Functional Attachment of Soft Tissues to Bone: Development, Healing, and Tissue Engineering

Abstract

Connective tissues such as tendons or ligaments attach to bone across a multitissue interface with spatial gradients in composition, structure, and mechanical properties. These gradients minimize stress concentrations and mediate load transfer between the soft and hard tissues. Given the high incidence of tendon and ligament injuries and the lack of integrative solutions for their repair, interface regeneration remains a significant clinical challenge. This review begins with a description of the developmental processes and the resultant structure-function relationships that translate into the functional grading necessary for stress transfer between soft tissue and bone. It then discusses the interface healing response, with a focus on the influence of mechanical loading and the role of cell-cell interactions. The review continues with a description of current efforts in interface tissue engineering, highlighting key strategies for the regeneration of the soft tissue–to-bone interface, and concludes with a summary of challenges and future directions.

Allometry of the Tendon Enthesis: Mechanisms of Load Transfer Between Tendon and Bone

“…Functional grading in mechanical properties across an interface between dissimilar materials decreases the stress concentrations that otherwise would occur at an abrupt change in mechanical properties and allows for more effective stress transfer [6]. In biological systems, graded structures can be found at many interfaces [43], including the beak-tomouth interface in squids [44], the anchor-to-foot interface in mussels [45], and as discussed here, the soft tissue-to-bone interface in mammals [21,22,[46][47][48][49][50]. The width of the supraspinatus tendon-to-bone mineral gradient has been previously examined in mice and found to span a distance of $20 lm [22].…”

Enthesis fibrocartilage cells originate from a population of Hedgehog-responsive cells modulated by the loading environment

“…This specialized tissue limits stress concentrations that arise at the interface between the two mechanically disparate materials via gradients in structure and composition (Lu and Thomopoulos, 2013;Thomopoulos et al, 2010). Entheses are broadly classified into two groups based on their morphology (Benjamin et al, 2002;Wang et al, 2013).…”

Enthesis regeneration: a role for Gli1+ progenitor cells

“…Development of this attachment requires synergy between a number of biochemical signals and cell types (Lu and Thomopoulos, 2013;Thomopoulos et al, 2010). Unfortunately, the mature enthesis heals via a scar-mediated process that does not recapitulate the developmental program, resulting in a mechanically insufficient attachment (Galatz et al, 2015;Thomopoulos et al, 2015;Voleti et al, 2012).…”