Periodic Reporting for period 4 - LASER OPTIMAL (Laser Ablation: SElectivity and monitoRing for OPTImal tuMor removAL)
Reporting period: 2022-11-01 to 2024-04-30
Minimally invasive thermal techniques represent promising therapeutic procedures, relying on the induction of controlled temperature change in tumor. In most cases, the local application of high temperature is provided to induce irreversible damage to the target cancer cells and consequently tumor apoptosis and coagulative necrosis. The optimal implementation of these minimally invasive treatments could show many advantages when compared to conventional surgical therapies. Among them, the reduction of the operative trauma would lead to the decrease of pain and the minimization of nonfunctional fibrotic scarring tissue formation, as well as the decrease of adhesions and wound dehiscence. Laser ablation, which refers to the exposure of biological tissues to near infrared laser light, represents an interesting thermal therapy for the potential management of cancer tissue, since it has shown encouraging results in solid tumors treatment, especially when associated with minimally invasive guidance techniques, e.g. the echo-endoscopy, suitable for specific and delicate organs, such as the pancreas. A key problem which has limited this technique in clinical practice could refer to the inaccurate monitoring of the ablation effects causing under-treatment (i.e. some cancerous cells still present) or over-treatment (i.e. excessive damage to adjacent healthy tissue or impairment of organ functionalities). Hence, solutions to optimize the real-time tissue damage control, and to make the treatment more selective, by means of dedicated tools for numerical simulation of the laser-tissue interaction and for improving the light absorbing properties of the target tissue are coveted. The development and optimization of these solutions are the missions of the LASER OPTIMAL project, which aims at establishing the following strategy: the use of biocompatible nanoparticles injected in the tumor, to enhance the selective absorption of laser light; the development of accurate and real-time heat-transfer model to simulate laser-tissue-nanoparticles interaction, predict and visualize the treatment dynamics; the development of measurement systems to monitor in real-time the laser effects on tissue, account for unpredictable physiological events and tune the settings. The action concluded with the achievement of all the project’s aims, proving the effectiveness of the strategic objectives on pre-clinical and clinical studies.
Within LASER OPTIMAL, the new frontiers of laser therapy for the minimally invasive treatment of cancer led the development of: measurement systems to monitor in real-time the thermal effect, to minimize the tissue damage; approaches for enhancing the selective absorption of the laser light in the tumor by using nanoparticles; simulation-based tools to predict treatment outcome.
The main achievements of LASER OPTIMAL are:
•Investigation of laser-tissue-nanoparticles interaction, from both a theoretical and experimental point of view:
- simulation of the laser-induced heating of several organs in the presence of biocompatible nanoparticles, aimed at predicting the thermal effect in the organ and tumor;
- implementation of a large campaign of in vitro experiments for evaluating biocompatibility, cytotoxicity, and photothermal effects of different biocompatible nanoparticles in pancreatic and breast tumor cell cultures, in collaboration with Mario Negri Pharmacologic Research Institute.
•Design and development of the first thermomechanical model to describe laser-tissue interaction for the patient-specific laser ablation planning platform. The model includes the optimization of laser dosimetry based on patient-specific anatomical models for the ablation of pancreatic ductal adenocarcinoma tumor. A clinical trial (in collaboration with Unit of Endoscopy of Fondazione Campus Bio-Medico di Roma) has been devised to assess the platform performance.
•Metrological assessment of different thermometry systems, including fiber optic sensors for accurate and millimeter resolved thermometry during laser ablation, and magnetic resonance-based measurement system. Development of a real-time monitoring system for closed-loop temperature feedback and therapy settings regulation and data-assimilation Bayesian framework.
•In vivo animal study in a murine model (in collaboration with the Beckman Institute at City of Hope and Mario Negri Pharmacologic Research Institute) to evaluate the thermal and biological effects of different gold nanorods for enhancing laser therapy. Two murine models of subcutaneous cancer of the breast and pancreas were studied. Studies in porcine models (at IHU-Strasbourg) were conducted to assess all the novel thermal monitoring strategies that were developed by the PI and her team at Politecnico di Milano.
All the clinical and pre-clinical studies were carried out in compliance with the EU ethical regulation and under the validation of ERCEA.
The main achievements of LASER OPTIMAL are:
•Investigation of laser-tissue-nanoparticles interaction, from both a theoretical and experimental point of view:
- simulation of the laser-induced heating of several organs in the presence of biocompatible nanoparticles, aimed at predicting the thermal effect in the organ and tumor;
- implementation of a large campaign of in vitro experiments for evaluating biocompatibility, cytotoxicity, and photothermal effects of different biocompatible nanoparticles in pancreatic and breast tumor cell cultures, in collaboration with Mario Negri Pharmacologic Research Institute.
