Periodic Reporting for period 3 - ThermalMR (Thermal Magnetic Resonance: A New Instrument to Define the Role of Temperature in Biological Systems and Disease for Diagnosis and Therapy)
Periodo di rendicontazione: 2021-01-01 al 2022-06-30
Problem to be addressed:
Temperature is a physical parameter with diverse biological implications and crucial clinical relevance. With an ever increasing interest in thermal applications, non-invasive in vivo methods to modulate temperature and characterize subsequent effects are imperative. Magnetic resonance (MR) is a mainstay of diagnosis but lacks inherent means for focal thermal modulation. Ultrahigh field (UHF) MR employs higher radio frequencies (RF) than conventional MR and has unique potential to provide focal temperature manipulation and high resolution imaging (ThermalMR). Our simulations show that we can adapt an UHF-MR device to generate heat in highly focused regions of tissue by using high-density RF transmitter arrays.
Overall objectives
This new instrument will provide a revolutionary method for precise in vivo temperature manipulations. To establish high-fidelity thermal dosimetry, we will investigate pioneering strategies that exploit electrical and heat transfer tissue properties. For thermal dosage control, novel methods of MR thermometry will be developed. The capacity of ThermalMR for thermal intervention will be demonstrated in model systems. Its efficacy for drug release will be explored using new thermo-responsive nanocarriers loaded with fluorinated probes, exquisitely quantifiable with 19F MR. The applicability and safety of ThermalMR will be demonstrated in animal models followed by a feasibility study in healthy subjects. To link thermal responses of MR contrasts with molecular signatures, gene expression profiling will be performed. The aim is to understand the thermal properties of healthy and pathological tissues and explore the use of temperature modulation as a therapeutic tool.
Why is it important for society
ThermalMR will eradicate the main barriers to the study and use of temperature - a critical dimension of life that is of intense clinical interest, but so far very poorly understood. This approach opens an entirely new research field of thermal phenotyping: where physics, biology and medicine meet.
Temperature is a physical parameter with diverse biological implications and crucial clinical relevance. With an ever increasing interest in thermal applications, non-invasive in vivo methods to modulate temperature and characterize subsequent effects are imperative. Magnetic resonance (MR) is a mainstay of diagnosis but lacks inherent means for focal thermal modulation. Ultrahigh field (UHF) MR employs higher radio frequencies (RF) than conventional MR and has unique potential to provide focal temperature manipulation and high resolution imaging (ThermalMR). Our simulations show that we can adapt an UHF-MR device to generate heat in highly focused regions of tissue by using high-density RF transmitter arrays.
Overall objectives
This new instrument will provide a revolutionary method for precise in vivo temperature manipulations. To establish high-fidelity thermal dosimetry, we will investigate pioneering strategies that exploit electrical and heat transfer tissue properties. For thermal dosage control, novel methods of MR thermometry will be developed. The capacity of ThermalMR for thermal intervention will be demonstrated in model systems. Its efficacy for drug release will be explored using new thermo-responsive nanocarriers loaded with fluorinated probes, exquisitely quantifiable with 19F MR. The applicability and safety of ThermalMR will be demonstrated in animal models followed by a feasibility study in healthy subjects. To link thermal responses of MR contrasts with molecular signatures, gene expression profiling will be performed. The aim is to understand the thermal properties of healthy and pathological tissues and explore the use of temperature modulation as a therapeutic tool.
Why is it important for society
ThermalMR will eradicate the main barriers to the study and use of temperature - a critical dimension of life that is of intense clinical interest, but so far very poorly understood. This approach opens an entirely new research field of thermal phenotyping: where physics, biology and medicine meet.
The major achievements obtained during the reporting period include:
Explorations into 3D temperature distributions in model phantoms and in the human brain for high radio frequency induced heating using numerical simulations.
This research provided the theoretical framework for ThermalMR to ensure timely hardware implementation. A virtual RF applicator design suitable for translation into experimental RF applicator was provided. This provided the theoretical framework for ThermalMR and theoretical foundations for the project. This work adds to the literature by examining the capacity of ThermalMR to achieve targeted precise thermal interventions in model systems resembling human brain tissue and brain tumors.
