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International Journal of Bioprinting 3D cell culture model for neural cell analysis

is critical for guiding clinicians and patients in the use of occur under excessive mechanical forces. In the current
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PEEK-OPTIMA™ in spinal implants, as the interactions study, neural cells were exposed to ZTA model particles at
with neural cells may influence the implants’ long-term a dosage of 50 μm³, and cell viability was assessed over 5
success and health implications. days. No significant changes in cell viability were observed
Previous studies have explored the biological responses in either C6 astrocyte-like or NG108-15 cells, compared
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to Ceridust 3615 particles using in vitro gel encapsulation to the cell-only negative control. Interestingly, significantly
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techniques. Green et al. encapsulated Ceridust 3615 lower ROS production was observed in the 3D ZTA model
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particles in 1% (w/v) agarose gel, then centrifuged the compared to other particle types. Although previous
mixture to create a monolayer of particles. Murine research has not explored neural cell responses to ZTA
peritoneal macrophages were seeded on top, and after 24 particles, similar studies on other cell types, such as L929
h, no significant impact on cell viability was observed at a fibroblasts, have reported comparable findings. Germain
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100 μm³ per cell concentration compared to the cell-only et al. observed no significant reduction in cell viability
control. This technique was later adapted by Liu et al., when fibroblasts were exposed to commercially available
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who used a 0.4% (w/v) agarose gel without centrifugation, ceramic powders but noted cytotoxic effects when U937
enhancing the gel’s porosity and dispersing the particles human macrophages were exposed to clinically relevant
more widely. They also replaced murine macrophages ceramic wear particles at a dose of 50 μm³ per cell. The
with human peripheral blood mononuclear cells and lack of cytotoxicity observed in our study with neural
found similar results, with no significant effect on cell cells aligns with the findings in fibroblasts. Additionally,
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viability after 24 h. Further supporting these findings, Asif reported no adverse effects on L929 cell viability
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Yarrow-Wright’s study confirmed that the Ceridust when exposed to BIOLOX Delta ceramic particles at a
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3615 particles did not adversely affect the viability of either similar dosage. Furthermore, ZTA particles in our study
human peripheral blood mononuclear cells or murine did not induce ROS production or DNA damage in
peritoneal macrophages in agarose and collagen gels. either C6 astrocyte-like or NG108-15 cells, reinforcing
However, no studies have yet investigated the response of the conclusion that ZTA particles are biologically inert
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neural cells to Ceridust 3615 particles in vitro. This gap in neural cell cultures. These results are consistent with
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highlights the need for further research into how Ceridust those of Asif, who found no significant oxidative stress
3615 interacts with neural cells, especially within 3D in or DNA damage in peripheral blood mononuclear cells
vitro models. The current study used GelMA hydrogels to exposed to ceramic particles. However, their study also
culture C6 astrocyte-like and NG108-15 cells, following revealed that clinically relevant ceramic wear particles at
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the method of Rad et al., who demonstrated cell viability the same dosage did induce DNA damage, highlighting
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over 7 days. The particle size of Ceridust 3615 (>99%) differences in biological effects between model particles
aligned with that reported by Green et al. Consistent with and clinically relevant materials. Future studies should
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prior findings, no significant reduction in cell viability, focus on using clinically relevant ceramic wear particles
ROS production, or DNA damage was observed in either at the same dosage (50 μm³ per cell) to determine if the
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cell type exposed to Ceridust 3615 particles. The lack of cytotoxic effects observed in fibroblasts extend to neural
adverse effects may be due to the particle size, as larger cells. This approach will provide a clearer understanding
particles are less likely to be internalized by cells. Future of the potential biological risks associated with ceramic-
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studies should investigate the impact of clinically relevant based spinal implants in a clinically relevant context.
particle sizes on neural cell responses. Additionally, studies Prior research by Lee et al. utilized Type I rat tail
by Hallab et al. and Liu et al. found no significant release collagen gel to examine the responses of primary astrocytes
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of osteolytic cytokines from cells exposed to Ceridust and microglia to CoCrMo wear particles at doses ranging
3615. Future research should explore its impact on neural from 0.5 to 50 μm³ per cell over 5 days. Their findings
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cell inflammatory responses, offering further insights for revealed a significant reduction in astrocyte viability at
clinical applications. the highest dose (50 μm³) after 2 and 5 days. However, the
The biological impact of BIOLOX Delta ZTA wear use of collagen hydrogels introduced limitations, such as
particles has been investigated in studies involving poor structural integrity and batch-to-batch variability,
fibroblasts and peripheral blood mononuclear cells, with which could affect the results. In contrast, the current
Asif reporting minimal biological effects and suggesting study demonstrated that C6 astrocyte-like cells maintained
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potential improvements in long-term clinical performance. viability across all CoCrMo particle doses (0.5–50 μm³ per
Although ZTA is used in spinal cages, concerns about cell) over the same exposure period. A notable reduction
the brittleness of ZTA under certain loading conditions in NG108-15 cell viability was observed only at the highest
continue to limit its use in spinal implants, as fractures can dose (50 μm³) after 5 days, compared to the cell-only

Volume 11 Issue 4 (2025) 272 doi: 10.36922/IJB025180174