Self-reporting electric quantity ion energy source microneedle battery and preparation method and application thereof

Abstract

The invention discloses an electric quantity self-reporting ion energy source microneedle battery as well as a preparation method and application thereof. The electric quantity self-reporting ion energy source microneedle battery with a structural color low-salt-concentration needle tip, a cation selective middle thin layer and a high-salt-concentration substrate layer is obtained through a vertical deposition technology and layered structure construction. An electric field is spontaneously generated due to the salt concentration gradient between the hierarchical structures and ion directional movement caused by the ion selective permeable membrane, an electrified microneedle can be constructed without external equipment, external stimulation and additional operation, the operation is simple and convenient, and the infection risk is reduced; meanwhile, the directional moving salt ions and the chelatable hydrogel are subjected to chelation reaction at the needle tip part, so that the volume change of the hydrogel is caused, and then the structural color change of the needle tip is caused, a visual signal is provided for the electrical property of the needle tip, and relevant measures such as real-time observation of the electrical property and convenience in timely replacement can be realized. The invention provides a convenient, efficient, safe and monitorable tool for wound repair and other disease treatment.

Description

Technical Field

[0001] The present invention belongs to the field of biomaterials, and in particular relates to a self-reporting charge ion energy source microneedle battery and a preparation method and application thereof. Background Art

[0002] Wounds are local tissue damage caused by external factors such as pressure, heat, and chemicals on the skin tissue. They are one of the most common diseases in humans. Microneedles have become a research hotspot in the field of wound treatment due to their advantages such as minimally invasive and painless. So far, a variety of microneedles with different structural functions have been designed and developed to promote wound healing. Among them, microneedles with electric fields are considered to be a powerful tool to accelerate wound healing because the electrical stimulation generated by their electric fields can promote cell metabolism, proliferation, differentiation, and migration. However, existing charged microneedles usually rely on external devices or external stimuli to generate electric fields, which is not only inconvenient to operate but also easy to cause infection and hinder wound healing. In addition, the electrical properties of existing charged microneedles during use are often difficult to monitor, which limits further practical applications. Summary of the invention

[0003] Purpose of the invention: The technical problem to be solved by the present invention is to provide a self-reporting charge ion energy source microneedle battery to provide visual electrical stimulation for wound healing and achieve efficient wound healing, in view of the defects of the prior art that the charged microneedles rely on external equipment, are inconvenient to operate, are prone to infection, and cannot realize electrical performance monitoring.

[0004] In order to achieve the above object, the technical solution adopted by the present invention is as follows: A self-reporting charge ion energy source microneedle battery comprises a low-salt concentration needle tip with structural color, a cation selective permeable intermediate layer and a high-salt concentration base layer; the structural color low-salt concentration needle tip is a low-salt concentration salt water gel that can chelate cations, and the surface of the structural color low-salt concentration needle tip has holes formed by removing photonic crystal nanoparticles with a corrosive agent, so that the needle tip forms a structural color; the cation selective permeable intermediate layer is located between the bottom of the low-salt concentration needle tip with structural color and the high-salt concentration base layer; the high-salt concentration base layer is a base hydrogel containing a high-salt concentration.

[0005] Specifically, the structural color low salt concentration needle tip surface photonic crystal nanoparticles are any one of silica nanoparticles and polystyrene nanoparticles; the low concentration salt water gel that can chelate cations is formed by mixing and solidifying any one of methacrylate gelatin and polyethylene glycol diacrylate with acrylic acid in a volume ratio of (3-7): (2-6); the high concentration salt base hydrogel is any one of methacrylate gelatin and polyethylene glycol diacrylate.

[0006] Specifically, the salt in the low-concentration salt water gel and the high-concentration salt base hydrogel is any one of sodium chloride, potassium chloride, calcium chloride, and magnesium chloride; the salt concentration in the low-concentration salt water gel is less than 0.01~1M, and the salt concentration in the high-concentration salt base hydrogel is 0.125M~2M.

[0007] Specifically, the cation selective permeable intermediate layer is formed by mixing and curing any one of polyethylene glycol diacrylate and methacrylate gelatin with poly (sodium 4-styrene sulfonate) in a volume ratio of (1-2):2.

