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Rationale: The use of ultrasound as an adjuvant to conservative treatment for neck pain is common, but the evidence of its benefit remains unclear. Objective: To determine the effectiveness of ultrasound as an adjuvant to exercise or/and manual therapy for the improvement of patient-centered outcomes in adults with non-specific neck pain. Methods: Electronic databases including MEDLINE, EMBASE, AMED, CINAHL, CENTRAL, PEDro and PubMed were searched from date of inception to March 2019 for controlled trials involving ultrasound or phonophoresis as an adjuvant to exercise or/and manual therapy in adults with non-specific neck pain. Review Manager 5.3 was used to calculate mean group differences. Main results: Six studies (361 participants) examining ultrasound or phonophoresis as an adjuvant to exercise or/and manual therapy for sub-acute and chronic non-specific neck pain were included. The quality of evidence was of very low GRADE. Phonophoresis with capsaicin plus exercise improved pain immediately post-treatment (MD -3.30, 95% CI: -4.05 to -2.55) but not with diclofenac sodium plus exercise as compared to exercise alone. Continuous ultrasound plus exercise improved pain and Pressure Pain Threshold (PPT) at immediate post-treatment (pain: MD -3.42, 95% CI: -4.08 to -2.7; PPT: MD 0.91, 95% CI: 0.68 to 1.14 ) and at intermediate - term (pain: MD -2.70 95% CI: -3.62 to -1.78; PPT: MD 0.27 95% CI: 0.03 to 0.51) as compared to exercise alone. Continuous ultrasound or High Power Pain Threshold (HPPT) ultrasound plus manual therapy and exercise showed no benefit for pain reduction (MD -0.75, 95% CI: -2.08 to 0.58), increase in PPT (MD -1.15, 95% CI: -2.55 to 0.25) or improved function/disability (MD -1.05, 95% CI: -4.27 to 2.17) at immediate or short-term as compared to manual therapy and exercise. Conclusion: Based on very low quality evidence, there is insufficient data to support ultrasound or phonophoresis as an adjuvant treatment for non-specific neck pain. / Thesis / Master of Science Rehabilitation Science (MSc) / Ultrasound therapy is widely used with exercise or manual therapy for the treatment of neck pain. Yet, its benefits are not clear. This review looked at the benefits of ultrasound added to exercise, manual therapy or both for the treatment of neck pain. The review contains six studies with 361 participants who suffered from neck pain. The results showed very low quality evidence. Applying capsaicin cream with ultrasound or continuous ultrasound in conjunction with exercise had some benefit for improving pain. The same treatment did not improve function as compared to exercise alone. There was no benefit in improving pain or function by adding continuous or high power ultrasound to manual therapy and exercise compared to manual therapy and exercise alone. Due to very low quality evidence, we are uncertain of whether there is a benefit to adding ultrasound to exercise or/and manual therapy for treatment of neck pain.

