Developing ultrasound contrast agents and signal processing for structural and functional imaging in type 1 diabetes

PROJECT SUMMARY Type 1 diabetes (T1D) results from the destruction of insulin producing β-cells upon immune infiltration and inflammation of the islets of Langerhans in the pancreas. Prior to T1D onset there is an asymptomatic phase of many years which presents a window for therapeutic intervention. However, there are limited means for detecting and tracking the development of insulitis in this ‘pre-symptomatic’ T1D window, to guide and monitor therapeutic interventions. Ultrasound imaging presents many advantages for clinical deployment, and gas- filled microbubble (MB) contrast agents are clinically approved, and used in detection and monitoring of a wide range of diseases. We previously used contrast-enhanced ultrasound to detect signatures of insulitis in pre- clinical models based on altered pancreas blood flow or inflammation-induced extravasation. While promising, a key limitation of pancreas imaging in general in T1D is that the islets of Langerhans represent only a few % of the pancreas volume. Any disease signatures will be ‘diluted’ by background signal, substantially reducing sensitivity. Thus high-resolution approaches to view the specific disease signatures in T1D are needed. Ultrasound localization microscopy (ULM) is a super-resolution microvascular imaging technique that provides microvessel-level spatial resolution noninvasively in vivo, thus potentially enabling the resolution of specific T1D disease associated changes in the pancreas. Our overall goal is to develop and apply novel ultrasound contrast agents in combination with ULM and signal processing to detect disease signatures associated with T1D, to provide image-based guidance and tracking of therapeutic interventions. We will conduct 3 specific aims: 1): Apply ultrasound localization microscopy to visualize vascular impairments in the pancreas. 2): Map the distribution of nanodrop accumulation and microvascular leakiness across the pancreas. 3): Apply molecularly targeted microbubbles and nanodrops to the inflamed and infiltrated islet microenvironment. Assessing inflammation and immune infiltration in the islet microenvironment using contrast-enhanced ultrasound imaging represents a fundamentally new paradigm for diagnosing and tracking T1D progression. The development and application of nanodrop agents and functionalized microbubbles, and use of super- resolution ULM techniques, represents further innovations which will have broader impact, aiding in diagnosing both the pace of T1D progression and the efficacy of any preventative treatment prior to clinical onset.