Research progress on the manufacturing technology of hollow microneedles_Journal of Biomedical Engineering

Authors：

ZHOU Shengshuo ¹ , ZHOU Huajian ¹ , DU Xiaoyu ¹ , YU Ziye ¹ , XU Tongle ¹ , ZHAO Shun ¹ , SU Peiqiang ² , ZHANG Leian ¹ , FU Guangyang ¹ ,  LIU Xuelei ^1,2

1. School of Mechanical Engineering, Shandong University of Technology , Zibo, Shandong 255000, P. R. China;
2. Shandong Huiyu Auto Parts Co., Ltd., Binzhou, Shandong 251702, P. R. China;

Corresponding author：

Keywords：

Microneedle; Hollow microneedle; Manufacturing technology; Process route; Hollow microneedle material

DOI：

10.7507/1001-5515.202408024

Video：

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Abstract Full text Figures/Tables Video References Cited by

Drug administration via hollow microneedles (HMN) have the advantages of painlessness, avoidance of first-pass effect, capability of sustained infusion, and no need for professional personnel operation. In addition, HMN can also be applied in the fields of body fluid extraction and biosensors, showing broad application prospects. However, traditional manufacturing technologies cannot meet the demand for low-cost mass production of HMN, limiting its widespread application. This paper reviews the main manufacturing technologies used for HMN in recent years, which include photolithography and etching, laser etching, sputtering and electroplating, micro-molding, three-dimensional (3D) printing and drawing lithography. It further analyzes the characteristics and limitations of existing manufacturing technologies and points out that the combination of various manufacturing technologies can improve production efficiency to a certain extent. In addition, this paper looks forward to the future trends of HMN manufacturing technology and proposes possible directions for its development. In conclusion, it is expected that this review can provide new ideas and references for follow-up research.

