Keywords

1 Infrared Radiation

Electromagnetic radiation is a form of energy propagation through space that travels at a constant speed in the form of waves or particles; light and radio waves, for instance, are types of radiation. Solar radiation reaching the earth, also known as the electromagnetic spectrum, exhibits a dual nature as it acts both like a wave and a particle travelling in packets of energy (photons) which propagate through space at the speed of light (2.998 × 108 m/s) [1,2,3]. The energy of electromagnetic radiation is quantified by the number of electron volts (eV) (1 eV describes the energy gained by an electron subjected through a potential difference of 1 Volt) [3]. The wavelike properties of electromagnetic radiation are described by the relationship of velocity (c) to wavelength (λ) (the distance between two consecutive peaks of a wave) and frequency (v) (number of cycles per second, or Hertz, Hz), expressed in the formula Eq. (23.1) [1].

$$ c=\lambda v $$
(23.1)

Regarding photons, the energy carried is described by Planck’s eq. 23.2:

$$ \mathrm{E}= hv $$
(23.2)

where E is the energy (given in Joule [J]); v is the frequency (Hz), and h is Planck’s constant (6.626 × 10−34 J·s). In both equations, the energy associated to the electromagnetic radiation is directly proportional to its frequency and inversely proportional to wavelength, meaning that longer wavelengths result in lower energy and vice versa [1].

The spectrum of electromagnetic radiation ranges from 290 nm to more than 1000,000 nm [4] and is generally divided into seven regions of decreasing wavelength (or increasing energy and frequency). The common designations, as shown in Fig. 23.1, are radio waves, microwaves, infrared (IR), visible light, ultraviolet, X-rays and gamma rays [2].

Fig. 23.1
figure 1

Electromagnetic spectrum and infrared radiation. IR-A (0.7 μm–1.4 μm); IR-B (1.4 μm–3 μm); IR-C (3 μm–1000 μm). λ wavelength, v frequency, UV ultraviolet

Full size image

Infrared radiation constitutes the waveband longer than 0.7 μm and up to 1000 μm. Corresponding frequencies and quantum energies are from the range 300 GHz–385 THz to 1.2 meV–1.6 eV, respectively [5]. Historically, infrared radiation has been divided into three bands, the definition of which differs across industries. The International Commission on Illumination (CIE) indicates the following nomenclature and ranges: IR-A (0.7–1.4 μm); IR-B (1.4–3 μm); IR-C (3–1000 μm) [6]. Alternatively, the International Standard Organization (ISO) 20,473 provides the following definitions: near-IR as 0.78–<3 μm; mid-IR ≥3–<50 μm; and far-IR, or FIR, ≥50–<1000 μm [7]. In this review, we will be using the CIE definition.

All matter (solid, liquid, gas) can absorb as well as emit energy in the form of electromagnetic radiation [8]. The absorption of energy in the visible region of the spectrum excites electrons in molecular bonding orbitals to a higher quantum energy state; this energy is either converted into heat (vibrational energy), and lost as emitted infrared radiation (radiative heat), or alternatively is emitted as visible light of a longer wavelength (fluorescence). For wavelengths in the infrared region, the energy is directly absorbed by molecular vibrational levels and later emitted as infrared radiation. For an object with a temperature T (Kelvin) and a surface area (A), the radiative heat transfer in a time t is given by the Stefan–Boltzmann law of radiation (Eq. 23.3), where P is net radiated power, e is emissivity, A is radiating area, T is temperature of radiator, σ is Boltzmann’s constant (σ = 5.6703 × 10−8), and Tc are the temperature of the surrounding matter [9].

$$ P= e\sigma A\left({T}^4-{T}_C^4\right) $$
(23.3)

