Jonathan T. Butcher

Prof. Butcher’s research initiative focuses on understanding the roles of mechanical forces in shaping cardiovascular morphogenesis and adult disease with an emphasis on heart valves. His long-term objectives are to use developmental paradigms to discover novel disease paradigms and regenerative strategies. He pursues three research thrusts:

1. Cardiovascular developmental mechanobiology. We are working to understand the complex engineering that drives the formation and function of the embryonic heart and its valves. We develop novel animal models of defective cardiogenesis and valvulogenesis using microsurgical and genetic approaches, and complement them with complex in vitro morphogenic organoids. We have innovated unique experimental tools to quantify how the local biomechanical and hemodynamic environment is altered as well as downstream morphogenesis. We further implement novel microfabricated mechanobiological test beds and imaging methods using Micro-computed tomography and ultrasound. We also conduct computational simulations of hemodynamic and mechanics using anatomically precise geometries of normal and malformed hearts, implementing spatial transcriptomics to elucidate local mechanobiological control mechanisms. Our long-term goal is to apply the governing engineering principles we identify to shift mechanobiological signaling to rescue malforming cardiac anatomy and enable long-term function.
2. Developmental paradigms in postnatal valve disease. Numerous postnatal diseases involve cell and tissue changes that mimic immature developmental phenotypes. Examples include myxomatous valve disease and valve sclerosis. We have discovered several proteins with unique expression patterns and functions in embryonic and adult valve mechanobiology. We have developed knockout and transgenic mice to study these proteins in this context, as well engineered tissue models and bioreactor systems capable of exposing these tissues to defined multimodal mechanical stimulation regimens. Long term goals will be to translate these findings into unique ligands and/or peptides with specificity to heart valve cells and efficacy to manage clinically relevant stages of heart valve disease.
3. Heart valve tissue engineering. We focus on engineering living complex tissue characteristics (shape, heterogeneity, anisotropy) via innovating 3D tissue printing technology. We have created living valved conduits incorporating native cellular interactions and defined matrix environments through patented and patent pending technologies. As our understanding of embryonic valvular maturation develops, we translate this “natural engineering” blueprint to improve the mechanobiological maturation of engineered heart valves for age and tissue specific applications. We then translate these designs through bioreactor conditioning and preclinical animal model testing. We further engineer and implement biomaterial modifications to stably endothelialize mechanical valve prostheses and encourage mature valvular cell phenotype development from stem/progenitor sources.