CAREER: Mechanobiology of Microbubble Induced Cellular Injury in the Pulmonary System

Lehigh University, Bethlehem PA

Investigators

Abstract

CBET-0747760, Ghadiali Microbubble flows are an important area of research in the biomedical sciences. Important applications of microbubbles include the enhancement of ultrasound images, drug delivery and cancer treatment. However, microbubbles can also cause significant cellular and tissue damage in the cardiopulmonary system. For example, patients suffering from acute lung injury (AcLI) cannot breathe on their own due to the collapse and fluid occlusion of small pulmonary airways. These patients must be placed on a mechanical ventilator in order to survive. However, the microbubbles generated during ventilation can exacerbate the existing lung injury. As a result, the mortality rate for AcLI is very high (30-40%). Microbubbles have been shown to impart complex fluid mechanical forces to the epithelial cells (EpC) which line airway walls. Depending on the EpC's biophysical properties, these forces may result in cell death and disruption of the epithelium. In addition, these fluid mechanical forces may also be transduced into injurious biological responses including the up-regulation of inflammatory pathways and altered surfactant secretion. However, the exact mechanisms responsible for microbubble induced cellular injury in the pulmonary system are not known. The research objective of this CAREER project is to use a combination of computational and experimental techniques from the biological, engineering and mathematical sciences to fill this knowledge gap. The PI will develop multi-scale, fluid-structure computational models of cellular deformation and detachment during microbubble flows. These models will be used to quantify mechanical parameters which are difficult to measure experimentally (i.e. cell deformation). The PI will also utilize an in-vitro, microfluidic cell culture system and sophisticated microscopy techniques to ascertain the biological response of EpCs to microbubble flows (i.e. protein expression). The correlation of computational and experimental results will be use to identify the biomechanical mechanisms responsible for microbubble induced cellular injury. The significance of this research is that once we understand the mechanisms responsible for cellular injury, this information can be used to develop novel pharmaco-protective therapies for AcLI that minimize ventilation induced lung injury by altering specific cellular and/or molecular properties. The main educational objective of this proposal is to develop a bioengineering workforce that not only understands the interaction between engineering and biological systems but can also translate this knowledge into commercially viable and life-saving medical products. The PI will collaborate with local medical device companies to solve real-world design issues and will play a key role in developing industrially sponsored bioengineering projects within Lehigh University's Integrated Product Development program. As a part of this program, the PI will advise multi-disciplinary student teams who will work closely with their industry sponsor to develop design plans and prototypes that satisfy technical, business and regulatory requirements. These hands-on, industrially sponsored projects will provide students with the team-work skills most valued by employers and first-hand knowledge of the complex issues involved in developing commercially viable and life-saving medical products.