角膜的鹼性灼傷佔嚴重眼科化學損傷的三分之二至四分之三。因為鹼性溶劑具有親脂性的關係，會迅速地滲透入眼部組織內，並滲入前房中，使眼部的細胞內引起皂化反應，持續地分泌蛋白水解酶，進而導致白內障的形成、睫狀體和小梁網損傷。嚴重的情況下，甚至可能會引起失明。目前臨床治療上，大多每 1–2 小時使用 0.1% 地塞米松 (Dexamethasone, DEX) 滴眼液進行給藥。DEX 是一種合成的皮質類固醇，廣泛用作眼科疾病的抗發炎藥。然而，此治療方式卻具有生物利用度低的問題，需要頻繁地進行給藥。羧甲基纖維素 (Carboxymethylcellulose, CMC) 是一種具有生物黏附性高黏度聚合物，可長期保留在角膜上，並且被 FDA 批准為非活性眼科潤滑劑成份。本研究製備一新型 DEX 接枝 CMC 水膠，除了期望改質後的水膠具有黏膜貼附的特性，以延長藥物停留於眼表的時間外，也期望藥物接枝後的水膠，能在鹼性和生理環境中達到藥物釋放，有效提升治療效果。本研究使用傅立葉轉換紅外線光譜、核磁共振光譜和分光光譜儀進行材料鑑定、場發射掃描式電子顯微鏡進行表面型態分析，並利用了流變儀探討流變性質，以及高效液相層析評估藥物的釋放率，另外評估材料體內及體外的生物相容性，除此之外，也以過氧化氫 (Hydrogen peroxide, H2O2) 建立角膜上皮細胞損傷模型，以評估材料對受損細胞的治療效果。

Corneal alkali injuries account for two-thirds to three-fourths of severe ocular chemical injuries. Due to their lipophilic nature, alkaline solvents can quickly penetrate ocular tissues and enter the anterior chamber, causing saponification reactions within ocular cells. This leads to sustained secretion of proteolytic enzymes, resulting in the formation of cataracts and damage to the ciliary body and trabecular meshwork. In severe cases, it can even cause blindness. Topical administration of 0.1% dexamethasone (DEX) is the first-line treatment for corneal alkali burns. DEX with antiinflammatory properties can suppress the inflammatory angiogenesis in cornea and even better than anti-vascular endothelial growth factor. However, low ocular bioavailability and high dosage frequency (every 1 to 2 hours for mild or severe chemical burns) may decrease the patient’s compliance. Carboxymethylcellulose (CMC) is a linear watersoluble polysaccharide and is a common composition of artificial tears. In the study, a novel DEX-grafted CMC hydrogel was developed to improve the mucoadhesive properties and prolong drug residence time on the ocular surface in alkaline and physiological environments, thereby enhancing therapeutic efficacy. The material characterization was performed using Fourier-transform infrared spectroscopy, nuclear magnetic resonance spectroscopy, spectrophotometer, field emission scanning electron microscopy and rheometer. In-vitro drug release study was evaluated using high performance liquid chromatography. In-vitro and in-vivo biocompatibility of developed hydrogels were demonstrated. The effects of developed hydrogels in corneal epithelial cells exposed to H2O2 were investigated.

[1] N. Sharma, M. Kaur, T. Agarwal, V.S. Sangwan, R.B. Vajpayee, Treatment of acute ocular chemical burns, Survey of ophthalmology 63(2) (2018) 214-235.
[2] M. Bizrah, A. Yusuf, S. Ahmad, Adherence to treatment and follow-up in patients with severe chemical eye burns, Ophthalmology and therapy 8 (2019) 251-259.
[3] G.L. Griffith, B. Wirostko, H.-K. Lee, L.E. Cornell, J.S. McDaniel, D.O. Zamora, A.J. Johnson, Treatment of corneal chemical alkali burns with a crosslinked thiolated hyaluronic acid film, Burns 44(5) (2018) 1179-1186.
[4] B.D. Kels, A. Grzybowski, J.M. Grant-Kels, Human ocular anatomy, Clinics in dermatology 33(2) (2015) 140-146.
[5] A.T. Comez, M. Ozbas, Evaluation and Management of Ocular Traumas, (2022).
[6] H.S. Dua, D.S.J. Ting, A. Al Saadi, D.G. Said, Chemical eye injury: pathophysiology, assessment and management, Eye 34(11) (2020) 2001-2019.
[7] M.D. Wagoner, Chemical injuries of the eye: current concepts in pathophysiology and therapy, Survey of ophthalmology 41(4) (1997) 275-313.
[8] M. Soleimani, M. Naderan, Management strategies of ocular chemical burns: current perspectives, Clinical Ophthalmology (2020) 2687-2699.
[9] P. Singh, M. Tyagi, Y. Kumar, K. Gupta, P. Sharma, Ocular chemical injuries and their management, Oman journal of ophthalmology 6(2) (2013) 83.
