Work-related muscle disorders are a main cause of missed work, globally, and arecostly for public health systems. However, development of musculoskeletal tissue diagnostics is lagging compared to other tissues and organs. Myofascial trigger points (MTP) are unique muscle tissue phenomenon that are challenging to address due to a lack of objective assessment methodology. This study seeks to meet this need by devising a non-invasive, objective methodology for evaluating musculoskeletal tissue following intervention or physical provocation, specific to the anterior forearm region. In Aim 1, current literature on MTP pathophysiology informs a multi-modal assessment approach, including: 1) pain pressure threshold (PPT), 2) power Doppler (PD) ultrasound, 3) strain elastography (SE), and 4) surface electromyography (sEMG). In Aim 2, controlled ultrasound image acquisition and standardization techniques are developed for imaging muscle tissue with PD (Aim 2a) and SE (Aim 2b) . These techniques improved differentiability of vascularity and compliance estimation after physical provocation or intervention. In Aim 3, the multi-modal approach is implemented in a human pilot study (n=34) investigating MTP response to osteopathic manipulative treatment, compared to rest and light exercise. Positive trends and significant changes are detected after OMT and rest. PPT significantly increased after OMT (p = 0.021). Tissue compliance significantly increase after rest (p ≪ 0.0001) and after OMT( p = 0.002). Principal component analysis finds 9 of 13 outcome measures to be salient features of MTP treatment effect. The data suggests high and low responders, yielding insights for improved patient screening and study design for future work. With further optimization and development, this method may be applied to a broad array of clinical scenarios for musculoskeletal tissue evaluation directed towards amelioration of neuromuscular symptoms.

Hypoxia is a pathophysiological condition which results from lack of oxygen supply in tumors. The assessment of tumor hypoxia and its response to therapies can provide guidelines for optimization and personalization of therapeutic protocols for better treatment. Previous research has shown the difficulty in measuring hypoxia anatomically due to its heterogenous nature. This makes the study of hypoxia through various imaging modalities and mapping techniques crucial. The potential of hypoxia targeting T1 contrast agent GdDO3NI in generating hypoxia maps has been studied earlier. In this work, the similarities between hypoxia maps generated by MRI using GdDO3NI and pimonidazole based immunohistochemistry (IHC) in non-small cell lung carcinoma bearing mice have been studied. Six NCI-H1975 tumor-bearing mice were studied. All animal studies were approved by Arizona State University’s Institute of Animal Care and Use Committee (IACUC). Post co-injection of GdDO3NI and pimonidazole, T1 weighted 3D gradient echo MR images were acquired. For ex-vivo analysis of hypoxia, 30 μm thick tumor sections were obtained for each harvested tumor and were stained for pimonidazole and counter-stained with DAPI for nuclear staining. Pimonidazole (PIMO) is clinically used as a “gold standard” hypoxia marker. The key process involved stacking and iterative registration based on quality metric SSIM (Structural Similarity) Index of DAPI stained images of 5 consecutive tumor sections to produce a 3D volume stack of 150 μm thickness. Information from the 3D volume is combined to produce one final slide by averaging. The same registration transform was applied to stack the pimonidazole images which were previously thresholded to highlight hypoxic regions. The registered IHC stack was then co-registered with a single thresholded T1 weighted gradient echo MRI slice of the same location (~156 μm thick) using an elastic B-splines transform. The same transform was applied to achieve the co-registration of pimonidazole and MR percentage enhancement image. Image similarity index after the co-registration was found to be greater than 0.5 for 5 of the animals suggesting good correlation. R2 values were calculated for both hypoxic regions as well as tumor boundaries. All the tumors showed a high boundary correlation value of R2 greater than 0.8. Half of the animals showed high R2 values greater than 0.5 for hypoxic fractions. The RMSE values for the co-registration of all the animals were found to be low further suggesting better correspondence and validating the MR based hypoxia imaging.

Modern medical conditions, including cancer, traumatic brain injury, and cardiovascular disease, have elicited the need for cell therapies. The ability to non-invasively track cells in vivo in order to evaluate these therapies and explore cell dynamics is necessary. Magnetic Resonance Imaging provides a platform to track cells as a non-invasive modality with superior resolution and soft tissue contrast. A new methodology for cellular labeling and imaging uses Nile Red doped hexamethyldisiloxane (HMDSO) nanoemulsions as dual modality (Magnetic Resonance Imaging/Fluorescence), dual-functional (oximetry/ detection) nanoprobes. While Gadolinium chelates and super paramagnetic iron oxide-based particles have historically provided contrast enhancement in MRI, newer agents offer additional advantages. A technique using 1H MRI in conjunction with an oxygen reporter molecule is one tool capable of providing these benefits, and can be used in neural progenitor cell and cancer cell studies. Proton Imaging of Siloxanes to Map Tissue Oxygenation Levels (PISTOL) provides the ability to track the polydimethylsiloxane (PDMS) labeled cells utilizing the duality of the nanoemulsions. 1H MRI based labeling of neural stem cells and cancer cells was successfully demonstrated. Additionally, fluorescence labeling of the nanoprobes provided validation of the MRI data and could prove useful for quick in vivo verification and ex vivo validation for future studies.