CN113893386B - Spray-coated dry powder gel dressing and preparation method thereof - Google Patents

Abstract

The invention discloses a gel dressing prepared by spraying dry powder, which is prepared by preparing gel from hydrophilic polymer, freezing, crushing and drying the gel into powder, enabling the powder to reach the surface of a tissue in a spraying mode, and realizing in-situ cross-linking and tissue adhesion through ion complexation, hydrogen bonds or electrostatic force after water absorption. The dressing is dry powder before application, is easy to store, does not contain an initiator and a monomer, has high biocompatibility, can absorb moisture on the surface of a wet tissue, eliminates an adhesion barrier, realizes quick adhesion of the wet tissue, and has high adhesion strength to the tissue, which can reach 10-50 kpa; the nature of the dry powder is modular, functional materials can be added as required, and the dry powder can be applied to the surface of a wound by a spraying device; the hydrogel dressing is initiated into a compact hydrogel layer by water and realizes strong tissue adhesion, and the swollen particles are self-assembled into a gel block on the surface of a wound in situ under the initiation of water, and realize the tight adhesion to the biological tissue of a large area and irregular wound.

Description

A kind of spraying dry powder gel dressing and preparation method thereof

technical field

The invention relates to the field of hydrogel adhesives, in particular to a preparation method of a gel dressing by spraying dry powder.

Background technique

Tissue adhesives have developed rapidly over the past few decades as an alternative to traditional surgical suturing. ^1-5 Compared with the time-consuming operation of traditional surgical thread suture, some positions are inconvenient to operate, which can damage the tissue and cause foreign body inflammatory reaction in the tissue. The tissue adhesive has the advantages of convenient use, short operation time, and small tissue damage. , is one of the effective methods to solve these problems, suitable for minimally invasive surgery. ⁶ At present, compared with the extensive research and development of tissue adhesives, there are few products for clinical use and their application scenarios are limited, which cannot fully meet clinical needs. The main reasons include: poor delivery ability of the gel material (cannot reach the narrow area); low biosafety; weak adhesion to tissues. The ideal hydrogel dressing should be easy to deliver to reach the narrow lesion space, high biosafety to avoid damage to surrounding tissue, strong tissue adhesion to avoid shedding during action, and also must consider the convenience of implementation to reduce the impact on clinical operators. requirements. Simply adhering to damaged tissue, which is often fluid-covered and irregularly shaped, is extremely challenging. ^7-8 For example, water and layers on the surface of the tissue act as an adhesion barrier, which hinders the construction of molecular bonds between the adhesive material and the tissue, and cannot achieve timely adhesion; the irregular wound of the damaged tissue can achieve intimacy between the adhesive material and the tissue. Fitting puts forward higher requirements. Considering the safety and simplicity of the materials used and their implementations, it becomes more difficult to develop tissue adhesives suitable for clinical use. Existing tissue adhesives can be roughly classified into ^{biomaterials9} , ^{cyanoacrylates10} and ^{hydrogels3,5,11-13} . Biomaterials, such as fibrin, are biodegradable and generally do not cause an inflammatory response, but provide weak adhesion and are not suitable for tissue repair where mechanical properties are critical. Cyanoacrylates can form strong adhesion to tissue, but their water-initiated polymerization strategy limits their adhesion to wet wounds (excessive blood prevents adhesion). Hydrogel-based tissue adhesives have broad development prospects due to their high water content and promote healing. They mainly include hydrogel blocks and injectable hydrogel adhesives, but they still face the above development difficulties. For example, bulk hydrogels are inconvenient to transport and difficult to be used for minimally invasive repair of narrow tissues; injectable hydrogels (sol-gel conversion is usually achieved by chemical cross-linking precursors) due to their potential biotoxicity and difficult to control The gel time greatly delays the pace of clinical application.

SUMMARY OF THE INVENTION

The present application provides a method for preparing a gel dressing by spraying dry powder, aiming at the problems of application difficulties such as poor transportability and low biological safety of the existing hydrogel dressing.

In order to achieve the above object, the technical scheme adopted in the present invention is: a gel dressing prepared by spraying dry powder, which is prepared from a hydrophilic polymer into a hydrogel, freeze-dried and pulverized into powder, and is sprayed on the surface of the tissue after absorbing water and passing through the action force. The powder-to-powder crosslinking and tissue adhesion are achieved in situ, and the forces include ionic complexation, hydrogen bonding or/and electrostatic forces (the design mechanism is shown in Figure 1).

