高分子微針有良好的給藥效率及無痛等諸多優點，是經皮給藥領域的研究熱點。本研究主要為開發具有不同釋放行為模式之高分子微針，並應用於經皮傳遞藥物及抗原。研究分為兩大部份：第一部份為包覆表沒食子兒茶素沒食子酸酯(Epigallocatechin gallate, EGCG)/L-抗壞血酸(L-ascorbic acid, AA)之快溶型聚麩胺酸微針，用於治療患有異位性皮膚炎的小鼠；第二部份則為開發具有快速和緩慢釋放行為的玻尿酸鈉/幾丁聚醣複合微針，做為單劑疫苗接種之劑型。
第一部份：異位性皮膚炎是一種常見的慢性皮膚發炎疾病，第二型輔助T細胞型(T helper type 2, Th2)為主的免疫反應與氧化壓力是致病的關鍵因素。以聚麩胺酸製成的微針具有免疫調節作用，可幫助下調Th2型免疫反應，緩解小鼠的異位性皮膚炎症狀。具有抗氧化與抗發炎活性的EGCG亦有治療氧化壓力引起的發炎性疾病的潛力。然而，EGCG本身之不穩定性大大限制了其生物可利用率與臨床療效。聚麩胺酸微針的包覆可有效地維持EGCG的穩定性，保護EGCG不被氧化，並標地傳輸到皮膚真皮層中，藉此改善異位性皮膚炎病症。將EGCG包覆在聚麩胺酸微針中，並利用AA作為穩定劑，儲存於4 oC下四週後，仍可維持95 %的EGCG穩定性及93 %的抗氧化活性。將此微針應用於患有異位性皮膚炎之Nc/Nga小鼠上，每週給藥一次並連續四週，可顯著降低血清中的Immunoglobulin E (IgE)及組織胺(Histamine)濃度，並抑制Interferon-γ (IFN-γ)和Th2型細胞因子(Cytokine)的產生，有效地改善皮膚發炎之症狀與表皮增厚情形。每週一次的微針給藥方式可達到與每日塗抹EGCG + AA溶液相同的治療效果，但卻能大大地降低了給藥頻率和所需劑量。
第二部份：許多傳統的疫苗，由於免疫效力不足，通常都需要接種多劑才能引起足夠強度的免疫保護力，但這對於施打疫苗的人來說是非常不方便的。因此，增強對疫苗的免疫反應並最大限度地減少重覆接種的需要是臨床上疫苗接種中的一大挑戰。第二部份開發了一款複合式微針，由玻尿酸鈉針尖與幾丁聚醣主體組成，用於快速及緩慢釋放抗原，並評估此種微針劑型作為單劑免疫接種劑型的潛力。將微針插入皮膚後，快溶型的玻尿酸鈉針尖溶解在皮膚內，迅速地釋放被包覆的抗原，從而啟動免疫系統，而生物可降解的幾丁聚醣主體則留在真皮層中，延長抗原釋放時間長達4週，進一步增強被刺激的免疫反應。從結果中證實，與傳統上的兩劑量(100 μg × 2)或雙倍劑量(200 μg × 1)皮下注射接種相比，使用包覆卵清蛋白之玻尿酸鈉/幾丁聚醣複合微針(100 μg × 1)進行單次免疫，可刺激大鼠產生第一型輔助T細胞(T helper type 1, Th1)型與Th2型免疫反應且誘導更高、更持久的免疫抗體濃度。此款微針的Prime-Boost免疫接種策略及佐劑效用，大大增强了抗原的免疫原性，達到更佳的免疫效力。
本研究所使用的高分子微針可以有效地經皮傳遞藥物及抗原進入皮膚真皮層中，避免藥物與抗原遭受外界環境因素的破壞，且避免了口服途徑會有的胃腸道藥物破壞問題。第一部份的快溶型聚麩胺酸微針，包覆EGCG及AA，不僅能提供聚麩胺酸的免疫調節功效，同時藉由EGCG的抗氧化及抗發炎效用，有效地緩解小鼠的異位性皮膚炎病症。第二部份的玻尿酸鈉/幾丁聚醣複合微針，具有快速和緩慢釋放行為，此單劑接種劑型可引發較傳統針劑注射更強大與持久的免疫反應，減少多次接種疫苗的需要。此兩部份的研究成果証實，本研究可依臨床需求及藥物種類，設計出適合的高分子微針劑型，很有潛力取代以往的治療或接種方式，成為新一代的經皮給藥技術。

The polymeric microneedles used in this study can effectively deliver drugs and antigens transdermally into the dermis, avoid damage to the drugs and antigens by external environmental factors, and avoid the destruction of drugs in the gastrointestinal tract caused by oral routes. In the first part, dissolving poly-γ-glutamate–based microneedles encapsulating EGCG and AA not only provided the immunomodulatory effects of poly-γ-glutamate but also effectively alleviated atopic dermatitis in mice through the antioxidant and anti-inflammatory effects of EGCG. In the second part, sodium hyaluronate/chitosan composite microneedles with rapid and sustained release behaviors were a single-dose inoculation formulation that induced higher and more durable immune responses than traditional injections, thus reducing the need for multiple vaccinations. The research results of these two parts confirmed that this study designed a suitable polymeric microneedle formulation according to clinical needs and drug types, and had the potential to replace previous treatments or inoculations as a new generation of transdermal drug delivery systems.

[1] Y. Hao, W. Li, X.L. Zhou, F. Yang, Z.Y. Qian, Microneedles-based transdermal drug delivery systems: a review, Journal of Biomedical Nanotechnology 13(12) (2017) 1581-1597.
[2] T.M. Blicharz, P. Gong, B.M. Bunner, L.L. Chu, K.M. Leonard, J.A. Wakefield, R.E. Williams, M. Dadgar, C.A. Tagliabue, R. El Khaja, Microneedle-based device for the one-step painless collection of capillary blood samples, Nature Biomedical Engineering 2(3) (2018) 151-157.
[3] T. Liu, G. Luo, M. Xing, Biomedical applications of polymeric microneedles for transdermal therapeutic delivery and diagnosis: current status and future perspectives, Advanced Therapeutics 3(9) (2020) 1900140.
[4] K. van der Maaden, W. Jiskoot, J. Bouwstra, Microneedle technologies for (trans) dermal drug and vaccine delivery, Journal of Controlled Release 161(2) (2012) 645-655.
[5] M.H. Ling, M.C. Chen, Dissolving polymer microneedle patches for rapid and efficient transdermal delivery of insulin to diabetic rats, Acta Biomaterialia 9(11) (2013) 8952-8961.
