CN114558166A

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Info

Publication number: CN114558166A
Application number: CN202210237643.2A
Authority: CN
Inventors: 冯祖建; 王伟伟; 黄平升; 张闯年
Original assignee: Institute of Biomedical Engineering of CAMS and PUMC
Current assignee: Institute of Biomedical Engineering of CAMS and PUMC
Priority date: 2022-03-11
Filing date: 2022-03-11
Publication date: 2022-05-31
Anticipated expiration: 2042-03-11
Also published as: CN114558166B

Abstract

The invention discloses a biodegradable ultraviolet curing medical adhesive, which is obtained by one-step reaction of itaconic acid, sebacic acid and xylitol through melt polycondensation. Also discloses a preparation method and application thereof in preparing medical adhesives. The method is simple and easy to control, and has no solvent residue; the prepared adhesive has strong adhesive property, degradability and good biocompatibility; and the curing and the use are convenient and quick, and the requirements of sealing different tissues can be met.

Description

Biodegradable ultraviolet-curing medical adhesive and preparation method and application thereof

Technical Field

The invention relates to the technical field of polymer material synthesis, in particular to a biodegradable ultraviolet curing medical adhesive and a preparation method and application thereof.

Background

Tissue wound closure is the last ring of surgery and is also critical to the success of the surgery. Traditional surgical suture and staple are the most common tissue closing means, but have the defects of high implementation technical difficulty, long time consumption, easy infection, incomplete healing and the like, and limit the clinical application.

Tissue adhesives are an alternative to sutures and staples, are easy to use, are short in time, produce less pain, do not require removal, and generally provide better cosmetic results. However, the existing tissue adhesives also have some inherent drawbacks, for example, cyanoacrylate-based tissue adhesives adhere very strongly to tissue, but are not elastic and cause severe inflammatory reactions and toxicity, limiting their application to biological tissues; hydrogels such as cross-linked polyethylene glycol and fibrinogen-based adhesives are good in biocompatibility, but relatively poor in adhesion, and therefore most hydrogels only act as topical dressings or sealants. The ideal tissue adhesive should be liquid for ease of use, but cure quickly after sizing; at the same time, adhesion and cohesive strength, biodegradability, elasticity and biocompatibility should be maintained.

In recent years, adhesives based on photocuring have shown great potential in tissue sealing during surgery due to their controllable curing rate and mechanical properties, better in vivo stability and tissue adhesion. However, most of the existing light-cured tissue adhesives are water-soluble materials, so that the adhesives can easily absorb body fluid, thereby reducing the adhesion and cohesion and causing the failure of the operation; and because of the difference between various tissues of a human body, how to develop the tissue sealant suitable for various conditions more specifically has huge challenges.

Therefore, there is a need to develop a tissue adhesive that is simple to prepare, low in cost, and has excellent adhesive properties, degradability, and biocompatibility.

Disclosure of Invention

In view of the above, the invention provides a biodegradable ultraviolet-curable medical adhesive and a preparation method thereof, wherein the method is simple and easy to control and has no solvent residue; the prepared adhesive has excellent adhesiveness, degradability and biocompatibility; and the curing and the use are convenient and quick.

In order to achieve the purpose, the invention adopts the following technical scheme:

the biodegradable ultraviolet curing medical adhesive is prepared with itaconic acid, sebacic acid and xylitol and through melt polycondensation.

Itaconic acid is unsaturated dibasic organic acid, is a product of glucose in vivo metabolism, has remarkable anti-inflammatory and antibacterial activities, widely participates in anti-inflammatory signal pathways, is introduced into the synthesis of adhesive, can relieve local inflammation caused by the adhesive, and effectively promotes the repair of related tissues. Moreover, the itaconic acid has a conjugated unsaturated double bond structure, and is introduced into the adhesive, so that the cohesion of the system can be improved through photocuring, the curing condition is simplified, and the curing time and the degradation period of the adhesive are effectively regulated and controlled. The bonding performance can be further effectively adjusted by the hydrogen bond of the xylitol polyhydroxy, and the elasticity of the system can be further adjusted by adding the sebacic acid, so that the xylitol polyhydroxy bonding adhesive, the sebacic acid and the sebacic acid are indispensable. The hydrophobic polyester material prepared from the material can effectively avoid the problem of reduced cohesion caused by water absorption; in addition, dibasic acid and polyalcohol which are derived from a metabolic system and have good biocompatibility are used as biodegradable adhesive material synthesis monomers, so that the prepared adhesive material has good biocompatibility.

