AccScience Publishing / IJB / Online First / DOI: 10.36922/IJB025180174
Submit to IJB
Cite this article
25
Download
246
Views
Journal Browser
Volume | Year
Issue
Search
Forthcoming Issue
Current Issue
View All
News and Announcements
View All
RESEARCH ARTICLE

Neural cell responses to spinal implant biomaterials in a 3D-bioprinted cell culture model

David J. Wen1† ,  Javad Tavakoli1,2†* ,  Joanne L. Tipper1,2*
Show Less
1 School of Biomedical Engineering, Faculty of Engineering and Information Technology, University of Technology Sydney, Sydney, Australia
2 School of Engineering, STEM College, RMIT University, Melbourne, Australia
†These authors contributed equally to this work.
IJB, 025180174 https://doi.org/10.36922/IJB025180174
Received: 29 April 2025 | Accepted: 10 June 2025 | Published online: 11 June 2025
(This article belongs to the Special Issue Bioprinting of Nanomaterials for Biomedical Applications)
© 2025 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
Download PDF
Cite
XML
Abstract

Spinal implants are vital for treating spinal disorders, yet wear particle-induced complications threaten their long-term success. Despite this, the direct effects of implant-derived particles on neural cells remain largely unexplored, especially given the limitations of conventional 2D culture models to capture such complex interactions. The current study introduces a novel in vitro platform consisting of a 3D-bioprinted gelatin methacryloyl (GelMA) hydrogel embedded with neural cells (C6 astrocyte-like and NG108-15 neurons) and spinal implant biomaterial particles, designed to model the spinal cord microenvironment with enhanced physiological relevance. As the first of its kind, this cell-particle-laden system supports the evaluation of neural cell responses to spinal biomaterial particles, including polymers, PEEK-OPTIMA™ and polyethylene Ceridust® 3615, zirconia-toughened alumina (ZTA) ceramic, and CoCrMo metal alloy. The bioprinted platform demonstrated excellent compatibility with various neural cell types and particle compositions, enabling a wide range of biological assays. Cell viability within the 3D model was comparable to traditional 2D cultures, affirming its ability to sustain cell survival while offering improved biomimicry. Biological assays assessing cell viability, reactive oxygen species (ROS) production, and DNA damage provided critical insights into material-specific and time-dependent cellular responses. While no significant cytotoxic effects were observed in short-term cultures, distinct variations in ROS production, and viability emerged based on biomaterial type and exposure duration. Overall, this versatile 3D-bioprinted system presents a robust, scalable tool for mechanistic and toxicological studies of spinal implant wear particles under physiologically relevant conditions.  

