Increased Blood Flow and Tendon Swelling Precedes Vascular Expansion and Tissue Matrix Changes In Early Human Tendinopathy: A Potential Window for Superior Treatment Response

Abstract Tendinopathy represents a major musculoskeletal health problem, yet its pathogenesis remains poorly understood. Tendinopathy development is studied in humans with early (< 3 months of symptoms, n = 14) (ET) or chronic (> 3 months, n = 16) (CT) patellar tendinopathy and in healthy subjects ( n = 15) (CTRL). Pain increases, and function declines with tendinopathy duration and correlated with tendon size (3T and 7T MRI). Tendon blood flow (Doppler ultrasonography) increases gradually in ET and CT, while peritendinous blood flow only rose in CT. Microscopy‐based mapping (immunofluorescence microscopy and Cell DIVE) of vasculature shows marked changes in CT only, indicating flow increases in existing vessels early in tendinopathy, whereas angiogenesis is a late phenomenon. Cell DIVE indicates perivascular cell recruitment and potential lymphatic expansion in tendinopathy. Further, proteomics reveals that most matrix regulation occurs late in tendinopathy. Data from a previous study from the lab demonstrate faster treatment effect in tendinopathy with shorter symptom duration, supporting that early tissue changes may be more receptive to treatment. It is concluded that early tendinopathy is dominated by pain correlating with tendon swelling and hyperperfusion, whereas chronic tendinopathy is characterized by neovascularization and matrisome changes. These findings suggest that targeting early tissue changes can lead to superior treatment effects in tendinopathy.