Background: In the hand, adhesion formation between the flexor tendon and its surrounding fibrosseous sheath results in decreased post-operative range of motion and poor function. The ability to modulate the tendon healing process to reduce adhesions and increase post-operative range of motion while maintaining the strength of the repair would be of great value clinically. Transforming growth factor beta (TGF-ß)is a key cytokine in the pathogenesis of tissue fibrosis. In this study the effects of two potential natural inhibitors of TGF-ß, decorin and mannose-6-phosphate (M6P), were investigated. We sought to examine the effectiveness of these two inhibitors in blocking TGF-ß induced collagen production in an in vitro model. Decorin and M6P were then subsequently studied in an in vivo model of zone II flexor tendon repair. Methods: In vitro study: Cells for the flexor tendon sheath (S), epitenon (E), and endotendon (T) were isolated from rabbit flexor tendons and cultured. Each cell culture was supplemented with 1 ng/ml of TGF-ß along with decorin or M6P. Collagen I production was measured by ELISA. In vivo study: Rabbit zone II flexor tendons were transected and then immediately repaired. A single intra-operative dose of decorin, M6P, or control substance was added to the repair site. Both decorin and mannose-6-phosphate were administered in two graded doses dissolved in 100 µl of sterile phosphate buffered saline solution (PBS). The decorin doses were 0.5mg/100µl (N = 8) and 1mg/100µl (N = 5). The mannose-6-phosphate doses were 1mg/100µl (N = 6) and 2mg/100µl (N = 7). Control rabbits (N = 6) were administered 100µl of PBS. Rabbits were sacrificed at 8 weeks post-operatively and forepaws were tested for range of motion and repair strength. Results: Both decorin and M6P reduced TGF-ß induced collagen production in the in vitro study. M6P reduced the collagen I-stimulating effects of TGF-ß in E cells. A reduction of 64% was observed (P<0.05). The addition of decorin reduced TGF-ß induced collagen I production in cultured E cells. The stimulatory effects of TGF-ß were reduced by 44% in E cells (P<0.05). Intraoperative application of both low-dose and high-dose M6P significantly improved the range of motion in operated digits (low-dose 58%, P<0.05% and high-dose 41.7%, P< 0.05). Both decorin dose-response groups showed an overall improvement in range of motion, however the data did not reach statistical significance (low-dose 24.3%, P>0.05 and high-dose 31.4%, P>0.05). There was no statistical difference in the mean breaking strength between the control and study groups (p < 0.05 all groups) Conclusions: This study provides additional evidence that inhibition of TGF-ß reduces post-operative scar formation after flexor tendon repair. Our data suggest that a single intraoperative dose of M6P is effective in optimizing tendon wound healing by improving post-operative range of motion while retaining repair strength. This simple carbohydrate is ubiquitous, non-immunogenic, and easily produced making it an ideal candidate for clinical application.