在精準醫療應用上，治療藥物與生物標記的快速監控可以提供個別患者精準有效的藥物劑量和代謝分析，並量身訂製最佳的治療方式。為了監控人體內的生物分子或藥物濃度，微針(microneedle, MN)貼片具有微創、無痛且易於使用的優勢，可從皮膚中提取細胞間質液(interstitial fluid, ISF)來進行檢測。然而，現行透過微針貼片的檢測策略，通常需要經過繁瑣的過程或大型儀器來回收和分析ISF內的待測物。因此本論文的研究目標為開發出能快速回收微針貼片內的待測物分子，同時兼顧具可快速分析能力的感測平台。
首先，此論文將微針貼片和紙基感測平台整合為一種快速、微創的生物流體分析系統。本研究與清大化工系王潔教授團隊合作，採用他們所開發的堅固、高生物相容性、且能調控膨潤度的微針貼片(controllable swellable MN, csMN)，經由模擬穿刺實驗證實csMN能夠快速可靠地從皮膚組織中提取足夠的ISF。接著，用微針去吸取亞甲基藍染劑，並以濕潤纖維素濾紙作為一個三維的回收微系統來獲得微針內的染劑，證實微針中的染劑分子可以被回收到潮濕的纖維素濾紙內。值得注意的是，可預先在纖維素濾紙上進行功能化修飾(如比色試劑奈或奈米粒子陣列)以提供特定的檢測能力，使其成為同時具有回收和快速分析能力的感測平台。舉例來說，比色感測平台包含了葡萄糖氧化酶、過氧化酶和呈色劑，當接觸葡萄糖時會催化呈色劑的氧化反應，以達到變色的效果。顏色變化的結果可以藉由眼睛或RGB直方圖分析量化來判別葡萄糖的濃度。
更進一步，為了實現超靈敏、無標記的檢測，在纖維素濾紙上以熱蒸鍍法直接塗佈一層奈米金粒子陣列，作為表面增強拉曼(surface-enhanced Raman spectroscopy, SERS)的感測平台。透過785-nm可攜式拉曼光譜儀，可觀察到亞甲基藍分子訊號增益幅度可達2.12 x 1010倍，且具有良好的訊號再現性(RSD = 4.73 %)。接著，再針對四種臨床待測物進行分析，例如：抗生素(頭孢若林)、神經興奮劑(尼古丁)、農藥(巴拉刈)、有機染劑(亞甲基藍)，最低檢測濃度可分別達到0.01, 0.01, 0.1, 0.001 ppb，其結果皆展現優異的靈敏度。最後，本研究選擇尼古丁作為模型藥物來驗證無痛、微創的藥物監測能力，在三位受試者的手臂上貼附FDA核准的尼古丁貼片，並以微針貼片結合SERS感測平台成功地觀察到人體ISF內的尼古丁訊號強度變化。因此，本論文所設計的微創感測平台能通過快速、無痛地監測個體患者體內生物分子的濃度，在精準醫療的應用上具有良好的潛力。
此外，全球糧食安全已成為國際社會關注的議題，一旦植物被感染，治愈它們並不容易。因此，早期診斷對於植物病害管理也很重要。本研究透過csMN採集黃金葛內的液體，再以SERS感測平台進行檢測，其結果顯示出微針貼片結合紙基感測平台在植物體內檢測分子的可行性，也展現在植物疾病檢測的應用潛力。

In precision medicine, therapeutic drug monitoring (TDM) can provide effective drug dosage and metabolic analysis, and tailor the optimal treatment for individual patients. To monitor molecular levels in the human body, microneedle (MN) patches have minimally invasive, painless, and easy-to-use advantages, allowing the extraction and analysis of skin interstitial fluid (ISF). However, the time-consuming, complicated procedure and bulky equipment obstruct the recovery and detection of ISF from MN patches. Therefore, the aim of this thesis is to develop sensing platforms that can rapidly recover the analytes from MN patch and provide desirable analysis capabilities.
First, the MN patch and paper-based sensing platform were integrated as the rapid, minimally invasive biofluid analysis system. Here, a robust, biocompatible controllable swellable MN (csMN) patch, developed by Prof. Jane Wang, Department of Chemical Engineering of NTHU, was utilized to allow rapidly and reliably extract ISF from skin tissue. Noteworthily, the analyte molecules in the csMN patch can be facilely recovered into a moist cellulose paper via spontaneous diffusion; more importantly, the paper can be accordingly functionalized with enzymatic colorimetric reagents or a plasmonic array, enabling a desirable detection capacity. In the case of paper-based colorimetric sensing platform, hydrogen peroxide (H2O2) was first produced while the glucose was specifically oxidized by glucose oxidase (GOx). Subsequently, the dye (ABTS) was further oxidized by the HRP/H2O2 system to yield bluish-green products. The color readout would be in response to the glucose concentration, allowing rapid diagnosis by the naked eye and quantification by RGB histogram analysis.
