External Basic Hyperthermia Devices for Preclinical Studies in Small Animals

Abstract

Preclinical studies have shown that application of mild hyperthermia (40-43 °C) is a promising adjuvant to solid tumor treatment. To improve preclinical testing, enhance reproducibility, and allow comparison of the obtained results, it is crucial to have standardization of the available methods. Reproducibility of methods in and between research groups on the same techniques is crucial to have a better prediction of the clinical outcome and to improve new treatment strategies (for instance with heat-sensitive nanoparticles). Here we provide a preclinically oriented review on the use and applicability of basic hyperthermia systems available for solid tumor thermal treatment in small animals. The complexity of these techniques ranges from a simple, low-cost water bath approach, irradiation with light or lasers, to advanced ultrasound and capacitive heating devices.

Keywords: hyperthermia; multimodal therapy; preclinical hyperthermia; small animals; standardization.

Figure 3

Illustrations of the cold light source for hyperthermia application. (A) The heat application through one or multiple flexible fiber optic light guides allows for relatively free positioning of the subcutaneous tumor location. The healthy tissue can be shielded from illumination by placement of, for instance, cotton wool; (B) the light source is placed above the target area without interference of any medium. The geometry of heat application is dependent on the width of the light beam and the distance of the light source in relation to the tumor; (C) the water-filtered infrared-A (wIRA) radiation system eliminates the presence of both IR-B and IR-C due to the water filter. This provides a light beam with a high penetration depth. Image C is adapted from Kelleher et al. and Vaupel et al. [76,90].

Figure 5

Illustrations of the high-intensity focused ultrasound (HIFU) device for hyperthermia application. (A) Both the entrance and the exit of the ultrasound wave should be guided by a coupling medium. At the interface between the HIFU transducer and the tumor, the coupling medium ensures acoustic wave propagation. Additionally, at the other side, where the wave exits the tissue, the presence of a medium in combination with an acoustic absorber prevents far field heating within the animal due to energy reflection; (B) the HIFU coupling cone holds both the transducer(s) and the coupling medium. Together, the cone configuration and the coupling medium determines the depth of focus. Incorporation of a split beam transducer allows for application of various heating geometries (element 1–5); (C) the sequence control for the therapeutic and imaging transducer. Acoustic interference between the transducers is prevented by non-simultaneous operation. Ultrasound imaging is performed during the “OFF” period of the therapeutic transducer with an interval of ~100 μs. Image B and C are adapted from Wu et al., Seip et al., Lee et al., and Farr et al. [117,121,122,134].

Figure 6

Illustrations of the capacitive hyperthermia device. (A) The positioning of the animal on the capacitive set up; (B) the lower and upper electrode should be placed plan-parallel for optimal heating. The upper electrode can either be a tissue electrode or a pole electrode; (C) the tissue electrode consists of a conducive fabric surrounded by a fabric cover ring. Placement of the tissue electrode is dependent on the use of rubber bands; (D) the pole electrode consists of multiple steel rods placed in a plastic casing. The bottom of the plastic casing is lined with a conductive fabric. Positioning of the pole electrode is facilitated by a height-adjustable arm. Figure 6 is adapted from Danics et al., Schvarcz et al., Vancsik et al., and Szasz et al. [141,142,144,155].

Figure 1

PRISMA flow diagram illustrating selection of the articles for each hyperthermia technique. This review presents a detailed description of the water bath (Section 3.1), cold light source (Section 3.2), NIR laser (Section 3.3), FUS (Section 3.4), and capacitive hyperthermia (Section 3.5) methods.

Figure 2

Illustrations of a water bath unit for hyperthermia application. (A) Immersion of the target region in a temperature-controlled water bath; (B) the intratumoral temperature distribution of a tumor-bearing leg immersed (43 °C, 5 min). The aligned temperature probes were placed in the tumor center at different depths in relation to the water surface. Image B is adapted from Nishimura et al. [29].

Figure 4

Illustrations of the near-infrared laser light device for hyperthermia application. (A) This system is based on a single laser applicator. The healthy tissues can be shielded either by cotton wool or through the use of an illuminator; (B) uniform laser light can be applied through the use of an illuminator. By passing the light through the chambers, reflections result in spatially homogenized light exiting the device; (C) laser beam adjustments can also be made through the use of two lenses and one prism. By moving the lenses (1,2) further from the prism (3) the beam width expands. Image B is adapted from Dou et al. [101] and image C is adapted from Willerding et al. [41].