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2.	Zhang X, Zhang W, Wu W, et al. Recent advances in the preparation of microneedle patches for interstitial fluid extraction and analysis. Microchemical Journal, 2023, 195: 109477.
3.	Abd-El-Azim H, Tekko I A, Ali A, et al. Hollow microneedle assisted intradermal delivery of hypericin lipid nanocapsules with light enabled photodynamic therapy against skin cancer. Journal of Controlled Release, 2022, 348: 849-869.
4.	Cheng J, Huang J, Xiang Q, et al. Hollow microneedle microfluidic paper-based chip for biomolecules rapid sampling and detection in interstitial fluid. Anal Chim Acta, 2023, 1255: 341101.
5.	Li H, Wu G, Weng Z, et al. Microneedle-based potentiometric sensing system for continuous monitoring of multiple electrolytes in skin interstitial fluids. ACS Sens, 2021, 6(6): 2181-2190.
6.	Li R, Liu X, Yuan X, et al. Fast customization of hollow microneedle patches for insulin delivery. International Journal of Bioprinting, 2022, 8(2): 553.
7.	Ren Y, Li J, Chen Y, et al. Customized flexible hollow microneedles for psoriasis treatment with reduced-dose drug. Bioeng Transl Med, 2023, 8(4): e10530.
8.	Monou P K, Andriotis E G, Tsongas K, et al. Fabrication of 3D printed hollow microneedles by digital light processing for the buccal delivery of actives. ACS Biomaterials Science & Engineering, 2023, 9(8): 5072-5083.
9.	Luo X, Yu Q, Liu Y, et al. Closed-loop diabetes minipatch based on a biosensor and an electroosmotic pump on hollow biodegradable microneedles. ACS Sens, 2022, 7(5): 1347-1360.
10.	Chen Y H, Wang F Y, Chan Y S, et al. Biofabricating hollow microneedle array with controllable microstructure for cell transplantation. Journal of Biomedical Materials Research Part B: Applied Biomaterials, 2022, 110(9): 1997-2005.
11.	Van Hileghem L, Kushwaha S, Piovesan A, et al. Innovative fabrication of hollow microneedle arrays enabling blood sampling with a self-powered microfluidic patch. Micromachines, 2023, 14(3): 615.
12.	Liu Y, He C, Qiao T, et al. Coral-inspired hollow microneedle patch with smart sensor therapy for wound infection. Advanced Functional Materials, 2024, 34(24): 2314071.
13.	Chinnamani M V, Hanif A, Kannan P K, et al. Soft microfiber-based hollow microneedle array for stretchable microfluidic biosensing patch with negative pressure-driven sampling. Biosensors and Bioelectronics, 2023, 237: 115468.
14.	Wu T, You X, Chen Z. Hollow microneedles on a paper fabricated by standard photolithography for the screening test of prediabetes. Sensors, 2022, 22(11): 4253.
15.	Parrilla M, Detamornrat U, Domínguez-Robles J, et al. Wearable hollow microneedle sensing patches for the transdermal electrochemical monitoring of glucose. Talanta, 2022, 249: 123695.
16.	崔闻宇, 王瑾. 微针技术在经皮给药系统中应用的研究进展. 微纳电子技术, 2023, 60(2): 195-204.
17.	Mighra R, Maiti T K, Bhattacharyya T K. Development of SU-8 hollow microneedles on a silicon substrate with microfluidic interconnects for transdermal drug delivery. Journal of Micromechanics and Microengineering, 2018, 28(10): 105017.
18.	O'Mahony C, Sebastian R, Tjulkins F, et al. Hollow silicon microneedles, fabricated using combined wet and dry etching techniques, for transdermal delivery and diagnostics. Int J Pharm, 2023, 637: 122888.
19.	Datta A, Biswas S, Dhar R, et al. Design and development of a piezoelectric driven micropump integrated with hollow microneedles for precise insulin delivery. Journal of Micromechanics and Microengineering, 2023, 33(7): 075003.
20.	朱锦涛,王华,李钰策,等.一种制备中空微针阵列的方法: CN201810706922.2. 2018-12-25. [2024-08-15].
21.	Evens T, Van Hileghem L, Dal Dosso F, et al. Producing hollow polymer microneedles using laser ablated molds in an injection molding process. Journal of Micro and Nano Manufacturing, 2021, 9(3): 030902.
22.	Dong C W, Jeon J Y, Kang H M, et al. Tip fabrication methods of hollow metal microneedles. Journal of Mechanical Science and Technology, 2022, 37: 261-269.
23.	Chen Y H, Wang F Y, Chan Y S, et al. Fabrication of hollow microneedle patch with controllable microstructure for cell therapy. SSRN Electronic Journal, 2020. DOI: 10.2139/ssrn.3757907.
24.	刘仁志. 独特而不可或缺的电镀技术. 表面工程与再制造, 2022, 22(1): 2-9.
25.	刘龙. 基于MEMS技术的微量采样/注射金属微针研究. 上海: 上海交通大学, 2016.
26.	Miller P R, Moorman M, Boehm R D, et al. Fabrication of hollow metal microneedle arrays using a molding and electroplating method. MRS Advances, 2019, 4(24): 1417-1426.
27.	Chen J, Cheng P, Sun Y, et al. A minimally invasive hollow microneedle with a cladding structure: ultra-thin but strong, batch manufacturable. IEEE Trans Biomed Eng, 2019, 66(12): 3480-3485.
28.	Lee D S, Li C G, Ihm C, et al. A three-dimensional and bevel-angled ultrahigh aspect ratio microneedle for minimally invasive and painless blood sampling. Sensors and Actuators B: Chemical, 2018, 255: 384-390.
29.	Liu Y, Yu Q, Ye L, et al. A wearable, minimally-invasive, fully electrochemically-controlled feedback minisystem for diabetes management. Lab on a Chip, 2023, 23(3): 421-436.
30.	Ren Y, Li J, Wang Z, et al. Polyimide (PI) flexible hollow microneedle array prepared based on optimized dual-moulding processes//2021 21st International Conference on Solid-State Sensors, Actuators and Microsystems (Transducers), Orlando: IEEE, 2021: 1452-1455.
31.	Zhou C, Tang H, Zhang L, et al. Hollow microneedle arrays produced by low-cost, high-fidelity replication of hypodermic needle tips for high-dose transdermal drug delivery. Advanced Engineering Materials, 2021, 23(6): 2001355.
32.	张怡心, 楚皓文, 李翔, 等. 光固化3D打印微针在透皮给药系统中的研究进展. 微纳电子技术, 2023, 60(7): 979-987.
33.	Parhi R. Recent advances in 3D printed microneedles and their skin delivery application in the treatment of various diseases. Journal of Drug Delivery Science and Technology, 2023, 84: 104395.
34.	Mathew E, Pitzanti G, Gomes Dos Santos A L, et al. Optimization of printing parameters for digital light processing 3D printing of hollow microneedle arrays. Pharmaceutics, 2021, 13(11): 1837.
35.	熊莎, 赖蓉蓉, 刘紫艺, 等. 微针经皮给药系统应用于皮肤肿瘤治疗的研究进展. 药学进展, 2022, 46(2): 128-137.
36.	万姗姗. 基于3D打印技术的微针结构设计和制造工艺研究. 农业装备与车辆工程, 2023, 61(5): 157-160.
37.	Sarker S, Wang J, Shah S A, et al. Geometric determinants of cell viability for 3d-printed hollow microneedle array-mediated delivery//2024 IEEE 37th International Conference on Micro Electro Mechanical Systems (MEMS), Austin: IEEE, 2024: 429-432.
38.	曾少枫, 刘付春俏, 周柏先, 等. 3D打印技术在透皮给药系统中应用的研究进展. 中国药学杂志, 2023, 58(14): 1265-1270.
39.	Sheikh M, Qassem M, Kyriacou P A. Optical detection of lithium therapeutic levels in porcine interstitial fluid collected using a hollow microneedle//2022 44th Annual International Conference of the IEEE Engineering in Medicine & Biology Society (EMBC), Glasgow, Scotland: IEEE, 2022: 4257-4260.
40.	Hu Z, Meduri C S, Ingrole R S J, et al. Solid and hollow metallic glass microneedles for transdermal drug-delivery. Applied Physics Letters, 2020, 116(20): 203703.

