Introduction to the Biological Effects of Terahertz Radiation

Abstract

Terahertz (THz) radiation has been noted to affect biological organisms to a unique degree with various effects ranging from modifications brought to protein activity to epigenetic changes that lead to altered metabolism or reproduction. These effects are classified into thermal and non-thermal, with the former being caused by THz’s capacity to induce localised thermal changes while the latter involves more complex interactions with cells’ macromolecules which are poorly understood. Terahertz’s ability to enhance actin polymerisation and alter gene expression leads to a number of possible applications in agriculture, as it has been observed that certain plant species have higher growth speeds post-exposure, and medicine, with cancer’s rapid division being possibly slowed down.

1. Introduction

Terahertz radiation (T-rays or THz) is known for inducing various changes in biological macromolecules and structures despite being a form of non-ionising radiation [1]. Genetic changes, metabolic shifts and general alterations in cells’, tissues’ and whole organisms’ functioning and structure have been recorded [2, 3, 4, 5]. Research is still in its early stages surrounding this type of radiation’s effects and as such its documented effects are not very well understood.

THz is known for inducing thermal and non-thermal changes in biological tissues. In most cases, it is unclear which of the types of alterations occur or whether it is a combination of the two that gives rise to the observed phenomena. In some instances, the entirety of the energy provided by THz gets transformed into thermal energy.

An important factor surrounding terahertz’s effects is the presence of water in the organism exposed. Its absorption coefficient is 300 cm⁻¹ at 1.5 THz which makes it a powerful T-rays absorption material [6]. Thus, in some instances, water can act as a shield or as an agent that exclusively stops non-thermal effects but enhances the latter form of energy transfer, all being reliant on the proportional quantity of water present in the tissue analysed.

To account for the thermal effects of THz, a heat transfer model can be developed. For preliminary characterisation of its effects on biological materials the relationships that describe the rate of heat generation and rise in temperature suffice.

The following protocol has been adapted from multiple sources. See [7, 8, 9, 10].

Due to the air-skin interface representing an optical system of two very different mediums, the refracted beam’s angle can be found by applying Snell’s law:

$$n_1\mathit{sin}{\theta }_1=n_2\mathit{sin}{\theta }_2$$E1

where n₁ and n₂ are the refractive indexes of air and skin, respectively, and θ₁ and θ₂ are the incident and refracted angles, respectively.

Next, the Fresnel equation helps determine how much THz power is lost to reflection:

$$R_S=\frac{1}{2}\left(\frac{{\mathit{tan}}^2\left({\theta }_1-{\theta }_2\right)}{{\mathit{tan}}^2\left({\theta }_1+{\theta }_2\right)}+\frac{{\mathit{sin}}^2\left({\theta }_1-{\theta }_2\right)}{{\mathit{sin}}^2\left({\theta }_1+{\theta }_2\right)}\right)$$E2

where R_S is the THz power lost due to reflection or specular reflectance.

It should be noted that R_S increases exponentially for angles of incidence greater than 60 degrees.

After accounting for this reflective loss, the final spectral flux that passes through the tissue is provided by Lambert–Beer’s law:

$$A=\frac{{\mathrm{\Phi }}_{\mathrm{e},\mathrm{\lambda },\mathrm{f}}}{{\mathrm{\Phi }}_{e,\mathrm{\lambda },\mathrm{o}}}=e^{\left(-{\mu }_{a}d\right)}$$E3

where A is absorbance, Φ_e,λ,f is the final spectral flux, Φ_e,λ,o is the initial spectral flux of the beam that hits the skin, μ_a is the absorption coefficient, and d is the distance traversed by the radiation. It is worth noting that a new set of equations is to be applied each time the medium changes to account for the different refractive index (n) and tissue absorption coefficient (μ_a). Moreover, the Poynting vector’s relationships may also be of use in calculating the value of the final spectral flux (Φ_e,λ,f):

$${\mathrm{\Phi }}_{e,f}\approx {\int }_{\Sigma }⟨|S|⟩\mathit{cos}{\theta }_1\mathit{d\Sigma }$$E4

where Φ_e,f is the final radiant flux, ⟨|S|⟩ is the time average of the Poynting vector, θ₁ is the incident angle of the beam, and A is the area of tissue exposed.

The final spectral flux is then obtained by applying the relationship:

$${\mathrm{\Phi }}_{e,\mathrm{\lambda },\mathrm{f}}=\frac{\partial {\mathrm{\Phi }}_{e,f}}{\mathrm{\partial \lambda }}$$E5

The equations surrounding the rise of temperature in biological tissues are governed by the following formula:

$$R\left(x,y,z\right)={\mu }_a\left(x,y,z\right){\Phi }_{e,\lambda ,f}\left(x,y,z\right)$$E6

where R is the rate of heat generation at a point of Cartesian coordinates x, y, z in the tissue measured in Wnm⁻¹, μ_a is the local absorption coefficient, and Φ_e,λ,f is the radiometric spectral flux. After finding the value of R, the equation that describes the increase in temperature can be used:

$$∆T\left(x,y,z\right)=\frac{R\left(x,y,z\right)∆t}{\mathit{\rho c}}$$E7

where ∆T is the localised temperature rise, ∆t is the duration of the exposure, ρ is the tissue density, and c is the tissue’s specific heat capacity.