Development of radio frequency antenna building blocks that support radio frequency induced heating, MR imaging. MR thermometry and fluorine (19F) MRI
In this work package we identified new RF antenna designs that provide best depth penetration and most efficient transmission of RF energy while balancing the competing constraints of imaging and RF induced heating. These solutions laid the groundwork for a multi-dimensional RF coil array.
Investigation of the efficacy of thermal intervention with thermo-responsive nanocarriers
To facilitate this work package we developed dedicated transmit/receive (Tx/Rx) switches that support high peak powers for MRI and high average powers for RF heating. Following the original working plan we demonstrated the feasibility of radiofrequency induced heating for controlled release of a model therapeutic from thermoresponsive nanogels in a thermal magnetic resonance feasibility study. As an outcome a manuscript was submitted.
Pioneering high-density RF coil array for RF heating, 1H MRI and 19F MRI
A high density RF array was constructed that supports 1H, MR thermometry and RF heating. The array can be adapted to 19F MRI. To achieve good anatomic coverage, high SNR and parallel imaging performance, building blocks of self-grounded bow tie antenna were redesigned and adopted in the RF array. The array’s applicability for accelerated high spatial resolution 2D FLASH CINE imaging was examined in a feasibility study in healthy volunteers.
Development of compact, near-coil, high-power RF amplifier configurations and setup of the RF chain
A majorproblem of setting up a 32 channel RF signal system was the lack of a multi-channel and scalable signal generator. For this purpose we developed a (scalable) 32-channel modular signal generator (SGPLL). Numerical temperature simulations and heating experiments controlled by the SGPLL revealed the same RF interference patterns. Upon RF heating similar temperature changes across the phantom were observed for the SGPLL and for the commercial devices.
Development of rapid MR thermometry free of image distortion
We developed a hybrid approach that integrates a RARE module and an EPI module (RARE-EPI). The feasibility was examined n phantoms mimicking brain tissue. The clinical applicability of 2in1-RARE-EPI was demonstrated in an in vivo feasibility study with healthy subjects and MS patients.
Explorations into 3D temperature distributions in model phantoms and in the human brain for high radio frequency induced heating using numerical simulations.
This research provided the theoretical framework for ThermalMR to ensure timely hardware implementation. A virtual RF applicator design suitable for translation into experimental RF applicator was provided. This provided the theoretical framework for ThermalMR and theoretical foundations for the project. This work adds to the literature by examining the capacity of ThermalMR to achieve targeted precise thermal interventions in model systems resembling human brain tissue and brain tumors.
Development of radio frequency antenna building blocks that support radio frequency induced heating, MR imaging. MR thermometry and fluorine (19F) MRI
In this work package we identified new RF antenna designs that provide best depth penetration and most efficient transmission of RF energy while balancing the competing constraints of imaging and RF induced heating. These solutions laid the groundwork for a multi-dimensional RF coil array.
Investigation of the efficacy of thermal intervention with thermo-responsive nanocarriers
To facilitate this work package we developed dedicated transmit/receive (Tx/Rx) switches that support high peak powers for MRI and high average powers for RF heating. Following the original working plan we demonstrated the feasibility of radiofrequency induced heating for controlled release of a model therapeutic from thermoresponsive nanogels in a thermal magnetic resonance feasibility study. As an outcome a manuscript was submitted.
Pioneering high-density RF coil array for RF heating, 1H MRI and 19F MRI
A high density RF array was constructed that supports 1H, MR thermometry and RF heating. The array can be adapted to 19F MRI. To achieve good anatomic coverage, high SNR and parallel imaging performance, building blocks of self-grounded bow tie antenna were redesigned and adopted in the RF array. The array’s applicability for accelerated high spatial resolution 2D FLASH CINE imaging was examined in a feasibility study in healthy volunteers.
