CRCNS US-German Research Proposal: Computational modeling and real-time visualization of microscale-forces-induced neurovascular unit permeability

The blood vessels in the central nervous system fulfill the complicated task of providing oxygen and nutrients to the neurons, while at the same time protecting the neurons from harmful molecules. This is accomplished through tight opposition and closure of the cells that cover the inner surfaces of these vessels. How these cells respond to microscale mechanical vibrations is a mystery.

Such vibrations occur when sound waves that are too high-pitched to be audible propagate through tissues. Another way to generate microscale vibrations is a brief laser pulse. The goal of this research is to develop a novel technology that creates controlled microscale vibrations, while at the same time microscopically visualizing the effect.

The neuronal layer in the back of the eye, the retina, will be used for this study. These experiments will provide for the first time insights into how cells react to mechanical alterations and will open the door to a new category of interventions. It is expected that cells distinguish the pitch and intensity of these microscale mechanical vibrations and gauge their responses accordingly.

During normal aging or in diseases, such as Alzheimer’s disease, aberrant molecules accumulate around neurons and impede their normal functioning. Controlled microscale mechanical vibrations bring about new possibilities for dislodging and removing these deleterious molecules before neurons are harmed and the individuals’ cognitive or visual functions decline.

The principal investigator will engage with students and educators in the broader community to share the novel technologies under development herein. A goal will be to attract, enroll, and train individuals with disabilities, women, and minorities in this area of research.

The Blood-Retina-Barrier (BRB) selectively regulates the permeability of molecules that reach the neurons. There is an unmet scientific and medical need for a temporal and non-injurious opening of the BRB. The goals of this project are A) development of a novel technology to deliver microscale mechanical vibrations to the retina under live microscopy, B) to visualize the effect of these microscale vibrations in the BRB, and C) to computationally model the process of the molecular passage through the BRB.

The expected outcome will be image-guided acoustic and/or photo-acoustic alterations of the BRB. The project team's approach combines in vivo animal experiments with computational modeling in silico. To modulate BRB’s permeability, the project team will implement a recently developed new laser-based photo-acoustic and pure acoustic technologies to study the resulting dynamic processes in real-time with an image-guided approach using custom-developed hardware.

A computational model will be developed based on mass balance equations. In rodents, BRB permeability will be measured through quantitative analysis of angiographic images. The results of the in vivo experiments will refine the computational modeling.

A companion project is being funded by the Federal Ministry of Education and Research, Germany (BMBF). This project is jointly funded by the following NSF programs: Disability and Rehabilitation Engineering and Collaborative Research in Computational Neuroscience.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.