Moreover, to achieve ultrasensitive, label-free detection, gold nanoparticles were directly deposited on cellulose paper by thermal evaporation method as a paper-based surface-enhanced Raman spectroscopy (SERS) sensing platform which displayed the Raman signal enhancement factor up to 2.12 x 1010 and a good reproducibility (RSD = 4.73 %). Thus, the analytes in ISF could be identified according to their fingerprint band through a portable 785-nm Raman spectrometer. For instance, the successful trace detection of diverse molecules could be achieved, including antibiotics (cefazolin), stimulants (nicotine), pesticides (paraquat), and organic dyes (methylene blue), even down to sub-ppb level. Finally, nicotine was further selected as a model drug to realize the ability of painless TDM. For proof of concept, the variations in nicotine level for three human volunteers wearing an FDA-approved nicotine patch were monitored. Therefore, the as-designed pain-free, minimally invasive sensing system opens a new way to precision medicine, especially for personal healthcare monitoring.
In addition, global food security has become an issue of concern for the international community, and it is difficult to cure plants once they are infected. Thus, early diagnosis is also important for plant disease management. Therefore, plant liquid from Pothos was also collected via the csMN patch; then, the paper-based SERS sensing platform was utilized to analyze molecules in the plant liquid. The results showed the feasibility of csMN-assisted paper-based sensing platform to detect molecules in plants and revealed the potential abilities for plant disease detection application.

致謝 I
摘要 III
Abstract V
Table of Contents VII
List of Figures X
List of Table XIX
Chapter 1 Introduction 1
1.1 Motivation 1
1.2 Thesis Structure 3
Chapter 2 Literature Review 4
2.1 Precision Medicine and Drug Monitoring 4
2.1.1 Precision Medicine 4
2.1.2 Therapeutic drug monitoring (TDM) 4
2.2 Surface-Enhanced Raman Spectroscopy, SERS 5
2.2.1 Raman Spectroscopy 5
2.2.2 Localized Surface Plasmon Resonance, LSPR 6
2.2.3 Surface-Enhanced Raman Spectroscopy (SERS) 10
2.2.4 SERS for Drug Monitoring 12
2.3 Plant Disease Detection 15
2.3.1 Food Security and Plant Disease 15
2.3.2 Diagnosis Technologies for Plant Disease 16
2.4 Paper-Based Sensing Platform 17
2.4.1 Colorimetric Method 17
2.4.2 Plasmonic Method 19
2.5 Alternative Biofluids 21
2.5.1 Sweat, Tear, and Saliva 21
2.5.2 Interstitial Fluid (ISF) 24
2.6 Biomedical Application of Microneedle Patch 26
2.6.1 Introduction of Microneedle Patch 26
2.6.2 Hydrogel-based Microneedle Patch 33
2.6.3 Plasmonic Microneedle Patch 37
2.6.4 Microneedle Patch for Plant Diseases Detection 41
Chapter 3 Experimental Section 43
3.1 Materials 43
3.2 Fabrication of csMN patches 43
3.3 In Vitro Skin Insertion and Extraction Capability of csMN Patch 44
3.4 Preparation and Colorimetric Measurement of Paper-based Colorimetric Sensing Platform 44
3.5 Preparation of Paper-based SERS Sensing Platform 46
3.6 SERS Performance of Au-deposited Plasmonic Paper 46
3.7 Three-dimensional Finite Difference Time Domain (3D-FDTD) Simulations of Plasmonic Paper 47
3.8 csMN-assisted SERS Measurement 48
3.9 Nicotine Monitoring in Human Volunteers 49
3.10 Detection of Analytes in Plant 49
Chapter 4 Result and Discussion 50
4.1 Design of Research 50
4.2 Characteristics of csMN Patch 52
4.3 Colorimetric Assay of csMN-assisted paper-based colorimetric sensing platform 62
4.4 The csMN-assisted Paper-based SERS Sensing Platform 68
4.5 Nicotine Monitoring in Human Volunteers 77
4.6 Feasibility of Monitoring Analyte in Plant 83
Chapter 5 Conclusion 84
5.1 Summary of Work 84
5.2 Future work and Prospects 84
Reference 86
Publication List 96

(1) Manzari, M. T.; Shamay, Y.; Kiguchi, H.; Rosen, N.; Scaltriti, M.; Heller, D. A. Targeted drug delivery strategies for precision medicines. Nature Reviews Materials 2021, 6 (4), 351-370.
(2) Ashley, E. A. Towards precision medicine. Nature Reviews Genetics 2016, 17 (9), 507-522.
(3) Mitchell, M. J.; Billingsley, M. M.; Haley, R. M.; Wechsler, M. E.; Peppas, N. A.; Langer, R. Engineering precision nanoparticles for drug delivery. Nature Reviews Drug Discovery 2021, 20 (2), 101-124.
(4) Clarke, N. J. Mass spectrometry in precision medicine: phenotypic measurements alongside pharmacogenomics. Clinical chemistry 2016, 62 (1), 70-76.
(5) Wicha, S. G.; Märtson, A. G.; Nielsen, E. I.; Koch, B. C.; Friberg, L. E.; Alffenaar, J. W.; Minichmayr, I. K.; International Society of Anti‐Infective Pharmacology , t. P. P. s. g. o. t. E. S. o. C. M., Infectious Diseases. From therapeutic drug monitoring to model‐informed precision dosing for antibiotics. Clinical Pharmacology & Therapeutics 2021, 109 (4), 928-941.