Graphical abstract
Keywords
3D model
Biomaterial particles
Bioprinting
C6 Astrocyte-like cells
Cell viability
Nevural cells
NG108-15 cells
Reactive oxygen species
Funding
Not applicable.
Conflict of interest
The authors declare they have no competing interests
References
  1. Tavakoli J, Diwan AD, Tipper JL. Advanced strategies for the regeneration of lumbar disc annulus fibrosus. Int J Mol Sci. 2020;21(14):4889. doi: 10.3390/ijms21144889
  2. Wen DJ, Tavakoli J, Tipper JL. Lumbar total disc replacements for degenerative disc disease: a systematic review of outcomes with a minimum of 5 years follow-up. Global Spine J. 2024;14(6):1827-1837. doi: 10.1177/21925682241228756
  3. Zeegers W, Bohnen L, Laaper M, Verhaegen M. Artificial disc replacement with the modular type SB Charite III: 2-year results in 50 prospectively studied patients. Eur Spine J. 1999;8:210-217. doi: 10.1007/s005860050160
  4. Vicars R, Hyde PJ, Brown TD, et al. The effect of anterior– posterior shear load on the wear of ProDisc-L TDR. Eur Spine J. 2010;19(8):1356-1362. doi: 10.1007/s00586-010-1396-8
  5. Vicars R, Prokopovich P, Brown TD, et al. The effect of anterior-posterior shear on the wear of CHARITÉ total disc replacement. Spine (Phila Pa 1976). 2012;37(9):E528-E534. doi: 10.1097/BRS.0b013e31823cbd6e
  6. Hallab NJ. A review of the biologic effects of spine implant debris: fact from fiction. SAS J. 2009;3(4):143-160. doi: 10.1016/j.esas.2009.11.005
  7. Chang B-S, Brown PR, Sieber A, Valdevit A, Tateno K, Kostuik JP. Evaluation of the biological response of wear debris. Spine J. 2004;4(6):S239-S244. doi: 10.1016/j.spinee.2004.07.014
  8. Ganko R, Madhavan A, Hamouda W, et al. Spinal implant wear particles: generation, characterization, biological impacts, and future considerations. iScience. 2025;28(4):112193. doi: 10.1016/j.isci.2025.112193
  9. Punt IM, Austen S, Cleutjens JP, et al. Are periprosthetic tissue reactions observed after revision of total disc replacement comparable to the reactions observed after total hip or knee revision surgery? Spine (Phila Pa 1976). 2012;37(2):150-159. doi: 10.1097/brs.0b013e3182154c22
  10. San-Juan R, Paredes I, Ramírez-Nava E, et al. Reduction of instrumentation-related spine surgical site infections after optimization of surgical techniques. a single center retrospective analysis. Global Spine J. 2024;14(2):438-446. doi: 10.1177/21925682221109557
  11. Xu R, Ebraheim NA, Nadaud MC, Phillips ER. Local tissue of the lumbar spine response to titanium plate-screw system. Spine (Phila Pa 1976). 1996;21(7):871-873. doi: 10.1097/00007632-199604010-00020
  12. Lin T-h, Tamaki Y, Pajarinen J, et al. Chronic inflammation in biomaterial-induced periprosthetic osteolysis: NF-κB as a therapeutic target. Acta Biomater. 2014;10(1):1-10. doi: 10.1016/j.actbio.2013.09.034
  13. Zairi F, Remacle JM, Allaoui M, Assaker R. Delayed hypersensitivity reaction caused by metal-on-metal total disc replacement: case report. J Neurosurg Spine. 2013;19(3):389-391. doi: 10.3171/2013.6.spine121010
  14. Zeh A, Planert M, Siegert G, Lattke P, Held A, Hein W. Release of cobalt and chromium ions into the serum following implantation of the metal-on-metal Maverick-type artificial lumbar disc (Medtronic Sofamor Danek). Spine (Phila Pa 1976). 2007;32(3):348-352. doi: 10.1097/01.brs.0000253599.89694.c0
  15. AlZeedi M, Al Rawahi S, Muwanis M, Alraiyes TM, Al Farii H, Jarzem P. Pseudotumor after total disc replacement in the lumbar spine: a case report and review of the literature. N Am Spine Soc J. 2022;9:100107. doi: 10.1016/j.xnsj.2022.100107
  16. Tavakoli J, Hu Q, Tipper JL, Tang Y. Aggregation-induced emission biomarkers for early detection of orthopaedic implant failure. Aggregate. 2024;5(6):e645. doi: 10.1002/agt2.645
