Dynamic landscape of chemiresistive breathomic nanosensors based on fifth-generation chips for complex disease diagnosis and healthcare monitoring

The growing global population is overwhelming the existing medical infrastructure, demanding a pressing need for the advancement of early-stage and point-of-care disease diagnostics. Conventional techniques are mostly invasive, time-consuming, expensive, sophisticated, and centered at urban facilities. Moreover, they are unable to address the biological complexities related to critical diseases, disorders, and pandemics, resulting in associated high morbidity and mortality. To address this gap, miniaturized fifth-generation sensing chips provide alternatives in terms of accessibility, affordability, and adaptability, being point-of-care and minimally invasive diagnostics. In this context, Breathomic chips based on nanoscale semiconductors have shown their potential for noninvasive, personalized, and on-site operation, offering the capability to identify volatile organic compounds/gases as disease biomarkers from exhaled breath and enabling early disease detection. However, the practical implementation of these sensors in real-time medical contexts remains challenging due to factors including the lack of clinical trials, dedicated data analysis, understanding of the complexities, public awareness, scalability, and accessibility. This comprehensive review critically summarizes the landscape of breath biomarkers detecting fifth-generation chemiresistive chips for human disease diagnosis, methodically outlining associated challenges, alternative strategies, and prospects for clinical implementations and commercial advancement. It details the biological origins of biomarkers, the diverse sensing modalities, and the underlying mechanisms pertaining to breathomic biomarker diagnosis. Furthermore, it highlights the integration of digital-age technologies, including nanotechnology, artificial intelligence, bioinformatics, and machine learning, for high-performance breathomic chips. These next-generation smart sensory chips have the potential to revolutionize medical healthcare facilities, improving patient outcomes, understanding prognosis, and aiding the UN's sustainable development goals.