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

Abstract

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.

Applications of Hydrogels in Osteoarthritis Treatment

“…Y. H. et al synthesized a thermosensitive chitosan-gelatin hydrogel that, through delivering glutathione, mitigated mitochondrial dysfunction, thereby reducing chondrocyte apoptosis and autophagy [137]. HA is also frequently used in thermosensitive hydrogels; Zhou et al formulated an injectable HAMA hydrogel microsphere responsive to hypoxia and MMP13 (Figure 8E) that degrades under MMP13 and releases drugs in hypoxic conditions [138]. Mechanical-responsive hydrogels react to pressure and friction (Figure 8B).…”

Transforming Osteoarthritis Treatment: Embracing Hydrogel Microspheres

“…191 Zhou et al's injectable hydrogel microsphere system (HAM-SA@ HCQ) incorporates an MMP-13-sensitive peptide that can be specifically cleaved upon encountering overexpressed MMP-13, leading to the release of SA@HCQ from the hydrogel microspheres. 105 This property enables targeted drug delivery and inhibition of inflammatory and degenerative changes, particularly in an inflammatory environment or OA cells with a high expression of MMP-13. The presence of MMP-sensitive peptides is inherent in gelatin.…”

“…However, in OA, induction of ROS along with stimulation from inflammatory factors leads to overexpression and activation of MMPs which subsequently destroy vital cartilage components like collagen fibers, HA, and other polysaccharides thereby accelerating the process of cartilage wear-and-tear. ,, MMP-13 plays a crucial role in cartilage degradation by cleaving type II collagen . Zhou et al’s injectable hydrogel microsphere system (HAM-SA@HCQ) incorporates an MMP-13-sensitive peptide that can be specifically cleaved upon encountering overexpressed MMP-13, leading to the release of SA@HCQ from the hydrogel microspheres . This property enables targeted drug delivery and inhibition of inflammatory and degenerative changes, particularly in an inflammatory environment or OA cells with a high expression of MMP-13.…”