Toward diagnostically relevant isotope-ratio biomarkers: what does MC-ICP-MS still need for standardized measurements?

Stable isotope-ratio analysis by inductively coupled plasma-mass spectrometry (ICP-MS) with a multi-collector (MC-ICP-MS) is increasingly used in life sciences, offering mechanistic insight and potential diagnostic specificity. This review asks the following: What limits biomedical isotope-ratio work, and what steps will make results comparable and fit for biomedical interpretation? Our target audience includes analytical chemists, MC-ICP-MS practitioners, liquid chromatography (LC) and capillary electrophoresis (CE) users, metrology and assurance/quality control specialists, and biomedical researchers adopting isotope-ratio workflows. We map the field from bulk delta (δ) values to chemical speciation, species-specific isotope ratios, and spatially resolved readouts. Specific choices in sampling, pre-analytics, separation, sample introduction, and instrument setup are linked to the main sources of bias and to the limits of precision and traceability. Recent progress is synthesized across automated clean-up, LC/ICP-MS and CE/ICP-MS workflows, transient-signal handling, and species-specific isotope dilution with enriched spikes. The review provides practical guidance on baseline correction, peak integration, mass-bias correction, scale realization, and uncertainty budgets. Across studies, the bottlenecks are species instability and interconversion, matrix and space-charge effects, sample-spike mismatch, spectral interferences, lack of species-specific reference materials, and inconsistent operating procedures. We close with an outlook that prioritizes (i) automation and transient-signal processing, (ii) matrix-matched species-specific reference materials, (iii) instrument advances for interference control and coupling efficiency, and (iv) harmonized data-processing standard operating procedures. Together, these steps can enable reproducible multi-site biomedical isotope-ratio workflows and support their translation towards clinical applicability by clarifying where MC-ICP-MS already adds value and where research is still needed.