Liquid metal nanoparticle, microneedle antibacterial patch and preparation method and application thereof

Abstract

The present application relates to the technical field of medical materials, and particularly relates to a liquid metal nanoparticle, a microneedle antibacterial patch and a preparation method and application thereof. The liquid metal nanoparticle has a core-satellite type structure, takes liquid metal as a core, and takes polydopamine as a shell, and silver nanoparticles are loaded on the surface of the polydopamine. The liquid metal nanoparticle is of a core-satellite type structure taking liquid metal as a core, taking polydopamine as a shell, and loading silver nanoparticles on the surface of the polydopamine. The liquid metal, the polydopamine and the silver nanoparticles all have antibacterial effects, and the three are combined to have a synergistic effect, so that a more excellent antibacterial effect can be achieved, and a wound healing effect for treating multiple drug-resistant bacterial infections can be achieved.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of medical materials, in particular to a liquid metal nanoparticle, a microneedle antibacterial patch and a preparation method and application thereof. BACKGROUND

[0002] After long-term exploration and research, bacterial infection, especially drug-resistant bacterial infection, has become one of the most intractable problems in the global healthcare field. Multi-drug resistant bacteria have little sensitivity to most traditional antibiotics. In the prior art, it has been proved that gallium ions can effectively inhibit the proliferation of microorganisms by interfering with iron homeostasis. However, the low targeting efficiency of metal ions, short circulation time and complex drug treatment mode greatly limit the application of gallium ions.

[0003] Therefore, the present application is proposed. SUMMARY

[0004] The present application provides a liquid metal nanoparticle, a microneedle antibacterial patch and a preparation method and application thereof, to solve the above problems existing in the prior art. The liquid metal nanoparticle is modified by polydopamine, and silver ions are reduced in situ to prepare a liquid metal nanoparticle with a core-satellite structure. The liquid metal nanoparticle is loaded in a high molecular hydrogel microneedle antibacterial patch, which can quickly treat multiple drug-resistant bacterial infection and promote wound healing.

[0005] According to a first aspect of the present application, a liquid metal nanoparticle is provided, the liquid metal nanoparticle has a core-satellite structure, with liquid metal as the core and polydopamine as the shell, and the surface of the polydopamine is loaded with silver nanoparticles.

[0006] In the above scheme, the liquid metal nanoparticle has a core-satellite structure with liquid metal as the core and polydopamine as the shell, and the surface of the polydopamine is loaded with silver nanoparticles. The liquid metal, polydopamine and silver nanoparticles all have antibacterial effects. The liquid metal has a low melting point and is more active at room temperature, so it is easy to react in a solution environment. The polydopamine serves as a modification layer, which can increase the overall stability of the nanoparticle, making it easier for gallium ions to be released into the solution to produce antibacterial effects. In addition, the polydopamine also serves as a carrier for silver nanoparticles, allowing them to be evenly dispersed on its surface and fully exert their antibacterial effects. The combination of the three materials in a synergistic manner can achieve more excellent antibacterial effects and promote wound healing in the treatment of multiple drug-resistant bacterial infections.

[0007] Further, the average particle size of the liquid metal nanoparticle is 100-600 nm, and the particle size of the silver nanoparticle is 10-80 nm.

[0008] In the above scheme, the sizes of the liquid metal nanoparticles and the silver nanoparticles are limited in a reasonable range, so that the three can play a better synergistic effect and have a more excellent antibacterial effect.

[0009] Further, the melting point of the liquid metal is 15-30℃; preferably, the liquid metal is a single metal gallium or an alloy based on metal gallium; more preferably, the liquid metal is a gallium-indium alloy.

[0010] In the above scheme, by selecting a suitable type of liquid metal, a better antibacterial effect can be achieved.

