Fabrication of 3D-printed scaffolds loaded with gallium acetylacetonate for potential application in osteoclastic bone resorption.

We recently reported the potential of a new gallium compound, gallium acetylacetonate (GaAcAc) in combating osteoclastic bone resorption through inhibition of osteoclast differentiation and function. Herein, we focused on 3D-printed polylactic acid scaffolds that were loaded with GaAcAc and investigated the impact of scaffold pretreatment with polydopamine (PDA) or sodium hydroxide (NaOH). We observed a remarkable increase in scaffold hydrophilicity with PDA or NaOH pretreatment while biocompatibility and in vitro degradation were not affected. NaOH-pretreated scaffolds showed the highest amount of GaAcAc loading when compared to other scaffolds (p < 0.05). NaOH-pretreated scaffolds with GaAcAc loading showed effective reduction of osteoclast counts and size. The trend was supported by suppression of key osteoclast differentiation markers such as NFAT2, c-Fos, TRAF6, & TRAP. All GaAcAc-loaded scaffolds, regardless of surface pretreatment, were effective in inhibiting osteoclast function as evidenced by reduction in the number of resorptive pits in bovine cortical bone slices (p < 0.01). The suppression of osteoclast function according to the type of scaffold followed the ranking: GaAcAc loading without surface pretreatment > GaAcAc loading with NaOH pretreatment > GaAcAc loading with PDA pretreatment. Additional studies will be needed to fully elucidate the impact of surface pretreatment on the efficacy and safety of GaAcAc-loaded 3D-printed scaffolds.

Fatty Acid Intake and Polyunsaturated Fatty Acid Biomarkers and Risk of Total Knee or Hip Arthroplasty Among Older Women in the Women's Health Initiative.

OBJECTIVE: The objective was to determine whether baseline fatty acid intake and erythrocyte omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) can predict risk of total hip arthroplasty (THA) and total knee arthroplasty (TKA) in older women. METHODS: This was a prospective analysis of 34,990 women in the Women's Health Initiative. Dietary fatty acids were estimated from food frequency questionnaires. Imputed erythrocyte PUFAs were available in a subcohort of 3,428 women. Arthroplasty (THA and TKA), used as a surrogate of severe osteoarthritis, was identified via linked Medicare data. Cox proportional hazards models were constructed to estimate risk of arthroplasty. RESULTS: Risk of THA was associated with higher intake of arachidonic acid, (multivariable hazard ratio [HR] quartile 4 [Q4] vs Q1: 1.16; 95% confidence interval [CI] 1.01-1.34; P = 0.03) and higher intake of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA; HR Q4 vs Q1: 1.20; 95% CI 1.05-1.39; P = 0.003). There was a linear trend (P = 0.04) for patients to have a higher risk of THA with higher erythrocyte EPA and DHA in body mass index-adjusted models; however, there was no significant difference in patients who had THAs by quartiles of erythrocyte EPA and DHA (P = 0.10). Dietary fatty acids and erythrocyte PUFAs were not significantly associated with risk of TKA. CONCLUSION: Higher baseline intakes of arachidonic acid and EPA and DHA were associated with a modestly higher risk of THA. No association was found between fatty acids and patients who had TKAs. Further research in populations with direct measures of osteoarthritis severity is needed to better understand the importance of PUFAs in modulating osteoarthritis and arthroplasty risk.

Efficacy assessment of methylcellulose-based thermoresponsive hydrogels loaded with gallium acetylacetonate in osteoclastic bone resorption.

Homeostatic imbalance involving progressive stimulation of osteoclast (OC) differentiation and function will lead to an increased risk of fragility fractures. In this regard, we investigated gallium acetylacetonate (GaAcAc) as a possible treatment for osteoclastic bone resorption. Further, the extent to which suitable delivery systems can enhance the therapeutic potential of GaAcAc was evaluated. GaAcAc solution (10-50 µg/mL) suppressed OC differentiation using murine monocytic RAW 264.7 or hematopoietic stem cells. Methylcellulose-based hydrogels were fabricated and characterized based on biocompatibility with bone cells, GaAcAc loading, and thermoresponsive behavior using storage (G') and loss (G″) moduli parameters. Compared to GaAcAc solution, hydrogels loaded with GaAcAc (GaMH) were more effective in suppressing OC differentiation and function. The number and extent of bone resorption pits from ex vivo studies were markedly reduced with GaMH treatment. Mechanistic assessment of GaMH efficacy showed superiority, compared to GaAcAc solution, in downregulating the expression of key markers involved in mediating OC differentiation (such as NFAT2, cFos, TRAF6, and TRAP) as well as in bone resorption by OCs (cathepsin K or CTSK). Additional studies (in vitro and in vivo) suggested that the performance of GaMH could be ascribed to controlled release of GaAcAc and the ability to achieve prolonged bio-retention after injection in BALB/c mice, which plausibly maximized the therapeutic impact of GaAcAc. Overall, the work demonstrated, for the first time, the therapeutic efficacy of GaAcAc and the therapeutic potential of GaMH delivery systems in osteoclastic bone resorption.