Optimally Aligned Nerve Scaffolds with Sustained Astaxanthin Release Enhance the Inflammatory Microenvironment Via Mitophagy Activation

Abstract

Effective repair of peripheral nerve injuries (PNI) hinges on scaffold orientation and the immunomodulatory capabilities of functionalized scaffolds, both of which significantly influence nerve regeneration. In this study, composite nerve scaffolds incorporating astaxanthin (AXT) and polycaprolactone (PCL) were developed to investigate how scaffold orientation and blend concentration affect cellular behaviors, including adhesion, migration, and proliferation. In vitro analysis identified 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 improved microenvironment by preserving mitochondrial homeostasis, promoting mitophagy, and reducing oxidative stress and inflammation. In vivo assessments revealed that the AXT/PCL group (0.2% AXT/PCL-400) achieved superior morphological, histological, electrophysiological, and functional recovery compared to 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 demonstrated superior regenerative outcomes compared to both the PCL and AXT/PCL+M0 groups, underscoring the critical role of mitophagy in regulating the regenerative microenvironment.

Keywords: peripheral nerve regeneration, mitophagy, astaxanthin, oxidative stress and inflammation, oriented nerve scaffold