[0008] Furthermore, the present invention also provides a method for preparing the above-mentioned self-reporting charge ion energy source microneedle battery, comprising the following steps: (1) Preparation of structural color tips: A solution containing a certain concentration of photonic crystal nanoparticles is poured into the microneedle template, and after removing excess air, the microneedle template is placed horizontally and vertically deposited to wait for the solvent to evaporate, thereby obtaining a needle tip template with structural color; a pre-gel solution containing a low concentration of saline gel that can chelate cations is poured into the groove of the structural color needle tip template, and the excess air in the template is removed by vacuum treatment; then, excess liquid outside the needle tip groove is removed and solidified; (2) Preparation of hierarchical microneedle batteries: The intermediate layer hydrogel pre-condensate containing cationic selective molecules is poured into the microneedle template containing the structural color needle tip prepared in step (1), and then the excess air is removed by vacuum treatment and solidified; then, the needle tip photonic crystal nanoparticles are removed by corrosive agent; finally, the base hydrogel pre-condensate containing high concentration of salt is poured into the microneedle template; after the excess air is removed, the template is solidified and peeled off to obtain the product.

[0009] Specifically, in step (1), the photonic crystal nanoparticles are selected from any one of silicon dioxide nanoparticles and polystyrene nanoparticles, the concentration of the photonic crystal nanoparticles in the dispersed solution is 1-10% w / v, in g / ml, and the dispersant is selected from any one of ethanol, benzene and dichloromethane; the standing condition is placed at 20-40° C. for 1-6 hours; In the chelated hydrogel pre-coagulation liquid containing low-concentration salt, the salt is selected from any one of sodium chloride, potassium chloride, calcium chloride, and magnesium chloride; the chelated hydrogel pre-coagulation liquid is a mixed aqueous solution of 15-35% v / v polyethylene glycol diacrylate or methacrylate gelatin, 10-30% v / v acrylic acid, 0.5-3% v / v 1173 photoinitiator, and 0.01-1M salt.

[0010] Specifically, in step (2), the cationic selective molecule is poly(sodium 4-styrene sulfonate); the intermediate layer hydrogel pre-gel solution is a mixed aqueous solution of 10-30% v / v polyethylene glycol diacrylate or 10-30% v / v methacrylate gelatin and 20% v / v poly(sodium 4-styrene sulfonate); and the corrosive agent is hydrofluoric acid.

[0011] Specifically, in step (2), the base hydrogel pre-gel solution is a mixed aqueous solution of 10-30% v / v polyethylene glycol diacrylate or 10-30% v / v methyl methacrylate gelatin, 0.5-3% v / v 1173 photoinitiator, and 0.125M-2M salt; and the curing method is ultraviolet lamp curing.

[0012] Furthermore, the self-reporting charge ion energy source microneedle battery prepared by the above method is also within the protection scope of the present invention.

[0013] Furthermore, the present invention also claims to protect the use of the self-reporting charge ion energy source microneedle battery in monitoring the electrical properties of charged microneedles in wound repair or painless drug delivery. Beneficial Effects

[0014] (1) Compared with traditional microneedles, the self-reporting charge ion energy source microneedle battery of the present invention utilizes the salt concentration gradient between its own hierarchical structure and the directional movement of ions caused by the ion selective permeable membrane to spontaneously generate an electric field. It does not require external equipment or external stimulation, and does not require additional operations to reduce the risk of infection. At the same time, due to the directional movement of salt ions, a chelating reaction occurs at the needle tip with the chelating hydrogel, causing a change in the volume of the hydrogel and then a change in the color of the needle tip structure, providing a visual signal for its electrical performance, enabling real-time observation of electrical performance, facilitating timely replacement and other related measures, and providing a convenient, efficient, safe and monitorable tool for the treatment of diseases such as wound repair.

[0015] (2) The method of the present invention obtains a self-reporting charge ion energy source microneedle battery with a structural color low salt concentration needle tip, a cation selective intermediate thin layer, and a high salt concentration base layer through vertical deposition technology and layered structure construction. Due to the salt concentration gradient between the hierarchical structures and the directional movement of ions caused by the ion selective permeation membrane, an electric field is spontaneously generated. No external equipment, external stimulation, or additional operation is required to construct a charged microneedle, which is simple and convenient and reduces the risk of infection. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] The present invention will be further described in detail below in conjunction with the accompanying drawings and specific embodiments, and the above and / or other advantages of the present invention will become more clear.

