The growing incidence of chronic ophthalmic diseases reported in developed countries in recent decades is mainly due to increased life expectancy and changes in lifestyle resulting in potentially harmful habits. These diseases cause deterioration and visual impairment. Among them, glaucoma and age-related macular degeneration are the most prevalent in the elderly population (Purola et al., 2021). Although the pathophysiology of the two diseases is complex, cellular senescence, oxidative stress and inflammatory pathways are common to them both (Dammak et al., 2021).

Oxidative stress and inflammation both generate reactive oxygen species (ROS). ROS can be produced by two pathways; one involves mitochondrial dysfunction while the other is related to the inflammatory response by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Dammak et al., 2021). In addition to oxidative stress, lipid peroxidation can also activate local para-inflammation, understood as “a tissue adaptive response to noxious stress or malfunction and has characteristics that are considered as intermediate between basal and inflammatory states” (Baudouin et al., 2021). Although a physiological response is essential to maintaining homeostasis and restoring tissue functionality, uncontrolled dysregulation can damage the retina and initiate and advance the disease. In fact, an excess of para-inflammation seems to cause production of cytokines/chemokines as a response to inflammation, resulting in neuroretinal damage (Baudouin et al., 2021, Rodrigo et al., 2021).

Treatments for chronic ocular diseases affecting the posterior segment require repeated intraocular administration to maintain effective concentrations in the retinal tissues. Intraocular injections, however, are poorly tolerated and the side effects increase with the number of interventions (Falavarjani and Nguyen, 2013). To address this issue, drug-delivery systems (DDS) have been developed with the main objective of dosing drug application since DDSs can control drug release for long periods, thereby significantly decreasing the number of interventions (Jain, 2020).

Hydrogels have attracted growing attention in recent decades. They are defined as highly hydrated mesh networks formed from natural, synthetic or semi-synthetic polymers that are physically or covalently crosslinked. In recent years, smart biomaterials such as smart and stimuli-responsive hydrogels have been developed and assessed for application in personalized precision medicine. Among their strengths are their ease of preparation and prolonged drug release (Bordbar-Khiabani and Gasik, 2022). Furthermore, use of small external triggers (e.g. changes in pH, temperature, electricity, magnetics, light or biomolecules) can produce changes in smart hydrogels’ physical properties.

Hydrogels are well suited to local drug delivery because of their biocompatibility, drug protection and, as mentioned, tuneable physicochemical properties (Vigata et al., 2020). Moreover, they offer a promising system for treating chronic retinal diseases since they are capable of sustaining drug release and thus extending their local presence, avoiding repeated administration (Ilochonwu et al., 2020). They can be made of natural polymers like chitosan, alginate, fibrin, gelatine or hyaluronic acid, or of synthetic polymers like poly(ethylene glycol) (PEG) or poly(vinyl alcohol). There are also semi-synthetic hydrogels made up of gelatine functionalized by synthetic groups such as methacryloyl (Vigata et al., 2020).

This paper develops two different injectable smart hydrogels for the treatment of ophthalmic diseases. One is composed of a natural polymer (hyaluronic acid) and the other comprises a synthetic hydrogel in which poly(lactic-co-glycolic acid) (PLGA) and PEG monomer units form the PLGA-PEG-PLGA (PPP) triblock.

Hyaluronic acid (HA), also called hyaluronan, is a glycosaminoglycan composed of repeating disaccharide units of α-1,4-D-glucuronic acid and β-1,3-N-acetyl-D-glucosamine. It is a naturally ubiquitous polymer present in all vertebrates and plays crucial roles in the composition and structure of the extracellular matrix; in tissue development, organization and remodelling; and in inflammation modulation, among others (Abatangelo et al., 2020, Bian et al., 2016). However, use of uncrosslinked HA is limited due to its rapid degradation, in vivo clearance and poor mechanical properties. To overcome this, HA can be chemically modified by means such as esterification of the carboxylic acid groups or modification of the alcohol groups (by divinyl sulfone or diglycidyl ethers) (Segura et al., 2005). Crosslinked hydrogels with injectable properties, obtained by the interaction of thiol (SH) and aldehyde (CHO) groups, have been described in the literature (Yang et al., 2021). This paper explores development of crosslinked hydrogels by combining HA-SH and HA-CHO.

In the case of synthetic PPP hydrogels, PEG is a non-toxic biodegradable polymer with no antigenic or immunogenic effects that is widely used in pharmacological applications. PEG can be copolymerized with PLGA as well as with other aliphatic polyesters such as polylactic acid (PLA) and poly(ε-caprolactone). Biodegradability and biocompatibility are key properties when developing hydrogels. For this reason, PPP hydrogels are widely studied as PLGA also possesses these properties (Wang et al., 2017). PPP hydrogels are thermosensitive and the gelation process involves micelle aggregation. Once formed, the micelles are composed of a hydrophobic core (PLGA) surrounded by PEG tails. At room temperature, the micelles are separate. As temperature increases, the micelles increase in size and aggregate (López-Cano et al., 2021, Wang et al., 2017).

In this study, the two hydrogels are developed and characterized to assess their suitability as regards sustained release of an anti-inflammatory drug. The ultimate aim is to use these hydrogels as an intravitreally administered drug-delivery platform for treating chronic ophthalmic diseases affecting the back of the eye. In vitro tolerance of the synthetized hydrogels is evaluated in retinal cells. Finally, a preliminary in vitro wound healing study is conducted with the final formulation.