A major challenge toward bio-based economy consists in the replacement of fossil fuels on a broad scale, not only for energy applications, but also for material, clothing and plastic application. In this view, the worldwide trend to a low-carbon economy and sustainable primary production stimulates the use of naturally derived raw materials as alternative resource to oil-based plastics for manufacturing. However, natural materials must be renewable, available, recyclable, and biodegradable to be competitive and they need to be processed by green and sustainable approaches. Moreover, natural biomaterial products should provide a higher technical performance for selected application in comparison to synthetic and plastic based counterpart. In this context, the manufacturing of biomedical devices for diagnostic or therapeutics offers a potential market opportunity for the use of natural biomaterials. Indeed, natural biomaterials due to their well-known intrinsic characteristics such as biodegradability, and high biocompatibility are ideally suited to develop innovative biomedical products such as those for tissue engineering and also medical sensing. Indeed, during the last three decades, the use of natural biomaterials in tissue engineering is rapidly evolving and innovative devices are able to support and recover the structure and the functionalities of injured hosting tissues [
1,
2]. Several evidences have consolidated the use of biomacromolecules for development of scaffold devices that enable the regeneration of different tissues (i.e. nerve, cartilage, bone) [
1,
2]. Natural biopolymers mainly includes proteins (i.e. collagens, gelatine, zein, silk fibroin, elastin), polysaccharides (i.e. chitin, alginates, chitosan, cellulose derivate), and amides (i.e. starch). Silks are natural proteins polymers produced by different species of insects, such as spiders, scorpions, silkworms [
3]. Among silks, Silk fibroin (SF) produced by Bombyx mori cocoon have been used clinically as sutures for centuries [
3]. Nonetheless, in recent years, SF-based materials have been extensively studied in tissue engineering and drug delivery due to their biocompatibility, slow degradability and remarkable mechanical and optical properties [
1‐
3]. Notably, through a process of reverse engineering Rockwood et al. [
4] have defined a water-based and sustainable process that enable to obtain an aqueous-based SF solution, called regenerated silk fibroin (RSF), from the cocoon fibre. The use of the RSF solution is particularly interesting in the context of biomedical application [
1‐
4] because it can be processed in various formats (films, fibres, nets, meshes, membranes, gels, sponges) retaining exceptional chemo-physical and biological properties. In this context, SF displays the potential to be exploited as a raw material to become a technological material platform [
3,
5] for eco-sustainable manufacturing. However, some chemical and physical post-processing treatments of SF could damage/denature the protein and completely modifying its primary structure properties, thus altering the properties of the obtained substrates. Nonetheless, when dealing with naturally derived products and biomedical application it is highly desirable to establish and control the whole product lifecycle: from the raw material production to substrate preparation to technology validation. In this view, the goal of our work is to define and control the whole silk chain by in loco production of the raw-material, the assessment and standardization of extraction/purification methodology the characterization of the chemo-physical and biocompatibility properties of the obtained SF products. Herein, we report on state of the art methods and protocols to use SF as new material for advanced bio-technological application and sustainable manufacturing (Sect.
19.2). The proposed approach is presented in Sect.
19.3 and further detailed in Sect.
19.4, whereas the experiments are reported in Sect.
19.5. In particular, we demonstrate the importance of the definition and control of the whole chain for biomanufacturing underpinning the silk fibroin-based technology. Furthermore, we demonstrate and report the results obtained on the fabrication, characterization and validation of microfluidic and photonic components of a lab-on-a-chip device for biodiagnostic based on biomanufactured SF.