Non-Fourier Bioheat Transfer Analysis in Brain Tissue During Interstitial Laser Ablation: Analysis of Multiple Influential Factors.

This work presents the dual-phase lag-based non-Fourier bioheat transfer model of brain tissue subjected to interstitial laser ablation. The finite element method has been utilized to predict the brain tissue's temperature distributions and ablation volumes. A sensitivity analysis has been conducted to quantify the effect of variations in the input laser power, treatment time, laser fiber diameter, laser wavelength, and non-Fourier phase lags. Notably, in this work, the temperature-dependent thermal properties of brain tissue have been considered. The developed model has been validated by comparing the temperature obtained from the numerical and ex vivo brain tissue during interstitial laser ablation. The ex vivo brain model has been further extended to in vivo settings by incorporating the blood perfusion effects. The results of the systematic analysis highlight the importance of considering temperature-dependent thermal properties of the brain tissue, non-Fourier behavior, and microvascular perfusion effects in the computational models for accurate predictions of the treatment outcomes during interstitial laser ablation, thereby minimizing the damage to surrounding healthy tissue. The developed model and parametric analysis reported in this study would assist in a more accurate and precise prediction of the temperature distribution, thus allowing to optimize the thermal dosage during laser therapy in the brain.

Theoretical Estimation of Tissue Thermal Response and Associated Thermal Damage During Gold Nanorod-enhanced Photothermal Therapy of Tumors.

In the present work, we implemented a computational framework of in vivo gold nanorod (GNR)-enhanced photothermal therapy (PTT) for tumor treatment. The temperature-dependent thermophysical properties of biological tissue and the optical properties of both GNRs and the biological media were included. The latter were modulated during the treatment simulation to account for their variation, from the native to the coagulated state. The contribution of tissue injury-dependent blood perfusion was also considered. The developed model allowed for the estimation of temperature distribution during the photothermal procedure at different procedural settings and amounts of GNRs embedded in the tumor region (i.e., 12.5 µg, 25 µg, and 50 µg). Furthermore, the influence of GNRs on thermal injury, estimated with different damage models, was assessed. The inclusion of GNRs in the tumor entailed an increment of maximum tissue temperature, and faster heating kinetics, as witnessed by the lower time needed to reach complete thermal damage at the tumor center. The percentage of tumor thermal damage evaluated at the end of the simulated treatment was 48%, 69%, and 90%, for PTT in the presence of 12.5 µg, 25 µg, and 50 µg of GNRs, respectively.Clinical Relevance-This establishes that simulation-based tools, modeling the tissue properties variation during the photothermal treatment, can serve as promising preplanning platforms for nanoparticle-assisted light therapies.

Characterization of the Optical and Thermal Properties of Cardiac Tissue as a Function of Temperature.

In this work, we devised the first characterization of the optical and thermal properties of ex vivo cardiac tissue as a function of different selected temperatures, ranging from room temperature to hyperthermic and ablative temperatures. The broadband (i.e., from 650 nm to 1100 nm) estimation of the optical properties, i.e., absorption coefficient (µa) and reduced scattering coefficient $({\mu ^{\prime}}_s)$, was performed by means of time-domain diffuse optics. Besides, the measurement of the thermal properties was based on the transient hot-wire technique, employing a dual-needle probe to estimate the tissue thermal conductivity (k), thermal diffusivity (α), and volumetric heat capacity (Cv). Increasing the tissue temperature led to variations in the spectral characteristics of µa (e.g., the redshift of the 780 nm peak, the rise of a new peak at 840 nm, and the formation of a valley at 900 nm). Moreover, an increase in the values of ${\mu ^{\prime}}_s$ was assessed as tissue temperature raised (e.g., for 800 nm, at 25 °C ${\mu ^{\prime}}_s = 9.8{\text{ c}}{{\text{m}}^{{\text{ - 1}}}}$, while at 77 °C ${\mu ^{\prime}}_s = 29.1{\text{ c}}{{\text{m}}^{{\text{ - 1}}}}$). Concerning the thermal properties characterization, k was almost constant in the selected temperature interval. Conversely, α and Cv were subjected to an increase and a decrease with temperature, respectively; thus, they registered values of 0.190 mm2/s and 3.03 MJ/(m3•K) at the maximum investigated temperature (79 °C), accordingly.Clinical Relevance- The experimentally obtained optical and thermal properties of cardiac tissue are useful to improve the accuracy of simulation-based tools for thermal therapy planning. Furthermore, the measured properties can serve as a reference for the realization of tissue-mimicking phantoms for medical training and testing of medical instruments.

