-
开放科学(资源服务)标识码(OSID):
-
提高医学诊断的准确性对于降低误诊率有着重要的意义,人工智能的应用使现代医疗诊断的准确性大幅上升[1]. 然而,在传统的医疗检测过程中,定期采集患者体液样本仍然是一个费时费力的过程,并且缺乏对患者健康状况的实时监测[2]. 采集体液样品的传统方法主要包括针管采血、纸质试纸收集和各种体液容器采集等[3-4]. 这些方法虽然能够采集到样本,但也存在一些缺点. 例如,针管采血是一种最常见的体液样品采集方法,但其操作过程中需要使用针头,可能引起患者的不适和疼痛感,甚至可能导致感染和出血等问题. 此外,针管采血需要专业的医疗人员和设备,不适合在家庭或社区等环境中进行[5]. 对于患者而言,准确、快速的样本采集不仅能够及时发现健康问题,还能在治疗过程中监测病情变化,从而提高治疗效果和生活质量. 对于医护人员来说,简便、安全的采样方法能够提高工作效率,减少患者的不适感,在急诊和远程医疗等情况下为患者提供及时的医疗援助.
微针技术作为一种新兴的体液采样方法,具有许多显著的优点[6]. 微针的尺寸通常在几百微米到几毫米之间,远远小于传统的针头,因此能够减少患者的疼痛感,降低出血和感染的风险[7]. 微针的尖端可以非常精细,使得样本的采集更加精准和可控[8]. 此外,微针传感器的使用还可以降低样本的采集量,对于儿童和老年人等特殊人群尤为适用[9]. 微针技术的另一个重要优势是其兼容性高,可以搭配各种分析仪器和方法,从而实现快速、灵敏及准确的样品检测[10]. 微针技术的应用范围广泛,包括临床诊断、药物监测、基因检测等领域. 因此,微针技术的研究和开发已成为生物医学和医疗诊断领域的热点之一,吸引了大量研究人员的关注.
电化学传感器是根据样品的电化学性质,将化学信号转化为电信号,并进行传感检测的装置[11]. 因其具有灵敏度高、操作简单、响应迅速、低成本等优点,已广泛应用于可穿戴电子设备等领域[12]. 得益于微机电系统技术的发展[13],小型电化学传感器既可以集成在不同类型的可穿戴柔性衬底中,又能与微针相结合制备出各种生物分析平台. 基于微针的电化学传感器可以分析和检测生物标志物、体内代谢物、药物浓度以及存在于间质液中的其他物质[14]. 最近,许多新型微针电化学传感器相继被报道,其应用范围更加广泛,其中比较突出的是可穿戴设备和即时检验领域. 本综述简要概述了基于微针的电化学传感器的研究进展及应用领域,并讨论了微针电化学传感器医用前景中的优势及局限性.
Recent Research Process in Microneedle-Based Electrochemical Sensors
-
摘要:
生物传感器是近几十年来引起广泛关注的医疗检测设备. 然而,许多传感器的稳定性或便携性较差,并且传统的体液样品采集方法费力且耗时,因此限制了其在临床诊断方面的应用. 微针是一种微创透皮设备,能够与小型电化学传感器相结合制备出各种生物分析平台,其技术已成为生物传感领域的重要方法,为改进现有生物传感器开辟了新道路. 采用微针阵列作为标准电极的创新性配置,可以提高电化学传感器的检测性能. 在基于微针的电化学生物传感器中,通常利用导电聚合物、酶、纳米颗粒及其复合材料修饰微针电极,以实现组织间质液内的葡萄糖、乳酸、酒精、尿素、氨基酸、治疗药物或生物信号的无痛透皮检测或可穿戴式监测. 另外,微针技术作为一种新兴的体液采样方法,可通过直接提取间质液用于进一步的电化学传感. 这不仅避免了传统间质液提取技术所需要的大型仪器,而且非侵入性方法的使用进一步提高了患者的依从性,简化了体液采集过程. 这两类基于微针的电化学传感技术已被广泛应用于疾病生物标志物分析、常规生化指标检测和治疗药物监测等领域. 该综述概述了微针电化学传感器的类型、传感构建模式及应用等方面的最新进展,并列举了不同微针电化学传感器的工作电极构造以及检测能力,最后对近年研究报道的微针电化学传感器的优势和局限性进行了总结分析.