As an implementation method of the present invention, the gel dressing is prepared based on ion complexation, and the hydrophilic polymer is polyacrylic acid (PAA). The specific steps include:

1) Preparation of PAA hydrogel: acrylic acid, complexing agent and APS are dissolved in deionized water, wherein the complexing agent is 0.1-1.0 mol% of acrylic acid, APS is 1/1000-1/100 wt% of acrylic acid, and the water content is Acrylic acid 1-20 times, stir evenly, degas the solution, transfer it to a sealed glass bottle, and place it in an oven above 20 °C to obtain PAA hydrogel;

2) Preparation of PAA dry powder: The PAA hydrogel was removed by dialysis to remove monomers and equilibrated to pH 4-7 pH, and the processed hydrogel block was broken into gel powder, transferred to a freeze dryer, and then lyophilized by lyophilization. way to obtain dry gel powder.

Further, the complexing agent includes Fe ³⁺ , Ag ⁺ , Ca ²⁺ , Ba ²⁺ or Zn ²⁺ metal salts.

Further, the complexing agent is FeCl ₃ .

As the second implementation method of the present invention, the gel dressing is prepared based on hydrogen bonds, and the hydrophilic polymer includes polyacrylic acid polyvinyl alcohol (PAA), and the specific steps include:

1) Preparation of PVA-TA hydrogel: add 20 g of PVA to 80 g of deionized water, heat and stir at 90°C for 4 h to prepare a 20 wt% PVA aqueous solution; add 20 g of tannic acid (TA) to 80 g of deionized water, and fully Dissolve to obtain 20wt% TA aqueous solution; mix PVA solution and TA solution according to 0.25-4, stir manually for 3-5min; ionize the mixed solution at 3000r/min for 30min, collect the precipitate as PVA-TA hydrogel;

2) Preparation of PVA-TA dry powder: the PVA-TA hydrogel obtained in step 1) is freeze-ground into hydrogel powder, and the PVA-TA dry powder is obtained by freeze-grinding and drying.

Further, the volume ratio of the PVA solution to the TA solution is 1:1, which is marked as PVA ₁₀ -TA ₁₀ .

As the third implementation method of the present invention, the gel dressing is prepared based on electrostatic interaction, the hydrophilic polymer includes polyelectrolyte, and the specific steps include:

1) Preparation of polyelectrolyte double network hydrogel: Weigh N,N,N-trimethyl-3-(2-methacrylamido)-1-propylammonium chloride (MPTC) 50w% monomer aqueous solution , Sodium p-styrene sulfonate (NaSS) is dissolved in deionized water, prepare 10-40wt% monomer aqueous solution, introduce 0.1-1mol% APS, after it is fully dissolved, degas, put it in an oven, the obtained PMPTC (PNaSS) ) solution drying, pulverizing to obtain PMPTC powder; Weigh MPTC 50w% monomer aqueous solution, NaSS dissolved in deionized water, prepare 10-40wt% monomer aqueous solution, add 0.5-2mol% MBAA, preferably 1mol%, and 5- 15wt% PMPTC (PNaSS) powder, after fully dissolving, introducing 0.1-1 mol% APS, degassing, placing in an oven to prepare PMPTC, NaSS double network gel;

2) Preparation of mixed dry powder of PMPTC and PNaSS: the PMPTC and PNaSS double network hydrogel obtained in step 1) is freeze-ground into hydrogel powder, and the dry powder of PMPTC and PNaSS is obtained by freeze-drying.

Further, in step (1), the concentration of the monomer aqueous solution is 20wt%.

Further, in step (1), the APS concentration is 0.5 mol%.

The use method of the dry powder of the present invention is as follows: the powder is loaded in a powder bottle, the powder is taken out by a carrier gas, and transported to a designated position through a thin tube, wherein the main body of the spray gun is a three-way device, one end is connected with the powder bottle, and one end is connected with the air intake One end of the channel is connected with a thin tube (powder outlet), and the diameter of the tube is 1-4mm.

