聚甲基丙烯酸羥基乙酯 (poly(2-hydroxyethyl methacrylate), poly(HEMA))已廣泛應用於許多生醫材料，並且可因應需求與不同單體形成共聚物。Poly(HEMA) 最常見的聚合方式為自由基聚合反應，如光起始聚合反應，單體藉由添加適合的起始劑、交聯劑等，在適當的環境條件下產生自由基並聚合交聯，形成網狀結構的高分子。而富含自由基、電子、離子等各種高能量粒子的電漿應具有潛力取代起始劑、交聯劑等試劑，並進行自由基聚合反應。故本研究討論光起始聚合poly(HEMA)以及與甲基丙烯酸六氟異丙酯 (1,1,1,3,3,3-hexafluoroisopropyl methacrylate, HFIMA)或甲基丙烯酸 (methacrylic acid, MAA)之不同配比共聚物，並比較其物化性質改變與磺胺嘧啶銀 (silver sulfadiazine, AgSD)藥物釋放快慢。除了以光起始聚合方式，研究中亦使用氣旋式常壓電漿系統 (atmospheric pressure plasma jet, APPJ) 聚合pp(HEMA) 以及pp(HEMA-co-HFIMA)，並討論兩種聚合方式對於物化性質以及AgSD藥物釋放的影響。物化性質檢測包含官能基測定、熱重分析、機械性質、分子量、含水率等。
光起始聚合UV-poly(HEMA)其平衡含水率約為37%，具有良好的透光度、機械性質，熱分解溫度約為334 °C，50% AgSD 釋放時間約為20 小時，且此AgSD 藥物釋放系統經過四天後達平衡；而HFIMA添加量增加將使得水膠的含水率、透光度隨之下降，其機械性質硬且脆，尤其是添加10% HFIMA 的HEMA共聚物，其50% AgSD釋放時間延長至約33小時，且約五天後達平衡；相對地，HEMA 與 MAA 之共聚物UV-poly(HEMA-co-MAA)其透光度與UV-poly(HEMA) 相仿，含水率則因MAA添加而略微下降，若浸泡於pH 7.4 磷酸緩衝溶液則會顯著地上升，MAA 2% 及 5% 的HEMA共聚物含水量在pH 7.4環境下分別是43 及 57%，然而UV-poly(HEMA-co-MAA) 水膠會加速AgSD釋放，50% AgSD釋放時間縮短至3小時，且系統經過24小時後即達平衡。
另一方面，APPJ 聚合HEMA以及與HFIMA共聚物之研究中，證實APPJ可在沒有起始劑、交聯劑的情況下，將HEMA、HFIMA混和溶液由液體狀態逐漸變黏稠狀，最後形成水膠，取代起始劑及交聯劑。其中，當APPJ施加功率為90瓦、氬氣流量為每分鐘3升時，可穩定製備pp(HEMA) 以及 pp(HEMA-co-HFIMA) 水膠，其含水率亦隨HFIMA含量增加而下降，pp(HEMA)的含水量是46% ，加入10、20、50% 的共聚物分別是44、44、38%。在AgSD藥物釋放實驗中，50% AgSD 釋放時間約為三到四小時，系統三天後達平衡。

Poly(2-hydroxyethyl methacrylate) (poly(HEMA)) hydrogel has been widely applied in biomedical applications. In order to promote its abilities, many kinds of HEMA copolymers are synthesized and developed. Poly(HEMA) is conventionally prepared by free radical polymerization, which usually involves monomers, initiator, and crosslinker. Instead of using initiator and crosslinker, the high energy reactive species generated in atmospheric pressure plasma jet (APPJ) are potential to achieve in-situ polymerization of HEMA. Therefore, we attempted to synthesize poly(HEMA) hydrogels and its copolymers with 2 different monomers: 1,1,1,3,3,3-hexafluoroisopropyl methacrylate (HFIMA) and methacrylic acid (MAA) by photo-initiated polymerization. In addition, poly(HEMA) and its copolymers with HIFMA were prepared by APPJ without initiator and crosslinker. The physicochemical properties of synthesized hydrogels were characterized by ATR-FTIR spectroscopy, TGA, UV-Vis transmittance, mechanical properties, gel permeation chromatography, and equilibrium water content (EWC). Furthermore, the effects of physicochemical properties of the hydrogels on the biocompatibility of L-929 mouse fibroblast cells and the silver sulfadiazine (AgSD) drug release behavior were studied.
