BIOLOGICAL (Human Body- tissues, cells, organs, skin, fluids, DMA, RNA, etc) ) EFFECTS OF TERAHERTZ (THZ) RADIATION‪‬Biological Effects of Terahertz RadiationAbstract Terahertz (THz) imaging and sensing technologies are increasingly being used in a host of medical, military, and security applications. For example, THz systems are now being tested at international airports for security screening purposes, at major medical centers for cancer and burn diagnosis, and at border patrol checkpoints for identification of concealed explosives, drugs, and weapons. Recent advances in THz have regarding the with this . Biological effects studies are a valuable type of basic science research because they serve to enhance our fundamental understanding of the mechanisms that govern THz interactions with . Such studies are also important because they often times lay the foundation for the development of future applications. In addition, from a practical standpoint, THzis also for the safe use of THz . Given the importance and timeliness of THz bioeffects data, the purpose of this review is twofold. First, to provide readers with a common reference, which contains the necessary background concepts in biophysics and THz technology, that are required to both conduct and evaluate THz biological research. Second, to provide a critical review of the scientific literature. Keywords Terahertz . THz . Thermal effects . Microarray . Cellular effects . Gene expression . Invited review . Biological effects . Review article .Radiation CONTENTS 1.Introduction ……………………………………..Background: composition and function of biological structures …………………………….Terahertz interactions with biological materials 3.1. Fundamental principles 3.2. Biological origin of tissue absorption properties 3.3. Thermal response of tissue. G. J. Wilmink (*) : J. E. Grundt 711th Human Performance Wing, Radio Frequency Radiation Branch, Air Force ResearchThermal effects in biological materials 4.1. Organisms and tissues4.2. Mammalian cells4.3. Cellular organelles4.4. Biological macromolecules4.5. Microthermal effectsTerahertz biological effects research5.1. Sources5.2. Detectors5.3. Equipment used for controlled exposures and dosimetry5.4. General challenges and considerationsMethodology and study-by-study analysis of the THz bioeffects literature 6.1. Organism level studies6.1.1. Vertebrates6.1.2. Insects6.1.3. Plants6.2. Excised tissues.applications1stimulated renewed interest biological effects associatedfrequency range biologicalsystems biological effectsresearch necessary accuratehealth hazard evaluation,development of empirically-basedsafety standards, systemsComment [i]: carbon nanotubes(CNTs) and graphene have emerged as extraordinary low-dimensional systems with a variety of outstanding electronic and photonic properties, 1 − 7 including those ideally suited for terahertz THz)devices6.3. Mammalian cells6.4. Cellular organelles: lipid membranes 6.5. Biological macromoleculesSummary and future prospectsIntroduction energy of THz is leveltype of because of below the fromeVs). Thus, are. This fundamental distinction is important vastly free to other free in that are is that only to cause direct. These direct effects are they result in the can causeIn contrast,.terahertz portionelectromagnetic does not but it can cause. For many years, data has been scarce at THz frequencies because suitable sources were notwidely available. However, a recent surge in research activity has resulted in the development of many new types of sources and components. These new THz technologies have bridged the proverbial “THz Gap,” and are increasingly being integrated into a host of practical medical, military, and security applications. For instance, THz imaging and Electromagnetic Spectrum Frequency (Hz) Spectral bands‪10 5 10 6 10 7 10 8 10 10 9 10 10 11 10 12 10 13 10 14 10 15 10 16 10 17 10 18 10 19 10 20 10 21‬Radio waves -wave THz IR VIS UV X- rays – rays Frequency (THz): Wavelength ( m): Wavenumber (cm-1): Period (picoseconds):Photon energy (meV): Temperature (K): h c/ k = 1/ 0.1 3000 3.3 10.0 0.41.0 300 33.4 1.0 4.1 47.810.0 30 334.0 0.1 41.0 478.0from from bulk frequency spectrumregion occupies located. The THz region is between 21 The (THz) a large of the (EM) that isthe (IR) and (MW)typically defined to include the frequencies ranging from 0.1 to 10 THz, where 1 THz equals 1012 Hz. In terms of other frequently used units, this range corresponds to the following: wavelength 1 (303000 m); wavenumber k (3.3334 cm-1); period t (0.110 picoseconds), temperature T (4.8478 K), and photon energy E (0.441 milli-electron volts) (Fig. 1). It is important to note that theinfrared photons several ordersmagnitude energy required toionize,or remove,valence electronsbiological molecules typically, several “T-rays” classified non-ionizing radiation nonionizing andionizing radiation generate differenteffects in biological structures.Perhaps,the most noteworthy difference ionizing radiation particles carry o water and to enough energy ionization effects tbiomolecules.particularly harmfulbiological structures formation ofhighly reactive radicals nonionizingsecondary or indirect damagebiomolecules radiation generateradicals biological structures, thermal effects indistinguishableeffects observed heating becausemicrowave regions as a whichT = h /kB 4.8‪Fig. 1 The Terahertz (THz) band of the electromagnetic spectrum.