Hypoxia and Matrix Metalloproteinase 13-Responsive Hydrogel Microspheres Alleviate Osteoarthritis Progression In Vivo

The occurrence of osteoarthritis (OA) is highly associated with the inflammatory hypoxic microenvironment. Yet currently no attention has been paid to fabricating hypoxia-responsive platforms for OA treatment. Herein, an injectable hydrogel microsphere system (HAM-SA@HCQ) focusing on the hypoxic inf...

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Published in:	Small (Weinheim an der Bergstrasse, Germany) Vol. 20; no. 19; p. e2308599
Main Authors:	Zhou, Tong, Xiong, Hao, Yao, Shun-Yu, Wang, Shuqin, Li, Shifen, Chang, Jieting, Zhai, Zihe, Guo, Dong-Sheng, Fan, Cunyi, Gao, Changyou
Format:	Journal Article
Language:	English
Published:	Germany Wiley Subscription Services, Inc 01-05-2024
Subjects:	Animals Arthritis Bonding strength Calixarenes Crosslinking Disease Progression Hyaluronic acid Hydrogels Hydrogels - chemistry Hypoxia Hypoxia - drug therapy Hypoxia - metabolism Inflammatory response Macrophages Matrix Metalloproteinase 13 - chemistry Matrix Metalloproteinase 13 - metabolism Matrix metalloproteinases Mice Microfluidic devices Microspheres Osteoarthritis Osteoarthritis - drug therapy Osteoarthritis - metabolism Osteoarthritis - pathology RAW 264.7 Cells Reactive Oxygen Species - metabolism Scavenging host–guest recognition hypoxia response hydrogel microspheres osteoarthritis inflammatory microenvironment
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Summary:	The occurrence of osteoarthritis (OA) is highly associated with the inflammatory hypoxic microenvironment. Yet currently no attention has been paid to fabricating hypoxia-responsive platforms for OA treatment. Herein, an injectable hydrogel microsphere system (HAM-SA@HCQ) focusing on the hypoxic inflamed joint is prepared with methacrylate-modified sulfonated azocalix[4]arene (SAC4A-MA), methacrylated hyaluronic acid (HA-MA), and dithiol-terminated matrix metalloproteinase 13 (MMP-13) sensitive peptide via a microfluidic device and photo crosslinking technique, followed by encapsulation of the anti-inflammatory drug hydroxychloroquine (HCQ) through host-guest interaction. Owing to the hydrophobic deep cavity, phenolic units, and azo bonds of SAC4A-MA, the hydrogel microspheres show strong drug loading capacity, prominent reactive oxygen species (ROS) scavenging capability, and specific hypoxia-responsive drug release ability. In the OA tissue microenvironment, the hydrogel microspheres undergo degradation by excessive MMP-13 and release HCQ under the hypoxia condition, which synergizes with the ROS-scavenging calixarene to inhibit the inflammatory response of macrophages. After being injected into the OA-inflamed joint, the HAM-SA@HCQ can significantly attenuate the oxidative stress, downregulate the expression of hypoxia-induced factor-1α and inflammatory cytokines, and prevent the cartilage from being destroyed.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1613-6810 1613-6829
DOI:	10.1002/smll.202308599