FGF가 고정화된 UV경화형 히알루론산 유도체를 이용한 Injectable한 수화젤의 제조

민성준; 김신웅; 이태훈; 권일근; 손태일; Sung-Jun Min; Shin-Woong Kim; Tae-Hoon Lee; Il-Keun Kwon; Tae-Il Son

Polymer(Korea), Vol.44, No.4, 451-458, July, 2020

DOI10.7317/pk.2020.44.4.451 Export Citation

FGF가 고정화된 UV경화형 히알루론산 유도체를 이용한 Injectable한 수화젤의 제조

Preparation of Injectable Hydrogels Immobilized with FGF Using UV-curable Hyaluronic Acid Derivatives

민성준, 김신웅, 이태훈, 권일근¹, 손태일^†

중앙대학교 생명공학대학 시스템생명공학과
¹경희대학교 치과대학 치의학과

Sung-Jun Min, Shin-Woong Kim, Tae-Hoon Lee, Il-Keun Kwon¹, and Tae-Il Son^†

Department of Systems Biotechnology, Chung-Ang University, Seodongdae-ro 4726, Anseong-si, Gyeonggi-do 17546, Korea
¹Department of Dentistry, Graduate School, Kyung-Hee University, Kyungheedae-ro 26, Dongdaemun-gu, Seoul 02447, Korea

E-mail:

초록

본 연구는 단백질약물이 고정화된 주사제 형태의 수화젤을 제조하는데 목적을 두었다. 생체적합성, 생분해성의 특징을 가지는 천연고분자 히알루론산을 이용하여 azidophenyl 히알루론산 유도체(Az-HA)를 제조하였다. FTIR 및 1H NMR 분석을 통하여 hyaluronic acid에 azido기가 성공적으로 도입되었음을 확인하였다. 또한 유변학적 분석을 통하여 제조된 유도체의 수화젤 특성 유지여부를 검토하였다. 광고정화방법을 이용하여 단백질의 고정화 가능여부를 형광현미경으로 확인하였다. Az-HA 유도체에 고정화된 단백질약물이 지속적으로 방출되는 여부를 확인하기 위해 단백질 방출 실험을 실시하였다. 세포 독성 실험을 통하여 Az-HA의 생체적합성과 광고정화된 섬유아세포 성장인자(FGF)의 세포증식 촉진효과를 확인하였다. 위와 같은 실험결과로부터 본 연구에서 제조한 Az-HA는 효과적으로 약물 전달이 가능한 의료용 생체소재로서 활용가능성을 가질 수 있을 것으로 사료된다.

The aim of this study was to prepare injectable hydrogels that can effectively deliver drugs. Azidophenyl-hyaluronic acid derivatives (Az-HA) were prepared using natural polymer hyaluronic acid with biocompatibility and biodegradability. It was confirmed that azido group was successfully introduced into hyaluronic acid by FTIR and 1H NMR analysis. In addition, The maintenance of hydrogel properties of the prepared derivatives was examined using rheological analysis. Protein immobilization was confirmed using the photo-immobilization method, and the protein release experiment was conducted to confirm whether the protein drug immobilized with Az-HA derivative was continuously released. Through cytotoxicity test, the biocompatibility of Az-HA was confirmed. As a result of the intracellular administration of Az-HA immobilized with fibroblast growth factor (FGF), cell proliferation was confirmed. According to the result of the above experiments, the prepared UV-curable Az-HA are considered to have applicability as a biomedical material capable of effective delivery of drugs.

