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Monitoring tissue temperature during photothermal therapy for cancer

West, Connor L.a,b; Doughty, Austin C.V.a,b; Liu, Kailia,b; Chen, Wei R.a,b,*

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doi: 10.1097/JBR.0000000000000050
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Light, when interacting with tissue, has extensive applications in medicine, spanning virtually the entire electromagnetic spectrum, from gamma rays and X-rays all the way to infrared and radio waves.[1–3] The medical applications of various light waves differ greatly to include imaging, monitoring, ablation, and phototherapy. The concept of phototherapy has been around for more than a century, and it has now grown into a prominent field in the scope of cancer therapies, particularly for metastatic cancers.[4]

Cancer is among the most resilient diseases to which humans have ever been subjected; its elusion of innate immune responses is largely responsible for its low treatability.[5] In order for the immune system to recognize cancer, tumor-specific markers must be uncovered, a task which can be accomplished through phototherapies.[2] In modern phototherapies, light-tissue and light-cell interactions can be manipulated and adjusted based on the desired outcomes to create an effective therapy for various types of cancer.[2,5–7]

Phototherapy can be broken down into several types, namely photothermal therapy (PTT), photochemical (eg, photodynamic therapy [PDT]), and photomechanical therapy (PMT). PDT offers a therapy largely independent of tissue temperature increase, but through light interactions with a photosensitizer that, in the presence of oxygen, creates reactive oxygen species (ROSs), and subsequently induce cell death. Oxidative stress caused by ROSs leads to the damage of tumor cells and tumor vasculature, provoking an inflammatory response in an effort to prompt a systemic immune response.[8]

PMT induces high impact on tissue without the need of a photosensitizer. Pulsed lasers with high power intensities are commonly used in PMT. The high dose of light delivered by a rapid pulse laser (≤1 × 10–6 second) increases biological tissue temperature at a rate that causes thermoelastic expansion, leading to rupturing of cells in a phenomenon called “spallation”.[9] Elastic recoil following spallation can add to mechanical stress in tissues as well. High temperatures achieved by PMT are also able to produce a “popcorn effect” due to explosive water vaporization, another type of sudden expansion phase change.[10]

Rather than ablating a tumor with excessive doses of energy (ie, PMT) or inducing cellular stress through ROSs (ie, PDT), PTT employs near-infrared (NIR) laser irradiation to elevate the local temperature of the target tumor to a specified range in an effort to induce cell death in order to release damage-associated molecular patterns and tumor specific antigens.[11–13] Cancer cells are sensitive to heat, and thus can be forced to release previously masked antigens and other signal proteins to antigen-presenting cells.[14,15] The uptake and recognition of these antigens ultimately leads to an anti-tumor immune response specific to that antigen.[13,16] Furthermore, the efficacy of photothermal treatment depends on the duration as well as tissue temperature. Over exposure and under exposure to the light dose will render vastly different outcomes. There is a quasi “Goldilocks Zone”, in which the temperature is just high enough to induce thermal stress, antigen release, and immunogenic cell death, while avoiding spallation or excessive necrosis from overheating. This zone is ideal for the maximization of immune response, as necrosis and exorbitant temperature have been shown to hamper an immunogenic cellular response.[15,17]

The recognition of tumor-associated antigens is vital to successful treatment of metastatic cancers, as PTT alone usually is not sufficient to induce a strong immune response; immunotherapy is therefore needed to combine with PTT to elicit a systemic immune response against cancer on a cellular level.[18] Immunotherapy can utilize immunostimulant to activate antigen-presenting cells, which aid in the uptake of antigens for presentation, and subsequently activate anti-tumor T-cells.[5,18] The combination of local PTT and in situ immunostimulant administration has been developed by Chen et al,[19] in an attempt to treat late-stage, metastatic cancers.

