A predictive mathematical framework for hemoglobin–material interactions: development of a hemoglobin sensitivity index (HSI) for next-generation biomedical applications

Current biocompatibility assessment paradigms inadequately predict hemoglobin-material interactions, limiting the rational design of blood-contacting biomedical devices. We developed a hemoglobin sensitivity index (HSI), a predictive mathematical framework integrating ten mechanistically derived parameters, namely binding thermodynamics, electrostatic interactions, hydrophobic forces, size-dependent diffusion kinetics, morphological effects, surface reactivity, oxidative stress generation, temporal stability, protein corona dynamics, and mechanical stress responses, through validated computational models. Each parameter was mathematically normalized using physical scaling laws and weighted through multi-objective optimization across ten biomedical applications. We computationally evaluated 25 materials spanning organic polymers, inorganic nanomaterials, and hybrid systems through literature results and predictive modeling. The HSI demonstrated exceptional theoretical predictive accuracy with a coefficient of determination (<i>R</i>²) of 0.943 and a root mean square error of 0.087 when validated against computational predictions and literature-derived cytotoxicity databases containing 1247 material-application pairs. Machine learning-enhanced parameter weighting revealed reactive oxygen species generation and binding affinity as dominant contributors with predicted weights of 0.247 ± 0.032 and 0.182 ± 0.023, respectively. Polymer-based material classes, including PEG polymers, exhibited predicted HSI values of 0.45-0.52, while carbon materials showed predicted risk profiles of 3.12-7.23. Application-specific optimization reduced the average predicted HSI by 67% compared to conventional designs. This HSI framework establishes the first quantitative, mechanistically grounded computational platform for predicting hemoglobin-material interactions, enabling rational biocompatible material design and supporting regulatory harmonization for accelerated clinical translation.