Final Report Summary - OILTEBIA (Optical Imaging and Laser TEchniques for BIomedical Applications)
The overall aim of the OILTEBIA (Optical Imaging and Laser TEchniques for BIomedical Applications, (http://www.uc3m.es/oiltebia) is to provide advance training to early stage researchers(ESR) in novel biomedical optical imaging and laser techniques for applications spanning from basic research and drug discovery to pre-clinical imaging and clinical translation. The duration of the project has been 4 years and commenced on 01/04/2013. The consortium is a multidisciplinary partnership of 10 beneficiaries.
FELLOW AND TRAINING
The network was formed by 12 early stage researches (ESR) recruited in the first 13 months. All of them were enrolled in PhD programs. Three of these ESRs have finished their PhD thesis and the other three thesis will be completed this year. The remaining thesis (5) will be presented the next year. One ESR submit his PhD project for a Marie Skłodowska-Curie Award (MSCA).
Every year the planned training events were organized inside the network hosted by different partners: 3 summer schools, 4 laboratory training platforms and 3 industrial involvement workshops. During these events 45 international experts gave lectures. In addition, some of these events were open to external audience. A total of 195 researchers outside the network attended these events.
DISSEMINATIONS
The results of the project have been presented in different publications: 18 peer-reviewed papers in high impact factor Journals, and 44 conference papers. In addition, Fellows and PIs have presented invited talks and presentations in international conferences and workshops all around the world advancing the OILTEBIA outreach and dissemination results by PIs and Fellows.
About outreach several activities was carry out in the project: Summer School with open visits, Workshop offered to high school and university students, participation in local promoting research events, disseminations on national TVs, open days and youtube videos. These multiples outreach activities have allowed to improve the general public knowledge of activities in OILTEBIA project, also the interaction between this public and the ESR have served as training and improve their communication skills with a non-specialist collective.
SCIENTIFIC ACHIEVEMENTS:
The research program goal was the development or improvement of novel optical probes and non-invasive or minimally invasive optical tomographic techniques. The scientific achievements are divided in the four research lines of the project:
1. New optical sources based on diode lasers have been developed for photoacoustic imaging and microscopy:
- An active mode-locking tunable laser 30 nm in the 850 nm range with pulses of few ps.
- Two different multiwavelength systems based on lateral multiplexing using a fiber bundle of high power diode lasers: One uses gain-switching technique generating sub-ns pulses of 1 µJ at 650 nm, 808 nm, 850 nm and 905 nm. The other relies on direct high current pulse sources to generate 15 µJ per wavelength and 75 ns pulse duration at 808nm, 870nm, 905nm and 970nm. Both systems are capable of very high repetition above 1 kHz.
- A new digital FPGA-based control electronics for phase control in a gain switching laser system for high power sub-nanosecond diode lasers.
2. New sensors and instrumentation systems for optical imaging techniques:
- A complete set of studies related to the ad hoc control of the propagation of light in scattering media with adaptive wavefront shaping and specific photonic structures has been developed for improvement of optical microscopy systems beyond their limits when imaging turbid media such as tissue.
- Development of new photoacoustic sensors base in cMUT (Capacitive micromachined ultrasonic transducers) technology. The broadband directivity and sensitivity of a cMUT transducer were characterized and compared to a conventional PZT transducer. The cMUT transducers sensitivity was significantly less angle-depended and outperformed the PZTs sensitivity for angles larger than 20° what has an important impact in optoacoustic imaging.
- Development a new imaging concept utilizing a frequency-tunable ultrasonic sensor based on CMUTs. An intracardiac catheter prototype having a diameter of 4-mm was demonstrated.
- A novel all-optical interconnect solution has been demonstrated for ultrasound imaging catheters to increase the level of integration, lower their costs and to enable magnetic resonance compatible and radiofrequency interference-less in-body ultrasound imaging. It is based on utilizing a LED for both the signal and power transmission in catheters.
- Next generation hybrid Diffuse Correlation Spectroscopy (DCS) and Time Resolved Spectroscopy (TRS) systems to study traumatic brain injuries and a dedicated DCS device and head probe to functional neuroimaging in infants was developed.
