Tendon healing: a concise review on cellular and molecular mechanisms with a particular focus on the Achilles tendon

Abstract

Tendon is a bradytrophic and hypovascular tissue, hence, healing remains a major challenge. The molecular key events involved in successful repair have to be unravelled to develop novel strategies that reduce the risk of unfavourable outcomes such as non-healing, adhesion formation, and scarring. This review will consider the diverse pathophysiological features of tendon-derived cells that lead to failed healing, including misrouted differentiation (e.g. de- or transdifferentiation) and premature cell senescence, as well as the loss of functional progenitors. Many of these features can be attributed to disturbed cell-extracellular matrix (ECM) or unbalanced soluble mediators involving not only resident tendon cells, but also the cross-talk with immigrating immune cell populations. Unrestrained post-traumatic inflammation could hinder successful healing. Pro-angiogenic mediators trigger hypervascularization and lead to persistence of an immature repair tissue, which does not provide sufficient mechano-competence. Tendon repair tissue needs to achieve an ECM composition, structure, strength, and stiffness that resembles the undamaged highly hierarchically ordered tendon ECM. Adequate mechano-sensation and -transduction by tendon cells orchestrate ECM synthesis, stabilization by cross-linking, and remodelling as a prerequisite for the adaptation to the increased mechanical challenges during healing. Lastly, this review will discuss, from the cell biological point of view, possible optimization strategies for augmenting Achilles tendon (AT) healing outcomes, including adapted mechanostimulation and novel approaches by restraining neoangiogenesis, modifying stem cell niche parameters, tissue engineering, the modulation of the inflammatory cells, and the application of stimulatory factors. Cite this article: Bone Joint Res 2022;11(8):561–574.

Human Muscle–Derived Cells Are Capable of Tenogenic Differentiation and Contribution to Tendon Repair

“…Nevertheless, it should be noted that although the regeneration potential ability of a tendon has been reported in patients with total tendon removal via a surgical procedure, 5,11,14 there was limited healing potential for tendinopathy or tendon rupture. 22,30 One potential reason is probably that the pathologic changes of tendon removal were different from those of tendinopathy in the clinic. Thus, how and when MDCs could participate in tendon repair and healing remains to be explored.…”

In vivo ligamentogenesis in embroidered poly(lactic-co-ε-caprolactone) / polylactic acid scaffolds functionalized by fluorination and hexamethylene diisocyanate cross-linked collagen foams

“…Hence, it is not surprising that there was no major difference in the degree of macrophage and FBGC accumulation at either the P(LA-CL) fibers (larger diameter fibers) and PLA with smaller fiber diameters. Immune cells, particularly macrophages, are well known to contribute to tendon healing (Schulze-Tanzil et al 2022) and hence, macrophage polarization has to be considered. ECM components such as collagen (Kajahn et al 2012), but also scaffold material, might influence macrophage polarization from pro-inflammatory M1 to anti-inflammatory M2 type, which is more favorable for healing processes in tendons (Schulze-Tanzil et al 2022).…”

“…Immune cells, particularly macrophages, are well known to contribute to tendon healing (Schulze-Tanzil et al 2022) and hence, macrophage polarization has to be considered. ECM components such as collagen (Kajahn et al 2012), but also scaffold material, might influence macrophage polarization from pro-inflammatory M1 to anti-inflammatory M2 type, which is more favorable for healing processes in tendons (Schulze-Tanzil et al 2022). Due to this observation, a cell-mediated fiber degradation should be considered.…”

TGF-β1 derived from macrophages contributes to load-induced tendon-bone healing in the murine rotator cuff repair model by promoting chondrogenesis

“… 12 The balance between M1 and M2 macrophages is essential for tissue regeneration. 13 Importantly, recent findings have indicated that macrophages exhibit mechanically sensitive characterization and that their polarization state could be regulated by mechanical cues, 14 which may account for load-induced T-B healing.…”