Abstract:Biosensors are medical test devices that have attracted widespread attention in recent decades. However, the application of biosensors in clinical diagnostics is restricted by poor stability or portability, as well as the laborious and time-consuming of traditional body fluid collection methods. Microneedles are minimally invasive transdermal devices that can be combined with miniaturized electrochemical sensors to prepare a variety of bioanalytical platforms, and their technology has emerged as a revolutionary approach to the biosensing field, offering new avenues for improving and advancing current biosensors. Innovative configurations using microneedle arrays as standard electrodes have the potential to improve the detection performance of electrochemical sensors. In microneedle-based electrochemical biosensors, conductive polymers, enzymes, nanoparticles, and their composites are usually utilized to modify microneedle electrodes for painless transdermal detection or wearable monitoring of glucose, lactic acid, alcohol, urea, amino acids, therapeutic drugs, or biosignals in tissue interstitial fluids. In addition, microneedle technology, as an emerging body fluid sampling method, can be used for further electrochemical sensing by directly extracting interstitial fluid. By utilizing non-invasive techniques, this approach not only eliminates the need for bulky instruments used in traditional interstitial fluid extraction, but also enhances patient compliance and simplifies the body fluid collection process. These two types of microneedle-based electrochemical sensing techniques have been widely used in the fields of disease biomarker analysis, routine biochemical indicator detection, and therapeutic drug monitoring. This review outlines recent advances in electrochemical microneedle sensors, including their types, sensing construction modes, and diverse applications, lists the working electrode configurations as well as the detection capabilities of different microneedle electrochemical sensors, also providing analyses of the advantages and limitations of currently developed sensors.
-
Key words:
- microneedle /
- electrochemical sensors /
- minimally invasive sensors /
- interstitial fluid .
-
表 1 微针电化学传感器的类型、材质、工作电极构造、检测物、检测限以及线性范围
微针类型 微针材质 工作电极构造 检测物 检测限 线性范围 参考文献 多孔 聚甲基丙烯酸缩水甘油酯 金/葡萄糖氧化酶 葡萄糖 - 0~20 mmol/L [46] 固体 碳纳米颗粒/聚苯乙烯 - 尿酸 2.85 μmol/L - [47] 固体 碳纳米颗粒/聚苯乙烯 - pH值 - - [48] 固体 不锈钢 - 葡萄糖 0.92 mmol/L 3~13 mmol/L [23] 涂层 硅 聚酰亚胺/金 肌电信号 - - [41] 涂层 不锈钢 还原氧化石墨烯/铂/聚乙烯吡咯烷酮 过氧化氢 [22] 涂层 铜 钛/铂 肌电信号 - - [49] 涂层 光刻胶/金 聚苯胺—硼酸/脲酶/全氟磺酸膜 尿素 0.9 mmol/L 3~18 mmol/L [50] 涂层 不锈钢 金/铂黑/全氟磺酸隔膜 葡萄糖 268 μmol/L 1~30 mmol/L [51] 涂层 不锈钢 碳纳米管/纳米纤维素晶体/聚苯胺 3-咖啡酰奎宁酸 11 mg/L 75~448 mg/L [26] 涂层 光刻胶/金 葡萄糖氧化酶 葡萄糖 0.63 mmol/L 2~12 mmol/L [32] 涂层 聚乳酸 金/金纳米颗粒/过氧化聚吡咯/葡萄糖氧化酶/全氟磺酸隔膜 葡萄糖 40 μmol/L 0~26 mmol/L [30] 涂层 钢 离子选择膜 Ca2+/K+/Na+ - Ca2+:0.01~100 mmol/L;K+:1~32 mmol/L;Na+:10~160 mmol/L [37] 涂层 不锈钢 铂/金纳米颗粒/聚苯胺 pH值 - pH:4~9 [38] 涂层 硅/金 表皮生长因子受体抗体 表皮生长因子受体 4.8 ng/mL 10~250 ng/mL [39] 涂层 聚甲基丙烯酸甲酯/铬/金 适配体 妥布霉素 - - [52] 涂层 聚甲基丙烯酸甲酯 聚(3,4-亚乙二氧基噻吩) Na+ - - [53] 涂层 不锈钢 碳层/镍锰双金属氧化物 抗坏血酸 0.1 μmol/L 1.0 μmol/L~2.0 mmol/L [54] 涂层 不锈钢 金/铂黑/全氟磺酸隔膜 