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Neutrophil-mediated biodegradation of medical implant materials
R S Labow1, E Meek, J P Santerre
1Cardiovascular Devices Division, University of Ottawa Heart Institute, ON, Canada. rlabow@ottawaheart.ca
Abstract:
During the acute inflammatory response to implanted medical devices, human neutrophils (PMN) release oxidative and hydrolytic activities which may ultimately contribute to the degradation of the biomaterial. In this study, the biological activities secreted by live PMNs which may contribute to biodegradation were investigated using a 14C label in the monomer unit of a poly(ester-urea-urethane) (PEUU) substrate. By using specific inhibitors, it was possible to propose a mechanism for PMN-mediated biodegradation. PMN, labeled with 3H-arachidonic acid, released significantly more 3H when adherent to PEUU than when adherent to tissue culture grade polystyrene (P<0.05). The phospholipase A2 (PLA2) inhibitors, aristolochic acid (ARIST) and quinacrine (QUIN), decreased the release of 3H and inhibited PEUU biodegradation (>50%, P<0.05). ARIST had no effect on cell viability, whereas QUIN significantly decreased it. The serine protease inhibitor, phenylmethylsulfonylfluoride inhibited biodegradation, but did not decrease cell survival. There is evidence to suggest that activation via the PLA2 pathway caused the release of hydrolytic activities which were able to elicit 14C release from PEUU. The role of oxidative compounds which were released via activation by phorbol myristate acetate (PMA), was not apparent, since PMA inhibited biodegradation and cell survival (>40%, P<0.05). This study has shown that it is possible to find out the differences in PMN activation through the PLA2 pathway when exposed to different material surfaces, making this a model system worthy of further investigation.
Insights
Human neutrophils (PMN) degrade biomaterials via phospholipase A2 (PLA2) pathway activation. Inhibiting PLA2 significantly reduced poly(ester-urea-urethane) biodegradation, offering insights into material-cell interactions.
Area of Science:
- Biomaterials Science
- Immunology
- Cell Biology
Background:
- Implanted medical devices can trigger inflammatory responses from human neutrophils (PMN).
- Neutrophil-secreted enzymes may degrade biomaterials, impacting device longevity.
- Understanding these degradation mechanisms is crucial for developing durable medical implants.
Purpose of the Study:
- To investigate the biological activities released by live human neutrophils (PMN) that contribute to the biodegradation of poly(ester-urea-urethane) (PEUU).
- To elucidate the specific pathways involved in PMN-mediated PEUU biodegradation using targeted inhibitors.
- To establish a model system for studying PMN activation on different material surfaces.
Main Methods:
- Utilized a 14C-labeled PEUU substrate to quantify biodegradation.
- Employed 3H-arachidonic acid labeling in PMNs to assess cellular activity and release.
- Administered specific inhibitors targeting phospholipase A2 (PLA2) and serine proteases.
- Investigated the effect of phorbol myristate acetate (PMA) on biodegradation and cell viability.
Main Results:
- PMNs released significantly more 3H when adhered to PEUU compared to polystyrene.
- PLA2 inhibitors (aristolochic acid, quinacrine) significantly reduced 3H release and inhibited PEUU biodegradation by over 50%.
- Serine protease inhibitor (phenylmethylsulfonylfluoride) inhibited biodegradation but not cell survival.
- Phorbol myristate acetate (PMA) inhibited both biodegradation and cell survival.
Conclusions:
- Activation of human neutrophils via the PLA2 pathway is a key mechanism driving the hydrolytic degradation of PEUU biomaterials.
- PLA2 inhibition offers a potential strategy to mitigate biomaterial biodegradation.
- The study provides a valuable model system for differentiating PMN activation responses on various material surfaces.