Thavasyappan Thambi (경희대학교) | 한빛사논문 > 한빛사

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경희대학교

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Bioact. Mater., Volume 49, July 2025, Pages 154-171 | https://doi.org/10.1016/j.bioactmat.2025.03.002 Tailoring hyaluronic acid hydrogels: Impact of cross-linker length and density on skin rejuvenation as injectable dermal fillers and their potential effects on the MAPK signaling pathway suppression

Mohanapriya Murugesan^a,1, Ramya Mathiyalagan ^a,1, Zelika Mega Ramadhania ^a, Jinnatun Nahar ^a, Cuong Hung Luu ^b, V.H. Giang Phan ^c, Deok Chun Yang ^a,d, Qihui Zhou ^e, Se Chan Kang ^a,d, Thavasyappan Thambi ^a

^aGraduate School of Biotechnology, College of Life Sciences, Kyung Hee University, Yongin Si, Gyeonggi do, 17104, Republic of Korea
^bQueensland Micro- and Nanotechnology Centre, Griffith University, Nathan, QLD, 4111, Australia
^cBiomaterials and Nanotechnology Research Group, Faculty of Applied Sciences, Ton Duc Thang University, Ho Chi Minh City, Vietnam
^dDepartment of Oriental Medicinal Biotechnology, College of Life Science, Kyung Hee University, Yongin-si, Gyeonggi-do, 17104, Republic of Korea
^eQingdao Key Laboratory of Materials for Tissue Repair and Rehabilitation, School of Rehabilitation Sciences and Engineering, University of Health and Rehabilitation Sciences, Qingdao, 266071, China
¹These authors contributed equally to this work.
Corresponding author : Thavasyappan Thambi

Abstract

Hyaluronic acid (HA) hydrogels, obtained through cross-linking, provide a stable 3D environment that is important for controlled delivery and tissue engineering applications. Cross-linking density has a significant impact on the physicochemical properties of hydrogels, including their shape stability, mechanical stiffness and macromolecular diffusivity. However, often cross-linking chemistries require photoinitiator and catalyst that may be toxic and cause unwanted tissue response. Here, we prepared a series of HA hydrogel with varying cross-linker length and cross-linking density, which can be obtained by altering the feed ratio of three different cross-linkers from small molecules to macromolecules (e.g., 1,4-butanediol diglycidyl ether (BDDE), ferulic acid (FA), pluronic (PLU)), to ameliorate skin wrinkles in mice models. HA cross-linked with FA and PLU exhibited enzyme and temperature-dependent sol-to-gel phase transition, respectively, and the gels possess good injectability. In vitro test confirmed that HA hydrogels co-cultured with RAW 264.7 and HDF cells showed good biocompatibility. In particular, HA cross-linked with PLU stimulated the growth of HDF cells and HaCaT cells. HA cross-linked with PLU suppressed the expression levels of proteins involved in collagen degradation including mitogen-activated protein kinases (ERK, JNK, p38) and matrix metalloproteases (MMP-1, MMP-3, and MMP-9) resulting in increased deposition of Collagen I. The free-flowing sols of HA hydrogel precursors are subcutaneously injected into the back of BALB/c mice and form stable gels at the dermis layer and found to be non-toxic. More importantly, HA hydrogel cross-linked with PLU showed an enhanced anti-wrinkling effect in the wrinkled mice model. Thus, properties of HA hydrogels such as injectability, biocompatibility, and good anti-wrinkling effect altered through varying cross-linking density must be considered in the context of soft tissue engineering applications.

논문정보

형식Research article
게재일2025년 07월 (BRIC 등록일 2025-07-04)
연구진국내(교신)+국외 연구진
분야 바이오·의료융합 > 바이오소재

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