Protection of osteoblasts from Zn²⁺ toxicity in titanium implant surface modification: Lipoic acid against induced metabolic collapse

Zinc-modified titanium coatings hold great promise for improving implant osseointegration through their osteoinductive properties. Excessive Zn²⁺ may induce cytotoxicity by metabolic dysfunction in osteoblasts. This study evaluates the metabolic and osteogenic responses of human fetal osteoblasts and primary osteoblasts derived from osteoarthritic patients following exposure to Zn²⁺, lipoic acid (LA), lipoamide (LAM) and their combinations. Cells were treated with Zn²⁺ (0.15 mM), LA (0.10 mM), LAM (0.10 mM), or their combinations. The citrate metabolism and mitochondrial activity were quantified as well as the parameters engaged in osteoblastic mineralization. Zn²⁺ reduced mitochondrial activity resulting in decreased viability. Zn²⁺ induced substantial lactate accumulation in POB and markedly suppressed ACLY activity, leading to intracellular citrate retention and altered epigenetic metabolic signatures. Zn²⁺ significantly upregulated RUNX2 expression in POB aligning with improved mineralization capacity. LA consistently rescued Zn-evoked metabolic dysfunction in POB, restoring aconitase and LDH activity. Lipoates markedly enhanced mineralization in osteoblastic cells. Primary osteoblasts exhibited substantially higher basal inflammatory activity than hFOB 1.19, reflecting their pathological origin, yet Zn²⁺ and lipoates did not exacerbate cytokine release. This study demonstrates that primary osteoblasts derived from osteoarthritic bone provide a more physiologically relevant model for evaluating implant-associated cytotoxicity and osteogenic potential. While Zn²⁺ at 0.15 mM impairs mitochondrial metabolism, LA effectively prevents Zn-induced oxidative dysfunction, restores key metabolic pathways, and markedly enhances mineralization. These findings identify lipoic acid as a promising cytoprotective additive for zinc-based titanium implant coatings, offering a strategy to preserve antibacterial efficacy while minimizing cytotoxicity and promoting osseointegration. • Increased Zn 2 + concentration interferes with mitochondrial metabolism of osteoblast, providing aggravated mortality. • The citrate and ATP-citrate lyase activity are crucial in osteoblastic differentiation and function. • Lipoic acid protects osteoblast from Zn toxicity by restoring the citrate metabolism. • Zn, below 0.15 mM concentration in combination with lipoic acid promote osteoblastic differentiation.