Photo-initiated difunctional glucan biological tissue adhesive, preparation method and application thereof, and biological tissue gel sheet

Abstract

The invention provides a photo-initiated difunctional glucan biological tissue adhesive as well as a preparation method and application thereof and a biological tissue gel sheet. The difunctional glucan biological tissue adhesive is obtained by polymerizing difunctional glucan and a photoinitiator under the initiation of illumination; according to the difunctional glucan, glucan, a carboxylic acid aldehyde group compound and a carboxylic acid olefin compound are subjected to an esterification reaction to introduce an aldehyde group and an olefin group on the glucan, and the molecular weight range of the glucan is 1-10000 kDa. Two active groups, namely an aldehyde group and an olefin group, are simultaneously introduced to glucan through esterification reaction to prepare difunctional polydextran, and the grafting proportion of the two active groups on the glucan can be adjusted as required, so that the tissue bonding strength and the mechanical strength of the adhesive are regulated and controlled; a mixed solution of the system and a photoinitiator can realize gelation and moderate mechanical strength under light triggering, so that the system can be applied to skin wounds and tissue mucosa wounds.

Description

Technical Field

[0001] This invention belongs to the field of biomedical materials technology, and particularly relates to a photo-initiated bifunctional dextran bio-tissue adhesive, its preparation method, application, and bio-tissue gel sheet. Background Technology

[0002] In the medical and emergency care fields, tissue adhesives are rapidly becoming the ideal choice for treating skin wounds, especially deep incisions. Compared to traditional sutures, these adhesives can quickly seal wounds, forming a flexible, airtight layer that promotes healing, reduces the risk of infection, and improves patient comfort. Typically made from highly biocompatible materials, tissue adhesives have great potential for use in common or deep wounds and can be applied simultaneously in both civilian and military applications.

[0003] A new adhesive for skin wounds has been synthesized using modern new materials technology, providing a quick and safe method for wound closure and solving many pain points in clinical applications and daily life.

[0004] Clinical pain points Reduce surgery time and pain: Traditional suturing: Traditional suturing methods are not only time-consuming, but also cause greater pain to patients, especially when local anesthesia is insufficient or multiple stitches are required. For children, the elderly, or patients with special conditions, suturing procedures can increase their psychological and physiological burden.

[0005] Wound adhesives: Using wound adhesives can significantly shorten operation time, eliminate the need for sutures, reduce patient pain and anxiety, and improve the work efficiency of medical staff.

[0006] Reduce the risk of infection: Traditional suturing: Sutures can become a breeding ground for bacteria, increasing the risk of wound infection. Scar tissue can also become unsightly due to the tension of the sutures.

[0007] Wound adhesives: The protective film formed by adhesives can effectively seal wounds, prevent the invasion of pathogens, reduce the risk of infection, and the adhesives themselves usually have antibacterial components, which help keep the wound clean.

[0008] Improves wound healing and appearance: Traditional suturing: Sutures may cause uneven tension on both sides of the wound, affecting wound healing and easily forming noticeable scars.

[0009] Wound adhesives: Wound adhesives can evenly distribute wound tension, reduce scar formation, and generally provide a more aesthetically pleasing healing effect, especially suitable for the face and other areas where appearance is a high concern.

[0010] Applicable to special cases: Traditional suturing: Not suitable for certain delicate skin types, such as the elderly or patients with skin diseases, whose skin is thinner and sutures are prone to tearing or causing discomfort.

[0011] Wound adhesive: Suitable for all skin types, including fragile or tense areas, providing a gentler approach to wound care.

[0012] Daily pain points Simplify first aid and home care: Traditional suturing: requires specialized medical equipment and professionals, and is not suitable for use in non-medical environments.

[0013] Wound adhesive: can quickly treat wounds at home, in the workplace or outdoors in emergencies, without requiring special medical skills, making it convenient for home first aid, especially suitable for home care and everyday minor injuries.

[0014] Improving the convenience of life: Traditional suturing requires subsequent suture removal and wound care, increasing the burden and cost of follow-up visits for patients.

[0015] Wound adhesive: No special care is required after application. The adhesive will fall off naturally, reducing the need for follow-up visits and the burden of follow-up, and improving patients' quality of life and freedom of daily activities.

[0016] Facilitating trauma management in children: Traditional suturing: Children are often afraid of suturing surgery and find it difficult to cooperate.