3. New algorithms for biomedical imaging applications:
- A new DCS/NIRS system has been developed, consist in a user-friendly, real-time data acquisition and analysis software. This device will enable the clinicians to operate the system without trained technical personnel present which will allow to study larger clinical populations under more challenging scenarios.
- New algorithms to model light propagation through biological tissue with increased optical complexity by implementing Monte Carlo (MC) approaches in GPU parallel processing platforms. Using MC methods low scattering regions can be accurately simulated in details enabling us to set a realistic comparison between the models, and draw conclusions on the importance of modelling the clear layer regions.
- A real-time phase retrieval algorithm for imaging hidden objects in turbid media was developed based on a Gerchberg-Saxton phase-retrieval algorithm applied in through dimensions for the reconstruction of data obtained from an in-house developed hybrid Optical Projection Tomography and Light Sheet Fluorescence Tomography system (OPT/LSFM). We have thus demonstrated that increased resolution can be achieved beyond the one transport mean free path limit of scattering.
- An imaging system forward model for both Optoacoustic and Ultrasound imaging was developed. The models have been employed for evaluation and characterization of the imaging system performance and as imaging operator for model based image reconstruction.
-Improvements to a novel Opto-Acoustic Microscope design with hybrid optical and acoustic resolution (HFOAM) system was carried out: dual-wavelength optics for functional imaging; reduced system preparation time from several hours to less than 30 minutes; improving in imaging time acquisition; improved image quality, due to better post processing.
4. Experimental studies on phantoms, small animals and clinical studies:
- The new NIRS/DCS device has been tested on phantoms and their performance has been satisfactory. Studies Measurements on healthy subjects was performed. The device will be moved to the hospital for measuring patients.
- MC Algorithms have been tested using realistic tissue-simulating phantoms. The anatomical structures are based on a highly detailed and accurate digital phantom which is composed by reconstructing images, obtained from slices of a mouse head cryosection block.
- The forward model for hybrid Optoacoustic/Ultrasound imaging was validated experimentally using a developed synthetic imaging system.
- A clinical prototype for broadband time-domain diffuse optics was developed and successfully validated on Phantom protocols. It was used to investigate new chromophore useful for clinical diagnostics.
- The HFOAM system was used for investigation of ultrasound propagation in and trough murine skull and in vivo mouse imaging.
- The multispectral diode laser system was used for optoacoustic spectroscopic measurements of phantoms with embedded nanoparticles.
- The feasibility of the frequency tuning cMUT concept was demonstrated in a preliminary phantom study.
SOCIO-ECONOMIC POTENTIAL IMPACT
Given the myriad of scientific results obtained in the OILTEBIA project in the non-invasive biomedical imaging field an important social and economic impact is foreseen. For instance, the DCS/NIRS system improved during the OILTEBIA project is planned to be used in traumatic brain injuries monitoring and was already tested for emergency room continuous monitoring of the ischemic stroke patients with and without rtPA treatment and hemodynamic studies in obstructive sleep apnea cases. These studies were largely impossible or very difficult without these developed improvements. Also, the dedicated DCS device and head probe permits to study functional activation following auditory stimulation in infants.
The investigation on new chromophore is useful for clinical diagnostics. In particular, the spectra of thyrosin and thyroglobulin in the 600-1200 nm range were derived for the first time. These findings can offer new diagnostic paths for monitoing thyroid.
Some of the new optoacoustic systems developed or enhanced in the framework of the OILTEBIA project allows non-invasive functional brain imaging of small animals potentionally improving neuroscience research in general.
The studies of cMUT sensors is a first step in their integration in an hybrid optoacoustic/ultrasonic intravascular catheter. This new kind of probe will allow to complement the morphological information of current intravascular ultrasound (IVUS) systems with spectroscopy information that will provide specificity that allow to distiguish between the different constituents of the atheroma plaques.
Finally, the diode laser sources for photoacoustic generation will reduce the costs, complexity and maintenaice of photoacoustic systems. This is one of the primary reasons that limits the penetration of this technology in the clinical practice.
CONCLUSION
In conclusion, the OILTEBIA project has been a multidisciplinary framework for the successful training of all ESR fellows in new biomedical imaging techniques. The training has been carry out not only in each host institution but through several annual events that promotes the synergies between the fellows.
