Sequentially-crosslinked bioactive hydrogels as nano-patterned substrates with customizable stiffness and degradation for corneal tissue engineering applications
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Abstract
Naturally-bioactive hydrogels like gelatin provide favorable properties for tissue-engineering
but lack sufficient mechanical strength for use as implantable tissue engineering
substrates. Complex fabrication or multi-component additives can improve material
strength, but often compromises other properties. Studies have shown gelatin methacrylate
(GelMA) as a bioactive hydrogel with diverse tissue growth applications. We hypothesize
that, with suitable material modifications, GelMA could be employed for growth and
implantation of tissue-engineered human corneal endothelial cell (HCEC) monolayer.
Tissue-engineered HCEC monolayer could potentially be used to treat corneal blindness
due to corneal endothelium dysfunction. Here, we exploited a sequential hybrid (physical
followed by UV) crosslinking to create an improved material, named as GelMA+, with
over 8-fold increase in mechanical strength as compared to regular GelMA. The presence
of physical associations increased the subsequent UV-crosslinking efficiency resulting
in robust materials able to withstand standard endothelium insertion surgical device
loading. Favorable biodegradation kinetics were also measured in vitro and in vivo.
We achieved hydrogels patterning with nano-scale resolution by use of oxygen impermeable
stamps that overcome the limitations of PDMS based molding processes. Primary HCEC
monolayers grown on GelMA+ carrier patterned with pillars of optimal dimension demonstrated
improved zona-occludin-1 expression, higher cell density and cell size homogeneity,
which are indications of functionally-superior transplantable monolayers. The hybrid
crosslinking and fabrication approach offers potential utility for development of
implantable tissue-engineered cell-carrier constructs with enhanced bio-functional
properties.