The paper explores and presents results of an investigation handling design methodologies using the bio-space and biological phenomena combined with the technical space for the development, design and application of products, machine tools, processes and manufacturing systems carried out by a multinational team including Fraunhofer and CIRP fellows. The main biological approach for designing was bio-inspiration. However, links and examples implementing bio-integration and bio-intelligence were also considered and analyzed during the investigation.The paper describes a systematic design procedure starting from requirements and applications related to manufacturing, using well-known theories and experience in engineering, however analyzing and applying biological materials, properties, structures, phenomena and complete systems. Sustainability aspects combined with the immense and ever growing capacity of ICT and digitization possibilities provided new options for design methodologies.A moveable and flexible machine tool was virtually used as a demonstrator to describe the new methodology. It was proved that the o ngoing process of learning from nature and applying biological phenomena, structures and materials, together with new technologies such as Additive Manufacturing (AM) can develop new ideas, processes, manufacturing systems, and products with benefits to performance, productivity, efficiency and sustainability. Nature and biological domains can be integrated, can inspire, be implemented or even applied as an intelligent system in the design procedure.