Bridging the gap: gradient scaffolds as bioinstructive platforms for peripheral nerve repair

Peripheral nerve injury remains a major clinical challenge due to its complex pathophysiology and limited intrinsic regenerative capacity. Effective nerve guidance conduits (NGCs) therefore require not only structural support but also bioinstructive cues capable of actively regulating cellular behavior. Spatial gradients play a fundamental biological role in directing cell migration and axonal elongation by providing long-range guidance cues that cannot be achieved with uniform biochemical or structural cues alone. From a materials and chemical perspective, gradient NGCs represent a distinctive class of biomaterials in which physical properties, such as topography, porosity, and stiffness, and biochemical components, including growth factors, chemokines, peptides, and extracellular matrix (ECM) molecules, are spatially encoded within the conduit structure. These gradients are established through physicochemical processes such as diffusion and adsorption kinetics, polymer network formation, crosslinking reactions, and interfacial chemistry. In this review, we discuss the mechanisms by which gradient cues regulate cellular and axonal responses, and summarize recent advances in the materials design and fabrication strategies used to introduce physical and biochemical gradients into NGCs. We further summarize representative in vitro and in vivo regenerative outcomes, highlighting how chemically engineered gradients synergize with structural guidance to promote organized nerve regeneration. Finally, we outline key challenges, including gradient stability, reproducibility, and compatibility with scalable manufacturing, and discuss future directions for the clinical translation of gradient-based NGCs.