Periodic Reporting for period 3 - CARDIS (Early stage CARdio Vascular Disease Detection with Integrated Silicon Photonics)
Okres sprawozdawczy: 2017-08-01 do 2019-01-31
A. Context
Cardiovascular disease (CVD) includes pathology of the heart and of the vessels (mainly arteries) supplying blood to organs and tissues from the heart. CVD and their risk factors are the major contributors to global morbidity and mortality. They are responsible for over 17.6 million deaths per year worldwide, representing 31% of all global deaths. Early identification of individuals at risk for CVD allows early intervention to delay, halt or reverse the pathological process.
Assessment of arterial stiffness by measurement of carotid-femoral pulse wave velocity (PWV), as surrogate for aortic stiffness, is included in the latest hypertension guidelines and there is ample evidence that arterial stiffness is the strongest known biomarker for cardiovascular risk in general, with predictive power above and beyond all known conventional risk factors. Early identification of arterial stenosis and heart dyssynchrony can be used to improve CVD risk classification. However, no tools are available today to screen a large population under primary care for these indicators.
Over the past few years the Universiteit Gent (UGent) and Queen Mary University of London (QMUL) and others have gathered evidence that mechanical vibrations induced by cardiovascular dynamics actually propagate up to skin level, where they can be detected using non-invasive contact or non-contact measurements such as laser Doppler vibrometry.
A laser Doppler vibrometer (LDV) is an instrument that is used to make non-contact vibration measurements of a surface. The laser beam from the LDV is directed at the surface of interest. Vibration amplitude and frequency are extracted from the Doppler shift of the reflected laser beam frequency due to the motion of the surface. Three approaches are followed to use LDV for cardiovascular risk assessment:
• Targeting the skin overlying an artery enables detection of skin vibrations induced by the flow in the artery.
• Targeting two adjacent points on the skin overlying an artery enables measurement of the time it takes the pulse wave to travel between these two points, providing a surrogate measurement of arterial stiffness
• Targeting the chest allows for detection of skin vibrations induced by the heart pumping action. Dyssynchrony will change the vibration pattern.
B. Overall objectives
The objective of CARDIS is to investigate and demonstrate the concept of a mobile, low-cost CVD screening device based on a silicon photonics integrated laser vibrometer and to validate the concept for the screening of arterial stiffness, detection of stenosis and heart dyssynchrony.It will be met by:
• Investigating, designing and fabricating optical subsystems and components: A Photonic Integrated Chip with a multi-branch laser interferometer with integrated photo detectors and input port for an external micro-optical laser assembly, a micro-optical laser assembly, a micro-optical lens system
• Integrating the subsystems and building a multi-beam laser Doppler vibrometer. Two rows of 6 beams are envisaged.
• Developing a process flow scalable to high volumes for all subsystems and their integration steps
• Investigating and developing experimental and computational biomechanical models to translate optical signals related to skin-level vibrations into underlying CVD physiological events
• Validating the system in a clinical setting.
Cardiovascular disease (CVD) includes pathology of the heart and of the vessels (mainly arteries) supplying blood to organs and tissues from the heart. CVD and their risk factors are the major contributors to global morbidity and mortality. They are responsible for over 17.6 million deaths per year worldwide, representing 31% of all global deaths. Early identification of individuals at risk for CVD allows early intervention to delay, halt or reverse the pathological process.
Assessment of arterial stiffness by measurement of carotid-femoral pulse wave velocity (PWV), as surrogate for aortic stiffness, is included in the latest hypertension guidelines and there is ample evidence that arterial stiffness is the strongest known biomarker for cardiovascular risk in general, with predictive power above and beyond all known conventional risk factors. Early identification of arterial stenosis and heart dyssynchrony can be used to improve CVD risk classification. However, no tools are available today to screen a large population under primary care for these indicators.
Over the past few years the Universiteit Gent (UGent) and Queen Mary University of London (QMUL) and others have gathered evidence that mechanical vibrations induced by cardiovascular dynamics actually propagate up to skin level, where they can be detected using non-invasive contact or non-contact measurements such as laser Doppler vibrometry.
