ABSTRACT

The oxidative stress-induced degeneration of the retinal pigment epithelium (RPE) and secondary photoreceptor  damage are the main causes of dry agerelated macular degeneration (AMD). No effective interventions are  currently available for use in clinical practice. Therefore, the aim of this study was to design and evaluate the  effects of an injectable hyaluronic acid (HA) hydrogel containing the natural antioxidant myricetin (MY) using  both in vitro and in vivo models. To improve the solubility of MY, MY-cyclodextrin (CD) complexes were prepared  via host-guest interactions. MY-loaded injectable hydrogel (H-MY) sustained-release formulations were fabricated using adipic acid dihydrazide-modified HA and aldehyde-functionalized HA. Intravitreal injection of the  HA hydrogel prolonged the retention time of MY in the eyes of mice, without damaging the normal physiological  structures and functions of the organ. Compared with the NaIO3-treated group, the percentage of reactive oxygen  species (ROS)-positive cells in the H-MY-treated group decreased from 30.7 % to 3.21 %, indicating effective  inhibition of intracellular ROS production. And the JC-1 aggregation ratio in the H-MY-treated group increased  from 49.4 % to 71.9 %, reflecting a notable alleviation of mitochondrial damage. Meanwhile, the proportion of  apoptotic cells was reduced from 37.1 % to 25.3 %, demonstrating a significant decrease in cell apoptosis rate.  Furthermore, a NaIO3-induced acute oxidative stress model of retinal degeneration in mice was employed. In this  model, intravitreal injection of the H-MY significantly protected retinal structure and preserved tissue physiological functionality. The HA hydrogel has been observed to exhibit modest antioxidant activity, along with  acceptable biocompatibility and stability under experimental conditions. These characteristics suggest that it  may offer certain reference significance for clinical management of dry AMD.

Keywords: Injectable hydrogel；Retinal pigment epithelium；Oxidative stress；Dry age-related macular degeneration.