparation method thereof Download PDF

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Publication number
CN117122725B
CN117122725B CN202311400756.0A CN202311400756A CN117122725B CN 117122725 B CN117122725 B CN 117122725B CN 202311400756 A CN202311400756 A CN 202311400756A CN 117122725 B CN117122725 B CN 117122725B
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component
solution
hydrogel
biological hydrogel
blood vessel
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CN117122725A (en
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祝腾蛟
王星
魏瑗
田耘
赵扬玉
乔杰
李璐瑶
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Peking University Third Hospital Peking University Third Clinical Medical College
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Peking University Third Hospital Peking University Third Clinical Medical College
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001Use of materials characterised by their function or physical properties
    • A61L24/0031Hydrogels or hydrocolloids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001Use of materials characterised by their function or physical properties
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/043Mixtures of macromolecular materials
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08JWORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00Processes of treating or compounding macromolecular substances
    • C08J3/02Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
    • C08J3/03Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
    • C08J3/075Macromolecular gels
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00Materials characterised by their function or physical properties
    • A61L2400/06Flowable or injectable implant compositions
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08JWORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2371/00Characterised by the use of polyethers obtained by reactions forming an ether link in the main chain; Derivatives of such polymers
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08JWORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2471/00Characterised by the use of polyethers obtained by reactions forming an ether link in the main chain; Derivatives of such polymers

Abstract

The invention discloses a biological hydrogel for umbilical vessel occlusion and a preparation method thereof, which is characterized by comprising a component A and a component B in a mass ratio of 1 (0.1-10), wherein the structural formula of the component A is as followsThe method comprises the steps of carrying out a first treatment on the surface of the The structural formula of the component B isThe method comprises the steps of carrying out a first treatment on the surface of the Wherein n and m are integers of from 2 to 1000. The component of the biological hydrogel adopted by the invention is an FDA approved substance and has good biocompatibility. The biological hydrogel has good vascular plugging performance, can form gel in situ in a blood environment in a blood vessel, and can completely plug the blood vessel. The biological hydrogel disclosed by the invention is convenient to operate in operation, can be punctured into a blood vessel under the guidance of B ultrasonic, is directly injected into the blood vessel to seal the blood vessel through a simple double-channel/single-channel injector, and is short in operation time, small in risk and definite in effect. The biological hydrogel can be used for multi-embryo pregnancy termination which cannot or is not suitable for plugging umbilical cord blood vessels by the conventional method.

Description

Biological hydrogel for umbilical vessel occlusion and preparation method thereof
Technical Field
The invention relates to the field of medical adhesives, in particular to a biological hydrogel for umbilical vessel occlusion and a preparation method thereof.
Background
With the development of assisted fertility technology, the probability of multiple pregnancy in clinic increases, the proportion of multiple pregnancy in complexity also increases greatly, and particularly, the risk of occurrence of fetal and maternal complications is particularly high for multiple pregnancy of single chorion twin or more than three fetuses.
The single chorion twin pregnancy refers to that two fetuses share one placenta, and blood vessels between the placenta are anastomosed, and the two fetuses have blood vessel traffic. When complications such as double-embryo transfusion syndrome (TTTS), selective intrauterine growth restriction (sIUGR), double-embryo arterial reverse perfusion sequence (trap), double-embryo lean hemoglobia (TAPS), one fetal abnormality of double-embryo, etc. occur in double-embryo, a selective embryo reduction operation is required to reduce complications and complications of gestation and improve the fatality of multiple-embryo pregnancy.
The traditional embryo reduction operation uses potassium chloride for intracardiac injection to reduce the embryo, but due to the specificity of the placenta with single chorion and double embryo, toxic substances can be damaged to the normal fetus to be reserved by the anastomosis traffic of the placenta when the potassium chloride is adopted for embryo reduction operation to reduce the embryo. In clinic, the method of single chorionic multiple pregnancy (single chorion single amniotic sac, single chorion double amniotic sac and the like) selective embryo reduction is mainly radio frequency ablation embryo reduction and microwave ablation embryo reduction. Radio frequency ablation and microwave ablation are methods for performing thermal injury by high frequency electric waves or microwaves to denature proteins and coagulate and necrotize cells to death.
