An anti-swelling asymmetric hemostatic dressing, its preparation method and application

Abstract

This invention discloses an anti-swelling asymmetric hemostatic dressing, comprising two layers: an upper layer of highly adhesive hydrogel and a lower layer of non-adhesive hydrogel. The anti-swelling asymmetric hemostatic dressing is prepared by first adding a non-adhesive solution A to a mold and photocuring it, then adding a highly adhesive solution B and photocuring it again. The dressing of this invention, with its highly adhesive hydrogel upper layer and non-adhesive hydrogel lower layer, possesses both adhesive and anti-adhesive properties. Furthermore, the hydrogel is anti-swelling, enabling rapid hemostasis within 10 seconds, easy peeling, and promotion of wound healing.

Description

Technical Field

[0001] This invention belongs to the field of medical materials technology, specifically relating to an anti-swelling asymmetric hemostatic dressing. Background Technology

[0002] Hemostasis is extremely time-sensitive, and rapid hemostatic intervention can determine the survival of injured patients. Currently, surgical gauze and sutures are the most commonly used methods for closing wounds and achieving hemostasis in clinical surgery. However, surgical suturing has some significant drawbacks, such as secondary bleeding during the suturing process, damage to normal tissues, time consumption, and the risk of leakage from perforated tissues. Hydrogel bioadhesives have attracted widespread attention due to their suitable mechanical compatibility with tissues and excellent biocompatibility. Compared to skin wound healing, developing effective hydrogel bioadhesives for repairing internal soft tissue defects is more challenging due to the extremely complex internal environment.

[0003] The greatest challenge in internal wound repair lies in the interaction between wet tissue surfaces and different organs within a continuous and dynamic internal environment, particularly in the abdomen and chest. This necessitates that hydrogels not only possess strong adhesion to wet tissue defects but also exhibit anti-adhesion properties with other normal tissues. However, most reported hydrogel bioadhesives either focus solely on preventing postoperative adhesions or on enhancing tissue adhesion strength, indiscriminately exhibiting double-sided adhesions and easily inducing severe adhesions between postoperative defects and normal tissues. Developing asymmetric hemostatic hydrogels with both adhesive and anti-adhesive properties is an effective approach to addressing these challenges.

[0004] Therefore, manufacturing asymmetric hemostatic hydrogels with high wet tissue adhesion and anti-adhesion properties, while also being easy to prepare, remains a significant challenge. Summary of the Invention

[0005] To address the technical problems existing in the prior art, the present invention provides an anti-swelling asymmetric hemostatic dressing with an upper layer of highly adhesive hydrogel and a lower layer of non-adhesive hydrogel, which has both adhesive and anti-adhesive properties. The hydrogel is also anti-swelling. This dressing can achieve rapid hemostasis within 10 seconds, can be peeled off as needed, and promotes wound healing.

[0006] The above-mentioned objectives of the present invention are achieved through the following technical solutions:

[0007] An anti-swelling asymmetric hemostatic dressing comprises two layers: an upper layer of highly adhesive hydrogel and a lower layer of non-adhesive hydrogel. The anti-swelling asymmetric hemostatic dressing is prepared by first adding a non-adhesive solution A to a mold and photocuring it, then adding a highly adhesive solution B and photocuring it.

[0008] Solution A comprises the following components by mass percentage:

[0009] Photocurable biomaterials: 10%–25%;

[0010] Polyether F127 diacrylate: 4%–12%;

[0011] Near-infrared stimulus-responsive smart nanofibers: 2%–15%;

[0012] Initiator: 0.05%–0.3%;

[0013] The rest is water;

[0014] Solution B comprises the following components by mass percentage:

[0015] Photocurable biomaterials: 10%–25%;

[0016] Polyether F127 diacrylate: 4%–12%;

[0017] 3,3'-Dithiodipropionic acid: 0.5%–3%;

[0018] Dual-aldehyde nanofibers: 1%–4%;

[0019] Initiator: 0.05%–0.3%;

[0020] The rest is water;

[0021] The near-infrared stimuli-responsive smart nanofibers are obtained by amidation reaction of amino-modified black phosphorus nanosheets and carboxylated cellulose nanofibers; the amino-modified black phosphorus nanosheets are prepared by liquid exfoliation of black phosphorus, and obtained by electrostatic adsorption between negatively charged black phosphorus nanosheets and positively charged mPEG-NH2.

