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2018 ; 9
(ä): 289
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gab.com Text
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English Wikipedia
Localized Delivery of Cl-Amidine From Electrospun Polydioxanone Templates to
Regulate Acute Neutrophil NETosis: A Preliminary Evaluation of the PAD4 Inhibitor
for Tissue Engineering
#MMPMID29643810
Fetz AE
; Neeli I
; Buddington KK
; Read RW
; Smeltzer MP
; Radic MZ
; Bowlin GL
Front Pharmacol
2018[]; 9
(ä): 289
PMID29643810
show ga
Upon interaction, neutrophils can potentially release neutrophil extracellular
traps (NETs) on the surface of an implanted electrospun template, which may be a
significant preconditioning event for implantable biomaterials of yet unknown
consequences. In this study, we investigated the potential of polydioxanone
templates as a delivery vehicle for Cl-amidine, an inhibitor of peptidyl arginase
deiminase 4 (PAD4), and if drug elution could attenuate PAD4-mediated NETosis in
the vicinity of implanted templates. Electrospun polydioxanone templates were
fabricated with distinct architectures, small diameter (0.4 ?m) or large diameter
(1.8 ?m) fibers, and incorporated with 0-5 mg/mL Cl-amidine to examine
dose-dependent effects. Acute neutrophil-template interactions were evaluated in
vitro with freshly isolated human neutrophils and in vivo with a rat subcutaneous
implant model. The in vitro results suggest large diameter templates with 0 mg/mL
Cl-amidine significantly attenuate NETosis compared to small diameter templates.
As the drug concentration increased, NETosis was significantly decreased on small
diameter templates in a dose-dependent manner. The opposite was observed for
large diameter templates, indicating multiple mechanisms of NETosis may be
regulating neutrophil template preconditioning. Similar results were observed in
vivo, verifying local NETosis inhibition by Cl-amidine eluting templates in a
physiological environment. Importantly, large diameter templates with Cl-amidine
enhanced neutrophil invasion and survival, supporting the potential for long-term
modulation of tissue integration and regeneration. This preliminary study
demonstrates a novel delivery vehicle for Cl-amidine that can be used to regulate
acute NETosis as the potential critical link between the innate immune response,
inflammation, and template-guided tissue regeneration.