The following problems exist in the radio frequency ablation fetal reduction operation and the microwave ablation fetal reduction operation: (1) the outer diameters of the radiofrequency ablation needle and the microwave needle are 17G, and the radiofrequency ablation needle and the microwave needle are commonly applied to the miscarriage in clinic, and the miscarriage week is closely related to prognosis (can not be applied to early stage); (2) the heat effect and operation time generated in the process of fetal reduction increase the risk of the matrix and increase the probability of premature rupture of the fetal membranes after operation; (3) if the two fetuses are in close position, the thermal ablation operation may cause damage to the reserved fetuses, and the risk of the other fetuses in dead womb after the operation is increased; (4) both tyre-reducing methods are expensive.
Therefore, how to provide a biological hydrogel capable of safely and effectively implementing multiple pregnancy miscarriage becomes a technical problem to be solved in the field.
Disclosure of Invention
The invention aims to provide a novel technical scheme of biological hydrogel capable of safely and effectively implementing multiple pregnancy miscarriage.
According to a first aspect of the present invention, there is provided a bio-hydrogel for umbilical vessel occlusion.
The biological hydrogel for umbilical vessel occlusion comprises a component A and a component B with the mass ratio of 1 (0.1-10), wherein,
the structural formula of the component A is shown as formula I:
a formula I;
the structural formula of the component B is shown as a formula II:
a formula II;
wherein n and m are integers of from 2 to 1000.
Alternatively, n and m are integers between 14 and 112.
Optionally, the mass ratio of the component A to the component B is 1 (0.1-1).
Optionally, the mass ratio of the component A to the component B is 1:1.
According to a second aspect of the present invention, there is provided a method of preparing a bio-hydrogel for umbilical vessel occlusion.
The preparation method of the biological hydrogel for umbilical vessel occlusion comprises the following steps:
(1) Preparing a component A into a first solution, wherein the structural formula of the component A is shown as a formula I:
a method for preparing the compound of formula I,
and n is an integer between 2 and 1000;
(2) Preparing the component B into a second solution, wherein the structural formula of the component B is shown as a formula II:
II, the step of setting the position of the base plate,
and m is an integer between 2 and 1000;
(3) According to the mass ratio of the component A to the component B of 1 (0.1-10), mixing the first solution and the second solution together to obtain the biological hydrogel for umbilical vessel occlusion.
Optionally, the mass concentration of the component A in the first solution in the step (1) is 50mg/mL-500mg/mL;
the mass concentration of the component B in the second solution in the step (2) is 50mg/mL-500mg/mL.
Optionally, the mass concentration of the component A in the first solution in the step (1) is 100mg/mL-300mg/mL;
the mass concentration of the component B in the second solution in the step (2) is 100mg/mL-300mg/mL.
Optionally, the solvent of the first solution in the step (1) is one of secondary water, ultrapure water, physiological saline or phosphate buffer with a pH of 7.4;
the solvent of the second solution in the step (2) is one of secondary water, ultrapure water, physiological saline or phosphate buffer solution with pH of 7.4.
Optionally, the mass ratio of the component A in the first solution in the step (1) to the component B in the second solution in the step (2) is 1 (0.1-1).
Optionally, the mass ratio of the component A in the first solution in the step (1) to the component B in the second solution in the step (2) is 1:1.
The component of the biological hydrogel adopted by the invention is an FDA approved substance and has good biocompatibility. The biological hydrogel has good vascular plugging performance, can form gel in situ in a blood environment in a blood vessel, and can completely plug the blood vessel. Moreover, the biological hydrogel disclosed by the invention is convenient to operate in operation, can be punctured into a blood vessel under the guidance of B ultrasonic, is directly injected into the blood vessel to seal the blood vessel through a simple double-channel/single-channel injector, and is short in operation time, small in risk and definite in effect. Thus, the biological hydrogels of the present invention can be used for multiple pregnancy termination where conventional methods are not capable or suitable for plugging umbilical vessels.