[0022] Furthermore, the initiator is lithium phenyl-2,4,6-trimethylbenzoylphosphinic acid.

[0023] Furthermore, the photocurable biomaterial is methacrylated gelatin, methacrylated silk fibroin, methacrylated hyaluronic acid, or methacrylated chitosan.

[0024] Further, the preparation method of the amino-modified black phosphorus nanosheets includes: mixing block black phosphorus and N-methylpyrrolidone, ultrasonically treating in an ice bath at 50-100W for 5-7 hours, and then continuing to ultrasonically treat in an ice bath at 300-600W for 5-7 hours to obtain a uniformly dispersed mixture; centrifuging the mixture and discarding the supernatant to obtain black phosphorus nanosheets; the amount of block black phosphorus and N-methylpyrrolidone added is 1 mL of N-methylpyrrolidone for every 1 mg of block black phosphorus; dispersing the black phosphorus nanosheets and mPEG-NH2 in deionized water, ultrasonically treating for 20-40 min, and then stirring for 3-5 hours to obtain amino-modified black phosphorus nanosheets; the mass ratio of the black phosphorus nanosheets to mPEG-NH2 is 1:1.

[0025] Furthermore, the mass ratio of the amino-modified black phosphorus nanosheets to the carboxylated cellulose nanofibers is 1:10.

[0026] Furthermore, the volume ratio of solution A to solution B is 1:0.5 to 2.

[0027] Furthermore, the photocuring process is performed by curing under light with a wavelength of 260–400 nm.

[0028] The anti-swelling asymmetric hemostatic dressing of the present invention can be used for wound hemostasis and promoting wound healing.

[0029] The present invention has the following beneficial effects:

[0030] (1) The anti-swelling asymmetric hemostatic dressing of the present invention can achieve rapid hemostasis within 10 seconds. The upper layer of double-aldehyde nanofibers contains a large number of aldehyde groups, which can form Schiff base bonds with amino groups on the skin, resulting in strong adhesion. The upper layer contains a high density of disulfide bonds and aldehyde groups, which can break Schiff base bonds and disulfide bonds in the eluent solution of a mixture of acetic acid and glutathione, achieving peeling on demand. This solves the problem that traditional hemostatic materials are difficult to combine good adhesion and easy peeling.

[0031] (2) The anti-swelling asymmetric hemostatic dressing of the present invention can be heated to 45°C to 50°C under near-infrared irradiation, thereby thermally ablation and killing bacteria and promoting wound healing.

[0032] (3) The upper layer of the anti-swelling asymmetric hemostatic dressing of the present invention has strong adhesiveness, while the lower layer is non-adhesive. It has strong adhesion to wet tissue defects, but has anti-adhesion to other normal tissues.

[0033] (4) The polyether F127 diacrylate in the anti-swelling asymmetric hemostatic dressing of the present invention can control the volume of the hydrogel to prevent it from expanding and has anti-swelling properties, which solves the problem that the mechanical strength of existing hydrogels weakens after swelling and easily causes adhesion of internal organs. Attached Figure Description

[0034] Figure 1 This is a schematic diagram of the anti-swelling asymmetric hemostatic dressing of the present invention.

[0035] Figure 2 It is the swelling rate of the patches prepared in Examples 1, 2, and 3 in a buffer solution at pH 7.4.

[0036] Figure 3 The results are from the rat tail hemostasis experiment prepared in Examples 1, 2, and 3.