Measurement of Thermal Conductivity and Thermal Diffusivity of Porcine and Bovine Kidney Tissues at Supraphysiological Temperatures up to 93 °C.

This experimental study aimed to characterize the thermal properties of ex vivo porcine and bovine kidney tissues in steady-state heat transfer conditions in a wider thermal interval (23.2-92.8 °C) compared to previous investigations limited to 45 °C. Thermal properties, namely thermal conductivity (k) and thermal diffusivity (α), were measured in a temperature-controlled environment using a dual-needle probe connected to a commercial thermal property analyzer, using the transient hot-wire technique. The estimation of measurement uncertainty was performed along with the assessment of regression models describing the trend of measured quantities as a function of temperature to be used in simulations involving heat transfer in kidney tissue. A direct comparison of the thermal properties of the same tissue from two different species, i.e., porcine and bovine kidney tissues, with the same experimental transient hot-wire technique, was conducted to provide indications on the possible inter-species variabilities of k and α at different selected temperatures. Exponential fitting curves were selected to interpolate the measured values for both porcine and bovine kidney tissues, for both k and α. The results show that the k and α values of the tissues remained rather constant from room temperature up to the onset of water evaporation, and a more marked increase was observed afterward. Indeed, at the highest investigated temperatures, i.e., 90.0-92.8 °C, the average k values were subject to 1.2- and 1.3-fold increases, compared to their nominal values at room temperature, in porcine and bovine kidney tissue, respectively. Moreover, at 90.0-92.8 °C, 1.4- and 1.2-fold increases in the average values of α, compared to baseline values, were observed for porcine and bovine kidney tissue, respectively. No statistically significant differences were found between the thermal properties of porcine and bovine kidney tissues at the same selected tissue temperatures despite their anatomical and structural differences. The provided quantitative values and best-fit regression models can be used to enhance the accuracy of the prediction capability of numerical models of thermal therapies. Furthermore, this study may provide insights into the refinement of protocols for the realization of tissue-mimicking phantoms and the choice of tissue models for bioheat transfer studies in experimental laboratories.

Optimization of laser dosimetry based on patient-specific anatomical models for the ablation of pancreatic ductal adenocarcinoma tumor.

Laser-induced thermotherapy has shown promising potential for the treatment of unresectable primary pancreatic ductal adenocarcinoma tumors. Nevertheless, heterogeneous tumor environment and complex thermal interaction phenomena that are established under hyperthermic conditions can lead to under/over estimation of laser thermotherapy efficacy. Using numerical modeling, this paper presents an optimized laser setting for Nd:YAG laser delivered by a bare optical fiber (300 µm in diameter) at 1064 nm working in continuous mode within a power range of 2-10 W. For the thermal analysis, patient-specific 3D models were used, consisting of tumors in different portions of the pancreas. The optimized laser power and time for ablating the tumor completely and producing thermal toxic effects on the possible residual tumor cells beyond the tumor margins were found to be 5 W for 550 s, 7 W for 550 s, and 8 W for 550 s for the pancreatic tail, body, and head tumors, respectively. Based on the results, during the laser irradiation at the optimized doses, thermal injury was not evident either in the 15 mm lateral distances from the optical fiber or in the nearby healthy organs. The present computational-based predictions are also in line with the previous ex vivo and in vivo studies, hence, they can assist in the estimation of the therapeutic outcome of laser ablation for pancreatic neoplasms prior to clinical trials.

Temperature Dependence of Thermal Properties of Ex Vivo Porcine Heart and Lung in Hyperthermia and Ablative Temperature Ranges.