‬sensing techniques are presently used at major airports for security screening purposes [1, 2], at major medical centers for cancer and burn diagnosis [38], and at border patrol checkpoints for identification of concealed explosives, drugs, and weapons [911]. Widespread deployment of new THz applications has prompted increased scientific interest regarding the biological effects associated with this frequency range. In recent years, many timely investigations have been performed to investigate the possible biological effects associated with THz radiation [1222]. Unfortunately, however, a comprehensive review has not yet appeared in the literature which both discusses the fundamental interaction mechanisms, and also critically reviews the bioeffects studies that have been conducted to date. Thus, the purpose of this review is twofold. First, to provide readers with a common reference, which contains the necessary background concepts in biophysics and THz technology that are required to both conduct and evaluate THz biological research. Second, to provide a review and analysis of the studies reported in the literature on the topic of THz bioeffects. This review is divided into seven sections. The first section provides a general introduction tothe THz spectral band. The the ofand an of the irradiation of materials. The fourth section summarizes the primary thermal effects that are observed in biological materials at an organism, tissue, cellular, organelle, and molecular level. The concepts described in this section are valuable because they provide the foundation to understand THz-induced effects at all levels of biological organization. In addition, they give the reader the tools to determine whether the effects observed in THz reports can be fully attributable to the temperature rise generated during exposure. The fifth section surveys the major types of THz sources, detectors, and equipment that are used in biological research. This section also addresses the common challenges and considerations that investigators face in this field. Following the description of THz technologies, the sixth section then describes our methodology to survey the literature. This section provides a comprehensive review and “study-by-study” analysis of the THz bioeffects reports that appear in the literature. The review concludes with a summary section that addresses challenges and future opportunities in this field.2 Background: composition and function of biological structures THz-induced biological effects are influenced by two general factors: the THz exposure(i.e., etc.) and the of the . This section provides background on the chemical composition and function of skin, the. It also discusses energy deposition processes and temperature transients that result from THz of THz with and3second section describes composition function biologicalstructures: skin tissue,mammalian cells,organelles,biological macromolecules.The third section provides fundamental mechanisms governinginteraction radiation biological materials overview the parametersfrequency, power,exposure duration,composition and/or properties biological target largest and primary biological target for THz radiation. Please note, the is also an an toproperties. 2.1 and Skin of two(Fig. 2a). The skin and cellfor THz in this we have not. This section also serves to provide the necessary foundation that is required to understand the biological origin of tissue opticalimportant for this cells are type of skin cell.The of a toasaquamousepitheliala biological target effort detailsmake section more concise tissue. The main function of the epidermis is is by 95% of all to and to provide a physical barrier that not only protects against water loss, but also prevents harmful external agents from entering. This protectivebarrier epithelial tissue consists of five distinct layers or strata: (sc), (sl), (sg), (ss), and (sb) (Fig.2a). as they the to theinclude: increases in keratin production, decreases in water content, decreases in cellular metabolism, loss of nuclei and organelles, and cellular flattening.a b Plasma membraneNucleus Cytosol Inorganic ions RNA H2O Ribosome DNA CytoskeletonMitochondria Endoplasmic reticulum O2 ATP Golgi apparatus Lysosome H+. In brief, these changes cornea4radiation; however,provided Humanskin: structure chemical composition consists primary layers: an outer epidermis and anunderlying dermis epidermis consists of water, keratin proteins,melanin granules,several types,including langerhans, melanocytes,keratinocytes keratinization achieved theRoughly keratinocytes,thus,they are the most common Keratinocytesare genetically programmed undergo cellular differentiationprocess known as keratinization.process results formation layeredbarrier referred stratified squamous tissue. S stratum corneum lucidumKeratinocytes granulosum spinosum basale undergo several phenotypicchanges progress from inner outerstratum Protein Extracellular matrixFig. 