[10] M. Bizrah, A. Yusuf, S. Ahmad, An update on chemical eye burns, Eye 33(9) (2019) 1362-1377.
[11] M. Eslani, A. Baradaran-Rafii, A. Movahedan, A.R. Djalilian, The ocular surface chemical burns, Journal of ophthalmology 2014 (2014).
[12] E.I. Paschalis, C. Zhou, F. Lei, N. Scott, V. Kapoulea, M.-C. Robert, D. Vavvas, R. Dana, J. Chodosh, C.H. Dohlman, Mechanisms of retinal damage after ocular alkali burns, The American journal of pathology 187(6) (2017) 1327-1342.
[13] G. Melilli, I. Carmagnola, C. Tonda-Turo, F. Pirri, G. Ciardelli, M. Sangermano, M. Hakkarainen, A. Chiappone, DLP 3D printing meets lignocellulosic biopolymers: Carboxymethyl cellulose inks for 3D biocompatible hydrogels, Polymers 12(8) (2020) 1655.
[14] N.V. Dubashynskaya, Y.A. Skorik, Patches as Polymeric Systems for Improved Delivery of Topical Corticosteroids: Advances and Future Perspectives, International Journal of Molecular Sciences 23(21) (2022) 12980.
[15] R.M. Rajendraprasad, G. Kwatra, N. Batra, Carboxymethyl cellulose versus hydroxypropyl methylcellulose tear substitutes for dry eye due to computer vision syndrome: Comparison of efficacy and safety, International Journal of Applied and Basic Medical Research 11(1) (2021) 4.
[16] S. Asati, S. Jain, A. Choubey, Bioadhesive or mucoadhesive drug delivery system: a potential alternative to conventional therapy, Journal of Drug Delivery and Therapeutics 9(4-A) (2019) 858-867.
[17] A. Zennifer, P. Senthilvelan, S. Sethuraman, D. Sundaramurthi, Key advances of carboxymethyl cellulose in tissue engineering & 3D bioprinting applications, Carbohydrate Polymers 256 (2021) 117561.
[18] V.L. Perez, B. Wirostko, M. Korenfeld, S. From, M. Raizman, Ophthalmic drug delivery using iontophoresis: recent clinical applications, Journal of Ocular Pharmacology and Therapeutics 36(2) (2020) 75-87.
[19] D. Aldrich, C.M. Bach, W. Brown, W. Chambers, J. Fleitman, D. Hunt, M. Marques, Y. Mille, A. Mitra, S. Platzer, Ophthalmic preparations, US Pharmacopeia 39(5) (2013) 1-21.
[20] O.M. Kolawole, W.M. Lau, V.V. Khutoryanskiy, Methacrylated chitosan as a polymer with enhanced mucoadhesive properties for transmucosal drug delivery, International Journal of Pharmaceutics 550(1-2) (2018) 123-129.
[21] S.R. Krishn, K. Ganguly, S. Kaur, S.K. Batra, Ramifications of secreted mucin MUC5AC in malignant journey: a holistic view, Carcinogenesis 39(5) (2018) 633-651.
[22] R.S. Malkar, A.L. Jadhav, G.D. Yadav, Innovative catalysis in Michael addition reactions for CX bond formation, Molecular Catalysis 485 (2020) 110814.
[23] N.V. Dubashynskaya, A.N. Bokatyi, A.S. Golovkin, I.V. Kudryavtsev, M.K. Serebryakova, A.S. Trulioff, Y.A. Dubrovskii, Y.A. Skorik, Synthesis and characterization of novel succinyl chitosan-dexamethasone conjugates for potential intravitreal dexamethasone delivery, International Journal of Molecular Sciences 22(20) (2021) 10960.
[24] N.V. Dubashynskaya, A.N. Bokatyi, Y.A. Skorik, Dexamethasone conjugates: Synthetic approaches and medical prospects, Biomedicines 9(4) (2021) 341.
[25] M. Everts, R.J. Kok, S.A. Asgeirsdóttir, B.N. Melgert, T.J. Moolenaar, G.A. Koning, M.J. van Luyn, D.K. Meijer, G. Molema, Selective intracellular delivery of dexamethasone into activated endothelial cells using an E-selectin-directed immunoconjugate, The Journal of Immunology 168(2) (2002) 883-889.
[26] D.M. Varma, G.T. Gold, P.J. Taub, S.B. Nicoll, Injectable carboxymethylcellulose hydrogels for soft tissue filler applications, Acta Biomaterialia 10(12) (2014) 4996-5004.
[27] X. Jia, G. Colombo, R. Padera, R. Langer, D.S. Kohane, Prolongation of sciatic nerve blockade by in situ cross-linked hyaluronic acid, Biomaterials 25(19) (2004) 4797-4804.
[28] T. Ito, I.P. Fraser, Y. Yeo, C.B. Highley, E. Bellas, D.S. Kohane, Anti-inflammatory function of an in situ cross-linkable conjugate hydrogel of hyaluronic acid and dexamethasone, Biomaterials 28(10) (2007) 1778-1786.