Although electromagnetic radiation occurs at all temperatures above absolute zero, the amount of energy (heat) an object can radiate depends greatly on the difference in temperature between the systems involved. In fact, energy transfer occurs from high to lower temperature bodies. It is also important to note that due to the First Law of Thermodynamics, the internal energy of all systems involved in the radiation (emitter or receiver) changes as a consequence of the energy transfer (energy can neither be created nor destroyed) [10] . Within molecules, internal energy can be stored in two main ways, either by exciting the electronic quantum energy levels to a higher state or by increasing the vibrational, rotational and translational energy levels of the bonds or molecules. Depending on the amount of energy transferred, radiation can be divided into ionizing and non-ionizing. Non-ionizing radiation (ultraviolet or visible light) transfers enough energy to the receiver to excite the electron in the highest occupied molecular orbital to the lowest unoccupied molecular orbital. By contrast, the energy carried by ionizing electromagnetic radiation is strong enough to entirely remove tightly bound electrons from an atom or molecule [3]. Ionizing radiation causes damage to biological matter and living cells; for instance, radiotherapy with high-energy radiation such as x-rays or gamma-rays is used to destroy tumor cells. Infrared is a type of non-ionizing radiation whose absorption leads to changes in the vibrational and rotational energy levels of molecules and bonds [5, 11]. All types of infrared radiation (IR-A, IR-B, IR-C) increase the temperature of the absorbing matter, which extent depends on the power density of the radiation, the absorption coefficient of the material, and the rate of energy lost by emission, convection, or conduction.

2 Photobiomodulation

Photobiomodulation (PBM) therapy employs the application of relatively low power levels of red or near-infrared (NIR) radiation to the human body [12]. The overall goal is to treat and heal wounds and injuries, reduce pain and inflammation, regenerate damaged tissue, and protect tissue at risk of dying. Recent studies have made significant advances in understanding the mechanisms of action of PBM [13]. It has long been realized that the cellular powerhouses, called mitochondria, function as major photoreceptors for light of these specific wavelengths (red and NIR). It appears that organs that are particularly rich in mitochondria respond very well to PBM. The photons are absorbed by chromophores present in the mitochondria, and cytochrome c oxidase (unit IV in the respiratory chain) is a leading candidate for this role. The mitochondrial membrane potential is raised and oxygen consumption and ATP generation are increased. Signaling pathways are triggered and transcription factors are activated, leading to fairly long-lasting effects after relatively brief exposure of the tissue to light.

The stimulation of mitochondrial metabolism by PBM can have important biological effects, beyond the simple increase in cellular ATP supplies. Let us consider stem cells and progenitor cells. Stem cells whether they are hemopoietic or mesenchymal in nature are relatively quiescent cells that inhabit hypoxic stem cell niches, which vary depending on the tissue or organ of origin [14]. One of the most important hypoxic niches for stem cells is the bone marrow [15]. Because stem cells are intended to survive for the entire lifespan of the organism, they must take exceptional care to avoid DNA damage that could introduce mutations that could cause cancer. The most common cause of this DNA damage is the oxidative stress produced by reactive oxygen species (ROS). ROS such as hydrogen peroxide and superoxide anion are a natural by-product of aerobic respiration and oxidative phosphorylation (OXPHOS), which takes place in the mitochondria. Because stem cells live in a niche with a low pO2 environment, their mitochondrial metabolism is skewed toward glycolysis and away from OXPHOS. However, under the influence of PBM, the mitochondrial electron transport chain is stimulated toward OXPHOS [16], which tends to produce ROS to induce stem cell differentiation and enhanced motility [17]. When the stem cells emerge from their hypoxic niche in search of higher oxygen concentrations to support their altered mitochondrial metabolism, they will be exposed to many cues and chemokines that direct them to sites of tissue injury or degeneration, where they can then fulfill their regenerative roles [18].