(6) Teymourian, H.; Parrilla, M.; Sempionatto, J. R.; Montiel, N. F.; Barfidokht, A.; Van Echelpoel, R.; De Wael, K.; Wang, J. Wearable electrochemical sensors for the monitoring and screening of drugs. ACS sensors 2020, 5 (9), 2679-2700.
(7) Li, P.; Lee, G.-H.; Kim, S. Y.; Kwon, S. Y.; Kim, H.-R.; Park, S. From diagnosis to treatment: Recent advances in patient-friendly biosensors and implantable devices. ACS nano 2021, 15 (2), 1960-2004.
(8) Raman, C. V.; Krishnan, K. S. A new type of secondary radiation. Nature 1928, 121 (3048), 501-502.
(9) Raman, C. V. A change of wave-length in light scattering. Nature 1928, 121 (3051), 619-619.
(10) Liu, K.; Zhao, Q.; Li, B.; Zhao, X. Raman Spectroscopy: A Novel Technology for Gastric Cancer Diagnosis. Frontiers in Bioengineering and Biotechnology 2022, 10.
(11) Cortés, E.; Wendisch, F. J.; Sortino, L.; Mancini, A.; Ezendam, S.; Saris, S.; de S. Menezes, L.; Tittl, A.; Ren, H.; Maier, S. A. Optical metasurfaces for energy conversion. Chem. Rev. 2022, 122 (19), 15082-15176.
(12) Kim, S.; Kim, J. M.; Park, J. E.; Nam, J. M. Nonnoble‐Metal‐Based Plasmonic Nanomaterials: Recent Advances and Future Perspectives. Advanced Materials 2018, 30 (42), 1704528.
(13) Liu, X. Colloidal plasmonic nanoparticles for ultrafast optical switching and laser pulse generation. Frontiers in Materials 2018, 5, 59.
(14) Petryayeva, E.; Krull, U. J. Localized surface plasmon resonance: Nanostructures, bioassays and biosensing—A review. Analytica chimica acta 2011, 706 (1), 8-24.
(15) Willets, K. A.; Van Duyne, R. P. Localized surface plasmon resonance spectroscopy and sensing. Annual review of physical chemistry 2007, 58 (1), 267-297.
(16) Linic, S.; Christopher, P.; Ingram, D. B. Plasmonic-metal nanostructures for efficient conversion of solar to chemical energy. Nature materials 2011, 10 (12), 911-921.
(17) Zhong, Z.; Patskovskyy, S.; Bouvrette, P.; Luong, J. H.; Gedanken, A. The surface chemistry of Au colloids and their interactions with functional amino acids. The Journal of Physical Chemistry B 2004, 108 (13), 4046-4052.
(18) Hong, Y. A.; Ha, J. W. Enhanced refractive index sensitivity of localized surface plasmon resonance inflection points in single hollow gold nanospheres with inner cavity. Scientific reports 2022, 12 (1), 1-9.
(19) Smith, E.; Dent, G. Modern Raman spectroscopy: a practical approach; John Wiley & Sons, 2019.
(20) Fleischmann, M.; Hendra, P. J.; McQuillan, A. J. Raman spectra of pyridine adsorbed at a silver electrode. Chemical physics letters 1974, 26 (2), 163-166.
(21) Verma, P. Tip-enhanced Raman spectroscopy: technique and recent advances. Chem. Rev. 2017, 117 (9), 6447-6466.
(22) Langer, J.; Jimenez de Aberasturi, D.; Aizpurua, J.; Alvarez-Puebla, R. A.; Auguié, B.; Baumberg, J. J.; Bazan, G. C.; Bell, S. E.; Boisen, A.; Brolo, A. G. Present and future of surface-enhanced Raman scattering. ACS nano 2019, 14 (1), 28-117.
(23) Zong, C.; Xu, M.; Xu, L.-J.; Wei, T.; Ma, X.; Zheng, X.-S.; Hu, R.; Ren, B. Surface-enhanced Raman spectroscopy for bioanalysis: reliability and challenges. Chem. Rev. 2018, 118 (10), 4946-4980.
(24) Hang, Y.; Boryczka, J.; Wu, N. Visible-light and near-infrared fluorescence and surface-enhanced Raman scattering point-of-care sensing and bio-imaging: a review. Chemical Society Reviews 2022.
(25) Ding, S.-Y.; Yi, J.; Li, J.-F.; Ren, B.; Wu, D.-Y.; Panneerselvam, R.; Tian, Z.-Q. Nanostructure-based plasmon-enhanced Raman spectroscopy for surface analysis of materials. Nature Reviews Materials 2016, 1 (6), 1-16.
(26) Pérez-Jiménez, A. I.; Lyu, D.; Lu, Z.; Liu, G.; Ren, B. Surface-enhanced Raman spectroscopy: benefits, trade-offs and future developments. Chemical science 2020, 11 (18), 4563-4577.
