The complex interactions that occur between oligodendrocytes and axons during the process of central nervous system myelination and remyelination remain unclear. Elucidation of the cell-biological and -biochemical mechanisms supporting myelin production and elaboration requires a robust in vitro system that recapitulates the relationship between axons and oligodendrocytes in a manner that is open to molecular dissection. We provide evidence for an artificial axon culture system in which we observed oligodendrocytes extending large plasma membrane projections that frequently completely ensheathed fibers coated with a variety of extracellular matrix molecules. These membrane projections varied in extent and thickness depending upon the substrate and upon the diameter of the coated fiber. Matrigel-coated glass microfibers were found to support the development of thick membrane sheaths that extended for hundreds of microns and exhibited many features suggestive of the potential for true myelin deposition. Likewise, Matrigel-coated Vicryl fibers supported plasma membrane extensions that covered extremely large surface areas and occasionally wrapped the coated Vicryl fibers in more than one membrane layer. Our findings suggest that the deposition of molecular cues onto glass or polymer fibers either via adsorption or chemical modification may be a useful tool for the discovery or validation of axonal factors critical for myelination and remyelination. Herein, we provide evidence that polyglactin 910 and glass microfibers coated with adhesion factors may provide a reasonable system for the in vitro analysis of myelination, and may eventually serve a role in engineering artificial systems for neural repair.