Tissue Engineering Meets Nanotechnology: MolecularMechanism Modulations in Cornea Regeneration

Nowadays, tissue engineering is one of the most promising approaches for the regeneration of various tissues and organs, including the cornea. However, the inability of biomaterial scaffolds to successfully integrate into the environment of surrounding tissues is one of the main challenges that sufficiently limits the restoration of damaged corneal tissues. Thus, the modulation of molecular and cellular mechanisms is important and necessary for successful graft integration and long-term survival. The dynamics of molecular interactions affecting the site of injury will determine the corneal transplantation efficacy and the post-surgery clinical outcome. The interactions between biomaterial surfaces, cells and their microenvironment can regulate cell behavior and alter their physiology and signaling pathways. Nanotechnology is an advantageous tool for the current understanding, coordination, and directed regulation of molecular cell–transplant interactions on behalf of the healing of corneal wounds. Therefore, the use of various nanotechnological strategies will provide new solutions to the problem of corneal allograft rejection, by modulating and regulating host–graft interaction dynamics towards proper integration and long-term functionality of the transplant.

The human cornea is a complex five-layer structure that both protects the eye and refracts light, contributing greatly to the eye’s optical power. Proper light refraction is ensured through collagen fibrils’ special organization in the three inner layers of the cornea. For example, in Bowman’s membrane collagen fibrils are randomly organized and tightly woven; at the same time, they form multiple lamellae in the stroma and hexagonal lattice in Descemet’s membrane. This unique microarchitecture, on the one hand, maintains corneal shape, and on the other hand ensures transparency, these two factors being essential for proper light refraction. Various mechanical, chemical or thermal traumatic factors can impair cornea integrity and homogeneity . The corneal epithelium, the outermost layer of the cornea, undergoes constant self-renewal due to the proliferation and migration of populations of the progenitor limbus cells located at the cornea and sclera border, and has good regenerative properties, allowing self-healing of superficial corneal injuries. However, deeper corneal damage can lead to severe vision impairment, requiring a corneal transplant. Currently, the only approved treatment strategy for corneal damage is keratoplasty. However, the lack of donor tissue, transplant rejection, and various complications following the surgery significantly reduce the effectiveness of the procedure. In recent years, in order to solve the problem of cornea allograft deficiency, attention had been drawn to artificial cornea manufacturing using various tissue engineering approaches. Despite significant advances, the engineering of corneal tissue still faces many limitations and has a number of disadvantages. One of the main limitations of artificial corneal transplants is poor integration with native host tissues and high rejection rates due to various immune responses in native corneal tissues, which are especially acute in the damaged area.

Nanomaterial-based approach in the combined therapy. Top left – healthy corneal tissue. The cornea is a complex vascular-free structure composed of five layers, three of which are of cellular nature (epithelium, stroma and endothelium). Throughout the lifetime, corneal cells are exposed to various traumatic and damaging factors from the external environment and inner disturbances in organism’s functionality. These pathological processes and damaging agents can compromise the integrity of the cornea and lead to vision loss. Top right – pathological corneal tissue. Due to the lack of modern approaches that allow the full restoration of the cornea tissue and vision, new treatment and therapeutic strategies are needed to be introduced. TE- and nanotechnology-based strategies can become a new chapter in the cornea restoration. TE constructs can act through active and passive targeting and controlled triggered release promoting the most effective approach for each set of specific molecular mechanisms and cellular events.

The problems of interactions between a tissue-engineered (TE) graft and the host microenvironment will be further discussed in this review, as well as the recent studies on the multiple molecular mechanisms modulating the processes of healing, inflammation, and remodeling of the extracellular matrix (ECM) and cell death. State-of-the-art nanotechnology-based methods seem to be able to help in modulating these molecular mechanisms that are crucial for successful graft integration, thus helping to overcome some existing drawbacks in corneal tissue engineering. Current research on corneal regeneration by the means of nanotechnology and nanomedicine implies the use of nanocarriers for drug delivery, gene therapy agents, etc., as well as the use of nanostructured matrices to improve cell adhesion and proliferation. Many studies were devoted to the development of effective strategies for intracorneal nanomaterial (NM)-based delivery of various biomolecules, such as DNA, antibodies, peptides, and therapeutic agents. In addition, extensive research has been conducted in the field of “smart” biocompatible nanoscaffolds, implying synthetic and semi-synthetic biomaterials with desired properties and customizable structures designed for specific tasks. Modulating molecular interactions between native cells and the transplanted biomaterial through various physicochemical and nanotechnological approaches will help to guide the healing processes in the damaged corneal tissues and improve clinical outcomes in patients with corneal injuries and diseases.

Mijanovi´c, O.; Pylaev, T.; Nikitkina, A.; Artyukhova, M.; Brankovi´c, A.; Peshkova, M.; Bikmulina, P.; Turk, B.; Bolevich, S.; Avetisov, S.; et al. Tissue Engineering Meets Nanotechnology: Molecular Mechanism Modulations in Cornea Regeneration. Micromachines 2021, 12, 1336. mi12111336