[0017] Figure 1 It is a schematic diagram of the structure of the self-reporting charge ion energy source microneedle battery of the present invention.

[0018] Figure 2 It is a schematic diagram of the preparation process of the self-reporting charge ion energy source microneedle battery of the present invention.

[0019] Figure 3 It is a characterization diagram of the structure and electrical performance of the self-reporting charge ion energy source microneedle battery of the present invention.

[0020] Figure 4 It is the principle and characterization diagram of the self-reporting function of the self-reporting charge ion energy source microneedle battery of the present invention.

[0021] Figure 5 This is a graph showing the results of using the self-reporting charge ion energy source microneedle battery of the present invention for wound repair. DETAILED DESCRIPTION

[0022] The present invention can be better understood with reference to the following examples. Example 1

[0023] like Figure 1 As shown, the self-reporting charge ion energy source microneedle battery of the present invention includes a low-salt concentration needle tip 1 with structural color, a cation selective permeable intermediate layer 2 and a high-salt concentration base layer 3.

[0024] Among them, the structural color low salt concentration needle tip 1 is a low-concentration salt water gel that can chelate with cations and has significant structural color. The photonic crystal nanoparticles deposited on the outer layer of the structural color low salt concentration needle tip 1 are removed by corrosive agents to form holes; the high salt concentration base layer 3 is a high-concentration salt base hydrogel.

[0025] In some embodiments, the photonic crystal nanoparticles in the structural color low salt concentration needle tip 1 are any one of silica nanoparticles and polystyrene nanoparticles; the inner layer of the structural color low salt concentration needle tip 1 contains a low concentration salt water gel which is formed by mixing any one of methacrylate gelatin and polyethylene glycol diacrylate with acrylic acid.

[0026] In some embodiments, the salt in the low-concentration salt water gel and the base hydrogel containing a high-concentration salt is any one of sodium chloride, potassium chloride, calcium chloride, and magnesium chloride.

[0027] In some embodiments, the cation selective permeable intermediate layer 2 is formed by mixing any one of polyethylene glycol diacrylate and methacrylate gelatin with poly (sodium 4-styrene sulfonate).

[0028] In some embodiments, the base hydrogel in the high salt concentration base layer 3 is selected from any one of methacrylate gelatin and polyethylene glycol diacrylate. Example 2

[0029] Preparation of self-reporting charge ion energy source microneedle battery, combined with Figure 2 shown.

[0030] (1) Preparation of structural color tip template: First, silica nanoparticles with a particle size of 250nm were dispersed in ethanol to prepare a 2% (w / v) silica ethanol solution. The above dispersion was added to the microneedle template and vacuum treated for one minute to remove excess air. Subsequently, the template containing the dispersion was placed horizontally at 25°C for 4 hours to allow the ethanol to evaporate and the silica particles to naturally deposit vertically.

[0031] (2) Preparation of hierarchical microneedle batteries: A chelating hydrogel pre-condensate containing 20% ​​(v / v) polyethylene glycol diacrylate, 20% (v / v) acrylic acid, 1% (v / v) 1173 photoinitiator, 0.01M potassium chloride, and the balance being solvent is added to the groove of the structural color needle tip template prepared in step (1), and the excess air is removed by vacuum treatment for 2 minutes. After removing the excess pre-condensate outside the needle tip groove, the solution is cured by ultraviolet light for 30 seconds. Subsequently, an intermediate layer hydrogel pre-condensate containing 20% ​​(v / v) poly (sodium 4-styrene sulfonate) and 20% (v / v) polyethylene glycol diacrylate and the balance being solvent is added to the microneedle template so that it just covers the cross section of the square groove of the microneedle template but does not completely fill the square groove. After vacuum treatment for one minute to remove the excess air, the solution is cured by ultraviolet light for 30 seconds. Subsequently, the cured hydrogel is peeled off the microneedle template and immersed in 10% (v / v) hydrofluoric acid for 2 hours to remove the needle tip silica. After rinsing the excess silica with ultrapure water, the cured hydrogel was placed back into the microneedle template, and a mixed solution containing 20% ​​(v / v) polyethylene glycol diacrylate, 1% (v / v) 1173 photoinitiator, 2M potassium chloride, and the remainder solvent was added to the template. After filling the square groove, the excess air was removed by vacuum treatment for 1 minute, and the ultraviolet light was irradiated for 30 seconds to cure. Finally, the cured hydrogel was peeled off from the microneedle template to obtain a self-reporting charge ion energy source microneedle battery. Example 3

