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Application of Bioprinting in Ophthalmology
of water. They can be engineered to support the cellular sensitive polymer that transforms between the solid and
growth, migration, and tissue formation [36,37] . Hydrogels liquid states when the temperature changes. With the
present strong biomimetic advantages in the clinical addition of methacryloyl component, GelMA can improve
translational applications attributed to their hydrophilic the thermal stability of gelatin, demonstrating properties
[46]
nature, good biocompatibility, biodegradability, controllable of both physicochemical strength and biocompatibility .
responsiveness to external stimuli, and tunable physical and Both simulation of the matrix microenvironment and
chemical properties such as adhesion or low mechanical 3D printing of GelMA hydrogels to produce artificial
properties. Both naturally derived and synthetically derived matrices with high transparency, biocompatibility, and
hydrogels are widely used in bioprinting. stability are the important pillars in the development of
[47]
A series of natural hydrogels have been used bioprinting in ophthalmology .
for bioprinting due to their similarity to the cell
microenvironment. The corneal stroma is rich in collagen, 2.2. Types of cells
proteoglycan, and matrix metalloproteinase, which play an To facilitate their application in printing, the cells can be
important role in the mechanical strength and transparency presented as cell-laden biomaterials, cell suspension or
of the cornea. Due to the good biocompatibility and low tissue spheroids for different printing technologies.
immunogenicity, collagen is widely used as a bioink in
3D bioprinting . However, low mechanical property (1) Cell composition
[38]
of the pure collagen is the main limitation of using it as The eyeball is a complex organ and composed of a variety
the bioink to form a stable structure. Crosslinking using of tissues. The cornea and retina are the two main types of
different methods (e.g., chemical, physical, or biological) tissues obtaining great attention in the ocular regenerative
or a mixture with other components (e.g., fibrin, medicine and tissue engineering.
agarose, and alginate) can be performed to improve the The cornea is located at the anterior section of
properties of collagen bioinks [39-41] . Depending on the the eye and formed by five layers: epithelium, bowman
types of strategies selected, the bioinks can be tuned to membrane, stroma, Descemet’s membrane, and
prepare suitable low-viscosity solutions for jetting-based endothelium. To form the stroma equivalent, the corneal
printing [42,43] or hydrogels with increased storage modules keratocytes can be isolated from the stromal cells of
for extrusion-based printing . In addition, synthesized cadaverous human corneal tissues and purified to print
[38]
[48]
peptide-based collagen is considered a good option to together with the biomaterials . Besides, the corneal
[49]
reduce the batch-to-batch variation effect and improve epithelium cells and endothelium cells also triggered the
the mechanical properties in bioprinting . attention from the researchers to be bio-printed [50,51] . The
[41]
Hyaluronic acid, which is another natural human corneal epithelial cells and endothelial cells can
component of ECM, is abundant in the subretinal space. be harvested from the donor corneas and made laden with
The hyaluronic acid hydrogel provides a biocompatible matrix gel to form bioinks.
environment for the culture of retinal cells but the The retina is a complex stratified structure, which
physiological property needs to be modified to fulfill is located at the posterior section of the eye. It embodies
the need of the native retina and printing requirements. more than 60 types of cells and nerve fibers that are
Crosslinking the hydrogel with methacrylate groups difficult to be regenerated when damaged . The cells
[52]
could mimic the mechanical properties of retina and isolated from the rat retinal tissues can be prepared as
contributed to a good survival rate for the retinal pigment cell suspensions and printed independently with inkjet
epithelial cells and differentiation of the fetal retinal printing method onto a substrate matrix [53,54] . Besides, the
progenitor cells (fRPCs) . fetal human retinal progenitor cells have been adopted
[44]
Gelatin is a type of hydrogel which shows in bioprinting, and have successfully differentiated into
good adhesive properties in the oculus usage and is photoreceptors after printing .
[44]
considered a good option for cornea engineering . It is
[45]
biocompatible, transparent and non-toxic. Besides, it can (2) Stem cell induction
be easily processed and has the reasonable mechanical The latest advances in the research of induced pluripotent
properties to mimic the ECM. Gelatin can gain different stem cell have paved the way for the production of patient-
viscoelastic and mechanical properties to facilitate the specific cells that are ideal for autologous cell replacement
functions of oculus. therapies in the treatment of various alternative diseases.
In addition to the natural hydrogels, synthetic bioinks Adipose-derived stem cells (ADSCs) are fat-derived stem
are also widely used in bioprinting. Gelatin methacrylate cells with self-renewal, proliferation, and differentiation
(GelMA) is a photopolymerized hydrogel comprising of potentials. ADSCs can differentiate into corneal cells both
modified natural ECM components and can be prepared in vivo and in vitro, and as reported in the previous studies,
from the water-soluble gelatin. Gelatin is a temperature- other researchers have printed differentiated ADSCs

150 International Journal of Bioprinting (2022)–Volume 8, Issue 2