Progressive microneedles for targeting and intelligent drug delivery

Abstract

Microneedle-mediated drug delivery systems (MDDS) have experienced robust growth in recent years, with designers leveraging their creativity to apply these systems for direct drug delivery to the skin, mucous membranes, blood vessel walls and even internal organs. In order to achieve precise drug delivery, various delicately conceived drug release modes based on MDDS have been developed. Herein, to elucidate the design concepts of numerous reported MDDS, we have categorized them into two levels (Level-Ⅰ MDDS and Level-Ⅱ MDDS) depending on whether nanoscale and microscale carriers are integrated within the microneedles. In this work, the design strategies of MDDS, as well as the current status of their applications in targeted and intelligent drug delivery were reviewed, while their prospects and challenges for future industrialization and clinical applications were also discussed.

Keywords

Microneedle / Drug delivery / Target / Intelligent / Responsive / Nanocarrier

Conflicts of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

Acknowledgments

This work was supported by the National Natural Science Foundation of China (Grant number 82074031), the Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning (Grant number TP2020054), Shanghai Sailing Program (21YF1447400), and the Program for Shanghai High-Level Local University Innovation Team (SZY20220315).

References

[1] Chen J, Ren H, Zhou P, Zheng S, Du B, Liu X, et al. Microneedle-mediated drug delivery for cutaneous diseases. Front Bioeng Biotechnol 2022; 10:1032041.

[2] You J, Juhng S, Song J, Park J, Jang M, Kang G, et al. Egg microneedle for transdermal delivery of active liraglutide. Adv Healthc Mater 2023; 12(9):2202473.

[3] Song K, Hao Y, Tan X, Huang H, Wang L, Zheng W. Microneedle-mediated delivery of ziconotide-loaded liposomes fused with exosomes for analgesia. J Control Release 2023; 356:448-62.

[4] Hu F, Gao Q, Liu J, Chen W, Zheng C, Bai Q, et al. Smart microneedle patches for wound healing and management. J Mater Chem B 2023; 11(13):2830-51.

[5] Yuan M, Liu K, Jiang T, Li S, Chen J, Wu Z, et al. GelMA/PEGDA microneedles patch loaded with HUVECs-derived exosomes and tazarotene promote diabetic wound healing. J Nanobiotechnol 2022; 20(1):147.

[6] Yerneni SS, Yalcintas EP, Smith JD, Averick S, Campbell PG, Ozdoganlar OB. Skin-targeted delivery of extracellular vesicle-encapsulated curcumin using dissolvable microneedle arrays. Acta Biomater 2022; 149:198-212.

[7] Vijayanand S, Patil S, Joshi D, Menon I, Braz Gomes K, Kale A, et al. Microneedle delivery of an adjuvanted microparticulate vaccine induces high antibody levels in mice vaccinated against coronavirus. Vaccines (Basel) 2022; 10(9):1491.

[8] Bandyopadhyay M, Morelli AE, Balmert SC, Ward NL, Erdos G, Sumpter TL, et al. Skin codelivery of contact sensitizers and neurokinin-1 receptor antagonists integrated in microneedle arrays suppresses allergic contact dermatitis. J Allergy Clin Immunol 2022; 150(1):114-30.

[9] Leone M, Monkare J, Bouwstra JA, Kersten G. Dissolving microneedle patches for dermal vaccination. Pharm Res 2017; 34(11):2223-40.

[10] Zhang X, Wang Z, Jiang H, Zeng H, An N, Liu B, et al. Self-powered enzyme-linked microneedle patch for scar-prevention healing of diabetic wounds. Sci Adv 2023; 9(28):eadh1415.

[11] Wang J, Ye Y, Yu J, Kahkoska AR, Zhang X, Wang C, et al. Core-shell microneedle gel for self-regulated insulin delivery. ACS Nano 2018; 12(3):2466-73.

[12] Duong HTT, Kim NW, Thambi T, Giang Phan VH, Lee MS, Yin Y, et al. Microneedle arrays coated with charge reversal pH -sensitive copolymers improve antigen presenting cells-homing DNA vaccine delivery and immune responses. J Control Release 2018; 269:225-34.

[13] Lan X, She J, Lin DA, Xu Y, Li X, Yang WF, et al. Microneedle-mediated delivery of lipid-coated cisplatin nanoparticles for efficient and safe cancer therapy. ACS Appl Mater Interfaces 2018; 10(39):33060-9.

[14] Chen M, Quan G, Wen T, Yang P, Qin W, Mai H, et al. Cold to hot: binary cooperative microneedle array-amplified photoimmunotherapy for eliciting antitumor immunity and the abscopal effect. ACS Appl Mater Interfaces 2020; 12(29):32259-69.

[15] Fan Z, Wei Y, Yin Z, Huang H, Liao X, Sun L, et al. Near-infrared light-triggered unfolding microneedle patch for minimally invasive treatment of myocardial ischemia. ACS Appl Mater Interfaces 2021; 13(34): 40278-40289.

[16] Yang D, Chen M, Sun Y, Jin Y, Lu C, Pan X, et al. Microneedle-mediated transdermal drug delivery for treating diverse skin diseases. Acta Biomater 2021; 121:119-33.

[17] Sabri A, Ogilvie J, McKenna J, Segal J, Scurr D, Marlow M. Intradermal delivery of an immunomodulator for basal cell carcinoma; expanding the mechanistic insight into solid microneedle-enhanced delivery of hydrophobic molecules. Mol Pharm 2020; 17(8):2925-37.

[18] Seetharam AA, Choudhry H, Bakhrebah MA, Abdulaal WH, Gupta MS, Rizvi SMD, et al. Microneedles drug delivery systems for treatment of cancer: a recent update. Pharmaceutics 2020; 12(11):1101.