[0017] Wound adhesives: The painless and rapid closure characteristics of wound adhesives significantly reduce children's fear in injury treatment, and make it easier for parents to handle minor wounds on their children.

[0018] Reduce the consumption of medical resources: Traditional suturing requires specialized medical equipment and facilities, increasing the hospital's resource consumption.

[0019] Wound adhesives: can effectively reduce the use of medical facilities and personnel, lower medical costs, and are suitable for use in community clinics and resource-limited areas.

[0020] The role of wound adhesives in addressing clinical and everyday pain points is undeniable. From accelerating wound treatment and healing and reducing the risk of infection to improving aesthetics and convenience, wound adhesives have become an essential tool in modern wound care. They not only provide healthcare professionals with an efficient means of wound management but also offer ordinary people a simple and effective home care solution, significantly improving the treatment experience and quality of life.

[0021] Faced with these challenges, and with advancements in medical technology, biomaterials have been extensively studied and applied in various clinical surgeries. Against this backdrop, the development of a novel bio-repair material to address these issues has become particularly urgent. This is not only to provide safer and more effective treatment options, but also to significantly reduce the risk of infection caused by cerebrospinal fluid leakage, thus offering greater protection for patients' lives. Summary of the Invention

[0022] To address the above technical problems, this invention provides a photoinitiated bifunctional dextran bio-tissue adhesive, its preparation method, applications, and bio-tissue gel sheets. By introducing both aldehyde and olefin groups onto the dextran through esterification, a bifunctional dextran is obtained. The grafting ratio of the two active units onto the dextran can be adjusted as needed, thereby controlling the tissue adhesion strength and the mechanical strength of the adhesive itself. A mixed solution of the above system and a photoinitiator can achieve gelation and moderate mechanical strength under photo-triggered conditions, making it suitable for healing skin wounds or mucous membranes.

[0023] To achieve the above objectives, the technical solution of the present invention is as follows: A photo-initiated bifunctional dextran bio-tissue adhesive is applied to skin or tissue mucosal wounds. The bifunctional dextran bio-tissue adhesive is obtained by polymerizing bifunctional dextran and a photoinitiator under photo-initiated conditions. The bifunctional dextran is formed by esterification of dextran with carboxylic acid aldehyde compounds or carboxylic acid olefin compounds to introduce aldehyde and olefin groups onto the dextran. The molecular weight of the dextran ranges from 1 to 10,000 kDa, preferably from 200 to 1,500 kDa. Typical non-limiting examples include 200 kDa, 300 kDa, 400 kDa, 500 kDa, 600 kDa, 700 kDa, 800 kDa, 900 kDa, 1000 kDa, 1100 kDa, 1200 kDa, 1300 kDa, 1400 kDa, 1500 kDa, etc., and any value within the range formed by any two of these values, with a further preferred value of 200-1,000 kDa.

[0024] Preferably, the mass ratio of the dextran, carboxylic aldehyde compound, and carboxylic olefin compound is 1:0.005-20:0.005-20. Adjusting the grafting ratio of aldehyde and olefin groups introduced onto the dextran can control the required adhesive strength and mechanical strength. Typical non-limiting examples are 1:0.1:0.3, 1:0.01:20, 1:20:0.01, 1:0.4:015, 1:0.3:018, and any ratio within the range of two of these ratios.

[0025] Preferably, the carboxylic acid aldehyde compound is selected from any one of 2-(4-formylphenyl)acetic acid, 2-(4-formylphenoxy)acetic acid, 3-(4-aldehydephenyl)propionic acid, 2-(2-formyl-6-methoxyphenoxy)acetic acid, and 4-formylcinnamic acid.

[0026] Preferably, the carboxylic acid olefin compound is selected from any one of 6-acryloylaminohexanoic acid, 5-hexenoic acid, 4-enpentanoic acid, 2-carboxyethyl acrylate, and 3-(allyloxy)propionic acid.

[0027] Preferably, the mass ratio of the bifunctional dextran to the photoinitiator is 1:0.01-10, and typical non-limiting examples are 1:0.056, 1:0.71, 1:0.01, 1:10, and any ratio within the range formed by any two of these ratios.

[0028] Preferably, the photoinitiator is selected from any one or more of the following: lithium phenyl (2,4,6-trimethylbenzoyl) phosphate, aromatic ketone photoinitiators, polycyclic aromatic hydrocarbon photoinitiators, polysilane photoinitiators, acylphosphonate photoinitiators, azo photoinitiators, or organometallic complexes.

