창상 치유를 위한 생체고분자 기반 광가교형 조직접착제 개발

이혜선; 성금용; 김소담; 아지시찬드라세카란; 황대연; 한영기; 백문창; 이준; 양승윤; Hyeseon Lee; Keum-Yong Seong; Sodam Kim; Ajeesh Chandrasekharan; Dae Youn Hwang; Young Ki Hahn; Moon-Chang Baek; Jun Lee; Seung Yun Yang

Polymer(Korea), Vol.46, No.2, 216-222, March, 2022

DOI10.7317/pk.2022.46.2.216 Export Citation

창상 치유를 위한 생체고분자 기반 광가교형 조직접착제 개발

In Situ Photo-crosslinkable Biodegradable Tissue Adhesive for Wound Healing

이혜선¹, 성금용¹, 김소담¹, 아지시찬드라세카란¹, 황대연¹, 한영기^{1, 2}, 백문창^{2, 3}, 이준^{4, †}, 양승윤^{1, †}

¹부산대학교 생명자원과학대학 바이오소재과학과
²경북대학교 의과대학 세포·기질연구소
³경북대학교 의과대학 분자의학교실
⁴원광대학교 원광대학교 치과대학

Hyeseon Lee¹, Keum-Yong Seong¹, Sodam Kim¹, Ajeesh Chandrasekharan¹, Dae Youn Hwang¹, Young Ki Hahn^{1, 2}, Moon-Chang Baek^{2, 3}, Jun Lee^{4, †}, and Seung Yun Yang^{1, †}

¹Department of Biomaterials Science (BK21 Four Program), College of Natural Resources & Life Science, Pusan National University, Miryang 50463, Korea
²Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu 41566, Korea
³Department of Molecular Medicine, School of Medicine, Kyungpook National University, Daegu 41566, Korea
⁴Department of Oral and Maxillofacial Surgery, School of Dentistry, College of Dentistry, Wonkwang University, Iksan 54538, Korea

E-mail:,

초록

조직접착제는 조직의 결합 및 상처 봉합의 목적으로 다양한 의료 분야에서 사용되고 있다. 기존의 액상 조직 접착제는 생체적합성이 낮거나 우수한 접착력을 달성하기 위해 반응 시간이 오래 걸린다는 단점이 있다. 본 연구에 서는 생분해성을 가진 히알루론산(hyaluronic acid, HA)에 광가교성 메타크릴레이트(methacrylate, MA) 그룹을 도입 하여, 빛에 의해 빠르게 경화되어 상처 부위를 즉각적으로 봉합할 수 있는 광가교형 조직접착제를 개발하였다. 광경 화형 조직접착제는 5초 이내의 짧은 UV 조사 후 조직에 높은 접착력을 보이면서 안정적인 하이드로젤 층을 형성하 였다. MA의 치환도 및 고분자의 농도를 변화시켜, 접착제의 기계적 물성과 조직접착력도 손쉽게 조절할 수 있었다. 창상 동물모델 실험에서 HA 기반 조직접착제는 기존 상용 접착제에 비해 우수한 조직접착력 및 빠른 상처 회복을 보였다. HA의 높은 생체적합성과 생분해성을 고려할 때, HA 기반 광가교형 조직접착제는 다양한 연조직의 상처 치료에 활용도가 높을 것으로 예상된다.

Tissue adhesives are widely used in various medical fields for tissue bonding and wound closure. Existing glue-type tissue adhesives have disadvantages such as low biocompatibility or a long reaction time to achieve firm tissue adhesion. Herein we developed photocurable tissue adhesives by introducing photocrosslinkable methacrylate (MA) groups into biodegradable hyaluronic acid (HA) that enables strong tissue adhesion and wound sealing. The photocurable tissue adhesive formed a stable hydrogel layer with good tissue adhesion following short UV exposure (<5 s). By controlling the substitution rate of MA and polymer concentration, the mechanical properties and adhesion strength of the tissue adhesive could be easily manipulated. From the incisional wound animal model, the HA-based tissue adhesive used in this study showed better tissue adhesion and faster wound healing efficacy compared to commercial glues. Considering the high biocompatibility and biodegradability of HA, this photocurable adhesive would be useful in wound healing of various soft tissues.