The OILTEBIA project has provided an important work on research and development of the hardware and software associated to optical imagining techniques. We expect that our new optical imaging techniques will enable early stage diagnosis. In clinical settings, the management of important diseases such as stroke and head-trauma as well as cancer therapy could be drastically improved.
OILTEBIA web site: http://gdo.uc3m.es/oiltebia
FELLOW AND TRAINING
The network was formed by 12 early stage researches (ESR) recruited in the first 13 months. All of them were enrolled in PhD programs. Three of these ESRs have finished their PhD thesis and the other three thesis will be completed this year. The remaining thesis (5) will be presented the next year. One ESR submit his PhD project for a Marie Skłodowska-Curie Award (MSCA).
Every year the planned training events were organized inside the network hosted by different partners: 3 summer schools, 4 laboratory training platforms and 3 industrial involvement workshops. During these events 45 international experts gave lectures. In addition, some of these events were open to external audience. A total of 195 researchers outside the network attended these events.
DISSEMINATIONS
The results of the project have been presented in different publications: 18 peer-reviewed papers in high impact factor Journals, and 44 conference papers. In addition, Fellows and PIs have presented invited talks and presentations in international conferences and workshops all around the world advancing the OILTEBIA outreach and dissemination results by PIs and Fellows.
About outreach several activities was carry out in the project: Summer School with open visits, Workshop offered to high school and university students, participation in local promoting research events, disseminations on national TVs, open days and youtube videos. These multiples outreach activities have allowed to improve the general public knowledge of activities in OILTEBIA project, also the interaction between this public and the ESR have served as training and improve their communication skills with a non-specialist collective.
SCIENTIFIC ACHIEVEMENTS:
The research program goal was the development or improvement of novel optical probes and non-invasive or minimally invasive optical tomographic techniques. The scientific achievements are divided in the four research lines of the project:
1. New optical sources based on diode lasers have been developed for photoacoustic imaging and microscopy:
- An active mode-locking tunable laser 30 nm in the 850 nm range with pulses of few ps.
- Two different multiwavelength systems based on lateral multiplexing using a fiber bundle of high power diode lasers: One uses gain-switching technique generating sub-ns pulses of 1 µJ at 650 nm, 808 nm, 850 nm and 905 nm. The other relies on direct high current pulse sources to generate 15 µJ per wavelength and 75 ns pulse duration at 808nm, 870nm, 905nm and 970nm. Both systems are capable of very high repetition above 1 kHz.
- A new digital FPGA-based control electronics for phase control in a gain switching laser system for high power sub-nanosecond diode lasers.
2. New sensors and instrumentation systems for optical imaging techniques:
- A complete set of studies related to the ad hoc control of the propagation of light in scattering media with adaptive wavefront shaping and specific photonic structures has been developed for improvement of optical microscopy systems beyond their limits when imaging turbid media such as tissue.
- Development of new photoacoustic sensors base in cMUT (Capacitive micromachined ultrasonic transducers) technology. The broadband directivity and sensitivity of a cMUT transducer were characterized and compared to a conventional PZT transducer. The cMUT transducers sensitivity was significantly less angle-depended and outperformed the PZTs sensitivity for angles larger than 20° what has an important impact in optoacoustic imaging.
- Development a new imaging concept utilizing a frequency-tunable ultrasonic sensor based on CMUTs. An intracardiac catheter prototype having a diameter of 4-mm was demonstrated.
- A novel all-optical interconnect solution has been demonstrated for ultrasound imaging catheters to increase the level of integration, lower their costs and to enable magnetic resonance compatible and radiofrequency interference-less in-body ultrasound imaging. It is based on utilizing a LED for both the signal and power transmission in catheters.
- Next generation hybrid Diffuse Correlation Spectroscopy (DCS) and Time Resolved Spectroscopy (TRS) systems to study traumatic brain injuries and a dedicated DCS device and head probe to functional neuroimaging in infants was developed.
3. New algorithms for biomedical imaging applications:
- A new DCS/NIRS system has been developed, consist in a user-friendly, real-time data acquisition and analysis software. This device will enable the clinicians to operate the system without trained technical personnel present which will allow to study larger clinical populations under more challenging scenarios.