[6] M. He, G. Yang, S. Zhang, X. Zhao, Y. Gao, Dissolving microneedles loaded with etonogestrel microcrystal particles for intradermal sustained delivery, Journal of Pharmaceutical Sciences 107(4) (2018) 1037-1045.
[7] P. Singh, A. Carrier, Y. Chen, S. Lin, J. Wang, S. Cui, X. Zhang, Polymeric microneedles for controlled transdermal drug delivery, Journal of Controlled Release 315 (2019) 97-113.
[8] W. Li, R.N. Terry, J. Tang, M.R. Feng, S.P. Schwendeman, M.R. Prausnitz, Rapidly separable microneedle patch for the sustained release of a contraceptive, Nature Biomedical Engineering 3(3) (2019) 220-229.
[9] J. Yu, Y. Zhang, Y. Ye, R. DiSanto, W. Sun, D. Ranson, F.S. Ligler, J.B. Buse, Z. Gu, Microneedle-array patches loaded with hypoxia-sensitive vesicles provide fast glucose-responsive insulin delivery, Proceedings of the National Academy of Sciences 112(27) (2015) 8260-8265.
[10] M.C. Chen, Z.W. Lin, M.H. Ling, Near-infrared light-activatable microneedle system for treating superficial tumors by combination of chemotherapy and photothermal therapy, ACS Nano 10(1) (2016) 93-101.
[11] S. Stander, Atopic dermatitis, The New England Journal of Medicine 384(12) (2021) 1136-1143.
[12] S.M. Langan, A.D. Irvine, S. Weidinger, Atopic dermatitis, The Lancet 396(10247) (2020) 345-360.
[13] N. Sivaranjani, S. Venkata Rao, G. Rajeev, Role of reactive oxygen species and antioxidants in atopic dermatitis, Journal of Clinical and Diagnostic Research 7(12) (2013) 2683-2685.
[14] S. Weidinger, L.A. Beck, T. Bieber, K. Kabashima, A.D. Irvine, Atopic dermatitis, Nature Reviews Disease Primers 4(1) (2018) 1.
[15] T. Kouro, K. Takatsu, IL-5-and eosinophil-mediated inflammation: from discovery to therapy, International Immunology 21(12) (2009) 1303-1309.
[16] K.D. Stone, C. Prussin, D.D. Metcalfe, IgE, mast cells, basophils, and eosinophils, Journal of Allergy and Clinical Immunology 125(2) (2010) S73-S80.
[17] Y.Y. Sung, A.Y. Lee, H.K. Kim, The gardenia jasminoides extract and its constituent, geniposide, elicit anti-allergic effects on atopic dermatitis by inhibiting histamine in vitro and in vivo, Journal of Ethnopharmacology 156 (2014) 33-40.
[18] T. Bierber, Mechanisms of disease: atopic dermatitis, New England Journal of Medicine 358(14) (2008) 1483-1494.
[19] D. Hijnen, E.F. Knol, Y.Y. Gent, B. Giovannone, S.J.P. Beijn, T.S. Kupper, C.A.F.M. Bruijnzeel-Koomen, R.A. Clark, CD8+ T cells in the lesional skin of atopic dermatitis and psoriasis patients are an important source of IFN-γ, IL-13, IL-17, and IL-22, Journal of Investigative Dermatology 133(4) (2013) 973-979.
[20] M. Yamamoto, T. Haruna, K. Yasui, H. Takahashi, M. Iduhara, S. Takaki, M. Deguchi, A. Arimura, A novel atopic dermatitis model induced by topical application with dermatophagoides farinae extract in Nc/Nga mice, Allergology International 56(2) (2007) 139-148.
[21] H. Kang, C.H. Lee, J.R. Kim, J.Y. Kwon, M.J. Son, J.E. Kim, K.W. Lee, Theobroma cacao extract attenuates the development of dermatophagoides farinae-induced atopic dermatitis-like symptoms in Nc/Nga mice, Food Chemistry 216 (2017) 19-26.
[22] Y. Souwer, K. Szegedi, M.L. Kapsenberg, E.C. de Jong, IL-17 and IL-22 in atopic allergic disease, Current Opinion in Immunology 22(6) (2010) 821-826.
[23] J. Klonowska, J. Gleń, R.J. Nowicki, M. Trzeciak, New cytokines in the pathogenesis of atopic dermatitis—new therapeutic targets, International Journal of Molecular Sciences 19(10) (2018) 3086.
[24] A. Cavani, D. Pennino, K. Eyerich, Th17 and Th22 in skin allergy, New Trends in Allergy and Atopic Eczema, Karger Publishers2012, pp. 39-44.
[25] H. Fujita, The role of IL-22 and Th22 cells in human skin diseases, Journal of Dermatological science 72(1) (2013) 3-8.
[26] W. Jin, C. Dong, IL-17 cytokines in immunity and inflammation, Emerging Microbes & Infections 2(1) (2013) 1-5.
[27] S. Weidinger, N. Novak, Atopic dermatitis, The Lancet 387(10023) (2016) 1109-1122.
[28] Q.Q. Yang, X.L. Wei, Y.P. Fang, R.Y. Gan, M. Wang, Y.Y. Ge, D. Zhang, L.Z. Cheng, H. Corke, Nanochemoprevention with therapeutic benefits: an updated review focused on epigallocatechin gallate delivery, Critical Reviews in Food Science and Nutrition 60(8) (2020) 1243-1264.
[29] A. Chiricozzi, P. Comberiati, E. D’Auria, G. Zuccotti, D.G. Peroni, Topical corticosteroids for pediatric atopic dermatitis: thoughtful tips for practice, Pharmacological Research 158 (2020) 104878.
[30] E.F. Wallin, D.L. Hill, M.A. Linterman, K.J. Wood, The calcineurin inhibitor tacrolimus specifically suppresses human T follicular helper cells, Frontiers in Immunology 9 (2018) 1184.
[31] R. Li, S. Hadi, E. Guttman-Yassky, Current and emerging biologic and small molecule therapies for atopic dermatitis, Expert Opinion on Biological Therapy 19(4) (2019) 367-380.
[32] E.E. Golli-Bennour, H. Bacha, Hsp70 expression as biomarkers of oxidative stress: mycotoxins’ exploration, Toxicology 287(1-3) (2011) 1-7.
[33] G. Pizzino, N. Irrera, M. Cucinotta, G. Pallio, F. Mannino, V. Arcoraci, F. Squadrito, D. Altavilla, A. Bitto, Oxidative stress: harms and benefits for human health, Oxidative Medicine and Cellular Longevity 2017 (2017) 8416763.
[34] H. Ji, X.K. Li, Oxidative stress in atopic dermatitis, Oxidative Medicine and Cellular Longevity 2016 (2016) 2721469.
