Down-regulating ERK1/2 and SMAD2/3 phosphorylation by physical barrier of celecoxib-loaded electrospun fibrous membranes prevents tendon adhesions.

Abstract

Peritendinous adhesions, as a major problem in hand surgery, may be due to the proliferation of fibroblasts and excessive collagen synthesis, in which ERK1/2 and SMAD2/3 plays crucial roles. In this study, we hypothesized that the complication progression could be inhibited by down-regulating ERK1/2 and SMAD2/3 phosphorylation of exogenous fibroblasts with celecoxib. Celecoxib was incorporated in poly(l-lactic acid)-polyethylene glycol (PELA) diblock copolymer fibrous membranes via electrospinning. Results of an in vitro drug release study showed celecoxib-loaded membrane had excellent continuous drug release capability. It was found that celecoxib-loaded PELA membranes were not favorable for the rabbit fibroblast and tenocyte adhesion and proliferation. In a rabbit tendon repair model, we first identified ERK1/2 and SMAD2/3 phosphorylation as a critical driver of early adhesion formation progression. Celecoxib released from PELA membrane was found to down-regulate ERK1/2 and SMAD2/3 phosphorylation, leading to reduced collagen I and collagen Ⅲ expression, inflammation reaction, and fibroblast proliferation. Importantly, the celecoxib-loaded PELA membranes successfully prevented tissue adhesion compared with control treatment and unloaded membranes treatment. This approach offers a novel barrier strategy to block tendon adhesion through targeted down-regulating of ERK1/2 and SMAD2/3 phosphorylation directly within peritendinous adhesion tissue.

• Authors: Shichao Jiang, Xin Zhao, Shuai Chen, Guoqing Pan, Jialin Song, Ning He, Fengfeng Li, Wenguo Cui, Cunyi Fan
• Journal: Biomaterials (Biomaterials) Vol. 35 Issue 37 Pg. 9920-9929 (Dec 2014) ISSN: 1878-5905 [Electronic] Netherlands
• PMID: 25201739 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical References

• Cyclooxygenase 2 Inhibitors
• Lactates
• Membranes, Artificial
• Pyrazoles
• Smad Proteins
• Smad2 Protein
• Smad3 Protein
• Sulfonamides
• poly(lactic acid-ethylene glycol)
• Polyethylene Glycols
• Extracellular Signal-Regulated MAP Kinases
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• Celecoxib

Topics

• Animals
• Celecoxib
• Cyclooxygenase 2 Inhibitors (administration & dosage, therapeutic use)
• Drug Delivery Systems
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Fibroblasts (drug effects, metabolism)
• Lactates (chemistry)
• Membranes, Artificial
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Phosphorylation (drug effects)
• Polyethylene Glycols (chemistry)
• Pyrazoles (administration & dosage, therapeutic use)
• Rabbits
• Smad Proteins (metabolism)
• Smad2 Protein (metabolism)
• Smad3 Protein (metabolism)
• Sulfonamides (administration & dosage, therapeutic use)
• Tendons (drug effects, metabolism)
• Tissue Adhesions (metabolism, prevention & control)