Aortic Valve Disease is a tremendous burden across the globe. To date, the only treatment that exists for those afflicted by this disease is total replacement with prosthetic valves. This presents a huge challenge for biomedical engineers as no functional tissue engineered replacement has been created. The closest biological analogue currently used for total valve replacement are porcine valves. Like their human counterparts, these porcine bioprosthetics have limited lifetimes in vivo and more than often require future replacement. A significant reason for this limited in vivo performance is due to immune-mediated degradation. Unfortunately, there is limited knowledge towards how immune cells, specifically macrophages, regulate valve interstitial cell behavior during disease or failure in animal-derived bioprosthetics. The valve field has yet to provide functional data that can garners insight into how cells of the innate immune system can regulate valve cell behavior. This information is critical for not only getting a better understanding of potential disease mechanisms and failure modes of animal-derived bioprosthetic valves, but for guiding principal strategies for future tissue engineering approaches. The work presented in this thesis, provides initial insight into how different phenotypes human macrophages can drive disease programming of porcine valve interstitial cells within mechanically constrained 3D-environments. Studying the effects of macrophage-derived factors provides clear unidirectional communication between these cell types which reduces complications of co-culture. Using 3D mechanically constrained hydrogels as a model system provides more insight into these features with more physiological relevance as valve cells are fibrotic and are exposed to high mechanical loads in vivo. This work shows how phenotypic extremes of human macrophages along an inflammatory continuum can differentially drive different disease programming in porcine valve cells, which is contrary to current approaches in the field which argue that one extreme is better than the other. Overall this work provides significant initial glimpses into macrophage regulation of valve cells and failure of porcine-derived bioprosthetic valves. This work clearly demonstrates that the extreme M1 / M2 delineation of macrophage phenotype that is a current target of many bioengineering approaches can worsen performance and behavior of valve interstitial cells.