Keywords:photo-crosslinking;hyaluronic acid;wound healing;tissue adhesive

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[1] Cimador M, Castagnetti M, Milazzo M, Sergio M, Urol. Int., 73, 320 (2004)

[2] Vote BJ, Elder MJ, Clin. Exp. Ophthalmol., 28, 437 (2000)

[3] Al-Mubarak L, Al-Haddab M, J. Cutan. Aesthet. Surg., 6, 178 (2013)

[4] Artzi N, Sci. Transl. Med., 5, 205ec161 (2013)

[5] Edmiston CE Jr, Krepel CJ, Marks RM, Rossi PJ, Sanger J, Goldblatt M, Graham MB, Rothenburger S, J. Clin. Microbiol., 51, 417 (2013)

[6] Ge L, Chen S, Polymer, 12, 939 (2020)

[7] Bouten PJM, Zonjee M, Bender J, Yauw STK, van Goor H, van Hest JCM, Hoogenboom R, Am. J. Emerg. Med., 19, 240 (2001)

[8] Edmonson MB, Am. J. Emerg. Med., 19, 240 (2001)

[9] Mehdizadeh M, Yang J, Macromol. Biosci., 13, 271 (2013)

[10] Anema JG, Morey AF, Harris R, MacPhee M, Cornum RL, World J. Surg., 25, 1573 (2001)

[11] Bitton R, Josef E, Shimshelashvili I, Shapira K, Seliktar D, Bianco-Peled H, Acta Biomater., 5, 1582 (2009)

[12] Lang N, Pereira MJ, Lee Y, Friehs I, Vasilyev NV, Feins EN, Ablasser K, O’Cearbhaill ED, Xu C, Fabozzo A, Sci. Transl. Med., 6, 218ra6 (2014)

[13] Wang T, Nie J, Yang D, Carbohydr. Polym., 90, 1428 (2012)

[14] Soucy JR, Shirzaei SE, Portillo LR, Diaz D, Dias F, Weiss AS, Koppes AN, Koppes RA, Annabi N, Tissue Eng. Pt. A, 24, 1393 (2018)

[15] Shirzaei SE, Kheirkhah A, Rana D, Sun Z, Foulsham W, Sheikhi A, Khademhosseini A, Dana R, Annabi N, Sci. Adv., 5, eaav1281 (2019)

[16] Taboada GM, Yang K, Pereira MJN, Liu SS, Hu Y, Karp JM, Artzi N, Lee Y, Nat. Rev. Mater., 5, 310 (2020)

[17] Chandrasekharan A, Seong KY, Yim SG, Kim S, Seo S, Yoon J, Yang SY, J. Polym. Sci. A: Polym. Chem., 57, 522 (2019)

[18] Kim S, Yim SG, Chandrasekharan A, Seong KY, Lee TW, Kim B, Kim K, Choi S, Yang SY, J. Control. Release, 322, 337 (2020)

[19] Zhou M, Lee BH, Tan YJ, Tan LP, Biofabrication., 11, 025011 (2019)

[20] Hong Y, Zhou F, Hua Y, Zhang X, Ni C, Pan D, Zhang Y, Jiang D, Yang L, Lin Q, Zou Y, Yu D, Arnot D, Nat. Commun., 10, 2060 (2019)

[21] Higham AK, Bonino CA, Raghavan SR, Khan SA, Soft Matter., 10, 4990 (2014)

[22] Annabi N, Zhang YN, Assmann A, Sani ES, Cheng G, Lassaletta AD, Vegh A, Dehghani B, Ruiz-Esparza GU, Sci. Transl. Med., 9, eaai7466 (2017)

[23] Peng B, Lai X, Chen L, Lin X, Sun C, Liu L, Qi S, Chen Y, Leong KW, ACS Omega., 2, 6053 (2017)

[24] Moon YJ, Yoon SJ, Koo JH, Yoon Y, Byun HJ, Kim HS, Khang G, Chun HJ, Yang DH, Int. J. Mol. Sci., 22, 700 (2021)

[25] Guo Y, Wang Y, Zhao X, Li X, Wang Q, Zhong W, Mequanint K, Zhan R, Xing M, Luo G, Sci. Adv., 7, eabf9635 (2021)

[26] Bellare A, Epperly MW, Greenberger JS, Fisher R, Glowacki J, MethodsX, 5, 337 (2018)

[27] Selvaraj TKR, Thiruselvi T, Sailakshmi G, Shanmugam G, Gnanamani A, Biochim. Biophys. Acta., 1830, 4898 (2013)

[28] Snyder T, Madhavan K, Intrator I, Dregalla R, Park DA, J. Biol. Eng., 8, 10 (2014)

[29] Zhu Z, Wang YM, Yang J, Luo XS, Plast Aesthet Res., 4, 219 (2017)

[30] Collins MN, Birkinshaw C, Carbohydr. Polym., 92, 1262 (2013)

[31] Rao NV, 22-Hyaluronic Acid-Based Hydrogels for Tissue Engineering. In Biomaterials for Organ and Tissue Regeneration; Vrana NE, Knopf-Marques H, Barthes J, Woodhead Publishing: Cambridge, pp 551-565, 2020.