More than 250 million people worldwide live with visual impairment, and without better treatments, as many as 115 million could be blind by 2050. A new review of nanofiber hydrogels suggests that a class of soft, water-rich biomaterials could help reshape how drugs are delivered to the eye—potentially replacing some of the most burdensome eye drops and repeated injections with long-lasting, responsive treatments. The materials are still largely at the preclinical stage, but studies in animal models of age-related macular degeneration, bacterial keratitis, uveitis and chemical eye injuries indicate that they can keep medicines at their target for substantially longer, reduce inflammation and improve tissue healing. One injectable system extended the effective treatment window of an anti-VEGF therapy threefold in mice, while another maintained an antibiotic concentration on the cornea for more than 25 hours.
The need for such technology arises from the eye’s extraordinary ability to keep foreign substances out. On its surface, the tear film is rapidly renewed and drained through the nasolacrimal system. Its lipid, aqueous and mucin layers create different chemical barriers for hydrophobic and water-loving molecules. Beneath it, the cornea’s epithelial, stromal and endothelial layers restrict penetration into the anterior chamber. The conjunctiva, sclera and blood–aqueous barrier add further obstacles. Reaching the retina is even harder: drugs must pass through or around the vitreous, choroid and blood–retinal barrier, whose tightly connected endothelial and retinal pigment epithelial cells regulate movement from the bloodstream. These defenses preserve the eye’s delicate optical environment, but they also mean that less than 5 percent of a conventionally applied topical drug may reach the aqueous humor.
Current treatments therefore force a compromise between convenience and effectiveness. Eye drops are non-invasive and widely accepted, yet rapid blinking, tear production, drainage and poor corneal permeability quickly remove them from the ocular surface. Systemic medicines are filtered by the blood–retinal barrier and may require doses high enough to cause toxicity elsewhere in the body. Intravitreal injections deliver drugs directly into the vitreous and are indispensable for many retinal diseases, but they carry risks including endophthalmitis, retinal detachment, increased intraocular pressure and retinal injury. Patients receiving anti-VEGF drugs for neovascular age-related macular degeneration may need injections approximately every month, creating a heavy clinical, financial and practical burden. Nanofiber hydrogels are being developed to occupy the middle ground: they can be injected or placed on the eye, conform to tissue, and release a therapeutic payload slowly instead of allowing it to disappear within minutes.
The basic design combines nanoscale fibers with a three-dimensional hydrogel network. Hydrogels are crosslinked polymers that swell in water, creating a soft matrix capable of holding and releasing molecules. Nanofibers add surface area, strength and structural organization, while their open network can imitate aspects of the extracellular matrix surrounding cells. Two families are attracting particular attention. Self-assembled peptide-based hydrogels, or SAPHs, are built from short peptide molecules that organize themselves into nanofibers through hydrogen bonding, hydrophobic interactions, electrostatic forces or molecular recognition. Their sequences can be engineered to form beta sheets, beta hairpins or alpha helices, allowing researchers to tune stiffness, biodegradation and responsiveness. Cellulose nanofiber hydrogels, by contrast, use the most abundant natural polymer on Earth. Repeating beta-D-glucose units form nanoscale cellulose fibers that connect through extensive hydrogen bonding, producing a porous, highly absorbent network with exceptional toughness.
The two materials offer different engineering advantages. Peptide hydrogels are generally softer and more chemically tunable, and their drug release can respond to pH, temperature, ions or enzymes. Their ability to shear-thin is especially useful for injection: under the force exerted by a syringe, the gel temporarily flows like a liquid, then rapidly rebuilds its network when the force disappears. This shear-thinning and self-healing behavior could allow a material to pass through a fine needle while remaining in place afterward. Cellulose nanofiber hydrogels are easier to scale in principle because cellulose is abundant and compatible with established industrial processing. They also provide impressive mechanical reinforcement; individual cellulose nanofibers can have a Young’s modulus approaching 138 gigapascals, comparable to steel and Kevlar. Composite hydrogels can therefore remain hydrated and flexible while resisting compression, tearing and repeated deformation—properties valuable for contact lenses, corneal patches and implants.
Researchers can build these networks through chemical, physical or hybrid crosslinking. Chemical methods create covalent bonds, improving stability and mechanical strength. In peptide systems, cysteine groups can form reversible disulfide bonds, while catechol groups can be stabilized through oxidation. In cellulose systems, oxidation can generate aldehyde groups that react with amines in a Schiff-base reaction, creating self-healing materials. Diels–Alder “click” chemistry offers another route, with reversible bonds that can be formed and broken by changing temperature. Physical crosslinking relies on reversible interactions such as hydrogen bonds, ionic attractions, metal coordination or host–guest chemistry between molecules such as cyclodextrin and adamantane. These bonds are weaker individually but can confer flexibility, injectability and self-repair. Combining both approaches produces double-network hydrogels that can tolerate more than 450 kilopascals of compression and 90 percent compressive strain without cracking. Electrospinning and three-dimensional bioprinting add further control, enabling fibers and pores to be arranged into structures with precise microarchitecture.