[0029] Based on the same inventive concept, this invention also provides a method for preparing a photo-initiated bifunctional dextran bio-tissue adhesive, comprising the following steps: S1: Dextran, carboxylic aldehyde compound, and carboxylic olefin compound are dissolved in an organic solvent to form a solution. An esterification catalyst is added, and the mixture is stirred for 4-12 hours. The mixture is then filtered and dried to obtain bifunctional dextran. S2: Dissolve the bifunctional dextran in water or a mixture of water and polar organic solvents such as isopropanol and / or ethanol, add a pre-proportioned photoinitiator to dissolve and mix, and obtain a prepolymer solution; S3: The prepolymer liquid from step S2 is dropped onto the application site, and then photoinitiation of the prepolymer liquid is initiated by irradiation with a photoinitiator.

[0030] Preferably, the esterification catalyst in step S1 is selected from any one or a mixture of several of dicyclohexylcarbodiimide, 4-dimethylaminopyridine, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride or pyridine-sulfonyl chloride.

[0031] Preferably, the organic solvent in step S1 is selected from any one or a mixture of several of dichloromethane, N,N-dimethylformamide, dimethyl sulfoxide, or tetrahydrofuran.

[0032] Preferably, in step S3, the wavelength of the light used to initiate the crosslinking reaction is 100-1000 nm, and the illumination time is 1-60 s. Typical non-limiting wavelengths include 100 nm, 200 nm, 300 nm, 400 nm, 500 nm, 600 nm, 700 nm, 800 nm, 900 nm, 100 nm, etc., and any value within the range formed by any two of these values. Typical non-limiting illumination times include 1 s, 2 s, 3 s, 4 s, 5 s, 6 s, 7 s, 8 s, 9 s, 10 s, 20 s, 30 s, 40 s, 50 s, 60 s, etc., and any value within the range formed by any two of these values. Preferably, the illumination time is 1-10 s.

[0033] Based on the same inventive concept, this invention also provides a bifunctional dextran biological tissue gel sheet. The biological tissue gel sheet is made of the aforementioned biological tissue adhesive or a sheet-like product obtained by photoinitiating and curing a photoinitiated biological tissue adhesive prepared by the aforementioned method. It can be cut to the required size, such as 2*3*0.5cm. 3 4*5*0.5cm 3 8*10*0.5cm 3 wait.

[0034] Application of a photo-induced bifunctional dextran bio-tissue adhesive in the preparation of skin wound or tissue mucosal adhesive products.

[0035] Because the present invention adopts the above technical solution, it has the following advantages and positive effects compared with the prior art: The biological tissue adhesive provided by this invention is based on a photoinitiator and a bifunctional dextran. The bifunctional dextran is prepared by simultaneously introducing two active units, aldehyde and olefin groups, through an esterification reaction. Then, the bifunctional dextran and the photoinitiator can achieve adhesive curing and adhesion to biological tissues under photoinitiation.

[0036] Dextran itself is a natural polysaccharide composed of glucose units, possessing excellent biocompatibility and degradability. It can be gradually broken down into harmless metabolites (such as glucose) by enzymes in the body (such as dextranase). After aldehyde modification, its degradation rate can be controlled by cross-linking density, making it suitable as a temporary scaffold for tissue regeneration. Therefore, using dextran and introducing aldehyde groups onto dextran offers good biocompatibility and a controllable degradation rate, allowing the degradation rate of the adhesive to match the tissue regeneration in skin wound repair.

[0037] Introducing aldehyde groups onto dextran allows for dynamic cross-linking with amino molecules in skin tissue (such as proteins, peptides, or chitosan) via Schiff base reactions, forming a reversible covalent network. This reaction is typically carried out under mild conditions (such as neutral pH and room temperature), avoiding high temperatures or the use of toxic cross-linking agents, making it suitable for encapsulating living cells or sensitive drugs. Therefore, introducing aldehyde groups onto dextran can increase the adhesive strength between the adhesive and the skin. Furthermore, as an active group, the aldehyde group can be further coupled with amino-containing bioactive molecules (such as RGD peptides and cytokines), endowing the adhesive with functions such as promoting cell adhesion, directed differentiation, or immunomodulation. Finally, aldehydes themselves possess certain antibacterial properties (by disrupting bacterial membranes), reducing the risk of infection and making them suitable for wound dressings.