[19] Jin X, Zhu DD, Chen BZ, Ashfaq M, Guo XD. Insulin delivery systems combined with microneedle technology. Adv Drug Deliv Rev 2018; 127:119-37.

[20] Wilke N, Mulcahy A, Ye SR, Morrissey A. Process optimization andcharacterization of silicon microneedles fabricated by wet etch technology. Microelectron J 2005; 36(7):650-6.

[21] Ingrole RSJ, Gill HS. Microneedle coating methods: a review with a perspective. J Pharmacol Exp Ther 2019; 370(3):555-69.

[22] Carcamo-Martinez A, Mallon B, Dominguez-Robles J, Vora LK, Anjani QK, Donnelly RF. Hollow microneedles: a perspective in biomedical applications. Int J Pharm 2021; 599:120455.

[23] Kearney MC, McKenna PE, Quinn HL, Courtenay AJ, Larraneta E, Donnelly RF. Design and development of liquid drug reservoirs for microneedle delivery of poorly soluble drug molecules. Pharmaceutics 2019; 11(11):605.

[24] Donnelly RF, Singh TR, Garland MJ, Migalska K, Majithiya R, McCrudden CM, et al. Hydrogel-forming microneedle arrays for enhanced transdermal drug delivery. Adv Funct Mater 2012; 22(23):4879-90.

[25] Cheng J, Huang J, Xiang Q, Dong H. Hollow microneedle microfluidic paper-based chip for biomolecules rapid sampling and detection in interstitial fluid. Anal Chim Acta 2023; 1255:341101.

[26] Choi IJ, Cha HR, Hwang SJ, Baek SK, Lee JM, Choi SO. Live vaccinia virus-coated microneedle array patches for smallpox vaccination and stockpiling. Pharmaceutics 2021; 13(2):209.

[27] Lee JW, Park JH, Prausnitz MR. Dissolving microneedles for transdermal drug delivery. Biomaterials 2008; 29(13):2113-24.

[28] Jeon EY, Lee J, Kim BJ, Joo KI, Kim KH, Lim G, et al. Bio-inspired swellable hydrogel-forming double-layered adhesive microneedle protein patch for regenerative internal/external surgical closure. Biomaterials 2019; 222:119439.

[29] Li W, Tang J, Terry RN, Li S, Brunie A, Callahan RL, et al. Long-acting reversible contraception by effervescent microneedle patch. Sci Adv 2019; 5(11):eaaw8145.

[30] Lopez-Ramirez MA, Soto F, Wang C, Rueda R, Shukla S, Silva-Lopez C, et al. Built-in active microneedle patch with enhanced autonomous drug delivery. Adv Mater 2020; 32(1):e1905740.

[31] Qi Z, Cao J, Tao X, Wu X, Kundu SC, Lu S. Silk fibroin microneedle patches for the treatment of insomnia. Pharmaceutics 2021; 13(12):2198.

[32] Guo M, Wang Y, Gao B, He B. Shark tooth-inspired microneedle dressing for intelligent wound management. ACS Nano 2021; 15(9):15316-27.

[33] Ito Y, Hirono M, Fukushima K, Sugioka N, Takada K. Two-layered dissolving microneedles formulated with intermediate-acting insulin. Int J Pharm 2012; 436(1-2):387-93.

[34] Song JE, Jun SH, Park SG, Kang NG. A semi-dissolving microneedle patch incorporating TEMPO-oxidized bacterial cellulose nanofibers for enhanced transdermal delivery. Polymers (Basel) 2020; 12(9):1873.

[35] Omolu A, Bailly M, Day RM. Assessment of solid microneedle rollers to enhance transmembrane delivery of doxycycline and inhibition of MMP activity. Drug Deliv 2017; 24(1):942-51.

[36] Shu W, Heimark H, Bertollo N, Tobin DJ, O'Cearbhaill ED, Annaidh AN. Insights into the mechanics of solid conical microneedle array insertion into skin using the finite element method. Acta Biomater 2021; 135:403-13.

[37] Anbazhagan G, Suseela SB, Sankararajan R. Design, analysis and fabrication of solid polymer microneedle patch using CO₂ laser and polymer molding. Drug Deliv Transl Res 2023; 13(6):1813-27.

[38] Tu J, Du G, Reza Nejadnik M, Mönkäre J, van der Maaden K, Bomans PHH, et al. Mesoporous silica nanoparticle-coated microneedle arrays for intradermal antigen delivery. Pharm Res 2017; 34(8):1693-706.

[39] van der Maaden K, Varypataki EM, Romeijn S, Ossendorp F, Jiskoot W, Bouwstra J. Ovalbumin-coated pH -sensitive microneedle arrays effectively induce ovalbumin-specific antibody and T-cell responses in mice. Eur J Pharm Biopharm 2014; 88(2):310-15.

[40] Shakya AK, Lee CH, Gill HS. Coated microneedle-based cutaneous immunotherapy prevents der p 1-induced airway allergy in mice. J Allergy Clin Immunol 2018; 142(6) 2007-11.e3.

[41] Vrdoljak A, McGrath MG, Carey JB, Draper SJ, Hill AV, O'Mahony C, et al. Coated microneedle arrays for transcutaneous delivery of live virus vaccines. J Control Release 2012; 159(1):34-42.

[42] Du G, van der Maaden K, Leone M, Romeijn S, Kros A, et al. Woythe L, Coated and hollow microneedle-mediated intradermal immunization in mice with diphtheria toxoid loaded mesoporous silica nanoparticles. Pharm Res 2018; 35(10):189.

[43] Li R, Liu X, Yuan X, Wu S, Li L, Jiang X, et al. Fast customization of hollow microneedle patches for insulin delivery. Int J Bioprint 2022; 8(2):553.

