Glaucoma is the main trigger of global irreversible vision loss. Because of the growingly aging population, it has been projected that the number of people with glaucoma will increase to over 100 million in 2040 [1]. Currently, it is recognized as optic neuropathy caused by a multitude of factors [2]. Although the pathogenesis of the disease is still under investigation, there is now broad consensus that IOP plays a critical role in the glaucoma etiology, and treatments lowering IOP have been proven to slow disease progression [3], [4], [5]. Glaucoma is a chronic disease that requires lifelong therapy, which is commonly treated with daily eye drops, but the adherence of patients is often unsatisfactory [6]. Discomfort caused by frequent medication may affect patient quality of life and may lead to undesirable poor IOP control [7]. Such traditional topical and mucosal drug delivery systems are followed with poor retention at the target site [8], [9]. Furthermore, due to the existence of various physical and biochemical barriers, this local application invariably displays limited bioavailability (< 5 %) [10], [11], [12]. To enhance the ocular treatment efficacy, eye drops need to be administered in high concentrations or frequent regimens, leading to poor compliance and severe side effects [13].

At present, ocular implants are a promising localized drug delivery system for prolonging retention time and improving therapeutic efficacy. These implants can be introduced directly in the vitreous, anterior chamber, lacrimal duct, or on the sclera for the drug formulation release into the eye [14]. Ocusert®, Vitrasert®, Retisert®, Ozurdex®, Iluvien®, Dextenza®, Yutiq®, and Durysta®, approved by the FDA, provide a platform for sustained release of drugs from biodegradable or non-biodegradable polymeric matrices from several days to years [15], [16]. Biodegradable implants are commonly prepared using polymers including polylactic acid (PLA), polyglycolic acid (PGA), polylactic-glycolic acid (PLGA), and polycaprolactones (PCL) [17]. Non-biodegradable implants are generally fabricated using polymers such as silicone composite, polyvinyl alcohol (PVA), and ethylene vinyl acetate (EVA) [15]. Such systems provide attractive strategies to optimize the therapeutic effects. However, most of the routes are invasive, which depress patient acceptability. In recent years, lacrimal implants are a few noninvasive options for ocular drug delivery and can be utilized in the treatment of glaucoma [18], [19].

Several diverse classes of drugs are currently applied in glaucoma therapy to lower IOP, which either impede the production of aqueous humor or enhance its outflow. Latanoprost, the first-line drug in glaucoma therapy, is a prostaglandin F2 analog that effectively lowers IOP by increasing aqueous outflow [20]. Timolol, one of the most used drugs in glaucoma therapy, is a β-blocker that reduces aqueous production to decrease the IOP [21]. The synergistic application of two drugs with distinct mechanisms can collectively lower IOP. Xalacom® eye drops which contain 0.5 % timolol and 0.005 % latanoprost have demonstrated superior therapeutic efficacy than monotherapy [22].

Consistent with previous studies, hydrogel or gel systems had been found to substantially improve retention time and superiorly sustain drug release [23], [24]. Hydrogels perform a three-dimensional hydrophilic network with high water content, whose structures can be modified to achieve degradability and functionality [25], [26]. Hydrogel degradation is capable to regulate the release rate of drugs and allow for hydrogel clearance after drugs were drained [27], [28], [29]. Thanks to their distinguishing characteristic, hydrogels provide an opportunity for ophthalmic drug delivery in the treatment of ocular diseases, which enable localized, prolonged, and co-delivered drug release [30]. Hayashi et al. have reported a hydrogel of tetra-armed poly (ethylene glycol) with ultralow swelling pressure and have demonstrated its use as an artificial vitreous body [31]. In addition, systems including nanoparticles, micelles, liposomes, and dendrimers have recently been exploited in the hydrogels, which further extended the residence time of drugs [32], [33].

Inspired by the progress of biomaterial technology, we envisaged a compatible lacrimal hydrogel implant with low polymer content for the treatment of glaucoma. The hydrogel was stretched by a unique molecular orientation fixation technology before complete dehydration to lock in the molecular orientation, allowing the implant to acquire anisotropic expansion properties. Once placed in the lacrimal duct, the implant harvested tears and then got shorter and thicker. This key property enables the implant to be fixed in the lacrimal duct, like an anchor, to prevent them from dropping out.

Herein, in the present study, a triple crosslinked micelle-hydrogel lacrimal implant was designed for the localized and prolonged therapy of glaucoma. In this system, two hydrophobic drugs including latanoprost and timolol were simultaneously entrapped in the PEG-PLA micelles with high encapsulation efficiency and further loaded into the hydrogels, facilitating a double sustained release of drugs. The critical properties such as physicochemical characterization, rheological characterization, and swelling performance were initially delineated, and in vitro release, in vivo pharmacodynamic effect, and in vivo safety were systematically evaluated (Fig. 1).