A major challenge in neuroscience is to reliably activate individual neurons, particularly those in deeper brain regions. Current optogenetic approaches require invasive surgical procedures to deliver light of specific wavelengths to target cells in order to activate or silence them. Here, we demonstrate the use of low-pressure ultrasound as a non-invasive trigger to activate specific ultrasonically-sensitized neurons in the nematode, Caenorhabditis elegans. We first show that wild-type animals are insensitive to low pressure ultrasound and require gas-filled microbubbles to transduce the ultrasound wave. We find that neuron-specific misexpression of TRP-4, the pore-forming subunit of a mechanotransduction channel, sensitizes neurons to ultrasound stimulus resulting in motor outputs. Furthermore, we use this approach to manipulate the function of sensory neurons and interneurons and identify a role for the PVD sensory neurons in modifying locomotory behaviors. We suggest this method can be broadly applied to manipulate cellular functions in vivo.

The inherently toxic nature of chemotherapy drugs is essential for them to kill cancer cells but is also the source of the detrimental side effects experienced by patients. One strategy to reduce these side effects is to limit the healthy tissue exposure by encapsulating the drugs in a vehicle that demonstrates a very low leak rate in circulation while simultaneously having the potential for rapid release once inside the tumor. Designing a vehicle with these two opposing properties is the major challenge in the field of drug delivery. A triggering event is required to change the vehicle from its stable circulating state to its unstable release state. A unique mechanical actuation type trigger is possible by harnessing the size changes that occur when microbubbles interact with ultrasound. These mechanical actuations can burst liposomes and cell membranes alike allowing for rapid drug release and facilitating delivery into nearby cells. The tight focusing ability of the ultrasound to just a few cubic millimeters allows for precise control over the tissue location where the microbubbles destabilize the vehicles. This allows the ultrasound to highlight the tumor tissue and cause rapid drug release from any carrier present. Different vehicle designs have been demonstrated from carrying drug on just the surface of the microbubble itself to encapsulating the microbubble along with the drug within a liposome. In the future, nanoparticles may extend the circulation half-life of these ultrasound triggerable drug-delivery vehicles by acting as nucleation sites of ultrasound-induced mechanical actuation. In addition to the drug delivery capability, the microbubble size changes can also be used to create imaging contrast agents that could allow the internal chemical environment of a tumor to be studied to help improve the diagnosis and detection of cancer. The ability to attain truly tumor-specific release from circulating drug-delivery vehicles is an exciting future prospect to reduce chemotherapy side effects while increasing drug effectiveness.

The use of focused ultrasound can be an effective method to locally highlight tumor tissue and specifically trigger the activation of echogenic drug delivery vehicles in an effort to reduce systemic chemotherapy side effects. Here we demonstrate a unique ultrasound triggered vehicle design and fabrication method where the payload and a perfluorocarbon gas microbubble are both encapsulated within the internal aqueous space of a liposome. This nested lipid shell geometry both stabilized the microbubble and ensured it was spatially close enough to interact with the liposome membrane at all times. The internal microbubble was shown to fragment the outer liposome membrane upon exposure to ultrasound at intensities of 1 - 1.5 MPa. The focused ultrasound allowed the release of the internal payload to localized regions within tissue phantoms. The vehicles showed high payload loading efficiency of 16%, stability in blood of several hours, and low level macrophage recognition in vitro. High speed fluorescent videos present the first optical images of such vehicles interacting with ultrasound. This ability to open the outer membrane in small regions of deep tissue could provide a second level of spatial and temporal control beyond biochemical targeting, making these particles promising for in vivo animal studies.

Stem cell fate is closely intertwined with microenvironmental and endogenous cues within the body. Recapitulating this dynamic environment ex vivo can be achieved through engineered biomaterials which can respond to exogenous stimulation (including light, electrical stimulation, ultrasound, and magnetic fields) to deliver temporal and spatial cues to stem cells. These stimuli‐responsive biomaterials can be integrated into scaffolds to investigate stem cell response in vitro and in vivo, and offer many pathways of cellular manipulation: biochemical cues, scaffold property changes, drug release, mechanical stress, and electrical signaling. The aim of this review is to assess and discuss the current state of exogenous stimuli‐responsive biomaterials, and their application in multipotent stem cell control. Future perspectives in utilizing these biomaterials for personalized tissue engineering and directing organoid models are also discussed.