Novel therapeutics in the prevention of flexor tendon adhesion formation.
Doctoral thesis, UCL (University College London).
Tendon injuries of the hand are common with nearly one-third of a million digital flexor tendon injuries per year in the United States. Injuries in zone II of the flexor tendon are notoriously difficult to repair and the main complications are either tendon rupture or adhesion formation. Adhesions remain a problem despite many attempts at prevention using various chemicals and physical barrier techniques. The overall aim of this thesis was to further understand the biology of tendon adhesion formation and to develop novel treatments targeting this process. Uninjured flexor tendons were obtained from New Zealand White rabbits. Tenocytes derived from different parts of the flexor tendon-sheath complex were grown using standard tissue culture techniques. Each of the three different cell types (endotenon, epitenon and tendon sheath) was subjected to various assays (proliferation/toxicology, cell adhesion, and mRNA expression,) using TGF-β1 and our proposed treatments; epigallocatechin-3-gallate (EGCG), Resveratrol and Pumactant. A further study then compared the three treatments in vivo. New Zealand White rabbits (n=8 per group; 32 in total) were anaesthetised and the flexor digitorum profundus (FDP) of digits 2 and 4 of the forepaw was subjected to a partial tenotomy. The three treatments (compared with control groups) were infiltrated into the flexor sheath of immobilised tendons and the wound was then sutured closed. After two weeks the tendons were harvested and randomised to either mechanical or histological assessment of adhesion formation. The major findings from the in vitro study were as follows: TGF-β1 showed a statistically significant increase in collagen type I gene expression in epitenon cells at 24 and 48 hours and an increase in collagen type III in sheath cells between 6 and 24 hours. There was a statistically significant down-regulation of collagen type III in endotenon and epitenon cells at various time points. Resveratrol showed a statistically significant increase in collagen type I gene expression in epitenon cells with a corresponding down-regulation of fibronectin and PAI-1 in both epitenon and sheath cells. Resveratrol also up-regulated collagen type III at late time points in tendon sheath cells. Pumactant also showed some therapeutic advantages at the gene expression level with a statistically significant increase in collagen type III in endotenon cells at late time points, corresponding with an overall down-regulation of PAI expression in the same cell type and sheath cells. The results from the in vivo study were that all three treatments showed a statistically significant reduction of tendon adhesion formation when compared to operated controls in both mechanical and histological assessments (p<0.05). However, Pumactant was the only treatment to demonstrate a statistically significant reduction in adhesion formation when compared to the H20-group using both methods (p<0.05). All three treatments displayed potential therapeutic advantages. However, Pumactant showed the most promising in vivo results and it would be worthwhile investigating this further with an in vivo model of tendon healing and if successful a pilot clinical trial. Hopefully this could act as a suitable adjunct to tendon repair in the future and improve the lives of patients with disabling tendon injuries.
|Title:||Novel therapeutics in the prevention of flexor tendon adhesion formation|
|Open access status:||An open access version is available from UCL Discovery|
|Additional information:||Copyright restricted material comprising one published article has been removed from the e-thesis.|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Surgery and Interventional Science (Division of) > Research Department of General Surgery|
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