Biological Effects of Intense Terahertz Pulses

• Author / Creator

  Hough, Cameron M.

• Terahertz (THz) radiation is a non-ionizing form of electromagnetic (EM) energy that occupies a broad frequency region at the interface between conventional microwave and infrared bands. The strong coupling between THz excitations and natural oscillatory dynamics in biological systems has motivated the development of novel biomedical imaging and spectroscopy technologies, with unique advantages for improved diagnostic power for diseases such as cancer. However, while THz radiation is non-ionizing, and therefore considered a non-destructive probe, the coupling to vibrational or rotational modes implies that external excitation with intense pulses of THz energy could non-thermally dysregulate structural dynamics of important structures (e.g., proteins, nucleic acids, or membrane structures) such that the associated function is compromised. These may then induce biological effects via a non-thermal interaction mechanism that is unique to the THz band, and therefore must be characterized to establish safe exposure levels for existing technologies, or to develop potentially novel clinical technologies. Historically, the study of biological systems with THz radiation has been hindered by high attenuation in aqueous media, and the lack of available sources that operate efficiently at THz frequencies. However, recent developments in laser-based source technologies have dramatically increased THz generation capabilities. This has led to a resurgence of research interest in biological systems and biomedical applications for this under-explored regime of the EM spectrum.

  For this thesis project, a system for THz exposure and analysis of biological systems is developed, and exposure studies are performed at the molecular, cellular, and tissue scale of biological organization. The radiation source utilizes nonlinear properties of crystal structures to generate and detect highly intense, picosecond-duration pulses of EM energy via optical rectification in lithium niobate and electro-optic sampling in gallium phosphide, respectively. Each single-cycle pulse has a peak electric field strength of up to 640 kV/cm, a broad frequency spectrum peaked at roughly 1.0±0.8 THz, and excites the associated dynamics in exposed samples under study. The pulsed radiation beam is delivered to an environmentally-controlled sample housing. Molecular-level experiments investigate structural changes to polymerized microtubules in solution in real-time via fluorescence microscopy. Cellular-level experiments characterize transient and long-term changes of membrane permeability in monolayer cell cultures induced by THz exposure. At the tissue level, the effects on 3D human skin models are investigated by measuring global differential gene expression for varying THz intensities. These data are used to determine biological processes and molecular signaling pathways that are likely to be dysregulated by THz exposures, particularly focusing on dysregulation of cancer-related processes.

  Intense THz pulses are found to induce significant non-thermal effects at all investigated levels of biological organization. At the molecular scale, disassembly of polymerized microtubules is observed to occur within minutes of an applied train of THz pulses, and this depends on the intensity and frequency content of the applied pulse. At the cellular level, detectable increases of membrane permeability are observed in human and rat cancer cell lines. At the tissue-level, THz exposure induces a large differential gene expression response (1088 genes downregulated, 593 genes upregulated). Processes predicted to be most significantly dysregulated are related to epidermal differentiation, cellular binding/adhesion, and cytokine activity. Several pathways that are commonly implicated in human cancers (e.g., Ras signaling and Calcium signaling) are predicted to be suppressed in an intensity-dependent fashion, and these are predominantly due to a subset of only 42 genes dominantly responsible for THz-induced dysregulation of cancer-related processes. Importantly, the dysregulations observed at the tissue scale are directly related to the structural effects observed in microtubule and cell samples.

  As innovation for applications of THz technologies continues to progress, human exposure levels can be expected to increase. Current technologies intended for human exposure (e.g., diagnostic imaging or security screening) are likely well-below the required intensity to induce significant biological or health effects. However, this thesis shows that intense THz pulses with high peak electric fields are sufficient to induce significant non-thermal biological effects at multiple scales of biological organization. Conclusions from these investigations are discussed in the context of potential clinical therapeutic applications of THz radiation, with the goal of targeted inhibition of pro-mitotic activity in diseased tissue.

• Subjects / Keywords

  • terahertz
  • THz
  • biological effects
  • terahertz exposure
  • cancer
  • cancer signaling
  • radiation
  • optical rectification
  • intense terahertz pulses
  • gene expression
  • ras signaling
  • calcium signaling
  • membrane
  • electroporation
  • electropermeabilization
  • membrane permeability
  • microtubules
  • therapy
  • electromagnetic radiation
  • bioelectromagnetism
  • electromagnetic field effects
  • dosimetry
  • ultrafast
  • biophotonics
  • spectroscopy
  • imaging
  • cancer

• Graduation date

  Fall 2021

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/r3-sfzj-n891

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.