Chronic total occlusions are a common problem in patients with coronary artery disease. The primary barrier to successful percutaneous coronary intervention is inability to cross the lesion with a guidewire. We seek to characterize polymer microspheres as a controlled delivery mechanism for collagenase and VEGF, novel intralesional therapies being investigated to alter CTO structural properties. Release profiles for protein-loaded PLGA [poly(lactic-co-glycolic acid)] microspheres showed sustained BSA and VEGF release over eight and 48 hours respectively. Polymer degradation products had no impact on endothelial cell growth and protein bioactivity was maintained post-release. In vivo localization of microsphere-released collagenase was not possible due to low concentrations remaining at the site. Histology confirmed microspheres remained in the collagen-dense, proximal 15 mm of the lesion, likely altering the structural integrity of the plaque.

Chronic total occlusions are a common problem in patients with coronary artery disease. The primary barrier to successful percutaneous coronary intervention is inability to cross the lesion with a guidewire. We seek to characterize polymer microspheres as a controlled delivery mechanism for collagenase and VEGF, novel intralesional therapies being investigated to alter CTO structural properties. Release profiles for protein-loaded PLGA [poly(lactic-co-glycolic acid)] microspheres showed sustained BSA and VEGF release over eight and 48 hours respectively. Polymer degradation products had no impact on endothelial cell growth and protein bioactivity was maintained post-release. In vivo localization of microsphere-released collagenase was not possible due to low concentrations remaining at the site. Histology confirmed microspheres remained in the collagen-dense, proximal 15 mm of the lesion, likely altering the structural integrity of the plaque.

Revascularization of Chronic Total Occlusions (CTO) by percutaneous coronary interventions is limited by low success rates, primarily due to difficulty in guidewire crossing. There are a number of contributing factors that make guidewire crossing challenging. Two of the most significant impediments are: a) inability to adequately visualize the CTO to appropriately plan a pathway to the distal lumen, and b) difficulty in physically crossing the rigid endcap at the proximal end of CTO without using stiff wires. Moreover, there is a significant knowledge gap in the composition of CTOs, and the consequent impact of that composition on crossability. This thesis presents tools and techniques to help mitigate the current shortcomings, while shedding new light on CTO composition and maturation. The tools and techniques presented herein are based upon ultrasound approaches with the intent of eventually developing these strategies into catheter based solutions. Recent studies have suggested that the presence of microvessels in CTO may provide a preferred pathway for guidewire crossing. However, due to limited resolution and a lack of soft tissue contrast in angiography, microvessels within CTO cannot generally be detected by in-vivo angiographic techniques, and when they are visualized, it is unknown whether or not they are intraluminal. In this thesis, high frequency ultrasound with Power Doppler overlays is shown to be capable of detecting and tracking transluminal recanalization channels using an in vivo porcine model of CTO. It is also shown that ultrasound is a more sensitive technique to detect and map these channels than MRI. Furthermore, features of microvasculature in CTOs that had not previously been seen are presented. A technique was then developed to facilitate guidewire crossing through the proximal endcap, also known as the proximal fibrous cap (PFC). In order to assess the ease with which a probe is able to iv perforate the PFC, a system was designed and to measure the force required for PFC puncture. This system was validated by examining the required puncture forces for CTOs of different ages. It was shown that CTOs less than 6 weeks in age are significantly easier to puncture than those greater than 12 weeks. This coincides with differences in composition, with the presence of softer materials at the earlier time point, such as thrombus and proteoglycans compared to stiffer fibrotic materials which predominate at late timepoints. After development and validation of a reliable technique to measure ease of PFC puncture, the efficacy of therapies designed to modify PFC compliance could be assessed. The use of ultrasound mediated microbubble (UMM) disruption to act as an adjuvant to accelerate collagenase therapy in CTO was examined. A significant reduction in puncture force and an increase in the amount of collagen degraded was achieved using a combined UMM + collagenase treatment compared with collagenase therapy alone and UMM treatment alone.

