The Driving Force of Hierarchical Collagen Fiber Formation: A Review of Tendon,Ligament,and Meniscus Mechanobiology

Abstract

In tendons, ligaments, and menisci, collagen fibers running the length of the tissue are the primary source of strength and function. Cells assemble these fibers hierarchically from nanometer-wide fibrils into larger fibers and fascicles, increasing in size throughout development and with mechanical loading. These fibers largely do not regenerate after injury or with repair, limiting recovery options. Engineered replacements are a promising treatment option; however, it remains a challenge to produce the hierarchical collagen fibers essential to tissue strength, limiting their applications. To better repair, regenerate, and engineer these tissues, we must better understand how cells regulate hierarchical fiber formation and maintenance. It is well established that mechanical cues are critical for cell-driven hierarchical fiber formation, which cells sense through several mechanisms, such as integrin-mediated adhesions, cell-to-cell connections, mechanosensitive ion channels, primary cilia, and caveolae. These mechanisms of mechanosensation have been well studied at the fibril scale of collagen organization, but as tissues mature, the loading environment becomes more complex, with cells experiencing increasing secondary shear and compressive loads generated by the developing hierarchical structure. Mechanical cues in this environment are likely sensed through several pathways, each likely playing a role in tissue maturation and injury. There remains a clear gap in our understanding of the later stages of hierarchical fiber formation, which are crucial to better understand since large hierarchical fibers dominate the human musculoskeletal system. Here, we review the role of mechanobiology in hierarchical fiber development and maintenance, and highlight what still needs further research to better regenerate fibers in engineered replacements or in vivo after injury. A better understanding of the mechanisms by which cells form hierarchically organized collagen fibers could help to overcome the limitations of current tissue engineering techniques and help to create functional repairs and replacements.

Impact Statement

Here we review the various mechanisms by which cells within tendons, ligaments, and menisci sense mechanical stimuli and the role that each mechanosensor has been shown to play in hierarchical fiber formation. Furthermore, we highlight potential future research directions to better understand the role of mechanobiology in hierarchical fiber formation. Understanding the mechanisms by which hierarchical fibers are formed, and by which mature tissues are maintained, is crucial to regenerating fibers after injury or in tissue-engineered replacements, and will help to inform the pathophysiological effects of unloading and overloading.