葡萄糖 22 μmol/L 1~30 mmol/L [55] 涂层 不锈钢 金/聚苯胺/乳酸氧化酶/全氟磺酸隔膜/聚(4-羟基-3-硝基苯乙烯) 乳酸 - 1.9~2.2 mmol/L [56] 涂层 聚碳酸酯 金/多壁碳纳米管/亚加蓝/酶(乳酸氧化酶或葡萄糖脱氢酶) 乳酸/葡萄糖 乳酸:3 μmol/L;葡萄糖:7 μmol/L 乳酸:10~100 μmol/L;葡萄糖:0.05~5 mmol/L [57] 涂层 不锈钢 氧化亚铜/钴铜双氢氧化物 葡萄糖 0.46 μmol/L 0.03~6.00 mmol/L [58] 涂层 金 尿素酶 尿素 2.8 μmol/L 50~2 500 μmol/L [25] 涂层 聚碳酸酯 分子印迹聚合物 白介素-6 1 pg/mL - [59] 涂层 硅 金/3-巯基丙酸自组装单层/二茂铁核心的聚酰胺—胺树枝状聚合物/葡萄糖氧化酶 葡萄糖 0.66 mmol/L 1~9 mmol/L [28] 涂层 硅 二氧化硅/金/肽受体 血管内皮生长因子 - 0.1~1 000 pmol/L [29] 涂层 不锈钢 金/铂黑/全氟磺酸隔膜 葡萄糖 22.5 μmol/L 1~20 mmol/L [60] 涂层 硅 金/氧化铝/白介素抗体 白介素8 - 62 pg/mL~539 ng/mL [61] 涂层 聚乳酸羟基乙酸共聚物 聚多巴胺/羟基磷灰石/1H,1H,2H,2H-全氟十二烷硫醇/金 亚甲基蓝 1 nmol/L - [62] 涂层 金 多孔金纳米材料 儿茶酚胺 100 nmol/L - [63] 涂层 聚氨酯丙烯酸酯 金/葡萄糖氧化酶 葡萄糖 - - [64] 涂层 导电银颗粒/环氧树脂 普鲁士蓝/单壁碳纳米管/葡萄糖氧化酶/甲基丙烯酸化透明质酸 葡萄糖 0~21 mmol/L [65] 空心 不锈钢 金/适配体 万古霉素 - 9~35 μmol/L [27] 空心 光刻树脂(BIO) - 利多卡因 0.13 μmol/L 1~120 μmol/L [66] 空心 蚕丝/山梨醇 葡萄糖氧化酶 葡萄糖 - 1.7~10.4 mmol/L [67] 空心 不锈钢 碳纳米管/纤维素纳米晶体/聚苯胺 3-咖啡酰奎尼酸 11 mg/L 75~448 mg/L [26] 空心 聚甲基丙烯酸甲酯 碳糊/有机磷水解酶 芬太尼/有机磷 - - [68] 空心 E-Shell 200光刻树脂 石墨烯/4-(3-丁基-1-咪唑)-1-丁烷磺酸盐 芬太尼 27.8 μmol/L 20~160 μmol/L [31] 空心 - 铂/胆固醇氧化酶/全氟磺酸隔膜 胆固醇 - 1~20 μmol/L [69] 空心 不锈钢 多壁碳纳米管/1,4-萘醌/戊二醛/壳聚糖/葡萄糖氧化酶/全氟磺酸隔膜/聚氨酯 葡萄糖 - 0~20 mmol/L [42] 空心 - 碳糊/离子液体/菲咯啉二酮/烟酰胺腺嘌呤二核苷酸/戊二醛/β-羟基丁酸脱氢酶/壳聚糖/聚氯乙烯 β-羟基丁酸 50 μmol/L 1~10 mmol/L [43] 空心 聚醚醚酮 石墨糊/戊二醛/壳聚糖 甲氨蝶呤 - 25~400 μmol/L [45] 空心 Anycubic光敏树脂 碳糊/铑纳米颗粒/全氟磺酸隔膜 阿扑吗啡 0.6 μmol/L - [44] 空心 聚甲基丙烯酸甲酯 碳糊/壳聚糖混合银—氧化石墨烯纳米材料/全氟磺酸隔膜 5-羟色胺 0.9 μmol/L 13.5~95 μmol/L [40] 空心 聚醚醚酮 碳糊/单壁碳纳米管 亚甲二氧甲基苯丙胺 0.75 μmol/L 1~50 μmol/L [70] 空心 热塑性聚氨酯 金/普鲁士蓝/葡萄糖氧化酶/壳聚糖/全氟磺酸隔膜 葡萄糖 - 0.8~34 mmol/L [71] 空心 聚碳酸酯 - 葡萄糖/pH 0.2 mmol/L 葡萄糖:4.4~6.6 mmol/L;pH:6.94~9.23 [72] 水凝胶 透明质酸/甲基丙烯酸化透明质酸 - Na+/K+/Ca2+/pH - Na+:0.75~200 mmol/L;K+:1~128 mmol/L;Ca2+:0.25~4.25 mmol/LpH:5.5~8.5 [33] 水凝胶 多巴胺共轭透明质酸 聚(3,4-亚乙二氧基噻吩)—聚(苯乙烯磺酸)/邻苯二酚 pH值 - pH:3.5~9 [34] 水凝胶 甲基丙烯酸化透明质酸 - 磷酸盐/尿酸/肌酐/尿素 - 磷酸盐:0.3~1.8 mmol/L;尿酸:50~550 μmol/L;肌酐:50~550 μmol/L;尿素:1~16 mmol/L [73] 水凝胶 甲基丙烯酸化透明质酸 - 葡萄糖/酒精 - 葡萄糖:0~12 mmol/L;酒精:0~20 mmol/L [74] -
[1] TOPOL E J. Toward the Eradication of Medical Diagnostic Errors[J]. Science, 2024, 383(6681): 9602. doi: 10.1126/science.adn9602 [2] DARDANO P, REA I, DE STEFANO L. Microneedles-Based Electrochemical Sensors: New Tools for Advanced Biosensing[J]. Current Opinion in Electrochemistry, 2019, 17: 121-127. doi: 10.1016/j.coelec.2019.05.012 [3] SAIFULLAH K M, FARAJI RAD Z. Sampling Dermal Interstitial Fluid Using Microneedles: A Review of Recent Developments in Sampling Methods and Microneedle-Based Biosensors[J]. Advanced Materials Interfaces, 2023, 10(10): 2201763. doi: 10.1002/admi.202201763 [4] SCOTT J F, ROBINSON G M, FRENCH J M, et al. Blood Pressure Response to Glucose Potassium Insulin Therapy in Patients with Acute Stroke with Mild to Moderate Hyperglycaemia[J]. Journal of Neurology, Neurosurgery and Psychiatry, 2001, 70(3): 401-404. doi: 10.1136/jnnp.70.3.401 [5] CARIGNAN C C, BAUER R A, PATTERSON A, et al. Self-Collection Blood Test for PFASs: Comparing Volumetric Microsamplers with a Traditional Serum Approach[J]. Environmental Science and Technology, 2023, 57(21): 7950-7957. doi: 10.1021/acs.est.2c09852 [6] SAMANT P P, PRAUSNITZ M R. Mechanisms of