Eqs. (6) and (7) describe optical phenomena taking place for one point of Cartesian coordinates x, y and z. To adapt them for a tissue area, the average THz absorption coefficient of the tissue and the spectral irradiance need to be calculated. The latter is obtained using the following relationship:

$$E_{e,\lambda ,f}=\frac{\partial {\Phi }_{e,\lambda ,f}}{\partial A}$$E8

where A is the area exposed.

For more advanced modelling of the heat transfer of THz in tissues, the Pennes’ bioheat equation and its Cartesian transformation can be used in modern computational and simulation techniques. Discussing these, however, is beyond the scope of this chapter.

Moreover, taking into account the complex interaction between water and terahertz radiation, a complete model describing heat generation would require taking into account rotational transitions, dielectric properties of water and the coupled oscillating electric and magnetic fields’ inter-relational excitations through a system of several equations such as Debye’s model, Maxwell’s set, Newton’s cooling and Von Neumann’s. Multiple accepted models may arise just as in the case of the mathematical relationships used to describe the phenomena that occur with microwave heating [11].

2. Interaction with animal tissue and cells

To properly interact with mammalian organisms’ tissues, terahertz radiation must first bypass the skin. The degree to which T-rays penetrate through the epidermis is not fully known due to the under-characterised optical properties of melanin, sulphated proteoglycans and other major components of the epidermis. The dermis, unlike its superficial homologue, has a composition that is very rich in glycosaminoglycans that are capable of holding large amounts of water molecules which impedes the passage of terahertz radiation. This makes it behave very similarly to free water from a reflectivity point of view [12]. Moreover, different concentrations and types of melanin drastically influence the optical properties of the dermis [13, 14].

There are conflicting reports regarding the importance that collagen has regarding skin THz absorption. In one study, it was found that isolated skin collagen has an insignificant response to T-rays [12]. In another, the authors found that the heat denaturation of collagen fibres is directly related to a decrease in the absorption capabilities of the dermis [15].

While THz can interact wildly differently with different organisms, there are a couple of effects that occur irrespective of the structure exposed. These include the formation of reactive oxygen species (ROS), reactive nitrogen species (RNS), cellular, nuclear and lysosomal membrane destabilisation and general hyperthermic shock responses [16, 17, 18, 19, 20, 21].

T-rays also affect the structure and activity of various proteins and enzymes [22].

Moreover, terahertz radiation has been placed under the spotlight due to its observed effects on genetic material. Specifically, it manages to break the hydrogen bonds that hold double-stranded DNA together by creating interference within its double helix structure through presumed nonthermal effects [23]. This type of EM radiation is also capable of demethylating various genes with a wide range of effects, showing promise as a potential cancer treatment [24]. It has also been shown capable of inducing histone H2AX phosphorylation in human skin fibroblasts, effects which last for at least 24 h [25]. THz has even been reported to induce aneuploidy in human lymphocytes [26] and of changing the gene expression of mouse stem cells so that they more readily differentiate into adipocytes via the activation of the transcription factor peroxisome proliferator-activated receptor gamma (PPARG) [27].

Additionally, terahertz radiation is capable of interfering with intracellular actin structures. There exist conflicting reports with some authors suggesting that THz collapses actin filaments [28] while others claim an enhancement of actin fibrils lengthening dynamics [29]. It has also been observed that cellular division is inhibited via actin-mediated interferences [30].

3. Medical implications

3.1 THz as a data acquisition tool

Terahertz radiation has seen applications in laboratory environments, helping detect the presence and concentration of various biomolecules with fine precision. The main method used is spectroscopy which has various subsets such as vibrational and attenuated total reflection [31, 32, 33, 34, 35, 36]. Considerable advances have been made with regard to THz analysis techniques of biomolecules in aqueous environments [37].

THz spectroscopy is very precise, being able to distinguish between different enantiomers and going as far as identifying the different hydrogen isotopes present within the structures of amino acids [38]. It is also able to assess the configuration and hydrogen bonding of various molecules [39]. Finally, by coupling T-rays to various subwavelength probes, a resolution that reaches ångströms can be achieved [40, 41].

There are also numerous claimed applications for terahertz radiation in in vivo and ex vivo medical analyses such as biopsies and dental scans [42, 43]. Various tissues interact differently with THz. Skin and adipose tissue have similar absorption coefficients but both differ from muscles. The main determining factor seems to be water content [44]. Thus, terahertz scanning methods should be able to distinguish between different tissues or even cell types based on their hydration, complementing existing medical screening techniques.

