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针对传统超声透皮给药技术中声场聚焦模式单一、药物粒子穿透深度及分布范围受限等关键瓶颈问题, 本研究提出了一种基于超声换能器阵列的多阶动态移焦发射策略, 旨在实现声能量在皮肤深度方向的动态重分布, 从而提升纳米粒子的透皮效率与分布均匀性. 通过调控换能器阵元激励相位, 构建多阶移动的声聚焦作用路径, 并通过在体动物实验与有限元仿真联合验证其透皮给药效果. 结果显示, 与固定焦点模式相比, 动态聚焦显著提升了药物粒子的经皮渗透深度与空间分布均匀性, 其平均渗透深度可提高65.7%, 荧光积分强度提升69.3%, 并在皮肤组织中形成更均匀的沉积带结构. 有限元仿真结果进一步揭示了该模式下粒子扩散演化行为与焦点动态轨迹之间的强耦合机制, 证实动态移焦模式下的“多焦点接力式”驱动效应可在显著优化粒子的经皮渗透效率的同时, 有效降低局部能量沉积引发的潜在风险, 为构建高效、安全、可控的超声透皮递药技术提供了重要的理论基础与技术支撑.Ultrasound-assisted transdermal drug delivery (UTDD) is a promising non-invasive strategy to overcome the skin barrier. The traditional fixed-focus ultrasound approaches encounter the problems such as limited penetration depth, localized accumulation, and risk of thermal damage. To address these challenges, we propose a phased-array based dynamic focusing strategy, in which the acoustic focus is shifted sequentially along the depth direction. This approach aims to construct a continuous longitudinal acoustic radiation pathway that can sustain particle migration into deeper skin layers. In vivo experiments are conducted with FITC-labeled nanoparticles on rat dorsal skin under three conditions: natural permeation, fixed focus (~0.5 mm beneath the skin), and dynamic focusing (scanned from the surface to 1 mm). After 10-min ultrasound, fluorescence microscopy reveals that fixed focus enhances penetration compared with natural permeation, while dynamic focusing further improves delivery, increasing average depth by 65.7%, maximum depth by 41.2%, and fluorescence intensity by 69.3%. Dynamic focusing also produces a more uniform and continuous deposition band, which is unlike the localized accumulation seen with fixed focus. To elucidate the underlying mechanisms, a two-dimensional finite element model is established in COMSOL Multiphysics. The simulation results reveal that this “multi-focus relay” effect provides a continuous driving force pathway, enabling particles to follow the shifting focal positions. Trajectory analysis confirms that the number of particles reaching deeper layers (up to 5 mm) increases by nearly 14 times under dynamic focusing compared with that in the case of fixed focus, while the width of the lateral distribution extends by 46.1%. In conclusion, both experimental and simulation results demonstrate that phased-array dynamic focusing significantly enhances penetration depth, migration efficiency, and distribution uniformity of nanoparticles in UTDD. By constructing a continuous acoustic radiation pathway in the depth dimension, this approach improves delivery efficiency while mitigating local energy accumulation, providing a safer and more effective strategy for ultrasound-mediated transdermal therapy.
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Keywords:
- ultrasound transdermal drug delivery /
- dynamic focusing /
- ultrasonic transducer array /
- finite element simulation
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图 2 (a) 实验操作示意图; (b) 粒子渗透示意图, 其中绿色圆球为荧光粒子
Fig. 2. (a) Schematic diagram of experimental operation; (b) schematic diagram of particle penetration, where green spheres are fluorescent particles.
图 3 (a) 聚焦发射的透皮给药原理示意图; (b) 有限元模型结构图
Fig. 3. (a) Schematic diagram of transdermal drug delivery principle with focused emission; (b) finite element model structure diagram
图 4 荧光显微镜下的组织切片 (a)自然渗透组; (b)固定焦点聚焦组; (c)动态聚焦组
Fig. 4. Tissue sections under fluorescence microscope: (a) Natural infiltration group; (b) fixed focus group; (c) dynamic focus group in turn.
图 5 组织切片荧光图像平均渗透深度、最大渗透深度、荧光积分强度三项指标柱状图
Fig. 5. Histogram of three indicators: average penetration depth, maximum penetration depth and fluorescence integral intensity of fluorescence images of tissue sections.
图 6 动态聚焦情况下不同聚焦深度的声场仿真结果(a)焦点位于皮下1 mm; (b)焦点位于皮下2 mm; (c)焦点位于皮下3 mm
Fig. 6. Simulation results of acoustic field with different focusing depths under dynamic focusing: (a) The focus is 1 mm under the skin; (b) the focus is 2 mm under the skin; (c) the focus is 3 mm under the skin.
图 8 5%, 10%和20%三种占空比条件下, 运动至皮下5 mm处的粒子数量
Fig. 8. The number of particles moving to 5 mm under the skin under three duty ratios of 5%, 10% and 20%.
图 9 三种典型位置粒子在两种声场中的三维运动路径(对应粉、绿、紫曲线), 其中黑色虚线描绘了声场焦点中心的变化 (a)固定焦点聚焦声场; (b)动态移焦声场
Fig. 9. Three-dimensional motion paths of particles in three typical positions (corresponding to pink, green and purple curves) in two kinds of acoustic fields: (a) Acoustic field with fixed focus; (b) dynamically focused acoustic field. The black dotted line depicts the change of the focus center of the sound field.