The percutaneous revascularization of chronic total occlusions represents a major challenge to interventional cardiologists. Procedural success is currently limited by the inadequate soft-tissue contrast of x-ray fluoroscopy and the inability to visualize the position and orientation of a revascularization device with respect to the lesion and the vessel wall. In this thesis methods are developed that enable the percutaneous revascularization of occlusive lesions to be guided using magnetic resonance (MR) imaging. Unlike x-rays, MR has excellent soft-tissue contrast and this can be exploited to provide valuable information regarding the composition and geometry of the lesion. The first method is a robust and redundant technique for determining the position and orientation of a catheter inside an MR scanner. The technique uses phase information introduced into the MR signal by a small receive coil located at the distal tip of the catheter. The technique is developed theoretically and is demonstrated with a feasibility experiment. A forward-looking intravascular imaging catheter is then presented that is capable of acquiring of high-resolution MR images of occlusive lesions and the vessel wall in front of the catheter. The imaging catheter consists of two orthogonal receive coils located at the distal tip of the catheter. The use of the imaging catheter is demonstrated in phantoms and in vivo. A third method enables active visualization of MR compatible guidewires. The method utilizes a catheter-based pick-up coil that is magnetically coupled to the guidewire. The proposed technique enables one to concentrate all active components on a catheter thereby facilitating the use of safety features. Complete characterization is presented theoretically and validated experimentally. In addition, the use of a practical catheter device is demonstrated in an in situ environment. Finally, future work required for the development of an integrated catheter-based device for the MR-guided revascularization of chronic total occlusions is discussed.

Revascularization of Chronic Total Occlusions (CTO) by percutaneous coronary interventions is limited by low success rates, primarily due to difficulty in guidewire crossing. There are a number of contributing factors that make guidewire crossing challenging. Two of the most significant impediments are: a) inability to adequately visualize the CTO to appropriately plan a pathway to the distal lumen, and b) difficulty in physically crossing the rigid endcap at the proximal end of CTO without using stiff wires. Moreover, there is a significant knowledge gap in the composition of CTOs, and the consequent impact of that composition on crossability. This thesis presents tools and techniques to help mitigate the current shortcomings, while shedding new light on CTO composition and maturation. The tools and techniques presented herein are based upon ultrasound approaches with the intent of eventually developing these strategies into catheter based solutions. Recent studies have suggested that the presence of microvessels in CTO may provide a preferred pathway for guidewire crossing. However, due to limited resolution and a lack of soft tissue contrast in angiography, microvessels within CTO cannot generally be detected by in-vivo angiographic techniques, and when they are visualized, it is unknown whether or not they are intraluminal. In this thesis, high frequency ultrasound with Power Doppler overlays is shown to be capable of detecting and tracking transluminal recanalization channels using an in vivo porcine model of CTO. It is also shown that ultrasound is a more sensitive technique to detect and map these channels than MRI. Furthermore, features of microvasculature in CTOs that had not previously been seen are presented. A technique was then developed to facilitate guidewire crossing through the proximal endcap, also known as the proximal fibrous cap (PFC). In order to assess the ease with which a probe is able to iv perforate the PFC, a system was designed and to measure the force required for PFC puncture. This system was validated by examining the required puncture forces for CTOs of different ages. It was shown that CTOs less than 6 weeks in age are significantly easier to puncture than those greater than 12 weeks. This coincides with differences in composition, with the presence of softer materials at the earlier time point, such as thrombus and proteoglycans compared to stiffer fibrotic materials which predominate at late timepoints. After development and validation of a reliable technique to measure ease of PFC puncture, the efficacy of therapies designed to modify PFC compliance could be assessed. The use of ultrasound mediated microbubble (UMM) disruption to act as an adjuvant to accelerate collagenase therapy in CTO was examined. A significant reduction in puncture force and an increase in the amount of collagen degraded was achieved using a combined UMM + collagenase treatment compared with collagenase therapy alone and UMM treatment alone.

The percutaneous revascularization of chronic total occlusions represents a major challenge to interventional cardiologists. Procedural success is currently limited by the inadequate soft-tissue contrast of x-ray fluoroscopy and the inability to visualize the position and orientation of a revascularization device with respect to the lesion and the vessel wall. In this thesis methods are developed that enable the percutaneous revascularization of occlusive lesions to be guided using magnetic resonance (MR) imaging. Unlike x-rays, MR has excellent soft-tissue contrast and this can be exploited to provide valuable information regarding the composition and geometry of the lesion. The first method is a robust and redundant technique for determining the position and orientation of a catheter inside an MR scanner. The technique uses phase information introduced into the MR signal by a small receive coil located at the distal tip of the catheter. The technique is developed theoretically and is demonstrated with a feasibility experiment. A forward-looking intravascular imaging catheter is then presented that is capable of acquiring of high-resolution MR images of occlusive lesions and the vessel wall in front of the catheter. The imaging catheter consists of two orthogonal receive coils located at the distal tip of the catheter. The use of the imaging catheter is demonstrated in phantoms and in vivo. A third method enables active visualization of MR compatible guidewires. The method utilizes a catheter-based pick-up coil that is magnetically coupled to the guidewire. The proposed technique enables one to concentrate all active components on a catheter thereby facilitating the use of safety features. Complete characterization is presented theoretically and validated experimentally. In addition, the use of a practical catheter device is demonstrated in an in situ environment. Finally, future work required for the development of an integrated catheter-based device for the MR-guided revascularization of chronic total occlusions is discussed.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20279号 / 医博第4238号 / 新制||医||1021(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 湊谷 謙司, 教授 福原 俊一, 教授 川村 孝 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

