Minimizing Injury and Maximizing Return to Play: Lessons from Engineered Ligaments

Abstract

Musculoskeletal injuries account for more than 70% of time away from sports. One of the reasons for the high number of injuries and long return to play is that we have only a very basic understanding of how our training alters tendon and ligament (sinew) structure and function. Sinews are highly dense tissues that are difficult to characterize both in vivo and in vitro. Recently, engineered ligaments have been developed in vitro using cells from human anterior cruciate ligaments or hamstring tendons. These three-dimensional tissues can be grown in a laboratory, treated with agents thought to affect sinew physiology, and then mechanically tested to determine their function. Using these tissues, we have learned that sinews, like bone, quickly become refractory to an exercise stimulus, suggesting that short (<10 min) periods of activity with relatively long (6 h) periods of rest are best to train these tissues. The engineered sinews have also shown how estrogen decreases sinew function and that a factor released following intense exercise increases sinew collagen synthesis and function. Last, engineered sinews are being used to screen possible nutritional interventions that may benefit tendon or ligament function. Using the data derived from these tissue-engineered sinews, new nutritional and training regimes are being designed and tested with the goal of minimizing injury and accelerating return to play.

Fig. 1

Regional mechanics of tendon. The mechanics of a healthy tendon or b tendon after 5 weeks of immobilization. Note that in a healthy tendon, the muscle end of the tendon (red) stretches much more than the bone end (green), whereas the mid-tendon region shows intermediate mechanics. By contrast, after forced inactivity, all regions of the tendon become stiffer Adapted from Arruda et al. [7]

Fig. 2

Change in patellar tendon cross-sectional area (CSA) with training and nutrition. Twelve weeks of strength training resulted in a 10% increase in the tendon CSA in the placebo control group and a 15% hypertrophy in the group that performed the resistance exercise training and supplemented their training with 19.5 g of whey protein. *Significantly different than pre-training (p < 0.05); ^† significantly different from pre-training (p < 0.001). Data are means ± standard error of the mean Adapted from Farup et al. [15]

Fig. 3

Slow turnover of collagen within the central core of the Achilles tendon. The amount of C¹⁴ as a percent modern carbon (pMC) in collagen isolated from the central core of the Achilles tendon was compared with that in the atmosphere over time to determine the rate of collagen turnover in the Achilles tendon. The relationship between the C¹⁴ levels in the central core and that found in the atmosphere indicates that the turnover rate of collagen is extremely slow. In fact, most of the samples measured indicated that the collagen in the center of the Achilles had not turned over since the individual was 17 years of age Adapted from Heinemeier [17]

Fig. 4

Engineered ligament model. Engineered ligaments can be formed by embedding human anterior cruciate ligament fibroblasts into a fibrin gel. A tubular ligament results from limiting the natural contraction of the gel using anchors pinned into a tissue culture plate that has been modified such that the bottom of the plate is coated with a silicone polymer (polydimethylsiloxane; Sylgard^®). Following plating, the cells within the fibrin gel (depicted in yellow) contract the gel around the anchors forming a tubular ligament by day 7 in culture