[35] I. Liguori, G. Russo, F. Curcio, G. Bulli, L. Aran, D. Della-Morte, G. Gargiulo, G. Testa, F. Cacciatore, D. Bonaduce, P. Abete, Oxidative stress, aging, and diseases, Clinical Interventions in Aging 13 (2018) 757-772.
[36] D.K. Kim, H.S. Kim, A.R. Kim, J.H. Kim, B. Kim, G. Noh, H.S. Kim, M.A. Beaven, Y.M. Kim, W.S. Choi, DJ-1 regulates mast cell activation and IgE-mediated allergic responses, Journal of Allergy and Clinical Immunology 131(6) (2013) 1653-1662.e1.
[37] E.L. Yarosz, C.H. Chang, The role of reactive oxygen species in regulating T cell-mediated immunity and disease, Immune Network 18(1) (2018) e14.
[38] B. Frossi, M. De Carli, M. Piemonte, C. Pucillo, Oxidative microenvironment exerts an opposite regulatory effect on cytokine production by Th1 and Th2 cells, Molecular Immunology 45(1) (2008) 58-64.
[39] J.H. Heo, Y. Heo, H.J. Lee, M. Kim, H.Y. Shin, Topical anti-inflammatory and anti-oxidative effects of porcine placenta extracts on 2,4-dinitrochlorobenzene-induced contact dermatitis, BMC Complementary and Alternative Medicine 18(1) (2018) 1-9.
[40] S. Jang, J. Ohn, J.W. Kim, S.M. Kang, D. Jeon, C.Y. Heo, Y.S. Lee, O. Kwon, K.H. Kim, Caffeoyl–Pro–His amide relieve DNCB-induced atopic dermatitis-like phenotypes in Balb/c mice, Scientific Reports 10(1) (2020) 1-9.
[41] M. Biagiotti, G. Borghese, P. Francescato, C.F. Morelli, A.M. Albertini, T. Bavaro, D. Ubiali, R. Mendichi, G. Speranza, Esterification of poly (γ-glutamic acid)(γ-PGA) mediated by its tetrabutylammonium salt, RSC Advances 6(50) (2016) 43954-43958.
[42] S.J. Park, H. Uyama, M.S. Kwak, M.H. Sung, Comparison of the stability of poly-γ-glutamate hydrogels prepared by UV and γ-ray irradiation, Journal of Microbiology and Biotechnology 29(7) (2019) 1078-1082.
[43] H. Poo, C. Park, M.S. Kwak, D.Y. Choi, S.P. Hong, I.H. Lee, Y.T. Lim, Y.K. Choi, S.R. Bae, H. Uyama, C.J. Kim, M.H. Sung, New biological functions and applications of high‐molecular‐mass poly‐γ‐glutamic acid, Chemistry & Biodiversity 7(6) (2010) 1555-1562.
[44] T.W. Kim, T.Y. Lee, H.C. Bae, J.H. Hahm, Y.H. Kim, C. Park, T.H. Kang, C.J. Kim, M.H. Sung, H. Poo, Oral administration of high molecular mass poly-γ-glutamate induces NK cell-mediated antitumor immunity, The Journal of Immunology 179(2) (2007) 775-780.
[45] T.Y. Lee, Y.H. Kim, S.W. Yoon, J.C. Choi, J.M. Yang, C.J. Kim, J.T. Schiller, M.H. Sung, H. Poo, Oral administration of poly-gamma-glutamate induces TLR4-and dendritic cell-dependent antitumor effect, Cancer Immunology, Immunotherapy 58(11) (2009) 1781.
[46] M.B. Hershenson, Rhinovirus-induced exacerbations of asthma and COPD, Scientifica 2013 (2013) 405876.
[47] T.Y. Lee, D.J. Kim, J.N. Won, I.H. Lee, M.H. Sung, H. Poo, Oral administration of poly-γ-glutamate ameliorates atopic dermatitis in Nc/Nga mice by suppressing Th2-biased immune response and production of IL-17A, Journal of Investigative Dermatology 134(3) (2014) 704-711.
[48] M.C. Chen, C.S. Chen, Y.W. Wu, Y.Y. Yang, Poly-γ-glutamate microneedles as transdermal immunomodulators for ameliorating atopic dermatitis-like skin lesions in Nc/Nga mice, Acta Biomaterialia 114 (2020) 183-192.
[49] R.Y. Gan, H.B. Li, Z.Q. Sui, H. Corke, Absorption, metabolism, anti-cancer effect and molecular targets of epigallocatechin gallate (EGCG): an updated review, Critical Reviews in Food Science and Nutrition 58(6) (2018) 924-941.
[50] B.N. Singh, S. Shankar, R.K. Srivastava, Green tea catechin, epigallocatechin-3-gallate (EGCG): mechanisms, perspectives and clinical applications, Biochemical Pharmacology 82(12) (2011) 1807-1821.
[51] M. Muzolf-Panek, A. Gliszczyńska-Świgło, H. Szymusiak, B. Tyrakowska, The influence of stereochemistry on the antioxidant properties of catechin epimers, European Food Research and Technology 235(6) (2012) 1001-1009.
[52] J. Zhang, S. Nie, S. Wang, Nanoencapsulation enhances epigallocatechin-3-gallate stability and its antiatherogenic bioactivities in macrophages, Journal of Agricultural and Food Chemistry 61(38) (2013) 9200-9209.
[53] T. Unno, T. Takeo, Absorption of (–)-epigallocatechin gallate into the circulation system of rats, Bioscience, Biotechnology, and Biochemistry 59(8) (1995) 1558-1559.
[54] O. Krupkova, S.J. Ferguson, K. Wuertz-Kozak, Stability of (−)-epigallocatechin gallate and its activity in liquid formulations and delivery systems, The Journal of Nutritional Biochemistry 37 (2016) 1-12.
[55] K. Nakagawa, T. Miyazawa, Chemiluminescence–high-performance liquid chromatographic determination of tea catechin,(−)-epigallocatechin 3-gallate, at picomole levels in rat and human plasma, Analytical Biochemistry 248(1) (1997) 41-49.
[56] T.W. Huang, Y.C. Ho, T.N. Tsai, C.L. Tseng, C. Lin, F.L. Mi, Enhancement of the permeability and activities of epigallocatechin gallate by quaternary ammonium chitosan/fucoidan nanoparticles, Carbohydrate Polymers 242 (2020) 116312.
[57] J. Zeng, H. Xu, Y. Cai, Y. Xuan, J. Liu, Y. Gao, Q. Luan, The effect of ultrasound, oxygen and sunlight on the stability of (−)-epigallocatechin gallate, Molecules 23(9) (2018) 2394.
