MRI of Tendon Structure and Metabolism

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PROJECT SUMMARY / ABSTRACT The objective of this proposal is to establish magnetic resonance imaging (MRI) for assessment of extracellular matrix (ECM) damage and cellular energy metabolism in human tendon. Tendinopathies are painful conditions effecting joints in upper and lower extremities, comprise 30% of referrals to musculoskeletal specialists, and remain challenging to treat. Tendinopathy is associated with accumulated damage to the ECM from chronic and repetitive overloading and exhibits complex and multifactorial pathogenesis altering both mechanical and cell biological function. The maintenance and repair (homeostasis) of tendon ECM is regulated by force- sensitive tendon cells that are coupled to local tissue loads through the ECM. Dysregulated ECM homeostasis can be related to extensive structural damage and diminished cellular response to environmental forces. Evaluation of tendinopathy in humans is limited by a lack of non-invasive approaches to assess both ECM (structure) and cellular response (function). Recent applications of ultrashort echo time (UTE) MRI have demonstrated exciting potential for providing quantitative indices of tendon properties that are sensitive to pathological changes. We have recently identified tendon ECM molecules and metabolites based on 1H NMR chemical shift assignments using high resolution magic angle spinning (HRMAS). We have also developed a novel in vivo UTE MRI approach in human tendon for accurate quantification of these chemical shift resonances showing correspondence with 1H NMR spectra, allowing for direct imaging quantification of matrix molecules and metabolites. Our team has recently developed a novel pipeline combining in vivo animal tendon-loading with ex vivo HRMAS NMR for directly studying load-induced metabolic activity in rat tendon. We are poised to combine detailed tissue explant, animal, and human experiments to establish new chemical shift-based measurements of ECM structure and functional imaging of load-induced tendon metabolism. In Aim 1, we will validate UTE MRI chemical shift markers of ECM damage and metabolism in tendinopathy using animal studies, human explant tissue, phantoms, and numerical simulations. In Aim 2, we will establish in- human UTE-derived chemical shift mapping of load-induced anaerobic metabolism in tendinopathy. This work will establish new MRI methods for in-human imaging studies to quantitatively investigate the interaction between ECM damage, in vivo loading, and tendon biological function, to be applied to subsequent studies of tendinopathy.