Preliminary Results of Laser Ablation during In Vivo Experiments: Comparison of Thermal Effects Obtained with Bare and Diffuser Tip Applicators.

This work is a step towards the analysis of the effect of different laser applicator tips used for laser ablation of liver for in vivo experiments. As the thermal outcome of this minimally invasive treatment for tumors depends upon the interaction between the tissue and the light, the emission pattern of the laser applicator has a key role in the shape and size of the final treated region. Hence, we have compared two different laser applicators: a bare tip fiber (emitting light from the tip and forward) and a diffuser tip fiber (emitting light at 360° circumferentially from the side of the fiber). The experiments have been carried out percutaneously in a preclinical scenario (anesthetized pigs), under computed tomography (CT) guidance. The thermal effects of the two applicators have been assessed in terms of real-time temperature distribution, by means of an array of 40 fiber Bragg grating (FBG) sensors, and in terms of cavitation and ablation volumes, measured through CT post-temperature due to breathing motion has been analyzed and filtered out. Results show that the maximum temperature reached 50.5 °C for the bare tip fiber experiment (measured at 6.24 mm distance from the applicator) and 60.9 °C for the diffuser tip fiber experiment (measured at 5.23 mm distance from the applicator). The diffuser tip fiber allowed to achieve a more symmetrical heat distribution than the bare tip fiber, and without cavitation volume.Clinical Relevance-This work shows the analysis of the thermal effects of different laser fiber tips to improve laser ablation treatment. The results obtained in the preclinical scenario well represent the expected clinical outcome in the treatment of hepatic tumors. Moreover, these findings can be applied to other fields in which laser ablation is the optimal therapeutic choice, such as neurosurgery.

In Vitro Antibody Quantification with Hyperspectral Imaging in a Large Field of View for Clinical Applications.

Hyperspectral imaging (HSI) is a non-invasive, contrast-free optical-based tool that has recently been applied in medical and basic research fields. The opportunity to use HSI to identify exogenous tumor markers in a large field of view (LFOV) could increase precision in oncological diagnosis and surgical treatment. In this study, the anti-high mobility group B1 (HMGB1) labeled with Alexa fluorophore (647 nm) was used as the target molecule. This is the proof-of-concept of HSI's ability to quantify antibodies via an in vitro setting. A first test was performed to understand whether the relative absorbance provided by the HSI camera was dependent on volume at a 1:1 concentration. A serial dilution of 1:1, 10, 100, 1000, and 10,000 with phosphatase-buffered saline (PBS) was then used to test the sensitivity of the camera at the minimum and maximum volumes. For the analysis, images at 640 nm were extracted from the hypercubes according to peak signals matching the specificities of the antibody manufacturer. The results showed a positive correlation between relative absorbance and volume (r = 0.9709, p = 0.0013). The correlation between concentration and relative absorbance at min (1 µL) and max (20 µL) volume showed r = 0.9925, p < 0.0001, and r = 0.9992, p < 0.0001, respectively. These results demonstrate the HSI potential in quantifying HMGB1, hence deserving further studies in ex vivo and in vivo settings.

Characterization of susceptibility artifacts in magnetic resonance thermometry images during laser interstitial thermal therapy: dimension analysis and temperature error estimation.