[0037] The markings in the diagram are as follows: 1 represents the lower layer, and 2 represents the upper layer. Detailed Implementation

[0038] like Figure 1 As shown, an anti-swelling asymmetric hemostatic dressing of the present invention includes a lower layer 1 and an upper layer 2. The upper layer 2 is a hydrogel with strong adhesion, and the lower layer 1 is a non-adhesive hydrogel. The anti-swelling asymmetric hemostatic dressing is prepared by first adding a non-adhesive solution A to a mold and photocuring it to obtain the lower layer 1, and then adding a strong adhesive solution B and photocuring it to obtain the upper layer 2. When solution B is added, solution B comes into contact with the surface of the lower layer, and some of the monomers in solution B will penetrate into the surface of the lower layer. Due to its adhesion, the two layers form a whole after photocuring.

[0039] Example 1

[0040] The preparation method of the anti-swelling asymmetric hemostatic dressing of the present invention is as follows:

[0041] S1. Preparation of amino-modified black phosphorus nanosheets: 10 mg of block black phosphorus and 10 mL of N-methylpyrrolidone were mixed in a 20 mL reagent bottle and kept in the dark; the mixture was sonicated in an ice bath (50 W) for 5 h, and then sonicated in an ice bath (300 W) for 5 h in a higher power sonicator to obtain a uniformly dispersed mixture; the mixture was centrifuged (8000 rpm, 10 min), and the supernatant was discarded to obtain black phosphorus nanosheets; 1 mg of black phosphorus nanosheets and 1 mg of mPEG-NH2 were dispersed in 5 mL of deionized water at a mass ratio of 1:1, sonicated for 20 min, and then stirred for 3 h to obtain amino-modified black phosphorus nanosheets.

[0042] Preparation of near-infrared stimuli-responsive smart nanofibers: 0.20 g of carboxylated cellulose nanofibers (dry weight) were placed in a 200.0 mL beaker, and 20 mL of ultrapure water was added. The mixture was sonicated for 20 min to ensure uniform dispersion. 0.20 g of EDC and 0.20 g of NHS were weighed and prepared into a solution, which was then added dropwise to the carboxylated cellulose nanofiber suspension. The mixture was stirred for 30 min to activate the carboxyl groups. 20 mg of amino-modified black phosphorus nanosheets were added to the above reaction system, and the reaction was carried out at room temperature for 24 h.

[0043] S2. Preparation of non-viscous solution A: Methacrylamide gelatin, polyether F127 diacrylate, near-infrared stimuli-responsive smart nanofibers, and lithium phenyl-2,4,6-trimethylbenzoylphosphinic acid are co-dissolved in water. The specific mass percentages of each component are as follows:

[0044] Methacrylamide gelatin: 10%;

[0045] Polyether F127 diacrylate: 4%;

[0046] Near-infrared stimulus-responsive smart nanofibers: 2%;

[0047] Lithium phenyl-2,4,6-trimethylbenzoylphosphinic acid: 0.05%;

[0048] Water: 83.95%.

[0049] S3. Preparation of highly viscous solution B: Methacrylamide gelatin, polyether F127 diacrylate, 3,3'-dithiodipropionic acid, dialdehyde-modified nanocrystalline fibers, and lithium phenyl-2,4,6-trimethylbenzoylphosphinic acid are dissolved in water. The specific mass fractions of each component are as follows:

[0050] Methacrylamide gelatin: 10%;

[0051] Polyether F127 diacrylate: 4%;

[0052] 3,3'-Dithiodipropionic acid: 0.5%;

[0053] Dual-aldehyde nanofibers: 1%;

[0054] Lithium phenyl-2,4,6-trimethylbenzoylphosphinic acid: 0.05%;

[0055] Water: 84.45%.

[0056] S4. Preparation of anti-swelling asymmetric hemostatic dressing: According to the volume ratio of solution A to solution B of 1:0.5, first add non-adhesive solution A to the mold and cure it under light with a wavelength of 260-400nm. Then add highly viscous solution B and cure it under light with a wavelength of 260-400nm.

