In vitro modeling of the peripheral nerve: cell culture embodiments and outcomes

Peripheral nerve injuries (PNI) are common and significantly affect the quality of life of patients. In vitro models of the peripheral nerve have emerged as a critical tool for studying peripheral nerve injury and regeneration. These existing models are cost-effective, reproducible, and offer controlled experimental conditions. However, they fail to adequately model the peripheral nerve because they lack the complex structural and functional interactions present in its in vivo environment. Advancements in cell culturing systems, biomaterials, and fabrication techniques are expected to bring in vitro models closer to physiological and clinical relevance, helping guide repair strategies for treating nerve injuries. In contrast to earlier reviews that focus on cell types or fabrication methods, this review takes a function-oriented approach, organizing in vitro models by the specific nerve processes or structures that they aim to replicate. This review begins with a discussion of the structure of the peripheral nerve, followed by a brief literature search methodology section, and a discussion on the advantages and challenges in the in vitro modeling of this tissue next. This is followed by a discussion focused on the creation of various in vitro models of the peripheral nerve used for the investigation of various nerve processes including a) axonal outgrowth, b) myelination, c) innervation, and d) vascularization along with illustrative figures and comparative analysis tables. Discussion includes also key aspects to be considered when designing in vitro models of the peripheral nerve such as selection of cell types, biomaterials, scaffold fabrication, nano-topography/fabrication, microfluidics/lab-on-a-chip, 3-D printing, deployment of growth factors and stem cells, and structural and functional characterization of the models. Finally, the clinical relevance of these models is discussed and the paper concludes with some impactful advances and future directions in the field.