Another very important function of PBMT is its anti-inflammatory effect [19]. The mechanism for this is based upon the division of many types of human immune cells into two completely different phenotypes. This division is most often seen in monocyte/macrophage cells that can either be the M1 or the M2 phenotype [20]. The M1 phenotype is pro-inflammatory in function, with secretion of cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), IL-6, IL-12, and type I interferons (IFN). M1 macrophages are involved in inflammatory responses by producing chemokine ligands, such as chemokine (C-X-C motif) ligands 1–3 (CXCL1–3), CXCL5, and CXCL8–10 [21]. They also produce nitric oxide and ROS to kill microbial cells. On the other hand, M2 macrophages show high phagocytosis capacity, produce extracellular matrix (ECM) components, secrete proangiogenic and chemotactic factors, and IL-10 [22]. M2 macrophages can clear apoptotic cells, and can mitigate the inflammatory response to promote wound healing [23]. One key difference between M1 and M2 macrophages involves arginine metabolism [24]. M1 macrophages express inducible nitric oxide synthase, which metabolizes arginine to nitric oxide (NO) and citrulline, while M2 macrophages express arginase, which hydrolyzes arginine to ornithine and urea. It was recently discovered that another major difference between M1 and M2 macrophages involves the mitochondrial metabolism [25]. M1 macrophages rely mainly on cytosolic glycolysis, while M2 macrophages are more dependent on mitochondrial OXPHOS. It has been shown in several studies that PBM can switch the macrophage polarization state away from the M1 and toward the M2 phenotype [26,27,28]. Therefore, the hypothesis is that PBM switches the mitochondrial metabolism from glycolysis to OXPHOS, thus turning M1 into M2 macrophages and producing the beneficial anti-inflammatory and wound healing effects.

A third biological effect of PBM is involved in pain. Mitochondrial dysfunction has recently been appreciated to be a major factor involved in a variety of painful conditions. These painful conditions include neuropathic pain [29], myalgic encephalomyelitis [30], tendinopathy [31], chemotherapy-induced peripheral neuropathy [32], trigeminal neuralgia [33], and intervertebral disc degeneration [34]. The hypothesis is that the widespread use of PBM to treat painful conditions, especially chronic pain which does not respond to opioid analgesics, could be based on improving the mitochondrial function and normalizing the mitochondrial membrane potential.

3 Heat Sensitive Ion Channels

Over recent years, a large number of stimulus-sensitive ion channels have been identified in all life forms, including humans, called transient receptor potential (TRP) channels. TRP channels were first discovered in 1969 in the “transient receptor potential” mutant (trp-mutant) strain of the fruit fly Drosophila melanogaster [35]. Since then, nine separate families have been proposed which are divided into two groups. Group 1 contains TRPC, TRPV, TRPVL, TRPA, TRPM, TRPS, and TRPN, while group 2 contains TRPP and TRPML [36]. TRPs are relatively non-selective ion channels allowing passage of Ca2+, Mg2+, and Na+ ions. TRP channels can be activated by a wide range of stimuli, including pain, temperature (heat and cold), molecules associated with different tastes, pH, pressure, stretching, vibration, and visible light [37]. There is considerable overlap between different individual TRP family members in terms of which stimulus they can respond to [38].

One of the most interesting sub-family of TRP channels is the TRPV (vanilloid) group [39]. TRPV1 was the first TRP channel to be discovered in humans and was identified as the receptor for capsaicin (the active ingredient in hot chili peppers) [40]. The same group showed that TRPV1 could be activated by a modest temperature increase (≈43 °C) [41]. Later studies described three different TRPV channels that were also heat sensitive, TRPV2 (≈52 °C), TRPV3 (≈33 °C), and TRPV4 (28–44 °C) [42]. These TRPV channels are widely expressed in neurons but are also expressed in other organs, such as tongue, bladder, kidneys, skin, inner ear, and endothelial cells [42]. The expression of TRPV1 in the skin is responsible for the clinically useful topical application of a capsaicin-containing cream as a pain-relieving treatment [43]. TRPV channels are mainly found in the plasma membrane of cells but have also been found to be present in the mitochondrial membrane, particularly in non-neuronal cells [44].