[58] S. Legeay, M. Rodier, L. Fillon, S. Faure, N. Clere, Epigallocatechin gallate: a review of its beneficial properties to prevent metabolic syndrome, Nutrients 7(7) (2015) 5443-5468.
[59] C. Minnelli, R. Galeazzi, E. Laudadio, A. Amici, D. Rusciano, T. Armeni, M. Cantarini, P. Stipa, G. Mobbili, Monoalkylated epigallocatechin-3-gallate (C18-EGCG) as novel lipophilic EGCG derivative: characterization and antioxidant evaluation, Antioxidants 9(3) (2020) 208.
[60] Y. Teng, J. Zhao, L. Ding, Y. Ding, P. Zhou, Complex of EGCG with Cu (II) suppresses amyloid aggregation and Cu (II)-induced cytotoxicity of α-synuclein, Molecules 24(16) (2019) 2940.
[61] A. Singh, S. Holvoet, A. Mercenier, Dietary polyphenols in the prevention and treatment of allergic diseases, Clinical & Experimental Allergy 41(10) (2011) 1346-1359.
[62] S.U. Noh, E.A. Cho, H.O. Kim, Y.M. Park, Epigallocatechin-3-gallate improves dermatophagoides pteronissinus extract-induced atopic dermatitis-like skin lesions in Nc/Nga mice by suppressing macrophage migration inhibitory factor, International Immunopharmacology 8(9) (2008) 1172-1182.
[63] S.C. Ahn, G.Y. Kim, J.H. Kim, S.W. Baik, M.K. Han, H.J. Lee, D.O. Moon, C.M. Lee, J.H. Kang, B.H. Kim, Y.H. Oh, Y.M. Park, Epigallocatechin-3-gallate, constituent of green tea, suppresses the LPS-induced phenotypic and functional maturation of murine dendritic cells through inhibition of mitogen-activated protein kinases and NF-κB, Biochemical and Biophysical Research Communications 313(1) (2004) 148-155.
[64] E.B. Byun, H.G. Choi, N.Y. Sung, E.H. Byun, Green tea polyphenol epigallocatechin-3-gallate inhibits TLR4 signaling through the 67-kDa laminin receptor on lipopolysaccharide-stimulated dendritic cells, Biochemical and Biophysical Research Communications 426(4) (2012) 480-485.
[65] J. Rogers, I. Perkins, A.v. Olphen, N. Burdash, T.W. Klein, H. Friedman, Epigallocatechin gallate modulates cytokine production by bone marrow-derived dendritic cells stimulated with lipopolysaccharide or muramyldipeptide, or infected with Legionella pneumophila, Experimental Biology and Medicine 230(9) (2005) 645-651.
[66] D. Wu, Z. Guo, Z. Ren, W. Guo, S.N. Meydani, Green tea EGCG suppresses T cell proliferation through impairment of IL-2/IL-2 receptor signaling, Free Radical Biology and Medicine 47(5) (2009) 636-643.
[67] C.P. Wong, L.P. Nguyen, S.K. Noh, T.M. Bray, R.S. Bruno, E. Ho, Induction of regulatory T cells by green tea polyphenol EGCG, Immunology Letters 139(1-2) (2011) 7-13.
[68] D. Liu, X. Zhang, L. Jiang, Y. Guo, C. Zheng, Epigallocatechin-3-gallate (EGCG) attenuates concanavalin A-induced hepatic injury in mice, Acta Histochemica 116(4) (2014) 654-662.
[69] H.Y. Shin, S.H. Kim, H.J. Jeong, S.Y. Kim, T.Y. Shin, J.Y. Um, S.H. Hong, H.M. Kim, Epigallocatechin-3-gallate inhibits secretion of TNF-α, IL-6 and IL-8 through the attenuation of ERK and NF-κB in HMC-1 cells, International Archives of Allergy and Immunology 142(4) (2007) 335-344.
[70] N. Yang, H. Zhang, X. Cai, Y. Shang, Epigallocatechin-3-gallate inhibits inflammation and epithelialmesenchymal transition through the PI3K/AKT pathway via upregulation of PTEN in asthma, International Journal of Molecular Medicine 41(2) (2018) 818-828.
[71] E. Hassanain, J.I. Silverberg, K.B. Norowitz, S. Chice, M.H. Bluth, N. Brody, R. Joks, H.G. Durkin, T.A. Smith-Norowitz, Green tea (camelia sinensis) suppresses B cell production of IgE without inducing apoptosis, Annals of Clinical & Laboratory Science 40(2) (2010) 135-143.
[72] T. Inoue, Y. Suzuki, C. Ra, Epigallocatechin-3-gallate inhibits mast cell degranulation, leukotriene C4 secretion, and calcium influx via mitochondrial calcium dysfunction, Free Radical Biology and Medicine 49(4) (2010) 632-640.
[73] K. Yamashita, Y. Suzuki, T. Matsui, T. Yoshimaru, M. Yamaki, M. Suzuki-Karasaki, S. Hayakawa, K. Shimizu, Epigallocatechin gallate inhibits histamine release from rat basophilic leukemia (RBL-2H3) cells: role of tyrosine phosphorylation pathway, Biochemical and Biophysical Research Communications 274(3) (2000) 603-608.
[74] Y. Fujimura, D. Umeda, Y. Kiyohara, Y. Sunada, K. Yamada, H. Tachibana, The involvement of the 67 kDa laminin receptor-mediated modulation of cytoskeleton in the degranulation inhibition induced by epigallocatechin-3-O-gallate, Biochemical and Biophysical Research Communications 348(2) (2006) 524-531.
[75] G.Z. Li, O.H. Chai, C.H. Song, Inhibitory effects of epigallocatechin gallate on compound 48/80-inducedmast cell activation and passive cutaneous anaphylaxis, Experimental & Molecular Medicine 37(4) (2005) 290-296.
[76] K. Amin, The role of mast cells in allergic inflammation, Respiratory Medicine 106(1) (2012) 9-14.
[77] M.A. Moser, O.K. Chun, Vitamin C and heart health: a review based on findings from epidemiologic studies, International Journal of Molecular Sciences 17(8) (2016) 1328.
[78] K. Wang, H. Jiang, W. Li, M. Qiang, T. Dong, H. Li, Role of vitamin C in skin diseases, Frontiers in Physiology 9 (2018) 819.
[79] R. Zuo, S. Zhou, Y. Zuo, Y. Deng, Determination of creatinine, uric and ascorbic acid in bovine milk and orange juice by hydrophilic interaction HPLC, Food Chemistry 182 (2015) 242-245.
[80] J.M. Pullar, A.C. Carr, M.C.M. Vissers, The roles of vitamin C in skin health, Nutrients 9(8) (2017) 866.
