Human-Systems Integration (HSI) can be considered as the combination of Systems Engineering and Human-Centered Design approaches. To support HSI, the system of interest (SoI) and its broader context should be developed with a specific engineering design objective and consider humans part of the system. Using a MedTech industry case study, this paper explores the influence of including MedTech end-users, such as Healthcare Professionals, within the SoI definition. The MBSE approach models the “fuzzy front end” of innovation for the MedTech Combination Product and places the end-users within the SoI boundaries. The paper advocates that such an approach shifts the paradigm of ena-bling the human factors considerations to the early innovation phases rather than waiting for the first physical prototype.