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International Journal of Bioprinting 3D bioprinting of composite hydrogels

Traditional artificial corneas, composed of natural constructs had poor mechanical strength (only 15–20
and synthetic materials, are manufactured based on four kPa) compared to the native cornea (3.8 MPa). 11,32 Mörö
common methods: casting, ultrastructure/microstructure et al. printed corneal stroma structures composed of
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reconstruction, decellularization to obtain a decellularized human adipose stem cells (hASCs) and hASC-derived
extracellular matrix (dECM) from native corneal corneal stromal keratocytes encapsulated in a hyaluronic/
tissue, and harvesting of extracellular matrix (ECM) dopamine bioink, demonstrating ex vivo integration with
deposited by cultured cells. These methods attempt to native tissue, in vitro innervation, and tissue formation.
7,8
recapitulate the complex structure of the cornea, which Ulag et al. developed corneal scaffolds based on polyvinyl
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provides its refractive power. However, common cornea alcohol and chitosan, with suitable mechanical stability
9
substitutes generally suffer from one or more limitations, and support for the proliferation of hASCs. However,
including a lack of control over scaffold thickness, limited these scaffolds were only moderately transparent
regeneration of cells that naturally reside in the corneal compared to the human cornea. In another approach,
ECM, poor mechanical strength, sub-optimal or complex bioprinted decellularized collagen films were implanted
optical properties, and inconsistent and inefficient into the stromal layer of the cornea in a rabbit model,
manufacturing. 8,10–13 To overcome these limitations, three- with post-implantation biocompatibility and integration
dimensional (3D) bioprinting has emerged as a versatile demonstrated by decreases in corneal thickness,
technology for the fabrication of precision hydrogel appropriate distribution of inflammatory cells, and lack of
scaffolds with the potential to recapitulate tissue structure immune rejection. 35
and function. 14–16 An ideal artificial cornea should comprise Following corneal repair, anti-inflammatory
a personalized, multilaminar structure that supports the compounds, such as betamethasone, are administered
growth of various corneal cell types, and 3D bioprinting is to reduce discomfort and aid in the healing process. 36,37
poised to meet these requirements. Ocular drug delivery systems are promising methods to
In corneal tissue engineering, 3D bioprinting has been increase bioavailability, decrease drug dosage, improve
used to recapitulate the native curvature of the cornea drug stability, promote the therapeutic efficiency of drugs,
with precise geometry, surpassing traditional fabrication reduce drug side effects, provide targeted, prolonged,
methods like spin casting, injection molding, lathe cutting, sustained, and controlled drug delivery to ocular tissue,
and cast molding. 17,18 Other advantages of 3D bioprinting and in some cases, deliver multiple drug compounds
are its reproducibility, cost-effectiveness, accuracy, simultaneously. 38,39 Hydrogels are promising candidates
resolution, ease of use, customization, and ability to print for ocular drug delivery as they can be tuned to mimic the
complex porous shapes with control over the orientation, physicochemical properties of ocular tissues and fluids
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size, distribution, and shape of the pores. 19–23 In addition, and are capable of sustaining drug release. 41,42 .
3D bioprinting enables the fabrication of hydrogels with Gellan gum (GG) is a potential candidate for corneal
interconnected porous structures from a diverse range tissue engineering and ocular drug delivery due to
of biomaterials, thereby allowing the material properties its unique physicochemical properties, such as high
to be tuned to support cell infiltration, growth, and the transparency, hydrophilicity, structural similarity with
formation of new tissue. 24–27 For corneal tissue engineering, native glycosaminoglycans (GAGs), biodegradability,
key considerations for selecting a bioink/biomaterial thermal stability, and the ability to form a hydrogel at low
include transparency, strength, stability, cytocompatibility, concentrations. 43–45 GG is a natural anionic polysaccharide
and the ability to process the material into a form that composed of repeating building blocks of β-D-glucose,
matches the thickness and curvature of the native cornea. β-D-glucuronic acid, and α-L-rhamnose. 46,47 In an aqueous
There are three main approaches for 3D bioprinting, solution at low temperature, the polysaccharide chains
including extrusion-based, inkjet-based, and laser-based transition from a random coil to a double helix structure,
3D bioprinting, which may be applied for this purpose. 28–30 forming junction zones that lead to gelation and the
Of these approaches, extrusion-based 3D bioprinting is formation of a 3D network. However, GG suffers from
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the most accessible and widely used bioprinting approach a lack of bioactive cell attachment sites, high solubility
because it is compatible with a wide range of biopolymers in aqueous environments, low mechanical strength,
and enables the direct printing of additives, such as and brittleness. 49,50 Chemical functionalization of GG is
bioactive compounds and cells. 31
possible due to the presence of free carboxyl groups and
Corneal stromal keratocyte-laden agarose-collagen multiple hydroxyl groups. Depending on the chemical
type I bioinks have been used to print corneal constructs. functionalization strategy, this can improve the mechanical
Although cells in these constructs express keratocan and strength, stability, and biological function of hydrogels
lumican (characteristic corneal stromal markers), these formed from GG.

Volume 10 Issue 4 (2024) 320 doi: 10.36922/ijb.3440