[44] Abd-El-Azim H, Tekko IA, Ali A, Ramadan A, Nafee N, Khalafallah N, et al. Hollow microneedle assisted intradermal delivery of hypericin lipid nanocapsules with light enabled photodynamic therapy against skin cancer. J Control Release 2022; 348:849-69.

[45] Badnikar K, Jayadevi SN, Pahal S, Vemula PK, Nayak MM, Subramanyam DN. Microscale engineering of hollow microneedle tips: design, manufacturing, optimization and validation. Drug Deliv Transl Res 2022; 12(2):350-67.

[46] van der Maaden K, Heuts J, Camps M, Pontier M, Terwisscha van Scheltinga A, Jiskoot W, et al. Hollow microneedle-mediated micro-injections of a liposomal HPV E743-63 synthetic long peptide vaccine for efficient induction of cytotoxic and T-helper responses. J Control Release 2018; 269:347-54.

[47] Turner JG, White LR, Estrela P, HS Leese. Hydrogel-forming microneedles: current advancements and future trends. Macromol Biosci 2021; 21(2):e2000307.

[48] Machekposhti SA, Kadian S, Vanderwal L, Stafslien S, Narayan RJ. Novel hollow biodegradable microneedle for amphotericin B delivery. Med Comm 2023; 4(4):e321.

[49] Hong X, Wei L, Wu F, Wu Z, Chen L, Liu Z, et al. Dissolving and biodegradable microneedle technologies for transdermal sustained delivery of drug and vaccine. Drug Des Devel Ther 2013; 7:945-52.

[50] Kim MJ, Seong KY, Kim DS, Jeong JS, Kim SY, Lee S, et al. Minoxidil-loaded hyaluronic acid dissolving microneedles to alleviate hair loss in an alopecia animal model. Acta Biomater 2022; 143:189-202.

[51] Ray S wirth DM, Ortega-Rivera OA, Steinmetz NF, Pokorski JK. Dissolving microneedle delivery of a prophylactic HPV vaccine. Biomacromolecules 2022; 23(3):903-12.

[52] Sabri AHB, Anjani QK, Utomo E, Ripolin A, Donnelly RF. Development and characterization of a dry reservoir-hydrogel-forming microneedles composite for minimally invasive delivery of cefazolin. Int J Pharm 2022; 617:121593.

[53] Migdadi EM, Courtenay AJ, Tekko IA, McCrudden MTC, Kearney MC, McAlister E, et al. Hydrogel-forming microneedles enhance transdermal delivery of metformin hydrochloride. J Control Release 2018; 285:142-51.

[54] Peng K, Vora LK, Dominguez-Robles J, Naser YA, Li M, Larraneta E, et al. Hydrogel-forming microneedles for rapid and efficient skin deposition of controlled release tip-implants. Mater Sci Eng C Mater Biol Appl 2021; 127:112226.

[55] Li Y, Bi D, Hu Z, Yang Y, Liu Y, Leung WK. Hydrogel-forming microneedles with applications in oral diseases management. Materials (Basel) 2023; 16(13):4805.

[56] Shi J, Ma Q, Su W, Liu C, Zhang H, Liu Y, et al. Effervescent cannabidiol solid dispersion-doped dissolving microneedles for boosted melanoma therapy via the "TRPV1-NFATc1-ATF3" pathway and tumor microenvironment engineering. Biomater Res 2023; 27(1):48.

[57] You J, Yang C, Han J, Wang H, Zhang W, Zhang Y, et al. Ultrarapid-acting microneedles for immediate delivery of biotherapeutics. Adv Mater 2023; 35(45):e2304582.

[58] Fu J, Yu W, Qian X, Wang Y, Ji J. A photocatalytic carbon monoxide-generating effervescent microneedle patch for improved transdermal chemotherapy. J Mater Chem B 2023; 11(24):5406-15.

[59] Yadav PR, Das DB, Pattanayek SK.Coupled diffusion-binding-deformation modelling for phase-transition microneedles-based drug delivery. J Pharm Sci 2023; 112(4):1108-18.

[60] Chen X, Wang L, Yu H, Li C, Feng J, Haq F, et al. Preparation, properties and challenges of the microneedles-based insulin delivery system. J Control Release 2018; 288:173-88.

[61] Chen H, Fan L, Peng N, Yin Y, Mu D, Wang J, et al. Galunisertib-loaded gelatin methacryloyl hydrogel microneedle patch for cardiac repair after myocardial infarction. ACS Appl Mater Interfaces 2022; 14(36):40491-500.

[62] Ouyang Q Zeng Y, Yu Y, Tan L, Liu X, Zheng Y, et al. Ultrasound-responsive microneedles eradicate deep-layered wound biofilm based on TiO₂ crystal phase engineering. Small 2023; 19(3):e2205292.

[63] Cai L, Luo Z, Chen H, Zhao Y. Lithographic microneedle-motors from multimodal microfluidics for cargo delivery. Small 2023; 19(12):e2206108.

[64] Su Y, Andrabi SM, Shahriar SMS, Wong SL, Wang G, Xie J. Triggered release of antimicrobial peptide from microneedle patches for treatment of wound biofilms. J Control Release 2023; 356:131-41.

[65] Song L, Chi J, Li Z, Tao Y, Sun Y, Zhou Q et al. An inflammation-responsive double-layer microneedle patch for recurrent atopic dermatitis therapy. Int J Pharm 2023; 643:123215.

[66] Hu C, Liu B, Huang X, Wang Z, Qin K, Sun L, et al. Sea cucumber-inspired microneedle nerve guidance conduit for synergistically inhibiting muscle atrophy and promoting nerve regeneration. ACS Nano 2024; 18(22):14427-40.

