Suppression of inflammatory macrophages is a potential strategy to improve rotator cuff healing and has shown promise in preclinical models.

Abstract

The pathophysiology of rotator cuff disease is complex, involving intrinsic and extrinsic factors that contribute to mechanical alterations, inflammation, apoptosis, and neovascularization. These changes result in structural and cellular disruptions, including inflammatory cell infiltration and collagen disorganization. Macrophages have recently gained attention as critical mediators of tissue repair and regeneration. M1 macrophages have traditionally been associated with pro-inflammatory cytokines involved in the acute inflammatory process after injury, whereas M2 macrophages are thought to play a role in resolution of inflammation and tissue healing. Therefore, achieving a balance between M1 and M2 macrophage phenotypes may be crucial in influencing tendon healing outcomes. Strategies have ranged from mediating circulating macrophage recruitment with CCR2 deficiency to promoting M2 macrophage polarization, increasing secretion of TGF-β1 from M2 macrophages, and subsequently enhancing chondrogenesis of mesenchymal progenitor cells to improve tendon-to-bone healing. Modulating macrophage activity to favor the M2 phenotype has also been hypothesized to not only enhance healing but also to reduce adhesion formation, making it an attractive potential therapeutic strategy for tendon injuries. However, inflammation is complex and multifactorial, and identifying the optimal targets to modulate and at what timepoints in the healing process, can be difficult. Additionally, while preclinical models of tendon disorders can be helpful in identifying promising cellular and molecular targets, recapitulating the human disease process, which often consists of chronic, degenerative tendinopathies, remains challenging. Many studies utilize young, healthy small animal models with acute injuries, which do not fully recreate the chronic degenerative conditions commonly seen in human rotator cuff injuries. Additionally, recent studies have utilized aged mice (∼18 to 20 months), which, while expensive, are likely closer in biological age relative to human patients.