Potential of collagen cross-linking therapies to mediate tendon mechanical properties

Collagen cross-links are fundamental to the mechanical integrity of tendon, with orderly and progressive enzymatic cross-linking being central to healthy development and injury repair. However, the nonenzymatic cross-links that form as we age are associated with increased tendon brittleness, diminished mechanical resistance to injury, and impaired matrix remodeling. Collagen cross-linking thus sits at the center of tendon structure and function, with important implications to age, disease, injury, and therapy. The current review touches on these aspects from the perspective of their potential relevance to the shoulder surgeon. We first introduce the most well-characterized endogenous collagen cross-linkers that enable fibrillogenesis in development and healing. We also discuss the glycation-mediated cross-links that are implicated in age- and diabetes-related tendon frailty and summarize work toward therapies against these disadvantageous cross-links. Conversely, we discuss the introduction of exogenous collagen cross-links to augment the mechanical properties of collagen-based implants or native tendon tissue. We conclude with a summary of our early results using exogenous collagen cross-linkers to prevent tendon tear enlargement and eventual failure in an in vitro model of partial tendon tear.