[67] Li Q, Xu R, Fan H, Xu J, Xu Y, Cao P, et al. Smart mushroom-inspired imprintable and lightly detachable (MILD) microneedle patterns for effective COVID-19 vaccination and decentralized information storage. ACS Nano 2022; 16(5):7512-24.

[68] Yin M, Wu J, Deng M, Wang P, Ji G, Wang M, et al. Multifunctional magnesium organic framework-based microneedle patch for accelerating diabetic wound healing. ACS Nano 2021; 15(11):17842-53.

[69] Chen L, Fang D, Zhang J, Xiao X, Li N, Li Y, et al. Nanomotors-loaded microneedle patches for the treatment of bacterial biofilm-related infections of wound. J Colloid Interface Sci 2023; 647:142-51.

[70] Wang H, Pastorin G, Lee C. Toward self-powered wearable adhesive skin patch with bendable microneedle array for transdermal drug delivery. Adv Sci (Weinh) 2016; 3(9):1500441.

[71] Ma S, Li J, Pei L, Feng N, Zhang Y. Microneedle-based interstitial fluid extraction for drug analysis: advances, challenges, and prospects. J Pharm Anal 2023; 13(2):111-26.

[72] He J, Zhang Y, Yu X, Xu C. Wearable patches for transdermal drug delivery. Acta Pharm Sin B 2023; 13(6):2298-309.

[73] Balmert SC, Carey CD, Falo GD, Sethi SK, Erdos G, Korkmaz E, et al. Dissolving undercut microneedle arrays for multicomponent cutaneous vaccination. J Control Release 2020; 317:336-46.

[74] Syafika N, Azis SBA, Enggi CK, Qonita HA, Mahmud TRA, Abizart A, et al. Glucose-responsive microparticle-loaded dissolving microneedles for selective delivery of metformin: a proof-of-concept study. Mol Pharm 2023; 20(2):1269-84.

[75] Liu F, Cheng Z, Yi H. NIR light-activatable dissolving microneedle system for melanoma ablation enabled by a combination of ROS-responsive chemotherapy and phototherapy. J Nanobiotechnology 2023; 21(1):61.

[76] Lopez-Ramirez MA, Kupor D, Marchiori L, Soto F, Rueda R, Reynoso M, et al. Combinatorial microneedle patch with tunable release kinetics and dual fast-deep/sustained release capabilities. J Mater Chem B 2021; 9(9):2189-99.

[77] Korkmaz E, Friedrich EE, Ramadan MH, Erdos G, Mathers AR, Ozdoganlar OB, et al. Tip-loaded dissolvable microneedle arrays effectively deliver polymer-conjugated antibody inhibitors of tumor-necrosis-factor-alpha into human skin. J Pharm Sci 2016; 105(11):3453-7.

[78] Yang G, Chen Q, Wen D, Chen Z, Wang J, Chen G, et al. A therapeutic microneedle patch made from hair-derived keratin for promoting hair regrowth. ACS Nano 2019; 13(4):4354-60.

[79] Yang J, Wang X, Wu D, Yi K, Zhao Y. Yunnan Baiyao-loaded multifunctional microneedle patches for rapid hemostasis and cutaneous wound healing. J Nanobiotechnology 2023; 21(1):178.

[80] Ohn J, Jang M, Kang BM, Yang H, Hong JT, Kim KH, et al. Dissolving candlelit microneedle for chronic inflammatory skin diseases. Adv Sci (Weinh) 2021; 8(14):2004873.

[81] Chi J, Zhang X, Chen C, Shao C, Zhao Y, Wang Y. Antibacterial and angiogenic chitosan microneedle array patch for promoting wound healing. Bioact Mater 2020; 5(2):253-9.

[82] Park JH, Choi SO, Seo S, Choy YB, Prausnitz MR. A microneedle roller for transdermal drug delivery. Eur J Pharm Biopharm 2010; 76(2):282-9.

[83] Zhang T, Sun B, Guo J, Wang M, Cui H, Mao H, et al. Active pharmaceutical ingredient poly (ionic liquid)-based microneedles for the treatment of skin acne infection. Acta Biomater 2020; 115:136-47.

[84] Jiang Y, Jin Y, Feng C, Wu Y, Zhang W, Xiao L, et al. Engineering hyaluronic acid microneedles loaded with Mn²⁺ and temozolomide for topical precision therapy of melanoma. Adv Healthc Mater 2023; 13(8):2303215.

[85] Wang B, Zhang S, Yang G, Zhou Z, Xing M, Liu H, et al. Dissolvable polymeric microneedles loaded with aspirin for antiplatelet aggregation. Asian J Pharm Sci 2023; 18(1):100776.

[86] Cui M, Zheng M, Wiraja C, Chew SwT, Mishra A, Mayandi V, et al. Ocular delivery of predatory bacteria with cryomicroneedles against eye infection. Adv Sci (Weinh) 2021; 8(21):2102327.

[87] Tang J, Wang J, Huang K, Ye Y, Su T, Qiao L, et al. Cardiac cell-integrated microneedle patch for treating myocardial infarction. Sci Adv 2018; 4(11):eaat9365.

[88] Yokoyama M, Chihara N, Tanaka A, Katayama Y, Taruya A, Ishida Y, et al. A biodegradable microneedle sheet for intracorporeal topical hemostasis. Sci Rep 2020; 10(1):18831.

[89] Lee J, Kim DH, Lee KJ, Seo IH, Park SH, Jang EH, et al. Transfer-molded wrappable microneedle meshes for perivascular drug delivery. J Control Release 2017; 268:237-46.

[90] Gadzinski P, Froelich A, Wojtylko M, Bialek A, Krysztofiak J, Osmalek T. Microneedle-based ocular drug delivery systems-recent advances and challenges. Beilstein J Nanotechnol 2022; 13:1167-84.

