Simultaneous Interpenetrating Polymer Network of Collagen and Hyaluronic Acid as an In Situ-Forming Corneal Defect Filler

Abstract

Timely treatment of corneal injuries injury can help to prevent corneal scarring, blindness, and the need for corneal transplantation. This work describes a novel hydrogel that can fill corneal defects and assist in corneal regeneration. This hydrogel is a simultaneous interpenetrating polymer network (IPN) composed of collagen cross-linked via strain-promoted azide−alkyne cycloaddition reaction and hyaluronic acid cross-linked via thiol−ene Michael click reaction. The formation of the IPN gel was confirmed via FTIR spectra, UV−vis spectra, and morphological changes. We compared the gelation time, mechanical properties, transmittance, and refractive index of the IPN gel to the collagen gel, hyaluronic acid gel, and semi-IPN gel. The IPN combined the advantages of collagen and hyaluronic acid gels and supported corneal epithelial cell growth on its surface. When applied to corneal stromal defects in vivo, the IPN avoided epithelial hyperplasia, decreased stromal myofibroblast formation, and increased tight junction formation in the regenerated epithelium.

A Simple Inner-Stopper Guarded Trephine for Creation of Uniform Keratectomy Wounds in Rodents

“…While this is less than ideal for the use of corneal transplantation and donor-recipient matching, this method nonetheless creates substantial stromal defects that can be filled with in situ forming hydrogels similar to what can be done in rabbits. [8][9][10] Figure 5 shows an OCT image of the application of an in situ forming hydrogel to a corneal defect introduced by the described method.…”

“…[7] This trephine was used to create defects to study the ocular wound-healing effects of novel in situ forming hydrogels in rabbits. [8][9][10] The development of a similar trephine for rats is equally important because one of the many advantages of using rodents is the availability of visual function tests available for rodents, but not larger animals. [11,12] Also, the cost for rat studies are much lower than that of larger animals.…”

Supramolecular Host–Guest Hydrogels for Corneal Regeneration

“…Hydrogels prepared from reconstituted type I collagen are commonly employed in ophthalmic tissue engineering due to the high native type I collagen content in the eye [3,20,21], with recently reported systems harnessing biorthogonal crosslinking chemistries to improve the mechanical properties of the reconstituted extracellular matrix (ECM) [22][23][24]. Other commonly used biopolymers for corneal regeneration include gelatin, silk, dextran, and hyaluronic acid.…”

“…Illustratively, copper-free, SPAAC-based click chemistry facilitates rapid gelation under physiological conditions without relying on light energy or chemical catalysts to initiate covalent crosslinking. Demonstrating the power of this approach in ophthalmic regeneration applications, our lab recently reported several differently bioorthogonally crosslinked, in situ forming corneal tissue substitutes that fill and stabilize deep corneal wounds in vivo, promoting multi-layered epithelialization and tight junction formation while presenting biomimetic optical properties [22][23][24].…”

“…Bioorthogonal crosslinking has already shown promise for primary hydrogel network formation in ophthalmic tissue engineering, suggesting that these chemistries are compatible with the ocular surface and display reaction times suitable for both delivery and defect site retention. For example, our group recently reported the development of in situ forming corneal stromal substitutes based on collagen type I crosslinked by bio-orthogonal strain-promoted azide-alkyne cycloaddition (SPAAC), as well as SPAAC crosslinked hyaluronate-collagen hydrogels for suture-free corneal defect repair [22][23][24]. These bioorthogonally crosslinked hydrogels exhibited favorable optical properties and promoted healthy wound-healing in organ culture and in vivo rabbit corneal defect models.…”