Long wait times in Canada have led to challenges in accessing timely care. Expanding the scopes of practice of non-physician health professionals may be a solution and has been implemented in Canada and abroad. In 2018, the College of Midwives of Ontario expanded the scope of practice of registered midwives to include obstetric ultrasound imaging. A mixed-methods study was conducted to investigate the interest of midwives in adopting ultrasound imaging in clinical practice and the factors that may influence their interest and support for the professional scope expansion. It investigated midwives’ perceived risks, benefits, enablers and barriers in performing ultrasound imaging and the ultrasound examinations or tasks considered most appropriate for them to do. The data were analyzed using qualitative coding and thematic analysis as well as descriptive statistics and regression analysis. It was found that both interest and support were generally high. The interest was found to be highest for limited examinations and tasks with specific clinical indications. Many believed the practice would improve access to care. There were, however, still many questions around remuneration, training, equipment and concerns around potential liability issues. / Thesis / Master of Health Sciences (MSc)

Tendinopathy is a common pathology of tendons characterized by pain and a decrease in function resulting from changes in the tissue's structure and/or composition due to injury. Diagnosis of tendinopathy is determined by the qualitative analysis of a trained physician usually with assistance from an imaging modality. Although physicians can often identify tendinopathy, there are no quantitative metrics to evaluate tendon fatigue, damage, or healing. Physical therapy (PT) is a common treatment for patients with tendinopathy, and recent studies have investigated Focused Ultrasound (FUS) for its treatment of tendons. Developments in the use of FUS as a therapeutic have led to studies of the underlying mechanisms by which it operates. Digital Image Correlation (DIC) is a non-contact method of quantifying tissue displacements and strains of a deforming material using high resolution imaging DIC programs can evaluate and interpolate strain data by applying statistical image processing algorithms and solid continuum mechanics principles using a set of sequential image frames capturing the mechanical deformation of the specimen during testing. The studies presented in this thesis investigate methodologies for using DIC with ultrasound imaging of mouse Achilles tendons to characterize strains resulting from FUS therapies. The first method is based upon an orthogonal configuration of therapy and imaging transducers while the second investigates a coaxial experimental configuration. This work explores DIC as a viable means of quantifying the mechanical stimulation caused by FUS therapies on tendon tissue through ultrasound imaging to better understand the underlying mechanisms of FUS therapy. / Master of Science / Tendinopathy is a common injury that many people will experience in their lifetime. Pain and swelling are common symptoms and can make daily actions uncomfortable to perform. Physical therapy (PT) is one of the most common ways to help relieve the symptoms of this condition. A therapy being investigated to help treat tendinopathy utilizes Focused Ultrasound (FUS) technology to help the healing process. PT can be difficult and painful for those experiencing tendinopathy, but if a therapeutic like FUS could mimic the effects of PT, then some patients would not need to perform these physically demanding tasks. To understand if this treatment is viable, we need to better understand the underlying mechanisms by which it operates. Therefore, we are investigating the mechanical stimulation that FUS imparts on tendons because it is believed that the mechanical stimulations from exercise are a primary contributor to healing. Specifically, we want to evaluate the kind of strains applied by FUS therapies to inform decisions about dosage. One method uses Digital Image Correlation (DIC). DIC is a method of evaluating displacements and strains using non-contact high resolution imaging. DIC works using statistically motivated algorithms to calculate the deformation between subsequent video frames in a given material undergoing a state of stress. Using this technology along with ultrasound imaging, this work gives a preliminary exploration of using DIC as a means of quantifying strain to better understand the underlying mechanisms of the mechanical stimulations caused by FUS therapy.

As the world population ages, hospital discharges of geriatric patients to nursing homes have increased. Patients with peripherally inserted central catheters (PICCs) are routinely discharged with the catheters in place. PICCs, only capable of being tracked through x-ray imaging, will routinely experience complications due to thrombosis or accidental dislodgement from poor at-home care. Routinely, elderly patients will be forced to revisit the hospital to have the catheter replaced using x-ray imaging, exposing them to hospital borne illness. Catheters with the capability to be tracked without the need of x-ray imaging would greatly benefit the ill and elderly, providing decreased stress to the patients and increase nursing home capabilities. This project seeks to develop the field of real-time ultrasound tracking of polymeric medical devices, through fabrication of ultrasound responsive polymer-glass composites. Optimal composition will be researched through three complimentary approaches. The first approach seeks to develop a polyurethane-glass microparticle composite to understand the relationship between microparticle loading and ultrasound imaging. In the second approach, manufacturing and end-use complications will be simulated to evaluate the effects on mechanical and ultrasonic properties. Furthermore, impacts from in-vitro long term catheterization to the sample mechanical and ultrasound morphologies would be analyzed. In the third approach, optimization from the previous approaches would assist in the replacement of medical grade polyurethane with medical grade thermoset silicone in hopes to prove the ability for the research to be transferable to other medical polymeric devices. The stated approaches will be useful for setting a path towards the development of ultrasonic imaging as the standard for medical device tracking. / Doctor of Philosophy / As the world population ages, hospital discharges of geriatric patients to nursing homes have increased. Patients with peripherally inserted central catheters (PICCs) are routinely discharged with the catheters in place. PICCs, only capable of being tracked through x-ray imaging, will routinely experience complications due to poor at-home care. Routinely, elderly patients will be forced to revisit the hospital to have the catheter replaced using x-ray imaging, exposing them to hospital borne illness. Catheters with the capability to be tracked without the need of x-ray imaging would greatly benefit the ill and elderly, providing decreased stress to the patients and increase nursing home capabilities. We hope to develop the field of real-time ultrasound tracking of plastic medical devices, through production of ultrasound activated plastic devices.

