The human eye can be divided into two chambers (2): the posterior and the anterior. The anterior segment of the eye includes the cornea, iris, pupil, ciliary body, lens, sclera, conjunctiva, and anterior chamber, which is filled with aqueous humor. The posterior segment includes the Vitreous body, retina, macula, optic nerves, choroid, and optic disc (65).

Ocular drug absorption is limited by various static, dynamic, and metabolic barriers. Static barriers consist of the corneal epithelium, blood-aqueous barrier, blood-retinal barrier, sclera, and endothelial cells of blood capillaries (66, 67).

In contrast, dynamic barriers include tear drainage, clearance mechanisms via conjunctival blood and lymphatic flow, and choroidal blood and lymphatic circulation. Collectively, these barriers restrict drug penetration and bioavailability within ocular tissues (68). Figure 4 illustrates the anatomy of the human eye anatomy and includes examples of diseases affecting the anterior and posterior segments of the eye.

Schematic illustration of the human eye anatomy, along with examples of diseases affecting the anterior and posterior segments of the eye

According to the National Eye Institute (NEI) and the Centers for Disease Control and Prevention (CDC), more than 7 million Americans have experienced vision loss or blindness caused by various eye diseases (69, 70). Eye diseases can be classified into two types based on their location: anterior and posterior. Anterior segment eye diseases (ASED) include conditions such as dry eye disease (DED), corneal alkali burns, and corneal neovascularization. Posterior segment eye diseases (PSED) include conditions such as age-related macular degeneration (AMD), diabetic retinopathy, and retinal neovascularization (RNV) (71). Both ASED and PSED can significantly impact vision and ocular health, potentially leading to vision loss (72,73,74).

Treatment for anterior segment eye disease (ASED) involves the topical administration of ophthalmic formulations. However, this approach has several challenges, primarily low bioavailability due to the intricate physiology of the human eye (75). The eye's natural defense mechanisms, such as blinking, tearing, and nasolacrimal drainage, significantly reduce the residence time of ophthalmic preparations on the ocular surface (58). Furthermore, ocular barriers restrict drug permeation, impeding efficient delivery to the posterior segment of the eye. Additionally, systemic administration is seldom used for ocular drug delivery because of the restrictive nature of the blood-retinal barrier, which severely limits drug penetration into ocular tissues (76, 77). To address these challenges, traditional strategies include frequent eye drop administration or increased drug concentration (78). However, both methods often result in poor patient compliance and potential side effects (65). Thermoresponsive hydrogels remain viscous on the ocular surface for an extended period, thereby prolonging the absorption window for therapeutic agents. This enhanced retention improves ocular drug bioavailability and efficacy, making thermoresponsive hydrogels a significant advancement in ophthalmic drug delivery (5, 79).

The treatment for posterior segment eye disease (PSED) relies on direct delivery of the therapeutic agent to the vitreous humor via intravitreal injection (32, 80). This route of administration effectively bypasses ocular barriers (33).

However, the intravitreal route of administration has several drawbacks, including the need for frequent administration. This can reduce patient compliance and also increase the risk of retinal detachment or endophthalmitis (81, 82).

According to the FDA Orange Book, 24 drugs have been approved for intravitreal injection, but only 5 are considered long acting. These drugs are listed in Table I (83). In addition, while there are numerous FDA-approved ophthalmic drug products available only five of these provide sustained release.

The majority of long-acting intravitreal therapies depend on insertion of an implants into the vitreous humor which gradually release the therapeutic agent over several months. This decreases injection frequency and related complications. However, currently approved implants have several drawbacks, including the need for a surgical procedure and the use of a large-gauge needle (up to 22 G). These procedure also carry a significant risk of elevation of intraocular pressure to 60–70 mmHg, which may necessitate removal of the implant via vitrectomy(19).

Thus, there is a need to design and develop innovative drug delivery systems that ensure sustained release of therapeutic agents, reduce administration frequency, and eliminate the drawbacks associated with current long-acting injectable implants.

As a result, thermoresponsive hydrogels have been extensively investigated to extend the therapeutic duration of intravitreal medications (84, 85). Thermoresponsive hydrogels have also been explored for other routes of ocular drug administration, including the subconjunctival route, the suprachoroidal route with a microcannula and microneedles, and the subretinal route (75, 76, 86, 87). Figure 5 depicts a schematic representation of ocular drug administration routes, including topical, subconjunctival, suprachoroidal, subretinal, and intravitreal administration.