[0032] like Figure 3As shown, the self-reporting charge ion energy source microneedle battery of the present invention includes a structural color low salt concentration needle tip, a cation selective permeable middle layer and a high salt concentration base layer. Due to the concentration gradient of salt between the base layer and the needle tip, and the presence of cation selective molecules in the middle layer, the cations in the salt move directionally from the base layer to the tip. The directional movement of the cations leads to the formation of a potential difference between the needle tip and the base layer, forming an inherent electric field with current. The electrical properties of its electric field are related to the salt concentration difference between the base layer and the needle tip. For example, when the salt concentration in the structural color low salt needle tip is 0.01M and the salt concentration in the high salt base layer is 2M, the self-reporting charge ion energy source microneedle battery can generate an electric field with a voltage of about 100mV and output a current with an intensity of about 10μA.

[0033] Since the tip is composed of acrylic acid, it is rich in free carboxyl groups (-COOH). Figure 4 As shown in the figure, when cations continue to migrate from the basal layer to the tip, the hydrogen bonds between the carboxyl groups dissociate to form COO-, which acts as a ligand to chelate with the cations to form a new coordinated covalent bond. Since the bond energy of the new coordinated covalent bond is weaker than -COOH, the needle tip undergoes a swelling process. This expansion process causes the diameter of the holes on the surface of the needle tip to increase, thereby changing the structural color of the needle tip. As the content of cations in the tip increases, the structural color of the tip gradually redshifts, which can serve as a visual signal to monitor the degree of cation movement, giving the ion energy source microneedle battery the ability to self-report. Example 4

[0034] To demonstrate the value of self-reporting charge ion energy source microneedle batteries in practical applications, they were used to treat a rat wound model. First, the retention of these microneedle batteries on mouse skin was evaluated. Figure 5 As shown, the microneedle batteries remained adhered to the mouse skin after the skin was stretched and twisted. In addition, after peeling them off the mouse skin, a negative array of microneedle shapes was observed on the skin, indicating that they were well retained on the mouse skin for further treatment. A wound with a diameter of 2 cm was established on the back of the rat to construct a wound model. The rats with the wound model were randomly divided into two groups, including a control group and an experimental group. Microneedle batteries were attached to the wound surface of the experimental group every day. The wound images were recorded, such as Figure 5 The results showed that the wound healing was better in the microneedle battery group, indicating the value of self-reporting charge ion energy source microneedle batteries in practical applications.

[0035] The present invention provides a self-reporting charge ion energy source microneedle battery and its preparation method and application ideas and methods. There are many methods and ways to implement the technical solution. The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, without departing from the principle of the present invention, several improvements and modifications can be made, and these improvements and modifications should also be regarded as the scope of protection of the present invention. All components not specified in this embodiment can be implemented by existing technologies.

Claims

1. A self-reporting charge ion energy source microneedle battery, characterized in that: The invention comprises a low-salt concentration needle tip with structural color (1), a cation selective permeable intermediate layer (2) and a high-salt concentration base layer (3); the low-salt concentration needle tip with structural color (1) is a low-salt concentration salt water gel that can chelate cations, and the surface of the low-salt concentration needle tip with structural color (1) has holes formed by removing photonic crystal nanoparticles by a corrosive agent; the cation selective permeable intermediate layer (2) is located between the bottom of the low-salt concentration needle tip with structural color (1) and the high-salt concentration base layer (3); the high-salt concentration base layer (3) is a base hydrogel containing a high-salt concentration.

