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In Vitro Cytotoxic Effects of Benzalkonium Chloride in Corticosteroid Injection Suspension

Davis, Daniel MSc; Cyriac, Mathew MBA, BSc; Ge, Dongxia MD; You, Zongbing MD, PhD; Savoie, Felix H. MD

Journal of Bone & Joint Surgery - American Volume: January 2010 - Volume 92 - Issue 1 - p 129–137
doi: 10.2106/JBJS.H.01561
Scientific Articles

Background: Some deleterious effects on cartilage and even severe arthropathy have been reported after intra-articular corticosteroid injections. The objective of the present in vitro study was to determine if an injectable corticosteroid suspension is toxic to articular chondrocytes and synovial cells.

Methods: Human and bovine articular chondrocytes, bovine synovial cells, mouse C3H10T1/2 cells, and human osteosarcoma MG-63 cells were treated for thirty minutes in monolayer or suspension culture with an injectable corticosteroid suspension or its chemical components, including betamethasone sodium phosphate, betamethasone acetate, and benzalkonium chloride (as preservative). Cell viability was determined by means of microscopy or flow cytometry analysis.

Results: In monolayer culture, the betamethasone corticosteroids per se did not cause cell death, whereas benzalkonium chloride caused death of articular chondrocytes. In suspension culture, betamethasone sodium phosphate at dosages of as high as 6 mg/mL did not cause significant death of human or bovine articular chondrocytes (p > 0.05). In contrast, benzalkonium chloride caused a death rate of 10.6% in human articular chondrocytes at a dosage of 10 μg/mL (p < 0.01), 21.0% at a dosage of 13.3 μg/mL (p < 0.01), and 99.3% and 99.4% at dosages of 20 and 200 μg/mL, respectively (p < 0.001 for both). Similarly, benzalkonium chloride caused death of bovine articular chondrocytes, bovine synovial cells, C3H10T1/2 cells, and MG-63 cells in a dose-dependent manner. When treated with a combination of betamethasone sodium phosphate and 200 μg/mL benzalkonium chloride, >99% of human or bovine articular chondrocytes were dead (p < 0.001).

Conclusions: The injectable corticosteroid suspension caused death in in vitro culture of human and bovine articular chondrocytes as well as bovine synovial cells because of its preservative benzalkonium chloride. The betamethasone corticosteroids per se did not cause significant chondrocyte death under the conditions tested.

Clinical Relevance: These findings should stimulate an in vivo animal study to test the degree to which the changes seen in vitro also occur in vivo.

1Tulane Institute of Sports Medicine, Department of Orthopaedic Surgery (D.D., Z.Y., and F.H.S.), and Department of Structural and Cellular Biology, Tulane Cancer Center, LCRC, Tulane Center for Aging (D.G. and Z.Y.), Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA 70112. E-mail address for Z. You:

2Albany Medical College, 43 New Scotland Avenue, Albany, NY 12208

3Institute of Biomedical Engineering, West China Medical Center, Sichuan University, No. 3-17 Ren Min Nan Lu Road, Chengdu, Sichuan, China 610041

Copyright 2010 by The Journal of Bone and Joint Surgery, Incorporated
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