Keywords:azidophenyl hyaluronic acid derivatives;injectable hydrogel;protein-immobilization;fibroblast growth factor

[References]

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[Referenced By]

[1] Dai C, Wang B, Zhao H, Colloids Surf. B: Biointerfaces, 41, 117 (2005)

[2] Wang Y, Zhang L, Wang Q, Zhang D, J. Control. Release, 172, 1126 (2013)

[3] Truong-Le V, Lovalenti P, Abdul-Fattah AM, Adv. Drug Deliv. Rev., 93, 95 (2015)

[4] Yang XC, Samanta B, Agasti SS, Jeong Y, Zhu ZJ, Rana S, Miranda OR, Rotello VM, Angew. Chem.-Int. Edit., 50, 477 (2011)

[5] Sadana A, Biotechnol. Bioeng., 48(5), 481 (1995)

[6] Ito Y, Yamauchi T, Omura K, Kobunshi Ronbunshu, 61, 501 (2004)

[7] Uhrich KE, Cannizzaro SM, Langer RS, Shakesheff KM, Chem. Rev., 99(11), 3181 (1999)

[8] Ali M, Manolios N, Lett. Pept. Sci., 8, 289 (2001)

[9] Matsuda T, Sugawara T, Langmuir, 11(6), 2272 (1995)

[10] Ito Y, Biotechnol. Prog., 22(4), 924 (2006)

[11] Na HN, Heo Y, Kim KI, Chung KH, Son TI, J. Chitin Chitosan, 15, 92 (2010)

[12] Heo Y, Park SH, Seo SY, Yun JY, Ito Y, Son TI, Macromol. Res., 22(5), 541 (2014)

[13] Shi Z, Gao X, Ullah MW, Li S, Wang Q, Yang G, Biomaterials, 111, 40 (2016)

[14] Kim JW, Kim EH, Han GD, Noh SH, Goo HC, Yun JY, Nah JW, Son TI, J. Chitin Chitosan, 22, 1 (2017)

[15] Kim EH, Han GD, Noh SH, Kim JW, Lee JG, Ito Y, Son TI, J. Ind. Eng. Chem., 54, 1 (2017)

[16] Kim JE, Sykes JM, Facial Plast. Surg., 27, 523 (2011)

[17] Monheit GD, Coleman KM, Dermatol. Ther., 19, 141 (2006)

[18] Joddar B, Kitajima T, Ito Y, Biomaterials, 32, 8404 (2011)

[19] Hamidi M, Azadi A, Rafiei P, Adv. Drug Deliv. Rev., 60, 1638 (2008)

[20] Hoffman AS, Adv. Drug Deliv. Rev., 54, 3 (2004)

[21] Peppas NA, Curr. Opin. Colloid Interface Sci., 2, 531 (1997)

[22] Lee KY, Mooney DJ, Chem. Rev., 101(7), 1869 (2001)

[23] Tan H, Marra KG, Materials, 3, 1746 (2010)

[24] Hickey MJ, Morrison WA, Biochem. Biophys. Res. Commun., 201, 1066 (1994)

[25] Yang N, Zhang H, Shi L, Hu XT, He Y, Chen L, Zhang QS, Zhao KY, React. Funct. Polym., 100, 73 (2016)

[26] Edelman ER, Mathiowitz E, Langer R, Klagsbrun M, Biomaterials, 12, 619 (1991)

[27] Vemuri S, Beylin I, Sluzky V, Stratton P, Eberlein G, Wang YJ, J. Pharm. Pharmacol., 46, 481 (1994)

[28] Ryu WH, Huang Z, Prinz FB, Goodman SB, Fasching R, J. Control. Release, 124, 98 (2007)

[29] Volpato FZ, Almodovar J, Erickson K, Popat KC, Migliaresi C, Kipper MJ, Acta Biomater, 8, 1551 (2012)

[30] Lee HJ, Park SH, Seo SY, Cho YM, Woo HD, Ito Y, Son TI, Macromol. Res., 21(2), 216 (2013)

[31] Woo HD, Lee HJ, Lee JW, Son TI, Macromol. Res., 22(5), 494 (2014)

[32] Rose MT, Vet. J., 193, 539 (2012)

[33] Liang CC, Park AY, Guan JL, Nat. Protoc., 2, 329 (2007)

[34] Fronza M, Heinzmann B, Hamburger M, Laufer S, Merfort I, J. Ethnopharmacol., 126, 436 (2009)

[35] Felice F, Zambito Y, Belardinelli E, Fabiano A, Santoni T, Stefano RD, Int. J. Biol. Macromol., 76, 236 (2015)