2 (ab). a. Skin anatomy. Histological cross section of porcine skin tissue (Hematoxylin and Eosin stain at 40X magnification). Epidermis (epi), basement membrane (bm), dermis (d). Legend for magnification: stratum corneum (sc), stratum lucidum (sl), stratum granulosum (sg), stratum spinosum (ss), and stratum basale (sb) b. Cellular chemistry and morphology. Image created with Ingenuity IPA software. Although keratinocytes in the sb layer are devoid of keratin, they do have high concentrations of melanin, a pigment responsible for skin (i.e., Fitzpatrick skin type). Melanin granules are produced by melanocytes, and they are transferred to keratinocytes via cytocrine secretion mechanisms. To date, studies have not been performed to characterize the optical properties of melanin at THz frequencies; however, comparable studies have been conducted at optical frequencies. These studies report that the absorption coefficient (a) of melanin decreases with wavelength, and can be approximated as: a (cm-1) = 1.70×1012 ×1-3.48 (nanometers, nm) [23]. Assuming this trend continues into the THz region, melanin absorption is probably weak at THz frequencies (i.e., a 10-4 cm-1). In addition to contributing to skin color, the sb layer also The BM is theand in of the the to few of patterncolor. It and have cassistsprimarily formation basement membrane (BM).layer that of type IV.Iseparates epidermis dermis. consists collagen, laminin,entactin,sulfated proteoglycans nterestingly,date,studies characterized the optical properties thesebiomolecules frequencies[24]. Such information would likely improve the accuracy of computational models that are currently used to predictTHz-tissue interactions. Immediately below the epidermis lies the dermis. The dermis provides skin with shape and structural integrity, and it ranges in thickness across the human body between 0.3 and 4 millimeters (Fig. 2a). The dermis consists of dermal fibroblasts that are anchored in an extracellular matrix (ECM). The ECM consists of fibrillar collagen embedded in a ground substance material. It is interesting to note that healthy fibrillar collagen exhibits a characteristic with a of ~60 nm,this The significance of this feature will be described in greater detail in Section 4.1. is of and that their own[25]. Due to this property, large volumes of water typically reside in the at THz banding thermallydamaged c gylcosaminoglycansground substance of the dermis. This is the THz. at THz is to note, thus, (see collagen loses Groundsubstance primarily comprisedSections 3.1-3.3). 2.2 Structure and chemical composition of mammalian cells Cells in the human body come in a wide variety of sizes and shapes; however, virtually all cells (Fig. 2b). First, all cells are enclosed by an outer protective barrier known as the plasma membrane. The plasma membrane provides a selective barrier between intracellular contents and extracellular fluids. The is composed of a periodicitywater,collagen,are whereassignature banding pattern.elastin,proteoglycans,(GAGs).GAGs hydrophilic molecules volumesequester water volumes roughly1000 times property importantbecause water primary chromophore frequencies presencestrongly governs where energydeposited share certain characteristics plasma membranephospholipid bilayer,which containsintegral proteinsComment [i]: Carbon C 60 would then bind with these carbons and make a person even more sensitive to a terra hertz hitComment [i]:are areComment [i]:that for and smalldigesting Lysosomes compartmentsresponsible damaged macromolecules,which are collectedduring phagocytosis autophagy,endocytosis,processes Mitochondria are a of that are allsecond the cell,’ the of in the of is toof class cytoplasmic organellespresent in nearly cells. Nicknamedpowerhouse mitochondria mainfunction generate chemical energyadenosine form triphosphate(ATP).and . The phospholipid bilayer is comprised of two elements: polar are the outer exact of on the cell type, and ratio of cholesterol composition,membranes hydrophilicsurface,and in the tails are in the interior of. The degree of saturation of the carbon-carbon hydrocarbonwhich bonds in the hydrocarbon tails governs the structure and order of the bilayer, where saturated hydrocarbons chains are more restricted and unsaturated chains are more fluid [26]. Overall, the properties and present bilayer interior heads, which orientedtowards thermal sensitivityplasma depend membranesaturated versus 27]. Two distinct regions exist inside the plasma membrane of all cells: and cytoplasm (Fig. 2b). The cytosol makes upthe largest volume of cells, and it is primarily composed of and ions (i.e.,unsaturated hydrocarbonsroles in a thick and ), and cytoskeleton cells, and they also play key. The is [27].that that are cytosol water,organicinorganic sodium,potassium, magnesium,calcium,phosphate,chloride Cytoskeleton filamentsprovide structural support intracellular transport and (pH ~7.17.2) liquid that cellular divisioncytoplasm alkaline contains allorganelles. Organelles are vitalin specialized membrane-boundcompartments provide cellularfunctions.

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