Brewer's spent grain (BSG) is the most abundant by-product of the brewing industry and its main application is limited to low-value cattle feed. Since BSG contains 20 to 25% of proteins, it has the potential to provide a new protein source to the food industry. In this research, an ultrasound-assisted enzymatic extraction was designed to extract protein hydrolysates from BSG. Original BSG and ultrasound pretreated BSG were hydrolyzed under different enzyme (Alcalase) loadings and incubation times. Centrifugation was applied to separate solubilized proteins from insoluble BSG residue. When the enzyme loading increased from 1 to 40 uL /g BSG, the solubilized proteins increased from 34% to 64.8%. The application of ultrasound further increased the solubilized proteins from 64.8% to 69.8%. Solubilized proteins from ultrasound pretreated BSG was significantly higher (p < 0.05) than that from the original BSG. Particle size distribution analysis showed that the application of ultrasound pretreatment reduced the BSG particle size from 331.2 to 215.7 um. Scanning electron microscopy images revealed that the BSG particle surface was partially ruptured by the ultrasound pretreatment. These two phenomena might have contributed to the increased protein separation efficiency with ultrasound pretreatment. The solubility (pH 1.0 to 11.0) of protein hydrolysate increased by the application of ultrasound and the ultrasound did not lead to the change of the amino acid composition of the separated protein hydrolysates. Based on sodium dodecyl sulfate-polyacrylamide gel electrophoresis profile, the protein was degraded to peptides which had molecular weights lower than 15 kDa. The color of the separated protein hydrolysates by enzymatic hydrolysis was brighter and lighter than the original BSG. The application of ultrasound did not affect the color of the separated protein hydrolysates. Overall, the ultrasound pretreatment prior to enzymatic hydrolysis enhanced the extraction of proteins from BSG in terms of higher protein separation efficiency, lower enzyme loadings, and reduced incubation time. This study developed a novel and green method to effectively extract value-added protein hydrolysates from the low-value food processing byproducts. / MSLFS / Brewer’s spent grain (BSG) is the most abundant waste generated by beer industries after beer production and it is mainly used to feed cattle. Since BSG contains 20 to 25% proteins, it has the potential to provide a new protein source to food industries. The aim of this research is to study if the ultrasound technology can assist the enzymatic extraction of proteins from BSG. If it can, the cost of the protein extraction from BSG can be reduced. In this research, the original BSG and the BSG pretreated with ultrasound were incubated under different enzyme loadings and incubation times. The protein-rich liquid was separated from fiber-rich solids using a centrifuge. When the enzyme loading increased from 1 to 40 L /g BSG, 34% to 64.8% of proteins were separated from the original BSG. The application of ultrasound further increased the solubilized proteins from 64.8% to 69.8%. For the BSG pretreated with ultrasound, there were significantly more proteins separated from BSG compared to the original BSG. Particle size of the original BSG and the ultrasound pretreated BSG was measured, and the results showed that the application of ultrasound pretreatment decreased the BSG particle size from 331.2 to 215.7 µm. Scanning electron microscopy images were taken to investigate the effect of ultrasound on the surface of BSG particles. Based on the photos, we found that the BSG particle surface was partially broken by the ultrasound pretreatment. The surface was rough and contained large amounts of holes instead of being flat and smooth observed without ultrasound. Therefore, there were more locations for the enzyme to attack. These two phenomena might have contributed to extracting more proteins from BSG. Protein solubility (pH 1.0 to 11.0) increased by the application of ultrasound. The nutritional value of the protein extracted was not altered by the ultrasound. The extracted protein hydrolysates had a small molecular weight and the application of ultrasound did not affect the color of the extracted protein hydrolysates. The ultrasound pretreatment prior to enzymatic hydrolysis increased the extraction of proteins from BSG, decreased the enzyme consumption and incubation time. This study developed a novel and green method to effectively extract value-added protein hydrolysates from the low-value food processing byproducts.

