Mild-temperature photothermal treatment method and system based on photoacoustic temperature measurement and control
Introduction
Photothermal therapy (PTT) is a new type of non-invasive tumor treatment method that has emerged in recent years as an alternative to surgery for tumors with undefined borders or embedded in vital organs [1], [2], [3], [4], [5]. In the process, the near-infrared laser is directly irradiated to the lesion to increase the local temperature and induce apoptosis of cancerous cell. Great progress has been made in early clinical trials for the application of PTT in breast and bladder cancers [6], [7]. Furthermore, PTT using light as a therapeutic medium can be combined with emerging tumor therapies such as photodynamic and sonodynamic therapy [8], [9], [10], [11], [12], [13].
The key to the success of PTT is accurate temperature control, which is hard to achieve given the open-loop control for the treatment laser. In addition, there is no clinical detection method for non-invasive, real-time temperature detection of the treatment target. Because of these factors, medical staff can only estimate the time of laser irradiation based on experience and appropriately expand the treatment area to ensure that the tumor tissue is effectively killed. This open-loop treatment increases the pain of patient and the workload of clinicians, and uncontrolled high temperature may cause cell carbonization that can decrease the effectiveness of tumor immunotherapy. Therefore, real-time control of the target area temperature and mild photothermal therapy (MPTT) technology are considered the key technical problems that require solutions to advance the field of PTT [14], [15].
Depending on whether the temperature sensor is in direct contact with the tissue, temperature measurement technology is divided into contact and non-invasive types. Contact temperature measurement technologies such as thermocouples or fluorescent temperature sensors are not suitable for PTT due to their invasive characteristics that may increase the possibility of cancer metastasis. Among many non-invasive solutions, infrared temperature measurement technology can provide high sensitivity and accuracy [16], [17], but it can only measure the surface temperature due to the strong scattering of the light within the tissue. Ultrasonic temperature measurement technology has strong penetration [18], [19], but it is easily affected by gas and bones, resulting in poor measurement accuracy and low imaging resolution. Temperature can also be estimated by magnetic resonance (MR), which has the advantages of high penetration and high resolution [20], and has been successfully used in clinical laser interstitial thermal therapy (LITT), such as the Medtronic Visualase system [21], and this provides a good experience and demonstration of PTT technology guided by thermometry. However, the cost of MR thermometry is high, the equipment is bulky, and the temperature measurement speed needs to be further improved for dynamic automatic temperature control. Given these issues with existing approaches, there is a strong demand for a robust non-invasive temperature measurement technology.
Photoacoustic (PA) temperature measurement technology is a new non-invasive temperature monitoring method developed in recent years, which can measure the relative change of temperature based on the reference temperature [22]. Under nanosecond, short-pulse laser irradiation, biological tissue will absorb energy and generate thermal expansion, and the initial sound pressure generated maintains a good linear relationship with the tissue temperature over a certain range [23], [24], [25]. PA technology combines the advantages of the high penetration of an ultrasonic method and high contrast of optical methods, which gives it the potential for higher precision tissue temperature measurement within a certain depth and range. Moreover, deeply embedded tumors can be detected by PA imaging based on the inherent optical contrast between cancerous and healthy tissues, and more comprehensive information before and after phototherapy will be provided by multi-modal image fusion of PA and other modalities such as ultrasound images [26], [27].
Although many studies have verified the feasibility of PA temperature measurement technology for biological tissues, the focus of many was on measuring temperature values without achieving temperature imaging. Moreover, previous investigations have not achieved the organic integration of PA thermometry imaging and temperature control of the target area to enhance the function of the PTT system, and the empirical open-loop power control method is still used in clinical treatment. It is necessary to combine temperature measurement with closed-loop temperature control of the target area to improve the efficacy of PTT.
Firstly, we propose the PA energy-based temperature mapping method (PETMM) to extract the temperature information contained in PA image, and based on this, multi-modal real-time imaging of ultrasound, photoacoustic and temperature has been realized. Secondly, the photoacoustic control sensitivity factors (PACSF) are extracted from the radio frequency (RF) signals to measure the temperature change in real time, and we put forward the target temperature control algorithm based on RF information. Based on the reference temperature combined with the measurement of temperature relative change, the real-time control of the target temperature is finally realized. Thirdly, a mild-temperature photoacoustic photothermal therapy (MPA-PTT) system with an integrated and compact handheld probe combining pulse and continuous wave (CW) laser for simultaneous multi-modal imaging and photothermal temperature control in PTT is developed. Agar based phantoms were prepared to verify the imaging and control algorithms. To further verify the potential of the system for clinical application in human PTT surgery, we simulated image-guided PTT with pig liver tissue and simulated image-guided PTT. A discussion on combined multimodal imaging to guide, monitor, and control the efficacy of PTT is also provided.
Section snippets
Principle of temperature measurement based on PA information
When the pulsed laser irradiates the tissue surface, light energy deposition occurs in the irradiated area, and part of the energy will be absorbed by the tissue. The resulting temperature gradient forms a pressure field inside the sample and begins to expand thermally, thus generating PA effect to excite ultrasonic waves. The initial pressure rise generated by this effect can be described as:
where is the optical fluence, represents exponential
Construction of the MPA-PTT system
A new integrated MPA-PTT system (Fig. 3) was assembled based on an open-platform commercial ultrasound imaging system (Prodigy, S-sharp, Taiwan). The system is mainly composed of light source module, power control module, timing control module, and temperature imaging module. The RF signals are converted into PA and temperature image by corresponding reconstruction algorithms, and the system simultaneously calculates the PACSF and feeds it back to the power control module to control the CW
PA temperature measurement
Fig. 7 shows the peak-to-peak measurement results of the PA signals of each group of phantoms at a temperature of 25 °C. Since the No. 1 phantom sample was manufactured without a small amount of India ink, the light absorption capacity and corresponding PA signals were very weak. The other groups obtained good PA signals and showed a linear relationship with the amount of ink added. This demonstrates that the PA signals are modulated by the light absorption coefficient, which is consistent
Discussion
The application of PA temperature measurement technology to measure the temperature of biological tissues is a very promising detection method in the field of tumor PTT. We designed a new type of MPA-PTT system which is designed in response to the specific functional requirements for target temperature imaging and control. The PETMM was used to extract temperature information contained in PA images to achieve real-time temperature detection and imaging. We designed an accurate temperature
Conclusion
Compared with the traditional open-loop PTT method, the mild-temperature photothermal treatment method based on photoacoustic temperature measurement and control can potentially be used: (1) to non-invasively measure temperature changes in tissue with an accuracy of better than 0.5 °C; (2) to perform real-time temperature imaging of tissue; (3) to assist in precisely control the temperature of ROI in PTT. More importantly, problems such as PTT-induced tissue carbonization could be avoided.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
This work was supported by National Key R&D Program of China [2018YFC0114800].
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