Development of compact, near-coil, high-power RF amplifier configurations and setup of the RF chain
A majorproblem of setting up a 32 channel RF signal system was the lack of a multi-channel and scalable signal generator. For this purpose we developed a (scalable) 32-channel modular signal generator (SGPLL). Numerical temperature simulations and heating experiments controlled by the SGPLL revealed the same RF interference patterns. Upon RF heating similar temperature changes across the phantom were observed for the SGPLL and for the commercial devices.
Development of rapid MR thermometry free of image distortion
We developed a hybrid approach that integrates a RARE module and an EPI module (RARE-EPI). The feasibility was examined n phantoms mimicking brain tissue. The clinical applicability of 2in1-RARE-EPI was demonstrated in an in vivo feasibility study with healthy subjects and MS patients.
The progress beyond state of the art encompasses three major results and conclusions:
• Our work using numerical simulations adds to the literature by examining for the first time the capacity of ThermalMR to achieve targeted precise thermal interventions in model systems resembling human brain tissue and brain tumors. This is a major achievement and a class of its own. Swift translation of the RF applicator designs examined with numerical simulations into experimental prototypes remains conceptually appealing and an ambitious undertaking en route to clinical feasibility studies of thermal interventions of glioblastoma multiforme as part of the long term goal.
• The developed wideband self-grounded bow tie RF antenna building block is the first of its kind and provides electric and magnetic characteristics that support 1H and 19F (MRI), broadband thermal intervention (RF hyperthermia), and real-time therapy control (MR thermometry) in an integrated device. With this accomplishment it is to be expected that compact design can be exploited for the design of high-density RF applicators offering an increased degree of freedom based on high channel count, phase and amplitude manipulation as well as adjustable intervention frequency for each channel. Uisng the developed RF building blocks we developed and manufactured a high density RF array that supports 1H, MR thermometry and RF heating. The array can be adapted to 19F MRI.
• MRI is a vital clinical tool for diagnosis and for guiding therapy. MRI has been described as one of the most important medical innovations. Current clinical MR approaches offer no integrated means for diagnosis and thermal intervention (thermo-theranostics) inherent to the RF fields applied. Simultaneously accommodating thermal diagnostics, intervention and response control is conceptually intriguing for the pursuit personalised therapeutic approaches for better patient care and for the study of the role of temperature in biology and disease. In conclusion, our accomplishments add a thermal intervention dimension to an MR imaging device and provide an ideal testbed for the study of temperature induced release of drugs, MR probes and other agents from thermoresponsive smart carriers.
• Our work using numerical simulations adds to the literature by examining for the first time the capacity of ThermalMR to achieve targeted precise thermal interventions in model systems resembling human brain tissue and brain tumors. This is a major achievement and a class of its own. Swift translation of the RF applicator designs examined with numerical simulations into experimental prototypes remains conceptually appealing and an ambitious undertaking en route to clinical feasibility studies of thermal interventions of glioblastoma multiforme as part of the long term goal.
• The developed wideband self-grounded bow tie RF antenna building block is the first of its kind and provides electric and magnetic characteristics that support 1H and 19F (MRI), broadband thermal intervention (RF hyperthermia), and real-time therapy control (MR thermometry) in an integrated device. With this accomplishment it is to be expected that compact design can be exploited for the design of high-density RF applicators offering an increased degree of freedom based on high channel count, phase and amplitude manipulation as well as adjustable intervention frequency for each channel. Uisng the developed RF building blocks we developed and manufactured a high density RF array that supports 1H, MR thermometry and RF heating. The array can be adapted to 19F MRI.
• MRI is a vital clinical tool for diagnosis and for guiding therapy. MRI has been described as one of the most important medical innovations. Current clinical MR approaches offer no integrated means for diagnosis and thermal intervention (thermo-theranostics) inherent to the RF fields applied. Simultaneously accommodating thermal diagnostics, intervention and response control is conceptually intriguing for the pursuit personalised therapeutic approaches for better patient care and for the study of the role of temperature in biology and disease. In conclusion, our accomplishments add a thermal intervention dimension to an MR imaging device and provide an ideal testbed for the study of temperature induced release of drugs, MR probes and other agents from thermoresponsive smart carriers.