Corneal Tissue

Corneal disease is the second cause of blindness with about ten million people suffering from corneal blindness every year in the world [160, 161]. Furthermore, the number of sick people increases with the growth of the elderly population, while corneal transplantation is only about 60,000 times a year in the world. At present, the only available treatment of corneal blindness is the human donor corneal transplantation [162, 163]. Apart from technical difficulties in surgery, the shortage of supply of health donor corneas is the international public health difficulties now. There is a need to develop alternatives of donor tissues to meet the growing demand for corneal transplantation [164, 165]. Over the past few years, the development of corneal substitutes has made some progress to fabricate a cell-scaffold constructs as a temporary corneas in corneal tissue engineering [166]. The success of a tissue- engineered cornea is significantly dependent on the scaffold’s performance similar to the microstructure and properties of the corneal ECM, whose major components are collagen fibrils and proteoglycans [167]. The highly-organized collagen fibrils with an aligned structure in the corneal matrix provide the physical strength, stable shape and transparency of the cornea [168-170]. The uniformity of collagen fibril diameter and the regularity of interfibrillar spacing are key factors affecting corneal transparency [171, 172]. The direction and orientation of collagen fibrils are directly related to the tensile strength of the cornea, which is resistant to external pressure and maintains corneal shape and curvature [168, 170]. Thus, the highly organized fibrous structure is a major factor that must be considered in the design of corneal tissue substitutes, which is directly related to whether the scaffolds have the desired mechanical and optical properties and spatial guidance for the corneal cell growth

[173]. The use of fiber reinforcements allows the biomaterial to have biological properties similar to those of the cornea, such as sufficient mechanical properties, morphological integrity and transparency of corneal tissue repair [174-176]. Considering these key features in the design, scientists have focused on designing appropriate methods for preparing fiber-reinforced scaffolds for corneal tissue regeneration.

Long et al. [177] designed a toughness silk fibroin reinforced collagen-based (CS) membrane as corneal grafts to improve the mechanical properties. It is well known that collagen having excellent biocompatibility is a promising candidate in corneal repair and regeneration, but their mechanical properties can’t meet the requirements of corneal scaffolds, especially the suture retention strength. In this study, collagen-based membranes reinforced by silk fibroin with different ratios of 5 wt%, 10 wt% and wt% were prepared by cross-linking with 1-ethyl-3 -(3-dimethyl (EDC) and N-hydroxysuccinimide (NHS) [127, 178]. By measuring the water content and mechanical properties of the CS membrane, it was found that their water content was depended by the weight percentage of silk fibroin, and the CS10 membrane with silk fibroin at 10 wt% showed the optimal mechanical properties. CS10 also had high suture retention strength, which can be sutured integrally in rabbit eyes according to the results of suturing experiments. The CS membranes had a better optical property in the optical test, with higher transmittance, for their construction and components were close to the native cornea with a multi-layer structure of highly-organized, anisotropic collagen fibrillar lamellae [179]. As for the biocompatibility of the membrane, the CS10 membrane supported the proliferation of human corneal epithelial cells (HCEC) and induced corneal repair in vitro animal experiments. The epithelial cells encapsulated in the CS10 membrane were completely epithelialized from 30 to 40 days, and their transparency was rapidly restored during the first month without conical cornea, neovascularization and corneal rejection. These properties make CS membrane a potential candidate for future corneal alternatives. In addition, the composite membranes may provide a promising approach for designing the corneal scaffolds in the field of corneal tissue engineering.

As opposed to the current attempt to regenerate corneal tissue using expensive materials in the design of corneal scaffolds with a similar corneal structure, Tonsomboon et al. [180] developed transparent nanofiber reinforced hydrogels from gelatin and alginate, both of which are cheap and non-immunogenic natural polymers, to mimic the cornea’s microstructure. Gelatin nanofibers were produced by the electrospinning and then infiltrated into alginate hydrogel to obtain a transparent fiber reinforced hydrogel. Due to the hydrophilicity of the gelatin, gelatin fibers attracted the accumulation of water molecules in the surrounding when the electrospun gelatin pad contacted the alginate solution. Then, with the water molecules bound to the alginate chain, the gelatin fibers were surrounded by the alginate chains. Under the help of Ca2+ ions, the alginate chains were cross-linked together to form a gel, in which the gelatin fibers were wrapped. The gelatin fiber reinforced alginate hydrogel had an elasticity modulus from 0.45 to 0.5 MPa very close to that of the natural cornea from 0.579 to 4.9 MPa [6, 17, 18]. The composite also had a desired optical transparency, which might be due to the fact that the diameter of the gelatin fibers was uniform and relatively small at 67 ± 7 nm as compared to the wavelengths of visible light at 400-700 nm so that the amount of light scattered from the material was minimized. Moreover, the orientation of the fibers also affected the performances of gelatin-alginate hydrogels, so the resulting hydrogel reinforced with the oriented fibers was slightly stiffer and stronger than that reinforced with the randomly oriented fibers, when the applied load was parallel to the fibers. However, the stiffness of the oriented gelatin fibers reinforced hydrogel was only along the fiber axis, and in the transverse direction the composite was very compliant. Thus, the next-generation reinforced composite should be provided with biaxial mechanical properties, i.e., reinforced with biaxially aligned fibers, to better simulate the biaxially rigid structure of the natural cornea. The adding of electrospun nanofibers gelatin into alginate hydrogels increased the mechanical properties of the hydrogels by about one order of magnitude. Thus, this study demonstrates that transparent hydrogels with excellent mechanical properties can be made simply from two inexpensive natural polymers: gelatin and alginate, and these novel nanofiber-reinforced composites have a wide range of prospects as scaffolds for corneal transplantation when the donor tissue is not available.

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