[0057] Example 2

[0058] The preparation method of the anti-swelling asymmetric hemostatic dressing of the present invention is as follows:

[0059] S1. Preparation of amino-modified black phosphorus nanosheets: 10 mg of block black phosphorus and 10 mL of N-methylpyrrolidone were mixed in a 20 mL reagent bottle and kept in the dark; the mixture was sonicated in an ice bath (60 W) for 6 h, and then sonicated in an ice bath (400 W) for 6 h in a higher power sonicator to obtain a uniformly dispersed mixture; the mixture was centrifuged (8000 rpm, 10 min), and the supernatant was discarded to obtain black phosphorus nanosheets; 1 mg of black phosphorus nanosheets and 1 mg of mPEG-NH2 were dispersed in 5 mL of deionized water at a mass ratio of 1:1, sonicated for 30 min, and then stirred for 4 h to obtain amino-modified black phosphorus nanosheets.

[0060] Preparation of near-infrared stimuli-responsive smart nanofibers: 0.20 g of carboxylated cellulose nanofibers (dry weight) were placed in a 200.0 mL beaker, and 20 mL of ultrapure water was added. The mixture was sonicated for 20 min to ensure uniform dispersion. 0.20 g of EDC and 0.20 g of NHS were weighed and prepared into a solution, which was then added dropwise to the carboxylated cellulose nanofiber suspension. The mixture was stirred for 30 min to activate the carboxyl groups. 20 mg of amino-modified black phosphorus nanosheets were added to the above reaction system, and the reaction was carried out at room temperature for 24 h.

[0061] S2. Preparation of non-viscous solution A: Methacrylamide gelatin, polyether F127 diacrylate, near-infrared stimuli-responsive smart nanofibers, and lithium phenyl-2,4,6-trimethylbenzoylphosphinic acid are co-dissolved in water. The specific mass percentages of each component are as follows:

[0062] Methacrylamide gelatin: 15%;

[0063] Polyether F127 diacrylate: 6%;

[0064] Near-infrared stimulus-responsive smart nanofibers: 6%;

[0065] Lithium phenyl-2,4,6-trimethylbenzoylphosphine: 0.1%;

[0066] Water: 72.9%.

[0067] S3. Preparation of highly viscous solution B: Methacrylamide gelatin, polyether F127 diacrylate, 3,3'-dithiodipropionic acid, dialdehyde-modified nanocrystalline fibers, and lithium phenyl-2,4,6-trimethylbenzoylphosphinic acid are dissolved in water. The specific mass fractions of each component are as follows:

[0068] Photocurable biomaterials: 15%;

[0069] Polyether F127 diacrylate: 6%;

[0070] 3,3'-Dithiodipropionic acid: 1%;

[0071] Dual-aldehyde nanofibers: 1.5%;

[0072] Lithium phenyl-2,4,6-trimethylbenzoylphosphine: 0.1%;

[0073] Water: 76.4%.

[0074] S4. Preparation of anti-swelling asymmetric hemostatic dressing: According to the volume ratio of solution A to solution B of 1:1, first add non-adhesive solution A to the mold and cure it under light with a wavelength of 260-400nm, then add highly viscous solution B and cure it under light with a wavelength of 260-400nm.

[0075] Example 3

[0076] The preparation method of the anti-swelling asymmetric hemostatic dressing of the present invention is as follows:

[0077] S1. Preparation of amino-modified black phosphorus nanosheets: 10 mg of block black phosphorus and 10 mL of N-methylpyrrolidone were mixed in a 20 mL reagent bottle and kept in the dark; the mixture was sonicated in an ice bath (100 W) for 7 h, and then sonicated in an ice bath (600 W) for 7 h in a higher power sonicator to obtain a uniformly dispersed mixture; the mixture was centrifuged (8000 rpm, 10 min), and the supernatant was discarded to obtain black phosphorus nanosheets; 1 mg of black phosphorus nanosheets and 1 mg of mPEG-NH2 were dispersed in 5 mL of deionized water at a mass ratio of 1:1, sonicated for 40 min, and then stirred for 5 h to obtain amino-modified black phosphorus nanosheets.

