Characterization of Focused Ultrasound-induced Modulation of the Vascular Permeability in Brain tissues
Year: 2026
Type: dissertation
Abstract: Focused ultrasound (FUS), combined with microbubbles, has emerged as a promising non-invasive technology to temporarily and safely permeabilize the blood-brain barrier (BBB) for targeted drug delivery to the central nervous system (CNS). Despite significant advances in understanding the biophysical effects of FUS, the brain's inherent heterogeneity poses critical challenges. Tissue architecture and vascular properties of distinct physiological brain regions, such as gray matter (GM) and white matter (WM), and pathological tissues like tumors, vary significantly, leading to inconsistent treatment outcomes. Optimizing FUS treatment schemes for these tissue-specific differences is crucial for effective and safe clinical translation. This thesis explored tissue-specific differences and investigated a novel repeated treatment strategy to overcome these challenges.The work proceeded through three aims, progressively narrowing its exploration, from whole-tissue assessment to the characterization of single-vessel extravasation and cellular responses. The first aim demonstrated that repeated FUS significantly enhance drug deposition in both GM and WM, with particular benefit for large molecules like bevacizumab. This study also provided translational evidence from both small and large preclinical animal models, highlighting the need for different FUS parameters to achieve comparable permeability in WM. The second aim delved into a single-vessel analysis, revealing that FUS-induced permeabilization varies among GM, WM, and tumors. This suggests that vascular density and the underlying barrier permeability status—whether leaky (as in tumors), impermeable (in untreated tissue), or FUS-induced permeable—affect treatment outcomes. Lastly, the third aim of this thesis provided biological evidence of the enhanced BBB permeabilization following repeated treatments. This highlighted tissue-specific differences also in key vascular integrity biomarkers, reporting downregulated tight junction proteins, altered water transport, increased transcellular transport and pro-inflammatory signaling. In conclusion, this thesis provides a realization for the field of ultrasound therapies, underscoring the necessity of optimizing treatments to tissue-specific architectures and responses. By demonstrating how a repeated treatment strategy can further permeabilize the BBB in heterogeneous tissue types and by investigating key molecular mechanisms, this body of work represents a significant step towards more effective clinical translation of FUS-mediated drug delivery to the brain, addressing a long-standing challenge in treating a wide range of CNS diseases.
Source: TSpace (University of Toronto)
Author: De Maio, Alessandro
Institution: University of Toronto
Language: English
Subfield: Biomedical Engineering
Field: Engineering
Domain: Physical Sciences
Open Access status: green
OpenAlex ID: W7148206176