The most striking results involve diseases that are difficult to treat with standard dosing. In a mouse model of laser-induced choroidal neovascularization, a nanofiber hydrogel made from betamethasone phosphate and calcium ions carried the anti-VEGF antibody ranibizumab into the vitreous. The material suppressed VEGF expression, reduced vascular leakage and limited fibrous scar formation while lowering inflammatory signaling involving tumor necrosis factor-alpha and NF-kappa B. It also reduced reactive oxygen species, molecules that can damage retinal pigment epithelial cells under chronic stress. Compared with conventional anti-VEGF treatment, the hydrogel prolonged the effective treatment period by roughly three times. That result could be clinically important because reducing injection frequency might lower complications and improve adherence, although success in a mouse model does not establish safety or efficacy in people. A conductive hydrogel–fiber scaffold incorporating polyaniline has also been engineered to mimic layers of Bruch’s membrane, supporting retinal pigment epithelial cells with more than 70 percent viability after seven days and offering a platform for retinal disease modeling and regenerative research.
On the eye’s surface, the materials have shown similarly promising effects. A gel made from guanosine-5′-monophosphate and tobramycin assembled into nanofibers through hydrogen bonding and pi–pi stacking, while the antibiotic connected the fibers through ionic interactions. In mice infected with Pseudomonas aeruginosa, the gel restored corneal transparency faster than tobramycin eye drops, reduced neutrophil infiltration and suppressed the inflammatory cytokines interleukin-1 beta and interleukin-6. The bacterial burden fell by an order of magnitude compared with free antibiotic, apparently because the gel maintained a local bactericidal concentration for more than 25 hours. A separate peptide–chloramphenicol hydrogel remained on the cornea longer and sustained antibacterial activity against both Gram-positive and Gram-negative bacteria in rabbits infected with Escherichia coli. Other systems are aimed at chemical injuries, in which reactive oxygen species amplify inflammation after an alkali burn. A transparent polyurethane and ROS-clearing hydrogel patch, containing copper sulfonate bonds, reduced inflammation and promoted corneal epithelial regeneration in rats. Its more than 90 percent water content helped limit light scattering, a crucial feature for any material placed over the visual axis.
Nanofiber hydrogels could also become the basis of smart ocular devices rather than simply drug depots. Hydrogel contact-lens electrodes made with metal-coated nanofiber meshes have combined optical transparency, flexibility, wettability and gas permeability. In rabbits, lenses worn for 12 hours caused no obvious corneal abrasion or irritation and successfully recorded electroretinogram signals, suggesting a route toward comfortable eye monitoring. Meanwhile, a calcium-coordinated dexamethasone hydrogel reduced inflammatory responses in a rat model of experimental autoimmune uveitis. Adjusting calcium concentration altered the density of ionic crosslinks and slowed drug release: increasing calcium from 2 to 4 milligrams per milliliter reduced the amount of dexamethasone released over 24 hours from about 70 percent to 60 percent. A self-delivering dexamethasone prodrug hydrogel also improved corneal retention and bioavailability in rabbits, while remaining stable in a freeze-dried form and reconstituting into a gel within 30 minutes.
Despite the viral appeal of an eye treatment that could replace monthly injections with a single, sustained dose, major barriers remain before these materials can enter routine care. Long-term exposure inside the eye must be examined carefully, because chronic inflammation, material accumulation, haze or changes in intraocular pressure could threaten vision. Anterior applications must preserve optical clarity and refractive performance, while implanted materials must remain mechanically stable without migrating. Sterilization is another unresolved problem: heat, gamma radiation and ethylene oxide can damage fragile nanofibers, active drugs or peptide assemblies, whereas gentler methods may fail to guarantee sterility or eliminate pyrogens. Manufacturing is also challenging. Peptide systems require costly synthesis and tight control of self-assembly, while cellulose systems offer a more practical path to large-scale production but still need consistent, Good Manufacturing Practice-compliant processing. Regulatory agencies may classify these products as combination devices because they pair a structural biomaterial with a drug, making the primary mode of action a crucial question. The clinical failure of the sustained-release NT-503 implant in a Phase II trial, despite encouraging preclinical data, is a reminder that animal models cannot fully reproduce human disease and that new delivery systems must demonstrate clear advantages over highly effective existing treatments. Nanofiber hydrogels therefore represent not an immediate cure for the eye’s delivery problem, but a rapidly advancing platform whose ultimate impact will depend on rigorous human trials, durable safety and reliable manufacturing.
Subject of Research: Nanofiber hydrogel systems for ocular drug delivery and ophthalmic biomaterials
Article Title: Nanofiber Hydrogels for Ocular Drug Delivery: Structures, Properties, Applications, and Challenges
Article References: Cui H, Wu H, Zhao B, Zhao Y, Zhang C, Wang M, Zhang J, Wang K, Wang Y, Song Z, Tao Y. Review of nanofiber hydrogels for ocular drug delivery and ophthalmic applications. Original research page URL not provided in the source material.
Image Credits: AI Generated
DOI: 10.1002/btm2.70099
Keywords: nanofiber hydrogels, ocular drug delivery, age-related macular degeneration, bacterial keratitis, cellulose nanofibers, self-assembled peptide hydrogels, sustained drug release, smart contact lenses
Tags: advances in eye tissue healing using nanogelscontrolled release of ophthalmic medicationsinjectable nanotechnologies for eye injurieslong-lasting eye drug delivery systemsnanofiber hydrogels for eye treatmentnanomaterials for eye disease therapynanotechnology in ocular drug deliverynanotechnology-based treatments for uveitisovercoming eye’s biological barriers with nanomaterialspreclinical studies of nanresponsive hydrogels for bacterial keratitistargeted drug delivery for age-related macular degeneration