Since the inception of PTT, various techniques have been employed and adapted to monitor and control its effects. Temperature distribution is critical to the efficacy of PTT, and methods of monitoring tissue temperature distribution are crucial to optimize the treatment procedures. In modern laboratories, ex vivo, in vivo, and in vitro treatments can be monitored by different imaging techniques.[20,21] Preeminent among modern techniques are magnetic resonance imaging (MRI), computed tomography, photoacoustic (PA) imaging, and infrared thermal imaging. MRI and computed tomography are at the forefront of medical imaging due to their non-invasive advantage, as well as their ability to produce three-dimensional (3D) renderings of the biological environment. However, they suffer from high cost and limitations within certain treatment parameters. PA tomography is a promising technique that can also produce 3D temperature distribution maps. PA imaging can be performed non-invasively or interstitially, but it suffers from poor response and low signal intensity outside of the sample area.[22] Some applications of PA imaging can even perform thermometry and thermal ablation with the same system. Infrared thermal imaging is useful for surface temperature measurement and quick acquisition time; however, it is not as comprehensive as other more sophisticated imaging techniques. In addition to imaging techniques, PTT can be successfully monitored directly by interstitial probes, such as thermocouples and fiber-optic sensors (FOSs). Ideally, temperature distribution in the target tissue should be quantified by one or multiple methods, often in conjunction with an interstitial, real-time feedback and calibration. The aim of this review is to introduce common techniques used to monitor PTT. The strengths and limitations of each technique will be discussed herein, as well as the future of PTT monitoring as highly sophisticated techniques continue to be developed and improved upon.

Database search strategy

The articles cited in this review of PTT monitoring for photothermal treatment were retrieved from multiple search engines and databases, including: MEDLINE, Google Scholar, and EMBASE. References were searched using key words/phrases including: photothermal therapy, photo-immunotherapy, tissue temperature, thermometry, and cancer treatment. Specifically, we searched literature describing relevant research using the following conditions: SCI (photothermal therapy) AND (cancer treatment) AND (temperature measurement) OR (imaging techniques). The results were further screened by titles and abstracts to only present studies for thermal effects in cancer treatment. Non-SCI articles were excluded.

Phototherapy using thermal effects


The premise behind all contemporary photothermal cancer therapies is the removal of a tumor with minimal harm to adjacent healthy tissue. As discussed, there are predominantly two avenues for thermal ablation: invasive (interstitial) and non-invasive. It is worth noting that all interstitial methods discussed herein are minimally invasive. Both treatment modalities experience their own respective obstacles, and are thus useful in their own respects, depending on the treatment set ups and laser operating parameters.

The most common non-invasive modalities involve a light absorbing agent that can selectively increase the local tumor environment to the cytotoxic temperature range.[2,7,20,23] The photothermal agents used in PTT differ from PDT photosensitizers in that they do not attempt to form ROSs via electron excitation. Rather, they selectively absorb and convert NIR light into thermal energy.[12,20] Previously, PTT utilized intratumoral administration of indocyanine green as the light-absorbing agent for selective photothermal effect to destroy tumors.[7] Recently, carbon nanostructures have been used for the purpose of selective light absorption. It has now been shown that there are toxicity and bioaccumulation risks associated with local and systemic administration of certain carbon nanostructures, and as a result, new photothermal agents have been sought.[23,24] More recently, gold nanomaterials have been employed by PTTs. Gold nanostructures (eg, nanoshells, nanorods, nanostars) have shown promise as comparable thermal agents, with lower risk of toxic side effects and a precedence of colloidal gold materials used in vivo.[25,26] Local injection of a thermal absorption agent allows NIR light to be selectively absorbed by the target tissue, allowing non-invasive irradiation using light source from outside the body.

Non-invasive PTT techniques are useful for target tissue destruction, but in many cases it may not be universally applicable.[27] Realistic clinical cases often involve tumors deeply embedded under healthy tissue or beneath heavily pigmented skin. Both of these factors contribute to increased incident light absorption on the surface tissue and less light penetration into the target tissue.[6,27,28] To combat this and further expand the applications of PTT, interstitial treatment methods have been developed.

Interstitial laser irradiation induces highly localized thermal effects, maximizing energy absorption by the target tissue. By inserting a cylindrically diffused optic fiber into a tumor, NIR light can be irradiated within the tumor. One drawback of this method is that close contact of the fiber with tissue increases the risk of exceeding the desired cytotoxic temperature range (Fig. 1).[27] To avoid this, interstitial PTT must be monitored to ensure the treatment temperature remains within the desired range, so as not to destroy vital stress markers that can subsequently be identified by immune cells. In many cases, the tumor environment has very limited space, making interstitial thermometry unfeasible when used in tandem with interstitial laser treatment. Therefore, non-invasive methods of monitoring are preferred for interstitial irradiation. Effective monitoring of interstitial PTT ideally results in the treatment temperature stabilizing in the cytotoxic and heat-shock range (ie, 40–60°C, as shown in Fig. 1). Exceeding this range will lead to cell death by coagulation necrosis (as is the objective of PMT), but also denatures the heat-shock proteins and antigenic peptides that are integral to provoking an immune response.[27]

Figure 1
Figure 1:
Interstitial temperature thresholds for biological responses. Monitoring techniques aim to keep the temperature within 40 to 60°C, which includes the cytotoxic (orange) and heat-shock (yellow) ranges.

