Transcriptomic Investigation of Bioeffects from Microbubble and Focused Ultrasound Assisted Blood Brain Barrier Opening

Microbubbles stimulated by focused ultrasound is a rapidly emerging technique for noninvasively permeabilizing the blood brain barrier (BBB) for the delivery of therapeutic agents. Despite its prevalence, much is still unknown regarding the bioeffects of blood brain barrier opening (BBBO), such as the sterile inflammatory response (SIR). Testing a range of 4 microbubble volume doses (MVD) and 3 mechanical indices (MI), our study aims to investigate how these two parameters influence BBBO and the subsequent SIR RNA transcriptomic responses following permeabilization. Our results highlight that MVD and MI both influence the onset and degree of BBBO, with higher MVD and MI exhibiting the greatest degree of agent delivery compared to lower doses. Additionally, RNA sequencing analysis revealed that the most enriched gene sets are indeed associated with an inflammatory response. Through analysis of BBBO volume and RNA transcriptomics, a therapeutic window was established and indicated a region between BBBO and the onset of SIR where the BBB is permeabilized without significant inflammation. These results may help to standardize BBBO parameters to improve the safety and efficacy of drug delivery into the brain and confront gaps in knowledge regarding the biological mechanisms behind BBBO.