Abstract
Neonatal white matter injury (WMI) arises from the interaction of developmental vulnerability with hypoxic–ischaemic, inflammatory, oxidative, and metabolic perturbations. Although experimental models have substantially advanced the understanding of these mechanisms and supported the investigation of anti-inflammatory and neuroprotective strategies, their translation into neonatal clinical practice remains challenging. Neonates are neither small adults nor little children, and experimental animals are not scaled representations of human neonates. Similar molecular pathways, cellular targets, or anatomical features across species may therefore indicate concordance in individual characteristics without establishing biological or pharmacological equivalence. In this narrative review, we examine the translational gap between experimental models of neonatal WMI and human neonatal pharmacology, focusing on developmental differences in inflammatory pathways, white matter maturation, physiology, drug disposition, and target engagement. We discuss the apparent discordance between preclinical biological plausibility and clinical neuroprotection. Thereafter, we propose an intervention-specific framework (“The Reticulum Framework”) that organizes developmental concordance, evidence gaps and uncertainty across species; its predictive value requires empirical validation. The framework conceptualizes anatomy, physiology, biochemistry, and developmental pharmacology as interacting domains constrained by biophysical principles and introduces “comparative developmental physionemes” as biologically interpret descriptors whose concordance or discordance contributes to translational equivalence. In this sense, current validated biomarkers and surrogate measures could be used to analyse the interconnection between these domains across species, considering especially cellular and molecular dynamics through omics pipelines. The Reticulum Framework proposes that biological correspondence should be evaluated according to the functional meaning that a physioneme acquires within a specific developmental system rather than by isolated similarity. Translational relevance is therefore considered intervention-specific and is assessed across anatomical, physiological, biochemical, pharmacological, biophysical, temporal, and outcome concordance as a multidimensional profile. This framework may support model selection, interpretation of experimental anti-inflammatory efficacy, identification of translational mismatches, and prioritization of candidate neuroprotective interventions for neonatal trials.