Orthopaedic devices comprise a significant portion of the medical devices that are imported into South Africa. Through case studies, we investigated the effect of contextual factors on knowledge development and exchange in the orthopaedic device innovation system, using the technological innovation systems framework. Our findings revealed that the drivers of knowledge development and exchange were inter-sectoral collaboration, availability of resources, affordability of available devices, creating legitimacy for devices, and the positive externalities of allied innovation systems. The main barriers identified were those that hindered inter-sectoral collaboration. The critical roles of the university and of healthcare actors were also highlighted. These findings may be used proactively to address problems in the innovation systems and to develop policy and institutional mechanisms that are aimed at building the domestic medical devices industry.