Non‐Invasive Ultrasound Quantification of Scar Tissue Volume Identifies Early Functional Changes During Tendon Healing

Abstract

Tendon injuries are very common and disrupt the transmission of forces from muscle to bone, leading to impaired function and quality of life. Successful restoration of tendon function after injury is a challenging clinical problem due to the pathological, scar‐mediated manner in which the tendons heal. Currently, there are no standard treatments to modulate scar tissue formation and improve tendon healing. A major limitation to the identification of therapeutic candidates has been the reliance on terminal endpoint metrics of healing in pre‐clinical studies, which require a large number of animals and result in destruction of the tissue. To address this limitation, we have identified quantification of scar tissue volume (STV) from ultrasound (US) imaging as a longitudinal, non‐invasive metric of tendon healing. STV was strongly correlated with established endpoint metrics of gliding function including gliding resistance and metatarsophalangeal (MTP) flexion angle. However, no associations were observed between STV and structural or material properties. To define the sensitivity of STV to identify differences between functionally discrete tendon healing phenotypes, we utilized S100a4 haploinsufficient mice (S100a4GFP/+), which heal with improved gliding function relative to wild‐type (WT) littermates. A significant decrease in STV was observed in S100a4GFP/+ repairs, relative to WT at day 14. Taken together, these data suggest US quantification of STV as a means to facilitate the rapid screening of biological and pharmacological interventions to improve tendon healing, and identify promising therapeutic targets, in an efficient, cost‐effective manner. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2476–2485, 2019

The S100A4 Transcriptional Inhibitor Niclosamide Reduces Pro-Inflammatory and Migratory Phenotypes of Microglia: Implications for Amyotrophic Lateral Sclerosis

“…Moreover, S100A4 is known to exert its effects by two different mechanisms: an intracellular pathway and an extracellular one [47]. In fact, like all the other members of the S100 family, it can be actively secreted by cells, and in the secreted form, it can act as an alarmin, or bind in an autocrine/paracrine way to different receptors (i.e., receptor for advanced glycation endproducts, toll-like receptor 4), inducing downstream intracellular signaling [7,11,48]. However, regardless of S100A4 mode of action, we have demonstrated here that niclosamide could be a potent inhibitor of microglia reactivity and, therefore, might represent a valuable strategy to attenuate uncontrolled processes of activation as those occurring during neurodegenerative pathologies where excessive microglial activation, migration, and phagocytosis overwhelm their protective function and actively contribute to neuronal damage [49].…”

“…It belongs to the very well-known markers characterizing the endothelial-to mesenchymal transition, a composite biological process in which endothelial cells adopt a mesenchymal phenotype, with typical cell morphology and functions, including the acquisition of cellular motility and contractile properties [3]. Indeed, S100A4 is highly expressed in fibroblasts and is a potent regulator of fibrosis in many tissues, such as liver [4], lung [5], heart [6], and tendons [7]. In several types of cancer cells, S100A4 is responsible for their capability to form metastases, promoting their motility and invasiveness [8].…”

Effects of tamoxifen on tendon homeostasis and healing: Considerations for the use of tamoxifen‐inducible mouse models

“…(D‐F) No differences in (D) Max load at failure, (E) stiffness, or (F) Energy to Max were observed in male tendon repairs regardless or Tmx or CO treatment regimen. Dashed line represents the average value of age‐matched untreated C57Bl/6J repairs on day 14 from previously published studies 22,24 . Data presented as mean ± standard deviation.…”

“…Eleven mice per sex per treatment regimen were used. To determine how Tmx or CO treatment alters healing or disrupts homeostasis, functional outcomes were compared to untreated C57Bl/6J repairs from previous studies (n = 14), 22,24 or age‐matched, untreated C57Bl/6J mice that did not undergo tendon repair (n = 8), respectively.…”

Comparing Absorbable and Nonabsorbable Suture Materials for Repair of Achilles Tendon Rupture: A Magnetic Resonance Imaging-Based Study

“…This complicated tendon healing process may take place either intrinsically, by epi- and endotenon tenocyte proliferation, or extrinsically, by the migration of tenocytes from the surrounding sheath and synovium [ 19 , 20 , 21 ]. To distinguish between the two, intrinsic healing produces a normal gliding mechanism within the tendon sheath along with fewer complications, while extrinsic healing results in scar formation, adhesion with adjacent tissue, and disruption of the gliding mechanism [ 22 , 23 ]. The relative contribution of intrinsic and extrinsic tendon healing may be influenced by the type of initial trauma, anatomical location, existence of a synovial sheath, and amount of motion-induced stress after the operative repair [ 24 ].…”