  17. Austen S, Punt IM, Cleutjens JP, et al. Clinical, radiological, histological and retrieval findings of Activ-L and Mobidisc total disc replacements: a study of two patients. Eur Spine J. 2012;21:513-520. doi: 10.1007/s00586-011-2141-7
  18. Yang G, Gu M, Chen W, et al. SPHK-2 promotes the particle-induced inflammation of RAW264.7 by maintaining consistent expression of TNF-α and IL-6. Inflammation. 2018;41(4):1498-1507. doi: 10.1007/s10753-018-0795-6
  19. Yoshitake F, Itoh S, Narita H, Ishihara K, Ebisu S. Interleukin-6 directly inhibits osteoclast differentiation by suppressing receptor activator of NF-kappaB signaling pathways. J Biol Chem. 2008;283(17):11535-11540. doi: 10.1074/jbc.m607999200
  20. Ayers R, Miller M, Schowinsky J, Burger E, Patel V, Kleck C. Three cases of metallosis associated with spine instrumentation. J Mater Sci Mater Med. 2017;29(1):3. doi: 10.1007/s10856-017-6011-7
  21. Punt IM, Cleutjens JPM, de Bruin T, et al. Periprosthetic tissue reactions observed at revision of total intervertebral disc arthroplasty. Biomaterials. 2009;30(11):2079-2084. doi: 10.1016/j.biomaterials.2008.12.071
  22. Cunningham BW, Orbegoso CM, Dmitriev AE, et al. The effect of spinal instrumentation particulate wear debris: an in vivo rabbit model and applied clinical study of retrieved instrumentation cases. Spine J. 2003;3(1):19-32. doi: 10.1016/S1529-9430(02)00443-6
  23. Lin T-h, Yao Z, Sato T, et al. Suppression of wear-particle-induced pro-inflammatory cytokine and chemokine production in macrophages via NF-κB decoy oligodeoxynucleotide: a preliminary report. Acta Biomater. 2014;10(8):3747-3755. doi: 10.1016/j.actbio.2014.04.034
  24. Luo G, Li Z, Wang Y, et al. Resveratrol protects against titanium particle-induced aseptic loosening through reduction of oxidative stress and inactivation of NF-κB. Inflammation. 2016;39(2):775-785. doi: 10.1007/s10753-016-0306-6
  25. Hallab NJ, Cunningham BW, Jacobs JJ. Spinal implant debris-induced osteolysis. Spine (Phila Pa 1976). 2003;28(20S):S125-S138. doi: 10.1097/00007632-200310151-00006
  26. Lee H, Phillips JB, Hall RM, Tipper JL. Neural cell responses to wear debris from metal-on-metal total disc replacements. Eur Spine J. 2020;29(11):2701-2712. doi: 10.1007/s00586-019-06177-w
  27. Papageorgiou I, Marsh R, Tipper JL, Hall RM, Fisher J, Ingham E. Interaction of micron and nano‐sized particles with cells of the dura mater. J Biomed Mater Res B Appl Biomater. 2014;102(7):1496-1505. doi: 10.1002/jbm.b.33129
  28. Behl B, Papageorgiou I, Brown C, et al. Biological effects of cobalt-chromium nanoparticles and ions on dural fibroblasts and dural epithelial cells. Biomaterials. 2013;34(14):3547-3558. doi: 10.1016/j.biomaterials.2013.01.023
  29. Papageorgiou I, Abberton T, Fuller M, Tipper JL, Fisher J, Ingham E. Biological effects of clinically relevant cocr nanoparticles in the dura mater: an organ culture study. Nanomaterials. 2014;4(2):485-504. doi: 10.3390/nano4020485
  30. Cunningham BW, Hallab NJ, Hu N, McAfee PC. Epidural application of spinal instrumentation particulate wear debris: a comprehensive evaluation of neurotoxicity using an in vivo animal model. J Neurosurg Spine. 2013;19(3):336-350. doi: 10.3171/2013.5.spine13166
  31. Stoodley MA, Jones NR, Brown CJ. Evidence for rapid fluid flow from the subarachnoid space into the spinal cord central canal in the rat. Brain Res. 1996;707(2):155-164. doi: 10.1016/0006-8993(95)01228-1
  32. Stoodley MA, Brown SA, Brown CJ, Jones NR. Arterial pulsation-dependent perivascular cerebrospinal fluid flow into the central canal in the sheep spinal cord. J Neurosurg. 1997;86(4):686-693. doi: 10.3171/jns.1997.86.4.0686
  33. Rad MA, Mahmodi H, Filipe EC, Cox TR, Kabakova I, Tipper JL. Micromechanical characterisation of 3D bioprinted neural cell models using Brillouin microspectroscopy. Bioprinting. 2022;25:e00179. doi: 10.1016/j.bprint.2021.e00179
