Chung-Hao Lee, a postdoctoral fellow in the Center for Cardiovascular Simulation (CCS), studies the biomechanics and cell mechanobiology of the heart's mitral valve—the organ that helps prevent the backflow of blood from the heart's left ventricle into the left atrium when the heart pumps blood to the body.
It's an area of multiscale study that involves understanding how different levels of life—from cells, to tissues, to organ parts—influence one another and, in effect, the overall functioning of the valve.
"I'm trying to better understand what's going on at the smaller scales, like tissue collagen fiber networks and mitral valve interstitial cells, and how they behave when the tissue respond to external mechanical stimuli or disease progression and how the corresponding microenvironments relate to collagen biosynthesis and tissue adaption," Lee said.
Biotransduction enables the mitral valve to adjust to its environment at multiple levels. However, it's also thought to be the reason why mitral valve repair surgery doesn't hold up in the long run. The surgical repair on the tissue inadvertently introduces new excessive stresses that are felt all the way down to the cellular level, which in turn, weaken the mitral valve tissue over time.
As a result, most patients who undergo surgery for mitral valve regurgitation—a condition where loose mitral valve leaflets allow blood to flow backwards into the left atrium—are in need of follow-up surgery only three to five years after initial operation.
Working with Dr. Michael Sacks, CCS director and a professor in the Department of Biomedical Engineering, Lee is investigating the biomechanics and mechanobiology of the healthy mitral valve. By adjusting treatment techniques to preserve these natural cellular transduction pathways, rather than disrupt them, introduction of stress overload onto the valve can be prevented, leading to improvement of long-term outcomes of mitral valve surgical repair.
Lee's research involves creating computational models that simulate healthy mitral valve tissue by modeling how the stress of the valve opening and closing is applied to tissues and cells that make up the valve. He is lead author on two papers published this year that describe the computational models, and experimental research that informed them. Research collaborators on the papers include Dr. Sacks and graduate student Salma Ayoub, as well as scientists from the Georgia Institute of Technology, and the University of Pennsylvania.
The first paper, published in the Journal of Theoretical Biology in March 2015, describes how cells and tissue layers in the mitral valve leaflet respond under physical loading conditions similar to that experienced in a beating heart. The second, published in Biomechanics and Modeling in Mechanobiology in May 2015, describes numerical predictions of re-orientation of fiber networks and overall stresses of the mitral valve tissues as the valve opens and closes.
In each of the papers the research first involved experimental studies on the mitral valve tissue in the CCS BME lab and medical image data from the collaborating institutes. For the cell analysis, it involved placing a small sample of leaflet tissue recovered from a sheep's mitral valve in a mechanical device that tugged away from the tissue in each direction to simulate physiological loads. The deformation of the cells in each of the four mitral valve leaflet tissue layers was tracked and analyzed during the loading using a multi-photon microscopy technique.
In the research on the re-orientation of the fiber networks and the stresses they bear, the anatomical data was collected by placing an entire ovine mitral valve in a device that simulated the physiological conditions of the valve's native environment, including pressure and suspension of the valve. Lee and his collaborators used micro-CT technology to capture details of the valves anatomy as the valve's leaflets opened and closed. High-resolution leaflet deformation and strain were measured and analyzed based on the quantified deformation of mitral valve leaflets.
The data collected during the experiments was used to develop and extensively validate computational models. In the case of the cell-modeling experiments, the data showed that the cells in each tissue layer undergo distinct deformations under biaxial stretching, instead of acting as one unit, and directly influenced the degree of tension experienced by the tissue. Predictions of the finite element model built by Lee and his collaborators were in good agreement with the experimental results, exhibiting similar tensions for each layer tissue when information on cell deformation was incorporated into it.
In the case of the mitral valve organ simulations, the micro-CT data enabled the creation of a computational finite element model that detailed both the anatomy and the fiber microstructure of the mitral valve. It successfully simulated the organ-level behavior that was observed experimentally, both in strains of the leaflet tissue and how the tissue fibers oriented while the valve leaflets were opening and closing.
"Understanding the normal stresses experienced by the mitral valve is the first step toward developing predictive computational models, such as those described in Lee's two papers, that can help improve treatments of the diseased valves at multiple levels," Lee said.
From leaflet repairs that better preserve the natural stress distribution and leaflet microstructure, to bioengineered materials that replicate the distribution of cells, matrix and tissue alignment for optimal health, accurate computational models can help guide research streams, as well as clinical outcomes.
Lee imagines his research expanding into these areas of application as chances arise.
"These studies have been of a more fundamental nature in biomechanical research, but I will be moving forward to the translational applications," Lee said.
Current parallel research in the CCS involves developing averaged geometric models of the mitral valve suitable for patient-specific modeling and surgical predictions. Lee also envisions utilizing similar approaches for other heart valve research, such as the tricuspid valve.
