Biology subjects

Yu, B. J.

Publications and source records attributed to Yu, B. J..

3 recordsLinked to original sources

bioRxiv2026

Ultrasonic local anesthetic uncaging enables noninvasive, targeted, and transient knock-out of brain function

Noninvasive, spatially localized brain inhibition would enable precise neural circuit interrogation, mapping, and treatment. We previously presented SonoRopi, an acoustically activatable liposomal formulation of ropivacaine, and demonstrated its utility for targeted peripheral nerve anesthesia. Here, we extend SonoRopi to localized brain anesthesia following intravenous administration and transcranial focused ultrasound application. Ultrasonic uncaging of SonoRopi releases ropivacaine, which crosses the intact blood-brain barrier to anesthetize the sonicated region. SonoRopi uncaging in mouse primary visual cortex suppressed visually evoked cortical activity for one hour, while uncaging in rat somatosensory hindlimb cortex produced lateralized, reversible hindlimb sensory anesthesia. Off-target control sonication preserved function in both paradigms. No acute histologic injury or open-field behavioral abnormalities were detected following this intervention. SonoRopi thereby enables noninvasive, spatially targeted, reversible brain inhibition with physiologic and behavioral efficacy in two rodent species.

bioengineering↗

bioRxiv2024

Ultrasonic cerebrospinal fluid clearance improves outcomes in hemorrhagic brain injury models

Introduction (Abstract)Impaired clearance of the byproducts of aging and neurologic disease from the brain exacerbates disease progression and severity. We have developed a noninvasive, low intensity transcranial focused ultrasound protocol that facilitates the removal of pathogenic substances from the cerebrospinal fluid (CSF) and the brain interstitium. This protocol clears neurofilament light chain (NfL) - an aging byproduct - in aged mice and clears red blood cells (RBCs) from the central nervous system in two mouse models of hemorrhagic brain injury. Cleared RBCs accumulate in the cervical lymph nodes from both the CSF and interstitial compartments, indicating clearance through meningeal lymphatics. Treating these hemorrhagic brain injury models with this ultrasound protocol reduced neuroinflammatory and neurocytotoxic profiles, improved behavioral outcomes, decreased morbidity and, importantly, increased survival. RBC clearance efficacy was blocked by mechanosensitive channel antagonism and was effective when applied in anesthetized subjects, indicating a mechanosensitive channel mediated mechanism that does not depend on sensory stimulation or a specific neural activity pattern. Notably, this protocol qualifies for an FDA non-significant risk designation given its low intensity, making it readily clinically translatable. Overall, our results demonstrate that this low-intensity transcranial focused ultrasound protocol clears hemorrhage and other harmful substances from the brain via the meningeal lymphatic system, potentially offering a novel therapeutic tool for varied neurologic disorders.

bioengineering↗

bioRxiv2023

Acoustomechanically activatable liposomes for ultrasonic drug uncaging

Ultrasound-activatable drug-loaded nanocarriers enable noninvasive and spatiotemporally-precise on-demand drug delivery throughout the body. However, most systems for ultrasonic drug uncaging utilize cavitation or heating as the drug release mechanism and often incorporate relatively exotic excipients into the formulation that together limit the drug-loading potential, stability, and clinical translatability and applicability of these systems. Here we describe an alternate strategy for the design of such systems in which the acoustic impedance and osmolarity of the internal liquid phase of a drug-loaded particle is tuned to maximize ultrasound-induced drug release. No gas phase, cavitation, or medium heating is necessary for the drug release mechanism. Instead, a non-cavitation-based mechanical response to ultrasound mediates the drug release. Importantly, this strategy can be implemented with relatively common pharmaceutical excipients, as we demonstrate here by implementing this mechanism with the inclusion of a few percent sucrose into the internal buffer of a liposome. Further, the ultrasound protocols sufficient for in vivo drug uncaging with this system are achievable with current clinical therapeutic ultrasound systems and with intensities that are within FDA and society guidelines for safe transcranial ultrasound application. Finally, this current implementation of this mechanism should be versatile and effective for the loading and uncaging of any therapeutic that may be loaded into a liposome, as we demonstrate for four different drugs in vitro, and two in vivo. These acoustomechanically activatable liposomes formulated with common pharmaceutical excipients promise a system with high clinical translational potential for ultrasonic drug uncaging of myriad drugs of clinical interest. One Sentence SummaryIncorporating a few percent sucrose into a liposome transforms it into an immediately translatable vehicle for noninvasive, on-demand ultrasound-targeted drug delivery.

bioengineering↗