Theoretical and Experimental Studies of the Dynamic Damage of Endothelial Cellular Networks under Ultrasound Cavitation
Endothelial cells play a crucial role in the vascular system, regulating hemostasis, vasodilation, immune responses, and inflammation through intercellular junctions (IJs). However, excessive mechanical loading can lead to endothelial cell damage and endothelial barrier dysfunction. Understanding the dynamic rupture mechanisms of intercellular junctions is significant for exploring practical applications such as tumor destruction, vascular remodeling, and drug delivery. Ultrasound cavitation, as an emerging technology, can generate localized high energy through bubble vibration and collapse, thereby causing damage to soft tissues. Yet, the damage mechanisms of ultrasound cavitation on endothelial cellular networks remain unclear, limiting its precise application in the medical field. Therefore, this study aims to reveal the dynamic damage mechanisms of ultrasound cavitation on endothelial cellular networks through theoretical modeling and experimental validation.
Source of the Paper
This paper was co-authored by Chuangjian Xia, Jiwen Hu, Kun Zhou, Yingjie Li, Sha Yuan, and Qinlin Li from the School of Mathematics and Physics, Hengyang Medical School, and the School of Electrical Engineering at the University of South China. The paper was published online on November 28, 2024, in the journal Cellular and Molecular Bioengineering, titled “Theoretical and Experimental Studies of the Dynamic Damage of Endothelial Cellular Networks under Ultrasound Cavitation.”
Research Process and Details
1. Theoretical Modeling
The research team first developed a cellular network model based on a composite hexagonal structure to simulate intercellular connections in endothelial cells. It was assumed that intercellular junctions consist of nonlinear spring systems with viscoelastic and damping properties. The model considered three types of connections: intercellular junctions, intracellular fiber connections, and cell-substrate connections. By introducing stress relaxation and strain accumulation methods, the dynamic response of the cellular network under external forces was simulated.
2. Numerical Simulation
The study employed the Runge-Kutta (4,5) method to numerically solve the model, simulating the damage evolution process of the cellular network under different external force conditions. By adjusting force amplitude, driving frequency, and pulse frequency, the cumulative effects of cellular network damage were analyzed. Simulation results showed that cellular network damage was positively correlated with force amplitude and pulse frequency but negatively correlated with driving frequency.
3. Experimental Validation
The experimental part used human umbilical vein endothelial cells (HUVECs) as the research subject. The experimental setup included a single-element focused ultrasound transducer to generate ultrasound cavitation effects. Using microscopy and the image processing software ImageJ, researchers recorded the damage morphology of HUVECs under different ultrasound energies and pulse frequencies. Experimental results demonstrated that ultrasound cavitation had a significant cumulative effect on endothelial cellular network damage, and the damage rate was positively correlated with ultrasound energy.
Main Results
1. Stress-Strain Response
Simulation results revealed that the stress-strain response of intercellular junctions exhibited significant nonlinear characteristics. When strain was less than 0.02, stress and strain were positively correlated; when strain ranged between 0.02 and 0.05, the connection entered a strengthening phase; and when strain exceeded 0.05, the connection entered a compression phase, ultimately leading to rupture. These results were consistent with the mechanical behavior of fibrin fibers.
2. Cumulative Cell Damage
Both simulations and experiments indicated that cellular network damage had a notable cumulative effect. Under low-load conditions, cell damage began to increase significantly after 1800 cycles, while under high-load conditions, the damage rate reached 60% after 3000 cycles. Experiments further validated the model’s effectiveness, showing that ultrasound cavitation-induced damage to endothelial cellular networks had a threshold effect, with damage significantly increasing when ultrasound energy exceeded 0.3 J.
3. Damage Morphology Evolution
Both simulations and experiments observed the tearing of cellular networks and cell migration. As external forces continued to act, intercellular connections gradually ruptured, forming large gaps, and some cells detached from their original positions, clustering to form “cell islands.” This phenomenon was highly consistent with observations in ultrasound cavitation experiments.
Conclusions and Significance
Through theoretical modeling and experimental validation, this study revealed the dynamic damage mechanisms of ultrasound cavitation on endothelial cellular networks. The results demonstrated that cellular network damage was closely related to the amplitude, frequency, and pulse frequency of external forces, and the damage exhibited a cumulative effect. These findings provide important theoretical support for the application of ultrasound cavitation in tumor therapy, vascular remodeling, and drug delivery. Additionally, the cellular network model proposed in this study offers a new platform for understanding the damage mechanisms of endothelial tissues, aiding in the development of more effective prevention and treatment methods.
Research Highlights
- Innovative Model: The first application of a composite hexagonal structure to model endothelial cellular networks, considering the nonlinear and viscoelastic properties of intercellular junctions.
- Multiscale Validation: Comprehensive revelation of the damage mechanisms of ultrasound cavitation on endothelial cellular networks through combined numerical simulations and experimental validation.
- Application Value: The research results provide crucial theoretical support for the precise application of ultrasound cavitation in the medical field, particularly in tumor therapy and drug delivery.
Other Valuable Information
The research team also found that low-frequency ultrasound is more likely to cause cellular network damage, offering important references for optimizing ultrasound cavitation parameters. Furthermore, the proposed model can be extended to other types of cells and tissues, providing a new tool for biomechanical research.