Description
Osteoarthritis (OA) is a progressive joint disease that affects millions of people worldwide and remains difficult to diagnose early and to treat effectively. Existing imaging techniques often only detect osteoarthritic damage after substantial structural loss has occurred. This thesis investigates two key aspects of OA management: (1) how hyaluronan (HA) therapy interacts with articular cartilage at the molecular and tissue level, and (2) whether quantitative ultrasound imaging can detect early degenerative changes in articular cartilage before irreversible osteoarthritic damage develops. By combining molecular characterisation, ex vivo cartilage experiments, and advanced ultrasound imaging, the research aims to improve understanding of HA therapy and to evaluate ultrasound as an accessible diagnostic tool for OA.
HA as a therapeutic agent for Osteoarthritis
The study begins by measuring the viscosity-average molecular weight of the HA preparation Ostenil using Ostwald viscometry. To examine how exogenous HA behaves within cartilage, fluorescein-labelled hyaluronan (fHA, 730 kDa) was applied to bovine and human ex vivo cartilage models, allowing direct visualisation of its movement through the extracellular matrix. These experiments show that HA can penetrate the cartilage matrix despite its size, entering the tissue within one hour. This finding challenges the traditional explanation of the treatment known as viscosupplementation, which assumes that HA acts primarily by increasing the viscosity of synovial fluid. Given that the biological half-life of HA in synovial fluid is approximately two days—far shorter than the duration of clinical benefit—the term viscosupplementation does not accurately reflect HA’s mechanism of activity. This research therefore supports adopting the broader and more accurate term “HA therapy” to describe its clinical use.
Ultrasound imaging as a measure of articular cartilage degeneration in knee Osteoarthritis
The diagnostic imaging component evaluates the Siemens S3000 ultrasound system across multiple modalities. B-mode ultrasound images were analysed using Grey Level Co-occurrence Matrix (GLCM) textural features to quantify cartilage surface integrity and internal microstructural organisation. This approach was validated in 30 human participants, enabling identification of ultrasound-based biomarkers related to articular cartilage degeneration in osteoarthritis. Additional experiments assessed shear-wave elastography (VTIQ/ARFI) for estimating cartilage elastic modulus and used hydrogel phantoms with known mechanical properties to determine the measurable range and limitations of elastographic stiffness estimation. Radiofrequency (RF) time-varying strain imaging was also evaluated in hydrogels and human tissue to assess its sensitivity to subtle mechanical deformation in cartilage compared with other soft tissues.
Methods
All human imaging procedures were conducted under appropriate ethical approval, and all participants provided informed consent. The combined dataset enables reproducibility of the viscometric calculations, fluorescence diffusion studies, hydrogel phantom testing, ultrasound acquisition protocol, textural analysis methods, and elastography performance evaluation.
Summary
These findings demonstrate that exogenous HA can enter and persist within cartilage despite its molecular size and highlight quantitative ultrasound textural analysis as a promising non-invasive method for detecting early osteoarthritic cartilage degeneration. This work helps refine the scientific understanding of HA therapy and supports the development of ultrasound-based tools for earlier OA diagnosis.
Description
Osteoarthritis (OA) is a progressive joint disease that affects millions of people worldwide and remains difficult to diagnose early and to treat effectively. Existing imaging techniques often only detect osteoarthritic damage after substantial structural loss has occurred. This thesis investigates two key aspects of OA management: (1) how hyaluronan (HA) therapy interacts with articular cartilage at the molecular and tissue level, and (2) whether quantitative ultrasound imaging can detect early degenerative changes in articular cartilage before irreversible osteoarthritic damage develops. By combining molecular characterisation, ex vivo cartilage experiments, and advanced ultrasound imaging, the research aims to improve understanding of HA therapy and to evaluate ultrasound as an accessible diagnostic tool for OA.
HA as a therapeutic agent for Osteoarthritis
The study begins by measuring the viscosity-average molecular weight of the HA preparation Ostenil using Ostwald viscometry. To examine how exogenous HA behaves within cartilage, fluorescein-labelled hyaluronan (fHA, 730 kDa) was applied to bovine and human ex vivo cartilage models, allowing direct visualisation of its movement through the extracellular matrix. These experiments show that HA can penetrate the cartilage matrix despite its size, entering the tissue within one hour. This finding challenges the traditional explanation of the treatment known as viscosupplementation, which assumes that HA acts primarily by increasing the viscosity of synovial fluid. Given that the biological half-life of HA in synovial fluid is approximately two days—far shorter than the duration of clinical benefit—the term viscosupplementation does not accurately reflect HA’s mechanism of activity. This research therefore supports adopting the broader and more accurate term “HA therapy” to describe its clinical use.