[91] Roy G, Galigama RD, Thorat VS, Mallela LS, Roy S, Garg P, et al. Amphotericin B containing microneedle ocular patch for effective treatment of fungal keratitis. Int J Pharm 2019; 572:118808.

[92] Gupta P, Yadav KS. Applications of microneedles in delivering drugs for various ocular diseases. Life Sci 2019; 237:116907.

[93] Lee K, Song HB, Cho W, Kim JH, Kim JH, Ryu W. Intracorneal injection of a detachable hybrid microneedle for sustained drug delivery. Acta Biomater 2018; 80:48-57.

[94] Caffarel-Salvador E, Kim S, Soares V, Tian RY, Stern SR, Minahan D, et al. A microneedle platform for buccal macromolecule delivery. Sci Adv 2021; 7(4):eabe2620.

[95] Zhou R, Yu J, Gu Z, Zhang Y. Microneedle-mediated therapy for cardiovascular diseases. Drug Deliv Transl Res 2022; 12(2):472-83.

[96] Lee J, Park S, Le PT, Lee G, Lee HW, Yun G, et al. Peripheral microneedle patch for first-aid hemostasis. Adv Healthc Mater 2023; 12(7):e2201697.

[97] Gao X, Li J, Li J, Zhang M, Xu J. Pain-free oral delivery of biologic drugs using intestinal peristalsis-actuated microneedle robots. Sci Adv 2024; 10(1):eadj7067.

[98] Flexner C, Owen A, Siccardi M, Swindells S. Long-acting drugs and formulations for the treatment and prevention of HIV infection. Int J Antimicrob Agents 2021; 57(1):106220.

[99] Shi Y, Lu A, Wang X, Belhadj Z, Wang J, Zhang Q. A review of existing strategies for designing long-acting parenteral formulations: focus on underlying mechanisms, and future perspectives. Acta Pharm Sin B 2021; 11(8):2396-415.

[100] Rouphael NG, Lai L, Tandon S, McCullough MP, Kong Y, Kabbani S, et al. Immunologic mechanisms of seasonal influenza vaccination administered by microneedle patch from a randomized phase I trial. NPJ Vacc 2021; 6(1):89.

[101] Chen G, Yu J, Gu Z. Glucose-responsive microneedle patches for diabetes treatment. J Diabetes Sci Technol 2019; 13(1):41-8.

[102] Chen M, Tian J, Liu Y, Cao H, Li R, Wang J, et al. Dynamic covalent constructed self-healing hydrogel for sequential delivery of antibacterial agent andgrowth factor in wound healing. Chem Eng J 2019; 373:413-24.

[103] Anderson A, Hegarty C, Casimero C, Davis J. Electrochemically controlled dissolution of nanocarbon-cellulose acetate phthalate microneedle arrays. ACS Appl Mater Interfaces 2019; 11(39):35540-7.

[104] Zhang X, Chen G, Fu X, Wang Y, Zhao Y. Magneto-responsive microneedle robots for intestinal macromolecule delivery. Adv Mater 2021; 33(44):e2104932.

[105] Seong KY, Seo MS, Hwang DY, O'Cearbhaill ED, Sreenan S, Karp JM, et al. A self-adherent, bullet-shaped microneedle patch for controlled transdermal delivery of insulin.J Control Release 2017; 265:48-56.

[106] Li S, Wang X, Yan Z, Wang T, Chen Z, Song H, et al. Microneedle patches with antimicrobial and immunomodulating properties for infected wound healing. Adv Sci (Weinh) 2023; 10(22):e2300576.

[107] Li Y, He G, Fu LH, Younis MR, He T, Chen Y, et al. A microneedle patch with self-oxygenation and glutathione depletion for repeatable photodynamic therapy. ACS Nano 2022; 16(10):17298-312.

[108] Li WX, Zhang XP, Chen BZ, Fei WM, Cui Y, Zhang CY, et al. An update on microneedle-based systems for diabetes. Drug Deliv Transl Res 2022; 12(10):2275-86.

[109] Wu M, Zhang Y, Huang H, Li J, Liu H, Guo Z, et al. Assisted 3D printing of microneedle patches for minimally invasive glucose control in diabetes. Mater Sci Eng C Mater Biol Appl 2020; 117:111299.

[110] Xu J, Danehy R, Cai H, Ao Z, Pu M, Nusawardhana A, et al. Microneedle patch-mediated treatment of bacterial biofilms. ACS Appl Mater Interfaces 2019; 11(16):14640-6.

[111] Vora LK, Sabri AH, Naser Y, Himawan A, Hutton ARJ, Anjani QK, et al. Long-acting microneedle formulations. Adv Drug Deliv Rev 2023; 201:115055.

[112] Wang Z, Yang Z, Jiang J, Shi Z, Mao Y, Qin N, et al. Silk microneedle patch capable of on-demand multidrug delivery to the brain for glioblastoma treatment. Adv Mater 2022; 34(1):e2106606.

[113] Yang Y, Li Z, Huang P, Lin J, Li J, Shi K, et al. Rapidly separating dissolving microneedles with sustained-release colchicine and stabilized uricase for simplified long-term gout management. Acta Pharm Sin B 2023; 13(8):3454-70.

[114] Yao S, Wang Y, Chi J, Yu Y, Zhao Y, Luo Y, et al. Porous MOF microneedle array patch with photothermal responsive nitric oxide delivery for wound healing. Adv Sci (Weinh) 2022; 9(3):e2103449.

[115] Lin W, Lin S, Zhou X, Yang F, Lin Z, Li S, et al. Biodegradable double-network GelMA-ACNM hydrogel microneedles for transdermal drug delivery. Front Bioeng Biotechnol 2023; 11:1110604.