Sampling Interstitial Fluid from Skin Using a Microneedle Patch[J]. Proceedings of the National Academy of Sciences of the United States of America, 2018, 115(18): 4583-4588. [7] MA G J, WU C W. Microneedle, Bio-Microneedle and Bio-Inspired Microneedle: A Review[J]. Journal of Controlled Release: Official Journal of the Controlled Release Society, 2017, 251: 11-23. doi: 10.1016/j.jconrel.2017.02.011 [8] HSIEH Y C, LIN C Y, LIN H Y, et al. Controllable-Swelling Microneedle-Assisted Ultrasensitive Paper Sensing Platforms for Personal Health Monitoring[J]. Advanced Healthcare Materials, 2023, 12(24): e2300321. doi: 10.1002/adhm.202300321 [9] FENG Y X, HU H, WONG Y Y, et al. Microneedles: an Emerging Vaccine Delivery Tool and a Prospective Solution to the Challenges of SARS-CoV-2 Mass Vaccination[J]. Pharmaceutics, 2023, 15(5): 1349. doi: 10.3390/pharmaceutics15051349 [10] KIM H, LEE J, HEO U, et al. Skin Preparation-Free, Stretchable Microneedle Adhesive Patches for Reliable Electrophysiological Sensing and Exoskeleton Robot Control[J]. Science Advances, 2024, 10(3): 5260. doi: 10.1126/sciadv.adk5260 [11] MA T J. Remote Sensing Detection Enhancement[J]. Journal of Big Data, 2021, 8(1): 127. doi: 10.1186/s40537-021-00517-8 [12] BOLAT G, DE LA PAZ E, AZEREDO N F, et al. Wearable Soft Electrochemical Microfluidic Device Integrated with Iontophoresis for Sweat Biosensing[J]. Analytical and Bioanalytical Chemistry, 2022, 414(18): 5411-5421. doi: 10.1007/s00216-021-03865-9 [13] SHIKIDA M, HASEGAWA Y, AL FARISI M S, et al. Advancements in MEMS Technology for Medical Applications: Microneedles and Miniaturized Sensors[J]. Japanese Journal of Applied Physics, 2021, 61: SA0803. [14] MILLER P R, NARAYAN R J, POLSKY R. Microneedle-Based Sensors for Medical Diagnosis[J]. Journal of Materials Chemistry B, 2016, 4(8): 1379-1383. doi: 10.1039/C5TB02421H [15] ABBOTT N J. Evidence for Bulk Flow of Brain Interstitial Fluid: Significance for Physiology and Pathology[J]. Neurochemistry International, 2004, 45(4): 545-552. doi: 10.1016/j.neuint.2003.11.006 [16] KOOL J, REUBSAET L, WESSELDIJK F, et al. Suction Blister Fluid as Potential Body Fluid for Biomarker Proteins[J]. Proteomics, 2007, 7(20): 3638-3650. doi: 10.1002/pmic.200600938 [17] HEIKENFELD J, JAJACK A, FELDMAN B, et al. Accessing Analytes in Biofluids for Peripheral Biochemical Monitoring[J]. Nature Biotechnology, 2019, 37(4): 407-419. doi: 10.1038/s41587-019-0040-3 [18] ALTENDORFER-KROATH T, SCHIMEK D, EBERL A, et al. Comparison of Cerebral Open Flow Microperfusion and Microdialysis when Sampling Small Lipophilic and Small Hydrophilic Substances[J]. Journal of Neuroscience Methods, 2019, 311: 394-401. doi: 10.1016/j.jneumeth.2018.09.024 [19] ULRICH J D, BURCHETT J M, RESTIVO J L, et al. In Vivo Measurement of Apolipoprotein E from the Brain Interstitial Fluid Using Microdialysis[J]. Molecular Neurodegeneration, 2013, 8: 13. doi: 10.1186/1750-1326-8-13 [20] VENTRELLI L, MARSILIO STRAMBINI L, BARILLARO G. Microneedles for Transdermal Biosensing: Current Picture and Future Direction[J]. Advanced Healthcare Materials, 2015, 4(17): 2606-2640. doi: 10.1002/adhm.201500450 [21] LARRAÑETA