Title: “Novel Strategies and Multiscale Modeling in Respiratory Mechanics”
Béla Suki, PhD – BU BME (Advisor)
Dimitrije Stamenović, PhD – BU BME (Chair)
Joe Tien, PhD – BU BME
Katherine Zhang, PhD – BU ME
Jason Bates, Ph.D, DSc – UVM
Despite tremendous technological and scientific advancements in the 20th century, clinically feasible assessment of detailed macroscopic respiratory mechanics is still limited. Additionally, a comprehensive understanding of macroscopic behavior in terms of microscopic description of alveolar mechanics and extracellular matrix properties is also absent. Combined together, these two limitations may explain why there has been a slow progress in optimizing mechanical ventilation for patients with lung disease. Addressing these two limitations, and, more importantly, linking macroscopic emergent phenomena to microscopic behavior could provide improved understanding and better health care. To this end, (1) a 3-D printed flow sensor was designed and evaluated to continuously measure airway opening flow and pressure in mice. (2) Using this sensor, we introduced a novel technique (ZVV) which provides continuous monitoring of the respiratory system’s physiological condition through evaluating cycle-by-cycle impedance (Z) during variable ventilation (VV). The feasibility and accuracy of ZVV was demonstrated by applying it in mice before and after inducing lung injury mimicking acute respiratory distress syndrome (ARDS), as well as in a computational study. Furthermore, when ZVV was applied to previously collected data, the analysis demonstrated for the first time that VV improved lung mechanics in human patients with ARDS. Additionally, two analytical models were developed to relate macroscopic to microscopic mechanical behavior of the lung parenchyma. (3) The first alveolar-unit model related alveolar septal wall properties (i.e., thickness) and constituents (i.e., fibers) to alveolar pressure-volume relationship providing insight into the importance of calculating true stress, the role of the collagen waviness and stiffness in alveolar stability and protection from over distension, as well as the multiscale relation between fiber stresses and macroscopic pressures. (4) The second intermediate tissue-level model described the mechanics of alveolar wall alignment under uniaxial stretching and estimated alveolar wall stiffness and stress demonstrating its ability to extract fiber-level properties from tissue strip stress-strain relations. When applied to pressure-volume and stress-strain data from lungs of old subjects, both models predicted alveolar wall and collagen fiber stiffening in aging. In summary, this study, presented a novel technique which can assess respiratory mechanics in clinical settings and multi-scale models to enhance our understanding of how macroscopic behavior is related to alveolar constituent properties.