An illustration of ocular drug administration routes, including topical, subconjunctival, suprachoroidal, subretinal, and intravitreal administration

To date, more than 100 hydrogel products have been approved (19), with more than 25 hydrogel-based products for ocular use approved by the FDA and/or EMA. In addition there are over 425 clinical trials are underway, and over 200 of these are focused on ocular drug delivery (88).

To design the thermoresponsive hydrogel compatible with ocular physiology, formulation goals should include: gelation near ocular temperature (~ 34 °C on the surface; ~ 37 °C in the vitreous), rapid gelation to prevent early drug leakage, optical clarity, controlled swelling and degradation profiles compatible with ocular tissues, and predictable release across varying physiological conditions (tear osmolarity/inflammation; vitreous aging or liquefaction) (32, 55).

In the following section, we present the latest research with thermoresponsive hydrogels that have potential for use in treating Anterior Segment Eye Diseases (ASED) and Posterior Segment Eye Diseases (PSED).

Between 16.7 million and 50.2 million Americans suffer from dry eyes. The economic impact of DED in the US exceeds $55.4 billion (89). According to the American Academy of Ophthalmology (AAO), DED is a condition characterized by insufficient lubrication of the eyes due to low tear production (90), resulting in symptoms such as visual disturbances, eye discomfort, pain, redness, and a burning sensation. The current standard of care includes artificial tears, but rapid clearance by the lacrimal drainage system requires frequent application (6).

While many therapeutic agents have been studied for dry eye disease (DED), a common limitation of traditional topical treatments is rapid precorneal clearance as a result of tear turnover, blinking, and nasolacrimal drainage, all of which greatly reduce ocular drug retention and bioavailability (111). Thermoresponsive hydrogels have been investigated as a method to improve retention on the ocular surface and to provide sustained release of therapy (25). These systems undergo a sol-to-gel transition at the ocular surface temperature (~ 34–35°C), thereby forming a drug depot on the corneal surface. This process extends the drug's residence time and enhances bioavailability compared to conventional eye drops (88). Drug retention and release kinetics are influenced not only by the physicochemical properties of the incorporated drug and excipients but also by polymer properties such as gelation temperature, viscosity, and mucoadhesive interactions with ocular mucins (91).

Thermoresponsive hydrogels have been widely studied as a potential treatment for DED. Ou et al. (92) developed an eye drop formulation by combining copper-selenium nanoparticles (Cu2-x Se NPs) with aldehyde-functionalized Pluronic F127 (AF127). Cu2-x Se is used as an antioxidant to remove excessive reactive oxygen species (ROS) that contribute to the development and progression of DED. Cu2 − x Se nanoparticles exhibit enzyme-mimicking capabilities in acting as superoxide dismutase and glutathione peroxidase. Additionally, Cu2 − x Se NPs have efficacy in scavenging reactive oxygen species (ROS) and mitigating oxidative damage, which was known to last for up to 72 h. Cu2-x Se NPs eliminated ROS in a concentration-dependent manner. Electron Spin Resonance (ESR), combined with a TMB chromogenic method, was used for determining the ·OH scavenging activity. It was shown that more than 90% of hydroxyl radical (OH) was eliminated when the concentration of Cu2-x Se NPs was 20 μg/mL. Furthermore, approximately 60% of hydrogen peroxide (H2O2) (10 mM) can be decomposed by 80 μg/mL Cu2-x Se NPs. The AF127 thermoresponsive hydrogel enhanced tissue adhesion by forming Schiff-base links with the free amino groups (-NH₂) in mucin and other proteins on the ocular surface (92). In vivo fluorescence imaging using Rhodamine B (RhB) was performed in male C57BL/6 J mice, where DED was induced using scopolamine. It showed that AF127 conjugated with Rhodamine B (RhB) (RhB-AF127 solution), and that sol–gel transitions occurred immediately. and emitted higher fluorescence intensity than RhB alone. In addition, the fluorescence intensity of RhB-AF127 could be maintained relatively constant within 60 min (92).

De Luca et al. (93) developed eyedrop formulations based on acetylated polyethyleneimine-modified polylactic-co-glycolic acid (PLGA-PEI) nanoparticles loaded with resveratrol (RSV-NPs) that were dispersed into poloxamer 407 hydrogel. Resveratrol (RSV) was selected due to its antioxidant and anti-inflammatory properties.

