Jonathan T. Butcher
Assistant Professor
Biomedical Engineering
Heart valves ensure unidirectional blood flow through the cardiovascular system, opening in a fraction of a second, and closing again some 3 billion times in an average lifespan. Defects in this critical mechanical function can become immediately apparent at birth or more subtle, presenting later in life. The current treatment therapy, prosthetic valve replacement (performed 300,000 times annually), is satisfactory for older adults but not acceptable for growing children. Tissue engineering has the potential to deliver a living valvular replacement capable of growth and integration, but many scientific hurdles need to be crossed before this can be realized. Very little is known about the resident valvular cells and how their behavior is regulated by mechanical forces, but what we do know suggests they are very unique. One can appreciate this most by studying how the valves are formed and malformed during embryonic development. As with adult valves, the mechanical environment in which these valves develop may provide key stimuli for normal and abnormal cellular differentiation. If we can decipher this mechanobiological blueprint from native valvulogenesis, we can then use it to motivate regenerative strategies, including tissue engineering of living valves. Dr. Butcher’s research focuses on understanding the roles of mechanical forces in the regulation of heart valve cell and tissue biology for the purposes of engineering regenerative strategies to target these vital organs. His research has three main thrusts.
First, Dr. Butcher seeks to understand the roles of mechanical forces in the regulation of embryonic valvulogenesis. His lab has designed unique mechanical bioreactors capable of stimulating embryonic valve cells and tissue models, as well as meso-scale mechanical testing systems to quantify biomechanical changes in valvular tissue during normal and defective embryonic growth. Additionally, his lab has developed specialized 3D imaging techniques to quantify embryonic hemodynamics in normal and defective valvulogenesis. The overall goal of this project is to develop a system-wide understanding of how changes in mechanical stimulation result in specific valvular morphogenetic programs, and to eventually use this knowledge to assist in the diagnosis and repair of valvular function in pediatric patients.
The second thrust seeks to understand how perturbations in mechanical signaling in adult valve diseases results in changes in cell behavior, specifically towards a reversion to embryonic phenotypes. His lab has developed 3D engineered tissue co-culture models of adult valves that can be stimulated via mechanical forces and/or bioactive ligands to induce physiological or pathological cell differentiation. They currently focus on two proteins, periostin and cadherin-11, whose proper embryonic and adult expression is important for valvular homeostasis. The overall goal is to develop targeted strategies to induce in vivo cellular repair of adult valve diseases at a stage prior to tissue failure to remove the need for replacement altogether.
The third research thrust is to engineer living valvular replacements capable of growth and integration particularly for pediatric patients. One critical yet unmet need is an autologous (patient specific) cell source that can recapitulate native valvular phenotypes. The current research goal is to differentiate autologously accessible stem cells toward valvular phenotypes using embryonic stimulation programs, which include mechanical and biochemical factors. The eventual goal is to induce the recruitment and differentiation of autologous stem cells to valvular phenotypes completely in vivo.
Education
- Post Doc, Developmental Biology, Medical University of South Carolina
- PhD 2004, Mechanobiology, Georgia Institute of Technology
- M.S. 2000, Impact Biomechanics, University of Virginia
- B.S. 2000, Mechanical Engineering, University of Virginia
Awards
- Lillihei Young Investigator Award, International Society for Heart Valve Disease, 2007
- Rita Shaffer Young Investigator Award - Biomedical Engineering Society 2009