Objective.Laser interstitial thermal therapy (LITT) is a minimally invasive procedure used to treat a lesion through light irradiation and consequent temperature increase. Magnetic resonance thermometry imaging (MRTI) provides a multidimensional measurement of the temperature inside the target, thus enabling accurate monitoring of the damaged zone during the procedure. In proton resonance frequency shift-based thermometry, artifacts in the images may strongly interfere with the estimated temperature maps. In our work, after noticing the formation of the dipolar-behavior artifact linkable to magnetic susceptibility changes duringin vivoLITT, an investigation of susceptibility artifacts in tissue-mimicking phantoms was implemented.Approach.The artifact was characterized: (i) by measuring the area and total volume of error regions and their evolution during the treatment; and (ii) by comparison with temperature reference provided by three temperature sensing needles. Lastly, a strategy to avoid artifacts formation was devised by using the temperature-sensing needles to implement a temperature-controlled LITT.Main results.The artifact appearance was associated with gas bubble formation and with unwanted treatment effects producing magnetic susceptibility changes when 2 W laser power was set. The analysis of the artifact's dimension demonstrated that in the sagittal plane the dipolar-shape artifact may consistently spread following the temperature trend until reaching a volume 8 times bigger than the ablated one. Also, the artifact shape is quite symmetric with respect to the laser tip. An absolute temperature error showing a negative Gaussian profile in the area of susceptibility artifact with values up to 64.4 °C was estimated. Conversely, a maximum error of 2.8 °C is measured in the area not-affected by artifacts and far from the applicator tip. Finally, by regulating laser power, susceptibility artifacts formation was avoided, and appreciable thermal damage was induced.Significance.These findings may help in improving the MRTI-based guidance of thermal therapies.

Gold Nanoparticles-Mediated Photothermal Therapy of Pancreas Using GATE: A New Simulation Platform.

This work presents the first investigation of gold nanorods (GNRs)-based photothermal therapy of the pancreas tumor using the Monte Carlo-based code implemented with Geant4 Application for Emission Tomography (GATE). The model of a human pancreas was obtained by segmenting an abdominal computed tomography (CT) scan, and its physical and chemical properties, were obtained from experimental and theoretical data. In GATE, GNRs-mediated hyperthermal therapy, simple heat diffusion as well as interstitial laser ablation were then modeled in the pancreas tumor by defining the optical parameters of this tissue when it is loaded with GNRs. Two different experimental setups on ex vivo pancreas tissue and GNRs-embedded water were devised to benchmark the developed Monte Carlo-based model for the hyperthermia in the pancreas alone and with GNRs, respectively. The influence of GNRs on heat distribution and temperature increase within the pancreas tumor was compared for two different power values (1.2 W and 2.1 W) when the tumor was exposed to 808 nm laser irradiation and with two different laser applicator diameters. Benchmark tests demonstrated the possibility of the accurate simulating of NPs-assisted thermal therapy and reproducing the experimental data with GATE software. Then, the output of the simulated GNR-mediated hyperthermia emphasized the importance of the precise evaluation of all of the parameters for optimizing the preplanning of cancer thermal therapy. Simulation results on temperature distribution in the pancreas tumor showed that the temperature enhancement caused by raising the power was increased with time in both the tumor with and without GNRs, but it was higher for the GNR-load tumor compared to tumor alone.

Feedback-controlled laser ablation for cancer treatment: comparison of On-Off and PID control strategies.

Laser ablation is a rising technique used to induce a localized temperature increment for tumor ablation. The outcomes of the therapy depend on the tissue thermal history. Monitoring devices help to assess the tissue thermal response, and their combination with a control strategy can be used to promptly address unexpected temperature changes and thus reduce unwanted thermal effects. In this application, numerical simulations can drive the selection of the laser control settings (i.e., laser power and gain parameters) and allow evaluating the thermal effects of the control strategies. In this study, the influence of different control strategies (On-Off and PID-based controls) is quantified considering the treatment time and the thermal effect on the tissue. Finite element model-based simulations were implemented to model the laser-tissue interaction, the heat-transfer, and the consequent thermal damage in liver tissue with tumor. The laser power was modulated based on the temperature feedback provided within the tumor safety margin. Results show that the chosen control strategy does not have a major influence on the extent of thermal damage but on the treatment duration; the percentage of necrosis within the tumor domain is 100% with both strategies, while the treatment duration is 630 s and 786 s for On-Off and PID, respectively. The choice of the control strategy is a trade-off between treatment duration and unwanted temperature overshoot during closed-loop laser ablation. Clinical Relevance-This work establishes that different temperature-based control of the laser ablation procedure does not have a major influence on the extent of thermal damage but on the duration of treatment.

Analysis of cavitation artifacts in Magnetic Resonance Imaging Thermometry during laser ablation monitoring.