[0011] According to the second aspect of the present application, the present application also provides a preparation method of the above-mentioned liquid metal nanoparticles, characterized in that it comprises the following steps:

[0012] Step (1) Preparation of polydopamine modified liquid metal nanoparticle solution: add liquid metal and dopamine to an aqueous solution, ultrasonic in an ice water bath environment, change the pH of the solution to initiate polymerization of dopamine; centrifuge to remove un-polymerized dopamine, wash to obtain polydopamine modified liquid metal nanoparticles; disperse the polydopamine modified liquid metal nanoparticles in water to obtain a polydopamine modified liquid metal nanoparticle solution;

[0013] Step (2) Preparation of silver particle modified liquid metal nanoparticles: add ammonia and silver nitrate to the polydopamine modified liquid metal nanoparticle solution prepared in step (1) and react, then add dopamine hydrochloride and continue to react; centrifuge to remove un-reacted silver nitrate and dopamine hydrochloride, wash to obtain silver particle modified liquid metal nanoparticles.

[0014] In the above scheme, the preparation method of the present application first uses ultrasonic to prepare dopamine modified liquid metal nanoparticles, initiates polymerization in an alkaline environment to form polydopamine modified liquid metal nanoparticles, and then reduces silver ions in situ to form liquid metal nanoparticles with core-satellite structure, which is simple and mild.

[0015] Further, the weight ratio of the liquid metal, the dopamine and the silver nitrate is 1:(1-10):(0.1-0.5).

[0016] In the above scheme, by limiting the weight ratio of the liquid metal, the dopamine and the silver nitrate in a reasonable range, liquid metal nanoparticles with a more excellent antibacterial effect can be obtained.

[0017] Further, in step (1), the polymerization reaction time is 3-5h.

[0018] In the above scheme, by limiting the polymerization reaction time within a reasonable range, the polymerization reaction can be more beneficial to proceed, and the reaction efficiency can be improved.

[0019] Further, in step (1), the pH of the solution is changed to 8-12 (preferably 8.5-10, more preferably 9); the raw materials used to change the pH of the solution include Tris-HCl buffer.

[0020] In the above scheme, by adjusting the pH of the reaction to a reasonable range value by selecting a suitable type of pH regulator during the reaction, the polymerization reaction can be more beneficial to initiate, and the reaction efficiency can be improved.

[0021] Further, in step (1), the ultrasonic time is 20-40 min, and the working time is 3-8 s, and the intermittent time is 3-8 s.

[0022] In the above scheme, by limiting the process parameters of ultrasonic within a reasonable range, the polymerization reaction can be more beneficial to initiate, and the reaction efficiency can be improved.

[0023] Further, in step (1), the mass concentration of the polydopamine modified liquid metal nanoparticle solution is 0.5-1.5 mg / mL.

[0024] Further, in step (2), the mass percentage of ammonia is 20%-30%.

[0025] Further, in step (2), the mass percentage of silver nitrate in the reaction solution is 0.1%-0.5%.

[0026] Further, in step (2), the mass percentage of dopamine hydrochloride in the reaction solution is 8%-12%.

[0027] In the above scheme, by limiting the weight percentage of each raw material within a reasonable range, the reaction efficiency between each raw material can be improved.

[0028] Further, in step (2), the reaction time of adding ammonia and silver nitrate is 1.5-2.5 h; the reaction time of adding dopamine hydrochloride and continuing to react is 20-40 min. Such design is beneficial to the modification effect of silver particles and further improves the modification effect of polydopamine modification.

[0029] According to a third aspect of the present application, the present application also provides a microneedle antibacterial patch, which comprises a substrate and a microneedle array formed on the substrate, the microneedle array has a plurality of microneedles; the microneedle comprises the liquid metal nanoparticles and the polymer hydrogel; preferably, the concentration of the liquid metal nanoparticles is 5-15 mg / mL (preferably 8-12 mg / mL).

[0030] Further, the high polymer hydrogel is one or both of polyvinyl alcohol hydrogel and polyvinylpyrrolidone hydrogel, preferably polyvinyl alcohol hydrogel.

[0031] And / or, the microneedle further comprises a growth factor; preferably, the growth factor is one or more of epidermal growth factor, vascular endothelial growth factor and fibroblast growth factor. More preferably, the growth factor accounts for 0.005%-0.015% (preferably 0.01%) of the total mass of the microneedle. By adding the growth factor, the wound can be better repaired.