[81] S.B. Nimse, D. Pal, Free radicals, natural antioxidants, and their reaction mechanisms, RSC Advances 5(35) (2015) 27986-28006.
[82] Y. Liu, C. Liu, J. Li, Comparison of vitamin C and its derivative antioxidant activity: evaluated by using density functional theory, ACS Omega 5(39) (2020) 25467-25475.
[83] L. Chen, W. Wang, J. Zhang, H. Cui, D. Ni, H. Jiang, Dual effects of ascorbic acid on the stability of EGCG by the oxidation product dehydroascorbic acid promoting the oxidation and inhibiting the hydrolysis pathway, Food Chemistry 337 (2021) 127639.
[84] K.M. Walingo, Role of vitamin C (ascorbic acid) on human health-a review, African Journal of Food, Agriculture, Nutrition and Development 5(1) (2005) 2005.
[85] M. Varvara, G. Bozzo, G. Celano, C. Disanto, C.N. Pagliarone, G.V. Celano, The use of ascorbic acid as a food additive: technical-legal issues, Italian Journal of Food Safety 5(1) (2016) 4313.
[86] Y. Nir, A. Paz, E. Sabo, I. Potasman, Fear of injections in young adults: prevalence and associations, The American Journal of Tropical Medicine and Hygiene 68(3) (2003) 341-344.
[87] P. Karande, S. Mitragotri, Transcutaneous immunization: an overview of advantages, disease targets, vaccines, and delivery technologies, Annual Review of Chemical and Biomolecular Engineering 1 (2010) 175-201.
[88] M.Y. Lee, M.C. Shin, V.C. Yang, Transcutaneous antigen delivery system, BMB Reports 46(1) (2013) 17-24.
[89] K.H.G. Mills, Regulatory T cells: friend or foe in immunity to infection?, Nature Reviews Immunology 4(11) (2004) 841-855.
[90] T.S. Kupper, R.C. Fuhlbrigge, Immune surveillance in the skin: mechanisms and clinical consequences, Nature Reviews Immunology 4(3) (2004) 211-222.
[91] S. Lee, M.T. Nguyen, Recent advances of vaccine adjuvants for infectious diseases, Immune Network 15(2) (2015) 51.
[92] B. Pulendran, P.S. Arunachalam, D.T. O’Hagan, Emerging concepts in the science of vaccine adjuvants, Nature Reviews Drug Discovery 20 (2021) 454-475.
[93] E. Nanishi, D.J. Dowling, O. Levy, Toward precision adjuvants: optimizing science and safety, Current Opinion in Pediatrics 32(1) (2020) 125-138.
[94] J.A. Burdick, G.D. Prestwich, Hyaluronic acid hydrogels for biomedical applications, Advanced Materials 23(12) (2011) H41-H56.
[95] N.M. Salwowska, K.A. Bebenek, D.A. Żądło, D.L. Wcisło‐Dziadecka, Physiochemical properties and application of hyaluronic acid: a systematic review, Journal of Cosmetic Dermatology 15(4) (2016) 520-526.
[96] M.B. Brown, S.A. Jones, Hyaluronic acid: a unique topical vehicle for the localized delivery of drugs to the skin, Journal of the European Academy of Dermatology and Venereology 19(3) (2005) 308-318.
[97] E. Papakonstantinou, M. Roth, G. Karakiulakis, Hyaluronic acid: a key molecule in skin aging, Dermatoendocrinology 4(3) (2012) 253-258.
[98] H. Obata, Y. Yamazaki, T. Matsunaga, T. Sato, Synthesis and evaluation of hyaluronic acid hydrogels modified with various crosslinkers as biodegradable polymers, Journal of Applied Polymer Science 134(43) (2017) 45453.
[99] J. Necas, L. Bartosikova, P. Brauner, J. Kolar, Hyaluronic acid (hyaluronan): a review, Veterinarni Medicina 53(8) (2008) 397-411.
[100] LGC Limited, Sodium Hyaluronate, 2021. https://is.gd/WU2X5S. (Accessed 08/09 2021).
[101] R. Rodríguez‐Rodríguez, Z.Y. García‐Carvajal, I. Jiménez‐Palomar, J.A. Jiménez‐Avalos, H. Espinosa‐Andrews, Development of gelatin/chitosan/PVA hydrogels: thermal stability, water state, viscoelasticity, and cytotoxicity assays, Journal of Applied Polymer Science 136(10) (2019) 47149.
[102] V.M. Gaspar, A.F. Moreira, D. de Melo-Diogo, E.C. Costa, J.A. Queiroz, F. Sousa, C. Pichon, I.J. Correia, Multifunctional nanocarriers for codelivery of nucleic acids and chemotherapeutics to cancer cells, Nanobiomaterials in Medical Imaging, Elsevier2016, pp. 163-207.
[103] P.N. Dave, A. Gor, Natural polysaccharide-based hydrogels and nanomaterials: recent trends and their applications, Handbook of Nanomaterials for Industrial Applications, Elsevier2018, pp. 36-66.
[104] M.S. Hasnain, A.K. Nayak, Chitosan as responsive polymer for drug delivery applications, Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications, Elsevier2018, pp. 581-605.
[105] N.G. Kandile, H.T. Zaky, M.I. Mohamed, A.S. Nasr, Y.G. Ali, Extraction and characterization of chitosan from shrimp shells, Open Journal of Organic Polymer Materials 8(3) (2018) 33-42.
[106] E.C. Carroll, L. Jin, A. Mori, N. Muñoz-Wolf, E. Oleszycka, H.B.T. Moran, S. Mansouri, C.P. McEntee, E. Lambe, E.M. Agger, P. Andersen, C. Cunningham, P. Hertzog, K.A. Fitzgerald, A.G. Bowie, E.C. Lavelle, The vaccine adjuvant chitosan promotes cellular immunity via DNA sensor cGAS-STING-dependent induction of type I interferons, Immunity 44(3) (2016) 597-608.
[107] Z.B. Wang, P. Shan, S.Z. Li, Y. Zhou, X. Deng, J.L. Li, Y. Zhang, J.S. Gao, J. Xu, The mechanism of action of acid-soluble chitosan as an adjuvant in the formulation of nasally administered vaccine against HBV, RSC Advances 6(99) (2016) 96785-96797.
[108] T. Strixner, U. Kulozik, Egg proteins, Handbook of Food Proteins, Elsevier2011, pp. 150-209.
[109] B.P. Chay Pak Ting, Y. Pouliot, S.F. Gauthier, Y. Mine, Fractionation of egg proteins and peptides for nutraceutical applications, Separation, Extraction and Concentration Processes in the Food, Beverage and Nutraceutical Industries, Elsevier2013, pp. 595-618.
