Synergistic effect of ultrasound transdermal drug delivery based on multi-stage dynamic focal-shifting

GONG Xinyue; XUE Honghui; SONG Renjie; GUO Yang; MA Yong; TU Juan

doi:10.7498/aps.74.20251023

Abstract

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.

Keywords:

Authors and contacts

1.
Key Laboratory of Modern Acoustics, Ministry of Education, Department of Sound Science and Engineering, School of Physics, Nanjing University, Nanjing 210093, China
2.
School of IOT and AI, Wuxi Vocational Institute of Commerce, Wuxi 214153, China
3.
Shanghai Lianying Medical Technology Co., Ltd., Shanghai 201807, China
4.
Key Laboratory of New-Techniques for Bone Injury Repair and Reconstruction, Nanjing University of Chinese Medicine, Nanjing 210023, China

Corresponding author: TU Juan, juantu@nju.edu.cn

Funds: Project supported by the Jiangsu Provincial Science and Technology Plan Special Fund (Key Research and Development Program - Social Development) Project, China (Grant No. BE2023818), the Fundamental Research Funds for the Central Universities of Ministry of Education of China (Grant No. 020414380195), and the National Natural Science Foundation of China (Grant No. 12274220).

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References

[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

Cited By

图 1 TDD药物吸收途径示意图

Figure 1. Schematic diagram of TDD drug absorption pathway

DownLoad: Full-Size Img PowerPoint

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

Figure 2. (a) Schematic diagram of experimental operation; (b) schematic diagram of particle penetration, where green spheres are fluorescent particles.

DownLoad: Full-Size Img PowerPoint

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

Figure 3. (a) Schematic diagram of transdermal drug delivery principle with focused emission; (b) finite element model structure diagram

DownLoad: Full-Size Img PowerPoint

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

Figure 4. Tissue sections under fluorescence microscope: (a) Natural infiltration group; (b) fixed focus group; (c) dynamic focus group in turn.

DownLoad: Full-Size Img PowerPoint

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

Figure 5. Histogram of three indicators: average penetration depth, maximum penetration depth and fluorescence integral intensity of fluorescence images of tissue sections.

DownLoad: Full-Size Img PowerPoint

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

Figure 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.

DownLoad: Full-Size Img PowerPoint

图 7 运动至皮下5 mm处的粒子分布情况, 其中分布宽度为运动至皮下5 mm的粒子左右两端的距离(见图2(b))

Figure 7. Distribution of particles moving to 5 mm under the skin. The distribution width is the distance between the left and right ends of particles moving to 5 mm under the skin, as shown in Fig. 2(b).

DownLoad: Full-Size Img PowerPoint

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

Figure 8. The number of particles moving to 5 mm under the skin under three duty ratios of 5%, 10% and 20%.

DownLoad: Full-Size Img PowerPoint

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

Figure 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.

DownLoad: Full-Size Img PowerPoint

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

DownLoad: CSV

map

[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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Vol. 74, Issue 21 - 2025-11-05

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