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While spider silk threads mainly consist of a core of partially crystalline silk proteins, it has been found that they also exhibit a very thin skin layer of distinct structure and a coating rich in lipids and glycoproteins. These outer layers are poorly researched, but can be assumed to be a major player governing the interaction of cells with spider silk threads, as observed in cell culture. Here we propose SAXS/WAXS mapping with ultra-high spatial resolution to examine the surface layer of thin cryo-cut sections of different spider silks that have shown different cell guiding behavior in cell culture. This approach allows studying surface layers from two orientations (along and normal to fiber axis) and the cryo-approach minimizes morphological changes. In a recent nano-SAXS/WAXS beamtime at ID13, we obtained very promising data, however with whole threads and with lower resolution. This follow-up work aims to characterize the surface layer systematically. 

Peripheral nerve reconstruction through the employment of nerve guidance conduits with Trichonephila dragline silk as a luminal filling has emerged as an outstanding preclinical alternative to avoid nerve autografts. Yet, it remains unknown whether the outcome is similar for silk fibers harvested from other spider species. This study compares the regenerative potential of dragline silk from two orb‐weaving spiders, Trichonephila naurata and Nuctenea umbratica, as well as the silk of the jumping spider Phidippus regius. Proliferation, migration, and transcriptomic state of Schwann cells seeded on these silks are investigated. In addition, fiber morphology, primary protein structure, and mechanical properties are studied. The results demonstrate that the increased velocity of Schwann cells on Phidippus regius fibers can be primarily attributed to the interplay between the silk's primary protein structure and its mechanical properties. Furthermore, the capacity of silk fibers to trigger cells toward a gene expression profile of a myelinating Schwann cell phenotype is shown. The findings for the first time allow an in‐depth comparison of the specific cellular response to various native spider silks and a correlation with the fibers’ material properties. This knowledge is essential to open up possibilities for targeted manufacturing of synthetic nervous tissue replacement.