Ultrasound technology allows in vivo estimation of carcass composition. Successful genetic evaluation of ultrasonic measures depends upon technician certification guidelines and a viable common-endpoint adjustment strategy for field data. Four technicians and three image interpreters ultrasonically evaluated 172 lambs to determine accuracy and repeatability of loin eye area (LEA), backfat thickness (BF), and body wall thickness (BW) estimations. Correlations between ultrasonic and carcass measurements were 0.66, 0.78, and 0.73 for LEA, BF, and BW, respectively. Performance was similar among technicians and interpreters. Mean bias ranged from -1.30 to -2.66 cm2, -0.12 to -0.17 cm, and 0.14 to -0.03 cm, for LEA, BF, and BW, respectively; prediction standard errors ranged from 1.86 to 2.22 cm2, 0.12 to 0.14 cm, and 0.35 to 0.38 cm, respectively. Repeatability standard errors ranged from 1.61 to 2.45 cm2, 0.07 to 0.11 cm, and 0.36 to 0.42 cm for LEA, BF, and BW, respectively. Changes in ultrasonic measurements were evaluated using seven serial scans on 24 growing Suffolk ram lambs. All equations had similar goodness of fit. Equations were tested on other populations, including similarly-managed rams across breeds and years and ewe lambs fed for slower gain. Correlations between predicted and actual measures ranged from 0.78 to 0.87 for BF and 0.66 to 0.93 for LEA in winter-born rams, were only slightly lower in fall-born rams, and ranged from 0.72 to 0.74 for BF and 0.54 to 0.76 for LEA in ewe lambs. Of the equations tested, linear and allometric forms appear best for general use. / Master of Science

Endometriosis is a heterogeneous chronic pain and inflammatory disease associated with negative impacts on quality of life. Among the phenotypes of endometriosis, deep endometriosis (DE) is the most aggressive form of the disease, associated with complex disease states, such as adhesions within the pouch of Douglas (POD) and bowel DE. The most common site of DE is the uterosacral ligaments (USLs), which are bilateral structures between the uterus and sacrum conjoined by the torus uterinus (TU), with a prevalence of 20 to 70%. The USLs have historically been the hardest to visualize using non-invasive modalities, such as transvaginal ultrasound (TVS), resulting in poor identification of endometriosis when present on/within the USLs, contributing to the significant diagnostic delay associated with the disease. This thesis details a novel diagnostic approach, utilizing TVS within the posterior vaginal fornix as the index test and laparoscopic visualization as the reference standard, aiming to evaluate the diagnostic accuracy of TVS for DE of the USLs and TU. Additionally, the USLs and TU are commonly associated with complex disease presentations, including POD obliteration and bowel DE, though the impact on diagnostic accuracy remains unknown. We theorize that these concurrent complex disease states will lead to the distortion of the anatomical environment and, in turn, negatively alter the diagnostic performance of the novel posterior approach. This thesis further aimed to determine the impact of concurrent complex disease states on diagnostic performance. We found enhanced diagnostic accuracy in the detection of endometriosis in the left USL, right USL, and TU compared to previous studies, with our sensitivity ranging from 75.0-100%, specificity of 100%, positive predictive values of 100%, and negative predictive value ranging from 88.6-100%. Furthermore, contrary to our hypothesis, diagnostic performance appeared unaffected by the presence of complex disease states. The ability to diagnose USL DE non-invasively can have profound implications for introducing personalized treatment plans in a timely manner, which should improve patient outcomes. With this enhanced diagnostic performance, fewer people will require a surgical diagnosis, which reduces the burden on the health system and decreases surgical complications associated with diagnostic surgery. / Thesis / Master of Science (MSc) / Endometriosis is a common gynecological disease involving the abnormal growth of uterine-like cells outside the uterus, causing significant negative impacts on quality of life and diagnostic delays. Deep endometriosis (DE) is the most aggressive form, infiltrating surrounding tissues and leading to complex disease states. The uterosacral ligaments (USLs; connective structures between the lower spine and uterus) are the most common site for DE, but diagnosing them non-invasively remains challenging, aiding the diagnostic delay. Following updated classification guidelines, the overarching aim of this thesis is to enhance our understanding of transvaginal ultrasound (TVS) as a safe and rapid diagnostic for DE of the USLs and TU. In doing so, this thesis aims to assess the accuracy of a new TVS technique for DE of the USLs and determine how other related health conditions might affect the accuracy of this diagnostic approach. The findings from this study indicate that using TVS could greatly assist in diagnosing DE in the USLs, potentially leading to more personalized treatment approaches by healthcare providers and better outcomes for individuals with endometriosis. In summary, this research contributes significantly to our understanding and management of this complex condition.