[0038] By adjusting the degree of aldehyde substitution and the ratio of olefin groups, the hardness and elastic modulus of hydrogel adhesives can be flexibly controlled to meet the mechanical needs of the skin. Under photoinitiation, the initiator crosslinks with the olefin to form a porous structure with a 3D crosslinked network based on dextran, which facilitates nutrient diffusion and cell migration.

[0039] Therefore, this tissue adhesive, composed solely of functionalized dextran and a photoinitiator, can significantly reduce the likelihood of tissue inflammation. Furthermore, the biocompatibility and biodegradability of the natural polymer provide strong safety assurance for tissue applications. Simultaneously, this adhesive can be easily and efficiently gelled via photoinitiation, exhibiting temporal and spatial tunability, making it convenient and flexible to use. By controlling the grafting ratio of aldehyde and olefin groups onto the dextran, the required biological tissue adhesion strength and the adhesive's mechanical strength can be achieved and controlled, making it suitable for suturing biological wounds on the skin.

[0040] The preparation method of the biological tissue adhesive of the present invention is simple and highly adjustable. The commercially available raw materials are low-cost. The bifunctional dextran requires only one-step chemical synthesis. The preparation process and components are simple. The specific structure and grafting ratio of the two active components are highly adjustable and have high conversion value. Attached Figure Description

[0041] Figure 1 Rheological behavior diagram of the biological tissue adhesive before and after photocrosslinking in Example 1 of this invention; Figure 2 This is a photograph of the wound in the Panamanian pig wound experimental group L1 in Application Example 1 of this invention; Figure 3 These are photographs of skin case sections L1 from the Panamanian pig wound experimental group L1 in Application Example 1 of this invention, taken at different magnifications. Figure 4 This is a photograph of the wound of the blank control group R2 of Panamanian pigs in Application Example 1 of the present invention; Figure 5This is a photograph of a skin section from the Panamanian pig wound blank control group R2 in Application Example 1 of the present invention, taken at 3.1x magnification. Figure 6 These are photographs of skin section R2-1 from the blank control group R2 of Panama pig wounds in Example 1 of the present invention, taken at 25x and 100x magnification. Figure 7 These are photographs of skin section R2-2 from the Panama pig wound blank control group R2 in Application Example 1 of this invention, taken at 25x and 100x magnification. Figure 8 This is a photograph of the wound in control group R3 of Panamanian pigs in Application Example 1 of this invention; Figure 9 This is a photograph of a skin section from the Panamanian pig wound control group R3 in Example 1 of the present invention, taken at 3.1x magnification. Figure 10 These are photographs of skin section R3-1 from the Panamanian pig wound control group R3 in Example 1 of the present invention, taken at 25x and 100x magnification. Figure 11 These are photographs of skin section R3-2 from the Panamanian pig wound control group R3 in Example 1 of the present invention, taken at 25x and 100x magnification. Figure 12 These are photographs of skin section R3-3 from the Panamanian pig wound control group R3 in Example 1 of the present invention, taken at 25x and 100x magnification. Figure 13 This is a skin stretching test diagram of the Panamanian pig wound experimental group L1 in Application Example 1 of the present invention; Figure 14 This is a skin stretch test diagram of the blank control group R2 of Panamanian pigs in Application Example 1 of the present invention; Figure 15 This is a skin stretch test diagram of the blank control group R3 of Panamanian pigs in Application Example 1 of the present invention; Figure 16 This is a photograph of the wound in control group R1 of Panamanian pigs in Application Example 1 of this invention; Figure 17 These are photographs taken on days 1, 4, and 9 after the application of adhesive to the wounds of Panamanian pigs in Application Example 1 of this invention. Figure 18 These are photographs taken on days 1, 4, and 9 after the application of adhesive to the wounds of the Panamanian pig wound control group R1 in Example 1 of the present invention. Figure 19 The images are photographs of skin sections from the wound control group R1 of Panama pigs in Application Example 1 of this invention, taken at magnifications of 3.1, 25, and 100. Detailed Implementation