Magnetic Resonance Thermometry Imaging (MRTI) holds great potential in laser ablation (LA) monitoring. It provides the real-time multidimensional visualization of the treatment effect inside the body, thus enabling accurate intraoperative prediction of the thermal damage induced. Despite its great potential., thermal maps obtained with MRTI may be affected by numerous artifacts. Among the sources of error producing artifacts in the images., the cavitation phenomena which could occur in the tissue during LA induces dipole-structured artifacts. In this work., an analysis of the cavitation artifacts occurring during LA in a gelatin phantom in terms of symmetry in space and symmetry of temperature values was performed. Results of 2 Wand 4 W laser power were compared finding higher symmetry for the 2 W case in terms of both dimensions of artifact-lobes and difference in temperature values extracted in specular pixels in the image. This preliminary investigation of artifact features may provide a step forward in the identification of the best strategy to correct and avoid artifact occurrence during thermal therapy monitoring. Clinical Relevance- This work presents an analysis of cavitation artifacts in MRTI from LA which must be corrected to avoid error in the prediction of thermal damage during LA monitoring.

Estimation of porcine pancreas optical properties in the 600-1100 nm wavelength range for light-based therapies.

This work reports the optical properties of porcine pancreatic tissue in the broad wavelength range of 600-1100 nm. Absorption and reduced scattering coefficients (µa and µs') of the ex vivo pancreas were obtained by means of Time-domain Diffuse Optical Spectroscopy. We have investigated different experimental conditions-including compression, repositioning, spatial sampling, temporal stability-the effect of the freezing procedure (fresh vs frozen-thawed pancreas), and finally inter-sample variability. Good repeatability under different experimental conditions was obtained (median coefficient of variation less than 8% and ~ 16% for µa and µs', respectively). Freezing-thawing the samples caused an irreversible threefold reduction of µs' and no effect on µa. The absorption and reduced scattering spectra averaged over different samples were in the range of 0.12-0.74 cm-1 and 12-21 cm-1 with an inter-sample variation of ~ 10% and ~ 40% for µa and µs', respectively. The calculated effective transport coefficient (µeff) for fresh pancreatic tissue shows that regions between 800-900 nm and 1050-1100 nm are similar and offer the lowest tissue attenuation in the considered range (i.e., µeff ranging from 2.4 to 2.7 cm-1). These data, describing specific light-pancreas interactions in the therapeutic optical window for the first time, provide pivotal information for planning of light-based thermotherapies (e.g., laser ablation) and instruction of light transport models for biophotonic applications involving this organ.

Thermomechanical Modeling of Laser Ablation Therapy of Tumors: Sensitivity Analysis and Optimization of Influential Variables.

In cancer treatment, laser ablation is a promising technique used to induce localized thermal damage. Different variables influence the temperature distribution in the tissue and the resulting therapy efficacy; thus, the optimal therapy settings are required for obtaining the desired clinical outcome. In this work, thermomechanical modeling of contactless laser ablation was implemented to analyze the sensitivity of independent variables on the optimal treatment conditions. The Finite Element Method was utilized to solve the governing equations, i.e., the bioheat, mechanical deformation, and the Navier-Stokes equations. Validation of the model was performed by comparing experimental and simulated temperatures, which indicated high accuracy for estimating temperature. In particular, the results showed that the model can estimate temperature with a good correlation factor (R = 0.98) and low Mean Absolute Error (3.9 °C). A sensitivity analysis based on laser irradiation time, power, beam distribution, and the blood vessel depth on temperature distribution and fraction of necrotic tissue was performed. An optimization process was performed based on the most significant variables, i.e., laser irradiation time and power. This resulted in an indication of the optimal therapy settings for achieving maximum procedure efficiency i.e., the required fraction of necrotic tissue within the target volume, constituted by tumor and safety margins around it.

Prediction of In Vivo Laser-Induced Thermal Damage with Hyperspectral Imaging Using Deep Learning.