[0078] Preparation of near-infrared stimuli-responsive smart nanofibers: 0.20 g of carboxylated cellulose nanofibers (dry weight) were placed in a 200.0 mL beaker, and 20 mL of ultrapure water was added. The mixture was sonicated for 20 min to ensure uniform dispersion. 0.20 g of EDC and 0.20 g of NHS were weighed and prepared into a solution, which was then added dropwise to the carboxylated cellulose nanofiber suspension. The mixture was stirred for 30 min to activate the carboxyl groups. 20 mg of amino-modified black phosphorus nanosheets were added to the above reaction system, and the reaction was carried out at room temperature for 24 h.

[0079] S2. Preparation of non-viscous solution A: Methacrylamide gelatin, polyether F127 diacrylate, near-infrared stimuli-responsive smart nanofibers, and lithium phenyl-2,4,6-trimethylbenzoylphosphinic acid are co-dissolved in water. The specific mass percentages of each component are as follows:

[0080] Methacrylamide gelatin: 25%;

[0081] Polyether F127 diacrylate: 12%;

[0082] Near-infrared stimulus-responsive smart nanofibers: 15%;

[0083] Lithium phenyl-2,4,6-trimethylbenzoylphosphinic acid: 0.3%;

[0084] Water: 47.7%.

[0085] S3. Preparation of highly viscous solution B: Methacrylamide gelatin, polyether F127 diacrylate, 3,3'-dithiodipropionic acid, dialdehyde-modified nanocrystalline fibers, and lithium phenyl-2,4,6-trimethylbenzoylphosphinic acid are dissolved in water. The specific mass fractions of each component are as follows:

[0086] Methacrylamide gelatin: 25%;

[0087] Polyether F127 diacrylate: 12%;

[0088] 3,3'-Dithiodipropionic acid: 3%;

[0089] Dual-aldehyde nanofibers: 4%;

[0090] Lithium phenyl-2,4,6-trimethylbenzoylphosphinic acid: 0.3%;

[0091] Water: 55.7%.

[0092] S4. Preparation of anti-swelling asymmetric hemostatic dressing: According to the volume ratio of solution A to solution B of 1:2, first add non-adhesive solution A to the mold and cure it under light with a wavelength of 260-400nm, then add highly viscous solution B and cure it under light with a wavelength of 260-400nm.

[0093] Performance testing of the anti-swelling asymmetric hemostatic dressings prepared in Examples 1, 2, and 3

[0094] ① The anti-swelling asymmetric hemostatic dressings prepared in Examples 1, 2, and 3 were subjected to a swelling test. The dressings were immersed in a buffer solution with pH = 7.4, and the temperature was maintained at 37°C. The mass of the swollen dressings was weighed until the mass no longer increased. The experimental results showed that the higher the content of polyether F127 diacrylate, the lower the swelling rate (see...). Figure 2 ).

[0095] ② The anti-swelling asymmetric hemostatic dressings prepared in Examples 1, 2, and 3 were subjected to near-infrared stimulus response performance tests. The materials were placed under 808nm near-infrared light irradiation, and the material temperature was recorded in real time using a near-infrared camera. The test results all showed good near-infrared stimulus response performance. By adjusting the near-infrared irradiation power, the temperature could be raised to 45℃~50℃. After 5 photothermal cycle experiments, the dressing still maintained a significant photothermal effect, and the temperature could be stabilized at 45℃.

[0096] ③ The hemostatic performance of the anti-swelling asymmetric hemostatic dressings prepared in Examples 1, 2, and 3 was tested on a rat tail amputation model. Pre-weighed filter paper was placed under the rat's tail, and the tail was cut off 1.5 cm from the bottom. The anti-swelling asymmetric hemostatic dressing was immediately applied to the bleeding site until bleeding stopped. Clotting time and blood loss were carefully recorded after hemostasis. The test results showed that all the anti-swelling asymmetric hemostatic dressings could achieve hemostasis within 10 seconds (see...). Figure 3 ).