The developed formulation exhibited sustained resveratrol (RSV) in vitro release for up to 3 days. In addition, using human corneal epithelial cells (HCECs) and quantitative assays to measure intracellular ROS and inflammatory markers, the formulation showed potent antioxidant and anti-inflammatory effects. This study used an in vitro hyperosmolarity-induced dry eye model to evaluate the formulation’s antioxidant abilities. The level of intracellular ROS was assessed using the CM-H2DCFDA assay, in which the non-fluorescent probe is oxidized by ROS to produce fluorescent 2`,7`-dichlorodihydrofluorescein (DCF). ROS formation was notably reduced in the presence of the thermoresponsive hydrogel PLGA-PEI encapsulating RSV-NPs (about 45%, p < 0.01) compared to HCECs cultured in isosmotic medium (312 mOsm/L) that received no treatment (93).

Chen et al. (94) reported the development of thermoresponsive hydrogel using poloxamer (P407) in combination with hypromellose (HPMC) and hyaluronic acid (HA) (13% P407, 2.5% HPMC, and 0.3% HA—(TES/P13H2.5 HA-L0.3)) to improve mucoadhesion for the treatment of DED. The formulation was designed to deliver hydroxypropyl-β-cyclodextrin (HPβCD)-solubilized testosterone (TES). Testosterone (TES) is known to stimulate lipid secretion from the meibomian glands, which is crucial for maintaining a stable tear film lipid layer and reducing tear evaporation. This is important for DED patients with meibomian gland dysfunction (MGD) (94).

The thermoresponsive hydrogel achieved prolonged retention in the corneal tissue. Fluorescent imaging was employed to determine corneal retention of TES on glass surfaces and freshly excised rabbit corneas. The TES solution was completely removed after four washes using simulated tear fluid (STF) on the glass surface. In contrast, over 60% of the thermoresponsive hydrogel remained on the glass slide after 10 washes. Similar results have been observed when applying a TES solution and thermoresponsive hydrogel to the rabbit cornea. After one wash, nearly 70% of the drug solution was removed, while 92% ± 3% of the thermoresponsive hydrogel formulation (TES/P13H2.5 HA-L0.3) remained on the rabbit cornea (94).

Overall, these studies show that thermoresponsive hydrogels can enhance ocular surface retention, and enable sustained release of antioxidant, anti-inflammatory, and hormonal treatments for DED. While different studies use various polymer systems and drugs, a common finding is that thermoresponsive gels increase drug residence time on the ocular surface compared with conventional dosage forms. Nonetheless, it is crucial to balance gel strength with patient comfort and clear vision, as excessive viscosity can cause transient visual disturbances.

In addition to DED, thermoresponsive hydrogels have been investigated for the treatment of acute corneal injuries. In these cases, sustained delivery of anti-inflammatory agents and wound-healing factors play a critical role in preventing long-term vision impairment.

Corneal alkali burns are severe ocular injuries caused by exposure to alkaline substances such as ammonia. Their effects can extend beyond the eye's surface, causing neovascularization and corneal scarring that may impair vision. They account for 11.5% to 22.1% of ocular trauma cases in the United States (95). The current standard of care is hourly applications of corticosteroids and antibiotics to treat corneal alkali burns. Studies have been conducted on thermoresponsive hydrogels to extend the residence time of therapeutic agents for patients with corneal alkali burns (96).

Augusto de Castro et al. (97) developed a poloxamer-based thermoresponsive hydrogel system containing hyaluronic acid and indomethacin as a potential treatment for corneal alkali burns. The formulation gelling temperature was 34.2 ± _0.11 ◦C, which is close to the ocular surface temperature (34–35◦C). In vitro release studies showed a sustained release profile with a cumulative release of 59.75 ± 3.17% up to 24 h. Changes in corneal opacity, which are associated with stromal disruption driven by alkali substance penetration, were used to assess corneal surface healing in rabbit eyes. A statistically significant decrease in corneal opacity scores was observed in animals treated with thermoresponsive hydrogel after 3days (average score: 2 ± 0) when compared to animals treated with the commercial formulation (*p = 0.0154) and the untreated group (NT) (****p ≤ _0.0001) (97).