Other features of the present invention and its advantages will become apparent from the following detailed description of exemplary embodiments of the invention, which proceeds with reference to the accompanying drawings.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description, serve to explain the principles of the invention.
FIG. 1 is a scanning electron microscope image of a biological hydrogel for umbilical vessel occlusion.
Fig. 2 is a compression curve of a bio-hydrogel for umbilical vessel occlusion.
Fig. 3 is a rheological profile of a bio-hydrogel for umbilical vessel occlusion.
FIG. 4 is a graph of the swelling rate of in vitro degradation of a bio-hydrogel for umbilical vessel occlusion.
Detailed Description
Various exemplary embodiments of the present invention will now be described in detail with reference to the accompanying drawings. It should be noted that: the relative arrangement of the components and steps, numerical expressions and numerical values set forth in these embodiments do not limit the scope of the present invention unless it is specifically stated otherwise.
The following description of at least one exemplary embodiment is merely exemplary in nature and is in no way intended to limit the invention, its application, or uses.
Techniques, methods, and apparatus known to one of ordinary skill in the relevant art may not be discussed in detail, but are intended to be part of the specification where appropriate.
In all examples shown and discussed herein, any specific values should be construed as merely illustrative, and not a limitation. Thus, other examples of exemplary embodiments may have different values.
The biological hydrogel for umbilical vessel occlusion provided by the invention comprises a component A and a component B with the mass ratio of 1 (0.1-10), wherein,
the structural formula of the component A is shown as formula I:
a formula I;
the structural formula of the component B is shown as a formula II:
a formula II;
wherein n and m are integers of from 2 to 1000.
The molecular weight of component A may be 2000-20000 daltons.
The molecular weight of component B may be 2000-20000 daltons.
The biological hydrogel for umbilical vessel occlusion is a four-arm polyethylene glycol (Tetra-PEG) hydrogel with injectable and strong tissue adhesion characteristics, has excellent mechanical strength, high swelling rate, long degradation time and excellent cell compatibility, and can realize umbilical vessel occlusion in a human body.
The biological hydrogel for umbilical vessel plugging disclosed by the invention is prepared by mixing two different components according to a certain mass ratio without adding any cross-linking agent, and can be quickly adhered to the surface of a tissue. Because the internal network structure of the four-arm polyethylene glycol hydrogel is regular, the four-arm polyethylene glycol hydrogel has excellent bulk strength. The cross-linking reaction can be quickly carried out with-NH 2 on the surface protein of the tissue at the moment of contacting the tissue, thereby endowing strong tissue adhesiveness.
In addition, hydrogels have a compact internal microstructure and good mechanical properties (e.g., compression, rheology).
In particular, since there are no readily hydrolyzable groups in the bio-hydrogels used for umbilical vessel occlusion, a long degradation time can be maintained in vivo or in the blood environment.
Further, n and m are integers between 14 and 112.
In order to achieve better in-situ gel forming effect, the mass ratio of the component A to the component B is 1 (0.1-1).
Further, the mass ratio of the component A to the component B is 1:1. The mass ratio of the component A to the component B1:1 is favorable for leading the structure of the hydrogel network to be more regular, thereby improving the mechanical property.
The preparation method of the biological hydrogel for umbilical vessel occlusion comprises the following steps:
(1) Preparing a component A into a first solution, wherein the structural formula of the component A is shown as a formula I:
a method for preparing the compound of formula I,
and n is an integer between 2 and 1000.
Further, n may be an integer between 14 and 112.
The molecular weight of component A may be 2000-20000 daltons.
To facilitate the use of the biological hydrogel, the mass concentration of component A in the first solution is 50mg/mL-500mg/mL. Further, the mass concentration of the component A in the first solution is 100mg/mL-300mg/mL.
