The Effect And Associated Mechanism Of The Celecoxib-loaded Electrospun PELA Fibrous Membranes In Prevention Of Tendon Adhesions

OBJECTIVESPeritendinous adhesions, as a major problem in hand surgery, may be due to the proliferation of fibroblasts and excessive collagen synthesis. The previous study indicated that ERK1/2 and SMAD2/3 played crucial roles in the proliferation of fibroblasts and excessive collagen synthesis, and celecoxib could inhibit fibroblast proliferation and collagen synthesis by down-regulating ERK1/2 and SMAD2/3phosphorylation. In this study, celecoxib loaded poly(L-lactic acid)-polyethylene glycol(PELA) diblock copolymer fibrous membranes and multi-layer electrospun membrane based on above were fabricated via electrospinning. The effects of anti-adhesion and mechanism were studied. This approach offers a novel barrier strategy and theory to block tendon adhesion and improve normal function.METHODSDifferent qualities of celecoxib was incorporated in PELA fibrous membranes via co-electrospinning for different concentration of celecoxib loaded PELA fibrous membranes, then, the characterization and in vitro drug release were studied. The physiology behavior of fibroblasts and tenocytes on different celecoxib loadedPELA fibrous membranes was observed; secondly, celecoxib loaded PELA fibrous membranes were used for prevention of tendon adhesion in rabbit tendon repair model, and the effect of anti-adhesion and tendon healing was indicated by macroscopic evaluation, histological evaluation and biomechanical evaluation compared with control group. Meanwhile, ERK1/2 and SMAD2/3 phosphorylation in adhesion tissues was detected. Finally, the mechanism of anti-adhesion was revealed by studying that whether or not celecoxib can prevent tendon adhesions via inhibiting the proliferation of fibroblasts and excessive collagen synthesis caused by ERK1/2 and SMAD2/3 phosphorylation. Furthermore, multi-layer biomimetic electrospun membrane were fabricated and the effects of anti-adhesion and tendon healing in vivo were evaluated.RESULTSResults indicated that the microfibers of celecoxib loaded PELA fibrous membrane were bead-free, round and continuous. Drug release study showed that celecoxib-loaded PELA membrane had excellent continuous drug release capability.In vitro cell study indicated that the proliferation and adhesion of fibroblasts and tenocytes decreased with raised celecoxib concentration of celecoxib loaded PELA fibrous membrane. In a rabbit tendon repair model, compared with the control group and unloaded PELA fibrous membrane group, celecoxib-loaded PELA membranes decreased peritendinous inflammation, down-regulated ERK1/2 and SMAD2/3phosphorylation in adhesion tissue(p < 0.05), and decreased collagen I and collagen III synthesis(p < 0.05), finally prevented tendon adhesion with impairing tendon healing partly. However, the in vivo study of multi-layer biomimetic membrane indicated that the membrane prevented tendon adhesions without poor tendon healing.CONCLUSIONSCelecoxib loaded PELA fibrous membrane inhibited the proliferation and adhesion of fibroblasts, and down-regulated ERK1/2 and SMAD2/3 phosphorylationin adhesion tissue by regulation of the MAPK and SMAD pathways, and finally prevented tendon adhesions. The multi-layer biomimetic fibrous membrane mimicked the native tendon sheath, optimized the effect of anti-adhesion and avoided impairing tendon healing. Taken together, celecoxib loaded PELA fibrous membranes not only reveal the mechanism of tendon adhesion, but also offer a novel prophylactic strategy in the management of patients with tendon adhesions.