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

Abstract

As dense connective tissues connecting bone to muscle and bone to bone, respectively, tendon and ligament (T/L) arise from the somitic mesoderm, originating in a recently discovered somitic compartment, the syndetome. Inductive signals from the adjacent sclerotome and myotome upregulate expression of Scleraxis, a key transcription factor for tenogenic and ligamentogenic differentiation. Understanding T/L development is critical to establishing a knowledge base for improving the healing and repair of T/L injuries, a high-burden disease due to the intrinsically poor natural healing response. Current treatment of the three most common tendon injuries-tearing of the rotator cuff of the shoulder, flexor tendon of the hand, and Achilles tendon-include mostly surgical repair and/or conservative approaches, including biophysical modalities such as rehabilitation and cryotherapy. Unfortunately, the fibrovascular scar formed during healing possesses inferior mechanical and biochemical properties, resulting in compromised tissue functionality. Regenerative approaches have sought to augment the injured tissue with cells, scaffolds, bioactive agents, and mechanical stimulation to improve the natural healing response. The key challenges in restoring full T/L function following injury include optimal combination of these biological agents as well as their delivery 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 biofactors with high spatiotemporal resolution and specificity, should lead to regenerative procedures that more closely recapitulate T/L morphogenesis, thereby offering future patients the prospect of T/L regeneration, as opposed to simple tissue repair.

Keywords: clinical treatment; tendon development; tendon regeneration; tendon tissue engineering.

Copyright © 2013 Wiley Periodicals, Inc.

Figures

Figure 1

An overview of tendon development. (A) Scx-expressing cells of trunk tendons appear between the myotome and sclerotome during early development, constituting a fourth compartment, syndetome, of the somite. Using a chimeric embryo model, syndetome is found emerging from sclerotome. FGF8 and 4 and their receptor, FREK, from myotome are involved in activating Scx-expression, while Pax1 from sclerotome suppresses Scx expression. Scx regulates downstream tendon-related genes including Col I and TNMD. (B-F) Visualized by in situ hybridization, Scx (C, blue) is found expressed in cells between myotomes (red arrowhead) of adjacent somites (black arrowheads), and its expression pattern does not overlap with that of Pax1 (B, blue) or MyoD (D, blue). Scx is expressed in all limb (E) and axial tendons (F) in chick embryos [Reproduced with permission from Schweitzer R, Chyung JH, Murtaugh LC, Brent AE, Rosen V, Olson EN, Lassar A, Tabin CJ. 2001. Analysis of the tendon cell fate using Scleraxis, a specific marker for tendons and ligaments. Development 128(19):3855-3866]. A variety of growth factors play critical roles in tendon development and maturation, including members of the TGFβ superfamily. (G, H) White arrows indicate the missing Deltoid tendon (green) in TGFβ2 deficient (TGFβ2 −/−) mouse embryo compared with wild type (WT) [Reproduced with permission from Pryce BA, Watson SS, Murchison ND, Staverosky JA, Dunker N, Schweitzer R. 2009. Recruitment and maintenance of tendon progenitors by TGFbeta signaling are essential for tendon formation. Development 136(8):1351-1361].

Figure 2

The hierarchical architecture of tendon. Collagen triple-helices self-assemble into fibrils. Bundles of fibrils form fibers, which constitute tendon fascicle. Tendon fibroblasts (tenocytes) reside between collagen fibers. Fascicles are wrapped by endotenon, a layer of connective tissue containing blood vessels, nerves and lymphatics. Multiple fascicles are further surrounded by another connective tissue layer, epitenon, to form the tendon tissue.

Figure 3

An overview of approaches for repair of tendon injuries. Briefly, surgical interventions and biophysical stimulation are currently employed in clinical care. Meanwhile, tissue engineering strategies are the cutting-edge of tendon healing and regeneration. Engineered replacement of injured tendon using a combination of cells, bioactive molecules, and scaffolds is under intensive investigation.