This work proposes the characterization of the temperature dependence of the thermal properties of heart and lung tissues from room temperature up to > 90 °C. The thermal diffusivity (α), thermal conductivity (k), and volumetric heat capacity (Cv) of ex vivo porcine hearts and deflated lungs were measured with a dual-needle sensor technique. α and k associated with heart tissue remained almost constant until ~ 70 and ~ 80 °C, accordingly. Above ~ 80 °C, a more substantial variation in these thermal properties was registered: at 94 °C, α and k respectively experienced a 2.3- and 1.5- fold increase compared to their nominal values, showing average values of 0.346 mm2/s and 0.828 W/(m·K), accordingly. Conversely, Cv was almost constant until 55 °C and decreased afterward (e.g., Cv = 2.42 MJ/(m3·K) at 94 °C). Concerning the lung tissue, both its α and k were characterized by an exponential increase with temperature, showing a marked increment at supraphysiological and ablative temperatures (at 91 °C, α and k were equal to 2.120 mm2/s and 2.721 W/(m·K), respectively, i.e., 13.7- and 13.1-fold higher compared to their baseline values). Regression analysis was performed to attain the best-fit curves interpolating the measured data, thus providing models of the temperature dependence of the investigated properties. These models can be useful for increasing the accuracy of simulation-based preplanning frameworks of interventional thermal procedures, and the realization of tissue-mimicking materials.

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.

Thermophysical and mechanical properties of biological tissues as a function of temperature: a systematic literature review.

BACKGROUND: Detailed information on the temperature dependence of tissue thermophysical and mechanical properties is pivotal for the optimal implementation of mathematical models and simulation-based tools for the pre-planning of thermal ablation therapies. These models require in-depth knowledge of the temperature sensitivity of these properties and other influential terms (e.g., blood perfusion and metabolic heat) to maximize the treatment prediction outcome. METHODOLOGY: A systematic literature review of experimental trials investigating thermophysical and mechanical properties of biological media, as well as blood perfusion and metabolic heat, as a function of temperature in hyperthermic and ablative thermal range, was conducted up to June 2021. RESULTS: A total of 61 articles was selected, thus enabling a comprehensive overview of the temperature dependence of thermophysical properties (i.e. thermal conductivity, specific heat, volumetric heat capacity, density, thermal diffusivity), and mechanical properties (shear, elastic, storage, loss and complex moduli, loss factor, stiffness) along with the principal measurement techniques. The reviewed studies considered different tissues, e.g., liver, fat, cartilage, brain, myocardium, muscle, bone, skin, pancreas tissues, and also some tumorous tissues. CONCLUSIONS: The thermophysical properties of soft tissues appear rather constant until 90 °C, with slight differences ascribable to tissues characteristics and measurement methods. Conversely, the information on mechanical properties is heterogeneous because most of the articles investigated different types of properties in different biological tissues. Furthermore, most of the experiments were conducted ex vivo; only a small percentage concerned in vivo studies. Limited recent information about the temperature dependence of metabolic heat and blood perfusion was observed.

Measurement of Ex Vivo Liver, Brain and Pancreas Thermal Properties as Function of Temperature.

The ability to predict heat transfer during hyperthermal and ablative techniques for cancer treatment relies on understanding the thermal properties of biological tissue. In this work, the thermal properties of ex vivo liver, pancreas and brain tissues are reported as a function of temperature. The thermal diffusivity, thermal conductivity and volumetric heat capacity of these tissues were measured in the temperature range from 22 to around 97 °C. Concerning the pancreas, a phase change occurred around 45 °C; therefore, its thermal properties were investigated only until this temperature. Results indicate that the thermal properties of the liver and brain have a non-linear relationship with temperature in the investigated range. In these tissues, the thermal properties were almost constant until 60 to 70 °C and then gradually changed until 92 °C. In particular, the thermal conductivity increased by 100% for the brain and 60% for the liver up to 92 °C, while thermal diffusivity increased by 90% and 40%, respectively. However, the heat capacity did not significantly change in this temperature range. The thermal conductivity and thermal diffusivity were dramatically increased from 92 to 97 °C, which seems to be due to water vaporization and state transition in the tissues. Moreover, the measurement uncertainty, determined at each temperature, increased after 92 °C. In the temperature range of 22 to 45 °C, the thermal properties of pancreatic tissue did not change significantly, in accordance with the results for the brain and liver. For the three tissues, the best fit curves are provided with regression analysis based on measured data to predict the tissue thermal behavior. These curves describe the temperature dependency of tissue thermal properties in a temperature range relevant for hyperthermia and ablation treatments and may help in constructing more accurate models of bioheat transfer for optimization and pre-planning of thermal procedures.