Ultrasound imaging as a measure of articular cartilage degeneration in knee Osteoarthritis
The diagnostic imaging component evaluates the Siemens S3000 ultrasound system across multiple modalities. B-mode ultrasound images were analysed using Grey Level Co-occurrence Matrix (GLCM) textural features to quantify cartilage surface integrity and internal microstructural organisation. This approach was validated in 30 human participants, enabling identification of ultrasound-based biomarkers related to articular cartilage degeneration in osteoarthritis. Additional experiments assessed shear-wave elastography (VTIQ/ARFI) for estimating cartilage elastic modulus and used hydrogel phantoms with known mechanical properties to determine the measurable range and limitations of elastographic stiffness estimation. Radiofrequency (RF) time-varying strain imaging was also evaluated in hydrogels and human tissue to assess its sensitivity to subtle mechanical deformation in cartilage compared with other soft tissues.
Methods
All human imaging procedures were conducted under appropriate ethical approval, and all participants provided informed consent. The combined dataset enables reproducibility of the viscometric calculations, fluorescence diffusion studies, hydrogel phantom testing, ultrasound acquisition protocol, textural analysis methods, and elastography performance evaluation.
Summary
These findings demonstrate that exogenous HA can enter and persist within cartilage despite its molecular size and highlight quantitative ultrasound textural analysis as a promising non-invasive method for detecting early osteoarthritic cartilage degeneration. This work helps refine the scientific understanding of HA therapy and supports the development of ultrasound-based tools for earlier OA diagnosis.
Description
Osteoarthritis (OA) is a progressive joint disease that affects millions of people worldwide and remains difficult to diagnose early and to treat effectively. Existing imaging techniques often only detect osteoarthritic damage after substantial structural loss has occurred. This thesis investigates two key aspects of OA management: (1) how hyaluronan (HA) therapy interacts with articular cartilage at the molecular and tissue level, and (2) whether quantitative ultrasound imaging can detect early degenerative changes in articular cartilage before irreversible osteoarthritic damage develops. By combining molecular characterisation, ex vivo cartilage experiments, and advanced ultrasound imaging, the research aims to improve understanding of HA therapy and to evaluate ultrasound as an accessible diagnostic tool for OA.
HA as a therapeutic agent for Osteoarthritis
The study begins by measuring the viscosity-average molecular weight of the HA preparation Ostenil using Ostwald viscometry. To examine how exogenous HA behaves within cartilage, fluorescein-labelled hyaluronan (fHA, 730 kDa) was applied to bovine and human ex vivo cartilage models, allowing direct visualisation of its movement through the extracellular matrix. These experiments show that HA can penetrate the cartilage matrix despite its size, entering the tissue within one hour. This finding challenges the traditional explanation of the treatment known as viscosupplementation, which assumes that HA acts primarily by increasing the viscosity of synovial fluid. Given that the biological half-life of HA in synovial fluid is approximately two days—far shorter than the duration of clinical benefit—the term viscosupplementation does not accurately reflect HA’s mechanism of activity. This research therefore supports adopting the broader and more accurate term “HA therapy” to describe its clinical use.
Ultrasound imaging as a measure of articular cartilage degeneration in knee Osteoarthritis
The diagnostic imaging component evaluates the Siemens S3000 ultrasound system across multiple modalities. B-mode ultrasound images were analysed using Grey Level Co-occurrence Matrix (GLCM) textural features to quantify cartilage surface integrity and internal microstructural organisation. This approach was validated in 30 human participants, enabling identification of ultrasound-based biomarkers related to articular cartilage degeneration in osteoarthritis. Additional experiments assessed shear-wave elastography (VTIQ/ARFI) for estimating cartilage elastic modulus and used hydrogel phantoms with known mechanical properties to determine the measurable range and limitations of elastographic stiffness estimation. Radiofrequency (RF) time-varying strain imaging was also evaluated in hydrogels and human tissue to assess its sensitivity to subtle mechanical deformation in cartilage compared with other soft tissues.
Methods
All human imaging procedures were conducted under appropriate ethical approval, and all participants provided informed consent. The combined dataset enables reproducibility of the viscometric calculations, fluorescence diffusion studies, hydrogel phantom testing, ultrasound acquisition protocol, textural analysis methods, and elastography performance evaluation.
Summary
These findings demonstrate that exogenous HA can enter and persist within cartilage despite its molecular size and highlight quantitative ultrasound textural analysis as a promising non-invasive method for detecting early osteoarthritic cartilage degeneration. This work helps refine the scientific understanding of HA therapy and supports the development of ultrasound-based tools for earlier OA diagnosis.