Preferably, the feeding molar ratio of the sebacic acid to the itaconic acid is 9:1-5: 5;

the molar ratio of the total feeding amount of the sebacic acid and the itaconic acid to the xylitol is 1:2-2: 1.

Further, the viscosity of the biodegradable ultraviolet-curing medical adhesive is 50-1100 Pa.s.

Further preferably, the feeding molar ratio of the sebacic acid to the itaconic acid is 9:1-7: 3;

the molar ratio of the total feeding amount of the sebacic acid and the itaconic acid to the xylitol is 1:2-1: 1.

The preparation method of the biodegradable ultraviolet curing medical adhesive comprises the following steps:

mixing itaconic acid, sebacic acid and xylitol, and heating and melting under the protection of inert gas; then reacting for 1-24h at 100-150 ℃ under the vacuum condition; and cooling to obtain the biodegradable ultraviolet curing medical adhesive PXIS.

Preferably, the reaction is carried out for 4-8h at 135-150 ℃ under vacuum.

Preferably, the heating and melting temperature is 130-150 ℃, and the time is 0.5-6 h;

the vacuum degree under vacuum condition is 5-100 Pa.

The biodegradable ultraviolet-curing medical adhesive is mixed with a photoinitiator with a catalytic amount, uniformly coated on the surface of an object to be bonded, and cured to form a film-shaped bonding material after ultraviolet irradiation.

Preferably, the photoinitiator comprises I2959, I1173, benzoin bis methyl ether, (2,4, 6-trimethylbenzoyl) diphenyl phosphine oxide; the amount of the photoinitiator catalyst is 0.05-1% of the molar amount of the itaconic acid.

Preferably, the ultraviolet light irradiation time is 10-300s, and the ultraviolet light wavelength is 365 nm.

The biodegradable ultraviolet curing medical adhesive is mixed with photoinitiator in catalytic amount, painted to the surface of the matter to be adhered and cured through ultraviolet irradiation.

A medical adhesive comprises the biodegradable ultraviolet-curing medical adhesive and a photoinitiator.

According to the technical scheme, the biodegradable ultraviolet curing medical adhesive is prepared from the monomer materials with good biocompatibility, namely itaconic acid, sebacic acid and xylitol, so that the biocompatibility of the adhesive can be improved; itaconic acid is introduced to prepare the adhesive, ultraviolet curing can be directly carried out, double bonds are introduced without adding a second step of reaction, and the curing time is short and the operation is easy; the adhesive is flowable viscous semisolid at normal temperature, has excellent tissue adhesion after being cured, and can further meet the requirements of sealing different tissues.

Drawings

FIG. 1 shows an IR spectrum of the binder obtained in example 1 (PXIS binder, sebacic acid, itaconic acid, and xylitol, respectively, from top to bottom);

FIG. 2 shows the shear adhesion strength of a PXIS adhesive and a commercial glue;

FIG. 3 shows the shear adhesion energy of a PXIS adhesive and a commercial glue;

FIG. 4 shows a pathological section of a PXIS adhesive after one month of subcutaneous implantation;

FIG. 5 is a graph comparing a PXIS adhesive to a suture-treated rat skin wound;

FIG. 6 is a pathological section of a PXIS adhesive and suture-treated rat skin wound at day 14.

Detailed Description

The technical solutions in the embodiments of the present invention are clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be obtained by a person skilled in the art without making any creative effort based on the embodiments in the present invention, belong to the protection scope of the present invention.