PTT + immunotherapy

Effect of PTT on tumors can be enhanced by incorporating immunotherapy. Such combination relies on 2 major tenets: NIR laser irradiation and immune system stimulation. The objective is to use PTT to heat a primary tumor to a cytotoxic temperature range, inducing cellular stress and prompting a heat-shock response.[2,7,13,18,27] Following release of heat-shock proteins and tumor-associated antigens, an immunostimulant is locally administered to increase host immune traffic, whereupon antigen-presenting cells can be activated and then capture tumor antigens and present them to the lymph nodes for maturation of cytotoxic T-cells.[11,13,15,16] In a unique combination of PTT and immunostimulation, a novel immunostimulant, N-dihydroglactochitosan (GC) was used.[2,5,12] GC, a biologically-derived long-chain polysaccharide, functions to increase immune cell traffic.[18] PTT + GC enhances immune response through local administration of GC after the laser irradiation, by inducing pathogen-associated molecular patterns (PAMPs) and/or damage-associated molecular patterns (DAMPs).[29] PTT + GC strategy has proven effective in inducing a systemic long-term anti-tumor immune response.[18,19,30]

PTT + GC can be performed in two ways: non-invasively and interstitially. Non-invasive PTT + GC uses a light absorbing agent to enhance the selectivity of laser irradiation, which typically comes from a laser diffuser positioned over the treatment site. Commonly, the photosensitive agent used is either indocyanine green or one of a suite of NIR-specific nanomaterials.[20,31–35] Nanomaterials are useful for many aspects of cancer treatment. Most commonly used in PTT + GC have been single-walled carbon nanotubes (SWNTs), a tubular graphene monolayer with a high length-to-diameter ratio. Tuning this ratio allows SWNTs to absorb any desired wavelength within the NIR window. SWNTs have been proven highly effective thermal agents, but are suspected to have potential adverse bioaccumulation effects.[12,20,23,34,35] For this reason, gold nanomaterials (specifically gold nanorods) have been explored in PTT + GC applications. Gold nanorods have similar thermal absorption characteristics to SWNTs, without the risk of adverse biological effects.[36]

In some cases, the non-invasive technique of PTT + GC can be rendered ineffective by darkly pigmented skin or deeply embedded tumor, as both will absorb incident light energy, thereby decreasing the amount of NIR light reaching the target tumor.[27] To overcome these problems, interstitial PTT + GC was developed.[27,28] Interstitial placement of the light-delivering fiber avoids the issue of incident light absorption and ensures that deeply embedded target tissues are locally irradiated. While interstitial PTT + GC eliminates many challenges posed by external irradiation, tissue interactions with NIR light must still be monitored to ensure that the temperature remains within the ideal range for heat-shock protein and antigen release, without exceeding destructive temperature thresholds.

Monitoring photothermal therapy

Basic imaging technology

The many facets of PTT require various techniques to accurately gauge or guide treatment. Efficacy of PTT depends largely on the precision of administration, and methods for increasing precision have become the crux of the therapy as a whole.[28,37,38] As with many fields of biological research, PTT outcomes have relied heavily upon post-treatment quantification and qualification methods such as heat-shock protein enzyme linked immunosorbent assay, confocal fluorescent microscopy, and western blot analysis.[11,15] These methods are staples of investigation, but do not aid in the treatment administration process. PTT is a highly sensitive process whose outcome is a direct result of the treatment conditions. New methods for guiding PTT are continuously being developed to track temperature in real time, render 3D profiles, and improve spatial resolution, thus allowing greater influence in the outcome of the treatment.[27,28,38]

As mentioned above, the main goal of PTT is to treat cancerous tissue without harming normal tissue. Furthermore, the cancerous tissue must be exposed to specific levels of thermal damage in order to induce the desired ablative effect, whether immunogenic or not. This can be difficult because tissues seldom absorb light at the same rate, and that rate is subject to change during treatment as a result of the photothermal effects. Real-time tracking techniques are necessary to quantify and monitor temperature distribution in target tumor tissue and surrounding normal tissue. Moreover, techniques that are able to render a 3D temperature distribution profile further enhance the precision of treatment.

