Microbubble formulation influences inflammatory response to focused ultrasound exposure in the brain.

Authors: McMahon D, Lassus A, Gaud E, Jeannot V, Hynynen K

Focused ultrasound and microbubble (FUS + MB)-mediated blood-brain barrier (BBB) permeability enhancement can facilitate targeted brain-drug delivery. While controlling the magnitude of BBB permeability enhancement is necessary to limit tissue damage, little work has attempted to decouple these concepts. This work investigated the relationship between BBB permeability enhancement and the relative transcription of inflammatory mediators 4 h following sonication. Three microbubble formulations, Definity, BG8774, and MSB4, were compared, with the dose of each formulation normalized to gas volume. While changes in the transcription of key proinflammatory mediators, such as Il1b, Ccl2, and Tnf, were correlated to the magnitude of BBB permeability enhancement, these correlations were not independent of microbubble formulation; microbubble size distribution may play an important role, as linear regression analyses of BBB permeability magnitude versus differential gene expression for these proinflammatory mediators revealed significantly greater slopes for MSB4, a monodisperse microbubble with mean diameter of 4 μm, compared to Definity or BG8774, both polydisperse microbubbles with mean diameters below 2 μm. Additionally, the function of an acoustic feedback control algorithm, based on the detection threshold of ultraharmonic emissions, was assessed. While this control strategy was effective in limiting both wideband emissions and red blood cell extravasation, microbubble formulation was found to influence the magnitude of BBB leakage and correlations to acoustic emissions. This work demonstrates that while the initial magnitude of FUS + MB-mediated BBB permeability enhancement has a clear influence on the subsequent inflammatory responses, microbubble characteristics influence these relationships and must also be considered.

Introduction

Purpose Drug delivery with BBB opening

Study Objective To determine how the magnitude of FUS+microbubble-induced BBB permeability enhancement and microbubble formulation influence early (4 h) inflammatory gene transcription and to evaluate an ultraharmonic-based acoustic feedback control strategy.

Disease model Healthy

Outcomes and Safety

Summary of Outcomes FUS+MB increased BBB permeability and upregulated proinflammatory genes (e.g., Il1b, Ccl2, Tnf, Il6, Cxcl1, Icam1), but the magnitude of inflammatory transcription per unit BBB leakiness depended on microbubble characteristics—monodisperse MSB4 (≈4 μm) produced steeper inflammatory responses and lower Ktrans for a given 2f emission compared to polydisperse Definity and BG8774. Successful ultrasound conditions reported: comparison of microbubble formulations Definity, BG8774, and MSB4 (dosed by gas volume); fixed peak-negative pressures (250, 350, 450 kPa) showing semi-log relationships between 2f emissions and Ktrans; and an acoustic feedback control algorithm triggered by ultraharmonic (1.5f) emissions that effectively limited wideband emissions and red blood cell extravasation.

Duration of biological effect 4 h

Safety-related matter When acoustic feedback control (PNP calibrated to ultraharmonic emissions) was used, wideband emissions and red blood cell (RBC) extravasation were largely avoided: small, transient RBC extravasations (<300 μm) were observed in <50% of targets at 24 h and none at 7 days. However, at high fixed peak negative pressures some targets exhibited sustained inertial cavitation and findings consistent with microhemorrhage, indicating that overt vascular damage can occur without proper control.

Brain Region

Visualization unavailable

Ultrasound Parameters

Focal Characteristics Focal depth: None; Focal length: None; Aperture size: None

Treatment frequency single session

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