[0032] According to a fourth aspect of the present application, the present application provides a preparation method of the microneedle antibacterial patch as described above, comprising the following steps:

[0033] Preparation of a high polymer hydrogel solution containing liquid metal nanoparticles: uniformly mixing liquid metal nanoparticles and high polymer hydrogel to obtain a high polymer hydrogel solution containing liquid metal nanoparticles;

[0034] Transferring the prepared high polymer hydrogel solution containing liquid metal nanoparticles into a microneedle mold to obtain a microneedle antibacterial patch.

[0035] According to a fifth aspect of the present application, the present application also provides the use of the microneedle antibacterial patch as described above in the preparation of a product for resisting multi-drug resistant bacterial infection. In the application process, the microneedle antibacterial patch as described above can be combined with infrared laser treatment.

[0036] The liquid metal nanoparticles provided by the present application are core-satellite type structures with liquid metal as the core, polydopamine as the shell, and silver nanoparticles loaded on the surface of the polydopamine. The liquid metal, polydopamine and silver nanoparticles all have antibacterial effects. The combination of the three can achieve more excellent antibacterial effects and achieve the wound healing effect of treating multi-drug resistant bacterial infection.

[0037] The liquid metal nanoparticles provided by the present application can be mixed with high polymer hydrogel to form a microneedle antibacterial patch. Such a microneedle antibacterial patch can quickly treat multi-drug resistant bacterial infection and promote wound healing. BRIEF DESCRIPTION OF DRAWINGS

[0038] In order to more clearly illustrate the technical solutions of the present application or the prior art, the following will briefly introduce the drawings needed to be used in the embodiments or prior art description. Obviously, the drawings in the following description are some embodiments of the present application, and those skilled in the art can also obtain other drawings according to these drawings without creative labor.

[0039] Figure 1TEM image of the liquid metal nanoparticle of Example 1 of the present application.

[0040] Figure 2 Schematic diagram for preparing the liquid metal nanoparticle of Example 1 of the present application.

[0041] Figure 3 Schematic diagram for preparing the microneedle antibacterial patch of Example 2 of the present application.

[0042] Figure 4 Comparison chart of antibacterial effect of the microneedle antibacterial patch of Example 2 and Comparative Example 1-2 of the present application.

[0043] Figure 5 Comparison chart of wound healing effect of the microneedle antibacterial patch of Example 2 and Comparative Example 1-2 of the present application. DETAILED DESCRIPTION

[0044] In order to make the objectives, technical solutions and advantages of the present application clearer, the technical solutions of the present application will be described clearly and completely below in combination with the drawings in the present application. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without any creative work under the premise of the present application, all belong to the scope of protection of the present application.

[0045] The beneficial effects of the present application will be described below in combination with specific embodiments and comparative examples.

[0046] Example 1

[0047] This embodiment provides a kind of liquid metal nanoparticle, as shown in Figure 1 It has core-satellite structure, liquid metal as core, polydopamine as shell, and silver nanoparticles are loaded on the surface of polydopamine. Among them, the average particle size of the whole particle of liquid metal nanoparticle is 300nm, liquid metal is EGaIn, the mass ratio of metal gallium and metal indium is 75.5:24.5, and the particle size of silver nanoparticle is 35.78±10.03nm.

[0048] Its preparation process is shown in Figure 2 Specifically, it includes the following steps:

[0049] Step (1) Preparation of polydopamine modified liquid metal nanoparticle solution: 10 mg of liquid metal LM, 100 mg of dopamine DA were added to 10 mL of aqueous solution, and ultrasonic treatment was performed in an ice water bath environment (ultrasonic treatment time was 30 min, with 5 s of work and 5 s of intermittent); the solution was adjusted to pH 9 basicity using Tris-HCl buffer to initiate dopamine polymerization, and the polymerization reaction time was 4 hours; un-polymerized dopamine was removed by centrifugation, and the polydopamine modified liquid metal nanoparticles LM@PDA were washed multiple times with ultrapure water, and finally redispersed in ultrapure water to obtain a polydopamine modified liquid metal nanoparticle solution with a mass percentage of 0.1%.

[0050] Step (2) Preparation of silver particle modified liquid metal nanoparticle solution: 0.5 mL of 28% (mass fraction) ammonia water and 2 mg of silver nitrate were added to the above solution and reacted for 2 hours, then 10 mg of dopamine hydrochloride was added and the reaction was continued for 0.5 hours; unreacted silver nitrate and dopamine hydrochloride were removed by centrifugation, and the silver particle modified liquid metal nanoparticles LM@PDA@Ag were washed multiple times with ultrapure water.