E, LUTTON R E M, WOOLFSON A D, et al. Microneedle Arrays as Transdermal and Intradermal Drug Delivery Systems: Materials Science, Manufacture and Commercial Development[J]. Materials Science and Engineering: Reports, 2016, 104: 1-32. doi: 10.1016/j.mser.2016.03.001 [22] JIN Q C, CHEN H J, LI X L, et al. Reduced Graphene Oxide Nanohybrid-Assembled Microneedles as Mini-Invasive Electrodes for Real-Time Transdermal Biosensing[J]. Small, 2019, 15(6): e1804298. doi: 10.1002/smll.201804298 [23] CHENG Y X, GONG X, YANG J, et al. A Touch-Actuated Glucose Sensor Fully Integrated with Microneedle Array and Reverse Iontophoresis for Diabetes Monitoring[J]. Biosensors and Bioelectronics, 2022, 203: 114026. doi: 10.1016/j.bios.2022.114026 [24] SINGH P, CARRIER A, CHEN Y L, et al. Polymeric Microneedles for Controlled Transdermal Drug Delivery[J]. Journal of Controlled Release: Official Journal of the Controlled Release Society, 2019, 315: 97-113. doi: 10.1016/j.jconrel.2019.10.022 [25] SENEL M, DERVISEVIC M, VOELCKER N H. Gold Microneedles Fabricated by Casting of Gold Ink Used for Urea Sensing[J]. Materials Letters, 2019, 243: 50-53. doi: 10.1016/j.matlet.2019.02.014 [26] MUGO S M, ROBERTSON S V, WOOD M. A Hybrid Stainless-Steel SPME Microneedle Electrode Sensor for Dual Electrochemical and GC-MS Analysis[J]. Sensors, 2023, 23(4): 2317. doi: 10.3390/s23042317 [27] DOWNS A M, BOLOTSKY A, WEAVER B M, et al. Microneedle Electrochemical Aptamer-Based Sensing: Real-Time Small Molecule Measurements Using Sensor-Embedded, Commercially-Available Stainless Steel Microneedles[J]. Biosensors and Bioelectronics, 2023, 236: 115408. doi: 10.1016/j.bios.2023.115408 [28] DERVISEVIC M, ALBA M, YAN L, et al. Transdermal Electrochemical Monitoring of Glucose via High-Density Silicon Microneedle Array Patch[J]. Advanced Functional Materials, 2022, 32(3): 2009850. doi: 10.1002/adfm.202009850 [29] SONG S, NA J, JANG M, et al. A CMOS VEGF Sensor for Cancer Diagnosis Using a Peptide Aptamer-Based Functionalized Microneedle[J]. IEEE Transactions on Biomedical Circuits and Systems, 2019, 13(6): 1288-1299. doi: 10.1109/TBCAS.2019.2954846 [30] ZHANG B, YANG Y, ZHAO Z, et al. A Gold Nanoparticles Deposited Polymer Microneedle Enzymatic Biosensor for Glucose Sensing[J]. Electrochimica Acta, 2020, 358: 136917. doi: 10.1016/j.electacta.2020.136917 [31] JOSHI P, RILEY P R, MISHRA R, et al. Transdermal Polymeric Microneedle Sensing Platform for Fentanyl Detection in Biofluid[J]. Biosensors, 2022, 12(4): 198. doi: 10.3390/bios12040198 [32] DERVISEVIC M, VOELCKER N H. Microneedles with Recessed Microcavities for Electrochemical Sensing in Dermal Interstitial Fluid[J]. ACS Materials Letters, 2023, 5(7): 1851-1858. doi: 10.1021/acsmaterialslett.3c00441 [33] ZHU D D, TAN Y R, ZHENG L W, et al. Microneedle-Coupled Epidermal Sensors for In-Situ-Multiplexed Ion Detection in Interstitial Fluids[J]. ACS Applied Materials and Interfaces, 2023, 15(11): 14146-14154. [34] ODINOTSKI S, DHINGRA K, GHAVAMINEJAD A, et al. A Conductive Hydrogel-Based Microneedle Platform for Real-Time pH Measurement in Live Animals[J]. Small, 2022, 18(45): e2200201. doi: 10.1002/smll.202200201 [35] LI J, Wei M, Gao B B. A Review of Recent Advances in Microneedle-Based Sensing within the DermalI SF That Could Transform Medical Testing[J]. ACS Sensors, 2024, 9: 1149-1161. doi: 10.1021/acssensors.4c00142 [36] MA S W LI J Q, PEI L X, et al. Microneedle-Based Interstitial Fluid Extraction for Drug Analysis: Advances, Challenges and Prospects[J]. Journal of Pharmaceutical Analysis, 2023, 13(2): 111-126. doi: 10.1016/j.jpha.2022.12.004 [37] HUANG X S, ZHENG S T, LIANG B M, et al. 3D-Assembled Microneedle Ion Sensor-Based Wearable System for the Transdermal Monitoring of Physiological Ion Fluctuations[J]. Microsystems and Nanoengineering, 2023, 9: 25. doi: 10.1038/s41378-023-00497-0 [38] MING T, LAN T T, YU M X, et al. Platinum Black/Gold Nanoparticles/Polyaniline Modified Electrochemical Microneedle Sensors for Continuous in Vivo Monitoring of pH Value[J]. Polymers, 2023, 15(13): 2796. doi: 10.3390/polym15132796 [39] DERVISEVIC M, ALBA M, ADAMS T E, et al. Electrochemical Immunosensor for Breast Cancer Biomarker Detection Using High-Density Silicon Microneedle Array[J]. Biosensors and Bioelectronics, 2021, 192: 113496. doi: 10.1016/j.bios.2021.113496 [40] PANICKER L R, SHAMSHEERA F, NARAYAN R, et al. Wearable Electrochemical Microneedle Sensors Based on the Graphene-Silver-Chitosan Nanocomposite for Real-Time Continuous Monitoring of the Depression Biomarker Serotonin[J]. ACS Applied Nano Materials, 2023, 6(22): 20601-20611. doi: 10.1021/acsanm.3c02976 [41] JI H W, WANG M Y, WANG Y T, et al. Skin-Integrated, Biocompatible and Stretchable Silicon Microneedle Electrode for Long-Term EMG Monitoring in Motion Scenario[J]. NPJ Flexible Electronics, 2023, 7: 46. doi: 10.1038/s41528-023-00279-8 [42] YIN S J, YU Z Q, SONG N N, et al. A Long Lifetime and Highly Sensitive Wearable Microneedle Sensor for the Continuous Real-Time Monitoring of Glucose in Interstitial Fluid[J]. Biosensors and Bioelectronics, 2024, 244: 115822. doi: 10.1016/j.bios.2023.115822 [43] TEYMOURIAN H, MOONLA C, TEHRANI F, et al. Microneedle-Based Detection of Ketone Bodies along with Glucose and Lactate: Toward Real-Time Continuous Interstitial Fluid Monitoring of Diabetic Ketosis and Ketoacidosis[J]. Analytical Chemistry, 2020, 92(2): 2291-2300. doi: 10.1021/acs.analchem.9b05109 [44] GOUD K Y, MAHATO K, TEYMOURIAN H, et al. Wearable Electrochemical Microneedle Sensing Platform for Real-Time Continuous Interstitial Fluid Monitoring of Apomorphine: Toward Parkinson Management[J]. Sensors and Actuators: B Chemical, 2022, 354: 131234. doi: 10.1016/j.snb.2021.131234 [45] PARRILLA M, DETAMORNRAT U, DOMÍNGUEZ-ROBLES J, et al. Wearable Microneedle-Based Array Patches for Continuous Electrochemical Monitoring and Drug Delivery: Toward a Closed-Loop System for Methotrexate Treatment[J]. ACS Sensors, 2023, 8(11): 4161-4170. doi: 10.1021/acssensors.3c01381 [46] KAI H, KUMATANI A. A Porous Microneedle Electrochemical Glucose Sensor Fabricated on a Scaffold of a Polymer Monolith[J]. Journal of Physics: Energy, 2021, 3(2): 024006. doi: 10.1088/2515-7655/abe4a1 [47] HEGARTY C, MCKILLOP S, MCGLYNN R J, et al. Microneedle Array Sensors Based on Carbon