Silk-derived nanofibrils have emerged as a promising biomaterial for corneal tissue engineering due to their unique combination of optical, mechanical, and biological properties. These protein-based nanomaterials offer significant advantages over synthetic polymers in creating transparent scaffolds for corneal repair, addressing critical requirements such as light transmission, epithelial cell integration, and surgical feasibility.

The optical clarity of silk nanofibrils is a key factor in their suitability for corneal applications. The natural molecular arrangement of silk proteins, particularly fibroin, allows for high light transmittance in the visible spectrum, closely matching that of the native human cornea. Studies have demonstrated that properly processed silk fibroin scaffolds achieve transparency levels exceeding 90%, comparable to synthetic alternatives like poly(lactic-co-glycolic acid) or polyethylene glycol. This transparency is maintained after hydration, a crucial requirement for corneal implants that must function in the aqueous environment of the eye. The nanofibrillar structure of silk materials scatters minimal light due to the uniformity of fibril dimensions, typically ranging between 10 to 100 nanometers in diameter, which is below the wavelength of visible light.

Epithelial cell adhesion and proliferation on silk nanofibril scaffolds outperform many synthetic polymer substrates. The surface chemistry of silk fibroin presents naturally occurring cell-binding motifs, such as RGD-like sequences, which facilitate integrin-mediated attachment of corneal epithelial cells. In vitro experiments show that primary human corneal epithelial cells achieve confluent monolayers on silk scaffolds within 7 to 10 days, with viability metrics comparable to tissue culture plastic controls. The nanofibrillar topography further enhances cell behavior by mimicking the basement membrane structure of the native cornea, promoting proper cell orientation and stratification. This contrasts with smooth synthetic polymer surfaces that often require additional coating steps with extracellular matrix proteins to achieve similar cellular responses.

Mechanical properties of silk nanofibril scaffolds are particularly advantageous for surgical handling and implantation. The balance between tensile strength and elasticity in hydrated silk materials allows for precise suturing without tearing, a common challenge with softer hydrogel-based alternatives. Silk scaffolds typically exhibit Young's modulus values in the range of 5 to 15 MPa when hydrated, closely matching the mechanical characteristics of natural corneal tissue. This prevents mechanical mismatch that could lead to implant failure or patient discomfort. The tear resistance of silk materials exceeds that of many synthetic options, reducing the risk of damage during surgical manipulation.

Compared to synthetic polymer scaffolds, silk nanofibrils demonstrate superior biocompatibility with reduced inflammatory responses in corneal applications. The gradual degradation profile of silk, mediated by proteolytic enzymes present in the ocular environment, avoids the sudden loss of structural integrity that can occur with rapidly degrading synthetic polymers. Degradation byproducts of silk are naturally metabolized, unlike some synthetic polymers that may produce acidic breakdown products affecting local pH. Long-term implantation studies show minimal fibrotic response to silk materials, a significant advantage over materials like polycaprolactone or poly(methyl methacrylate) that often trigger capsule formation.

The fabrication of silk nanofibril corneal scaffolds utilizes aqueous-based processing, avoiding harsh solvents required for many synthetic polymers. This environmentally benign approach preserves the native structure of silk proteins while allowing control over pore architecture and fibril alignment. Electrospinning and solvent-free gelation techniques produce scaffolds with interconnecting pores in the 5 to 20 micrometer range, facilitating nutrient diffusion and cellular infiltration. The ability to precisely control scaffold thickness between 50 to 200 micrometers matches the dimensional requirements of corneal stromal replacement.

Sterilization protocols for silk nanofibril scaffolds are less damaging than those required for synthetic polymers. Ethylene oxide treatment or gamma irradiation at doses up to 25 kGy maintains the structural integrity and transparency of silk materials, whereas similar treatments can degrade many synthetic polymers through chain scission or crosslinking. This reliability in sterilization ensures consistent clinical performance of the scaffolds.

Clinical translation of silk nanofibril corneal scaffolds benefits from the established safety profile of silk in medical applications. Unlike novel synthetic polymers that require extensive toxicology testing, silk has a history of use in FDA-approved devices, potentially accelerating regulatory pathways. The absence of immunogenic sericin in properly processed silk fibroin minimizes adverse reactions, making it suitable for widespread ophthalmic use.

The future development of silk nanofibril corneal scaffolds focuses on enhancing functional outcomes through structural refinement. Current research optimizes fibril alignment patterns to mimic the orthogonal collagen lamellae of the native cornea, improving both optical and mechanical performance. Integration of bioactive factors through non-covalent binding to silk fibrils offers potential for promoting nerve regeneration and maintaining corneal homeostasis without compromising transparency.

While synthetic polymer scaffolds continue to play a role in corneal tissue engineering, silk nanofibrils present a biomimetic alternative that better addresses the complex requirements of corneal regeneration. Their combination of optical clarity, cellular compatibility, and surgical practicality positions them as a leading material candidate for addressing the global need for corneal replacements. The natural origin and tunable properties of silk proteins provide a versatile platform for developing next-generation corneal scaffolds that bridge the gap between synthetic and biological materials.