[0051] Example 2

[0052] The present example provides a microneedle antibacterial patch, which comprises a substrate and a microneedle array formed on the substrate, and the microneedle array has a plurality of microneedles; the microneedle comprises the liquid metal nanoparticles and the polymer hydrogel of Example 1.

[0053] The preparation process of the microneedle antibacterial patch is as shown in Figure 3 , and the specific process is as follows:

[0054] Preparation of polyvinyl alcohol hydrogel solution containing liquid metal nanoparticles: 1 g of polyvinyl alcohol was dissolved in 10 mL of ultrapure water to obtain a polymer hydrogel, and the above prepared liquid metal nanoparticles and polymer hydrogel solution were uniformly mixed, and the final concentration of liquid metal nanoparticles was controlled to be 10 mg / mL, to obtain a polyvinyl alcohol hydrogel solution containing liquid metal nanoparticles.

[0055] The above prepared polyvinyl alcohol hydrogel solution containing liquid metal nanoparticles was transferred to a microneedle mold to obtain a gallium nanostructure microneedle antibacterial patch.

[0056] Comparative Example 1

[0057] The present comparative example provides a microneedle antibacterial patch, which is different from Example 2 in that the liquid metal nanoparticles of the present application are replaced by liquid metal that is not modified by polydopamine and silver nanoparticles.

[0058] Comparative Example 2

[0059] The comparative example provides a microneedle antibacterial patch, which is different from example 2 in that the microneedle is liquid metal nanoparticles modified by polydopamine but not silver nanoparticles instead of the liquid metal nanoparticles of the application.

[0060] The microneedle antibacterial patches of example 2 and comparative examples 1-2 are subjected to antibacterial comparative experiments, and the experimental method is plate counting method, as shown in Figure 4 The antibacterial effect is: the microneedle antibacterial patch of example 2 is the best, basically no colony exists, the antibacterial effect is significant, the antibacterial effect of comparative example 2 is the second, and the antibacterial effect of comparative example 1 is the worst.

[0061] Example 3

[0062] The microneedle antibacterial patches of example 2, comparative examples 1-2 are used to treat bacterial infected skin wounds. By removing the hair on the back of the mouse, a circular skin wound with a diameter of 0.8 cm is made by using a circular punch, and the wound is infected by methicillin-resistant Staphylococcus aureus (MRSA) to establish a drug-resistant bacteria infected wound model. The treatment method is to paste the microneedle patch on the wound, and to fix and protect it by using a commercial waterproof patch, and the treatment result is to tightly paste the microneedle patch on the skin wound until the wound heals (about ten days). As shown in Figure 5 The wound treated by the microneedle antibacterial patch of example 2 of the application is significantly reduced compared with comparative examples 1-2, and the effect of antibacterial is significant.

[0063] Finally, it should be noted that: the above examples are only used to illustrate the technical solutions of the application, but not to limit it; although the application has been described in detail with reference to the foregoing examples, those skilled in the art should understand that: it can still modify the technical solutions recorded in the foregoing examples, or make equivalent replacement for part of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the spirit and scope of the technical solutions of the embodiments of the application.

Claims

1. A liquid metal nanoparticle, characterized in that, The liquid metal nanoparticles have a core-satellite structure, with liquid metal as the core and polydopamine as the shell, and silver nanoparticles are loaded on the surface of the polydopamine. The average particle size of the liquid metal nanoparticles is 100-600 nm; the particle size of the silver nanoparticles is 10-80 nm; the melting point of the liquid metal is 15-30 °C; the liquid metal is elemental gallium or an alloy based on gallium. The method for preparing the liquid metal nanoparticles includes the following steps: Step (1) Preparation of polydopamine-modified liquid metal nanoparticle solution: Add liquid metal and dopamine to aqueous solution, sonicate in ice water bath environment, change solution pH to initiate dopamine polymerization; remove unpolymerized dopamine by centrifugation, wash to obtain polydopamine-modified liquid metal nanoparticles; redisperse polydopamine-modified liquid metal nanoparticles in water to obtain polydopamine-modified liquid metal nanoparticle solution; Step (2) Preparation of silver particle-modified liquid metal nanoparticles: Add ammonia and silver nitrate to the polydopamine-modified liquid metal nanoparticle solution prepared in step (1), then add dopamine hydrochloride and continue the reaction; centrifuge to remove unreacted silver nitrate and dopamine hydrochloride, wash, and obtain silver particle-modified liquid metal nanoparticles.