In vivo treatments, especially using murine models, often involve very small target tissue areas, leaving room for only the most necessary treatment tools within the local tumor environment. In interstitial PTT, an optic fiber with a diffusion lens is placed inside the tumor, limiting the thermal damage within the tumor volume. However, methods for determining temperature distribution accurately using interstitial means have been developed and proven effective as an alternative.[28,38]

Thermal imaging for surface temperature

Thermal imaging has been widely used since its advent in 1929 in research, military, and astronomy applications, among numerous applications.[39] The ability to detect passive infrared radiation makes thermal cameras fundamental instruments in the field of thermometry. Furthermore, infrared thermal imaging is non-invasive, relatively cheap, capable of real-time imaging, and simple to operate, making it an exceptionally valuable tool for basic monitoring of temperature change in biological tissue. In addition to PTT, infrared imaging has been clinically relevant for detecting abnormal skin temperature elevations, which often stem from increased metabolic activity of an underlying tumor.[40] Skin temperature is also frequently imaged to investigate circulation-compromising conditions, such as diabetes mellitus, rheumatoid arthritis, and Raynaud's phenomenon.[41,42] Lawson et al[43] were among the first to use infrared thermography, not only to quantify abnormal temperature elevation as it relates to detection of cancer, but also to determine a correlation between temperature increase and tumor malignancy. Since then, infrared thermography has been highly prevalent in cancer monitoring, especially breast cancer.[44–46]

Thermal cameras have been widely used for in vitro and in vivo temperature monitoring during PTT. Zhou et al[47] were able to monitor temperature increase of SWNTs under NIR laser irradiation in vitro and in vivo using a handheld thermal camera. Surface temperature of EMT6 murine mammary tumors was monitored to gauge the distribution of heat for treatments with and without photoabsorbing SWNTs. Using a thermographic camera, a correlation was determined between laser dosage and apparent temperature increase of SWNT solutions, as well as a correlation between SWNT concentration and apparent temperature increase (Fig. 2). Furthermore, the temperature increase observed by infrared thermography was corroborated by the consequent cellular effects; that is, higher temperature treatments (reached by laser + SWNT) lead to decreased average tumor volume and decreased cell viability. Infrared thermography was the most practical monitoring candidate in this case, as the in vivo tumors were not embedded, allowing surface temperature to be reasonably inferred as an approximation of the whole tumor temperature.

Figure 2
Figure 2:
Thermal imaging during non-invasive photothermal therapy. (A) Thermographic image of laser + single-walled carbon nanotubes (SWNTs) versus Laser alone in the EMT6 tumor model in response to NIR illumination. (B) Temperature on the surface of tumor during irradiation with or without SWNT-polyethylene glycol (SWNT-PEG) by the 980-nm laser. This result clearly demonstrated the selective thermal effect caused by SWNT-PEG absorption of 980-nm light in the tumor. Reprinted with permission from Zhou et al.[47] NIR = near-infrared.

Li et al[35] similarly used a thermographic camera to observe the photothermal conversion efficiency of SWNT-GC in a treatment combining laser immunotherapy with checkpoint inhibition therapy. SWNT-GC solutions were irradiated by a 1064-nm Nd:YAG laser to investigate the thermal effects of various laser power densities and SWNT-GC concentrations, as well as the stability of SWNT-GC throughout intermittent irradiation periods. Surface temperature was able to determine optimal laser dosage and SWNT concentration, as well as stability of SWNT-GC in in vivo and in vitro laser immunotherapy applications. This thermography method has been successfully utilized for in vivo treatments. However, infrared thermography is only able to obtain surface temperature, thereby facing limitations due to intratumoral temperature ignorance. For this reason, thermal imaging often necessitates paired use with interstitial thermocouples to monitor temperature distribution, ensuring no significant difference between intratumoral temperature and surface temperature.