[0097] ④ The anti-swelling asymmetric hemostatic dressings prepared in Examples 1, 2, and 3 were tested for their on-demand elution performance. The dressings were adhered to pigskin, and a mixture of acetic acid and glutathione was added as an elution solution before removal with tweezers. The control group was removed without adding the elution solution. The experimental results showed that the dressings could be easily removed after adding the elution solution, while they were difficult to remove without it.

[0098] ⑤ The anti-swelling asymmetric hemostatic dressings prepared in Examples 1, 2 and 3 were subjected to plate coating antibacterial performance tests. The test results showed that the antibacterial rate against Staphylococcus aureus was higher than 90%, with the antibacterial rate of Example 1 being 91.3%, and the antibacterial rates of Examples 2 and 3 both reaching 100%.

Claims

1. An anti-swelling asymmetric hemostatic dressing characterized in that, It consists of two layers: an upper layer of highly adhesive hydrogel and a lower layer of non-adhesive hydrogel. The anti-swelling asymmetric hemostatic dressing is prepared by first adding a non-adhesive solution A to a mold and then photocuring it, followed by adding a highly adhesive solution B and photocuring it. Solution A comprises the following components by mass percentage: Photocurable biomaterials: 10%~25%; Polyether F127 diacrylate: 4%~12%; Near-infrared stimuli-responsive smart nanofibers: 2%~15%; Initiator: 0.05%~0.3%; The rest is water; Solution B comprises the following components by mass percentage: Photocurable biomaterials: 10%~25%; Polyether F127 diacrylate: 4%~12%; 3,3'-Dithiodipropionic acid: 0.5%~3%; Dual-aldehyde nanofibers: 1%~4%; Initiator: 0.05%~0.3%; The rest is water; The near-infrared stimuli-responsive smart nanofibers are obtained by amidation reaction of amino-modified black phosphorus nanosheets and carboxylated cellulose nanofibers; the amino-modified black phosphorus nanosheets are obtained by electrostatic adsorption between negatively charged black phosphorus nanosheets and positively charged mPEG-NH2; and the black phosphorus nanosheets are prepared by liquid exfoliation of black phosphorus.

2. The anti-swelling asymmetric hemostatic dressing according to claim 1, characterized in that, The initiator is lithium phenyl-2,4,6-trimethylbenzoylphosphine.

3. The anti-swelling asymmetric hemostatic dressing according to claim 1, characterized in that, The photocurable biomaterial is methacrylated gelatin, methacrylated silk fibroin, methacrylated hyaluronic acid, or methacrylated chitosan.

4. The anti-swelling asymmetric hemostatic dressing according to claim 1, characterized in that, The preparation method of the amino-modified black phosphorus nanosheets includes: mixing block black phosphorus and N-methylpyrrolidone, ultrasonically treating in an ice bath at 50-100W for 5-7 h, and then continuing to ultrasonically treat in an ice bath at 300-600W for 5-7 h to obtain a uniformly dispersed mixture; centrifuging the mixture and discarding the supernatant to obtain black phosphorus nanosheets; the amount of block black phosphorus and N-methylpyrrolidone added is 1 mL of N-methylpyrrolidone for every 1 mg of block black phosphorus; dispersing the black phosphorus nanosheets and mPEG-NH2 in deionized water, ultrasonically treating for 20-40 min, and then stirring for 3-5 h to obtain amino-modified black phosphorus nanosheets; the mass ratio of the black phosphorus nanosheets to mPEG-NH2 is 1:

1.

5. The anti-swelling asymmetric hemostatic dressing according to claim 1, characterized in that, The mass ratio of the amino-modified black phosphorus nanosheets to the carboxylated cellulose nanofibers is 1:

10.

6. The anti-swelling asymmetric hemostatic dressing according to claim 1, characterized in that, The volume ratio of solution A to solution B is 1:0.5~2.

7. The anti-swelling asymmetric hemostatic dressing according to claim 1, characterized in that, The photocuring process involves curing the material under light with a wavelength of 260-400 nm.

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