•Design and development of the first thermomechanical model to describe laser-tissue interaction for the patient-specific laser ablation planning platform. The model includes the optimization of laser dosimetry based on patient-specific anatomical models for the ablation of pancreatic ductal adenocarcinoma tumor. A clinical trial (in collaboration with Unit of Endoscopy of Fondazione Campus Bio-Medico di Roma) has been devised to assess the platform performance.
•Metrological assessment of different thermometry systems, including fiber optic sensors for accurate and millimeter resolved thermometry during laser ablation, and magnetic resonance-based measurement system. Development of a real-time monitoring system for closed-loop temperature feedback and therapy settings regulation and data-assimilation Bayesian framework.
•In vivo animal study in a murine model (in collaboration with the Beckman Institute at City of Hope and Mario Negri Pharmacologic Research Institute) to evaluate the thermal and biological effects of different gold nanorods for enhancing laser therapy. Two murine models of subcutaneous cancer of the breast and pancreas were studied. Studies in porcine models (at IHU-Strasbourg) were conducted to assess all the novel thermal monitoring strategies that were developed by the PI and her team at Politecnico di Milano.
All the clinical and pre-clinical studies were carried out in compliance with the EU ethical regulation and under the validation of ERCEA.
LASER OPTIMAL project has been on the forefront for the development of four main methodologies which go beyond the state of the art, such as: temperature-based closed-loop of laser ablation, the first patient-specific anatomical models for the laser ablation of pancreatic ductal adenocarcinoma tumor, nanoparticle-mediated photothermal therapy for the treatment of pancreas and breast tumors, hyperspectral imaging for assessing the laser-induced thermal response in biological tissues.
The PI and the team have devised the first closed-loop platform based on fiber optic sensors, for controlling and monitoring laser thermal ablation for tumor treatment. The platform allows for the modulation of the delivered laser light based on tumor temperature. This approach guarantees efficient ablation in the desired tumor volume and precise control on the ablation margins, thus preventing thermal damage in unwanted locations of the tissue.
The PI and the team have conceived and developed the first patient-specific anatomical models for the laser ablation of pancreatic ductal adenocarcinoma tumor and has started the first clinical trial. The settings of the laser are calculated and optimized by a custom-made numerical model, in order to cover the tumor volume while spreading the healthy tissue and delicate anatomical structures around it.
The PI and the team have produced advanced work and results also in the field of nanoparticle-mediated photothermal therapy for the treatment of pancreas and breast tumors. This strategy has been applied in in vitro and in vivo models, with exceptional promises for clinical applications, due to the increased selectivity of the laser treatment.
The PI has pioneered the use of hyperspectral imaging for assessing the laser-induced thermal response in biological tissues. This approach is based on the dentification of tissue biomarkers (in the visible and near infrared ranges) which are temperature dependent. The imaging technique allows combination of spatial and spectral tissue/tumor information, so to provide the spectral fingerprint of the thermally damaged tissue. The team proved the concept, and this imaging modality was used to predict the thermal effect achieved in living tissues.
The PI and the team have devised the first closed-loop platform based on fiber optic sensors, for controlling and monitoring laser thermal ablation for tumor treatment. The platform allows for the modulation of the delivered laser light based on tumor temperature. This approach guarantees efficient ablation in the desired tumor volume and precise control on the ablation margins, thus preventing thermal damage in unwanted locations of the tissue.
The PI and the team have conceived and developed the first patient-specific anatomical models for the laser ablation of pancreatic ductal adenocarcinoma tumor and has started the first clinical trial. The settings of the laser are calculated and optimized by a custom-made numerical model, in order to cover the tumor volume while spreading the healthy tissue and delicate anatomical structures around it.
The PI and the team have produced advanced work and results also in the field of nanoparticle-mediated photothermal therapy for the treatment of pancreas and breast tumors. This strategy has been applied in in vitro and in vivo models, with exceptional promises for clinical applications, due to the increased selectivity of the laser treatment.
The PI has pioneered the use of hyperspectral imaging for assessing the laser-induced thermal response in biological tissues. This approach is based on the dentification of tissue biomarkers (in the visible and near infrared ranges) which are temperature dependent. The imaging technique allows combination of spatial and spectral tissue/tumor information, so to provide the spectral fingerprint of the thermally damaged tissue. The team proved the concept, and this imaging modality was used to predict the thermal effect achieved in living tissues.