Several materials do not interact strongly with THz and could be used in diagnostic and laboratory scans. Such an example is high-density polyethylene (HDPE) (Figure 1).

Figure 1.

THz absorption spectrum of HDPE. Image owned by the author. See notes for more information.

Acrylic is not very suitable due to its peak absorbance coefficient reaching values of 15 cm⁻¹. Cycloolefins seem to be the optimal window material choice, as they display close to no optical interaction with THz. Other materials such as teflon have very low absorption spectra but should not be used due to their environmental and health impact [45].

3.2 Curative and toxic properties

Terahertz radiation has also seen therapeutic usage. It can demethylate cancer cells and increase the speed of regeneration at injuries’ site [46, 47, 48]. It has even been found to be beneficial against psoriasis [49] and in the recovery from an acute ischemic stroke [50].

However, the use of these therapeutic effects faces barriers due to the adverse effects often caused by terahertz radiation exposure. Most reports describe general inflammation responses and apoptosis that have been recorded across a vast array of cell types and species. Loss of adhesion to basal membrane, cellular permeability increases, lysis and marked increases in cell growth factors and cytokines have all been connected to T-rays exposure, although these seem to mainly stem from its thermal effects [51, 52, 53]. However, there are also reports that contrast these findings, albeit very few [54, 55].

Nervous tissue cells in particular have been found to release their intracellular proteolytic enzymes and suffer membrane protein changes under THz. No great morphological changes such as axon number or size have been recorded [56, 57]. Various types of neurons also show different reactions to T-rays as seen by their marked changes in neurotransmitter production [58]. There also seems to be a threshold of 0.15 THz under which exposure will not induce any detectable adverse reactions [59].

3.3 Other uses

It has been reported that terahertz radiation can be successfully used to sterilise liquids [60].

4. Effects on plant and fungi matter

4.1 Plants

There are very few studies that investigate the use of terahertz radiation on plants. The few that do exist have mostly shown variable effects. Depending on the dosage, there has been an increase, decrease or no change in the growth rate of adult plants [61]. Meanwhile, a report shows that dry wheat seeds exposed during their dormant state and with no additional T-rays received afterwards have a lowered rate of successful germination contrasted by variable growth speed changes [62].

The absorption coefficients of starch, chlorophyll and other plant compound have been determined [63, 64, 65, 66, 67]. Moreover, the separation of seeds based on their bacterial blight resistance or genetic modifications has been described [68, 69].

4.2 Fungi

There is almost no literature on the effects of THz exposure on fungi with the exception of one report that found an increase in cellular growth in the S. cerevisiae yeast [70].

5. Environmental effects

Terahertz radiation may be able to penetrate the soil to a considerable depth and, having in mind its effects on tissues of animals and plants alike, disturb local ecological systems. This raises concerns regarding the rising trend of new agricultural tools that implement this type of EM radiation as a means to keep track of plant development or soil content in microplastics [71, 72, 73, 74, 75, 76]. Locations suffering from a generally dry climate or desertification are at the highest risk of being affected by THz due to the lack of water that could otherwise act as a barrier.

6. Conclusion

The general applications and risks of terahertz radiation usage on living matter prove this type of EM radiation particularly interesting. With applications including cancer treatment and detection, enhanced agricultural output, increased tissue healing and new genetic engineering tools, the technology may lead to an improvement in most scientific fields surrounding biological organisms. However, the lack of understanding of how THz exhibits its effects on living matter remains this field’s weakest point.

The most important steps that should follow are the precise determination of the health effects of exposure to terahertz radiation, taking into account the induced genetic, metabolic and structural changes surrounding both short- and long-term exposure. Characterisation of thermal and non-thermal effects would be the following step to better understand the full complexity surrounding its mechanism of action. Moreover, any experiments performed should outline all the important variables pertaining to them in a standardised fashion. These factors must include the frequency, intensity, source of terahertz, whether the samples are exposed to continuous wave (CW) or pulsating lasers, any temperature changes and the water content. This list is not exhaustive.

Acknowledgments

The author is grateful for the financial support provided by the University of Medicine and Pharmacy “Carol Davila”.

Conflict of interest

The author declares no conflict of interest.

Notes

The spectrometer TeraView (TPS Spectra 3000) was used for the production of Figure 1. It is capable of emitting terahertz radiation through an optical tunable Ti: Sapphire ultrashort pulsed laser with a spectral range of 0.1–3 THz. During the identification of the absorption spectrum of HDPE, it was set to 150 mW, half its original power.

Thanks

A special note of thanks is addressed to my brother, family, friends and tutors who are tirelessly supportive of all of my endeavours.