水凝胶微针的结构设计与响应性释药行为

Structural Design and Responsive Drug Delivery Behavior of Hydrogel Microneedles

摘要: 背景：痛风性关节炎由尿酸钠(MSU)晶体沉积诱发，口服抗炎药存在系统毒性和关节靶向性差的问题。透皮微针可避免首过效应，但现有微针缺乏对炎症微环境的响应释药能力，且难以从源头抑制MSU结晶。本研究设计了一种负载三种中药活性成分(附子生物碱、车前子苷、熟地黄多糖)的温度/pH双响应四层水凝胶微针，实现病灶触发的按需给药。目的：构建并表征该双响应水凝胶微针，考察其形貌结构、机械穿刺性能、温度/pH响应释药行为、生物粘附性以及对MSU晶体形成的抑制作用。方法：采用逐层浇筑法制备四层微针(针尖层/过渡层/核心层/背衬层)。使用SEM和荧光显微镜观察微针形貌与层状结构。通过万能试验机测定穿刺力与压缩模量。采用Franz扩散池法，分别考察不同温度(25℃、37℃)和pH (7.4、6.5)条件下三种活性成分的累积释放率。通过离体猪皮45˚剥离试验评价粘附强度。将微针与过饱和MSU溶液共孵育，显微镜观察晶体数量与尺寸。结果：微针针高800 μm，底部直径220 μm，阵列密度400针/cm²。单针穿刺力为0.142 N (离体猪皮)，压缩模量85.3 kPa，均满足无痛穿刺要求。在正常条件(25℃/pH 7.4)下，24 h累积释放率为34.6%；当模拟炎症微环境(37℃/pH 6.5)时，双响应协同使24 h释放率达98.5%，显著高于单一温度响应(91.3%)或pH响应(88.2%)。微针贴片粘附强度为42.3 mN/cm²，显著高于市售水胶体敷料(18.6 mN/cm²)，24 h滞留率良好。此外，含熟地黄多糖纳米粒的微针使MSU晶体产率从100%降至7.5%，晶体尺寸从12.4 μm减小至0.8 μm。结论：成功构建了温度/pH双响应四层水凝胶微针，该微针具备良好的机械性能与生物粘附性，能够在炎症关节微环境触发快速、近乎完全的药物释放，并显著抑制MSU结晶形成。该研究为痛风性关节炎的局部精准治疗提供了新型透皮递药平台。

Abstract: Background: Gouty arthritis is triggered by the deposition of monosodium urate (MSU) crystals. Oral anti-inflammatory drugs suffer from systemic toxicity and poor joint targeting. Although transdermal microneedles can bypass first-pass metabolism, existing microneedles lack microenvironment-responsive drug release and fail to inhibit MSU crystallization at the source. Herein, we designed a thermo/pH dual-responsive four-layer hydrogel microneedle loaded with three active ingredients from traditional Chinese medicine (aconite alkaloids, plantainoside, and rehmannia polysaccharide) for on-demand drug delivery triggered by the arthritic microenvironment. Objective: To fabricate and characterize the dual-responsive hydrogel microneedle, evaluating its morphology, mechanical penetration performance, thermo/pH-responsive drug release behavior, bioadhesion, and ability to inhibit MSU crystal formation. Methods: The four-layer microneedle (tip layer/transition layer/core layer/backing layer) was fabricated using a layer-by-layer casting method. SEM and fluorescence microscopy were used to observe microneedle morphology and layered structure. Penetration force and compressive modulus were measured using a universal testing machine. Cumulative release rates of the three active ingredients were investigated under different temperatures (25˚C, 37˚C) and pH conditions (7.4, 6.5) using Franz diffusion cells. Bioadhesion strength was evaluated by a 45˚ peel test on excised porcine skin. The microneedle was co-incubated with a supersaturated MSU solution, and crystal count and size were observed under microscopy. Results: The microneedle had a height of 800 μm, base diameter of 220 μm, and array density of 400 needles/cm². Single-needle penetration force was 0.142 N (excised porcine skin), and compressive modulus was 85.3 kPa, both meeting the requirement for painless insertion. Under normal conditions (25˚C/pH 7.4), the 24 h cumulative release rate was 34.6%. When exposed to the simulated inflammatory microenvironment (37˚C/pH 6.5), the dual-responsive system achieved a 24 h release rate of 98.5%, significantly higher than that of temperature-responsive alone (91.3%) or pH-responsive alone (88.2%). The microneedle patch exhibited a bioadhesion strength of 42.3 mN/cm², significantly greater than that of a commercial hydrocolloid dressing (18.6 mN/cm²), with good 24 h retention. Furthermore, the microneedle containing rehmannia polysaccharide nanoparticles reduced MSU crystal yield from 100% to 7.5% and decreased crystal size from 12.4 μm to 0.8 μm. Conclusion: A thermo/pH dual-responsive four-layer hydrogel microneedle was successfully fabricated. It possesses favorable mechanical properties and bioadhesion, enables rapid and nearly complete drug release triggered by the inflamed joint microenvironment, and significantly inhibits MSU crystallization. This study provides a novel transdermal drug delivery platform for localized and precision treatment of gouty arthritis.