Novel Osteogenic Behaviors around Hydrophilic and Radical-Free 4-META/MMA-TBB: Implications of an Osseointegrating Bone Cement.

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

doi:10.3390/ijms21072405

Abstract

Poly(methyl methacrylate) (PMMA)-based bone cement, which is widely used to affix 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.

Highlights

Bone fractures and degenerative joint changes related to osteoporosis and arthritis are common problems in elderly patients and their incidence is increasing as the population ages
The temperature of polymethyl methacrylate (PMMA)-benzoyl peroxide (BPO) peaked at 45.9 ◦C 4 min and 40 s after mixing, while the temperature of 4-methacryloyloxylethyl trimellitate anhydride (4-META)/methyl methacrylate (MMA)-tri-n-butyl borane (TBB) peaked at 38.5 ◦C 7 min after mixing
The Vickers test showed that the surface hardness of 4-META/MMA-TBB was significantly lower than PMMA-BPO at 1 h, whereas the difference was insignificant at 24 h (Figure 1B)

Summary

Introduction

Bone fractures and degenerative joint changes related to osteoporosis and arthritis are common problems in elderly patients and their incidence is increasing as the population ages. When bone and joint fractures fail to heal naturally, metallic implants are used for immobilization, restoration, and reconstruction, and bone cement is used to stabilize the implants in a significant proportion of these procedures. Implant loosening remains the most important complication, resulting in a high incidence of revision surgeries and considerable patient morbidity [2,3,4,5,6,7]. Bone cement can induce multiple adverse tissue reactions including impaired bone remodeling, necrosis, fibrosis, and histiocytosis, which may directly cause implant loosening and failure [12,13]. A dire adverse systemic complication known as bone cement implantation syndrome (BCIS) is a critical concern. BCIS is characterized by hypotension, hypoxemia, cardiac arrhythmias, cardiac arrest, or their combination and can cause immediate death (0.6%–1% in some recipient groups) [18,19]

Methods

Results

Conclusion