(27) Jaworska, A.; Fornasaro, S.; Sergo, V.; Bonifacio, A. Potential of surface enhanced Raman spectroscopy (SERS) in therapeutic drug monitoring (TDM). A critical review. Biosensors 2016, 6 (3), 47.
(28) Fornasaro, S.; Cialla-May, D.; Sergo, V.; Bonifacio, A. The Role of Surface Enhanced Raman Scattering for Therapeutic Drug Monitoring of Antimicrobial Agents. Chemosensors 2022, 10 (4), 128.
(29) Ashley, J.; Wu, K.; Hansen, M. F.; Schmidt, M. S.; Boisen, A.; Sun, Y. Quantitative detection of trace level cloxacillin in food samples using magnetic molecularly imprinted polymer extraction and surface-enhanced Raman spectroscopy nanopillars. Analytical chemistry 2017, 89 (21), 11484-11490.
(30) Berger, A. G.; Restaino, S. M.; White, I. M. Vertical-flow paper SERS system for therapeutic drug monitoring of flucytosine in serum. Analytica chimica acta 2017, 949, 59-66.
(31) Panikar, S. S.; Banu, N.; Escobar, E.-R.; García, G.-R.; Cervantes-Martínez, J.; Villegas, T.-C.; Salas, P.; De la Rosa, E. Stealth modified bottom up SERS substrates for label-free therapeutic drug monitoring of doxorubicin in blood serum. Talanta 2020, 218, 121138.
(32) Godfray, H. C. J.; Beddington, J. R.; Crute, I. R.; Haddad, L.; Lawrence, D.; Muir, J. F.; Pretty, J.; Robinson, S.; Thomas, S. M.; Toulmin, C. Food security: the challenge of feeding 9 billion people. science 2010, 327 (5967), 812-818.
(33) van Dijk, M.; Morley, T.; Rau, M. L.; Saghai, Y. A meta-analysis of projected global food demand and population at risk of hunger for the period 2010–2050. Nature Food 2021, 2 (7), 494-501.
(34) Savary, S.; Ficke, A.; Aubertot, J.-N.; Hollier, C. Crop losses due to diseases and their implications for global food production losses and food security. Springer: 2012; Vol. 4, pp 519-537.
(35) Bourke, P. A. Emergence of potato blight, 1843–46. Nature 1964, 203 (4947), 805-808.
(36) Goss, E. M.; Tabima, J. F.; Cooke, D. E.; Restrepo, S.; Fry, W. E.; Forbes, G. A.; Fieland, V. J.; Cardenas, M.; Grünwald, N. J. The Irish potato famine pathogen Phytophthora infestans originated in central Mexico rather than the Andes. Proceedings of the National Academy of Sciences 2014, 111 (24), 8791-8796.
(37) Hu, C.-H.; Perez, F. G.; Donahoo, R.; McLeod, A.; Myers, K.; Ivors, K.; Secor, G.; Roberts, P. D.; Deahl, K. L.; Fry, W. E. Recent genotypes of Phytophthora infestans in the eastern United States reveal clonal populations and reappearance of mefenoxam sensitivity. Plant Disease 2012, 96 (9), 1323-1330.
(38) Fry, W.; McGrath, M.; Seaman, A.; Zitter, T.; McLeod, A.; Danies, G.; Small, I.; Myers, K.; Everts, K.; Gevens, A. The 2009 late blight pandemic in the eastern United States–causes and results. Plant Disease 2013, 97 (3), 296-306.
(39) Rubio, L.; Galipienso, L.; Ferriol, I. Detection of plant viruses and disease management: Relevance of genetic diversity and evolution. Frontiers in plant science 2020, 11, 1092.
(40) Fang, Y.; Ramasamy, R. P. Current and prospective methods for plant disease detection. Biosensors 2015, 5 (3), 537-561.
(41) Lievens, B.; Brouwer, M.; Vanachter, A. C.; Cammue, B. P.; Thomma, B. P. Real-time PCR for detection and quantification of fungal and oomycete tomato pathogens in plant and soil samples. Plant science 2006, 171 (1), 155-165.
(42) Kliot, A.; Kontsedalov, S.; Lebedev, G.; Brumin, M.; Cathrin, P. B.; Marubayashi, J. M.; Skaljac, M.; Belausov, E.; Czosnek, H.; Ghanim, M. Fluorescence in situ hybridizations (FISH) for the localization of viruses and endosymbiotic bacteria in plant and insect tissues. JoVE (Journal of Visualized Experiments) 2014, (84), e51030.
(43) López, M. M.; Bertolini, E.; Olmos, A.; Caruso, P.; Gorris, M. T.; Llop, P.; Penyalver, R.; Cambra, M. Innovative tools for detection of plant pathogenic viruses and bacteria. International Microbiology 2003, 6 (4), 233-243.
(44) Wullings, B.; Van Beuningen, A.; Janse, J.; Akkermans, A. Detection of Ralstonia solanacearum, which causes brown rot of potato, by fluorescent in situ hybridization with 23S rRNA-targeted probes. Applied and Environmental Microbiology 1998, 64 (11), 4546-4554.