[0042] This invention specifically targets skin wounds, proposing a biological tissue adhesive for use in skin wounds. This tissue adhesive addresses the disadvantages of current sutureless wound adhesives for small wounds by applying it to medical and everyday bodily trauma scenarios. Due to the exudate from skin wounds and other tissues, adhesives applied to skin or mucous membranes need to have strong adhesion in wet or liquid environments. Skin, in particular, has a certain degree of tension, especially in wounds 2-5 cm deep, where the tension is greater than in superficial wounds. The adhesive needs to maintain a good seal under strong skin edge tension and pressure from inside and outside body cavities. Therefore, this invention designs and prepares a photoinitiated dextran biological tissue adhesive for skin tissue repair applications. This biological tissue adhesive includes a bifunctional dextran and a photoinitiator, achieving gelation and excellent mechanical strength under photoinitiation. The bifunctional dextran of this invention introduces both aldehyde and olefin groups onto a natural polymer dextran via esterification. This dextran exhibits excellent biocompatibility and biodegradability, providing strong safety for use as a skin wound adhesive. After application to tissue bonding, the adhesive can fuse with and degrade within the tissue. The aldehyde groups react efficiently with the amino groups in skin tissue, thereby promoting wound healing. The olefin groups can crosslink the bifunctional dextran based on photoinitiation, resulting in a three-dimensional crosslinked gel network. This three-dimensional crosslinked microenvironment supports cell proliferation and migration. After the aldehyde groups are introduced, dynamic crosslinking with amino groups occurs via a Schiff base reaction. The acid-base responsiveness of the Schiff base bonds enables the gel... It possesses self-repairing capabilities, resisting skin tension and partially restoring its structure after mechanical damage. Furthermore, this cross-linked network uses dextran as a scaffold and introduces only aldehyde and olefin functional groups. Although there are currently peptide polymers with good biocompatibility with skin tissue, such as gelatin, this application does not use these peptide polymers. Instead, it uses dextran as a scaffold and introduces only aldehyde and olefin functional groups to form a three-dimensional gel network. This allows for gradual degradation in a specific physiological environment, achieving a degradation rate that matches tissue regeneration. Using other peptide polymers or reintroducing peptide polymers would result in a final adhesive degradation rate that does not match tissue regeneration.

[0043] Compared to other adhesives, this invention introduces aldehyde groups for stronger adhesion, which is beneficial for tension-reducing healing of skin wounds; it uses a single skeleton modification, which makes standardized production highly operable, and it also allows for faster biodegradation and better biocompatibility; the high concentration of aldehyde polymers can effectively inhibit bacterial infection.

[0044] This dextran bio-tissue adhesive can be conveniently and efficiently gelled via photoinitiation, exhibiting temporal and spatial controllability and offering ease and flexibility in use. Furthermore, the grafting ratio of the two active groups in the dextran can be adjusted as needed to achieve and control the subsequent tissue adhesion strength and the mechanical strength of the adhesive, specifically addressing the healing problems of skin wounds or mucosal wounds in different locations.

[0045] The following detailed description, in conjunction with the accompanying drawings and specific embodiments, provides a photoinitiated bifunctional dextran bio-tissue adhesive, its preparation method, applications, and bio-tissue gel sheets based on the present invention. The advantages and features of the present invention will become clearer from the following description.

[0046] Example 1 Preparation of bifunctional dextran: 2.0 g dextran (molecular weight 200 kDa), 0.8 g 2-(4-formylphenoxy)acetic acid, and 0.3 g 2-carboxyethyl acrylate were added to 50 mL dimethyl sulfoxide and stirred at room temperature to obtain a solution; then 1.56 g 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and 80 mg 4-dimethylaminopyridine were added and stirred for 12 hours; the resulting solution was precipitated in 600 mL of ice-cold ethanol and centrifuged at low temperature to obtain the polymer; the polymer was dissolved again in 80 mL of deionized water and precipitated again in ice-cold ethanol, and the bifunctional dextran was obtained by low-temperature centrifugation and freeze-drying.

[0047] 720 mg of the bifunctional dextran prepared in Example 1 was dissolved in 8 mL of deionized water to obtain a bifunctional dextran solution. 40 mg of the photoinitiator lithium phenyl (2,4,6-trimethylbenzoyl) phosphate was added and the solution was shaken or stirred until it was completely dissolved to obtain a prepolymer solution.

