Orthopedic hip implant failure due to adverse events, such as infection, are still a major problem leading to high morbidity and mortality. Over the years, various innovative biomaterials have been investigated to improve safety and functionality of implants. Although novel biomaterials show initial promising results, many fail at the (later) stages of safety testing. We performed a literature review serving as a first step in a Safe-by-Design (SbD) approach. SbD is a strategy which includes safety considerations at early development stages and that streamlines the pre-clinical safety assessment of innovative medical implants. In a SbD approach, the standard safety assessment of medical implants (e.g., ISO10993) is complemented with insights on cell-biomaterial interactions allowing for a better