Thermal ablation is an acceptable alternative treatment for primary liver cancer, of which laser ablation (LA) is one of the least invasive approaches, especially for tumors in high-risk locations. Precise control of the LA effect is required to safely destroy the tumor. Although temperature imaging techniques provide an indirect measurement of the thermal damage, a degree of uncertainty remains about the treatment effect. Optical techniques are currently emerging as tools to directly assess tissue thermal damage. Among them, hyperspectral imaging (HSI) has shown promising results in image-guided surgery and in the thermal ablation field. The highly informative data provided by HSI, associated with deep learning, enable the implementation of non-invasive prediction models to be used intraoperatively. Here we show a novel paradigm "peak temperature prediction model" (PTPM), convolutional neural network (CNN)-based, trained with HSI and infrared imaging to predict LA-induced damage in the liver. The PTPM demonstrated an optimal agreement with tissue damage classification providing a consistent threshold (50.6 ± 1.5 °C) for the damage margins with high accuracy (~0.90). The high correlation with the histology score (r = 0.9085) and the comparison with the measured peak temperature confirmed that PTPM preserves temperature information accordingly with the histopathological assessment.

Quasi-distributed fiber optic sensor-based control system for interstitial laser ablation of tissue: theoretical and experimental investigations.

This work proposes the quasi-distributed real-time monitoring and control of laser ablation (LA) of liver tissue. To confine the thermal damage, a pre-planning stage of the control strategy based on numerical simulations of the bioheat-transfer was developed to design the control parameters, then experimentally assessed. Fiber Bragg grating (FBG) sensors were employed to design the automatic thermometry system used for temperature feedback control for interstitial LA. The tissue temperature was maintained at a pre-set value, and the influence of different sensor locations (on the direction of the beam propagation and backward) on the thermal outcome was evaluated in comparison with the uncontrolled case. Results show that the implemented computational model was able to properly describe the temperature evolution of the irradiated tissue. Furthermore, the realized control strategy allowed for the accurate confinement of the laser-induced temperature increase, especially when the temperature control was actuated by sensors located in the direction of the beam propagation, as confirmed by the calculated fractions of necrotic tissues (e.g., 23 mm3 and 53 mm3 for the controlled and uncontrolled LA, respectively).

Hyperspectral Imagery for Assessing Laser-Induced Thermal State Change in Liver.

This work presents the potential of hyperspectral imaging (HSI) to monitor the thermal outcome of laser ablation therapy used for minimally invasive tumor removal. Our main goal is the establishment of indicators of the thermal damage of living tissues, which can be used to assess the effect of the procedure. These indicators rely on the spectral variation of temperature-dependent tissue chromophores, i.e., oxyhemoglobin, deoxyhemoglobin, methemoglobin, and water. Laser treatment was performed at specific temperature thresholds (from 60 to 110 °C) on in-vivo animal liver and was assessed with a hyperspectral camera (500-995 nm) during and after the treatment. The indicators were extracted from the hyperspectral images after the following processing steps: the breathing motion compensation and the spectral and spatial filtering, the selection of spectral bands corresponding to specific tissue chromophores, and the analysis of the areas under the curves for each spectral band. Results show that properly combining spectral information related to deoxyhemoglobin, methemoglobin, lipids, and water allows for the segmenting of different zones of the laser-induced thermal damage. This preliminary investigation provides indicators for describing the thermal state of the liver, which can be employed in the future as clinical endpoints of the procedure outcome.

Fiber Optic Sensors-Based Thermal Analysis of Perfusion-Mediated Tissue Cooling in Liver Undergoing Laser Ablation.

The current challenge in the field of thermo-ablative treatments of tumors is to achieve a balance between complete destruction of malignant cells and safeguarding of the surrounding healthy tissue. Blood perfusion plays a key role for thermal ablation success, especially in the case of highly vascularized organs like liver. This work aims at monitoring the temperature within perfused swine liver undergoing laser ablation (LA). Temperature was measured through seven arrays of Fiber Bragg Grating sensors (FBGs) around the laser applicator. To mimic reality, blood perfusion within the ex-vivo liver was simulated using artificial vessels. The influence of blood perfusion on LA was carried out by comparing the temperature profiles in two different spatial configurations of vessels and fibers. The proposed setup permitted to accurately measure the heat propagation in real-time with a temperature resolution of 0.1 °C and to observe a relevant tissue cooling near to the vessel up to 65%.