[0048] Example 2 Preparation of bifunctional dextran: 2.0 g of dextran (molecular weight 500 kDa), 0.3 g of 2-(4-formylphenoxy)acetic acid, and 0.8 g of 2-carboxyethyl acrylate were added to 60 mL of dimethyl sulfoxide and stirred at room temperature to obtain a solution; then 1.86 g of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and 80 mg of 4-dimethylaminopyridine were added and stirred for 4 hours; the resulting solution was precipitated in 600 mL of ice-cold ethanol and centrifuged at low temperature to obtain the polymer; the polymer was dissolved again in 80 mL of deionized water and precipitated again in ice-cold ethanol, and the bifunctional dextran was obtained by low-temperature centrifugation and freeze-drying.

[0049] Take 0.70 g of the bifunctional dextran prepared in Example 2 and dissolve it in 8 mL of deionized water and 1.5 mL of isopropanol to obtain a polymer solution. Add 50 mg of photoinitiator lithium phenyl (2,4,6-trimethylbenzoyl) phosphate and shake or stir to completely dissolve it to obtain a prepolymer solution.

[0050] Comparative Example S1: Add 2.0 g of sodium carboxymethyl cellulose to 200 mL of deionized water and stir at room temperature to obtain a sodium carboxymethyl cellulose solution; S2: Add 1.38 g of amidating agent 4-(4,6-dimethoxytriazine-2-yl)-4-methylmorpholine hydrochloride to the sodium carboxymethyl cellulose solution in step S1, and dissolve to obtain a homogeneous solution; add 114 mg of dopamine hydrochloride and 100 mg of 2-amino methacrylate hydrochloride to the above mixed solution, and stir under the dark until completely dissolved; adjust the pH of the above solution to 6.5 with 0.5 M NaOH solution, and stir at room temperature for 24 h to obtain the reaction solution; S3: The reaction solution obtained in step S2 was precipitated in 800 mL of ice-cold ethanol and centrifuged at low temperature to obtain the polymer; the polymer was dissolved again in 200 mL of deionized water and precipitated again in ice-cold ethanol, and the bifunctional polymer was obtained by low-temperature centrifugation and freeze-drying. S4: Dissolve 45 mg of the bifunctional polymer in 3 mL of deionized water to obtain a bifunctional polymer solution. Add 6 mg of the photoinitiator lithium phenyl (2,4,6-trimethylbenzoyl) phosphate and shake or stir until completely dissolved to obtain a prepolymer solution of the biological tissue adhesive. Irradiate the obtained biological tissue adhesive with a 365 nm ultraviolet lamp for 2 s to complete the photocrosslinking process, and obtain the cured biological tissue adhesive. 1. Verify the mechanical strength of the adhesive on a rotational rheometer (Thermo Scientific, Mars60): The rotational time-scan mode was selected, the temperature was 37℃, the rotational speed was set to 10 rad / s, and the scan time was 15 min. A prepolymer solution containing a photocrosslinking agent was applied to the rheometer stage to a thickness greater than 2 mm to test the rheological behavior before crosslinking. Subsequently, the applied polymer solution was photocrosslinked for approximately 30 s to achieve in-situ crosslinking, allowing the rheological behavior of the crosslinked adhesive to be tested. Figure 1 As shown, the storage modulus G' and loss modulus G'' of the system before crosslinking are both small and similar, indicating that it belongs to the sol state; the storage modulus G' of the sample after crosslinking is increased by about 10 times and is significantly greater than its loss modulus G", indicating that the system is in the gel state, and the storage modulus G' is close to 10 kPa, which has excellent mechanical strength.

[0051] Application Example 1 A 5 cm long and 3 cm deep skin wound was created on the skin of a live Panamanian pig. The prepolymer solution from Example 2 was then applied into the wound. The wound was then irradiated with UV light for 2 seconds to complete the photocrosslinking process. This group was designated as experimental group L1. (See details below.) Figure 2 In another group, a comparative proportion of the prepolymer solution of biological tissue adhesive was applied to the skin wounds, and then the prepolymer solution at the wound site was irradiated with ultraviolet light for 2 seconds to complete the photocrosslinking process. This group served as the control group R1. (See details below.) Figure 16 In another group of skin wounds, no other solvents were applied as a blank control group (R2). (See figure for reference.) Figure 4 In another group, existing Compal Medical Adhesive (n-butyl cyanoacrylate) was applied to the skin wounds as the control group R3. See details... Figure 8 Then, the four experimental groups of Panamanian pigs were fed normally. During this period, the wounds were not bandaged and were directly exposed to the air to heal. The wound healing status was recorded daily. After 9 days, the Panamanian pigs died suddenly. The skin wounds were then used for pathological sectioning and observation.

