Preparation method of mineralized hydrogel microneedle

Abstract

The invention relates to a preparation method of a mineralized hydrogel microneedle, and belongs to the technical field of biological medicines. Specifically, a polydimethylsiloxane microneedle mold is filled with a mineralized hydrogel precursor solution, the mineralized hydrogel precursor solution is cured into hydrogel microneedles through ultraviolet radiation, mineralization and demolding are conducted, and the mineralized microneedle array is obtained. According to the mineralized hydrogel microneedle disclosed by the invention, on the basis of ensuring medication safety, the flexibility and biocompatibility of the hydrogel and the rigid support and functionalization characteristics of a mineralized structure are synergistically integrated, the comprehensive performance of the microneedle is optimized, and a key technical support is provided for development and application of the microneedle in the field of biological medicine.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology and relates to the preparation of mineralized hydrogel microneedles. Background Technology

[0002] Microneedles (MNs) are tiny needles used for drug delivery and other target applications. Compared to traditional subcutaneous injection needles, their tiny size provides advantages such as painlessness, minimal invasiveness, and ease of operation. Currently, the commonly used materials for microneedle fabrication are biocompatible polymers, which generally suffer from being too soft, leading to easy bending and breakage during skin puncture, reducing delivery efficiency and therapeutic effect. Mineralized hydrogels combine the biocompatibility of hydrogels with the high mechanical strength of minerals, and the mineralization process can be controlled. When filled into a microneedle mold, alendronate (AP) bisphosphate ligands form strong coordination bonds with calcium ions, optimizing the mineralization effect. The crosslinking agent triethylene glycol dimethacrylate (TEG) constructs a three-dimensional network structure, enhancing its mechanical properties, regulating swelling properties, promoting the mineralization process, and improving stability. This avoids the buckling failure problem of traditional polymer microneedles, balancing minimally invasive safety and reliable drug delivery.

[0003] Therefore, the application of mineralized hydrogels as filler materials in microneedles has significant research value and application prospects. Summary of the Invention

[0004] Therefore, it is necessary to provide a method for preparing mineralized hydrogel microneedles to address the aforementioned technical problems.

[0005] To solve the above-mentioned technical problems, the present invention adopts two preparation technology solutions:

[0006] 1. The preparation method employs a combined template method, UV curing, and "in-situ mineralization," with the following steps:

[0007] 1) Dissolve an appropriate amount of monomer AP and acrylamide (AM) in a mineralization solution, and add cross-linking agent TEG, alkaline phosphatase (ALP), and photoinitiator (LAP) to prepare a hydrogel precursor solution.

[0008] 2) Take an appropriate amount of the solution obtained in step 1) and fill it into the PDMS microneedle mold, then irradiate it with ultraviolet light to initiate cross-linking and curing;

[0009] 3) Place the cured hydrogel microneedles into a microneedle mold for mineralization reaction, and finally demold.

[0010] 2. The preparation method employs a combined template method, UV curing, and "post-mineralization" process, with the following steps:

[0011] 1) Dissolve appropriate amounts of AP and AM in pure water, and add TEG, ALP, and LAP to prepare a hydrogel precursor solution;

[0012] 2) Take an appropriate amount of the solution obtained in step 1) and fill it evenly into the cavity of the PDMS microneedle mold. UV-initiated cross-linking and curing are then carried out to obtain the mineralized hydrogel precursor.

[0013] 3) Take the precursor from 2) and immerse it in the mineralization solution to form mineralized hydrogel microneedles.

[0014] In a preferred embodiment of the method for preparing the hydrogel precursor solution provided by the present invention, the following amounts are used in the "in-situ mineralization": AP 50 mg; AM 500 mg; TEG 80 μL; ALP 20 μL; LAP 100 μL; and mineralization solution 50 mg / mL. In the "post-mineralization," the following amounts are used: AP 60 mg; TEG 60 μL; DA 20 μL; ddH2O 300 μL; and the rest remain unchanged.

[0015] In a preferred embodiment of the mineralized hydrogel microneedle preparation method provided by the present invention, the mineralization solution is a triethanolamine (TEA) buffer (0.2M, pH=9.8) containing calcium glycerophosphate (CAGP, 5g / L).