A laser Doppler vibrometer (LDV) is an instrument that is used to make non-contact vibration measurements of a surface. The laser beam from the LDV is directed at the surface of interest. Vibration amplitude and frequency are extracted from the Doppler shift of the reflected laser beam frequency due to the motion of the surface. Three approaches are followed to use LDV for cardiovascular risk assessment:
• Targeting the skin overlying an artery enables detection of skin vibrations induced by the flow in the artery.
• Targeting two adjacent points on the skin overlying an artery enables measurement of the time it takes the pulse wave to travel between these two points, providing a surrogate measurement of arterial stiffness
• Targeting the chest allows for detection of skin vibrations induced by the heart pumping action. Dyssynchrony will change the vibration pattern.
B. Overall objectives
The objective of CARDIS is to investigate and demonstrate the concept of a mobile, low-cost CVD screening device based on a silicon photonics integrated laser vibrometer and to validate the concept for the screening of arterial stiffness, detection of stenosis and heart dyssynchrony.It will be met by:
• Investigating, designing and fabricating optical subsystems and components: A Photonic Integrated Chip with a multi-branch laser interferometer with integrated photo detectors and input port for an external micro-optical laser assembly, a micro-optical laser assembly, a micro-optical lens system
• Integrating the subsystems and building a multi-beam laser Doppler vibrometer. Two rows of 6 beams are envisaged.
• Developing a process flow scalable to high volumes for all subsystems and their integration steps
• Investigating and developing experimental and computational biomechanical models to translate optical signals related to skin-level vibrations into underlying CVD physiological events
• Validating the system in a clinical setting.
C. Work performed during Period 3
Demonstrator Device
A Demonstrator has been made based on the experience from a first version demonstrator device and the outcome of an earlier conducted user study.
The Demonstrator device consists of two handpiece half parts, which may be used in a connected state to measure local carotid pulse wave velocity or as separate units to measure carotid-femoral pulse wave velocity, arterial stenosis (only one handpiece half part) and cardiac contraction patterns (only one handpiece halfpart). The two handpiece half parts are tethered to an external data acquisition rack system.
The Demonstrator device has been developed, validated and released for use in a clinical feasibility study setting. As a part of the development, a risk analysis and risk mitigation process has been conducted to assure safety of the patient as well as the operator.
The demonstrator device has successfully been used in the planned clinical feasibility studies.
Biomechanical modelling
3D Computational Fluid Dynamics (CFD) simulations, resolving the flow turbulences induced by a stenosis, were performed to assess the impact of the grade of stenosis and trans-stenotic carotid flow. Simulations indicated that moderate to severe stenosis can be detected from the analysis of the power spectrum in the 50-200 Hz frequency band. These findings were confirmed by hydraulic bench simulations.
In parallel with the computational and experimental work, software was developed for the automated off-line processing of multi-beam LDV data obtained with demonstrators 1 and 2, mainly focusing on measurement of local carotid PWV. The skin acceleration, rather than displacement or velocity, was identified as the signal most suited for further processing. A data set of 100 subjects, collected at HEGP in Paris, was analyzed, yielding plausible values of local PWV in all subjects.
Clinical feasibility trials
A PWV pilot clinical study has been conducted at George Pompidou Hospital (INSERM Paris) collecting a substantial clinical dataset, 100 both from healthy subjects as well as from patients with cardiovascular conditions. The quality of the CARDIS device readings was found to be very good. Also, the measurement data and variability within sessions were in line with reference techniques showing a clear correlation.
Another clinical study was being conducted at Maastricht University Hospital to assess the capability of the CARDIS prototype to assess cardiac dyssynchrony, a parameter related to hear failure occurrence, and the preliminary results showed also a consistent accordance between the gold standard and the investigational device from this project.
Demonstrator Device
A Demonstrator has been made based on the experience from a first version demonstrator device and the outcome of an earlier conducted user study.