Example 1

16.18g (0.08mol) of sebacic acid, 2.60g (0.02mol) of itaconic acid and 15.2g (0.1mol) of xylitol were weighed out separately and put into a three-necked round-bottomed flask, and the mixture was subjected to magnetic stirring in an oil bath at 140 ℃ under nitrogen protection for 30min to completely melt the reaction monomers. Then the system pressure is reduced to 10Pa by a vacuum pump, and polycondensation reaction is carried out for 8h at 135 ℃ to obtain the PXIS-1 adhesive. FIG. 1 shows an infrared spectrum of a PXIS-1 binder, demonstrating the successful synthesis of polymer PXIS.

Examples 2 to 10

The amount of each monomer used, the polycondensation reaction temperature, and the polycondensation reaction time were adjusted in addition to those of example 1, and are shown in table 1.

TABLE 1 raw materials, compounding ratio, reaction time and temperature for examples 2-10

The tissue adhesives should be flowable, viscous semi-solids prior to curing to facilitate sizing for subsequent application. The complex viscosity of the PXIS binder obtained in examples 1 to 10 at normal temperature was measured by a rheometer, and the results are shown in the following table, where the viscosity of PXIS has a close relationship with the raw material ratio, the reaction temperature and the reaction time.

TABLE 2 viscosity and curing time of the adhesives obtained in examples 1-10

The tissue adhesive should also have a suitable cure time, neither too fast nor too slow for practical operation. PXIS is uniformly mixed with a photoinitiator and then is subjected to laser irradiation at 365nm (200 mW/cm)^-2) The lower cure time, 90s, was recorded and as shown in table 2, was primarily affected by the itaconic acid content, which increased with increasing itaconic acid content.

The viscosity and curing time of PXIS are considered together, and then PXIS-1, PXIS-3 and PXIS-6 are selected to perform the following experiments.

The adhesion performance of the PXIS adhesive was tested using the lap shear tensile test:

firstly, selecting a glass plate with the width of 1cm as a base material, and uniformly coating a gelatin solution with the weight percent of 20 on the glass plate to simulate the tissue surface; after drying for 24h at normal temperature, the lap shear test is carried out. Uniformly mixing the PXIS with a photoinitiator I2959 with the molar weight of itaconic acid being 0.58% before sizing, dropwise adding the mixture to one end of a treated glass plate, and uniformly coating the treated glass plate; then, overlapping the other glass plate on the glass plate coated with the PXIS, wherein the overlapping area is 1cm multiplied by 1 cm; then the mixture is subjected to in-situ light curing (the wavelength is 365nm, and the concentration is 200 mW/cm)^-2) So that the two lapped glass plates are well bonded and the whole body does not generate relative displacement. Further testing the anti-shearing tensile strength of each group of glass plates by using a universal tensile machine, and testing commercial PEG glue, polyurethane glue, PVC glue and collagen fiber by using the same methodShear adhesion strength of biological glue and cyanate ester glue. The shear adhesion strength refers to the maximum tensile strength of the glass sheet in complete peeling, and the shear adhesion energy refers to the work in the whole process from stretching to complete peeling, and is obtained by integrating the stretching curve. Fig. 2 shows the shear adhesion strength of PXIS adhesive and commercial glue, and fig. 3 shows the shear adhesion energy of PXIS adhesive and commercial glue.

The result of the attached figure 2 shows that the shear adhesion strength of the PXIS after ultraviolet curing reaches 2.7-7.5 MPa, and the maximum shear adhesion strength is 8.4 times that of polyurethane glue, 122 times that of PEG glue, 167 times that of collagen fiber biological glue, 16.5 times that of PVC glue and 2.0 times that of cyanate ester glue. And moreover, since the cured PXIS has good elasticity and ductility, the shear tensile stress on the bonding part can be effectively dissipated. For example, cyanate ester glue has strong interfacial force, but it is an interface without any elasticity after curing, so that the dissipation of stress is poor and the adhesion energy is low. As shown in figure 3, the adhesion of the PXIS adhesive can reach 13.3-22.8 kJ/m^-2The maximum adhesion energy is 11.4 times of that of polyurethane glue, 51 times of that of PEG glue, 77 times of that of collagen fiber biological glue, 11.6 times of that of PVC glue and 8.3 times of that of cyanate ester glue. Thus PXIS adhesives have excellent adhesion properties.