[116] Kim DS, Choi JT, Kim CB, Shin YR, Park PG, Kim H, et al. Microneedle array patch (MAP) consisting of crosslinked hyaluronic acid nanoparticles for processability and sustained release. Pharm Res 2020; 37(3):50.

[117] Kochhar JS, Lim WX, Zou S, Foo WY, Pan J, Kang L. Microneedle integrated transdermal patch for fast onset and sustained delivery of lidocaine. Mol Pharm 2013; 10(11):4272-80.

[118] Zhu M, Liu Y, Jiang F, Cao J, Kundu SC, Lu S. Combined silk fibroin microneedles for insulin delivery. ACS Biomater Sci Eng 2020; 6(6):3422-9.

[119] Courtenay AJ, McCrudden MTC, McAvoy KJ, McCarthy HO, Donnelly RF. Microneedle-mediated transdermal delivery of bevacizumab. Mol Pharm 2018; 15(8):3545-56.

[120] Wan T, Pan Q, Ping Y.Microneedle-assisted genome editing: a transdermalstrategy oftargeting NLRP3 by CRISPR-Cas9 forsynergistic therapy of inflammatory skin disorders. Sci Adv 2021; 7(11):eabe2888.

[121] Yang P, Lu C, Qin W, Chen M, Quan G, Liu H, et al. Construction of a core-shell microneedle system to achieve targeted co-delivery of checkpoint inhibitors for melanoma immunotherapy. Acta Biomater 2020; 104:147-57.

[122] Xie X, Pascual C, Lieu C, Oh S, Wang J, Zou B, et al. Analgesic microneedle patch for neuropathic pain therapy. ACS Nano 2017; 11(1):395-406.

[123] Xu J, Xu B, Tao J, Yang Y, Hu Y, Huang Y. Microneedle-assisted, DC-targeted codelivery of pTRP-2 and adjuvant of paclitaxel for transcutaneous immunotherapy. Small 2017; 13(28):1700666.

[124] Huang Y, Li J, Wang Y, Chen D, Huang J, Dai W, et al. Intradermal delivery of an angiotensin II receptor blocker using a personalized microneedle patch for treatment of hypertrophic scars. Biomater Sci 2023; 11(2):583-95.

[125] GhavamiNejad A, Lu B, Samarikhalaj M, Liu JF, Mirzaie S, Pereira S, et al. Transdermal delivery of a somatostatin receptor type 2 antagonist using microneedle patch technology for hypoglycemia prevention. Drug Deliv Transl Res 2022; 12(4):792-804.

[126] Yin Y, Su W, Zhang J, Huang W, Li X, Ma H, et al. Separable microneedle patch to protect and deliver DNA nanovaccines against COVID-19. ACS Nano 2021; 15(9):14347-59.

[127] Han X, Li H, Zhou D, Chen Z, Gu Z. Local and targeted delivery of immune checkpoint blockade therapeutics. Acc Chem Res 2020; 53(11):2521-33.

[128] Littauer EQ, Mills LK, Brock N, Esser ES, Romanyuk A, Pulit-Penaloza JA, et al. Stable incorporation of GM-CSF into dissolvable microneedle patch improves skin vaccination against influenza. J Control Release 2018; 276:1-16.

[129] Qu F, Geng R, Liu Y, Zhu J. Advanced nanocarrier- and microneedle-based transdermal drug delivery strategies for skin diseases treatment. Theranostics 2022; 12(7):3372-406.

[130] Zaid Alkilani A, Nimrawi S, NK Al-Nemrawi, Nasereddin J. Microneedle-assisted transdermal delivery of amlodipine besylate loaded nanoparticles. Drug Dev Ind Pharm 2022; 48(7):322-32.

[131] Wang H, Zhao Z, Wu C, Tong X, Shi Y, Chen S. Microneedle patch delivery of methotrexate-loaded albumin nanoparticles to immune cells achieves a potent antipsoriatic effect. Int J Nanomedicine 2022; 17:3841-51.

[132] Chen SX, Ma M, Xue F, Shen S, Chen Q, Kuang Y, et al. Construction of microneedle-assisted co-delivery platform and its combining photodynamic/immunotherapy. J Control Release 2020; 324:218-27.

[133] Jing Q, Ruan H, Li J, Wang Z, Pei L, Hu H, et al. Keratinocyte membrane-mediated nanodelivery system with dissolving microneedles for targeted therapy of skin diseases. Biomaterials 2021; 278:121142.

[134] Wu T, Hou X, Li J, Ruan H, Pei L, Guo T, et al. Microneedle-mediated biomimetic cyclodextrin metal organic frameworks for active targeting and treatment of hypertrophic scars. ACS Nano 2021; 15(12):20087-104.

[135] Ding H, Cui Y, Yang J, Li Y, Zhang H, Ju S, et al. ROS-responsive microneedles loaded with integrin avbeta6-blocking antibodies for the treatment of pulmonary fibrosis. J Control Release 2023; 360:365-75.

[136] Cheng X, Hu S, Cheng K. Microneedle patch delivery of PROTACs for anti-cancer therapy. ACS Nano 2023; 17(12):11855-68.

[137] Shan Y, Tan B, Zhang M, Xie X, Liao J. Restorative biodegradable two-layered hybrid microneedles for melanoma photothermal/chemo co-therapy and wound healing. J Nanobiotechnology 2022; 20(1):238.

[138] Bian Q, Huang L, Xu Y, Wang R, Gu Y, Yuan A, et al. A facile low-dose photosensitizer-incorporated dissolving microneedles-based composite system for eliciting antitumor immunity and the abscopal effect. ACS Nano 2022; 15(12):19468-79.