[29] J. Sun, C. Xiao, H. Tan, X. Hu, Covalently crosslinked hyaluronic acid‐chitosan hydrogel containing dexamethasone as an injectable scaffold for soft tissue engineering, Journal of applied polymer science 129(2) (2013) 682-688.
[30] M. Dewan, B. Bhowmick, G. Sarkar, D. Rana, M.K. Bain, M. Bhowmik, D. Chattopadhyay, Effect of methyl cellulose on gelation behavior and drug release from poloxamer based ophthalmic formulations, International journal of biological macromolecules 72 (2015) 706-710.
[31] E.E. Hassan, J.M. Gallo, A simple rheological method for the in vitro assessment of mucin-polymer bioadhesive bond strength, Pharmaceutical research 7 (1990) 491-495.
[32] K. Wang, L. Jiang, Y. Zhong, Y. Zhang, Q. Yin, S. Li, X. Zhang, H. Han, K. Yao, Ferrostatin‐1‐loaded liposome for treatment of corneal alkali burn via targeting ferroptosis, Bioengineering & Translational Medicine 7(2) (2022) e10276.
[33] Y. Zhang, M. Huo, J. Zhou, A. Zou, W. Li, C. Yao, S. Xie, DDSolver: an add-in program for modeling and comparison of drug dissolution profiles, The AAPS journal 12 (2010) 263-271.
[34] M. Vigata, C. Meinert, D.W. Hutmacher, N. Bock, Hydrogels as drug delivery systems: A review of current characterization and evaluation techniques, Pharmaceutics 12(12) (2020) 1188.
[35] Q. Li, X. Wu, M. Xin, Strengthened rebamipide ocular nanoformulation to effectively treat corneal alkali burns in mice through the HMGB1 signaling pathway, Experimental Eye Research 213 (2021) 108824.
[36] M. Yáñez-S, B. Matsuhiro, S. Maldonado, R. González, J. Luengo, O. Uyarte, D. Serafine, S. Moya, J. Romero, R. Torres, Carboxymethylcellulose from bleached organosolv fibers of Eucalyptus nitens: synthesis and physicochemical characterization, Cellulose 25 (2018) 2901-2914.
[37] R. Salzillo, C. Schiraldi, L. Corsuto, A. D’Agostino, R. Filosa, M. De Rosa, A. La Gatta, Optimization of hyaluronan-based eye drop formulations, Carbohydrate polymers 153 (2016) 275-283.
[38] R. Kol, T. De Somer, D.R. D'hooge, F. Knappich, K. Ragaert, D.S. Achilias, S. De Meester, State‐Of‐The‐Art Quantification of Polymer Solution Viscosity for Plastic Waste Recycling, ChemSusChem 14(19) (2021) 4071-4102.
[39] M. Lee, Y. Li, Y. Feng, C. Carter, Study of frequency dependence modulus of bulk amorphous alloys around the glass transition by dynamic mechanical analysis, Intermetallics 10(11-12) (2002) 1061-1064.
[40] L.-F. Hu, D.-J. Chen, J.-L. Yang, X.-H. Zhang, An investigation of the organoborane/Lewis base pairs on the copolymerization of propylene oxide with succinic anhydride, Molecules 25(2) (2020) 253.
[41] Y.-H. Wen, T.-Y. Lee, P.-C. Fu, C.-L. Lo, Y.-T. Chiang, Multifunctional polymer nanoparticles for dual drug release and cancer cell targeting, Polymers 9(6) (2017) 213.
[42] N. Zashikhina, S. Gladnev, V. Sharoyko, V. Korzhikov-Vlakh, E. Korzhikova-Vlakh, T. Tennikova, Synthesis and characterization of nanoparticle-based dexamethasone-polypeptide conjugates as potential intravitreal delivery systems, International Journal of Molecular Sciences 24(4) (2023) 3702.
[43] P.S. Chan, Q. Li, B. Zhang, K.K. To, S.S. Leung, In vivo biocompatibility and efficacy of dexamethasone-loaded PLGA-PEG-PLGA thermogel in an alkali-burn induced corneal neovascularization disease model, European Journal of Pharmaceutics and Biopharmaceutics 155 (2020) 190-198.
[44] R. Zhang, Y. Tao, W. Xu, S. Xiao, S. Du, Y. Zhou, A. Hasan, Rheological and controlled release properties of hydrogels based on mushroom hyperbranched polysaccharide and xanthan gum, International journal of biological macromolecules 120 (2018) 2399-2409.
[45] Y. Wei, T. Fan, M. Yu, Inhibitor of apoptosis proteins and apoptosis, Acta biochimica et biophysica Sinica 40(4) (2008) 278-288.
[46] P. Kralik, M. Ricchi, A basic guide to real time PCR in microbial diagnostics: definitions, parameters, and everything, Frontiers in microbiology 8 (2017) 108.