Yes / Most cancer patients receive chemotherapy at some stage of their treatment which makes improving the efficacy of cytotoxic drugs an ongoing and important goal. Despite large numbers of potent anti-cancer agents being developed, a major obstacle to clinical translation remains the inability to deliver therapeutic doses to a tumor without causing intolerable side effects. To address this problem, there has been intense interest in nanoformulations and targeted delivery to improve cancer outcomes. The aim of this work was to demonstrate how vascular endothelial growth factor receptor 2 (VEGFR2)-targeted, ultrasound-triggered delivery with therapeutic microbubbles (thMBs) could improve the therapeutic range of cytotoxic drugs. Methods: Using a microfluidic microbubble production platform, we generated thMBs comprising VEGFR2-targeted microbubbles with attached liposomal payloads for localised ultrasound-triggered delivery of irinotecan and SN38 in mouse models of colorectal cancer. Intravenous injection into tumor-bearing mice was used to examine targeting efficiency and tumor pharmacodynamics. High-frequency ultrasound and bioluminescent imaging were used to visualise microbubbles in real-time. Tandem mass spectrometry (LC-MS/MS) was used to quantitate intratumoral drug delivery and tissue biodistribution. Finally, 89Zr PET radiotracing was used to compare biodistribution and tumor accumulation of ultrasound-triggered SN38 thMBs with VEGFR2 targeted SN38 liposomes alone. Results: ThMBs specifically bound VEGFR2 in vitro and significantly improved tumor responses to low dose irinotecan and SN38 in human colorectal cancer xenografts. An ultrasound trigger was essential to achieve the selective effects of thMBs as without it, thMBs failed to extend intratumoral drug delivery or demonstrate enhanced tumor responses. Sensitive LC-MS/MS quantification of drugs and their metabolites demonstrated that thMBs extended drug exposure in tumors but limited exposure in healthy tissues, not exposed to ultrasound, by persistent encapsulation of drug prior to elimination. 89Zr PET radiotracing showed that the percentage injected dose in tumors achieved with thMBs was twice that of VEGFR2-targeted SN38 liposomes alone. Conclusions: thMBs provide a generic platform for the targeted, ultrasound-triggered delivery of cytotoxic drugs by enhancing tumor responses to low dose drug delivery via combined effects on circulation, tumor drug accumulation and exposure and altered metabolism in normal tissues. / EPSRC funding (EP/I000623/1, EP/K023845/1 and EP/P023266/1) and the MRC for a Confidence in Concept award and MR/L01629X. L.E. McVeigh was funded by an EPSRC PhD Studentship (EP/L504993/1).

Yes / In this work, effect of ultrasound on molecular structure development of Polylactide (PLA) was studied. It was found that the intrinsic viscosity of PLA decreased with increasing treating time, temperature and ultrasound time. Different from traditional thermal degradation of PLA, the degradation of PLA under ultrasound treatment showed that chain scission and chain combination of PLA competed with each other in the degradation process, which could be divided into two steps. The mechanism of ultrasound degradation of PLA was proposed. Furthermore, Thermal properties were characterized by DSC to show heat and ultrasound effects on molecular structure development of PLA.