2. The self-reporting charge ion energy source microneedle battery according to claim 1, characterized in that: The surface photonic crystal nanoparticles of the structural color low salt concentration needle tip (1) are any one of silicon dioxide nanoparticles and polystyrene nanoparticles; the low-concentration salt water gel that can chelate cations is formed by mixing and solidifying any one of methacrylate gelatin and polyethylene glycol diacrylate with acrylic acid in a volume ratio of (3-7): (2-6); the high-concentration salt base hydrogel is any one of methacrylate gelatin and polyethylene glycol diacrylate.

3. The self-reporting charge ion energy source microneedle battery according to claim 1, characterized in that: The salt in the low-concentration salt water gel and the high-concentration salt base hydrogel is any one of sodium chloride, potassium chloride, calcium chloride, and magnesium chloride; the salt concentration in the low-concentration salt water gel is less than 0.01~1M, and the salt concentration in the high-concentration salt base hydrogel is 0.125M~2M.

4. The self-reporting charge ion energy source microneedle battery according to claim 1, characterized in that: The cation selective permeable intermediate layer (2) is formed by mixing and curing any one of polyethylene glycol diacrylate and methacrylate gelatin with poly (sodium 4-styrene sulfonate) in a volume ratio of (1-2):

2.

5. The method for preparing the self-reporting charge ion energy source microneedle battery according to claim 1, characterized in that: The steps include: (1) Preparation of structural color tips: A solution containing a certain concentration of photonic crystal nanoparticles is poured into the microneedle template, and after removing excess air, the microneedle template is placed horizontally and vertically deposited to wait for the solvent to evaporate, thereby obtaining a needle tip template with structural color; a pre-gel solution containing a low concentration of saline gel that can chelate cations is poured into the groove of the structural color needle tip template, and the excess air in the template is removed by vacuum treatment; then, excess liquid outside the needle tip groove is removed and solidified; (2) Preparation of hierarchical microneedle batteries: The intermediate layer hydrogel pre-condensate containing cationic selective molecules is poured into the microneedle template containing the structural color needle tip prepared in step (1), and then the excess air is removed by vacuum treatment and solidified; then, the needle tip photonic crystal nanoparticles are removed by corrosive agent; finally, the base hydrogel pre-condensate containing high concentration of salt is poured into the microneedle template; after the excess air is removed, the template is solidified and peeled off to obtain the product.

6. The method for preparing the self-reporting charge ion energy source microneedle battery according to claim 5, characterized in that: In step (1), the photonic crystal nanoparticles are selected from any one of silicon dioxide nanoparticles and polystyrene nanoparticles, the concentration of the photonic crystal nanoparticles in the dispersed solution is 1-10% w / v, in g / ml, and the dispersant is selected from any one of ethanol, benzene and dichloromethane; the standing condition is to place the solution at 20-40°C for 1-6 hours; In the chelated hydrogel pre-coagulation liquid containing low-concentration salt, the salt is selected from any one of sodium chloride, potassium chloride, calcium chloride, and magnesium chloride; the chelated hydrogel pre-coagulation liquid is a mixed aqueous solution of 15-35% v / v polyethylene glycol diacrylate or methacrylate gelatin, 10-30% v / v acrylic acid, 0.5-3% v / v 1173 photoinitiator, and 0.01-1M salt and solvent.

7. The method for preparing the self-reporting charge ion energy source microneedle battery according to claim 5, characterized in that: In step (2), the cationic selective molecule is poly(sodium 4-styrene sulfonate); the intermediate layer hydrogel pre-gel solution is a mixed aqueous solution of 10-30% v / v polyethylene glycol diacrylate or 10-30% v / v methyl methacrylate gelatin and 20% v / v poly(sodium 4-styrene sulfonate); and the corrosive agent is hydrofluoric acid.

8. The method for preparing the self-reporting charge ion energy source microneedle battery according to claim 5, characterized in that: In step (2), the base hydrogel pre-gel solution is a mixed aqueous solution of 10~30% v / v polyethylene glycol diacrylate or 10~30% v / v methyl methacrylate gelatin, 0.5~3% v / v 1173 photoinitiator, and 0.125M~2M ​​salt; the curing method is ultraviolet lamp curing.

9. A self-reporting charge ion energy source microneedle battery prepared by any one of the methods of claims 5 to 8.

10. Use of the self-reporting charge ion energy source microneedle battery of claim 1 for monitoring the electrical properties of charged microneedles in wound repair or painless drug delivery.

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