[139] Lu Y, Xiao T, Lai R, Liu Z, Luo W, Wang Y, et al. Co-delivery of loxoprofen and tofacitinib by photothermal microneedles for rheumatoid arthritis treatment. Pharmaceutics 2023; 15(5):1500.

[140] Yang L, Zhang D, Li W, Lin H, Ding C, Liu Q, et al. Biofilm microenvironment triggered self-enhancing photodynamic immunomodulatory microneedle for diabetic wound therapy. Nat Commun 2023; 14(1):7658.

[141] GhavamiNejad A, Li J, Lu B, Zhou L, Lam L, Giacca A, et al. Glucose-responsive composite microneedle patch for hypoglycemia-triggered delivery of native glucagon. Adv Mater 2019; 31(30):e1901051.

[142] Qu M, Kim HJ, Zhou X, Wang C, Jiang X, Zhu J, et al. Biodegradable microneedle patch for transdermal gene delivery. Nanoscale 2020; 12(32):16724-9.

[143] Yu J, Wang J, Zhang Y, Chen G, Mao W, Ye Y, et al. Glucose-responsive insulin patch for the regulation of blood glucose in mice and minipigs. Nat Biomed Eng 2020; 4(5):499-506.

[144] Zhang Y, Feng P, Yu J, Yang J, Zhao J, Wang J, et al. ROS-responsive microneedle patch for acne vulgaris treatment. Adv. Therap 2018; 1(3):1800035.

[145] Han M, Yang H, Lu X, Li Y, Liu Z, Li F, et al. Three-dimensional-cultured MSC-derived exosome-hydrogel hybrid microneedle array patch for spinal cord repair. Nano Lett 2022; 22(15):6391-401.

[146] Wang Y, Zheng C, Li M, et al. Wang Q Zhong Q Xu Y, Immunomodulatory microneedle patch for enhanced ferroptosis and immunogenic cell death in postoperative tumor therapy. J Control Release 2024; 376:766-76.

[147] Zhang Y, Wu M, Tan D, Liu Q, Xia R, Chen M, et al. A dissolving and glucose-responsive insulin-releasing microneedle patch for type 1 diabetes therapy. J Mater Chem B 2021; 9(3):648-57.

[148] Zhao X, Li X, Zhang P, Du J, Wang Y. Tip-loaded fast-dissolving microneedle patches for photodynamic therapy of subcutaneous tumor. J Control Release 2018; 286:201-9.

[149] Li X, Xu Q, Zhang P, Zhao X, Wang Y. Cutaneous microenvironment responsive microneedle patch for rapid gene release to treat subdermal tumor. J Control Release 2019; 314:72-80.

[150] Li W, Terry RN, Tang J, Feng MR, Schwendeman SP, Prausnitz MR. Rapidly separable microneedle patch for the sustained release of a contraceptive. Nat Biomed Eng 2019; 3(3):220-9.

[151] Zhao W, Zheng L, Yang J, Ma Z, Tao X, Wang Q. Dissolving microneedle patch-assisted transdermal delivery of methotrexate improve the therapeutic efficacy of rheumatoid arthritis. Drug Deliv 2023; 30(1):121-32.

[152] Rajendran K, Pahal S, Badnikar K, Nayak MM, Subramanyam DN, Vemula PK, et al. Methotrexate delivering microneedle patches for improved therapeutic efficacy in treatment of rheumatoid arthritis. Int J Pharm 2023; 642:123184.

[153] Peng H, Zhou Y, Zhang C, Wang M, Zhao S, Xu Y, et al. An accurate and dual-effective body slimming method through a soluble microneedle patch with variable temperature. J Mater Chem B 2021; 9(2):421-7.

[154] Kim E, Erdos G, Huang S, Kenniston TW, Balmert SC, Carey CD, et al. Microneedle array delivered recombinant coronavirus vaccines: immunogenicity and rapid translational development. EBioMedicine 2020; 55:102743.

[155] Paredes AJ, Volpe-Zanutto F, Permana AD, Murphy AJ, Picco CJ, Vora LK, et al. Novel tip-loaded dissolving and implantable microneedle array patches for sustained release of finasteride. Int J Pharm 2021; 606:120885.

[156] Wang P, Wang Y, Yi Y, Gong Y, Ji H, Gan Y, et al. MXenes-integrated microneedle combined with asiaticoside to penetrate the cuticle for treatment of diabetic foot ulcer. J Nanobiotechnology 2022; 20(1):259.

[157] Ma W, Zhang X, Liu Y, Fan L, Gan J, Liu W, et al. Polydopamine decorated microneedles with Fe-MSC-derived nanovesicles encapsulation for wound healing. Adv Sci (Weinh) 2022; 9(13):e2103317.

[158] Liu W, Zhai X, Zhao X, Cai Y, Zhang X, Xu K, et al. Multifunctional double-layer and dual drug-loaded microneedle patch promotes diabetic wound healing. Adv Healthc Mater 2023; 12(23):e2300297.

[159] Shi Y, Zhao J, Li H, Yu M, Zhang W, Qin D, et al. A drug-free, hair follicle cycling regulatable, separable, antibacterial microneedle patch for hair regeneration therapy. Adv Healthc Mater 2022; 11(19):e2200908.

[160] Limcharoen B, Toprangkobsin P, Kroger M, Darvin ME, Sansureerungsikul T, Rujwaree T, et al. Microneedle-facilitated intradermal proretinal nanoparticle delivery. Nanomaterials (Basel) 2020; 10(2):368.

[161] Roy G, Garg P, Venuganti VVK. Microneedle scleral patch for minimally invasive delivery of triamcinolone to the posterior segment of eye. Int J Pharm 2022; 612:121305.

