Highly Sensitive and Reliable Internal-Standard Surface-Enhanced Raman Scattering Microneedles for Determination of Bacterial Metabolites as Infection Biomarkers in Skin Interstitial Fluid

Microneedles (MNs) are currently one of the most promising tools for skin interstitial fluid (ISF)-based biosensing, while it is still a challenge to expand the detectable biomarkers in ISF due to limited MNs types and detection techniques. Herein, highly sensitive internal-standard surface-enhanced Raman scattering microneedles (IS-SERS-MNs) were developed, which enabled the reliable detection of bacterial metabolites in ISF as new detectable biomarkers for infection diagnosis. The developed IS-SERS-MNs can not only directly detect pyocyanin (a representative bacterial metabolite) present in mouse dermal ISF but also indirectly detect pyocyanin in the hypodermis via its diffusion into the dermis, revealing a new possible pathway for the source of biomarkers in dermal ISF. Moreover, the SERS signal of pyocyanin was also clearly detected at real mouse wounds, indicating that the developed IS-SERS-MNs have great potential in minimally invasive and painless diagnosis of bacterial infection via a new ISF route. This work not only develops IS-SERS-MNs as a powerful tool for expanding the application of SERS-based MNs but also provides a new chance for ISF-related infection diagnosis.