Repair of peripheral nerve injuries depends upon complex biology stemming from the manifold and challenging injury‐healing processes of the peripheral nervous system. While surgical treatment options are available, they tend to be characterized by poor clinical outcomes for the injured patients. This is particularly apparent in the clinical management of a nerve gap whereby nerve autograft remains the best clinical option despite numerous limitations; in addition, effective repair becomes progressively more difficult with larger gaps. Nerve conduit strategies based on tissue engineering approaches and the use of silk as scaffolding material have attracted much attention in recent years to overcome these limitations and meet the clinical demand of large gap nerve repair. This review examines the scientific advances made with silk‐based conduits for peripheral nerve repair. The focus is on enhancing bioactivity of the conduits in terms of physical guidance cues, inner wall and lumen modification, and imbuing novel conductive functionalities.

Solution blow spinning (SBS) has emerged as a rapid and scalable technique for the production of polymeric and ceramic materials into micro/nano- fibers. Here, SBS was employed to produce sub-micron fibers of regenerated silk fibroin (RSF) from Bombyx mori (silkworm) cocoons based on formic acid or aqueous systems. Spinning in the presence of vapor permitted the production of fibers from aqueous solutions, and high alignment could be obtained by modifying the SBS set-up to give a concentrated channeled airflow. The combination of SBS and a thermally induced phase separation technique (TIPS) resulted in the production of macro/micro- porous fibers with 3D interconnected pores. Furthermore, a co-axial SBS system enabled a pH gradient and kosmotropic salts to be applied at the point of fiber formation, mimicking some of the aspects of the natural spinning process, fostering fiber formation by self-assembly of the spinning dope. This scalable and fast production of various types of silk based fibrous scaffolds could be suitable for a myriad of biomedical applications.

The cellular microenvironment is dynamic, remodeling tissues lifelong. The biomechanical properties of the extracellular matrix (ECM) influence the function and differentiation of stem cells. While conventional artificial matrices or scaffolds for tissue engineering are primarily static models presenting well-defined stiffness, they lack the responsive changes required in dynamic physiological settings. Engineering scaffolds with varying elastic moduli is possible, but often lead to stiffening and chemical crosslinking of the molecular structure with limited control over the scaffold architecture. A family of indirectly 3D printed elastomeric nanohybrid scaffolds with thermoresponsive mechanical properties that soften by reverse self-assembling at body temperature have been developed recently. The initial stiffness and subsequent stiffness relaxation of the scaffolds regulated proliferation and differentiation of human bone-marrow derived mesenchymal stem cells (hBM-MSCs) towards the chondrogenic and osteogenic lineages over 4 weeks, as measured by immunohistochemistry, histology, ELISA and qPCR. hBM-MSCs showed enhanced chondrogenic differentiation on softer scaffolds and osteogenic differentiation on stiffer ones, with similar relative expression to that of human femoral head tissue. Overall, stiffness relaxation favored osteogenic activity over chondrogenesis in vitro.

Stimuli-responsive materials are very attractive candidates for on-demand drug delivery applications. Precise control over therapeutic agents in a local area is particularly enticing to regulate the biological repair process and promote tissue regeneration. Macromolecular therapeutics are difficult to embed for delivery, and achieving controlled release over long-term periods, which is required for tissue repair and regeneration, is challenging. Biohybrid composites incorporating natural biopolymers and electroconductive/active moieties are emerging as functional materials to be used as coatings, implants or scaffolds in regenerative medicine. Here, we report the development of electroresponsive biohybrid composites based on Bombyx mori silkworm fibroin and reduced graphene oxide that are electrostatically loaded with a high-molecular-weight therapeutic (i.e., 26 kDa nerve growth factor-β (NGF-β)). NGF-β-loaded composite films were shown to control the release of the drug over a 10-day period in a pulsatile fashion upon the on/off application of an electrical stimulus. The results shown here pave the way for personalized and biologically responsive scaffolds, coatings and implantable devices to be used in neural tissue engineering applications, and could be translated to other electrically sensitive tissues as well.