[110] W. Yang, Z. Tu, H. Wang, L. Zhang, Y. Gao, X. Li, M. Tian, Immunogenic and structural properties of ovalbumin treated by pulsed electric fields, International Journal of Food Properties 20(sup3) (2017) S3164-S3176.
[111] M.K. Sharif, M. Saleem, K. Javed, Food Materials Science in Egg Powder Industry, Role of Materials Science in Food Bioengineering, Elsevier2018, pp. 505-537.
[112] T. Nakahara, M. Kido‐Nakahara, G. Tsuji, M. Furue, Basics and recent advances in the pathophysiology of atopic dermatitis, The Journal of Dermatology 48(2) (2021) 130-139.
[113] T. Tempark, V. Phatarakijnirund, S. Chatproedprai, S. Watcharasindhu, V. Supornsilchai, S. Wananukul, Exogenous Cushing’s syndrome due to topical corticosteroid application: case report and review literature, Endocrine 38(3) (2010) 328-334.
[114] J.A. Broeders, U.A. Ali, G. Fischer, Systematic review and meta-analysis of randomized clinical trials (RCTs) comparing topical calcineurin inhibitors with topical corticosteroids for atopic dermatitis: a 15-year experience, Journal of the American Academy of Dermatology 75(2) (2016) 410-419.e3.
[115] T. Hussain, B. Tan, Y. Yin, F. Blachier, M.C.B. Tossou, N. Rahu, Oxidative stress and inflammation: what polyphenols can do for us?, Oxidative Medicine and Cellular Longevity 2016 (2016) 7432797.
[116] S. Chirumbolo, Dietary assumption of plant polyphenols and prevention of allergy, Current Pharmaceutical Design 20(6) (2014) 811-839.
[117] J.F. Fangueiro, A. Parra, A.M. Silva, M.A. Egea, E.B. Souto, M.L. Garcia, A.C. Calpena, Validation of a high performance liquid chromatography method for the stabilization of epigallocatechin gallate, International Journal of Pharmaceutics 475(1-2) (2014) 181-190.
[118] M.C. Chen, S.F. Huang, K.Y. Lai, M.H. Ling, Fully embeddable chitosan microneedles as a sustained release depot for intradermal vaccination, Biomaterials 34(12) (2013) 3077-3086.
[119] Y.H. Chiu, M.C. Chen, S.W. Wan, Sodium hyaluronate/chitosan composite microneedles as a single-dose intradermal immunization system, Biomacromolecules 19(6) (2018) 2278-2285.
[120] Skinetrate, Trans-Epidermal Water Loss (TEWL) Test, 2021. https://is.gd/zP3DAG. (Accessed 05/14 2021).
[121] S. Dudonné, X. Vitrac, P. Coutière, M. Woillez, J.M. Mérillon, Comparative study of antioxidant properties and total phenolic content of 30 plant extracts of industrial interest using DPPH, ABTS, FRAP, SOD, and ORAC assays, Journal of Agricultural and Food Chemistry 57(5) (2009) 1768-1774.
[122] A.M. Pisoschi, G.P. Negulescu, Methods for total antioxidant activity determination: a review, Biochemistry and Analytical Biochemistry 1(1) (2011) 106.
[123] D.C. Christodouleas, C. Fotakis, A. Nikokavoura, K. Papadopoulos, A.C. Calokerinos, Modified DPPH and ABTS assays to assess the antioxidant profile of untreated oils, Food Analytical Methods 8(5) (2015) 1294-1302.
[124] S.J. Park, H.A. Lee, J.W. Kim, B.S. Lee, E.J. Kim, Platycodon grandiflorus alleviates DNCB-induced atopy-like dermatitis in NC/Nga mice, Indian Journal of Pharmacology 44(4) (2012) 469-474.
[125] H. Kim, J.R. Kim, H. Kang, J. Choi, H. Yang, P. Lee, J. Kim, K.W. Lee, 7,8,4'-Trihydroxyisoflavone attenuates DNCB-induced atopic dermatitis-like symptoms in NC/Nga mice, PLoS One 9(8) (2014) e104938.
[126] J.F. Stalder, A. Taïeb, D.J. Atherton, P. Bieber, E. Bonifazi, A. Broberg, A. Calza, R. Coleman, Y. De Prost, C. Gelmetti, A. Cuannetti, J. Harper, B. Künz, J.M. Lachapelle, T. Langeland, R. Lever, A.P. Oranje, C. Oueille-Roussel, J. Revuz, J. Ring, J.C. Roujeau, J.H. Saurat, M. Song, D. Tennstedt, D. Van Neste, D. Vieluf, M. Poncet, Severity scoring of atopic dermatitis: the SCORAD index: consensus report of the european task force on atopic dermatitis, Dermatology 186(1) (1993) 23-31.
[127] Y.J. Choi, H.J. Lee, D.H. Lee, S.Y. Woo, K.H. Lee, S.T. Yun, J.M. Kim, H.J. Kim, J.W. Kim, Therapeutic effects and immunomodulation of suanbo mineral water therapy in a murine model of atopic dermatitis, Annals of Dermatology 25(4) (2013) 462.
[128] J.M. Hanifin, M. Thurston, M. Omoto, R. Cherill, S.J. Tofte, M. Graeber, The Easi Evaluator Group, The eczema area and severity index (EASI): assessment of reliability in atopic dermatitis, Experimental Dermatology 10(1) (2001) 11-18.
[129] 楊茵茵, 以γ-PGA/PLGA雙層式微針經皮緩釋他克莫司應用於異位性皮膚炎之治療, 化學工程學系, 國立成功大學, 台灣, 2020.
[130] M. Sharma, C. Levenson, I. Clements, P. Castella, K. Gebauer, M.E. Cox, East Indian sandalwood oil (EISO) alleviates inflammatory and proliferative pathologies of psoriasis, Frontiers in Pharmacology 8 (2017) 125.
[131] Thermo Fisher Scientific, Luminex Assays, 2021. https://is.gd/tDHKyc. (Accessed 03/23 2021).
[132] Merck, Multiplex Assays Using Luminex®, 2021. https://is.gd/Z43Fen. (Accessed 03/23 2021).
[133] Houston Omics Collaborative, Luminex® Platform, 2021. https://is.gd/4MQRjb. (Accessed 03/23 2021).
[134] A. Cano, M. Ettcheto, J.H. Chang, E. Barroso, M. Espina, B.A. Kühne, M. Barenys, C. Auladell, J. Folch, E.B. Souto, A. Camins, P. Turowski, M.L. García, Dual-drug loaded nanoparticles of epigallocatechin-3-gallate (EGCG)/ascorbic acid enhance therapeutic efficacy of EGCG in a APPswe/PS1dE9 alzheimer's disease mice model, Journal of Controlled Release 301 (2019) 62-75.
