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International Journal of Bioprinting 3D bioprinting for corneal regeneration

have undergone terminal differentiation, the endothelial 4. Extracellular matrix proteins in
layer lacks regenerative capacity. These cells fulfill crucial the cornea
roles, including maintaining corneal transparency,
supplying nutrients to the cornea, and ensuring hydration A crucial determinant of achieving optimal visual acuity
by permitting the passage of water into the stroma. is the correct composition, structure, and interplay of the
Additionally, their pivotal function extends to preventing extracellular matrix (ECM) situated within the cornea,
overhydration of the stroma through active transport forming what is known as the corneal stroma (Table 1).
mechanisms. This dual role is vital in preserving the An illustrative instance of this is the organized network
organized structure of collagen fibers within the stroma, of keratocytes within the stroma, situated amidst collagen
which is essential for facilitating light transmission and fibers and layers. This arrangement serves as a cornerstone
upholding corneal transparency. The endothelium and for one of the main functions of the stroma, specifically
stroma are formed during eye development from the imparting mechanical strength to the cornea while
periocular mesenchyme—also known as periocular neural significantly contributing to its transparency.
crest cells. 4,16-18 The primary constituent of the ECM is collagen,
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3.4. Limbal epithelial stem cells accompanied by various leucine-rich proteoglycans. The
Adult limbal epithelial stem cells (LESCs) are located in collagen matrix forming the corneal stroma incorporates
the peripheral limbus, playing a pivotal role in the renewal diverse collagen types, including type I, type IV, type V,
of the corneal epithelium, specifically in the continuous and type VIII. Unlike collagen layers in other connective
replacement of the upper 4–6 layers, predominantly tissues, the corneal collagen matrix is notably thinner, a
composed of squamous cells. These LESCs are located characteristic that contributes to corneal transparency.
in the basal layer of the limbal epithelium, forming The collagen fibers within the cornea serve as pivotal load-
distinctive niches. Despite their essential function, it bearing elements, enduring tensile and compressive forces
is noteworthy that the proliferation potential of these generated by intraocular pressure and external impacts
stem cells is extremely low. The potential loss or damage to safeguard inner ocular tissues. This robust strength of
of these stem cells can occur due to various factors collagen fibers is attributed to their rope-like structure and
such as physical, chemical, or thermal impact, genetic the different lateral orientations of the layers. Dermatan
diseases, or infections. Consequently, limbal stem cell sulfate-containing proteoglycans in the stroma prevent
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deficiency triggers neovascularization and angiogenesis the adhesion of neighboring collagen fibers. Among the
in the conjunctiva, leading to vision loss. To address this, collagens, type I collagen prevails in abundance throughout
clinically cultured LESCs are employed as a therapeutic the human body, with exceptions such as the eye’s vitreous
strategy. These cultured cells are transplanted into the body or brain. Conversely, type V collagen is notably more
patient’s cornea, and it is important to note that LESCs can abundant in the cornea. This collagen variant, characterized
be derived from either autologous or allogeneic sources. 19 by its small fibrillar structure, plays an important role
in fiber formation. The stroma layers mainly consist of
3.5. Corneal stromal stem cells type I and type V collagens, with an estimated count of
Corneal stromal stem cells (CSSCs) represent another approximately 250–300 layers enveloping the entire cornea.
crucial cell type within the cornea, specifically located in The distribution of particular collagen types may vary
the limbal stoma. Functioning as mesenchymal progenitors depending on the cornea’s structure and condition. Given
of keratocytes, these cells contribute to wound healing and that type I and type V collagens collectively contribute to
regeneration, essential processes for maintaining corneal corneal transparency, any changes in their distribution or
transparency. The therapeutic potential of CSSCs extends ratio can affect this transparency. For example, structural
to applications in artificial tissue replacement. Notably, changes in type I collagen resulting from corneal wounds
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CSSCs demonstrate the capability to produce matrix or scarring may lead to a decrease in transparency. 16
components resembling the composition of the collagen
matrix present in the stroma. In research endeavors, Type VII collagen assumes a significant role in
it was observed that stromal stem cells, when cultured facilitating adhesion between the epithelial layer and the
on nanorods arranged in parallel, generated a collagen stroma, as well as in fiber fixation and wound healing.
layer mirroring the structure and composition of the Unlike the previously discussed collagens, type VIII and
natural stroma. These findings suggest that CSSCs hold type XII collagens lack the ability to independently form
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promise for in vitro production of stroma-like tissue. Such fibers. Nevertheless, they can engage in interactions
advancements could open avenues for replacing the stroma with other collagen types, actively participating in fiber
in transplantation procedures. formation. 23,24

Volume 10 Issue 2 (2024) 110 doi: 10.36922/ijb.1669