- New algorithms to model light propagation through biological tissue with increased optical complexity by implementing Monte Carlo (MC) approaches in GPU parallel processing platforms. Using MC methods low scattering regions can be accurately simulated in details enabling us to set a realistic comparison between the models, and draw conclusions on the importance of modelling the clear layer regions.
- A real-time phase retrieval algorithm for imaging hidden objects in turbid media was developed based on a Gerchberg-Saxton phase-retrieval algorithm applied in through dimensions for the reconstruction of data obtained from an in-house developed hybrid Optical Projection Tomography and Light Sheet Fluorescence Tomography system (OPT/LSFM). We have thus demonstrated that increased resolution can be achieved beyond the one transport mean free path limit of scattering.
- An imaging system forward model for both Optoacoustic and Ultrasound imaging was developed. The models have been employed for evaluation and characterization of the imaging system performance and as imaging operator for model based image reconstruction.
-Improvements to a novel Opto-Acoustic Microscope design with hybrid optical and acoustic resolution (HFOAM) system was carried out: dual-wavelength optics for functional imaging; reduced system preparation time from several hours to less than 30 minutes; improving in imaging time acquisition; improved image quality, due to better post processing.
4. Experimental studies on phantoms, small animals and clinical studies:
- The new NIRS/DCS device has been tested on phantoms and their performance has been satisfactory. Studies Measurements on healthy subjects was performed. The device will be moved to the hospital for measuring patients.
- MC Algorithms have been tested using realistic tissue-simulating phantoms. The anatomical structures are based on a highly detailed and accurate digital phantom which is composed by reconstructing images, obtained from slices of a mouse head cryosection block.
- The forward model for hybrid Optoacoustic/Ultrasound imaging was validated experimentally using a developed synthetic imaging system.
- A clinical prototype for broadband time-domain diffuse optics was developed and successfully validated on Phantom protocols. It was used to investigate new chromophore useful for clinical diagnostics.
- The HFOAM system was used for investigation of ultrasound propagation in and trough murine skull and in vivo mouse imaging.
- The multispectral diode laser system was used for optoacoustic spectroscopic measurements of phantoms with embedded nanoparticles.
- The feasibility of the frequency tuning cMUT concept was demonstrated in a preliminary phantom study.
SOCIO-ECONOMIC POTENTIAL IMPACT
Given the myriad of scientific results obtained in the OILTEBIA project in the non-invasive biomedical imaging field an important social and economic impact is foreseen. For instance, the DCS/NIRS system improved during the OILTEBIA project is planned to be used in traumatic brain injuries monitoring and was already tested for emergency room continuous monitoring of the ischemic stroke patients with and without rtPA treatment and hemodynamic studies in obstructive sleep apnea cases. These studies were largely impossible or very difficult without these developed improvements. Also, the dedicated DCS device and head probe permits to study functional activation following auditory stimulation in infants.
The investigation on new chromophore is useful for clinical diagnostics. In particular, the spectra of thyrosin and thyroglobulin in the 600-1200 nm range were derived for the first time. These findings can offer new diagnostic paths for monitoing thyroid.
Some of the new optoacoustic systems developed or enhanced in the framework of the OILTEBIA project allows non-invasive functional brain imaging of small animals potentionally improving neuroscience research in general.
The studies of cMUT sensors is a first step in their integration in an hybrid optoacoustic/ultrasonic intravascular catheter. This new kind of probe will allow to complement the morphological information of current intravascular ultrasound (IVUS) systems with spectroscopy information that will provide specificity that allow to distiguish between the different constituents of the atheroma plaques.
Finally, the diode laser sources for photoacoustic generation will reduce the costs, complexity and maintenaice of photoacoustic systems. This is one of the primary reasons that limits the penetration of this technology in the clinical practice.
CONCLUSION
In conclusion, the OILTEBIA project has been a multidisciplinary framework for the successful training of all ESR fellows in new biomedical imaging techniques. The training has been carry out not only in each host institution but through several annual events that promotes the synergies between the fellows.
The OILTEBIA project has provided an important work on research and development of the hardware and software associated to optical imagining techniques. We expect that our new optical imaging techniques will enable early stage diagnosis. In clinical settings, the management of important diseases such as stroke and head-trauma as well as cancer therapy could be drastically improved.
OILTEBIA web site: http://gdo.uc3m.es/oiltebia