[0052] For experimental group L1, see [link / reference] Figure 17 One day after applying the adhesive, the wound can be observed to have adhered; after four days, healing has begun, and there is virtually no scab on the skin surface; after nine days, the wound has completely healed, the wound on the skin surface is barely noticeable, and there is no scab; see the skin biopsy for details. Figure 3 As shown, the skin sample wound has completely healed, and the newly formed tissue is mainly composed of a large number of fibroblasts. No obvious blood cells were observed, but a very small number of inflammatory cells were visible.

[0053] For the control group R1, see [link to relevant documentation]. Figure 18 One day after applying the adhesive, the wound reopened and bled; four days later, it began to heal, with a large amount of scabs forming on the skin surface; nine days later, the skin surface still showed obvious scabs; see the skin section for details. Figure 19 As shown, the skin sample wound has basically healed, and the newly formed tissue is mainly composed of a large number of fibroblasts. No obvious blood cells were observed, but a very small number of inflammatory cells were visible.

[0054] For the blank control group R2, see Figures 5-7 As shown, the skin sample wound has not fully healed, and a large number of inflammatory cells are present in the unhealed area. The newly formed tissue in the healing area is mainly composed of numerous fibroblasts, with a small number of inflammatory cells accumulating around blood vessels, and a small number of new blood vessels and erythrocytes are also visible. For the control group R3, see [reference needed]. Figures 9-12 As shown, the skin sample exhibits impaired wound healing, insufficient inward fibroblast growth, and unabsorbed blood clots in the area. Numerous inflammatory cells are visible at the edge of the inward fibroblast growth zone, along with localized neovascularization and a certain amount of erythrocytes.

[0055] Compared with experimental group L1 and blank control group R2 and control group R3, the biological tissue adhesive of the present invention, when applied to a 3cm deep skin wound, was able to heal the wound and showed certain antibacterial properties, indicating that it has strong adhesive strength and can resist the tension of the skin at a wound depth of 3cm. At the same time, after nine days of application to the skin wound of Panamanian pigs, the skin sample of experimental group L1 was completely healed, and the newly formed tissue was mainly composed of a large number of fibroblasts, with no obvious blood cells and a very small number of inflammatory cells. In contrast, blank control group R2 and control group R3 had a large number of inflammatory cells, indicating that the adhesive of the present invention has good biocompatibility and excellent degradation and absorption advantages.

[0056] Compared to the control group R1, the experimental group L1 showed better healing of deeper (3cm deep) skin wounds. Post-operative photographs showed that while the control group R1 healed to a near-complete state after 9 days, the healing effect was not as good as that of the experimental group L1 (as evidenced by skin biopsies). Particularly on the first day post-surgery, the control group R1 experienced wound dehiscence and significant bleeding. This was primarily due to the adhesive's insufficient strength to withstand skin tension, leading to wound dehiscence and consequently, slower and less effective healing. This demonstrates that the adhesive of this invention provides better and faster healing, resulting in more aesthetically pleasing healed skin, and its clinical application can alleviate patient suffering.

[0057] Then, mechanical property tests were performed on the skin at the wound sites of experimental group L1, blank control group R2, and control group R3. The upper and lower clamps were spaced 2 cm apart, with a preload of 5 N and a tensile speed of 10 mm / min. The test results are as follows: Figures 13-15 As shown, The tensile strength of experimental group L1 was 2884.36 cN, the tensile strength of blank control group R2 was 2475.65 cN, and the tensile strength of control group R3 was 915.38 cN. Tensile tests also showed that the wound in experimental group L1 healed well.

[0058] When using the adhesive of the present invention, in addition to filling the skin wound with adhesive, a certain amount of adhesive is also applied to the skin surface of the wound. After curing, a protective interface is formed, which further strengthens the wound. Moreover, the interface on the wound surface can also prevent bacterial infection and reduce the infection rate.

[0059] The embodiments of the present invention have been described in detail above with reference to the accompanying drawings, but the present invention is not limited to the above embodiments. Even if various changes are made to the present invention, if these changes fall within the scope of the claims of the present invention and their equivalents, they shall still fall within the protection scope of the present invention.

