Successful anterior cruciate ligament (ACL) reconstruction requires a functional enthesis, the interface between a bone and ligament or tendon. The enthesis normally exhibits a gradient of tissue phenotypes to smooth the transition from the compliant ligament to stiff bone and decrease stress concentrations between the 2 tissues. However, this structure does not fully regenerate after surgical repair leading to increased rupture rates and incidence of osteoarthritis. We have previously engineered ligaments between 2 cylindrical brushite cement anchors using human ACL fibroblasts entrapped in a fibrin gel. Using this model, we hypothesized that the local application and release of growth factors from the brushite cement anchors will promote fibrocartilage formation and improve interface failure load. Of 5 chondrogenic growth factors (BMP‐2, BMP‐4, and BMP‐7 and TGF‐β1 and TGF‐β3) tested, we identified TGF‐β1 as having a significant negative effect (P = .0001), while the local release of BMP‐4 at the enthesis of engineered ligaments improved the interface failure load by up to 38% compared to control conditions. BMP‐4 treatment increased the expression of the enthesis‐related genes Sox9, aggrecan, and tenascin C and the inhibitor of mineralization osteopontin. These data suggest that BMP‐4 drives a shift toward a fibrocartilaginous phenotype resulting in a stronger engineered enthesis.
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