One interesting involvement of TRPV channels concerns the production of nitric oxide. It has long been realized that both IR therapy and PBMT produce vasodilation in the skin and increased blood flow, which has been attributed to increased nitric oxide production. There are many sources of NO in the human body, with the principle ones being the three isoforms of nitric oxide synthase (NOS), inducible (iNOS), endothelial (eNOS), and neuronal (nNOS), as well as dissociation from stores such as hemoglobin and myoglobin, and reduction of nitrite to nitric oxide [45]. Miyamoto et al. showed that activation of TRPV3 in the skin triggered the production of nitric oxide from nitrite that was independent of NOS activity [46].

There is a field of research based on pulsed infrared laser stimulation of neurons (INS) [47]. This technique employs the delivery of circa 1 ms pulses of infrared radiation to depolarize the neuronal membrane and generate an action potential. The mechanism of INS is due to the transient and localized heating caused by absorption of IR radiation by water causing a local temperature increase of between 3.8 and 6.4 °C [48]. It was originally designed to be more versatile than using electrical stimulation, in that it does not require any implantation of wires, but still has good spatial resolution because the laser spot can be 100–400 μm in diameter. When the technique of optogenetics (which uses the introduction of a genetically engineered channel-rhodopsin ion channel into specific neurons using the spatially controlled delivery of virus) became widespread [49], it was realized that INS did not require any genetic modification, and could therefore be more practical for human use [50]. In fact a fiberoptic array for multiple channel INS of the brain has been described [51].

There are two main mechanisms that have been proposed to explain how INS actually works at the level of the axon. The most popular mechanism involves TRPV channels (and particularly TRPV4) being stimulated to produce intracellular calcium changes [52]. The second mechanism involves altering the electrical capacitance of the cell membrane by producing a rapid local increase in the temperature of water, thus depolarizing the target cell [53].

4 Infrared-Emitting Fabrics and Garments

There are several ways to deliver infrared radiation for therapeutic use, varying from heat lamps, saunas, and water-filtered IRA (wIRA), all of which require an external power source, to infrared-emitting materials that rely solely on body heat as a source of power [5, 54]. Bioceramic describes a specific type of mineral material that emits IR-C radiation at body temperature, and which can produce biological effects on the tissue, particularly when worn in close contact with the body for extended periods of time [55, 56]. While the power density emitted by these fabrics is very small when compared to electrically powered IR sources, this is compensated by the fact that garments and patches can be worn for extended periods of time (hours or days), while lamps or saunas are usually only used for minutes at a time. Bioceramic materials are produced by a combination of polymers with ceramic-containing mineral oxides, such as silicon dioxide (SiO2), aluminium oxide (Al2O3), and titanium dioxide (TiO2) [5]. In industrial applications, these minerals are often used in the construction of firebricks and gas mantles. In domestic kitchens, the use of a clay cooking pot is often preferred to a metal cooking pot, because of its ability to emit more infrared radiation at lower temperatures. There have been some attempts to characterize the properties of these infrared-emitting fabrics in the laboratory, including reflectance, transmittance, and emissivity. Emissivity is a measure of how much radiation (7.5–14 μm) an object can absorb and emit compared with a black body (a body that absorbs and emits all radiation falling in it), whose emissivity is defined as 1.0 [57]. Emissivity is a surface phenomenon, therefore nanoparticles or microparticles (which have a large ratio of surface area to mass) are considered to be the most efficient configuration for emitting infrared radiation compared to bulk ceramic material. Anderson et al. utilized Fourier transform infrared spectroscopy to measure the spectral optical properties of textile fabrics woven with varying percentages of ceramic particle-bearing polymeric fibers and found that the emissivity of polyester fabric can be engineered controllably via the inclusion of ceramic microparticles within the fabric fibers [58, 59].

In general, the mechanism of action of infrared radiating materials is to absorb heat energy from the body (radiation, convection, and conduction) and maintain the temperature at sufficiently high levels to be able to re-emit the IR-C energy back to the body with a broad peak centered at 10 μm, according to the Stefan–Boltzmann law [5, 60].