The transparency of UV-poly(HEMA) hydrogel synthesized by photo-initiated polymerization method was found to be 95%, the thermal decomposition temperature was 334 °C, and the EWC was 37%. In the AgSD delivery experiments, t50 of AgSD was 20 h and the system was equilibrium after 4 days. The transmittance and the EWC of UV-poly(HEMA-co-HFIMA) hydrogels decreased as the HFIMA content in copolymers increase. Especially, copolymer with 10% of HIFMA can extent t50 ¬¬of AgSD to 33 h and prolong the release time for 5 days. In addition, the cumulative release percentage can reach 100% finally. On the contrary, the EWC of UV-poly(HEAM-co-MAA) with 2 and 5% MAA were 37 and 33 %, respectively. However, when UV-poly(HEMA-co-MAA) hydrogels were immersed in PBS pH7.4, the EWC of 2 and 5% MAA incorporated were 43 and 57%, respectively. The in vitro drug release experiments showed that t50 of AgSD was achieved within 3 h and the system reached equilibrium after 24 h in the case 5% MAA copolymerized with HEMA.
In another part of this study, pp(HEMA) and pp(HEMA-co-HFIMA) hydrogels were successfully prepared from monomer solution by APPJ in the absent of initiator and crosslinker at the applied power 90 W and Ar flow rate of 3 L/min using a scanning mode for 30-40 min. In such system, the mixtures of HEMA, HFIMA and water transformed from liquid to viscous solution and finally became solid. The EWC of pp(HEMA) was 46%. With 10, 20, and 50% HFIMA HEMA-copolymers, the EWC were 44, 44 and 38%, respectively. From the in vitro drug release point of view, the time for t50 was attained within 3-4 h and the system reached equilibrium after 3 days.

[1] Lewis CL, Anthamatten M. Synthesis, swelling behavior, and viscoelastic properties of functional poly (hydroxyethyl methacrylate) with ureidopyrimidinone side-groups. Soft Matter. 2013;9:4058-4066.
[2] Tomić SL, Mićić MM, Dobić SN, Filipović JM, Suljovrujić EH. Smart poly (2-hydroxyethyl methacrylate/itaconic acid) hydrogels for biomedical application. Radiation Physics and Chemistry. 2010;79:643-649.
[3] Caló E, Khutoryanskiy VV. Biomedical applications of hydrogels: A review of patents and commercial products. European Polymer Journal. 2015;65:252-267.
[4] Nguyen KT, West JL. Photopolymerizable hydrogels for tissue engineering applications. Biomaterials. 2002;23:4307-4314.
[5] Otto Wichterle, Drahoslav Lim. Hydrophilic gels for biological use. Nature 1960;185:117-118.
[6] Dobić SN, Filipović JM, Tomić SL. Synthesis and characterization of poly (2-hydroxyethyl methacrylate/itaconic acid/poly (ethylene glycol) dimethacrylate) hydrogels. Chemical Engineering Journal. 2012;179:372-380.
[7] Bostan L, Trunfio-Sfarghiu AM, Verestiuc L, Popa MI, Munteanu F, Rieu JP, Berthier Y. Mechanical and tribological properties of poly(hydroxyethyl methacrylate) hydrogels as articular cartilage substitutes. Tribology International. 2012;46:215-224.
[8] Williams CG, Malik AN, Kim TK, Manson PN, Elisseeff JH. Variable cytocompatibility of six cell lines with photoinitiators used for polymerizing hydrogels and cell encapsulation. Biomaterials. 2005;26:1211-1218.
