Modeling low-intensity ultrasound mechanotherapy impact on growing cancer stem cells

TL;DR

A multiscale model and computational framework is introduced to comprehensively explore the therapeutic LIUS on poroelastic tumor dynamics, thereby unraveling the intricacies of mechanotransduction mechanisms at play.

Abstract

Targeted therapeutic interventions utilizing low-inten\-sity ultrasound (LIUS) exhibit substantial potential for hindering the proliferation of cancer stem cells. This investigation introduces a multiscale model and computational framework to comprehensively explore the therapeutic LIUS on poroelastic tumor dynamics, thereby unraveling the intricacies of mechanotransduction mechanisms at play. Our model includes both macroscopic timescales encompassing days and rapid timescales spanning from microseconds to seconds, facilitating an in-depth comprehension of tumor behavior. We unveil the discerning suppression or reorientation of cancer cell proliferation and migration, enhancing a notable redistribution of cellular phases and stresses within the tumor microenvironment. Our findings defy existing paradigms by elucidating the impact of LIUS on cancer stem cell behavior. This endeavor advances our fundamental understanding of mechanotransduction phenomena in the context of LIUS therapy, thus underscoring its promising as a targeted therapeutic modality for cancer treatment. Furthermore, our results make a substantial contribution to the broader scientific community by shedding light on the intricate interplay between mechanical forces, cellular responses, and the spatiotemporal evolution of tumors. These insights hold the promising to promote a new perspective for the future development of pioneering and highly efficacious therapeutic strategies for combating cancer in a personalized manner.

Figures (9)

• Figure 1: Mechanotransduction function in an ultrasonic interval. Cells perceive the average of the sigmoid function $\mathcal{M}_{B}$. The slow ultrasound stress is constant at an ultrasonic time interval, while ultrasound stress exhibits dynamic behavior, oscillating between rarefaction and compression -- for this case, we have plotted the absolute stress of a wave with an amplitude of 1kPa --. To account for the dynamic nature of ultrasound stress, the static stress limit $\sigma_L$ is decreased by a coefficient $\beta_u$. However, if the limit is exceeded, it may result in cell disruption and cessation of proliferation or migration, indicated by $\mathcal{M}_B=0$.
• Figure 2: Flowchart of the multiscale system. The system is initialized on a slow scale, where displacements, fluid pressure and solid phases are obtained. The solid phases are added to the fast-scale model of wave propagation to consider the viscosity of the tumor cell phase dependence, and it evolves until the stationary wave is achieved, where the ultrasonic hydrostatic stress is computed. Together with the slow hydrostatic stress, the ultrasonic stress is considered to compute the evolution of the system accounting for mechanotransduction. The results are again included at the slow and fast scale to complete the time loop until the final time of the simulations is achieved.
• Figure 3: Setup of the measurements. The Arduino is connected to the computer and the software is loaded, allowing the switch of mechanical signals. The Arduino also serves as a trigger to restart the signal and prevent any delay. The wave is generated using Matlab software and then loaded into the wave generator. Before connecting the wave generator to the amplifier, the signal is first verified using an oscilloscope to ensure that the frequencies and connections are correct. Once the signals have been tested, the transducer is connected and placed on the support, and the coupling gel is extended on the transducers and bioreactor faces as a coupling material to avoid air bubbles. The relays are then connected. As the final step, cells are transferred to their designated chambers in the bioreactor and placed in the incubator until subsequent analysis.
• Figure 4: Sonication scheme. The transducer emits an ultrasonic wave through the first medium of water, which prevents the temperature from increasing. The wave then travels through the culture containing cells and attenuating media, causing the acoustic pressure to decrease as it encounters different materials and viscosities. As a result, the same bioreactor can be used for a given frequency and various acoustic pressures.
• Figure 5: Hydrostatic stresses during growth. a) Slow hydrostatic stress of sonicated CSC at t = 1day and b) slow hydrostatic stress of sonicated CSC at t = 3days. Slow hydrostatic compression increases at the center of the spheroid as it grows. c) Fast ultrasound stress before reaching tumor spheroid and d) fast ultrasound stress when stationary state is achieved, where a slight decrease in stress is perceived after reaching the tumor spheroid. The main parameters for sonication are: frequency $f=5$MHz, $A=1.5$kPa, tumor viscosity $\eta_T=2\mathrm{Pa\cdot s}$ and culture medium viscosity $\eta_c=0.05\mathrm{Pa\cdot s}$.