[0016] In a preferred embodiment of the preparation method of the mineralized hydrogel microneedles provided by the present invention, the ultraviolet curing time is 10 min and the mineralization time is 5 d.

[0017] It is clear without a doubt that the technical solution described above in this application can solve the technical problem that this application aims to address.

[0018] Meanwhile, through the above technical solutions, the present invention has at least the following beneficial effects:

[0019] 1. The mineralized hydrogel preparation method provided by this invention utilizes alendronate-based diphosphate network, which can efficiently chelate Ca. 2+ It significantly improves the formation efficiency and binding stability of calcium phosphate mineralization phase, and has a better mechanical enhancement effect than conventional mineralization systems; it simultaneously solves the problem of buckling failure of traditional microneedles, and combined with PDMS molds, ensures the uniformity of microneedle morphology, and realizes effective puncture of the stratum corneum and stable construction of drug delivery channels.

[0020] 2. The hydrogel microneedles prepared in this invention can reduce skin irritation and release Ca. 2+ PO43- can assist in tissue repair, and TEA buffer provides gentle demolding to ensure the structural and biosafety of microneedles, laying the foundation for biomedical scenarios such as minimally invasive drug delivery. Attached Figure Description

[0021] To more clearly illustrate the technical solutions of the present invention, the accompanying drawings used in the description of the embodiments will be briefly introduced below. Obviously, the accompanying drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0022] Figure 1 This is a schematic diagram illustrating the morphology characterization of the mineralized hydrogel of the present invention;

[0023] Figure 2 This is a schematic diagram illustrating the characterization of the mineralized hydrogel microneedles of the present invention;

[0024] Figure 3 This is a schematic diagram of the mineralization of the microneedle patch of the present invention;

[0025] Figure 4 This is a schematic diagram illustrating the condition optimization of the "in-situ mineralization" hydrogel microneedles of the present invention;

[0026] Figure 5 This is a schematic diagram illustrating the condition optimization of the "post-mineralized" hydrogel microneedles of the present invention; Detailed Implementation

[0027] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0028] To enable those skilled in the art to better understand the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings.

[0029] It should be noted that, unless otherwise specified, the embodiments and features and technical solutions in the embodiments of the present invention can be combined with each other.

[0030] It should be noted that similar labels and letters in the following figures indicate similar items. Therefore, once an item is defined in one figure, it does not need to be further defined and explained in subsequent figures.

[0031] Example 1

[0032] Reference Figure 1 and Figure 2 The preparation method of mineralized hydrogel microneedles includes the following steps:

[0033] An appropriate amount of AP, AM, TEG and LAP were mixed to prepare a hydrogel precursor solution; then a certain amount of the precursor solution was dropped into a PDMS mold and the air bubbles in the system were removed by vacuum negative pressure treatment; after the air bubbles were removed, the system was solidified by ultraviolet crosslinking method, and finally mineralized hydrogel microneedles were prepared by mineralization treatment and demolding operation.

[0034] Preferably, the in-situ mineralization dosage is 50 mg of AP; 500 mg of AM; 80 μL of TEG; 20 μL of ALP; and 100 μL of LAP.

[0035] Preferably, the "post-mineralized" AP is 60 mg; TEG is 60 μL; and ddH2O is 300 μL.

[0036] Example 2

[0037] The present invention is based on the above-described Embodiment 1.

[0038] The preparation was carried out using the template method, UV curing, and "in-situ mineralization". The steps are as follows: a hydrogel precursor solution was prepared and filled into a PDMS microneedle mold. The air bubbles were removed by vacuum negative pressure and UV crosslinking was performed for 5 minutes. The cured microneedle precursor was then left in the PDMS mold for mineralization for 5 days. Finally, the mold was demolded.

[0039] The hydrogel precursor solution was prepared using a combined template method, UV curing, and post-mineralization process. The steps are as follows: A hydrogel precursor solution was prepared and filled into a PDMS microneedle mold. The mold was then degassed under vacuum and subjected to UV crosslinking for 5 minutes. After demolding, the hydrogel microneedles were removed and immersed in a mineralization solution for 5 days. The morphology of the mineralized hydrogel is as follows: Figure 1 As shown; the morphology of the obtained mineralized hydrogel microneedles is as follows. Figure 2 As shown, this method produces a microneedle array with complete morphology, clear tip outline, and uniform shape; the degree of mineralization of the hydrogel microneedles is as follows: Figure 3 As shown, this method induces microneedle mineralization.