In specific implementation, the solvent of the first solution is one of secondary water, ultrapure water, physiological saline or phosphate buffer solution with pH of 7.4.
(2) Preparing the component B into a second solution, wherein the structural formula of the component B is shown as a formula II:
II, the step of setting the position of the base plate,
and m is an integer between 2 and 1000.
Further, m may be an integer between 14 and 112.
The molecular weight of component B may be 2000-20000 daltons.
In order to facilitate the use of the biological hydrogel, the mass concentration of the component B in the second solution is 50mg/mL-500mg/mL. Further, the mass concentration of the component B in the second solution is 100mg/mL-300mg/mL.
In specific implementation, the solvent of the second solution is one of secondary water, ultrapure water, physiological saline or phosphate buffer solution with pH of 7.4.
(3) According to the mass ratio of the component A to the component B of 1 (0.1-10), mixing the first solution and the second solution together to obtain the biological hydrogel for umbilical vessel occlusion.
Further, the mass ratio of the component A in the first solution in the step (1) to the component B in the second solution in the step (2) is 1 (0.1-1).
Further, the mass ratio of the component A in the first solution in the step (1) to the component B in the second solution in the step (2) is 1:1.
Hereinafter, the present disclosure will be described with specific examples. The experimental procedures used in the examples below are conventional, and the materials and reagents used, unless otherwise indicated, are commercially available, and the equipment used in the experiments, unless otherwise indicated, are well known to those skilled in the art.
Example 1
400 and mg of component A (molecular weight 20000 daltons) was weighed and dissolved in 2 and mL of pure water to obtain a first solution. 400 and mg of component B (molecular weight 20000 daltons) was dissolved in 2 and mL of pure water to obtain a second solution. The first solution and the second solution were aspirated using a double syringe and simultaneously injected into the sample vials, then the vials were inverted and the gel time was recorded. The time when the gel does not flow backwards is the gel forming time. The gel time was tested by inversion. Experimental results show that the gel forming time is 3-5 seconds, and meets the operation requirement in operation.
Example 2
200 mg component A (molecular weight 2000 daltons) was weighed and dissolved in 1 mL pure water to give a first solution. 180 mg of component B (molecular weight 2000 daltons) was weighed out as 1 mL pure water to obtain a second solution. The double-tube injector is adopted to absorb the first solution and the second solution, the first solution and the second solution are injected into the sample bottle at the same time, and then the scanning electron microscope is used for observing that the PEG hydrogel internal structure visible hydrogel has a compact internal microstructure (shown as figure 1), which shows that the umbilical vessel can be effectively plugged, and the requirement of umbilical vessel plugging in operation is met.
Example 3
300 and mg of component A (molecular weight 20000 daltons) was weighed and dissolved in 2 and mL of pure water to obtain a first solution. 300 and mg of component B (molecular weight 20000 daltons) was dissolved in 2 and mL of pure water to obtain a second solution. Sucking the first solution and the second solution by adopting a double-tube syringe, and simultaneously injecting the first solution and the second solution into a sample bottle to form gel. The mechanical strength of the hydrogel was evaluated by compression experiments, and as can be seen from fig. 2, when the compression set was 90%, the compressive strength of the hydrogel could reach 1.8MPa, and the surface had excellent compressive strength.
The rheological properties of the hydrogels were measured using a rheometer, and as can be seen in FIG. 3, the storage modulus (G ') of the hydrogels obtained in example 3 was always greater than the loss modulus (G'), indicating a gel state. Moreover, the storage modulus of the hydrogel was about 5000Pa, indicating that it has a high modulus and excellent mechanical strength.
Example 4
600 mg of component A (molecular weight 10000 daltons) was weighed and dissolved in 3 mL pure water to obtain a first solution. 600 mg of component B (molecular weight 10000 daltons) was dissolved in 3 mL pure water to obtain a second solution. The first solution and the second solution are sucked by a double-tube injector, and in-vitro experiments simulate that the first solution and the second solution can be directly injected into umbilical vessels through the double-tube injector, and the umbilical vessels are completely plugged by in-situ gel formation.