A200. mu.L sample of cured PXIS binder was placed in 5mL of 100U/mL lipase-containing PBS solution and tested for in vitro degradation cycle of the PXIS binder by simulating an in vivo environment in a 37 ℃ thermostat. The complete degradation time of each sample is shown in table 3, which indicates that the obtained PXIS adhesive has good biodegradability.

TABLE 3 degradation cycle of PXIS adhesive

After curing, 200. mu.L of the XIS adhesive was implanted on the lateral dorsal side of Balb/C mice. After one month, the skin tissue at the site of implantation was subjected to eosin-hematoxylin staining to test the biocompatibility and inflammatory response of the material in vivo. The results are shown in fig. 4, where the tissue at the site of material implantation had a small amount of inflammatory cell infiltration compared to normal skin tissue. However, the material does not cause a large amount of inflammatory reaction or structural pathological changes of the skin, and the PXIS adhesive obtained by the invention is proved to have good tissue biocompatibility.

In order to expand the application of the PXIS adhesive, a rat skin injury model is constructed, and the effect of the PXIS adhesive in wound closure is investigated.

First, adult SD rats were anesthetized for skin preparation, and wounds 1cm long were wounded on the backs of the rats with surgical scissors. The rats were randomly divided into two groups, one group was wound-sutured by conventional suture, the other group was directly smeared with PXIS-1, and then photo-cured (photoinitiator I2959, used in an amount of 0.58% by mole of itaconic acid, curing conditions: curing time 60s, illumination wavelength 365nm, andillumination power 200 mW/cm)^-2). And (5) inspecting the skin wound closed operation time, the blood loss condition and the wound later-stage repair condition. As a result, as shown in table 4, fig. 5 and fig. 6, the PXIS adhesive greatly reduced the operation time, had more convenient operability, and also reduced blood loss during the closure process, compared to the suture set. More importantly, compared with suture, the PXIS adhesive accelerates the repair of skin wounds and shortens the time for wound repair because the adhesive has good histocompatibility, no secondary wound to the wounds and good fit to the wound area.

Table 4 PXIS adhesive and suture treatment skin wound indices

The general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. The biodegradable ultraviolet curing medical adhesive is characterized in that,

is prepared by one-step reaction of itaconic acid, sebacic acid and xylitol through melt polycondensation.

2. The biodegradable UV-curable medical adhesive according to claim 1,

the feeding molar ratio of the sebacic acid to the itaconic acid is 9:1-5: 5;

3. The biodegradable UV-curable medical adhesive according to claim 1 or 2,

the viscosity before curing is 50-1100 pas.

4. The method for preparing the biodegradable ultraviolet-curable medical adhesive according to any one of claims 1 to 3, characterized by comprising the steps of:

5. The method for preparing biodegradable UV-curable medical adhesive according to claim 4,

the heating and melting temperature is 130-150 ℃, and the time is 0.5-6 h;

the vacuum degree under the vacuum condition is 5-100 Pa.

6. Use of the biodegradable UV-curable medical adhesive according to any one of claims 1 to 3 for the preparation of a bonding material,

the biodegradable ultraviolet-curing medical adhesive is mixed with a photoinitiator with a catalyst amount, uniformly coated on the surface of an object to be bonded, and cured to form a film-shaped bonding material after ultraviolet irradiation.

7. The use according to claim 6,

the photoinitiator comprises I2959, I1173, benzoin dimethyl ether, (2,4, 6-trimethylbenzoyl) diphenyl phosphine oxide; the amount of the photoinitiator catalyst is 0.05-1% of the molar amount of the itaconic acid.

8. The use according to claim 6,

the ultraviolet irradiation time is 10-300s, and the wavelength of the ultraviolet light is 365 nm.

9. A medical adhesive is characterized in that,

mixing the biodegradable ultraviolet-curable medical adhesive of any one of claims 1 to 3 with a catalyst amount of photoinitiator, uniformly coating the mixture on the surface of an object to be bonded, and curing the mixture after ultraviolet irradiation.

10. A medical adhesive is characterized in that,

comprising the biodegradable uv curable medical adhesive according to any one of claims 1 to 3 and a photoinitiator.