Thermal analysis of laser irradiation-gold nanorod combinations at 808 nm, 940 nm, 975 nm and 1064 nm wavelengths in breast cancer model.

BACKGROUND: Photothermal therapy is currently under the spotlight to improve the efficacy of minimally invasive thermal treatment of solid tumors. The interplay of several factors including the radiation wavelengths and the nanoparticle characteristics underlie the thermal outcome. However, a quantitative thermal analysis in in vivo models embedding nanoparticles and under different near-infrared (NIR) wavelengths is missing. PURPOSE: We evaluate the thermal effects induced by different combinations of NIR laser wavelengths and gold nanorods (GNRs) in breast cancer tumor models in mice. MATERIALS AND METHODS: Four laser wavelengths within the therapeutic window, i.e., 808, 940, 975, and 1064 nm were employed, and corresponding GNRs were intratumorally injected. The tissue thermal response was evaluated in terms of temperature profile and time constants, considering the step response of a first-order system as a model. RESULTS: The 808 nm and 1064 nm lasers experienced the highest temperature enhancements (>24%) in presence of GNRs compared to controls; conversely, 975 nm and 940 nm lasers showed high temperatures in controls due to significant tissue absorption and the lowest temperature difference with and without GNRs (temperature enhancement <10%). The presence of GNRs resulted in small time constants, thus quicker laser-induced thermal response (from 67 s to 33 s at 808 nm). CONCLUSIONS: The thermal responses of different GNR-laser wavelength combinations quantitatively validate the widespread usage of 808 nm laser for nanoparticle-assisted photothermal procedures. Moreover, our results provide insights on other usable wavelengths, toward the identification of an effective photothermal treatment strategy for the removal of focal malignancies.

Laser-induced thermal response and controlled release of copper oxide nanoparticles from multifunctional polymeric nanocarriers.

Multifunctional nanocarriers have attracted considerable interest in improving cancer treatment outcomes. Poly(lactide-co-glycolide) (PLGA) nanospheres encapsulating copper oxide nanoparticles (CuO-NPs) are characterized by antitumor activity and exhibit dual-modal contrast-enhancing capabilities. An in vitro evaluation demonstrates that this delivery system allows controlled and sustained release of CuO-NPs. To achieve localized release on demand, an external stimulation by laser irradiation is suggested. Furthermore, to enable simultaneous complementary photothermal therapy, polydopamine (PDA) coating for augmented laser absorption is proposed. To this aim, two formulations of CuO-NPs loaded nanospheres are prepared from PLGA polymers RG-504 H (H-PLGA) and RG-502 H (L-PLGA) as scaffolds for surface modification through in situ polymerization of dopamine and then PEGylation. The obtained CuO-NPs-based multifunctional nanocarriers are characterized, and photothermal effects are examined as a function of wavelength and time. The results show that 808 nm laser irradiation of the coated nanospheres yields maximal temperature elevation (T = 41°C) and stimulates copper release at a much faster rate compared to non-irradiated formulations. Laser-triggered CuO-NP release is mainly depended on the PLGA core, resulting in faster release with L-PLGA, which also yielded potent anti-tumor efficacy in head and neck cancer cell line (Cal-33). In conclusion, the suggested multifunctional nanoplatform offers the integrated benefits of diagnostic imaging and laser-induced drug release combined with thermal therapy.

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.

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.

Linearly chirped fiber Bragg grating response to thermal gradient: from bench tests to the real-time assessment during in vivo laser ablations of biological tissue.

The response of a fiber optic sensor [linearly chirped fiber Bragg grating (LCFBG)] to a linear thermal gradient applied on its sensing length (i.e., 1.5 cm) has been investigated. After these bench tests, we assessed their feasibility for temperature monitoring during thermal tumor treatment. In particular, we performed experiments during ex vivo laser ablation (LA) in pig liver and in vivo thermal ablation in animal models (pigs). We investigated the following: (i) the relationship between the full width at half maximum of the LCFBG spectrum and the temperature difference among the extremities of the LCFBG and (ii) the relationship between the mean spectrum wavelength and the mean temperature acting on the LCFBG sensing area. These relationships showed a linear trend during both bench tests and LA in animal models. Thermal sensitivity was significant although different values were found with regards to bench tests and animal experiments. The linear trend and significant sensitivity allow hypothesizing a future use of this kind of sensor to monitor both temperature gradient and mean temperature within a tissue undergoing thermal treatment.