(45) Chitarra, L. G.; Van Den Bulk, R. W. The application of flow cytometry and fluorescent probe technology for detection and assessment of viability of plant pathogenic bacteria. European journal of plant pathology 2003, 109 (5), 407-417.
(46) Paul, R.; Ostermann, E.; Chen, Y.; Saville, A. C.; Yang, Y.; Gu, Z.; Whitfield, A. E.; Ristaino, J. B.; Wei, Q. Integrated microneedle-smartphone nucleic acid amplification platform for in-field diagnosis of plant diseases. Biosensors and Bioelectronics 2021, 187, 113312.
(47) Teymourian, H.; Barfidokht, A.; Wang, J. Electrochemical glucose sensors in diabetes management: An updated review (2010–2020). Chemical Society Reviews 2020, 49 (21), 7671-7709.
(48) Liu, J.; Geng, Z.; Fan, Z.; Liu, J.; Chen, H. Point-of-care testing based on smartphone: The current state-of-the-art (2017–2018). Biosensors and Bioelectronics 2019, 132, 17-37.
(49) Brangel, P.; Sobarzo, A.; Parolo, C.; Miller, B. S.; Howes, P. D.; Gelkop, S.; Lutwama, J. J.; Dye, J. M.; McKendry, R. A.; Lobel, L. A serological point-of-care test for the detection of IgG antibodies against Ebola virus in human survivors. ACS nano 2018, 12 (1), 63-73.
(50) Nguyen, P. Q.; Soenksen, L. R.; Donghia, N. M.; Angenent-Mari, N. M.; de Puig, H.; Huang, A.; Lee, R.; Slomovic, S.; Galbersanini, T.; Lansberry, G. Wearable materials with embedded synthetic biology sensors for biomolecule detection. Nature Biotechnology 2021, 39 (11), 1366-1374.
(51) Kim, W.; Lee, S. H.; Ahn, Y. J.; Lee, S. H.; Ryu, J.; Choi, S. K.; Choi, S. A label-free cellulose SERS biosensor chip with improvement of nanoparticle-enhanced LSPR effects for early diagnosis of subarachnoid hemorrhage-induced complications. Biosensors and Bioelectronics 2018, 111, 59-65.
(52) Wu, W.; Wang, L.; Yang, Y.; Du, W.; Ji, W.; Fang, Z.; Hou, X.; Wu, Q.; Zhang, C.; Li, L. Optical flexible biosensors: From detection principles to biomedical applications. Biosensors and Bioelectronics 2022, 114328.
(53) Kim, J.; Campbell, A. S.; de Ávila, B. E.-F.; Wang, J. Wearable biosensors for healthcare monitoring. Nature biotechnology 2019, 37 (4), 389-406.
(54) Kim, J.; Kim, M.; Lee, M.-S.; Kim, K.; Ji, S.; Kim, Y.-T.; Park, J.; Na, K.; Bae, K.-H.; Kyun Kim, H. Wearable smart sensor systems integrated on soft contact lenses for wireless ocular diagnostics. Nature communications 2017, 8 (1), 1-8.
(55) Wang, Y.; Zhao, C.; Wang, J.; Luo, X.; Xie, L.; Zhan, S.; Kim, J.; Wang, X.; Liu, X.; Ying, Y. Wearable plasmonic-metasurface sensor for noninvasive and universal molecular fingerprint detection on biointerfaces. Science Advances 2021, 7 (4), eabe4553.
(56) Kim, S. K.; Lee, G. H.; Jeon, C.; Han, H. H.; Kim, S. J.; Mok, J. W.; Joo, C. K.; Shin, S.; Sim, J. Y.; Myung, D. Bimetallic Nanocatalysts Immobilized in Nanoporous Hydrogels for Long‐Term Robust Continuous Glucose Monitoring of Smart Contact Lens. Advanced Materials 2022, 34 (18), 2110536.
(57) Kim, J.; Imani, S.; de Araujo, W. R.; Warchall, J.; Valdés-Ramírez, G.; Paixão, T. R.; Mercier, P. P.; Wang, J. Wearable salivary uric acid mouthguard biosensor with integrated wireless electronics. Biosensors and Bioelectronics 2015, 74, 1061-1068.
(58) Shrivastava, S.; Trung, T. Q.; Lee, N.-E. Recent progress, challenges, and prospects of fully integrated mobile and wearable point-of-care testing systems for self-testing. Chemical Society Reviews 2020, 49 (6), 1812-1866.
(59) Pundir, M.; Papagerakis, S.; De Rosa, M. C.; Chronis, N.; Kurabayashi, K.; Abdulmawjood, S.; Prince, M. E. P.; Lobanova, L.; Chen, X.; Papagerakis, P. Emerging biotechnologies for evaluating disruption of stress, sleep, and circadian rhythm mechanism using aptamer-based detection of salivary biomarkers. Biotechnology Advances 2022, 107961.