表 1 不同聚焦深度下的焦域参数
Table 1. Focal parameters at different depth of focus.
预设焦点皮下深度 焦点横向宽度/mm 焦点纵向长度/mm x/mm y/mm 0.00 1.00 0.93 3.63 0.00 2.00 0.98 4.13 0.00 3.00 1.05 4.56 
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[1] Jeong W Y, Kwon M, Choi H E, Kim K S 2021 Biomater. Res. 25 24
Google Scholar
[2] Gaikwad S S, Zanje A L, Somwanshi J D 2024 Int. J. Pharm. 652 123856
Google Scholar
[3] Wiedersberg S, Guy R H 2014 J. Controlled Release 190 150
Google Scholar
[4] Zhang H, Zhai Y J, Yang X Y, Zhai G X 2015 Curr. Pharm. Des. 12 2713
Google Scholar
[5] Prausnitz M R, Langer R 2008 Nat. Biotechnol. 26 1261
Google Scholar
[6] Polat B E, Deen W M, Langer R, Blankschtein D 2012 J. Controlled Release 158 250
Google Scholar
[7] Yu C, Shah A, Amiri N, et al. 2023 Adv. Mater. 35 2300066
Google Scholar
[8] Akhtar N, Singh V, Yusuf M, Khan R A 2020 Biomed. Eng.- Biomed. Tech. 65 243
Google Scholar
[9] Smith N B 2008 Expert Opin. Drug Deliv. 5 1107
Google Scholar
[10] Tian Y H, Liu Z, Tan H Y, Hou J H, Wen X, Yang F, Cheng W 2020 Int. J. Nanomed. 15 401
Google Scholar
[11] Sabbagh F, Muhamad I I, Niazmand R, Dikshit P K, Kim B S 2022 Int. J. Biol. Macromol. 203 222
Google Scholar
[12] Al-Bataineh O M, Lweesy K, Fraiwan L 2011 1st Middle East Conference on Biomedical Engineering Sharjah, United Arab Emirates, February 21–24, 2011 p316
[13] Maione E, Shung K K, Meyer R J, et al. 2002 IEEE Trans. Ultrason. Ferroelect. Freq. Contr. 49 1430
Google Scholar
[14] 丁亚军, 钱盛友, 胡继文, 邹孝 2012 61 144301
Google Scholar
Ding Y J, Qian S Y, Hu J W, Zou X 2012 Acta Phys. Sin. 61 144301
Google Scholar
[15] 徐丰, 陆明珠, 万明习, 方飞 2010 52 1349
Google Scholar
Xu F, Lu M Z, Wan X M, Fang F 2010 Acta Phys. Sin. 52 1349
Google Scholar
[16] Burgess A, Shah K, Hough O, Hynynen K 2015 Expert Rev. Neurother. 15 477
Google Scholar
[17] Meng Y, Hynynen K, Lipsman N 2021 Nat. Rev. Neurol. 17 7
Google Scholar
[18] Biskanaki F, Tertipi N, Sfyri E, Kefala V, Rallis E 2025 Appl. Sci. 15 4958
Google Scholar
[19] Özsoy Ç, Lafci B, Reiss M, Deán-Ben X L, Razansky D 2023 Photoacoustics 31 100508
Google Scholar
[20] 钱骏, 谢伟, 周小伟, 谭坚文, 王智彪, 杜永洪, 李雁浩 2022 71 037201
Google Scholar
Qian J, Xi W, Zhou X W, Tan J W, Wang Z B, Du Y H, Li Y H 2022 Acta Phys. Sin. 71 037201
Google Scholar
[21] Zhang H J, Pan Y P, Hou Y, Li M H, Deng J, Wang B C, Hao S L 2024 Small 20 2306944
Google Scholar
[22] Caprifico A E, Polycarpou E, Foot P J S, Calabrese G 2020 Trends Pharmacol. Sci. 41 686
Google Scholar
[23] Moreno V M, Baeza A, Vallet-Regí M 2021 Acta Biomater. 121 263
Google Scholar
[24] Nguyen T T, Nguyen H N, Nghiem T H L, et al. 2024 Sci. Rep. 14 6969
Google Scholar
[25] Do Nascimento V M, Nantes Button V L D S, Maia J M, et al. 2003 Medical Imaging San Diego, United States, May 23, 2003 p86
[26] Husseini G A, Pitt W G 2008 Adv. Drug Delivery Rev. 60 1137
Google Scholar
[27] Paris J L, Mannaris C, Cabañas M V, Carlisle R, Manzano M, Vallet-Regí M, Coussios C C 2018 Chem. Eng. J. 340 2
Google Scholar
[28] Gor'kov L P 1961 Dokl. Akad. Nauk SSSR 140 88
[29] 孙芳, 曾周末, 王晓媛, 靳世久, 詹湘琳 2011 60 094301
Google Scholar
Sun F, Zeng Z M, Jin S J, Zhan X L 2011 Acta Phys. Sin. 60 094301
Google Scholar
[30] Lintzeri D A, Karimian N, Blume-Peytavi U, Kottner J 2022 J. Eur. Acad. Dermatol. Venereol. 36 1191
Google Scholar
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