Optimally Aligned Nerve Scaffolds with Sustained Astaxanthin Release Improve the Inflammatory Microenvironment through Mitophagy Activation

Abstract Effective repair of peripheral nerve injury (PNI) depends on the scaffold orientation and immunomodulatory capabilities of functionalized scaffolds, both of which substantially influence nerve regeneration. In this study, composite nerve scaffolds incorporating astaxanthin (AXT) and polycaprolactone (PCL) are developed to investigate the influence of scaffold orientation and blend concentration on cellular behavior, including adhesion, migration, and proliferation. In vitro analysis identifies 0.2% AXT/PCL fabricated at a rotational speed of 400 rpm as the optimal configuration for facilitating directed cell growth and guiding nerve repair. Moreover, the controlled release of AXT improves the microenvironment by preserving mitochondrial homeostasis, promoting mitophagy, and reducing oxidative stress and inflammation. In vivo assessments reveal that the AXT/PCL group (0.2% AXT/PCL‐400) achieves better morphological, histological, electrophysiological, and functional recovery than the PCL, AXT/PCL+M0, and AXT/PCL+M4 groups, approaching the outcomes observed in the autograft (Auto) group. Moreover, the AXT/PCL+M4 group demonstrates better regenerative outcomes than the PCL and AXT/PCL+M0 groups, underscoring the critical role of mitophagy in regulating the regenerative microenvironment.