Laser-induced optothermal response of gold nanoparticles: From a physical viewpoint to cancer treatment application.

Gold nanoparticles (GNPs)-based photothermal therapy (PTT) is a promising minimally invasive thermal therapy for the treatment of focal malignancies. Although GNPs-based PTT has been known for over two decades and GNPs possess unique properties as therapeutic agents, the delivery of a safe and effective therapy is still an open question. This review aims at providing relevant and recent information on the usage of GNPs in combination with the laser to treat cancers, pointing out the practical aspects that bear on the therapy outcome. Emphasis is given to the assessment of the GNPs' properties and the physical mechanisms underlying the laser-induced heat generation in GNPs-loaded tissues. The main techniques available for temperature measurement and the current theoretical simulation approaches predicting the therapeutic outcome are reviewed. Topical challenges in delivering safe thermal dosage are also presented with the aim to discuss the state-of-the-art and the future perspective in the field of GNPs-mediated PTT.

Closed-Loop Temperature Control Based on Fiber Bragg Grating Sensors for Laser Ablation of Hepatic Tissue.

Laser ablation (LA) of cancer is a minimally invasive technique based on targeted heat release. Controlling tissue temperature during LA is crucial to achieve the desired therapeutic effect in the organs while preserving the healthy tissue around. Here, we report the design and implementation of a real-time monitoring system performing closed-loop temperature control, based on fiber Bragg grating (FBG) spatial measurements. Highly dense FBG arrays (1.19 mm length, 0.01 mm edge-to-edge distance) were inscribed in polyimide-coated fibers using the femtosecond point-by-point writing technology to obtain the spatial resolution needed for accurate reconstruction of high-gradient temperature profiles during LA. The zone control strategy was implemented such that the temperature in the laser-irradiated area was maintained at specific set values (43 and 55 °C), in correspondence to specific radii (2 and 6 mm) of the targeted zone. The developed control system was assessed in terms of measured temperature maps during an ex vivo liver LA. Results suggest that the temperature-feedback system provides several advantages, including controlling the margins of the ablated zone and keeping the maximum temperature below the critical values. Our strategy and resulting analysis go beyond the state-of-the-art LA regulation techniques, encouraging further investigation in the identification of the optimal control-loop.

Fiber Bragg Grating Sensors for Performance Evaluation of Fast Magnetic Resonance Thermometry on Synthetic Phantom.

The increasing recognition of minimally invasive thermal treatment of tumors motivate the development of accurate thermometry approaches for guaranteeing the therapeutic efficacy and safety. Magnetic Resonance Thermometry Imaging (MRTI) is nowadays considered the gold-standard in thermometry for tumor thermal therapy, and assessment of its performances is required for clinical applications. This study evaluates the accuracy of fast MRTI on a synthetic phantom, using dense ultra-short Fiber Bragg Grating (FBG) array, as a reference. Fast MRTI is achieved with a multi-slice gradient-echo echo-planar imaging (GRE-EPI) sequence, allowing monitoring the temperature increase induced with a 980 nm laser source. The temperature distributions measured with 1 mm-spatial resolution with both FBGs and MRTI were compared. The root mean squared error (RMSE) value obtained by comparing temperature profiles showed a maximum error of 1.2 °C. The Bland-Altman analysis revealed a mean of difference of 0.1 °C and limits of agreement 1.5/-1.3 °C. FBG sensors allowed to extensively assess the performances of the GRE-EPI sequence, in addition to the information on the MRTI precision estimated by considering the signal-to-noise ratio of the images (0.4 °C). Overall, the results obtained for the GRE-EPI fully satisfy the accuracy (~2 °C) required for proper temperature monitoring during thermal therapies.