Novel osteogenic behaviors around hydrophilic and radical-free 4-META/MMA-TBB: Implications of an osseointegrating bone cement

Yoshihiko Sugita, Takahisa Okubo, Makiko Saita, Manabu Ishijima, Yasuyoshi Torii, Miyuki Tanaka, Chika Iwasaki, Takeo Sekiya, Masako Tabuchi, Naser Mohammadzadeh Rezaei, Takashi Taniyama, Nobuaki Sato, Juri Saruta, Masakazu Hasegawa, Makoto Hirota, Wonhee Park, Masaichi Chang Il Lee, Hatsuhiko Maeda, Takahiro Ogawa

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Abstract

Poly(methyl methacrylate) (PMMA)-based bone cement, which is widely used to affx orthopedic metallic implants, is considered bio-tolerant but lacks osteoconductivity and is cytotoxic. Implant loosening and toxic complications are significant and recognized problems. Here we devised two strategies to improve PMMA-based bone cement: (1) adding 4-methacryloyloxylethyl trimellitate anhydride (4-META) to MMA monomer to render it hydrophilic; and (2) using tri-n-butyl borane (TBB) as a polymerization initiator instead of benzoyl peroxide (BPO) to reduce free radical production. Rat bone marrow-derived osteoblasts were cultured on PMMA-BPO, common bone cement ingredients, and 4-META/MMA-TBB, newly formulated ingredients. After 24 h of incubation, more cells survived on 4-META/MMA-TBB than on PMMA-BPO. The mineralized area was 20-times greater on 4-META/MMA-TBB than PMMA-BPO at the later culture stage and was accompanied by upregulated osteogenic gene expression. The strength of bone-to-cement integration in rat femurs was 4- and 7-times greater for 4-META/MMA-TBB than PMMA-BPO during early- and late-stage healing, respectively. MicroCT and histomorphometric analyses revealed contact osteogenesis exclusively around 4-META/MMA-TBB, with minimal soft tissue interposition. Hydrophilicity of 4-META/MMA-TBB was sustained for 24 h, particularly under wet conditions, whereas PMMA-BPO was hydrophobic immediately after mixing and was unaffected by time or condition. Electron spin resonance (ESR) spectroscopy revealed that the free radical production for 4-META/MMA-TBB was 1/10 to 1/20 that of PMMA-BPO within 24 h, and the substantial difference persisted for at least 10 days. The compromised ability of PMMA-BPO in recruiting cells was substantially alleviated by adding free radical-scavenging amino-acid N-acetyl cysteine (NAC) into the material, whereas adding NAC did not affect the ability of 4-META/MMA-TBB. These results suggest that 4-META/MMA-TBB shows significantly reduced cytotoxicity compared to PMMA-BPO and induces osteoconductivity due to uniquely created hydrophilic and radical-free interface. Further pre-clinical and clinical validations are warranted.

Original languageEnglish
Article number2405
JournalInternational Journal of Molecular Sciences
Volume21
Issue number7
DOIs
StatePublished - 2020 Apr 1

Keywords

  • Arthroplasty
  • Cytotoxicity
  • Free radical
  • Implants
  • PMMA
  • Total hip replacement

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    Sugita, Y., Okubo, T., Saita, M., Ishijima, M., Torii, Y., Tanaka, M., Iwasaki, C., Sekiya, T., Tabuchi, M., Rezaei, N. M., Taniyama, T., Sato, N., Saruta, J., Hasegawa, M., Hirota, M., Park, W., Lee, M. C. I., Maeda, H., & Ogawa, T. (2020). Novel osteogenic behaviors around hydrophilic and radical-free 4-META/MMA-TBB: Implications of an osseointegrating bone cement. International Journal of Molecular Sciences, 21(7), [2405]. https://doi.org/10.3390/ijms21072405