According to the experimental results, the hydrogel obtained in example 4 can effectively seal umbilical vessels, and the sealing strength results show that the hydrogel can bear 3000 mm water column pressure after sealing the vessels, which is far greater than the normal blood pressure range (1224-1904 mm water column).
Example 5
360 mg of component A (molecular weight 20000 daltons) was weighed out and dissolved in 2 mL of pure water to obtain a first solution. 360 mg of component B (molecular weight 20000 daltons) was weighed and dissolved in 2 mL of pure water to obtain a second solution. Aspiration of the first solution and second solution Using a double syringeSolution and simultaneously injecting the first solution and the second solution into a cylindrical mold to prepare a PEG hydrogel having a diameter of 15mm and a height of 7.5 mm. The hydrogel was weighed and the initial weight (W 0 ) Then placed in 50 mL phosphate buffer (pH 7.4) at 37 ℃. After a specified time interval, the sample is removed and weighed (W t ) And the swelling ratio was calculated. The calculation formula of the swelling ratio is as follows: swelling ratio= (W) t –W 0 )/W 0
As shown in FIG. 4, the hydrogel obtained in example 5 was not degraded after 6 months in vitro, and was effective in providing a durable blocking effect. The recanalization after the vascular occlusion is one of the great concerns of applying the vascular occlusion agent, and the degradation time of the product is greatly prolonged compared with that of similar products, thereby being beneficial to realizing long-term vascular occlusion in vivo.
While certain specific embodiments of the invention have been described in detail by way of example, it will be appreciated by those skilled in the art that the above examples are for illustration only and are not intended to limit the scope of the invention. It will be appreciated by those skilled in the art that modifications may be made to the above embodiments without departing from the scope and spirit of the invention. The scope of the invention is defined by the appended claims.

Claims (7)

1. A biological hydrogel for umbilical vessel occlusion is characterized by comprising a component A and a component B in a mass ratio of 1 (0.1-1), wherein,
the structural formula of the component A is shown as formula I:
the structural formula of the component B is shown as a formula II:
wherein n and m are integers of 14 to 112.
2. The biological hydrogel for umbilical vessel occlusion according to claim 1, wherein the mass ratio of the component a and the component B is 1:1.
3. The preparation method of the biological hydrogel for umbilical vessel occlusion is characterized by comprising the following steps:
(1) Preparing a component A into a first solution, wherein the structural formula of the component A is shown as a formula I:
and n is an integer between 14 and 112;
(2) Preparing the component B into a second solution, wherein the structural formula of the component B is shown as a formula II:
and m is an integer between 14 and 112;
(3) According to the mass ratio of the component A to the component B of 1 (0.1-1), mixing the first solution and the second solution together to obtain the biological hydrogel for umbilical vessel occlusion.
4. The method according to claim 3, wherein the mass concentration of component a in the first solution of step (1) is 50mg/mL to 500mg/mL;
the mass concentration of the component B in the second solution in the step (2) is 50mg/mL-500mg/mL.
5. The method according to claim 4, wherein the mass concentration of component A in the first solution of step (1) is 100mg/mL-300mg/mL;
the mass concentration of the component B in the second solution in the step (2) is 100mg/mL-300mg/mL.
6. The method according to claim 3, wherein the solvent of the first solution in the step (1) is one of secondary water, ultrapure water, physiological saline or phosphate buffer solution having a pH of 7.4;
the solvent of the second solution in the step (2) is one of secondary water, ultrapure water, physiological saline or phosphate buffer solution with pH of 7.4.
7. A method of preparation according to claim 3, wherein the mass ratio of component a in the first solution of step (1) to component B in the second solution of step (2) is 1:1.
CN202311400756.0A 2023-10-26 2023-10-26 Biological hydrogel for umbilical vessel occlusion and preparation method thereof Active CN117122725B (en)

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