Temperature monitoring and lesion volume estimation during double-applicator laser-induced thermotherapy in ex vivo swine pancreas: a preliminary study.

Tissue temperature distribution plays a crucial role in the outcome of laser-induced thermotherapy (LITT), a technique employed for neoplasias removal. Since recent studies proposed LITT for pancreatic tumors treatment, assessment of temperature and of its effects around the laser applicator could be useful to define optimal laser settings. The aims of this work are temperature monitoring and measurement of ablated tissue volume in an ex vivo porcine pancreas undergoing double-applicator LITT. A three-dimensional numerical model is implemented to predict temperature rise and volumes of ablated tissue in treated pancreas. Experiments are performed to validate the model, with two modalities: (1) 12-fiber Bragg grating sensors are adopted to monitor the heating and cooling during LITT at several distances from the applicators tip, and (2) 1.5-T MR imaging is used to estimate the ablated volume. Experimental data agree with theoretical ones: at 2 mm from both applicators tips, the maximum temperature increase is approximately 60 °C downward from the tips, while it increases of about 40 °C and 30 °C, respectively, at the level and upward from the tips. This behavior occurs also at other distances, proving that the tissue downward from the tip is mostly heated. Furthermore, the estimated volume with MRI agrees with theoretical one (i.d., 0.91 ± 0.09 vs. 0.95 cm(3)). The encouraging results indicate that the model could be a suitable tool to choose the optimal laser settings, in order to control the volume of ablated tissue.

Techniques for temperature monitoring during laser-induced thermotherapy: an overview.

Laser-induced thermotherapy (LITT) is a hyperthermic procedure recently employed to treat cancer in several organs. The amount of coagulated tissue depends on the temperature distribution around the applicator, which plays a crucial role for an optimal outcome: the removal of the whole neoplastic tissue, whilst preventing damage to the surrounding healthy tissue. Although feedback concerning tissue temperature could be useful to drive the physician in the adjustment of laser settings and treatment duration, LITT is usually performed without real-time monitoring of tissue temperature. During recent decades, many thermometric techniques have been developed to be used during thermal therapies. This paper provides an overview of techniques and sensors employed for temperature measurement during tissue hyperthermia, focusing on LITT, and an investigation of their performances in this application. The paper focuses on the most promising and widespread temperature monitoring techniques, splitting them into two groups: the former includes invasive techniques based on the use of thermocouples and fibre-optic sensors; the second analyses non-invasive methods, i.e. magnetic resonance imaging-, computerised tomography- and ultrasound-based thermometry. Background information on measuring principle, medical applications, advantages and weaknesses of each method are provided and discussed.

Theoretical analysis and experimental evaluation of laser-induced interstitial thermotherapy in ex vivo porcine pancreas.

Laser-induced interstitial thermotherapy (LITT) has been recently applied to pancreas in animal models for ablation purpose. Assessment of thermal effects due to the laser-pancreatic tissue interaction is a critical factor in validating the procedure feasibility and safety. A mathematical model based on bioheat equation and its experimental assessment was developed. The LITT procedure was performed on 40 ex vivo porcine pancreases, with an Nd:YAG (1064 nm) energy of 1000 J and power from 1.5 up to 10 W conveyed by a quartz optical fiber with 300 µm diameter. Six fiber Bragg grating sensors have been utilized to measure temperature distribution as a function of time at fixed distances from the applicator tip within pancreas undergoing LITT. Simulations and experiments show temperature variations Δ T steeply decreasing with distance from the applicator at higher power values: at 6 W, ∆T > 40 °C at 5 mm and Δ T is approximately equal to 5 °C at 10 mm. Δ T nonlinearly increases with power close to the applicator. Ablated and coagulated tissue volumes have also been measured and experimental results agree with theoretical ones. Despite the absence of data in the current literature on pancreas optical parameters, the model allowed a quite good prediction of thermal effects. The prediction of LITT effects on pancreas is necessary to assess laser dosimetry.