Nanoparticle Composites: Interfacial Chemistry and Electroanalytical Properties[J]. Journal of Materials Science, 2019, 54(15): 10705-10714. doi: 10.1007/s10853-019-03642-1 [48] HEGARTY C, MCCONVILLE A, MCGLYNN R J, et al. Design of Composite Microneedle Sensor Systems for the Measurement of Transdermal pH[J]. Materials Chemistry and Physics, 2019, 227: 340-346. doi: 10.1016/j.matchemphys.2019.01.052 [49] LI Y F, ZHOU W, LIU C Z, et al. Fabrication and Characteristic of Flexible Dry Bioelectrodes with Microstructures Inspired by Golden Margined Century Plant Leaf[J]. Sensors and Actuators A: Physical, 2021, 321: 112397. doi: 10.1016/j.sna.2020.112397 [50] DERVISEVIC M, JARA FORNEROD M J, HARBERTS J, et al. Wearable Microneedle Patch for Transdermal Electrochemical Monitoring of Urea in Interstitial Fluid[J]. ACS Sensors, 2024, 9(2): 932-941. doi: 10.1021/acssensors.3c02386 [51] KIM Y J, CHINNADAYYALA S R, LE H T N, et al. Sensitive Electrochemical Non-Enzymatic Detection of Glucose Based on Wireless Data Transmission[J]. Sensors, 2022, 22(7): 2787. doi: 10.3390/s22072787 [52] WU Y, TEHRANI F, TEYMOURIAN H, et al. Microneedle Aptamer-Based Sensors for Continuous, Real-Time Therapeutic Drug Monitoring[J]. Analytical Chemistry, 2022, 94(23): 8335-8345. doi: 10.1021/acs.analchem.2c00829 [53] AJMAL MOKHTAR S M, YAMADA M, PROW T W, et al. PEDOT Coated Microneedles towards Electrochemically Assisted Skin Sampling[J]. Journal of Materials Chemistry B, 2023, 11(22): 5021-5031. doi: 10.1039/D3TB00485F [54] JIA H L, ZHAO J W, QIN L R, et al. The Fabrication of an Ni6MnO8Nanoflake-Modified Acupuncture Needle Electrode for Highly Sensitive Ascorbic Acid Detection[J]. RSC Advances, 2019, 9(46): 26843-26849. doi: 10.1039/C9RA03850G [55] CHINNADAYYALA S R, CHO S. Porous Platinum Black-Coated Minimally Invasive Microneedles for Non-Enzymatic Continuous Glucose Monitoring in Interstitial Fluid[J]. Nanomaterials, 2020, 11(1): 37. doi: 10.3390/nano11010037 [56] CHIEN M N, FAN S H, HUANG C H, et al. Continuous Lactate Monitoring System Based on Percutaneous Microneedle Array[J]. Sensors, 2022, 22(4): 1468. doi: 10.3390/s22041468 [57] BOLLELLA P, SHARMA S, CASS A E G, et al. Minimally-Invasive Microneedle-Based Biosensor Array for Simultaneous Lactate and Glucose Monitoring in Artificial Interstitial Fluid[J]. Electroanalysis, 2019, 31(2): 374-382. doi: 10.1002/elan.201800630 [58] ZHU J L, WANG F Q, CHEN J Y, et al. An Efficient Biosensor Using a Functionalized Microneedle of Cu2O-Based CoCu-LDH for Glucose Detection[J]. RSC Advances, 2023, 13(46): 32558-32566. doi: 10.1039/D3RA05957J [59] OLIVEIRA D, CORREIA B P, SHARMA S, et al. Molecular Imprinted Polymers on Microneedle Arrays for Point of Care Transdermal Sampling and Sensing of Inflammatory Biomarkers[J]. ACS Omega, 2022, 7(43): 39039-39044. doi: 10.1021/acsomega.2c04789 [60] CHINNADAYYALA SOMASEKHAR R, JINSOOP, SATTI AFRAIZ T, et al. Minimally Invasive and Continuous Glucose Monitoring Sensor Based on Non-Enzymatic Porous Platinum Black-Coated Gold Microneedles[J]. Electrochimica Acta, 2020, 369: 137691. [61] SONG N X, XIE P F, SHEN W, et al. A Microwell-Based Impedance Sensor