SonoScaffolds and Sentinels: Ultrasound-Responsive Biomaterials for Remote Control of Cell Signaling

As engineered tissues become ever more spatially complex through advanced biofabrication techniques, there is a critical need to also coordinate the temporal complexity of cell behavior. Advancements in disease modeling and regenerative therapies require the ability to direct cell processes within these structures after they are formed and throughout their maturation. This direction can be achieved by manipulating the protein presentation of selected cells within 3D scaffolds through targeted gene expression. However, these dynamic genetic perturbations are challenging to remotely coordinate in fully formed biofabricated tissues using traditional gene delivery methods. To address this challenge, our team has pioneered development of ultrasound-responsive cell culture platforms (SonoScaffolds) for noninvasive and spatiotemporally-controlled genetic manipulation of cells in 3D tissue constructs. Our approach utilizes focused ultrasound as an external non-invasive trigger for biomaterial-mediated gene delivery with unique advantages due to its significant penetration depth and ability to be focused to small volumes within tissue.

Our work demonstrates the use of SonoScaffolds for controlled delivery of multiple genes in user-defined locations of scaffolds and heterogeneous 3D-bioprinted structures, including ultrasound-patterned vascular growth factor expression. We show controlled HER2 oncogene overexpression in individual cells within matrix-embedded mammary spheroids for studying interactions with surrounding healthy cells in early-stage disease. We are also extending this technology to develop vascularized and organ-on-chip models. As these dynamic 3D tissue constructs become larger and more intricate, there is also a need to develop non-destructive tools for monitoring cell state. These “sentinels” consist of embedded optical metabolic nanosensors and microwave-assisted immunofluorescence staining techniques for 3D culture. Together, this work presents a new class of 3D-programmable cell culture materials that enable researchers to control the temporal coordination of cell processes, with important applications in disease modeling and tissue regeneration.