CAREER: LungEx for Probing Multiscale Mechanobiology of Pulmonary Respiration-Circulation Coupling in Real-Time

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This Faculty Early Career Development (CAREER) grant will provide unprecedented insight into the real-time and multiscale lung mechanobiology that bridges single-air sac to whole-organ functions of the lung. This will be achieved by utilizing a novel transparent ribcage that provides transformative capabilities to probe lung mechanobiology at high spatial and temporal resolutions. The planned research will provide foundational understanding of lung function including respiration, circulation, and immunity, at the cellular level and in real-time. Understanding the lung function (and dysfunction) at an unprecedented spatiotemporal resolution will address key challenges in the emerging fields of lung mechanobiology and mechano-immunity. The focus on multidisciplinary and multiscale approaches, both experimental and mathematical, will also provide exciting opportunities for students on all levels to participate in the unexplored area of pulmonary biomechanics and mechanobiology. The central goal of this research and educational program is to inspire and train students from K-12 to graduate school to think conceptually about how quantitative and interdisciplinary approaches can help understand lung microphysiology. This work will utilize a novel platform, termed LungEx, that includes the ex vivo maintenance of the mouse lung in near in vivo physiological conditions. A key and novel element of LungEx is a transparent ribcage, termed “crystal” ribcage, with geometrical and physical properties of the intact native ribcage. Use of the crystal ribcage will allow, for the first time, visualization of the dynamics of lung microphysiology in real-time, at the cellular resolution, and over nearly the entire surface of the lung. Utilizing the transformative LungEx technology, the project goals will be achieved by 1) probing how alveolar distension is coupled to red blood cell trafficking and oxygen transport at the capillary level, 2) determining whether alveolar lymphatics serves as the main driver of flow in visceral lymphatics, and 3) probing the real-time dynamic mechanical interactions of immune cells with capillaries at the single cell level. By integrating this research with a carefully designed educational plan for students at all levels, we will train the next generation workforce in pulmonary biomechanics and mechanobiology to make discoveries in foundational pulmonary biology and physiology.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.