on an Insertable Microneedle for Real-Time in Vivo Cytokine Detection[J]. Microsystems and Nanoengineering, 2021, 7: 96. doi: 10.1038/s41378-021-00297-4 [62] LINH V T N, YIM S G, MUN C, et al. Bioinspired Plasmonic Nanoflower-Decorated Microneedle for Label-Free Intradermal Sensing[J]. Applied Surface Science, 2021, 551: 149411. doi: 10.1016/j.apsusc.2021.149411 [63] TORTOLINI C, CASS A E G, POFI R, et al. Microneedle-Based Nanoporous Gold Electrochemical Sensor for Real-Time Catecholamine Detection[J]. Mikrochimica Acta, 2022, 189(5): 180. doi: 10.1007/s00604-022-05260-2 [64] PIAO H L, CHOI Y H, KIM J, et al. Impedance-Based Polymer Microneedle Patch Sensor for Continuous Interstitial Fluid Glucose Monitoring[J]. Biosensors and Bioelectronics, 2024, 247: 115932. doi: 10.1016/j.bios.2023.115932 [65] ZHANG Y Y, ZHAO G Y, ZHENG M J, et al. A Nanometallic Conductive Composite-Hydrogel Core-Shell Microneedle Skin Patch for Real-Time Monitoring of Interstitial Glucose Levels[J]. Nanoscale, 2023, 15(40): 16493-16500. doi: 10.1039/D3NR01245J [66] SACHINK, SUNDAR S S, PRATIMAK, et al. Machine Learning Enabled Onsite Electrochemical Detection of Lidocaine Using a Microneedle Array Integrated Screen Printed Electrode[J]. Electrochimica Acta, 2024, 475: 143664. doi: 10.1016/j.electacta.2023.143664 [67] ZHAO L, WEN Z Z, JIANG F J, et al. Silk/Polyols/GOD Microneedle Based Electrochemical Biosensor for Continuous Glucose Monitoring[J]. RSC Advances, 2020, 10(11): 6163-6171. doi: 10.1039/C9RA10374K [68] MISHRA R K, GOUD K Y, LI Z H, et al. Continuous Opioid Monitoring along with Nerve Agents on a Wearable Microneedle Sensor Array[J]. Journal of the American Chemical Society, 2020, 142(13): 5991-5995. doi: 10.1021/jacs.0c01883 [69] LI Z H, KADIAN S, MISHRA R K, et al. Electrochemical Detection of Cholesterol in Human Biofluid Using Microneedle Sensor[J]. Journal of Materials Chemistry B, 2023, 11(26): 6075-6081. doi: 10.1039/D2TB02142K [70] ANA-MARIA D, MARCP, SOFIEC, et al. Microneedle Array-Based Electrochemical Sensor Functionalized with SWCNTS for the Highly Sensitive Monitoring of MDMA in Interstitial Fluid[J]. Microchemical Journal, 2023, 193: 109257. doi: 10.1016/j.microc.2023.109257 [71] LIU Y Q, YU Q, YE L, et al. A Wearable, Minimally-Invasive, Fully Electrochemically-Controlled Feedback Minisystem for Diabetes Management[J]. Lab on a Chip, 2023, 23(3): 421-436. doi: 10.1039/D2LC00797E [72] ABBASIASL T, MIRLOU F, MIRZAJANI H, et al. A Wearable Touch-Activated Device Integrated with Hollow Microneedles for Continuous Sampling and Sensing of Dermal Interstitial Fluid[J]. Advanced Materials, 2024, 36(2): e2304704. doi: 10.1002/adma.202304704 [73] ZHENG L W, ZHU D D, XIAO Y, et al. Microneedle Coupled Epidermal Sensor for Multiplexed Electrochemical Detection of Kidney Disease Biomarkers[J]. Biosensors and Bioelectronics, 2023, 237: 115506. doi: 10.1016/j.bios.2023.115506 [74] ZHENG M J, ZHANG Y Y, HU T L, et al. A Skin Patch Integrating Swellable Microneedles and Electrochemical Test Strips for Glucose and Alcohol Measurement in Skin Interstitial Fluid[J]. Bioengineering and Translational Medicine, 2022, 8(5): e10413.