O rastreamento de objetos em vídeos representa um importante problema na área de processamento de imagens, quer seja pelo grande número de aplicações envolvidas, ou pelo grau de complexidade que pode ser apresentado. Como exemplo de aplicações, podemos citar sua utilização em áreas como robótica móvel, interface homem-máquina, medicina, automação de processo industriais até aplicações mais tracionais como vigilância e monitoramento de trafego. O aumento na complexidade do rastreamento se deve principalmente a interação do objeto rastreado com outros elementos da cena do vídeo, especialmente nos casos de oclusões parciais ou totais. Quando uma oclusão ocorre a informação sobre a localização do objeto durante o rastreamento é perdida parcial ou totalmente. Métodos de filtragem estocástica, utilizados para o rastreamento de objetos, como os Filtros de Partículas não apresentam resultados satisfatórios na presença de oclusões totais, onde temos uma descontinuidade na trajetória do objeto. Portanto torna-se necessário o desenvolvimento de métodos específicos para tratar o problema de oclusão total. Nesse trabalho, nós desenvolvemos uma abordagem para tratar o problema de oclusão total no rastreamento de objetos utilizando Filtro de Partículas baseados em Monte Carlo via Cadeia de Markov (MCCM) com função geradora de partículas adaptativa. Durante o rastreamento do objeto, em situações onde não há oclusões, nós utilizamos uma função de probabilidade geradora simétrica. Entretanto, quando uma oclusão total, ou seja, uma descontinuidade na trajetória é detectada, a função geradora torna-se assimétrica, criando um termo de “inércia” ou “arraste” na direção do deslocamento do objeto. Ao sair da oclusão, o objeto é novamente encontrado e a função geradora volta a ser simétrica novamente. / The object tracking on video is an important task in image processing area either for the great number of involved applications, or for the degree of complexity that can be presented. How example of application, we can cite its use from robotic area, machine-man interface, medicine, automation of industry process to vigilance and traffic control applications. The increase of complexity of tracking is occasioned principally by interaction of tracking object with other objects on video, specially when total or partial occlusions occurs. When a occlusion occur the information about the localization of tracking object is lost partially or totally. Stochastic filtering methods, like Particle Filter do not have satisfactory results in the presence of total occlusions. Total occlusion can be understood like discontinuity in the object trajectory. Therefore is necessary to develop specific method to handle the total occlusion task. In this work, we develop an approach to handle the total occlusion task using MCMC-Particle Filter with adaptive sampling probability function. When there is not occlusions we use a symmetric probability function to sample the particles. However, when there is a total occlusion, a discontinuity in the trajectory is detected, and the probability sampling function becomes asymmetric. This break of symmetry creates a “drift” or “inertial” term in object shift direction. When the tracking object becomes visible (after the occlusion) it is found again and the sampling function come back to be symmetric.

