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International Journal of Bioprinting Dual ions mixed GelMA for hair follicle regeneration

Figure 9. Proposed mechanism of GelMA-Zn/Si hydrogel promoting in situ regeneration of hair follicles in mouse excisional model.

Fibrosis and tissue regeneration are frequently believed we noticed that GelMA-Zn/Si group had more hair in the
to be opposing. Once the appropriate cues are modified, wound center than other groups. Histological analysis also
regeneration may be achieved after injury, rather than indicated that in GelMA-Zn/Si group, hair follicles started
fibrotic repair [36,37] . Establishing developmental signals to grow in the center of the wound first and then spread
in dermis after trauma may be a practicable method to to the margin. The phenomenon is named in situ hair
achieve regenerative repair [38,39] . Therefore, potential tools follicle regeneration and has been considered the same as
to revert skin cells to an “embryonic status” so as to achieve hair follicle development in the embryonic stage [5,41,42] . It
regeneration may be existing. In this study, we adopted has been reported that hair follicle neogenesis is regulated
GelMA loaded with bioactive ions and attempted to break by microenvironment consisting of fibroblasts, stem cells
the balance to regenerate hair follicles. As expected, the use and endothelial cells [43,44] . Our immunofluorescence results
of 3D-printed GelMA scaffold with mixed Zn/Si dual ions suggested that GelMA-Zn/Si hydrogel can activate HFSCs
lead to an improvement in in situ hair follicle regeneration and angiogenesis to facilitate hair follicle regeneration.
and wound healing. Apart from that, the expression of genes associated with
angiogenesis and hair follicle development was significantly
Generally, both Zn and Si ions display good
biocompatibility and stimulatory effect on fibroblasts, improved, which was not observed in the control group.
Therefore, it is reasonable to assume that besides direct
keratinocytes, and endothelial cells [9,40] . Further analyses regulation through stem cells, ions may indirectly regulate
indicate that 1/32 Zn/Si dual-ion solution is optimal hair follicle neogenesis via surrounding cells, such as
because it can maximally improve fibroblasts wound endothelial cells. The speculation above was further
healing and promote vessel tube formation. Zn ion confirmed by blood perfusion measurement, which showed
solution alone cannot significantly influence the behavior that the mice treated with GelMA-Zn/Si hydrogel had more
of cells. Pure Si ion solution has the stimulatory effect but favorable blood perfusion. Good perfusion can provide
is slightly weaker than the mixture of two ions, implying sufficient nutrition and accelerate the transport of ions to
that synergistic effects between the ions may be existing. the dermis to strengthen their biological effect, which may
Additionally, we investigated the effect of ions on hair form a positive cycle in the end [45,46] . In addition, in this
follicle in vitro by employing DP cells, which are located work, we employed in situ 3D bioprinting technology to
at the base of hair follicle and play an important role print hydrogels to the wound. It has been reported that 3D
in regeneration. The ions can promote migration and bioprinting may provide the dressing with a tightly fitting
proliferation of DP cells, indicating the beneficial impact surface and suitable topography and profoundly affect
of ions on hair follicle in vitro. To overcome the limits mechanotransduction, which may also contribute to the
of bioactive ions, in this work, the Zn/Si dual ions were activation of hair follicle regeneration signaling pathways
incorporated into GelMA to prepare the GelMA-Zn/Si to some extent . Therefore, we speculate that GelMA-
[47]
hydrogel and to match the demand of in situ regeneration.
Zn/Si hydrogel may provide signals to break the balance
To investigate the efficacy of this combination on between scar formation and regenerative wound healing,
stimulating hair follicle regeneration, we first verified and then, the repair process starts with cells reverted to
that GelMA-Zn/Si hydrogel has no significant changes “embryonic status” so as to achieve regenerative healing
in physicochemical properties compared to pure GelMA (Figure 9) .
[5]
hydrogel. After treatment, excisional wound healing in
mice could recapitulate aspects of true tissue regeneration, Our study is the first to combine Zn/Si dual ions with
i.e., the formation of new hair follicles, and presented with GelMA to treat excisional wounds and achieve in situ
less scar formation. Intriguingly, in the gross observation, regeneration of hair follicle. GelMA-Zn/Si hydrogel not

Volume 9 Issue 3 (2023) 212 https://doi.org/10.18063/ijb.703