Rabbit medial collateral ligament scar weakness is associated with decreased collagen pyridinoline crosslink density

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Abstract
This study was carried out to quantify the potential associations between material strength and both collagen concentration and pyridinoline collagen crosslink density in the healing medial collateral ligament of the rabbit and to compare these parameters with those of normal ligaments. The right hindlimbs of 24 skeletally mature (12-month-old) New Zealand White rabbits were subjected to a standardized 4 mm midsubstance “gap” injury to the medial collateral ligament. The animals were killed in groups of six at postoperative intervals of 3, 6, 14, or 40 weeks, and the femur-medial collateral ligament-tibia complexes were mechanically tested in tension to failure. Subsequent to mechanical testing, the failure sites of the ligaments were assessed for concentrations of hydroxyproline and hydroxylysyl pyridinoline. Nine additional rabbits served as age-matched normal controls. In healing ligaments, normal collagen concentrations were reached in less than 14 weeks, but the hydroxylysyl pyridinoline crosslink densities remained low and were only 45% of the control values after 40 weeks of healing. Similarly, mechanical values remained much less than the controls. Linear regression analysis of data on scar tissue alone showed a moderately strong positive correlation between hydroxyproline concentration and material strength (r2 = 0.51, p = 0.0001) but no correlation between crosslink density and strength of scar tissue. A similar pattern of correlation was obtained between the elastic modulus of the scar tissue and the biochemical variables, but the r2 values were lower. When control data were included, the results of stepwise regression showed a very high positive correlation between crosslink density and material strength (r2 = 0.83, p < 0.0001) and discriminant analysis demonstrated crosslink density to be the best classifier of group membership. Combined with hydroxyproline concentration, crosslink values correctly identified healing interval and group 90% of the time. These results suggest that although collagen concentration definitely plays a more important role in determining the early material behaviour of healing medial collateral ligaments, reduced crosslink density in collagen in scar tissue may offer a more specific explanation for the mechanical inferiority, in the rabbit, of healing medial collateral ligaments compared with normal ligaments over time.