In vitro modulation of macrophage phenotype and inhibition of polymer degradation by dexamethasone in a human macrophage/Fe/stress system.
A new in vitro accelerated biological model, the macrophage-FeCl2-stress system was used for the evaluation of dexamethasone (DEX)-polymer formulations. This model combines the effects of cells (macrophages), transition metal ions (Fe2+), and polymer stress to promote material biodegradation. The cell and material effects of DEX, either in solution or incorporated into a polyetherurethane matrix (DEX/PEU), were monitored. Cell morphology and hydroperoxide formation in the polymer during cell culturing were characterized. After a subsequent treatment with FeCl2 the development of environmental stress cracking in the polymer was evaluated. We attempted to duplicate the biodegradation of PEU in terms of environmental stress cracking (ESC). Our results support the direct involvement of macrophages in polyetherurethane oxidation, probably by inducing hydroperoxide formation in the polymer structure. Under the influence of stress or strain, polymers with sufficient hydroperoxides degrade in the presence of Fe2+ metal ions in a manner that closely resembles the stress cracking that is observed in vivo. By contrast, polymers treated with either agents that inhibit cell activation and/or the oxidative burst, or with cells with no oxidative burst did not show signs of the biodegradative process. We demonstrated a reduction in hydroperoxide formation and no later ESC development in macrophage-cultured PEU in the presence of DEX in solution or in DEX-loaded PEU. We believe the prevention of initial polymer oxidation by reducing the cell's potential to produce oxidative stress at the tissue-biomaterial interface can directly inhibit the ESC degradation of chronically implanted polymers. The in vitro macrophage-Fe-stress system is a valuable tool for reliable assessment and cost-effective evaluation of biomaterials.
Casas
J
J
Biosciences Laboratory, Materials and Biosciences Center, Medtronic, Inc., Minneapolis, Minnesota 55430, USA.
Zhao
Q
Q
Donovan
M
M
Schroeder
P
P
Stokes
K
K
Untereker
D
D
D000328:Adult; D001673:Biodegradation, Environmental; D002448:Cell Adhesion; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology*; D005296:Ferrous Compounds; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008422:Materials Testing; D008855:Microscopy, Electron, Scanning; D018384:Oxidative Stress; D010641:Phenotype; D011140:Polyurethanes / Q000494:pharmacology*; D013499:Surface Properties
D005296:Ferrous Compounds; D011140:Polyurethanes; D003907:Dexamethasone; D006861:Hydrogen Peroxide; C029451:ferrous chloride