(60) Tehrani, F.; Teymourian, H.; Wuerstle, B.; Kavner, J.; Patel, R.; Furmidge, A.; Aghavali, R.; Hosseini-Toudeshki, H.; Brown, C.; Zhang, F. An integrated wearable microneedle array for the continuous monitoring of multiple biomarkers in interstitial fluid. Nature Biomedical Engineering 2022, 1-11.
(61) Zhu, D. D.; Duong, P. K.; Cheah, R. H.; Liu, X. Y.; Wong, J. R.; Wang, W. J.; Guan, S. T. T.; Zheng, X. T.; Chen, P. Colorimetric microneedle patches for multiplexed transdermal detection of metabolites. Biosensors and Bioelectronics 2022, 114412.
(62) DeSaix, P.; Betts, G. J.; Johnson, E.; Johnson, J. E.; Oksana, K.; Kruse, D. H.; Poe, B.; Wise, J. A.; Young, K. A. Anatomy & Physiology (OpenStax). OpenStax: 2013.
(63) Kashaninejad, N.; Munaz, A.; Moghadas, H.; Yadav, S.; Umer, M.; Nguyen, N.-T. Microneedle arrays for sampling and sensing skin interstitial fluid. Chemosensors 2021, 9 (4), 83.
(64) Heikenfeld, J.; Jajack, A.; Feldman, B.; Granger, S. W.; Gaitonde, S.; Begtrup, G.; Katchman, B. A. Accessing analytes in biofluids for peripheral biochemical monitoring. Nature biotechnology 2019, 37 (4), 407-419.
(65) Bailey, T.; Bode, B. W.; Christiansen, M. P.; Klaff, L. J.; Alva, S. The performance and usability of a factory-calibrated flash glucose monitoring system. Diabetes technology & therapeutics 2015, 17 (11), 787-794.
(66) Samant, P. P.; Niedzwiecki, M. M.; Raviele, N.; Tran, V.; Mena-Lapaix, J.; Walker, D. I.; Felner, E. I.; Jones, D. P.; Miller, G. W.; Prausnitz, M. R. Sampling interstitial fluid from human skin using a microneedle patch. Sci. Transl. Med. 2020, 12 (571), eaaw0285.
(67) Ebah, L. M.; Wiig, H.; Dawidowska, I.; O'toole, C.; Summers, A.; Nikam, M.; Jayanti, A.; Coupes, B.; Brenchley, P.; Mitra, S. Subcutaneous interstitial pressure and volume characteristics in renal impairment associated with edema. Kidney international 2013, 84 (5), 980-988.
(68) Wang, Z.; Luan, J.; Seth, A.; Liu, L.; You, M.; Gupta, P.; Rathi, P.; Wang, Y.; Cao, S.; Jiang, Q. Microneedle patch for the ultrasensitive quantification of protein biomarkers in interstitial fluid. Nature biomedical engineering 2021, 5 (1), 64-76.
(69) Makvandi, P.; Jamaledin, R.; Chen, G.; Baghbantaraghdari, Z.; Zare, E. N.; Di Natale, C.; Onesto, V.; Vecchione, R.; Lee, J.; Tay, F. R. Stimuli-responsive transdermal microneedle patches. Mater. Today 2021, 47, 206-222.
(70) Yang, J.; Zhang, H.; Hu, T.; Xu, C.; Jiang, L.; Zhang, Y. S.; Xie, M. Recent advances of microneedles used towards stimuli-responsive drug delivery, disease theranostics, and bioinspired applications. Chemical Engineering Journal 2021, 426, 130561.
(71) Liu, G.-S.; Kong, Y.; Wang, Y.; Luo, Y.; Fan, X.; Xie, X.; Yang, B.-R.; Wu, M. X. Microneedles for transdermal diagnostics: Recent advances and new horizons. Biomaterials 2020, 232, 119740.
(72) Yi, K.; Yu, Y.; Wang, Y.; Zhao, Y. Inverse opal microneedles arrays for fluorescence enhanced screening skin interstitial fluid biomarkers. Nano Today 2022, 47, 101655.
(73) Al Sulaiman, D.; Chang, J. Y. H.; Bennett, N. R.; Topouzi, H.; Higgins, C. A.; Irvine, D. J.; Ladame, S. Hydrogel-Coated Microneedle Arrays for Minimally Invasive Sampling and Sensing of Specific Circulating Nucleic Acids from Skin Interstitial Fluid. ACS Nano 2019, 13 (8), 9620-9628. DOI: 10.1021/acsnano.9b04783.
(74) Bollella, P.; Sharma, S.; Cass, A. E. G.; Antiochia, R. Microneedle-based biosensor for minimally-invasive lactate detection. Biosensors and Bioelectronics 2019, 123, 152-159.
(75) Parrilla, M.; Detamornrat, U.; Domínguez-Robles, J.; Donnelly, R. F.; De Wael, K. Wearable hollow microneedle sensing patches for the transdermal electrochemical monitoring of glucose. Talanta 2022, 249, 123695.
(76) Chang, H.; Zheng, M.; Yu, X.; Than, A.; Seeni, R. Z.; Kang, R.; Tian, J.; Khanh, D. P.; Liu, L.; Chen, P. A swellable microneedle patch to rapidly extract skin interstitial fluid for timely metabolic analysis. Advanced Materials 2017, 29 (37), 1702243.
