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.