Interstitial measurement of tissue temperature

Interstitial monitoring of PTT has an advantage over non-invasive techniques by offering easily-implemented and cost-effective thermometry. PTT mainly employs the use of two types of interstitial temperature sensors: FOSs and thermocouples.[48–52] FOSs can be further broken down into the two leading types: fiber Bragg grating (FBG) and fluoroptic sensors. The cost, ease of use, quick response time, and accuracy of thermocouples and FOSs contribute to their widespread implementation in photothermal therapies; however, each sensor has its respective complications that can render its use impractical under certain circumstances.[49,51] While some FOSs have the ability to record quasi-distributed or multipoint measurements, thermocouples are limited to recording one spatial temperature point; an ideal technique would have the potential to record temperature distribution within an entire tumor.[51] Moreover, metallic thermocouple sensors experience high heat conductivity and radiation absorption, often resulting in temperature underestimation and overestimation, respectively.[48,49] Metallic conductors in thermocouples also bar use of MRI guidance, as they could cause serious image artifacts.[48]

FOSs are reliable and accurate, with notable spatial resolution and low cost.[50] Two types of FOSs are commonly used for thermometry: fluorescence based sensors and FBG sensors. Fluoroptic sensors, developed by LumaSense Technologies, have been used for thermometry for several decades.[51] These sensors function on the decay time of temperature-sensitive fluorescent materials that can be placed upon an interstitial fiber.[51–53] Quick fluorescent decay times generally allow fluoroptic sensors to have a quick response time. These types of FOSs were developed for photothermal therapies because of their wide thermometry range (>100°C above and below target range for PTT), accuracy (<0.2°C), and compatibility with an electromagnetic field.[51] Fluoroptic probes are frequently employed in MRI-guided PTT, where they serve as reliable temperature references for image-based thermometry.[54] The main drawback of fluoroptic probes is their propensity to self-heat. Most fluoroptic probes are coated in a black pigment, which can cause measurement error when the probe is placed too close to the fiber.[55,56]

FBGs share ideal properties with fluoroptic probes in that they are also very flexible and electrically inert, allowing them to be inserted into deep-tissue tumors and guided by image-based techniques such as MRI.[49,56] While fluoroptic sensors are reliable, FBG sensors are favored for their ability to detect temperatures at various spatial points when multiple sensors are fabricated on the same fiber.[50,57] Rao et al[58] pioneered the capabilities of FBG sensors, especially in a magnetic field by testing their sensor system in a 4.7T nuclear magnetic resonance machine. This team was able to obtain temperature feedback from the FBG sensor within a range of 30–60°C, with a resolution of 0.1°C, and accuracy of 0.5°C, solidifying the status of FBG sensors as one of the most accurate and practical thermometry methods available. FBG sensors do not experience the self-heating phenomenon that hinders fluoroptic probes; however, FBG sensors are sensitive to strain, which leads to complications, especially for in vivo scenarios in which respiration can cause significant error. Furthermore, FBG sensors require expensive analytical instruments in order to accurately detect optical signals, further decreasing their implementation.

PTT has been monitored using thermocouples. Thermocouples are a staple in modern temperature sensing and are the most widely implemented temperature sensor. Using metallic conductors encased in a thin needle, thermocouples are able to record temperature with quick response time and marked accuracy while remaining inexpensive.[48] Thermocouples are not without their limitations, as they must be calibrated and corrected to reduce temperature over-estimation from laser absorption by the metal. This can be achieved by excluding short-response time temperatures recordings, as the absorption is ostensibly instantaneous, and regarding long-response time temperature recordings as true reflections of the actual temperature.[48,59–61]

Liu et al[28] have developed a novel technique for monitoring interstitial laser immunotherapy, involving an ex vivo tumor simulation model that employs a thermostatic incubator, and an array of thermocouples to replicate in vivo tumor conditions as closely as possible (Fig. 3). In this study, a tumor model was created by placing bovine liver inside a phantom gel, mimicking a tumor surrounded by healthy tissue. Bovine liver is commonly chosen for its higher similarity to real tumor tissue in temperature increase and spatial distribution properties.[27,61,62] By placing eight thermocouple needle probes equidistant from each other and in sequence starting at the light-delivering fiber, the model showed a comprehensive spatial temperature distribution with a radial range of 10.24 mm. The thermostatic incubator (set to 35°C) functioned to replicate mammalian body temperature, which reduced the treatments heat loss to the environment, thus increasing likeness to in vivo conditions. Additionally, the rapid response of the thermocouples allowed this model to monitor temperature distribution in real time. Centered on interstitial irradiation, this model analyzed intratumoral temperature data to give insights into the relationship between laser dosage, temperature, and peripheral tumor cytotoxicity. This data allowed the researchers to increase optimization of laser dosage in PTT. Temperature overestimation due to light absorption by metallic conductors has been suspected to skew temperature measurements in thermocouples; however, Liu et al[28] reported no significant difference between the temperature measured by thermocouple and magnetic resonance thermometry (MRT).