The beneficial technical effects of the present invention are as follows: the dressing of the present invention is dry powder before application, which is easy to store, does not contain initiators and monomers, and has high biocompatibility. The dry powder can absorb moisture on the surface of wet tissues, eliminate adhesion barriers, and achieve Fast tissue adhesion, high adhesion strength to tissue, can reach 10-50kpa; dry powder is modular in nature, functional materials can be added as needed, and dry powder can be applied to the wound surface by spraying device; hydrogel dressing Initiated by water to form a dense hydrogel layer and achieve strong tissue adhesion, that is, under the initiation of water, the swollen particles self-assemble into a gel block on the wound surface in situ, and achieve large-area, irregular wound biological Tight adhesion of tissue.

Description of drawings

In order to illustrate the embodiments of the present invention or the technical solutions in the prior art more clearly, the following briefly introduces the accompanying drawings that need to be used in the description of the embodiments or the prior art. Obviously, the drawings in the following description are only These are some embodiments of the present invention, and for those of ordinary skill in the art, other drawings can also be obtained from these drawings without any creative effort.

1 is a schematic diagram of the design mechanism and application display of the present invention;

Fig. 2 is the macroscopic and microscopic morphology of the preparation of PAA dry powder based on ion complexation in Example 1;

Fig. 3 is application embodiment 4 spraying PAA dry powder dusting device diagram of the present invention;

Fig. 4 is the mechanical property test of hydrogel prepared in situ by the PAA _0.5 powder strategy using the wound closure test method of Example 4;

Fig. 5 is the adhesion of PAA gel to various tissues prepared by the dry powder of Example 4;

6 is a graph of the adhesion strength of various samples of Application Example 4 to pigskin;

Figure 7 is a view of the back tissue section of mice after 14 days of implantation of PAA, PVA-TA and PMPTC/PNaSS hydrogels in Application Example 4;

Detailed ways

The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.

Example 1

A preparation method based on ion complex spraying dry powder gel dressing, the used preparation raw material is polyacrylic acid (PAA), and the concrete steps include:

1) Preparation of PAA hydrogel: Dissolve 2g acrylic _acid , 0.5mol% FeCl3, 2mg APS in 8g deionized water, stir well, degas the solution, transfer it to a sealed glass bottle, and place it in an oven at 20-40°C , after 24 hours, PAA hydrogels were obtained;

Following the above steps, adjusting the content of FeCl ₃ , various PAA hydrogels were prepared: PAA _0.1 , PAA _0.25 , PAA _0.75 and PAA ₁ .

2) Preparation of PAA dry powder: The PAA hydrogel was removed by dialysis to remove monomers and equilibrated to pH 5. Specifically, the gel was placed in a 3500 dialysis bag, and then dialyzed in a large amount of deionized water and PBS buffer. , until the pH is 5, the treated hydrogel blocks are broken into gel powder, transferred to a freeze dryer, and the dry gel powder is obtained by freeze-drying. The macroscopic and microscopic morphologies of the prepared dry powder are shown in Figure 2. shown.

Example 2

A hydrogen bond-based spraying dry powder gel dressing is based on a hydrogen bond preparation method, and the preparation raw materials are polyvinyl alcohol (PVA) and tannic acid (TA), and the specific steps include:

1) Preparation of PVA-TA hydrogel: 20g of PVA was added to 80g of deionized water, heated and stirred at 90°C for 4 hours to prepare a 20wt% PVA aqueous solution, 20g of TA was added to 80g of deionized water, and fully dissolved to obtain 20wt% PVA solution. % TA aqueous solution, mix PVA solution and TA solution 1:1, stir manually for 3-5min, ionize the mixed solution at 3000r/min for 30min, collect the precipitate as PVA10-TA10 hydrogel;

According to the above steps, changing the ratio, the other three kinds of PVA ₂₀ -TA ₂₀ , PVA ₂₀ -TA ₁₀ , PVA ₁₀ -TA ₅ hydrogels can be obtained;

2) Preparation of PVA-TA dry powder: the PVA-TA hydrogel obtained in step 1) is frozen and ground into a hydrogel powder, and the PVA-TA dry powder is obtained by freeze-drying.

