Photoacoustic Imaging for Biophysical Physiological Indicators of Neonatal Intestinal Health and Necrotizing Enterocolitis - PROJECT SUMMARY Necrotizing enterocolitis (NEC) is a devastating intestinal disease affecting the most fragile premature infants, with mortality rates that persist at 20-40%. Accurate and conclusive early diagnosis of NEC remains elusive, with limited diagnostic confidence complicating timely and effective medical management efforts to prevent disease progression to urgent surgical removal of necrotic intestine. As the population of premature infants at the highest risk for NEC continues to rise, a critical need has emerged to develop innovative clinically translatable diagnostic methods to enable early interventional opportunities to combat this disease. Motivated by the significance of the translational potential, clinical need, and extensive promising preliminary data, we propose to investigate the development and use of photoacoustic imaging (PAI), an emerging non-invasive imaging modality, in healthy neonatal intestine and NEC disease, representing a novel first-in-disease preclinical investigation. PAI methods present enormous potential for fundamentally changing current clinical paradigms by non-invasively detecting, diagnosing, and monitoring intestinal pathologies, such as NEC, in premature infants. We hypothesize that PAI can accurately and quantitatively characterize changes in the NEC vascular hallmark of intestinal tissue hypoxia and NEC intestinal functional hallmark of motility to improve the diagnosis and monitoring of intestinal disease in premature infants. The aims of this application reflect a stepwise development and validation study to optimize PAI acquisition and analysis methods to assess early healthy development and NEC disease onset and progression in the neonatal intestine. In Aim 1, we will optimize PAI measurements of neonatal intestinal tissue oxygenation. In Aim 2, we will optimize PAI measurements of functional neonatal intestinal motility. Under each aim, we will compare quantitative characterization of physiological biophysical indicators for neonatal intestinal microvasculature and function from PAI with paired histopathological analysis. This enables our study to uncover the cellular and molecular origins of observed changes on PAI. Combined, the proposed studies will establish PAI as a non-invasive detection and quantitative imaging methodology to detect differences in neonatal intestinal tissue oxygenation and functional motility in the healthy developing infant intestine and in NEC disease onset and progression. The development of new advanced non-invasive imaging methods for neonatal intestinal disease presents significant translational opportunity to improve the quality of care in the NICU. With considerable rationale and strong preliminary data establishing feasibility for the use of PAI to detect changes in intestinal microvasculature and function, this project has a high likelihood of demonstrating success in quantitative characterization of NEC in these proposed first-in-disease studies. Our multi-disciplinary study team is well- positioned to develop these innovative imaging methods specifically designed for feasible clinical translation as a first-in-disease investigation to make a significant impact in intestinal health in premature infants.