1. 陈鑫, 张永萍, 徐剑, 等. 微针现代研究进展. 亚太传统医药, 2021, 17(7): 210-213.
2. Zhang X, Zhang W, Wu W, et al. Recent advances in the preparation of microneedle patches for interstitial fluid extraction and analysis. Microchemical Journal, 2023, 195: 109477.
3. Abd-El-Azim H, Tekko I A, Ali A, et al. Hollow microneedle assisted intradermal delivery of hypericin lipid nanocapsules with light enabled photodynamic therapy against skin cancer. Journal of Controlled Release, 2022, 348: 849-869.
4. Cheng J, Huang J, Xiang Q, et al. Hollow microneedle microfluidic paper-based chip for biomolecules rapid sampling and detection in interstitial fluid. Anal Chim Acta, 2023, 1255: 341101.
5. Li H, Wu G, Weng Z, et al. Microneedle-based potentiometric sensing system for continuous monitoring of multiple electrolytes in skin interstitial fluids. ACS Sens, 2021, 6(6): 2181-2190.
6. Li R, Liu X, Yuan X, et al. Fast customization of hollow microneedle patches for insulin delivery. International Journal of Bioprinting, 2022, 8(2): 553.
7. Ren Y, Li J, Chen Y, et al. Customized flexible hollow microneedles for psoriasis treatment with reduced-dose drug. Bioeng Transl Med, 2023, 8(4): e10530.
8. Monou P K, Andriotis E G, Tsongas K, et al. Fabrication of 3D printed hollow microneedles by digital light processing for the buccal delivery of actives. ACS Biomaterials Science & Engineering, 2023, 9(8): 5072-5083.
9. Luo X, Yu Q, Liu Y, et al. Closed-loop diabetes minipatch based on a biosensor and an electroosmotic pump on hollow biodegradable microneedles. ACS Sens, 2022, 7(5): 1347-1360.
10. Chen Y H, Wang F Y, Chan Y S, et al. Biofabricating hollow microneedle array with controllable microstructure for cell transplantation. Journal of Biomedical Materials Research Part B: Applied Biomaterials, 2022, 110(9): 1997-2005.
11. Van Hileghem L, Kushwaha S, Piovesan A, et al. Innovative fabrication of hollow microneedle arrays enabling blood sampling with a self-powered microfluidic patch. Micromachines, 2023, 14(3): 615.
12. Liu Y, He C, Qiao T, et al. Coral-inspired hollow microneedle patch with smart sensor therapy for wound infection. Advanced Functional Materials, 2024, 34(24): 2314071.
13. Chinnamani M V, Hanif A, Kannan P K, et al. Soft microfiber-based hollow microneedle array for stretchable microfluidic biosensing patch with negative pressure-driven sampling. Biosensors and Bioelectronics, 2023, 237: 115468.
14. Wu T, You X, Chen Z. Hollow microneedles on a paper fabricated by standard photolithography for the screening test of prediabetes. Sensors, 2022, 22(11): 4253.
15. Parrilla M, Detamornrat U, Domínguez-Robles J, et al. Wearable hollow microneedle sensing patches for the transdermal electrochemical monitoring of glucose. Talanta, 2022, 249: 123695.
16. 崔闻宇, 王瑾. 微针技术在经皮给药系统中应用的研究进展. 微纳电子技术, 2023, 60(2): 195-204.
17. Mighra R, Maiti T K, Bhattacharyya T K. Development of SU-8 hollow microneedles on a silicon substrate with microfluidic interconnects for transdermal drug delivery. Journal of Micromechanics and Microengineering, 2018, 28(10): 105017.
18. O'Mahony C, Sebastian R, Tjulkins F, et al. Hollow silicon microneedles, fabricated using combined wet and dry etching techniques, for transdermal delivery and diagnostics. Int J Pharm, 2023, 637: 122888.
19. Datta A, Biswas S, Dhar R, et al. Design and development of a piezoelectric driven micropump integrated with hollow microneedles for precise insulin delivery. Journal of Micromechanics and Microengineering, 2023, 33(7): 075003.