2. The liquid metal nanoparticle of claim 1, wherein, The liquid metal is a gallium-indium alloy.

3. The method for producing liquid metal nanoparticles according to claim 1 or 2, characterized by, Includes the following steps: Step (1) Preparation of polydopamine-modified liquid metal nanoparticle solution: Add liquid metal and dopamine to aqueous solution, sonicate in ice water bath environment, change solution pH to initiate dopamine polymerization; remove unpolymerized dopamine by centrifugation, wash to obtain polydopamine-modified liquid metal nanoparticles; redisperse polydopamine-modified liquid metal nanoparticles in water to obtain polydopamine-modified liquid metal nanoparticle solution; Step (2) Preparation of silver particle-modified liquid metal nanoparticles: Add ammonia and silver nitrate to the polydopamine-modified liquid metal nanoparticle solution prepared in step (1), then add dopamine hydrochloride and continue the reaction; centrifuge to remove unreacted silver nitrate and dopamine hydrochloride, wash, and obtain silver particle-modified liquid metal nanoparticles.

4. The production method according to claim 3, characterized by, The weight ratio of the liquid metal, the dopamine, and the silver nitrate is 1:(1-10):(0.1-0.5).

5. The preparation method according to claim 3, characterized in that, In step (1), the polymerization reaction time is 3-5 hours; And / or, in step (1), the solution pH is changed to 8-12; the raw materials used to change the solution pH include Tris-HCl buffer; And / or, in step (1), the ultrasound duration is 20-40 min, with 3-8 s of operation and 3-8 s of interval; And / or, in step (1), the mass concentration of the polydopamine-modified liquid metal nanoparticle solution is 0.5-1.5 mg / mL; And / or, in step (2), the reaction time for adding ammonia and silver nitrate is 1.5-2.5 h; the reaction time for adding dopamine hydrochloride and continuing the reaction is 20-40 min. And / or, in step (2), the mass percentage of the ammonia water is 20%-30%; And / or, in step (2), the silver nitrate accounts for 0.1%-0.5% of the mass of the reaction solution; And / or, in step (2), the dopamine hydrochloride accounts for 8%-12% of the mass of the reaction solution.

6. A microneedle antimicrobial patch, characterized by, The microneedle antibacterial patch includes a substrate and a microneedle array formed on the substrate, the microneedle array having a plurality of microneedles; the microneedles include the liquid metal nanoparticles and polymer hydrogel as described in claim 1 or 2.

7. The microneedle antimicrobial patch of claim 6, wherein, The concentration of the liquid metal nanoparticles is 5-15 mg / mL.

8. The microneedle antibacterial patch according to claim 6, characterized in that, The polymeric hydrogel is selected from one or both of polyvinyl alcohol hydrogel and polyvinylpyrrolidone hydrogel; And / or, the microneedles may also include growth factors.

9. The microneedle antibacterial patch according to claim 8, characterized in that, The polymer hydrogel is a polyvinyl alcohol hydrogel.

10. The microneedle antibacterial patch according to claim 8, characterized in that, The growth factor is selected from one or more of epidermal growth factor, vascular endothelial growth factor, and fibroblast growth factor.

11. The method for preparing the microneedle antibacterial patch according to any one of claims 6-10, characterized in that, Includes the following steps: Preparation of a polymer hydrogel solution containing liquid metal nanoparticles: Liquid metal nanoparticles and polymer hydrogel are mixed evenly to obtain a polymer hydrogel solution containing liquid metal nanoparticles; The prepared polymer hydrogel solution containing liquid metal nanoparticles was transferred into a microneedle mold to obtain a microneedle antibacterial patch.

12. The use of the microneedle antibacterial patch according to any one of claims 6-10 in the preparation of products for treating multidrug-resistant bacterial infections.

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