(77) Laszlo, E.; De Crescenzo, G.; Nieto‐Argüello, A.; Banquy, X.; Brambilla, D. Superswelling microneedle arrays for dermal interstitial fluid (prote) omics. Advanced Functional Materials 2021, 31 (46), 2106061.
(78) He, R.; Niu, Y.; Li, Z.; Li, A.; Yang, H.; Xu, F.; Li, F. A hydrogel microneedle patch for point‐of‐care testing based on skin interstitial fluid. Advanced Healthcare Materials 2020, 9 (4), 1901201.
(79) Cowan, D. Biomolecular stability and life at high temperatures. Cellular and Molecular Life Sciences CMLS 2000, 57 (2), 250-264.
(80) Park, J. E.; Yonet-Tanyeri, N.; Vander Ende, E.; Henry, A.-I.; Perez White, B. E.; Mrksich, M.; Van Duyne, R. P. Plasmonic microneedle arrays for in situ sensing with surface-enhanced Raman spectroscopy (SERS). Nano letters 2019, 19 (10), 6862-6868.
(81) Ju, J.; Hsieh, C.-M.; Tian, Y.; Kang, J.; Chia, R.; Chang, H.; Bai, Y.; Xu, C.; Wang, X.; Liu, Q. Surface enhanced Raman spectroscopy based biosensor with a microneedle array for minimally invasive in vivo glucose measurements. ACS sensors 2020, 5 (6), 1777-1785.
(82) Linh, V. T. N.; Yim, S.-G.; Mun, C.; Yang, J.-Y.; Lee, S.; Yoo, Y. W.; Sung, D. K.; Lee, Y.-I.; Kim, D.-H.; Park, S.-G. Bioinspired plasmonic nanoflower-decorated microneedle for label-free intradermal sensing. Applied Surface Science 2021, 551, 149411.
(83) Wang, Y.; Ni, H.; Li, H.; Chen, J.; Zhang, D.; Fu, L. Plasmonic microneedle arrays for rapid extraction, SERS detection, and inactivation of bacteria. Chemical Engineering Journal 2022, 442, 136140.
(84) Kolluru, C.; Gupta, R.; Jiang, Q.; Williams, M.; Gholami Derami, H.; Cao, S.; Noel, R. K.; Singamaneni, S.; Prausnitz, M. R. Plasmonic paper microneedle patch for on-patch detection of molecules in dermal interstitial fluid. ACS sensors 2019, 4 (6), 1569-1576.
(85) Paul, R.; Saville, A. C.; Hansel, J. C.; Ye, Y.; Ball, C.; Williams, A.; Chang, X.; Chen, G.; Gu, Z.; Ristaino, J. B. Extraction of plant DNA by microneedle patch for rapid detection of plant diseases. ACS nano 2019, 13 (6), 6540-6549.
(86) 林芝羽. 運用光固化高分子材料開發水膠型微針應用於經皮血糖檢測. 國立清華大學, 新竹市, 2021.
(87) Park, M.; Jung, H.; Jeong, Y.; Jeong, K.-H. Plasmonic schirmer strip for human tear-based gouty arthritis diagnosis using surface-enhanced Raman scattering. ACS nano 2017, 11 (1), 438-443.
(88) Park, S. G.; Xiao, X.; Min, J.; Mun, C.; Jung, H. S.; Giannini, V.; Weissleder, R.; Maier, S. A.; Im, H.; Kim, D. H. Self‐assembly of nanoparticle‐spiked pillar arrays for plasmonic biosensing. Advanced Functional Materials 2019, 29 (43), 1904257.
(89) Davis, S. P.; Landis, B. J.; Adams, Z. H.; Allen, M. G.; Prausnitz, M. R. Insertion of microneedles into skin: measurement and prediction of insertion force and needle fracture force. Journal of biomechanics 2004, 37 (8), 1155-1163.
(90) Zheng, M.; Wang, Z.; Chang, H.; Wang, L.; Chew, S. W.; Lio, D. C. S.; Cui, M.; Liu, L.; Tee, B. C.; Xu, C. Osmosis‐powered hydrogel microneedles for microliters of skin interstitial fluid extraction within minutes. Advanced healthcare materials 2020, 9 (10), 1901683.
(91) Célino, A.; Fréour, S.; Jacquemin, F.; Casari, P. The hygroscopic behavior of plant fibers: a review. Frontiers in chemistry 2014, 1, 43.
(92) Manaia, J. P.; Manaia, A. T.; Rodriges, L. Industrial hemp fibers: An overview. Fibers 2019, 7 (12), 106.
(93) Costantini, F.; Tiggelaar, R.; Sennato, S.; Mura, F.; Schlautmann, S.; Bordi, F.; Gardeniers, H.; Manetti, C. Glucose level determination with a multi-enzymatic cascade reaction in a functionalized glass chip. Analyst 2013, 138 (17), 5019-5024.
