title: 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.affiliation: Department of Orthopaedics, Shanghai Jiaotong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, PR China. Electronic address: mailjsc@163.com.
authors.forename: Shichao
authors.initials: S
authors.lastname: Jiang
authors.affiliation: Orthopedic Institute, Soochow University, 708 Renmin Rd, Suzhou, Jiangsu 215006, PR China. Electronic address: Xinzhao1@mit.edu.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Orthopaedics, Shanghai Jiaotong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, PR China. Electronic address: 723997068@qq.com.
authors.forename: Shuai
authors.initials: S
authors.lastname: Chen
authors.affiliation: Orthopedic Institute, Soochow University, 708 Renmin Rd, Suzhou, Jiangsu 215006, PR China; Department of Orthopedics, The First Affiliated Hospital of Soochow University, 188 Shizi St, Suzhou, Jiangsu 215006, PR China. Electronic address: yueer@suda.edu.cn.
authors.forename: Guoqing
authors.initials: G
authors.lastname: Pan
authors.affiliation: Department of Orthopaedics, Shanghai Jiaotong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, PR China. Electronic address: songjialinsjtu@126.com.
authors.forename: Jialin
authors.initials: J
authors.lastname: Song
authors.affiliation: Department of Orthopaedics, Shanghai Jiaotong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, PR China. Electronic address: desmask@163.com.
authors.forename: Ning
authors.initials: N
authors.lastname: He
authors.affiliation: Department of Orthopaedics, Shanghai Jiaotong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, PR China. Electronic address: fengmale@yahoo.com.cn.
authors.forename: Fengfeng
authors.initials: F
authors.lastname: Li
authors.affiliation: Orthopedic Institute, Soochow University, 708 Renmin Rd, Suzhou, Jiangsu 215006, PR China; Department of Orthopedics, The First Affiliated Hospital of Soochow University, 188 Shizi St, Suzhou, Jiangsu 215006, PR China. Electronic address: wgcui80@hotmail.com.
authors.forename: Wenguo
authors.initials: W
authors.lastname: Cui
authors.affiliation: Department of Orthopaedics, Shanghai Jiaotong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, PR China. Electronic address: fancunyi888@hotmail.com.
authors.forename: Cunyi
authors.initials: C
authors.lastname: Fan
mesh_terms: D000818:Animals; D000068579:Celecoxib; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage* / Q000627:therapeutic use; D016503:Drug Delivery Systems; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D007773:Lactates / Q000737:chemistry; D008567:Membranes, Artificial; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011092:Polyethylene Glycols / Q000737:chemistry; D011720:Pyrazoles / Q000008:administration & dosage* / Q000627:therapeutic use; D011817:Rabbits; D051785:Smad Proteins / Q000378:metabolism*; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D013449:Sulfonamides / Q000008:administration & dosage* / Q000627:therapeutic use; D013710:Tendons / Q000187:drug effects / Q000378:metabolism; D000267:Tissue Adhesions / Q000378:metabolism / Q000517:prevention & control*
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D007773:Lactates; D008567:Membranes, Artificial; D011720:Pyrazoles; D051785:Smad Proteins; D051899:Smad2 Protein; D051900:Smad3 Protein; D013449:Sulfonamides; C088513:poly(lactic acid-ethylene glycol); D011092:Polyethylene Glycols; D048049:Extracellular Signal-Regulated MAP Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D000068579:Celecoxib
keywords: Celecoxib; ERK; Electrospun fiber; Phosphorylation; SMAD; Tendon adhesions