O rastreamento de objetos em vídeos representa um importante problema na área de processamento de imagens, quer seja pelo grande número de aplicações envolvidas, ou pelo grau de complexidade que pode ser apresentado. Como exemplo de aplicações, podemos citar sua utilização em áreas como robótica móvel, interface homem-máquina, medicina, automação de processo industriais até aplicações mais tracionais como vigilância e monitoramento de trafego. O aumento na complexidade do rastreamento se deve principalmente a interação do objeto rastreado com outros elementos da cena do vídeo, especialmente nos casos de oclusões parciais ou totais. Quando uma oclusão ocorre a informação sobre a localização do objeto durante o rastreamento é perdida parcial ou totalmente. Métodos de filtragem estocástica, utilizados para o rastreamento de objetos, como os Filtros de Partículas não apresentam resultados satisfatórios na presença de oclusões totais, onde temos uma descontinuidade na trajetória do objeto. Portanto torna-se necessário o desenvolvimento de métodos específicos para tratar o problema de oclusão total. Nesse trabalho, nós desenvolvemos uma abordagem para tratar o problema de oclusão total no rastreamento de objetos utilizando Filtro de Partículas baseados em Monte Carlo via Cadeia de Markov (MCCM) com função geradora de partículas adaptativa. Durante o rastreamento do objeto, em situações onde não há oclusões, nós utilizamos uma função de probabilidade geradora simétrica. Entretanto, quando uma oclusão total, ou seja, uma descontinuidade na trajetória é detectada, a função geradora torna-se assimétrica, criando um termo de “inércia” ou “arraste” na direção do deslocamento do objeto. Ao sair da oclusão, o objeto é novamente encontrado e a função geradora volta a ser simétrica novamente. / The object tracking on video is an important task in image processing area either for the great number of involved applications, or for the degree of complexity that can be presented. How example of application, we can cite its use from robotic area, machine-man interface, medicine, automation of industry process to vigilance and traffic control applications. The increase of complexity of tracking is occasioned principally by interaction of tracking object with other objects on video, specially when total or partial occlusions occurs. When a occlusion occur the information about the localization of tracking object is lost partially or totally. Stochastic filtering methods, like Particle Filter do not have satisfactory results in the presence of total occlusions. Total occlusion can be understood like discontinuity in the object trajectory. Therefore is necessary to develop specific method to handle the total occlusion task. In this work, we develop an approach to handle the total occlusion task using MCMC-Particle Filter with adaptive sampling probability function. When there is not occlusions we use a symmetric probability function to sample the particles. However, when there is a total occlusion, a discontinuity in the trajectory is detected, and the probability sampling function becomes asymmetric. This break of symmetry creates a “drift” or “inertial” term in object shift direction. When the tracking object becomes visible (after the occlusion) it is found again and the sampling function come back to be symmetric.

O rastreamento de objetos em vídeos representa um importante problema na área de processamento de imagens, quer seja pelo grande número de aplicações envolvidas, ou pelo grau de complexidade que pode ser apresentado. Como exemplo de aplicações, podemos citar sua utilização em áreas como robótica móvel, interface homem-máquina, medicina, automação de processo industriais até aplicações mais tracionais como vigilância e monitoramento de trafego. O aumento na complexidade do rastreamento se deve principalmente a interação do objeto rastreado com outros elementos da cena do vídeo, especialmente nos casos de oclusões parciais ou totais. Quando uma oclusão ocorre a informação sobre a localização do objeto durante o rastreamento é perdida parcial ou totalmente. Métodos de filtragem estocástica, utilizados para o rastreamento de objetos, como os Filtros de Partículas não apresentam resultados satisfatórios na presença de oclusões totais, onde temos uma descontinuidade na trajetória do objeto. Portanto torna-se necessário o desenvolvimento de métodos específicos para tratar o problema de oclusão total. Nesse trabalho, nós desenvolvemos uma abordagem para tratar o problema de oclusão total no rastreamento de objetos utilizando Filtro de Partículas baseados em Monte Carlo via Cadeia de Markov (MCCM) com função geradora de partículas adaptativa. Durante o rastreamento do objeto, em situações onde não há oclusões, nós utilizamos uma função de probabilidade geradora simétrica. Entretanto, quando uma oclusão total, ou seja, uma descontinuidade na trajetória é detectada, a função geradora torna-se assimétrica, criando um termo de “inércia” ou “arraste” na direção do deslocamento do objeto. Ao sair da oclusão, o objeto é novamente encontrado e a função geradora volta a ser simétrica novamente. / The object tracking on video is an important task in image processing area either for the great number of involved applications, or for the degree of complexity that can be presented. How example of application, we can cite its use from robotic area, machine-man interface, medicine, automation of industry process to vigilance and traffic control applications. The increase of complexity of tracking is occasioned principally by interaction of tracking object with other objects on video, specially when total or partial occlusions occurs. When a occlusion occur the information about the localization of tracking object is lost partially or totally. Stochastic filtering methods, like Particle Filter do not have satisfactory results in the presence of total occlusions. Total occlusion can be understood like discontinuity in the object trajectory. Therefore is necessary to develop specific method to handle the total occlusion task. In this work, we develop an approach to handle the total occlusion task using MCMC-Particle Filter with adaptive sampling probability function. When there is not occlusions we use a symmetric probability function to sample the particles. However, when there is a total occlusion, a discontinuity in the trajectory is detected, and the probability sampling function becomes asymmetric. This break of symmetry creates a “drift” or “inertial” term in object shift direction. When the tracking object becomes visible (after the occlusion) it is found again and the sampling function come back to be symmetric.