20. 朱锦涛,王华,李钰策,等.一种制备中空微针阵列的方法: CN201810706922.2. 2018-12-25. [2024-08-15].
21. Evens T, Van Hileghem L, Dal Dosso F, et al. Producing hollow polymer microneedles using laser ablated molds in an injection molding process. Journal of Micro and Nano Manufacturing, 2021, 9(3): 030902.
22. Dong C W, Jeon J Y, Kang H M, et al. Tip fabrication methods of hollow metal microneedles. Journal of Mechanical Science and Technology, 2022, 37: 261-269.
23. Chen Y H, Wang F Y, Chan Y S, et al. Fabrication of hollow microneedle patch with controllable microstructure for cell therapy. SSRN Electronic Journal, 2020. DOI: 10.2139/ssrn.3757907.
24. 刘仁志. 独特而不可或缺的电镀技术. 表面工程与再制造, 2022, 22(1): 2-9.
25. 刘龙. 基于MEMS技术的微量采样/注射金属微针研究. 上海: 上海交通大学, 2016.
26. Miller P R, Moorman M, Boehm R D, et al. Fabrication of hollow metal microneedle arrays using a molding and electroplating method. MRS Advances, 2019, 4(24): 1417-1426.
27. Chen J, Cheng P, Sun Y, et al. A minimally invasive hollow microneedle with a cladding structure: ultra-thin but strong, batch manufacturable. IEEE Trans Biomed Eng, 2019, 66(12): 3480-3485.
28. Lee D S, Li C G, Ihm C, et al. A three-dimensional and bevel-angled ultrahigh aspect ratio microneedle for minimally invasive and painless blood sampling. Sensors and Actuators B: Chemical, 2018, 255: 384-390.
29. Liu Y, Yu Q, Ye L, et al. A wearable, minimally-invasive, fully electrochemically-controlled feedback minisystem for diabetes management. Lab on a Chip, 2023, 23(3): 421-436.
30. Ren Y, Li J, Wang Z, et al. Polyimide (PI) flexible hollow microneedle array prepared based on optimized dual-moulding processes//2021 21st International Conference on Solid-State Sensors, Actuators and Microsystems (Transducers), Orlando: IEEE, 2021: 1452-1455.
31. Zhou C, Tang H, Zhang L, et al. Hollow microneedle arrays produced by low-cost, high-fidelity replication of hypodermic needle tips for high-dose transdermal drug delivery. Advanced Engineering Materials, 2021, 23(6): 2001355.
32. 张怡心, 楚皓文, 李翔, 等. 光固化3D打印微针在透皮给药系统中的研究进展. 微纳电子技术, 2023, 60(7): 979-987.
33. Parhi R. Recent advances in 3D printed microneedles and their skin delivery application in the treatment of various diseases. Journal of Drug Delivery Science and Technology, 2023, 84: 104395.
34. Mathew E, Pitzanti G, Gomes Dos Santos A L, et al. Optimization of printing parameters for digital light processing 3D printing of hollow microneedle arrays. Pharmaceutics, 2021, 13(11): 1837.
35. 熊莎, 赖蓉蓉, 刘紫艺, 等. 微针经皮给药系统应用于皮肤肿瘤治疗的研究进展. 药学进展, 2022, 46(2): 128-137.
36. 万姗姗. 基于3D打印技术的微针结构设计和制造工艺研究. 农业装备与车辆工程, 2023, 61(5): 157-160.
37. Sarker S, Wang J, Shah S A, et al. Geometric determinants of cell viability for 3d-printed hollow microneedle array-mediated delivery//2024 IEEE 37th International Conference on Micro Electro Mechanical Systems (MEMS), Austin: IEEE, 2024: 429-432.
38. 曾少枫, 刘付春俏, 周柏先, 等. 3D打印技术在透皮给药系统中应用的研究进展. 中国药学杂志, 2023, 58(14): 1265-1270.
39. Sheikh M, Qassem M, Kyriacou P A. Optical detection of lithium therapeutic levels in porcine interstitial fluid collected using a hollow microneedle//2022 44th Annual International Conference of the IEEE Engineering in Medicine & Biology Society (EMBC), Glasgow, Scotland: IEEE, 2022: 4257-4260.
40. Hu Z, Meduri C S, Ingrole R S J, et al. Solid and hollow metallic glass microneedles for transdermal drug-delivery. Applied Physics Letters, 2020, 116(20): 203703.

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