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Review
.2014 Apr 17;7(4):3106-3135.
doi: 10.3390/ma7043106.

Gelatin-Based Materials in Ocular Tissue Engineering

Affiliations
Review

Gelatin-Based Materials in Ocular Tissue Engineering

James B Rose et al. Materials (Basel)..

Abstract

Gelatin has been used for many years in pharmaceutical formulation, cell culture and tissue engineering on account of its excellent biocompatibility, ease of processing and availability at low cost. Over the last decade gelatin has been extensively evaluated for numerous ocular applications serving as cell-sheet carriers, bio-adhesives and bio-artificial grafts. These different applications naturally have diverse physical, chemical and biological requirements and this has prompted research into the modification of gelatin and its derivatives. The crosslinking of gelatin alone or in combination with natural or synthetic biopolymers has produced a variety of scaffolds that could be suitable for ocular applications. This review focuses on methods to crosslink gelatin-based materials and how the resulting materials have been applied in ocular tissue engineering. Critical discussion of recent innovations in tissue engineering and regenerative medicine will highlight future opportunities for gelatin-based materials in ophthalmology.

Keywords: biocompatibility; cornea; gelatin; ophthalmology; retinal epithelium; tissue engineering.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1.
Figure 1.
Schematic representation of the eye; gelatin-based materials have found application in the repair of the ocular components shown above.
Figure 2.
Figure 2.
Assessment of thein vivo biocompatibility of cultured corneal stromal cells with GA crosslinked gelatin. (A) Culture of primary corneal stromal cell spheroids seeded upon a GA crosslinked gelatin hydrogel; (B,C) Implantation of construct within intra-stromal pockets in the rabbit cornea; (D,E,F) Visual appearance of constructs 4 weeks after implantation showing; (D) Gelatin; (E) Keratocyte and gelatin; and (F) Keratocyte precursor and gelatin; (G) Histological analysis of the implants 4 weeks after implantation showing no immune cell infiltration of the gelatin implants in any group. Keratocyte precursor cells showing more intense staining for laminin, type I and type IV collagen, and vimentin, Scale bar = 100 μm; (H) Immunolocalization of CD34 positive or nestin positive cells within the transplanted keratocytes precursor gelatin implants 4 weeks after transplantation. Rhodamine (red colour) shows the transplanted labelled corneal keratocyte precursors in the gelatin hydrogels, and FITC (green colour) shows the CD34- or nestin- positive cells. Scale bar = 100 μm. Courtesy of Mimuraet al. [70] and Molecular Vision. Copyright by Mimura (2008). The work was originally published in [70].
Figure 2.
Figure 2.
Assessment of thein vivo biocompatibility of cultured corneal stromal cells with GA crosslinked gelatin. (A) Culture of primary corneal stromal cell spheroids seeded upon a GA crosslinked gelatin hydrogel; (B,C) Implantation of construct within intra-stromal pockets in the rabbit cornea; (D,E,F) Visual appearance of constructs 4 weeks after implantation showing; (D) Gelatin; (E) Keratocyte and gelatin; and (F) Keratocyte precursor and gelatin; (G) Histological analysis of the implants 4 weeks after implantation showing no immune cell infiltration of the gelatin implants in any group. Keratocyte precursor cells showing more intense staining for laminin, type I and type IV collagen, and vimentin, Scale bar = 100 μm; (H) Immunolocalization of CD34 positive or nestin positive cells within the transplanted keratocytes precursor gelatin implants 4 weeks after transplantation. Rhodamine (red colour) shows the transplanted labelled corneal keratocyte precursors in the gelatin hydrogels, and FITC (green colour) shows the CD34- or nestin- positive cells. Scale bar = 100 μm. Courtesy of Mimuraet al. [70] and Molecular Vision. Copyright by Mimura (2008). The work was originally published in [70].
Figure 3.
Figure 3.
Schematic diagram of HCEC-gelatin sheet implantation reported by Laiet al. [73]. Primary endothelial cells were cultured upon a pNIPAM culture surface until confluent. The cell sheet was detached and transferred to a gelatin disc. The gelatin disc was implanted into the anterior chamber of the rabbit eye in which the endothelium had been removed surgically. The gelatin disc swelled localizing the corneal endothelial cells against the posterior surface of the cornea, where the cells proliferated and restored the cornea to health. Figure adapted from Hsiueet al. [74].
Figure 4.
Figure 4.
Potential treatment of RPE degeneration with RPE sheet-gelatin constructs. (A) Schematic of healthy eye, presenting an intact retinal pigment between the retina and the choroid; (B) degenerated RPE cell layer leading to potential loss of vision; (C) small portion of retina detached from RPE layer through introduction of fluid in the sub-retinal space; (D) cell sheet and carrier introduced into sub-retinal space through cannula delivery; (E) vitreous replacement fluids used to restore intraocular pressure and position detached portion of retina back in contact with implant.
Figure 5.
Figure 5.
Potential treatments of retinal tears with m-TG. (A) Retinal tear initially forms; (B) if large enough vitreous humor diffuses into sub-retinal space exacerbating the tear and forcing more retinal tissue away from the RPE; (C) sub-retinal vitreous humor aspirated; (D) a homogenous mixture of gelatin and m-TG solutions mixed and applied to the sub-retinal space; (E) normal ocular pressure restored through infusion of vitreous replacement fluid.
Scheme I.
Scheme I.
Crosslinking reaction of gelatin by genipin with: (A) primary reaction through Michael addition to form stable intermediate; and (B) secondary reaction with nucleophilic substitution of free lysine amine molecules into genipin activated ester.
Scheme II.
Scheme II.
Schematic of the mechanism of the crosslinking reaction between carboxylic acids and lysine, through activation with 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide (EDC) and N-hydroxysuccinamide (NHS). The amide bond is formed directly between the two amino acids of gelatin with no linker in between.
Scheme III.
Scheme III.
Methacrylation of gelatin to afford gelatin methacrylamide. Free amino groups of gelatin react with methacrylic anhydride in phosphate buffered saline solution (PBS) at 50 °C. The gelatin methacrylamide product can be photocrosslinked through the use of a photo activated radical initiator and UV light [89].
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