[0040] Example 3

[0041] refer to Figure 4 This invention optimizes the conditions for "in-situ mineralization".

[0042] Regarding the TEG dosage, variable experiments were conducted with values ​​of 20 μL, 40 μL, 60 μL, 80 μL, and 100 μL, respectively. The results are as follows: Figure 4 As shown in Figure a, when the TEG dosage is 80 μL, the system exhibits low expansion rate characteristics, and this dosage is the preferred dosage; after optimization, the results are as follows. Figure 4 As shown in b, a clear array of needle tips can be seen, with the microneedles exhibiting a regular conical shape.

[0043] Example 4

[0044] refer to Figure 5 This invention optimizes the conditions for "post-mineralization".

[0045] Different amounts of TEG (20 μL, 40 μL, 60 μL, 80 μL, 100 μL, 120 μL) were selected for observation, and the results are as follows: Figure 5 As shown in Figure a, the needle tip structure integrity was optimal when TEG was 60 μL; subsequently, ddH2O was set as a variable condition (200 μL, 250 μL, 300 μL, 350 μL, 400 μL, 500 μL), and the results are as follows. Figure 5 As shown in b, when ddH2O is 300 μL, the microneedles exhibit a sharp, conical structure.

[0046] The preferred embodiments of the present invention disclosed above are merely illustrative of the invention. These preferred embodiments do not exhaustively describe all details, nor do they limit the invention to the specific implementations described. Clearly, many modifications and variations can be made based on the content of this specification. This specification selects and specifically describes these embodiments to better explain the principles and practical applications of the invention, thereby enabling those skilled in the art to better understand and utilize the invention. The invention is limited only by the claims and their full scope and equivalents.

Claims

1. Preparation method of mineralized hydrogel microneedles: This invention adopts two methods for preparation: template method-ultraviolet curing-"in-situ mineralization" and template method-ultraviolet curing-"post-mineralization".

2. Template method - UV curing - "in-situ mineralization" synthesis method, including the following steps: Take an appropriate amount of monomer AP and acrylamide (AM) and dissolve them in the mineralization solution. Add crosslinking agent TEG, alkaline phosphatase (ALP) and photoinitiator (LAP) to prepare a hydrogel precursor solution. Fill the solution into a PDMS microneedle mold. Initiate crosslinking and curing by UV irradiation. Place the cured hydrogel microneedles in the microneedle mold for mineralization reaction. Finally, demolding is completed.

3. The preparation method of template method-ultraviolet curing-"in-situ mineralization" according to claim 2, characterized in that, The dosage of AP is 50 mg; AM is 500 mg; TEG is 80 μL; ALP is 20 μL; LAP is 100 μL; and the mineralization solution is 50 mg / mL.

4. Template method - UV curing - "post-mineralization" synthesis method, including the following steps: Take an appropriate amount of AP and AM and dissolve them in ddH2O, add TEG, ALP and LAP to prepare a hydrogel precursor solution; fill the cavity of the obtained solution uniformly into the PDMS microneedle mold, UV initiate cross-linking and curing to obtain a mineralized hydrogel precursor, immerse the precursor in the mineralization solution, and form mineralized hydrogel microneedles.

5. The template method-UV curing-"post-mineralization" preparation method according to claim 4, characterized in that, The amount of AP added was 60 mg; the amount of TEG added was 60 μL; and the amount of ddH2O added was 300 μL.

6. The method for preparing mineralized hydrogel microneedles according to claims 2 and 4, characterized in that, The mineralization solution is a triethanolamine (TEA) buffer solution (0.2M, pH=9.8) containing calcium glycerophosphate (CAGP, 5 g / L).

7. The method for preparing mineralized hydrogel microneedles according to claims 2 and 4, characterized in that, The UV irradiation curing time is 10 minutes, and the mineralization time is 5 days.

Images