[162] Lee K, Park S, Jo DH, Cho CS, Jang HY, Yi J, et al. Self-plugging microneedle (SPM) for intravitreal drug delivery. Adv Healthc Mater 2022; 11(12):e2102599.

[163] Sapowadia A, Ghanbariamin D, Zhou L, Zhou Q, Schmidt T, Tamayol A, et al. Biomaterial drug delivery systems for prominent ocular diseases. Pharmaceutics 2023; 15(7): 1959.

[164] Fitaihi R, Abukhamees S, Orlu M, Craig DQM. Transscleral delivery of dexamethasone-loaded microparticles using a dissolving microneedle array. Pharmaceutics 2023; 15(6):1622.

[165] Zeng Y, Gao Y, He L, Ge W, Liu J, Yu Y, et al. Multifunctional polysaccharide composited microneedle for oral ulcers healing. Mater Today Bio 2023; 22:100782.

[166] Jiang X, Chen P, Niu W, Fang R, Chen H, An Y, et al. Preparation and evaluation of dissolving tofacitinib microneedles for effective management of rheumatoid arthritis. Eur J Pharm Sci 2023; 188:106518.

[167] Li Y, Zheng L, Cao W, Yang X, Wang Q, Gu X, et al. 5-aminolevulinic acid-loaded dissolving microneedle array for photodynamic therapy of rheumatoid arthritis on rats. Biomed Pharmacother 2023; 162:114684.

[168] Zhang C, Jia S, Huang J, Peng H, Zhang J, Liu L, et al. A carbonized wormwood modified photothermal microneedle patch for the repair of damaged skeletal muscles. J Mater Chem B 2021; 9(38):8014-20.

[169] Jamaledin R, Yiu CKY, Zare EN, Niu LN, Vecchione R, Chen G, et al. Advances in antimicrobial microneedle patches for combating infections. Adv Mater 2020; 32(33):e2002129.

[170] Lin Z, Zheng K, Zhong J, Zheng X. Advances in microneedle-based therapy for bone disorders. Biomed Pharmacother 2023; 165:115013.

[171] Abla MJ, Chaturvedula A, O'Mahony C, Banga AK. Transdermal delivery of methotrexate for pediatrics using silicon microneedles. Ther Deliv 2013; 4(5):543-51.

[172] Abdalla HB, Jain AK, Napimoga MH, Clemente-Napimoga JT, Gill HS. Microneedles coated with tramadol exhibit antinociceptive effect in a rat model of temporomandibular hypernociception. J Pharmacol Exp Ther 2019; 370(3): 834-842.

[173] WangJ, ZengJ, Liu Z, Zhou Q, Wang X, Zhao F, et al. Promising strategies for transdermal delivery of arthritis drugs: microneedle systems. Pharmaceutics 2022; 14(8):1736.

[174] Naito C, Katsumi H, Suzuki T, Quan YS, Kamiyama F, Sakane T, et al. Self-dissolving microneedle arrays for transdermal absorption enhancement of human parathyroid hormone (1-34). Pharmaceutics 2018; 10(4):215.

[175] Li Y, Ju XJ, Fu H, Zhou CH, Gao Y, Wang J, et al. Composite separable microneedles for transdermal delivery and controlled release of salmon calcitonin for osteoporosis therapy. ACS Appl Mater Interfaces 2023; 15(1):638-50.

[176] Nazary Abrbekoh F, Salimi L, Saghati S, Amini H, Fathi Karkan S, Moharamzadeh K, et al. Application of microneedle patches for drug delivery; doorstep to novel therapies. J Tissue Eng 2022; 13:20417314221085390.

[177] Chinnamani MV, Hanif A, Kannan PK, Kaushal S, Sultan MJ, NE Lee. Soft microfiber-based hollow microneedle array for stretchable microfluidic biosensing patch with negative pressure-driven sampling. Biosens Bioelectron 2023; 237:115468.

[178] Li S, Li C, Khan MI, Liu J, Shi Z, Gao D, et al. Microneedle array facilitates hepatic sinusoid construction in a large-scale liver-acinus-chip microsystem. Microsyst Nanoeng 2023; 9:75.

[179] Yin M, Xiao L, Liu Q, Kwon SY, Zhang Y, Sharma PR, et al. 3D printed microheater sensor-integrated, drug-encapsulated microneedle patch system for pain management. Adv Healthc Mater 2019; 8(23):e1901170.

[180] Ciui B, Martin A, Mishra RK, Brunetti B, Nakagawa T, Dawkins TJ, et al. Wearable wireless tyrosinase bandage and microneedle sensors: toward melanoma screening. Adv Healthc Mater 2018; 7(7):e1701264.

[181] Seoane-Viano I, Januskaite P, Alvarez-Lorenzo C, Basit AW, Goyanes A. Semi-solid extrusion 3D printing in drug delivery and biomedicine: personalised solutions for healthcare challenges. J Control Release 2021; 332:367-89.

[182] Zhang X, Gan J, Fan L, Luo Z, Zhao Y. Bioinspired adaptable indwelling microneedles for treatment of diabetic ulcers. Adv Mater 2023; 35(23):e2210903.

[183] Wang Y, Gao B, He B. Toward efficient wound management: bioinspired microfluidic and microneedle patch. Small 2023; 19(3):e2206270.

[184] Zhang X, Ma Y, Chen Z, Jiang H, Fan Z. Implantable nerve conduit made of a self-powered microneedle patch for sciatic nerve repair. Adv Healthc Mater 2023; 12:e2301729.

[185] Huang X, Liang B, Huang S, Liu Z, Yao C, Yang J, et al. Integrated electronic/fluidic microneedle system for glucose sensing and insulin delivery. Theranostics 2024; 14(4):1662-82.