Qin et al. (98) developed thermoresponsive hydrogel eye drops from polyamino acid-based poly-S-nitrosothiols (PGlu-TEPA-SNAP) as a potential treatment for corneal alkali burns. The formulation was used to deliver Nitric Oxide (NO), a therapeutic agent used to promote corneal epithelial healing and reduce inflammation. The formulation enhanced the retention of NO carrier on the ocular surface, with NO delivery lasting more than 12 h. The retention ability of PGlu-TEPA-SNAP was investigated by topically administering hydrophobic fluorescent probe RhoB-labeled polymers on mice. Fluorescence from free Rho B completely disappeared 6 h after administration. On the other hand, NO-RhoB still remained on the ocular surface 12 h after administration, as calculated from fluorescence intensity. It has been hypothesized that the improvement in residence time was the result of bonding interactions between the negatively charged cornea surface and the cationic side of the thermoresponsive hydrogel. PGlu-TEPA-SNAP thermoresponsive hydrogel induced rapid corneal wound recovery in an in vivo study conducted in C57BL/6 J mice. Cornea treated with 30 μM PGlu-TEPA-SNAP demonstrated reduced choroidal neovascularization vessel length and size than those treated with saline (0.25 ± 0.05 mm and 0.74 ± 0.16 mm2 vs. 0.66 ± 0.07 mm and 2.63 ± 0.37 mm2, respectively), and was as good as the positive control dexamethasone (Dexp; 0.27 ± 0.06 mm and 1.01 ± 0.19 mm2) (98).

Zhou et al. (99) developed a thermoresponsive hydrogel for ocular tissue protection upon serious injury using poly (lactic-co-glycolic acid)-poly (ethylene glycol)- poly (lactic-co-glycolic acid) (PLGA-PEG-PLGA) triblock polymer to deliver anti- vascular endothelial growth factor (VEGF) antibodies and tumor necrosis factor-alpha (TNF-α) inhibitors (0.7 mg of adalimumab and 1.4 mg of aflibercept). According to an in vivo study conducted in Dutch-belted rabbits, the developed formulation achieved dual delivery and sustained release for 3 months. Following corneal alkali burn, subconjunctival application of the thermoresponsive hydrogel reduced the infiltration of CD45 + immune cells into the cornea, prevented retinal ganglion cell (RGC) and optic nerve axon loss, and prevented corneal neovascularization (CNV) for three months. It also expedited corneal re-epithelialization and wound healing. On the other hand, at three months, there was a significant loss of RGCs (combined: 2.7%; anti-VEGF: 63%; IgG: 45%), a persistent corneal epithelial defect (combined: < 1%; anti-VEGF: 15%; IgG: 10% of cornea area), and increased infiltration of CD45 + immune cells into the cornea (combined: 28 ± 20; anti-VEGF: 730 ± 178; anti-IgG: 360 ± 186 cells/section) using anti-VEGF alone or IgG-based Drug Delivery Systems (DDS) treatment (99).

Overall, these studies demonstrate the versatility of thermoresponsive hydrogels in delivering treatments for corneal injuries. In addition to increasing ocular surface residence time, many formulations reduce inflammation and support epithelial healing in preclinical tests. Combining sustained drug release with targeted tissue protection could be advantageous compared to conventional topical treatments, which typically require frequent application and have limited contact time with the eye.

Corneal Neovascularization (CNV) is a disorder in which the cornea grows new blood vessels and is characterized by increased levels of VEGF. Approximately 1.4 million people are impacted by CNV yearly, and 12% of cases result in blindness within 5–10 years of diagnosis (100). The current treatment of CoN entails the subconjunctival administration of anti-VEGF therapeutic agents. However, several challenges, including rapid clearance and limited permeation, hinder effective drug delivery (101).

Nan et al. (102) prepared a thermosensitive hydrogel composed of poloxamer-oxidized sodium alginate (F127-OSA) loaded with bone morphogenetic protein 4 (BMP4). BMP4 was shown to downregulate VEGF-factor A, a key driver of CNV. The drug release of the F127-OSA thermoresponsive hydrogel continued for more than 72 h (78% at 72 h). The ability of the BMP4/F127-OSA thermoresponsive hydrogel formulation to alleviate CNV symptoms was investigated using a suture-induced rat CNV model in combination with BMP4 Eye Drops. Corneal epithelial cell thickness and its configuration, both indicators of corneal inflammation, were studied using HE stains. It was observed that the BMP4/F127-OSA formulation prevented abnormal epithelial cell growth, alleviated corneal edema, and decreased the length and area of CNV, which was statistically significant when compared to the BMP4 eye drops. In addition, F127-OSA thermoresponsive hydrogel performed better on Day 5 than BMP4 eye drops (102).

These findings demonstrate that thermoresponsive hydrogels are an effective method for delivering anti-angiogenic therapies to treat corneal neovascularization. Sustained drug release and improved ocular retention may help overcome the limitations of conventional eye drops, which often fail to maintain therapeutic drug concentrations due to rapid tear clearance. Further studies are necessary to evaluate long-term safety, optimal dosing strategies, and the translational feasibility of these systems in clinical settings.

