In situ Tissue Regeneration in the Cornea from Bench to Bedside

Abstract

Corneal blindness accounts for 5.1% of visual deficiency and is the fourth leading cause of blindness globally. An additional 1.5–2 million people develop corneal blindness each year, including many children born with or who later develop corneal infections. Over 90% of corneal blind people globally live in low- and middle-income regions (LMIRs), where corneal ulcers are approximately 10-fold higher compared to high-income countries. While corneal transplantation is an effective option for patients in high-income countries, there is a considerable global shortage of corneal graft tissue and limited corneal transplant programs in many LMIRs. In situ tissue regeneration aims to restore diseases or damaged tissues by inducing organ regeneration. This can be achieved in the cornea using biomaterials based on extracellular matrix (ECM) components like collagen, hyaluronic acid, and silk. Solid corneal implants based on recombinant human collagen type III were successfully implanted into patients resulting in regeneration of the corneal epithelium, stroma, and sub-basal nerve plexus. As ECM crosslinking and manufacturing methods improve, the focus of biomaterial development has shifted to injectable, in situ gelling formulations. Collagen, collagen-mimetic, and gelatin-based in situ gelling formulas have shown the ability to repair corneal wounds, surgical incisions, and perforations in in-vivo models. Biomaterial approaches may not be sufficient to treat inflammatory conditions, so other cell-free therapies such as treatment with tolerogenic exosomes and extracellular vesicles may improve treatment outcomes. Overall, many of the technologies described here show promise as future medical devices or combination products with cell or drug-based therapies. In situ tissue regeneration, particularly with liquid formulas, offers the ability to triage and treat corneal injuries and disease with a single regenerative solution, providing alternatives to organ transplantation and improving patient outcomes.

Advances in Biomaterials for Corneal Regeneration

“…The risk of parasurgical infection, patient discomfort, or scar formation is reduced. The in-situ forming hydrogel can adapt to complex tissue cavities, mold, or irregular wounds with better integration [61]. It is easy to encapsulate therapeutic molecules such as peptides, drugs, or exosomes into the hydrogel for synergistic effect.…”

“…It is easy to encapsulate therapeutic molecules such as peptides, drugs, or exosomes into the hydrogel for synergistic effect. The clinical potential of in-situ forming hydrogels for corneal regeneration has been reviewed by Poudel et al [61].…”

CAM Model: Intriguing Natural Bioreactor for Sustainable Research and Reliable/Versatile Testing

“…TE can be conducted ex vivo or in situ [ 147 , 148 ]: the first approach requires the seeding of donor stem cells onto a scaffold that is inserted into the affected tissue for the purpose of stimulating cell growth and differentiation [ 149 , 150 , 151 , 152 ]; the in situ method, on the other hand, avoids the step of seeding cells onto the scaffold and involves the fabrication of scaffolds that can adapt to tissue damage in terms of their size and shape. The latter contain biocompatible materials that can be implanted at the site of damaged tissue, where they attract the surrounding host cells necessary for healing to the repair site [ 145 , 147 , 148 , 153 , 154 ]. Specifically, among the components of TE constructs emerge biomaterials which hold many key characteristics for in vivo implantation into host tissues.…”

Biomaterials for Tissue Engineering Applications and Current Updates in the Field: A Comprehensive Review

“…This approach presents scaffolds of good mechanical properties and allows the use of many biomaterials [24][25][26][27][28]; however, it requires sophisticated optimization of the conditions in the bioreactors to allow initial cell proliferation, high cost, donor site morbidity, and rejection of the implanted tissue may occur [29]. While (ii) in situ tissue engineering represents a simple and convenient solution that involves the pre-fabrication of a scaffold made from biocompatible biomaterials with a specific size and shape and its implantation directly into the required tissue without the need for prior seeding with cells, it relies on attracting the surrounding cells by promoting the host's tissue regeneration [8,14,15,30,31]. As a result, it provides an immune-compatible alternative for the ex vivo approach so the rejection of the implanted scaffold is avoided [32].…”