Claims

1. A photo-initiated bifunctional dextran bio-tissue adhesive, applied to skin wounds and tissue / mucosal wounds, characterized in that, The bifunctional dextran bio-tissue adhesive is obtained by polymerizing bifunctional dextran and a photoinitiator under photoinitiation. The bifunctional dextran is formed by introducing aldehyde and olefin groups onto the dextran through an esterification reaction with carboxylic aldehyde compounds or carboxylic olefin compounds. The molecular weight of the dextran ranges from 1 to 10,000 kDa.

2. The photo-initiated bifunctional dextran bio-tissue adhesive according to claim 1, characterized in that, The mass ratio of the dextran, carboxylic aldehyde compound, and carboxylic olefin compound is 1:0.005-20:0.005-20.

3. The photo-initiated bifunctional dextran bio-tissue adhesive according to claim 1 or 2, characterized in that, The carboxylic acid aldehyde compound is selected from any one of 2-(4-formylphenyl)acetic acid, 2-(4-formylphenoxy)acetic acid, 3-(4-aldehydephenyl)propionic acid, 2-(2-formyl-6-methoxyphenoxy)acetic acid, and 4-formylcinnamic acid.

4. The photo-initiated bifunctional dextran bio-tissue adhesive according to claim 1 or 2, characterized in that, The carboxylic acid olefin compound is selected from any one of 6-acryloylaminohexanoic acid, 5-hexenoic acid, 4-envalic acid, 2-carboxyethyl acrylate, and 3-(allyloxy)propionic acid.

5. The photo-initiated bifunctional dextran bio-tissue adhesive according to claim 1, characterized in that, The mass ratio of the bifunctional dextran to the photoinitiator is 1:0.01-10.

6. The photo-initiated bifunctional dextran bio-tissue adhesive according to claim 1 or 5, characterized in that, The photoinitiator is selected from any one or more of the following: lithium phenyl (2,4,6-trimethylbenzoyl) phosphate, aromatic ketone photoinitiators, polycyclic aromatic hydrocarbon photoinitiators, polysilane photoinitiators, acylphosphonate photoinitiators, azo photoinitiators, or organometallic complexes.

7. A method for preparing a photo-initiated bifunctional dextran bio-tissue adhesive as described in any one of claims 1-6, characterized in that, Includes the following steps: S1: Dextran, carboxylic aldehyde compound, and carboxylic olefin compound are dissolved in an organic solvent to form a solution. An esterification catalyst is added, and the mixture is stirred for 4-12 hours. The mixture is then filtered and dried to obtain bifunctional dextran. S2: Dissolve the bifunctional dextran in water or a mixture of water and a polar organic solvent, add a photoinitiator in a predetermined ratio to dissolve and mix, and obtain a prepolymer solution; S3: The prepolymer liquid from step S2 is dropped onto the application site, and then photoinitiation of the prepolymer liquid is initiated by irradiation with a photoinitiator.

8. The method for preparing the photo-initiated bifunctional dextran bio-tissue adhesive according to claim 7, characterized in that, In step S1, the esterification catalyst is selected from any one or a mixture of several of dicyclohexylcarbodiimide, 4-dimethylaminopyridine, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, or pyridine-sulfonyl chloride.

9. The method for preparing the photo-initiated bifunctional dextran bio-tissue adhesive according to claim 7, characterized in that, The organic solvent in step S1 is selected from any one or a mixture of several of dichloromethane, N,N-dimethylformamide, dimethyl sulfoxide, or tetrahydrofuran; The polar organic solvent in step S2 is isopropanol and / or ethanol.

10. The method for preparing the photo-initiated bifunctional dextran bio-tissue adhesive according to claim 7, characterized in that, In step S3, the wavelength of the light used to initiate the crosslinking reaction is 100-1000 nm, and the illumination time is 1-60 s.

11. A bifunctional dextran biological tissue gel sheet, characterized in that, The biological tissue gel sheet is made of the biological tissue gel sheet as described in any one of claims 1-6 or a sheet product obtained by photoinitiating and curing a photo-initiated biological tissue adhesive obtained by the preparation method described in any one of claims 7-10.

12. The application of a photo-initiated bifunctional dextran bio-tissue adhesive as described in any one of claims 1-6 in the preparation of skin wound and tissue mucosal adhesive products.

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