Interestingly, thermoresponsive hydrogels were utilized in the treatment of SARS-CoV-2 to prevent infection of the ocular epithelia and mucosa. The potential for SARS-CoV-2 to infiltrate the anterior portion of the human eye arises from the presence of angiotensin-converting enzyme 2 (ACE2) receptors and transmembrane protease serine 2 (TMPRSS2) protein in ocular tissues (103).

S. Xu et al. (104) developed a thermoresponsive hydrogel that interrupts the spread of coronavirus 2 (SARS-CoV-2) through corneal and conjunctival routes. The formulation consists of a selenium-containing polymer, specifically di-(1-hydroxylundecyl) selenide (DHSe), along with poly (ethylene glycol) (PEG) and poly (propylene glycol) (PPG), which are copolymerized to form the poly (DHSe/PEG/PPG urethane) polymer. The poorly water-soluble COVID-19 therapy remdesivir (RDV) was incorporated into the thermoresponsive polymer. The sol-to-gel transition was determined to be 35°C. Dialysis-based in vitro release studies indicated that the thermoresponsive hydrogels prolonged RDV release compared to the RDV-cyclodextrin inclusion complex solution. The thermoresponsive hydrogel demonstrated an initial release of 50%, while the RDV-cyclodextrin solution exhibited over 90% release after 1 h. The release from the thermoresponsive hydrogel was sustained for more than 12 h (104).

Overall, these studies collectively demonstrate that thermoresponsive hydrogels serve as a versatile drug delivery platform for various anterior segment eye diseases. In different disease models including dry eye disease, corneal injuries, neovascularization, and viral infections these systems consistently enhance ocular residence time and enable sustained therapeutic delivery. Despite these promising results, further research is necessary to optimize formulation parameters, assess long-term ocular safety, and develop scalable manufacturing strategies to facilitate the clinical translation of thermoresponsive hydrogel-based ocular therapies.

Age-related macular degeneration (AMD) is an eye disease caused by age-related damage to the macula (the part of the retina that is responsible for sharp and straight-ahead vision). According to the CDC, approximately 19.8 million Americans aged 40 and older have some form of AMD (105). AMD is classified into wet and dry AMD based on the cause of the macular damage. In wet AMD, macular damage is caused by choroidal neovascularization (CoN), which is the abnormal growth of blood vessels in the choroid into the subretinal region. On the other hand, in dry AMD, macula distortion results from lipid dispositions. Currently, there is no effective treatment that can prevent the degenerative progression of dry AMD (106). Wet AMD, on the other hand, is controlled by intravitreal injection of anti-VEGF therapeutic agents, although data show that one-third of wet AMD patients are unresponsive to mono-VEGF target therapies (107).

Thermoresponsive hydrogels have therefore been investigated as sustained drug delivery platforms for posterior segment diseases such as age-related macular degeneration (107, 108). The need for such delivery strategies arises because conventional anti-VEGF therapies often require repeated intravitreal injections, which can increase the risk of complications and reduce patient compliance (107, 109). The following studies highlight different thermoresponsive polymer strategies designed to prolong anti-angiogenic drug exposure and reduce the frequency of intravitreal injections required for AMD management.

H. Gao et al. (110, 111) prepared an injectable supramolecular nanofiber thermoresponsive hydrogel loaded with betamethasone phosphate (BetP), an anti-inflammatory agent, and the anti-VEGF monoclonal antibody ranibizumab, using an aqueous solution of CaCl2 (anti-VEGF BetP-Gel). The formulation serves two purposes. It provides a long-term sustained release of ranibizumab to inhibit vascular proliferation in the retina and reduce choroidal neovascularization. Additionally, it can scavenge reactive oxygen species to minimize local inflammation. An in vivo fluorescence imaging system was utilized to observe the ability of BetP-Gel to deliver ranibizumab into the vitreous humor. In this study, a group of C57BL/6 J mice received either Cyanine 5.5-labeled IgG (free IgG-Cy5.5) or BetP-Gel encapsulating IgG-Cy5.5 (IgG-Cy5.5 BetP-Gel) and were monitored. On day 14, strong fluorescence signals remained evident in the IgG-Cy5.5 BetP-Gel-treated mice, while signals disappeared for free IgG-Cy5.5. The BetP-Gel demonstrated in vitro sustained release of entrapped ranibizumab, with 50% of the entrapped antibodies being released within 3 days in phosphate-buffered saline (110,