Body Biofluids for Minimally-Invasive Diagnostics: Insights, Challenges, Emerging Technologies, and Clinical Potential.

Recent advances in diagnostics have accelerated the development of miniaturized wearable technologies for the continuous monitoring of diseases. This paradigm is shifting healthcare away from invasive, centralized blood tests toward decentralized monitoring, using alternative body biofluids. Biofluids such as sweat, saliva, urine, and interstitial fluid (ISF) emerged as promising candidates in this context, due to their accessibility and potential ability to reflect physiological states. This review examines recent progress in non- and minimally-invasive diagnostics, with focus on sweat and ISF as potentially suitable biofluids. For biofluids to achieve clinical utility, they must contain quantifiable and disease-specific biomarker levels, supported by standardized collection and analysis protocols. However, sweat presents inherent limitations for diagnostics, such as intra- and interpersonal variability, biomarker concentration fluctuations, etc., and thus only suitable for non-clinical applications. In contrast, ISF, a robust plasma-like biofluid potentially fulfills all requirements posed by clinical applications, being readily accessed by minimally-invasive microneedle-based platforms. These developing platforms may advance this field by eliminating the need for biofluid extraction, enabling continuous sensing in clinical diagnostics. Future integration of these platforms with AI/ML-driven algorithms may lead to powerful technologies for real-time, predictive personalized diagnostics. These technological innovations establish a strong foundation for next-generation diagnostics and transformative healthcare solutions.