Tendon and ligament regeneration and repair: Clinical relevance and developmental paradigm

Abstract

Tendon and ligament (T/L) are dense connective tissues connecting bone to muscle and bone to bone, respectively. Similar to other musculoskeletal tissues, T/L arise from the somitic mesoderm, but they are derived from a recently discovered somitic compartment, the syndetome. The adjacent sclerotome and myotome provide inductive signals to the interposing syndetome, thereby upregulating the expression of the transcription factor Scleraxis, which in turn leads to further tenogenic and ligamentogenic differentiation. These advances in the understanding of T/L development have been sought to provide a knowledge base for improving the healing of T/L injuries, a common clinical challenge due to the intrinsically poor natural healing response. Specifically, the three most common tendon injuries involve tearing of the rotator cuff of the shoulder, the flexor tendon of the hand, and the Achilles tendon. At present, injuries to these tissues are treated by surgical repair and/or conservative approaches, including biophysical modalities such as physical rehabilitation and cryotherapy. Unfortunately, the healing tissue forms fibrovascular scar and possesses inferior mechanical and biochemical properties as compared to native T/L. Therefore, tissue engineers have sought to improve upon the natural healing response by augmenting the injured tissue with cells, scaffolds, bioactive agents, and mechanical stimulation. These strategies show promise, both in vitro and in vivo, for improving T/L healing. However, several challenges remain in restoring full T/L function following injury, including uncertainties over the optimal combination of these biological agents as well how to best deliver tissue engineered elements to the injury site. A greater understanding of the molecular mechanisms involved in T/L development and natural healing, coupled with the capability of producing complex biomaterials to deliver multiple growth factors with high spatiotemporal resolution and specificity, will allow tissue engineers to more closely recapitulate T/L morphogenesis, thereby offering future patients the prospect of T/L regeneration, as opposed to simple tissue repair.

Tendon development and musculoskeletal assembly: emerging roles for the extracellular matrix

“…Current efforts to treat tendon injuries or diseases focus either on ameliorating inflammation or driving MSCs towards the tenocyte fate with hopes of stem cell therapy (Yang et al, 2013). Both approaches leave out the crucial role of establishing the appropriate ECM for a specific tendon type and the loads that it needs to bear.…”

“…These fibrils are crosslinked to one another and wrapped in a tendon sheath (Banos et al, 2008;Kannus et al, 1998;Ros et al, 1995). This basic structure is shared among tendons and ligaments, and the fibroblasts that produce the ECM develop from common progenitors with similar gene expression profiles (Juneja and Veillette, 2013;Sugimoto et al, 2013;Tozer and Duprez, 2005;Yang et al, 2013). However, each tendon or ligament differs in its precise ECM composition, size and strength .…”

“…Only a handful of factors are known to help specify tenocyte progenitor cells (TPCs) at muscle attachments, induce them to differentiate, and maintain and repair them in the adult (Aslan et al, 2008;Huang et al, 2015;Liu et al, 2012Liu et al, , 2014Schweitzer et al, 2010;Yang et al, 2013). Studies in animal models (e.g.…”

Tendon-Derived Extracellular Matrix Enhances Transforming Growth Factor-β3-Induced Tenogenic Differentiation of Human Adipose-Derived Stem Cells

“…[1][2][3] The natural healing process of tendons is slow and insufficient, resulting in fibrotic scar formation and inferior mechanical strength at the injured sites. 4 Current clinical outcomes of tendon repair remain unsatisfactory due to limitations including autograft donor site morbidity, risk of injury recurrence, and limited longterm function recovery. [5][6][7] Therefore, tissue engineering approaches, which use a combination of cells, scaffolds, and bioactive molecules, are gaining increasing research interest as a promising alternative strategy to treat tendon injuries.…”

Role of regeneration in tissue repairing and therapies

“…However, semitendinosus tendon can regenerate after being harvested in its whole length and thickness for anterior cruciate ligament (ACL) reconstruction, but it is not applicable to make a neo-tendon. Hence both biologically and functionally these could be used for iterative ligament reconstruction [111] (Table 1).…”