Ultrasound-guided Ultra-steerable Histotripsy Array System for Non-invasive treatment of Soft Tissue Sarcoma Summary The goal of this project is to develop a novel ultra-steerable histotripsy array system for non-invasive treatment of soft tissue sarcomas (STS). STS are malignant tumors that grow in soft tissues like fat, muscle, cartilage, fibrous tissues, blood vessels, or subcutaneous tissues. The American Cancer Society reports 13,190 new cases and 5,130 deaths of STS annually in the US. Surgery is the first-line treatment for STS. However, when STS encompass or grow near critical structures (e.g., major nerves, blood vessels, and bones), surgical resection is particularly challenging and sometimes these cancers are deemed unresectable. Radiation, chemotherapy, and minimally invasive or non-invasive ablation methods are not effective for STS treatment or have major drawbacks, such that they have very limited use in STS therapy. Histotripsy is a non-invasive ultrasound therapy that mechanically liquefies the target tissue to acellular debris via controlled cavitation. Histotripsy is well-suited for STS treatment because it can debulk and shrink the tumor non-invasively while sparing critical structures, such as major vessels, nerves, and bones. Histotripsy can be used for non-invasive debulking of STS to facilitate or potentially replace surgery. Even though histotripsy has been investigated for the treatment of various tumor types, STS treatment presents unique challenges. 1) STS can grow significantly larger than other types of tumors (>10 cm or >400mL), requiring very fast treatment speed. 2) STS often grow near critical structures and/or close to the skin surface. Treatment strategies need to be developed to avoid damage to critical structures and the skin. 3) Histotripsy treatment is typically guided by 2D B-mode ultrasound imaging, but fast treatment of a large STS requires 3D monitoring capabilities. In this proposal, we will develop a novel ultra-steerable histotripsy phased array system with 3D cavitation monitoring capabilities and special strategies for ultra-fast STS ablation and safe treatment near the skin surface and critical structures. We propose the following three specific aims. Aim 1: To design and construct an integrated histotripsy STS system, consisting of an ultra-steerable histotripsy phased array with transmit-receive capability for 3D cavitation monitoring, ultrasound image guidance, robotic arm assistance, and acoustic coupling. Aim 2: To optimize histotripsy parameters for fast (>10 mL/min) and safe treatment near the skin surface and critical structures and test in ex vivo tissue and excised human and canine STS samples of different histological subtypes. Aim 3: To test the in vivo safety and efficacy of the integrated histotripsy STS system (Aim 1) and optimized parameters for fast and safe treatment near the skin and critical structures (Aim 2) in canine STS patients at the Virginia Tech Animal Cancer Care and R...