[135] A.P. Neilson, B.J. Song, T.N. Sapper, J.A. Bomser, M.G. Ferruzzi, Tea catechin auto-oxidation dimers are accumulated and retained by Caco-2 human intestinal cells, Nutrition Research 30(5) (2010) 327-340.
[136] A. Dube, K. Ng, J.A. Nicolazzo, I. Larson, Effective use of reducing agents and nanoparticle encapsulation in stabilizing catechins in alkaline solution, Food Chemistry 122(3) (2010) 662-667.
[137] C.H. Salamanca, A. Barrera-Ocampo, J.C. Lasso, N. Camacho, C.J. Yarce, Franz diffusion cell approach for pre-formulation characterisation of ketoprofen semi-solid dosage forms, Pharmaceutics 10(3) (2018) 148.
[138] N. Li, L.S. Taylor, M.G. Ferruzzi, L.J. Mauer, Kinetic study of catechin stability: Effects of pH, concentration, and temperature, Journal of Agricultural and Food Chemistry 60(51) (2012) 12531-12539.
[139] Y.Q. Xu, P. Yu, W. Zhou, Combined effect of pH and temperature on the stability and antioxidant capacity of epigallocatechin gallate (EGCG) in aqueous system, Journal of Food Engineering 250 (2019) 46-54.
[140] I.R. Ilyasov, V.L. Beloborodov, I.A. Selivanova, R.P. Terekhov, ABTS/PP decolorization assay of antioxidant capacity reaction pathways, International Journal of Molecular Sciences 21(3) (2020) 1131.
[141] G.B. Golubitskii, E.V. Budko, E.M. Basova, A.V. Kostarnoi, V.M. Ivanov, Stability of ascorbic acid in aqueous and aqueous-organic solutions for quantitative determination, Journal of Analytical Chemistry 62(8) (2007) 742-747.
[142] J.P. Yuan, F. Chen, Degradation of ascorbic acid in aqueous solution, Journal of Agricultural and Food Chemistry 46(12) (1998) 5078-5082.
[143] C. Kadakal, T. Duman, R. Ekinci, Thermal degradation kinetics of ascorbic acid, thiamine and riboflavin in rosehip (Rosa canina L) nectar, Food Science and Technology 38(4) (2017) 667-673.
[144] H. Jin, R. He, M. Oyoshi, R.S. Geha, Animal models of atopic dermatitis, Journal of Investigative Dermatology 129(1) (2009) 31-40.
[145] S. Kim, S.Y. Lee, S. Bae, J.K. Lee, K. Hwang, H. Go, C.W. Lee, Pellino1 promotes chronic inflammatory skin disease via keratinocyte hyperproliferation and induction of the T helper 17 response, Experimental & Molecular Medicine 52(9) (2020) 1537-1549.
[146] K. Arima, S. Ohta, A. Takagi, H. Shiraishi, M. Masuoka, K. Ontsuka, H. Suto, S. Suzuki, K.i. Yamamoto, M. Ogawa, O. Simmons, Y. Yamaguchi, S. Toda, M. Aihara, S.J. Conway, S. Ikeda, K. Izuhara, Periostin contributes to epidermal hyperplasia in psoriasis common to atopic dermatitis, Allergology International 64(1) (2015) 41-48.
[147] T.A. Wilgus, B.C. Wulff, The importance of mast cells in dermal scarring, Advances in Wound Care 3(4) (2014) 356-365.
[148] M. Krystel-Whittemore, K.N. Dileepan, J.G. Wood, Mast cell: a multi-functional master cell, Frontiers in Immunology 6 (2016) 620.
[149] M. Metz, M. Maurer, Mast cells–key effector cells in immune responses, Trends in Immunology 28(5) (2007) 234-241.
[150] D.Y.M. Leung, Role of IgE in atopic dermatitis, Current Opinion in Immunology 5(6) (1993) 956-962.
[151] S.H. Park, J.E. An, S. Jang, J.Y. Kim, J.W. Lee, H.K. Kim, Gardenia jasminoides extract without crocin improved atopic dermatitis-like skin lesions via suppression of Th2-related cytokines in Dfe-induced Nc/Nga mice, Journal of Ethnopharmacology 241 (2019) 112015.
[152] S.J. Galli, M. Tsai, IgE and mast cells in allergic disease, Nature Medicine 18(5) (2012) 693-704.
[153] J. Knight, Y. Nigam, The lymphatic system 4: allergies, anaphylaxis and anaphylactic shock, Nursing Times 117(1) (2021) 54-58.
[154] F.T. Liu, H. Goodarzi, H.Y. Chen, IgE, mast cells, and eosinophils in atopic dermatitis, Clinical Reviews in Allergy & Immunology 41(3) (2011) 298-310.
[155] H.J. An, J.Y. Kim, W.H. Kim, M.G. Gwon, H.M. Gu, M.J. Jeon, S.M. Han, S.C. Pak, C.K. Lee, I.S. Park, K.K. Park, Therapeutic effects of bee venom and its major component, melittin, on atopic dermatitis in vivo and in vitro, British Journal of Pharmacology 175(23) (2018) 4310-4324.
[156] Y.Y. Sung, T. Yoon, J.Y. Jang, S.J. Park, G.H. Jeong, H.K. Kim, Inhibitory effects of cinnamomum cassia extract on atopic dermatitis-like skin lesions induced by mite antigen in Nc/Nga mice, Journal of Ethnopharmacology 133(2) (2011) 621-628.
[157] L. Maintz, N. Novak, Histamine and histamine intolerance, The American Journal of Clinical Nutrition 85(5) (2007) 1185-1196.
[158] L. Chen, O. Martinez, L. Overbergh, C. Mathieu, B.S. Prabhakar, L.S. Chan, Early up‐regulation of Th2 cytokines and late surge of Th1 cytokines in an atopic dermatitis model, Clinical & Experimental Immunology 138(3) (2004) 375-387.
[159] L. Tang, X. Li, L. Wan, H. Wang, Q. Mai, Z. Deng, H. Ding, Ameliorative effect of orally administered different linoleic acid/α-linolenic acid ratios in a mouse model of DNFB-induced atopic dermatitis, Journal of Functional Foods 65 (2020) 103754.
[160] H. Kanoh, A. Ishitsuka, E. Fujine, S. Matsuhaba, M. Nakamura, H. Ito, N. Inagaki, Y. Banno, M. Seishima, IFN-γ reduces epidermal barrier function by affecting fatty acid composition of ceramide in a mouse atopic dermatitis model, Journal of Immunology Research 2019 (2019) 3030268.