[9] Allcock HR, Lampe FW, Mark JE. Contemporary Polymer Chemistry. Pearson/Prentice Hall; 2003. p. 59-65.
[10] P. Paradiso, R. Galante, L. Santos, A. P. Alves de Matos, R. Colaco, A. P. Serro, Saramago B. Comparison of two hydrogel formulations for drug release in ophthalmic lenses. Journal of Biomedical Materials Research Part B: Applied Biomaterials. 2014;102:1170-1180.
[11] Palapparambil Sunny Gils, Debajyoti Ray, Prafulla Kumar Sahoo. Characteristics of xanthan gum-based biodegradable superporous hydrogel. International journal of biological macromolecules. 2009;45:364-371.
[12] Priyanka Tyagi, Amit Kumar, Yougesh Kumar, Sitanshu S. Lahiri. Synthesis and characterization of poly (HEMA‐MAA) hydrogel carrier for oral delivery of insulin. Journal of Applied Polymer Science. 2011;122:2004-2012.
[13] Li L, Lee LJ. Photopolymerization of HEMA/DEGDMA hydrogels in solution. Polymer. 2005;46:11540-11547.
[14] Lecamp L, Youssef B, Bunel C, Lebaudy P. Photoinitiated polymerization of a dimethacrylate oligomer: 1. Influence of photoinitiator concentration, temperature and light intensity. Polymer. 1997;38:6089-6096.
[15] Beers KL, Boo S, Gaynor SG, Matyjaszewski K. Atom transfer radical polymerization of 2-hydroxyethyl methacrylate. Macromolecules. 1999;32:5772-5776.
[16] Robinson K, Khan M, de Paz Banez M, Wang X, Armes S. Controlled polymerization of 2-hydroxyethyl methacrylate by ATRP at ambient temperature. Macromolecules. 2001;34:3155-3158.
[17] Elif Vargün, Ali Usanmaz. Degradation of poly (2-hydroxyethyl methacrylate) obtained by radiation in aqueous solution. Journal of Macromolecular Science, Part A: Pure and Applied Chemistry. 2010;47:882-891.
[18] Hirao A, Kato H, Yamaguchi K, Nakahama S. Polymerization of monomers containing functional groups protected by trialkylsilyl groups. 5. Synthesis of poly(2-hydroxyethyl methacrylate) with a narrow molecular weight distribution by means of anionic living polymerization. Macromolecules. 1986;19:1294-1299.
[19] Matsuo Y, Konno R, Ishizone T, Goseki R, Hirao A. Precise synthesis of block polymers composed of three or more blocks by specially designed linking methodologies in conjunction with living anionic polymerization system. Polymers. 2013;5:1012-1040.
[20] Bongiovanni R, Malucelli G, Priola A. UV-Curing of Fluorinated Systems: Synthesis and Properties. Photoinitiated Polymerization: American Chemical Society; 2003. p. 499-510.
[21] Roussel F, Saidi S, Guittard F, Geribaldi S. Thermophysical properties of fluorinated acrylate homopolymers: Mixing and phase separation. The European Physical Journal E. 2002;8:283-288.
[22] Haijiao Xie, Zhengbai Zhao, Shuangshuang An, Jiang Y. The influence of the surface properties of silicon–fluorine hydrogel on protein adsorption. Colloids and Surfaces B: Biointerfaces. 2015;136:1113-1119.
[23] Fridman A. Plasma chemistry: Cambridge university press; 2008.
[24] Chen M, Zhang Y, Yao X, Li H, Yu Q, Wang Y. Effect of a non-thermal, atmospheric-pressure, plasma brush on conversion of model self-etch adhesive formulations compared to conventional photo-polymerization. Dental materials. 2012;28:1232-1239.
[25] Mateescu A, Wang Y, Dostalek J, Jonas U. Thin hydrogel films for optical biosensor applications. Membranes. 2012;2:40-69.