Example 3

A preparation method for spraying dry powder gel dressing based on electrostatic interaction, the preparation raw material is poly-N,N,N-trimethyl-3-(2-methacrylamido)-1-propylammonium chloride (PMPTC ), sodium poly-p-styrene sulfonate (PNaSS), the concrete steps include:

1) Preparation of polyelectrolyte double network hydrogel: Weigh 4 g of poly-N,N,N-trimethyl-3-(2-methacrylamido)-1-propylammonium chloride (MPTC) 50w% mono Body aqueous solution, 2g sodium p-styrene sulfonate (NaSS) were dissolved in 6g deionized water, 0.5mol% APS was introduced, after it was fully dissolved, degassed, placed in an oven at 60°C for 8h, the obtained PMPTC solution was dried and powdered , obtain PMPTC powder; Weigh 4g MPTC 50w% monomer aqueous solution, 2g NaSS dissolve in 6g deionized water, add 1mol% MBAA and 1g PMPTC, NaSS powder, after fully dissolved, introduce 0.5mol% APS, degas, put at 60 ℃ Oven for 8h to obtain PMPTC, NaSS double network gel;

2) Preparation of mixed dry powder of PMPTC and PNaSS: the PMPTC and PNaSS double network hydrogel obtained in step 1) is freeze-ground into hydrogel powder, and the dry powder of PMPTC and PNaSS is obtained by freeze-drying.

Application Example 1

Take the prepared dry powder of PAA based on ionic complexation as an example.

The prepared dry PAA powder was filled into the powder-carrying box of the electric duster and sprayed directly on the wet pig skin (in vitro) or the back wound of mice (in vivo). The adhesion properties and biocompatibility of the gel were explored through in vitro wound closure tests and mouse back tissue sections, respectively.

1. Powder coating

As shown in Figure 3, the powder is loaded in a powder bottle, and the powder is carried out by a carrier gas and transported to a designated location through a thin tube. The main body of the spray gun is a three-way device, one end is connected with a powder bottle, one end is connected with an air inlet channel, and one end is connected with a thin tube (powder outlet), the diameter of the tube (1mm-4mm).

2. Adhesion properties of powder-assembled hydrogels to tissues

As shown in Figure 4, the adhesion strength of the hydrogel to the tissue was measured by the wound closure test. Figure 5 shows the adhesion strength of PAA powder-assembled gels to different tissues. In addition, the adhesion strength of different powders to pigskin was also tested and shown in Figure 6.

3. In vivo biocompatibility

In vitro biocompatibility was tested by subcutaneous implantation of the gel in mice. Subcutaneously implanted tissue sections of different gel materials are shown in Figure 7. The results showed that the hydrogel dressings prepared by this scheme showed high biosafety.

Finally, it should be noted that the above embodiments are only used to illustrate rather than limit the technical solutions of the present invention. Although the present invention has been described in detail with reference to the above embodiments, those of ordinary skill in the art should understand that the present invention can still be modified. Or equivalent replacements, without departing from the spirit and scope of the present invention, any modifications or partial replacements shall be included in the scope of the claims of the present invention.

references

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Claims (2)

1. a method for preparing a gel dressing prepared by spraying dry powder, the hydrogel prepared from a hydrophilic polymer is pulverized into powder through freeze-drying, and after absorbing water on the tissue surface by spraying, in-situ cross-linking between powders is realized by acting force and Tissue adhesion, the action force includes ion complexation, and it is characterized in that the specific steps include: 1) Preparation of polyacrylic acid (PAA) hydrogel: Dissolve acrylic acid, complexing agent and APS in deionized water, wherein the complexing agent is 0.1-1.0 mol% of acrylic acid, and APS is 1/1000-1/100 wt of acrylic acid %, the water content is 1-20 times that of acrylic acid, stir evenly, degas the solution, transfer it to a sealed glass bottle, and place it in an oven above 20 °C to obtain PAA hydrogel; 2) Preparation of PAA dry powder: The PAA hydrogels were removed by dialysis to remove monomers and equilibrated to pH 4-7 pH. way to obtain dry gel powder; The complexing agent is an ionic complexing agent, including Fe ³⁺ , Ag ⁺ , Ca ²⁺ , Ba ²⁺ or Zn ²⁺ metal salts. 2 . The preparation method of the gel dressing according to claim 1 , wherein the complexing agent is FeCl ₃ . 3 .

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