Figure 3
Figure 3:
Ex vivo temperature measurement during interstitial photothermal therapy using thermocouples. (A) Schematic of the model for determination of temperature distributions. (B) A sectional view of temperature distribution in target tissue during interstitial laser irradiation, using eight needle probes of thermocouple that are inserted in the tissue parallel to the fiber tip. (C) Three-dimensional temperature elevation in bovine liver at stable phase during interstitial laser irradiation (3W for 15 minutes), based on the characteristic temperature increase. (D) Three dimensional simulation graph for the correlation of stable temperature at different locations with different laser powers. Reprinted with permission from Liu et al.[28].

PA imaging for temperature measurement

PA imaging is a promising structural, functional, and molecular imaging modality that induces acoustic waves through pulsed laser irradiation. These waves can be detected and correlated to temperature change based on the linear relationship between PA signals and temperature in the range of 10 to 55°C.[22,28,63] PA imaging has been used to measure temperature in high intensity focused ultrasound ablation, PTT, and PMT, all with the potential to obtain real-time temperature data.[22,63–65] Most applications of PA imaging focus on single-wavelength excitation to monitor temperature; however, dual-wavelength techniques have also been developed to monitor tissue optical properties altered by cell necrosis, condensation, and protein denaturation.[66] Recently, a PA device for temperature monitoring was even developed for use during cryotherapy for colorectal cancer patients.[67]

As discussed above, photothermal effects depend on both temperature elevation and the specific optical properties of tissue. Li et al[64] have devised a PTT treatment modality (Fig. 4) that delivers continuous-wave and pulsed laser irradiation through a single optical fiber, allowing simultaneous thermal treatment and monitoring of temperature and tissue optical properties, respectively. Continuous-wave NIR light was able to elevate the temperature of ex vivo tumor models, while pulsed NIR light created acoustic waves to detect both temperature increase and change in tissue properties. Using thermocouples for reference, the technique put forth by Li et al[64] successfully correlated PA amplitude to temperature increase. Furthermore, this technique showed three distinct heating periods. A linear correlation between amplitude and temperature was seen from 20 to 60°C, a “transition period” was observed between 60 and 65°C, followed by another linear correlation from 65 to 80°C. These heating periods demonstrated a change in tissue properties for the porcine liver tissue in the ex vivo model.

Figure 4
Figure 4:
Photoacoustic imaging for temperature detection during interstitial photothermal therapy. (A) Schematic of the model for determination of temperature distributions using photoacoustic system. Both pulse laser light and continuous-wave laser light were directed through two different fibers (1 and 2) into the same active tip (1-cm length and 1-mm diameter) in the tissue through a fiber coupler (FC). The photoacoustic signals at position A were detected for temperature determination. A thermocouple needle probe was placed at position B, symmetric to position A, to calibrate the photoacoustic measurement of tissue temperature. A water tank was placed on top of the tissue to enhance the acoustics coupling. (B) Photoacoustic amplitude versus irradiation time under laser irradiation at 1.24W. Reprinted with permission from Li et al.[64].

While Li et al[64] sampled 60 s after irradiation, it was noted that PA imaging feedback could be feasibly obtained in real-time. The multi-faceted capabilities of PA imaging, which allow it to deliver thermal treatment, produce 3D temperature profiles, and monitor tissue optical properties simultaneously, making it one of the top choices for monitoring PTT.


The advent of non-invasive in vivo thermal profiling is indispensable in PTT. Image-based temperature monitoring is also a useful method for treatment accuracy, particularly for cancer therapies. Ideally, monitoring PTT should be non-invasive, as interstitial methods could interfere with PTT treatment. The commonality of interstitial laser ablation has led many treatments to turn to newer technologies that allow monitoring without invasive sensors like thermocouples and FOSs. While still in their inchoate stages, image-based temperature tracking methods are promising avenues for controlling highly efficient in vivo 3D mapping and temperature profiling in real-time.