[26] Tarducci C, Schofield W, Badyal J, Brewer S, Willis C. Monomolecular functionalization of pulsed plasma deposited poly (2-hydroxyethyl methacrylate) surfaces. Chemistry of materials. 2002;14:2541-2545.
[27] Pfluger CA, Carrier RL, Sun B, Ziemer KS, Burkey DD. Cross‐Linking and Degradation Properties of Plasma Enhanced Chemical Vapor Deposited Poly (2‐hydroxyethyl methacrylate). Macromolecular rapid communications. 2009;30:126-132.
[28] Schutze A, Jeong JY, Babayan SE, Park J, Selwyn GS, Hicks RF. The atmospheric-pressure plasma jet: a review and comparison to other plasma sources. IEEE transactions on plasma science. 1998;26:1685-1694.
[29] Fei XM, Kondo Y, Qian XY, Kuroda S, Mori T, Hosoi K. Functional-Group-Retaining Polymerization of Hydroxyethyl Methacrylate by Atmospheric Pressure Non-Equilibrium Plasma. Key Engineering Materials: Trans Tech Publ; 2014. p. 65-69.
[30] Okada M, Matsuda K, Sato T, Yamada K, Matsuda K, Hiaki T. Polymerization of Methyl Methacrylate Initiated by Atmospheric Pressure Plasma Jet. Journal of Photopolymer Science and Technology. 2015;28:461-464.
[31] Garrett Q, Laycock B, Garrett RW. Hydrogel lens monomer constituents modulate protein sorption. Investigative ophthalmology & visual science. 2000;41:1687-1695.
[32] Santos WG, Schmitt CC, Neumann MG. Polymerization of HEMA photoinitiated by the Safranine/diphenylborinate system. Journal of Photochemistry and Photobiology A: Chemistry. 2013;252:124-130.
[33] Young C-D, Wu J-R, Tsou T-L. Fabrication and characteristics of polyHEMA artificial skin with improved tensile properties. Journal of Membrane Science. 1998;146:83-93.
[34] Heal GR. Thermogravimetry and Derivative Thermogravimetry. Principles of Thermal Analysis and Calorimetry: The Royal Society of Chemistry; 2002. p. 10-54.
[35] Choi B, Loh XJ, Tan A, Loh CK, Ye E, Joo MK, Jeong B. Introduction to In Situ Forming Hydrogels for Biomedical Applications. In-Situ Gelling Polymers: Springer; 2015. p. 5-35.
[36] Klimundová J, Šatinský D, Sklenářová H, Solich P. Automation of simultaneous release tests of two substances by sequential injection chromatography coupled with Franz cell. Talanta. 2006;69:730-735.
[37] Valter Castelvetro, Lorenzo Montagnini di Mirabello, Mauro Aglietto, Passaglia E. Homo‐and copolymers of hexafluoroisopropyl methacrylate and α‐fluoroacrylate with alkyl vinyl ethers: Microstructure and thermal properties. Journal of Polymer Science Part A: Polymer Chemistry. 2001;39:32-45.
[38] Stella K. Papadopoulou, Panayiotou C. Thermodynamic characterization of poly (1, 1, 1, 3, 3, 3-hexafluoroisopropyl methacrylate) by inverse gas chromatography. Journal of Chromatography A. 2012;1229:230-236.
[39] Meng-Fang Lin, Pooi See Lee. Formation of PVDF-g-HEMA/BaTiO3 nanocomposites via in situ nanoparticle synthesis for high performance capacitor applications. Journal of Materials Chemistry A. 2013;1:14455-14459.
[40] Erhardt R, Zhang M, Böker A, Zettl H, Abetz C, Frederik P, Krausch G, Abetz V, Müller AH. Amphiphilic Janus micelles with polystyrene and poly (methacrylic acid) hemispheres. Journal of the American Chemical Society. 2003;125:3260-3267.