The Demonstrator device consists of two handpiece half parts, which may be used in a connected state to measure local carotid pulse wave velocity or as separate units to measure carotid-femoral pulse wave velocity, arterial stenosis (only one handpiece half part) and cardiac contraction patterns (only one handpiece halfpart). The two handpiece half parts are tethered to an external data acquisition rack system.
The Demonstrator device has been developed, validated and released for use in a clinical feasibility study setting. As a part of the development, a risk analysis and risk mitigation process has been conducted to assure safety of the patient as well as the operator.
The demonstrator device has successfully been used in the planned clinical feasibility studies.
Biomechanical modelling
3D Computational Fluid Dynamics (CFD) simulations, resolving the flow turbulences induced by a stenosis, were performed to assess the impact of the grade of stenosis and trans-stenotic carotid flow. Simulations indicated that moderate to severe stenosis can be detected from the analysis of the power spectrum in the 50-200 Hz frequency band. These findings were confirmed by hydraulic bench simulations.
In parallel with the computational and experimental work, software was developed for the automated off-line processing of multi-beam LDV data obtained with demonstrators 1 and 2, mainly focusing on measurement of local carotid PWV. The skin acceleration, rather than displacement or velocity, was identified as the signal most suited for further processing. A data set of 100 subjects, collected at HEGP in Paris, was analyzed, yielding plausible values of local PWV in all subjects.
Clinical feasibility trials
A PWV pilot clinical study has been conducted at George Pompidou Hospital (INSERM Paris) collecting a substantial clinical dataset, 100 both from healthy subjects as well as from patients with cardiovascular conditions. The quality of the CARDIS device readings was found to be very good. Also, the measurement data and variability within sessions were in line with reference techniques showing a clear correlation.
Another clinical study was being conducted at Maastricht University Hospital to assess the capability of the CARDIS prototype to assess cardiac dyssynchrony, a parameter related to hear failure occurrence, and the preliminary results showed also a consistent accordance between the gold standard and the investigational device from this project.
D. Progress beyond the state of the art and expected potential impact
With Medtronic, SIOS, imec, Tyndall-UCC, the Universiteit Gent, Queen Mary University of London, INSERM and the Universiteit Maastricht, CARDIS is partnering European leaders in respectively medical devices, laser interferometers, silicon photonics and arterial biomechanics.
The possibility for earlier detection of risk for CVD makes it possible to start earlier treatment. In these early stages of the disease this could be achieved simply by a change in life style and/or relatively cheap cholesterol lowering drugs, thus avoiding more complicated treatments.
CARDIS will enable Medtronic to enter a new market segment and extend its diagnostic business, currently focused on Implantable Cardiac Monitors. SIOS is a growing company and the project will enable them to enter the medical market.
The new knowledge and expertise developed by imec, UGent, Tyndall-UCC and QMUL in CARDIS will be made available to EU companies in the medical diagnostics market and other markets. It will be used to bring integrated photonics to the next level, opening its use to all kind of applications. It is the Corporate Mission of these institutions to transfer technology to industrial partners, thus creating a significant economical and societal impact.
With Medtronic, SIOS, imec, Tyndall-UCC, the Universiteit Gent, Queen Mary University of London, INSERM and the Universiteit Maastricht, CARDIS is partnering European leaders in respectively medical devices, laser interferometers, silicon photonics and arterial biomechanics.
The possibility for earlier detection of risk for CVD makes it possible to start earlier treatment. In these early stages of the disease this could be achieved simply by a change in life style and/or relatively cheap cholesterol lowering drugs, thus avoiding more complicated treatments.
CARDIS will enable Medtronic to enter a new market segment and extend its diagnostic business, currently focused on Implantable Cardiac Monitors. SIOS is a growing company and the project will enable them to enter the medical market.
The new knowledge and expertise developed by imec, UGent, Tyndall-UCC and QMUL in CARDIS will be made available to EU companies in the medical diagnostics market and other markets. It will be used to bring integrated photonics to the next level, opening its use to all kind of applications. It is the Corporate Mission of these institutions to transfer technology to industrial partners, thus creating a significant economical and societal impact.