Host response of different cross-linked hyaluronic acid
composite gels and matrix metalloproteinase-9 expression

doi:10.3969/j.issn.2095-4344.2243

Abstract

Abstract:

BACKGROUND: The interaction between hydroxyl in hydroxypropyl methylcellulose and hydroxyland carboxyl in hyaluronic acid can reduce the enzymatic hydrolysis of hyaluronic acid and increase the usability when used as a skin filling material.

OBJECTIVE: To investigate the host response of different cross-linked hyaluronic acid composite gels after they were implanted in vivo and matrix metalloproteinase-9 expression.

METHODS: Twelve New Zealand white rabbits (purchased from Beijing Longan Laboratory Animal Breeding Center) were injected with cross-linked hyaluronic acid composite gels through 10 points in subcutaneous tissue at both sides of the spine. On the left side, chemically cross-linked sodium hyaluronate-hydroxypropyl methylcellulose gel was injected via 4 points (chemical cross-linking group). On the right side, physically mixed sodium hyaluronate-hydroxypropyl methylcellulose gel was injected via 4 points (physical cross-linking group). The modified sodium hyaluronate gel which was marketed was injected via 1 point on each side (control group). Subcutaneous tissues including implant material was excised at 1, 4, and 12 weeks after injection. Hematoxylin-eosin staining was performed to evaluate the degree of inflammation and fibrosis. Masson staining was performed to observe the formation of collagen fibers. Immunohistochemical staining was performed to detect the expression of matrix metalloproteinase-9. This study was approved by the Animal Ethics Committee of Tianjin Institute of Medical and Pharmaceutical Sciences (approval No. IMPS-EAEP-H-2017030).

RESULTS AND CONCLUSION: Hematoxylin-eosin staining: In the chemical cross-linking group, at 1 and 4 weeks after injection, inflammatory reaction was more obvious, and the capsule wall and the microcapsule wall were thicker compared with the control group. At 12 weeks after injection, the degree of inflammation and fibrosis were similar between chemical cross-linking and control groups. At 1 week after injection, in the physical cross-linking group, a small amount of inflammatory cells were observed, and the fiber wrap and microcapsule wall formation were slightly more obvious than those in the control group. At 4 weeks after injection, the fiber wrap and microcapsule wall were thicker in the physical cross-linking group compared with the control group. At 12 weeks after injection, the degrees of inflammatory reaction and fibrosis in the physical cross-linking group were similar to those of the control group. Masson staining: In the chemical cross-linking group and physical cross-linking group, at 1 and 4 weeks after injection, the collagen fibers were increased compared with the control group and they further increased at 12 weeks, and at this time, there was no significant difference between chemical cross-linking and physical cross-linking groups. Immunohistochemical staining: in the chemical cross-linking group, matrix metalloproteinase-9 expression in the chemical cross-linking group was lower than that in the control group at 1 week after injection, and there was no significant difference at other time points. At 1 week after injection, matrix metalloproteinase-9 expression in the physical cross-linking group was lower than that in the control group. At 4 weeks after injection, matrix metalloproteinase-9 expression in the physical cross-linking group was higher than that in the control group. At 12 weeks after injection, there was no significant difference in matrix metalloproteinase-9 expression between physical cross-linking and control groups. These results showed that the biocompatibility of the two cross-linked sodium hyaluronate composite gels was good in 12 weeks after subcutaneous implantation. The expression of collagen fiber and matrix metalloproteinase-9 was gradually increased. All these are conducive to tissue remodeling. In the physical cross-linking gel, tissue reaction is smaller at the early stage, and matrix metalloproteinase-9 expression is significantly increased at the middle stage, which are more conducive to tissue repair and remodeling.

Key words: cross-linking, hyaluronic acid, gel, hydroxypropyl methyl cellulose, implantation, subcutaneous, host response, matrix metalloproteinase-9

CLC Number:

Nie Wei, Liu Weiwei, Liu Dawei, Cui Xiaoxue, Liu Shanhai, Li Xu, Xiao Guangli, Wang Shiwei, Niu Huanyun, Li Ruizhi. Host response of different cross-linked hyaluronic acid composite gels and matrix metalloproteinase-9 expression[J]. Chinese Journal of Tissue Engineering Research, 2020, 24(10): 1557-1562.

Figures/Tables 5

References

[1] KOGAN G, SOLTÉS L, STERN R, et al. Hyaluronic acid: a natural biopolymer with a broad range of biomedical and industrial applications.Biotechnol Lett.2007;29(1):17-25.
[2] 田廷璀,解从霞,于世涛.透明质酸水凝胶制备的研究进展[J].粘接,2016,37(5):81-84.
[3] 张政朴.天然高分子材料透明质酸及羟丙基甲基纤维素介绍[J].中国美容整形外科杂志,2010,21(3):159-160.
[4] 罗盛,陈光平.医用羟丙基甲基纤维素-透明质酸钠溶液在鼻唇部年轻化中的应用体会[J].中国美容整形外科杂志,2013,24(6): 358-360.
[5] MYTHILI P, JANIS L, KRISTINE SA, et al.Biodegradable materials and metallic implants-a review.J Funct Biomater. 2017;8(4):44-58.
[6] AMINI AR, WALLACE JS, NUKAVARAPU SP.Short-term and long-term effects of orthopedic biodegradable implants. J Long Term Eff Med Implants.2011;21(2):93-122.
[7] JONES JA, MCNALLY AK, CHANG DT, et al.Matrix metalloprotei- nases and their inhibitors in the foreign body reaction on biomaterials.J Biomed Mater Res A. 2008;84(1): 158-166.
[8] MEZNARICH N, KYRIAKIDES T, DONALDSON E, et al. Matrix-metalloproteinase (MMP-9) and its role in wound healing and the foreign body response.J Undergraduate Res Bioeng.2004;4:84-89.
[9] GB/T 16886.6-2015医疗器械生物学评价第6部分:植入后局部反应实验[S].北京:中国标准出版社,2015.
[10] 张建民.国内透明质酸产品市场现状和发展前景[J].中国医疗美容,2012,2(2):48-54.
[11] SHEIKH Z, BROOKS PJ, BARZILAY O, et al.Macrophages, Foreign Body Giant Cells and Their Response toImplantable Biomaterials.Materials(Basel).2015;8(9):5671-5701.
[12] 沈丽琳.羟丙甲纤维素在药物制剂方面的应用与研究[J].中国药业,2007,16(12):64-II.
[13] 叶君,黎青勇,熊犍.羟丙基甲基纤维素在不同界面的表面活性[J].华南理工大学学报(自然科学版),2013,41(12):18-23.
[14] 李睿智,张秀明,尹永磊,等.羟丙基甲基纤维素的体外自由基降解研究[J].化学与生物工程,2013,30(6):72-74.
[15] JONSSON A, HJALMARSSON C, FALK P,et al. Stability of matrix metalloproteinase 9 as biological marker in colorectal cancer.Med Oncol.2018;35(4):50-55.
[16] ALEXANDER J, ROBERT S, CARSTEN R, et al.Adiponectin attenuates profibrotic extracellular matrix remodeling following cardiac injury by upregulating matrix metalloproteinase 9 expression in mice. Physiol Rep. 2017; 5(24):e13523,page1-15.
[17] MACLAUCHLAN S, SKOKOS EA, MEZNARICH N, et al. Macrophage fusion, giant cell formation, and the foreign body response require matrix metalloproteinase 9.J Leukoc Biol. 2009;85(4):617-626.