  34. Asif IM. Characterisation and Biological Impact of Wear Particles from Composite Ceramic Hip Replacements. University of Leeds; 2018. https://etheses.whiterose.ac.uk/id/oai_id/oai:etheses. whiterose.ac.uk:20563
  35. Liu A, Richards L, Bladen CL, Ingham E, Fisher J, Tipper JL. The biological response to nanometre-sized polymer particles. Acta Biomater. 2015;23:38-51. doi: 10.1016/j.actbio.2015.05.016
  36. Kim A, Mo K, Choe S, Shin M, Yoon H. Comprehensive insight into 3D bioprinting technology for brain tumor modelling. IJB. 2024;10(6):4166. doi: 10.36922/ijb.4166
  37. Tang H, Zhao E, Lai Y, et al. 3D bioprinting techniques and hydrogels for osteochondral integration regeneration. IJB. 2024;10(6):4472. doi: 10.36922/ijb.4472
  38. Hou Y-C, Cui X, Qin Z, et al. Three-dimensional bioprinting of artificial blood vessel: process, bioinks, and challenges. IJB. 2023;9(4):740. doi: 10.18063/ijb.740
  39. Du Z, Zhu Z, Wang Y. The degree of peri-implant osteolysis induced by PEEK, CoCrMo, and HXLPE wear particles: a study based on a porous Ti6Al4V implant in a rabbit model. J Orthop Surg Res. 2018;13(1):23. doi: 10.1186/s13018-018-0736-y
  40. Hallab NJ, McAllister K, Brady M, Jarman-Smith M. Macrophage reactivity to different polymers demonstrates particle size- and material-specific reactivity: PEEK-OPTIMA® particles versus UHMWPE particles in the submicron, micron, and 10 micron size ranges. J Biomed Mater Res B Appl Biomater. 2012;100B(2):480-492. doi: 10.1002/jbm.b.31974
  41. Green TR, Fisher J, Stone M, Wroblewski BM, Ingham E. Polyethylene particles of a ‘critical size’ are necessary for the induction of cytokines by macrophages in vitro. Biomaterials. 1998;19(24):2297-2302. doi: 10.1016/s0142-9612(98)00140-9
  42. Germain M, Hatton A, Williams S, et al. Comparison of the cytotoxicity of clinically relevant cobalt–chromium and alumina ceramic wear particles in vitro. Biomaterials. 2003;24(3):469-479. doi: 10.1016/s0142-9612(02)00360-5
  43. Bishop ES, Mostafa S, Pakvasa M, et al. 3-D bioprinting technologies in tissue engineering and regenerative medicine: Current and future trends. Genes Dis. 2017;4(4): 185-195. doi: 10.1016/j.gendis.2017.10.002
  44. Yu J, Park SA, Kim WD, et al. Current advances in 3D bioprinting technology and its applications for tissue engineering. Polymers. 2020;12(12):2958. doi: 10.3390/polym12122958
  45. Hallab NJ, Bao Q-B, Brown T. Assessment of epidural versus intradiscal biocompatibility of PEEK implant debris: an in vivo rabbit model. Eur Spine J. 2013;22:2740-2751. doi: 10.1007/s00586-013-2904-4
  46. Stratton-Powell AA, Pasko KM, Brockett CL, Tipper JL. The biologic response to polyetheretherketone (PEEK) wear particles in total joint replacement: a systematic review. Clin Orthop Relat Res. 2016;474(11):2394-2404. doi: 10.1007/s11999-016-4976-z
  47. Yarrow-Wright LE. Development of a Novel 3D In Vitro Model to Measure Cellular Response to Antioxidant Doped Highly Cross-Linked Ultra High Molecular Weight Polyethylene Wear Debris. University of Leeds; 2018. https://etheses.whiterose.ac.uk/id/oai_id/oai:etheses. whiterose.ac.uk:24128
  48. Kölle L, Ignasiak D, Ferguson SJ, Helgason B. Ceramics in total disc replacements: a scoping review. Clin Biomech. 2022;100:105796. doi: 10.1016/j.clinbiomech.2022.105796
  49. Jaksa L, Aryeetey OJ, Hatamikia S, et al. 3D-printed multi-material liver model with simultaneous mechanical and radiological tissue-mimicking features for improved realism. IJB. 2023;9(4):721. doi: 10.18063/ijb.721
  50. Yuk JC, Nam KH, Park SH. Additive-manufactured synthetic bone model with biomimicking tunable mechanical properties for evaluation of medical implants. IJB. 2024;10(1):1067. doi: 10.36922/ijb.1067

 

 

 

Share
Back to top
International Journal of Bioprinting, Electronic ISSN: 2424-8002 Print ISSN: 2424-7723, Published by AccScience Publishing
We use cookies on our website to ensure you get the best experience.
Read more about our cookies here
Accept