(94) Wang, Z.; Li, H.; Wang, J.; Chen, Z.; Chen, G.; Wen, D.; Chan, A.; Gu, Z. Transdermal colorimetric patch for hyperglycemia sensing in diabetic mice. Biomaterials 2020, 237, 119782.
(95) Yu, C.-C.; Chou, S.-Y.; Tseng, Y.-C.; Tseng, S.-C.; Yen, Y.-T.; Chen, H.-L. Single-shot laser treatment provides quasi-three-dimensional paper-based substrates for SERS with attomolar sensitivity. Nanoscale 2015, 7 (5), 1667-1677.
(96) Li, C.; Huang, Y.; Lai, K.; Rasco, B. A.; Fan, Y. Analysis of trace methylene blue in fish muscles using ultra-sensitive surface-enhanced Raman spectroscopy. Food Control 2016, 65, 99-105.
(97) Blumenthal, K. G.; Ryan, E. E.; Li, Y.; Lee, H.; Kuhlen, J. L.; Shenoy, E. S. The impact of a reported penicillin allergy on surgical site infection risk. Clinical Infectious Diseases 2018, 66 (3), 329-336.
(98) Zawertailo, L.; Hendershot, C. S.; Tyndale, R. F.; Le Foll, B.; Samokhvalov, A. V.; Thorpe, K. E.; Pipe, A.; Reid, R. D.; Selby, P. Personalized dosing of nicotine replacement therapy versus standard dosing for the treatment of individuals with tobacco dependence: study protocol for a randomized placebo-controlled trial. Trials 2020, 21 (1), 1-11.
(99) Wei, T.-Y.; Yen, T.-H.; Cheng, C.-M. Point-of-care testing in the early diagnosis of acute pesticide intoxication: The example of paraquat. Biomicrofluidics 2018, 12 (1), 011501.
(100) Caffarelli, A. D.; Holden, J. P.; Baron, E. J.; Lemmens, H. J.; D’Souza, H.; Yau, V.; Olcott IV, C.; Reitz, B. A.; Miller, D. C.; van der Starre, P. J. Plasma cefazolin levels during cardiovascular surgery: effects of cardiopulmonary bypass and profound hypothermic circulatory arrest. The Journal of Thoracic and Cardiovascular Surgery 2006, 131 (6), 1338-1343.
(101) Sweeney, C. T.; Fant, R. V.; Fagerstrom, K. O.; McGovern, J. F.; Henningfield, J. E. Combination nicotine replacement therapy for smoking cessation. CNS drugs 2001, 15 (6), 453-467.
(102) Kuan, C.-M.; Lin, S.-T.; Yen, T.-H.; Wang, Y.-L.; Cheng, C.-M. based diagnostic devices for clinical paraquat poisoning diagnosis. Biomicrofluidics 2016, 10 (3), 034118.
(103) Ganeshvar, P.; Gunasekaran, S.; Gnanasambandan, T.; Viswanathan, K. Cefalexin: molecular structure, vibrational spectroscopy, natural bond orbital analysis and HOMO, LUMO studies. Int. J. Sci. Res. 2015, 4 (10), 182-189.
(104) Li, C.; Lin, W.; Shao, Y.; Feng, Y. Application of Pretreatments in Prediction Models of Raman Spectra. In 2013 5th International Conference on Intelligent Human-Machine Systems and Cybernetics, 2013; IEEE: Vol. 2, pp 482-485.
(105) Mamián-López, M. B.; Poppi, R. J. Standard addition method applied to the urinary quantification of nicotine in the presence of cotinine and anabasine using surface enhanced Raman spectroscopy and multivariate curve resolution. Analytica chimica acta 2013, 760, 53-59.
(106) Fang, H.; Zhang, X.; Zhang, S. J.; Liu, L.; Zhao, Y. M.; Xu, H. J. Ultrasensitive and quantitative detection of paraquat on fruits skins via surface-enhanced Raman spectroscopy. Sensors and Actuators B: Chemical 2015, 213, 452-456.
(107) Botta, R.; Eiamchai, P.; Horprathum, M.; Limwichean, S.; Chananonnawathorn, C.; Patthanasettakul, V.; Maezono, R.; Jomphoak, A.; Nuntawong, N. 3D structured laser engraves decorated with gold nanoparticle SERS chips for paraquat herbicide detection in environments. Sensors and Actuators B: Chemical 2020, 304, 127327.
(108) Hukkanen, J.; Jacob, P.; Benowitz, N. L. Metabolism and disposition kinetics of nicotine. Pharmacological reviews 2005, 57 (1), 79-115.
(109) Movasaghi, Z.; Rehman, S.; Rehman, I. U. Raman spectroscopy of biological tissues. Applied Spectroscopy Reviews 2007, 42 (5), 493-541.
(110) Brauchle, E.; Knopf, A.; Bauer, H.; Shen, N.; Linder, S.; Monaghan, M. G.; Ellwanger, K.; Layland, S. L.; Brucker, S. Y.; Nsair, A. Non-invasive chamber-specific identification of cardiomyocytes in differentiating pluripotent stem cells. Stem Cell Reports 2016, 6 (2), 188-199.