Abstract: The advancement of biotechnology enabled the development of "biotic video games", where human players manipulate real biological samples for fun and educational human-biology interactions. However, new design principles are needed to both leverage and mitigate biological properties (e.g., variability and stochasticity), and create unique play experiences that transcend traditional video games. This paper describes the implementation of Pac-Euglena, a biotic Pac-Man analog, where players guide live microscopic Euglena cells with light stimuli through a physical microfluidic maze. Through use of multi-modal stimuli, a mixed biology-digital-human reality is achieved, enabling cell interactions with virtual ghosts and collectibles. Through an iterative design process, we illustrate challenges and strategies for designing games with living organisms. A user study (n=18, conducted at a university event) showed that Pac-Euglena was fun, stimulated curiosity, and taught users about Euglena. We conclude with five general guidelines for the design and development of biotic games and HBI interfaces.