[161] A. Chiricozzi, M. Maurelli, K. Peris, G. Girolomoni, Targeting IL-4 for the treatment of atopic dermatitis, ImmunoTargets and Therapy 9 (2020) 151-156.
[162] D. Simon, L.R. Braathen, H.U. Simon, Eosinophils and atopic dermatitis, Allergy 59(6) (2004) 561-570.
[163] T. Bieber, Interleukin‐13: targeting an underestimated cytokine in atopic dermatitis, Allergy 75(1) (2020) 54-62.
[164] M. Kaurav, S. Minz, K. Sahu, M. Kumar, J. Madan, R.S. Pandey, Nanoparticulate mediated transcutaneous immunization: Myth or reality, Nanomedicine: Nanotechnology, Biology and Medicine 12(4) (2016) 1063-1081.
[165] I. Valdés, L. Lazo, L. Hermida, G. Guillén, L. Gil, Can complementary prime-boost immunization strategies be an alternative and promising vaccine approach against dengue virus?, Frontiers in Immunology 10 (2019) 1956.
[166] Z. Ma, L.Y. Lim, Uptake of chitosan and associated insulin in Caco-2 cell monolayers: a comparison between chitosan molecules and chitosan nanoparticles, Pharmaceutical Research 20(11) (2003) 1812-1819.
[167] H. Lee, H. Mok, S. Lee, Y.K. Oh, T.G. Park, Target-specific intracellular delivery of siRNA using degradable hyaluronic acid nanogels, Journal of Controlled Release 119(2) (2007) 245-252.
[168] P.C. DeMuth, Y. Min, D.J. Irvine, P.T. Hammond, Implantable silk composite microneedles for programmable vaccine release kinetics and enhanced immunogenicity in transcutaneous immunization, Advanced Healthcare Materials 3(1) (2014) 47-58.
[169] M. Lee, C.G. Park, B.K. Huh, S.N. Kim, S.H. Lee, R. Khalmuratova, J.W. Park, H.W. Shin, Y.B. Choy, Sinonasal delivery of resveratrol via mucoadhesive nanostructured microparticles in a nasal polyp mouse model, Scientific Reports 7(1) (2017) 1-13.
[170] M.C. Chen, K.Y. Lai, M.H. Ling, C.W. Lin, Enhancing immunogenicity of antigens through sustained intradermal delivery using chitosan microneedles with a patch-dissolvable design, Acta Biomaterialia 65 (2018) 66-75.
[171] Y.H. Chen, K.Y. Lai, Y.H. Chiu, Y.W. Wu, A.L. Shiau, M.C. Chen, Implantable microneedles with an immune-boosting function for effective intradermal influenza vaccination, Acta Biomaterialia 97 (2019) 230-238.
[172] 太鼎生物科技, 蛋白質BCA定量, 2021. https://is.gd/CCpkiz. (Accessed 08/31 2021).
[173] K.P. Mishra, S. Chanda, K. Shukla, L. Ganju, Adjuvant effect of aqueous extract of rhodiola imbricata rhizome on the immune responses to tetanus toxoid and ovalbumin in rats, Immunopharmacology and Immunotoxicology 32(1) (2010) 141-146.
[174] S. Ménard, L. Guzylack-Piriou, C. Lencina, M. Leveque, M. Naturel, S. Sekkal, C. Harkat, E. Gaultier, M. Olier, R. Garcia-Villar, Perinatal exposure to a low dose of bisphenol A impaired systemic cellular immune response and predisposes young rats to intestinal parasitic infection, PLoS One 9(11) (2014) e112752.
[175] M. Abril-Gil, A. Garcia-Just, F.J. Pérez-Cano, À. Franch, M. Castell, Development and characterization of an effective food allergy model in brown norway rats, PLoS One 10(4) (2015) e0125314.
[176] S.G. Thakkar, Z.N. Warnken, R.F. Alzhrani, S.A. Valdes, A.M. Aldayel, H. Xu, R.O. Williams III, Z. Cui, Intranasal immunization with aluminum salt-adjuvanted dry powder vaccine, Journal of Controlled Release 292 (2018) 111-118.
[177] Y. Li, X. Hu, Z. Dong, Y. Chen, W. Zhao, Y. Wang, L. Zhang, M. Chen, C. Wu, Q. Wang, Dissolving microneedle arrays with optimized needle geometry for transcutaneous immunization, European Journal of Pharmaceutical Sciences 151 (2020) 105361.
[178] D. Jacofsky, E.M. Jacofsky, M. Jacofsky, Understanding antibody testing for COVID-19, The Journal of Arthroplasty 35(7) (2020) S74-S81.
[179] R.J. Verheul, B. Slütter, S.M. Bal, J.A. Bouwstra, W. Jiskoot, W.E. Hennink, Covalently stabilized trimethyl chitosan-hyaluronic acid nanoparticles for nasal and intradermal vaccination, Journal of Controlled Release 156(1) (2011) 46-52.
[180] J. Lee, B. Lozano-Ruiz, F.M. Yang, D.D. Fan, L. Shen, J.M. González-Navajas, The multifaceted role of Th1, Th9, and Th17 cells in immune checkpoint inhibition therapy, Frontiers in Immunology 12 (2021) 625667.
[181] U. Dittmer, K.E. Peterson, R. Messer, I.M. Stromnes, B. Race, K.J. Hasenkrug, Role of interleukin-4 (IL-4), IL-12, and gamma interferon in primary and vaccine-primed immune responses to friend retrovirus infection, Journal of Virology 75(2) (2001) 654-660.
[182] F.S. Dhabhar, Immune function, stress-induced enhancement, Encyclopedia of stress (second edition), Elsevier Incorporation2007, pp. 455-461.
[183] N.V. Bhagavan, C.E. Ha, Essentials of medical biochemistry: with clinical cases, Academic Press2011.
[184] M. Jeyanathan, S. Afkhami, F. Smaill, M.S. Miller, B.D. Lichty, Z. Xing, Immunological considerations for COVID-19 vaccine strategies, Nature Reviews Immunology 20(10) (2020) 615-632.
[185] N.W. Lukacs, C.A. Malinczak, Harnessing cellular immunity for vaccination against respiratory viruses, Vaccines 8(4) (2020) 783.
[186] T. Rivera-Hernandez, M.S. Rhyme, A.J. Cork, S. Jones, C. Segui-Perez, L. Brunner, J. Richter, N. Petrovsky, M. Lawrenz, D. Goldblatt, Vaccine-induced Th1-type response protects against invasive group A streptococcus infection in the absence of opsonizing antibodies, MBio 11(2) (2020) e00122-20.