【Biomaterials】400kHz与2MHz的完美碰撞！机械结构启发而设计的集成式双频超声换能器，实现空化增强透皮给药
文章标题：A mechanism-inspired integrated dual-frequency ultrasound transducer for cavitation-enhanced transdermal drug delivery
通讯作者：Chunlong Fei, Jing Xu, Zeyu Chen, Xiang Chen, Shuang Zhao
文章概要
引言
超声透皮递药技术作为一种非侵入性的给药方式，在皮肤病治疗和医疗美容领域展现出巨大潜力。尽管该技术应用广泛，但临床研究长期依赖经验选择单一频率超声，缺乏从气泡成核到崩溃全生命周期的超声调控空化机制的深刻理解，这限制了超声透皮递药系统的理性设计。过往的研究模型往往将空化核的产生与后续的生长崩溃割裂开来，无法提供统一的设计指导。为了打破这一理论与实际应用之间的断层，研究团队提出了一个全过程多尺度仿真框架，并据此设计出一种新型一体化双频超声换能器，实现了空化效应的协同增强，为临床高效给药提供了全新的技术参考。
Fig. 1. Schematic of the Sequential High-then-Low-Frequency Approach in the Integrated Dual-Frequency Ultrasound Transducer (iDFUT) for Enhancing Drug Delivery (Principle: High-frequency ultrasound pre-generates numerous “seed” cavitation nuclei; low-frequency ultrasound drives their growth and collapse, releasing shock waves to disrupt the stratum corneum and expand microchannels (see end of Section 3)).
主要实验及结论
研究团队首先将ZGB空化模型与MATLAB中的KM方程相结合，系统对比了不同频率在成核、生长及崩溃阶段的物理表现。数值模拟发现，2MHz的高频超声能显著扩大成核区域并提高液气相变速率，在短时间内催生海量的空化核“种子”；相反，400kHz的低频超声则更接近微气泡的固有共振频率，能够显著降低瞬态空化阈值，强烈激发已有气泡的剧烈生长与暴力崩溃。基于这一“高频预成核、低频强放大”的协同机制，团队开发出一种同轴嵌套结构的一体化双频超声换能器。该设计成功克服了传统双换能器系统对准困难和操作复杂的弊端，通过巧妙调节高低频的占空比交替工作，使机械冲击力精准作用于微环境。
Fig. 2. Simulation of the Relationship Between Ultrasound Frequency and Cavitation Effects. A. Schematic of an Ultrasonic Transducer Emitting Ultrasound in Water. B. Two-Dimensional Schematic of the Model in Fluent. C. Cavitation nucleation under different frequencies: (a)–(c) at 125 μs (vapor volume fraction, mass transfer rate, absolute pressure); (d) vapor volume fraction after 20 cycles for each frequency. D. Variation of Bubble Radius Ratio with Time for Different Frequencies at an Initial Radius of 1 μm. E. Maximum Bubble Radius Ratio versus Initial Bubble Radius for Different Frequencies within the Same Time Frame. F. Variation of Inertial Cavitation Threshold with Initial Bubble Radius for Different Frequencies.
Fig. 3. Design, Fabrication and Characterization of iDFUT. A. Fabrication Process Flow of iDFUT. B. Photograph of the Fabricated Device. C. Experimental Setup for Measuring Acoustic Power of the Ultrasonic Transducer. D. Impedance Phase of Low-Frequency Ultrasonic Transducer. E. Impedance Phase Response of High-Frequency Ultrasonic Transducer. F. Acoustic Power Output versus Excitation Voltage for Low and High Frequencies.
在随后的体外猪皮递药实验中，亲水性模型药物的渗透结果显示，采用两轮高低频交替工作的调控模式效果最为显著。在不产生严重热损伤的安全范围内，该模式使药物的累计渗透面积相比于自由扩散提升了3.5倍，且递药深度成功推进至皮下1毫米深处。体内银屑病小鼠模型治疗实验进一步证实了该系统的转化潜力，通过交替双频超声递送甲氨蝶呤，小鼠皮肤的红斑、鳞屑及表皮厚度得到极大程度的缓解。组织学观察表明，皮肤附属器如毛囊周围出现了由空化效应产生的微孔分布，且促炎细胞因子IL-23的表达水平显著下调，疗效明显优于传统单频超声给药模式。
Fig. 4. In vitro transdermal drug delivery of iDFUT. A. Schematic diagram of in vitro transdermal drug delivery testing setup. B. Quantitative analysis of the MB penetration area in vitro. Statistical analysis was performed using one-way analysis of variance (ANOVA). C. 2D side view of MB permeation of porcine skin and after image processing. Scale bar: 1 mm. D. Photo of the temperature-variation setup for thermistors measurement. E. Temperature changes of iDFUT operated for 120 s measured by an infrared thermal camera. F. Time-temperature curve was captured by thermistors every 30 s.
Fig. 5. Therapeutic evaluation of iDFUT-mediated MTX delivery in the treatment of psoriasis. A. Schematic illustration of psoriasis treatment by iDFUT. B. Representative images of mouse dorsal skin obtained after MTX treatment. C. Heatmap of the PASI score (total) of each mouse. D. PASI score (total) measured from days 1 to 7 (n = 5) (ns, p > 0.05; *, p < 0.1; **, p < 0.001). E. Weight statistics of varying mice groups (n = 5). F. Representative H&E staining images of the dorsal skin tissues in different treatment groups. Scale bars: 100 μm. G. Epidermal thickness statistics of varying mice groups (n = 5). H. Representative IL-23 immunohistochemical staining of mice back skin sections on day 7. Scale bar: 50 μm. I. Quantitative analysis of IHC staining of IL-23. Data are presented as the mean ± SD (n = 5) (p < 0.05; **p < 0.01; ***p < 0.001; and ****p < 0.0001).
总结及展望
这项工作成功构建了从多尺度模拟、机制驱动器件设计到动物在体验证的完整闭环，证实了双频超声协同调控空化动力学在提高透皮给药效率方面的核心价值。尽管当前模型在处理复杂皮肤介质的粘弹性影响及器件阻抗匹配上仍有优化空间，但其展示的科学范式极具前瞻性。未来，研究团队计划进一步引入实时空化监测技术，深化复杂介质中的多物理场耦合仿真，并将这种机制驱动的一体化双频换能器拓展应用于皮肤肿瘤的光动力治疗及瘢痕的局部管理等更广泛的生物医学临床场景中。