MRI is a long-standing pillar of diagnostic imaging and is unrivaled in 3D image rendering and safety. The principles of MRI have been adapted in recent decades to detect temperature change non-invasively in a technique called MRT. MRT is able to profile temperature using several methods, including: proton resonance frequency (PRF), proton density, magnetization transfer, and diffusion coefficient.[68–71] Most common among these MRT parameters is PRF, which can accurately produce 3D temperature models of a target area without interfering with the local biological environment.[69,72,73] Temperature increase inherently weakens the local magnetic field in tissue, causing a shift in water PRF.[74] Water protons are found in all tissues and have been shown to produce the same chemical shift, independent of tissue composition, allowing PRF to be implemented in any tissue.[68,72,75]

Image-based techniques are still being developed and thus often require external calibration. FOSs are commonly used to test the accuracy of image-based thermometry, and have demonstrated a good correlation between the two measurement techniques, as good as <1°C difference between MRT and FOS measurements.[72,76] Le et al[27] have pioneered the use of a small animal MRI for monitoring temperature during interstitial PTT. To investigate MRT accuracy, thermocouples were used in a parallel study. Interstitial PTT was administered at various low power densities for 10 minutes in ex vivo and in vivo models. By comparing temperature increase measured by PRF and thermocouples (Fig. 5), it was determined that PRF could accurately monitor temperature distribution with marked spatial resolution. Furthermore, PRF was able to assess temperature change at multiple spatial points of a rat tumor to determine temperature distribution, finding a sharp increase within a 1 mm radius of the applicator tip, but not at 3 mm. Using this thermal distribution data, Le et al[27] were able to determine how a change in laser power would affect in vivo tumors, allowing them to modify future interstitial PTT treatments to achieve desired temperature distribution.

Figure 5
Figure 5:
Magnetic resonance thermometry imaging for interstitial photothermal therapy. (A) Schematic of an animal inside the bore of an magnetic resonance imager under laser irradiation. (B) Two-dimensional map of temperature elevation in a rat immediately after interstitial laser treatment (1.25W for 10 minutes). (C) Two-dimensional temperature distribution of a rat tumor using five different transverse slices, immediately after interstitial laser irradiation (1.25W for 10 minutes). The end of the active tip can be seen in slice 5. Higher temperature elevations are correlated with increasing slice number, which is consistent with our liver results. Each temperature distribution map (left column) is shown with its corresponding magnitude image (right column). Reprinted with permission from Le et al.[27] RF = resonance frequency.

PRF is subject to certain artifacts that must be corrected in order to obtain accurate results.[77] Additionally, MRT faces motion artifacts (ie, breathing, heartbeat) that must be corrected with gating in order to obtain steady temperature data. Moreover, the PRF modality inherently faces anomalies due to the decrease in resolution above a certain temperature.[78] Given the obstacles involved in MRT, specifically using PRF, improvements are still required if it is to become a viable replacement for cheaper and often more reliable thermometry techniques in PTT. Nevertheless, PRF based MRT does show the most promise of all the modern, non-invasive thermometry techniques.


Numerous techniques for monitoring photothermal therapies have led to great strides in the field. Improvements on techniques to assess temperature distribution in a tumor have given researchers the ability to deliver highly specific treatments with maximal benefit and minimal adversity. We have seen vastly different methods for monitoring PTT, all of which are contemporary and serve respective purposes. Interstitial techniques, including FOSs, thermocouples, and specific PA models, have proven to be useful thermometry; however, imaging technology is burgeoning into several very promising techniques for monitoring PTT. Specifically, MRT using PRF has seen significant developments that have enabled researchers to produce highly accurate 3D temperature profiles during treatment in real-time.

While some of the most promising imaging techniques face serious complications, they are not far from widespread implementation in cancer therapies. The advent of novel treatment modalities such as that proposed by Li et al[38] shows the potential for growth and development of both thermometry and imaging in PTT. Continued development of imaging techniques will further enhance the specificity of PTT, further improving the efficacy of PTT + immunotherapy. This could help tremendously in the road to clinical applications of the combination of PTT with other modalities. Future treatments could potentially be monitored with real-time feedback and accurate temperature maps, allowing researchers to optimize laser power, irradiation duration, and other treatment settings to ensure the exact desired photothermal and immunological effects are achieved.



Author contributions

CLW and WRC participated in literature retrieval, manuscript drafting and writing of the main part in the manuscript. ACVD and KL reviewed and modified the manuscript. All authors approved the final version of the paper.

Financial support

This work was supported in part by grants from the U.S. National Institutes of Health, No. R01 CA205348 (to WRC), the Oklahoma Center for Advancement of Science and Technology, No. HR16–085 (to WRC).

Conflicts of interest

The authors declare that they have no conflicts of interest.


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photo-immunotherapy; photothermal therapy; thermometry; tissue temperature

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