The effects of infrared-emitting ceramics on skin blood flow have been investigated by analyzing the changes observed on several biomarkers. For instance, in a study conducted on 153 healthy individuals wearing shirts containing ceramics compared with standard polyester shirts, changes in arterial oxygen saturation and transcutaneous partial pressure of oxygen (tcPO2) were measured [61]. Similar findings were observed in another study which found increased blood flow (measured as tcPO2 changes) and improved muscular performance (measured as mean hand grip strength) [60]. The benefits of infrared on blood circulation were supported further by a study on patients with Raynaud’s syndrome, where reduced pain and disability of the arm, shoulder, and hand were recorded after wearing infrared-emitting gloves [62]. The topical use of compressive infrared-emitting ceramic containing socks reduced edema and pain in the feet compared with control socks [63].

Other studies have used infrared-emitting nanoparticles incorporated into apparel, such as gloves, socks, belts, or patches, to provide an easy and practical application of therapeutic IR [56, 64]. Bagnato et al. evaluated the efficacy of an IR-C emitting plaster in the treatment of knee osteoarthritis (OA) in a randomized, placebo-controlled clinical study [65]. Loturco et al. investigated the effects of IR-C-emitting non-compressive pants on indirect markers of exercise-induced muscle damage and physical performance recovery in soccer players [64]. The use of IR-C emitting socks showed a beneficial effect on chronic foot pain resulting from diabetic neuropathy or other disorders [66]. The efficacy of an IR-C-emitting sericite (a common mineral) belt in patients with primary dysmenorrhea was evaluated over three menstrual cycles (and 2 follow-up cycles) by Lee et al. in a multicentre, randomized, double-blind, placebo-controlled trial (n = 104) [67]. Lai et al. used a IR-C emitting neck device to partly reduce muscle stiffness in chronic neck pain [68]. These infrared-emitting materials (ceramics and fabrics) are well tolerated, and the only side effect that was occasionally reported was skin irritation and itching (which disappeared within a few days without treatment) [62, 67].

5 Application to Water-Filtered IR-A

It is interesting to compare the two treatments discussed above (PBM and IR emitting bioceramics) with wIRA. The big difference of course is that PBM and bioceramics were designed to produce no detectable heating effect in the tissue. wIRA is very different, in that it was originally designed to produce therapeutic tissue heating. Mild hyperthermia (39 °C– 43 °C) has long been known to be an effective adjuvant in cancer treatment, and the main question is what is the best approach to increase the temperature of the tumor to a therapeutically effective level, without causing unacceptable side effects either to the whole body or to surrounding normal tissue? The wIRA device (hydrosun, Müllheim, Germany) can focus the IR radiation onto a discrete region of the body and is basically a modern sophisticated version of an infrared heat lamp. The big unanswered question is to what extent do the medical benefits of wIRA depend on biological processes that do not require measurable tissue heating to be stimulated? By now everybody will accept that PBMT using red or NIR radiation (or indeed blue and green wavelengths) can produce biological effects by a photochemical mechanism as opposed to a photothermal mechanism. In contrast, it would appear that IR emitting fabrics cannot carry out a photochemical effect because they do not emit light, neither can they carry out a thermal effect because the temperature of the tissue is not increased to a measurable effect. The only solution to this dilemma is the concept of IR energy absorption by nanostructured water clusters that could alter the protein conformation at the nanoscale [69]. The concept of nanostructured water was introduced by Gerald Pollack, who observed the build-up of an “exclusion zone” on certain types of hydrophobic surfaces immersed in water [70]. In fact Pollack called this phenomenon of interfacial water “the fourth phase of water’ [71]. Pollack has also suggested many ways that this interfacial water could be involved in cells and in human biology [72, 73].

Certainly, wIRA does cause a measurable increase in the tissue temperature. This fact does not exclude the possibility of a similar alteration in protein conformation occurring at the same time. The activation of heat-sensitive TRP channels is the main hypothesis to explain the beneficial effects of IR-emitting fabrics, and it is only reasonable to expect this to occur to an even greater extent with the application of wIRA. Future studies should examine the role of TRP channels in the biological activity of wIRA, especially those applications related to wound healing, and the reduction of pain and inflammation.