The Fidelity Paradox in Spinal Cord Injury: Reframing Biomechanical Mimicry and Neurobiological Relevance for...

Despite abundant neuroprotective successes in rodents, effective clinical therapies for spinal cord injury (SCI) remain elusive. This translational disconnect stems from a fidelity paradox. The over-reliance on rodent models that achieve biomechanical mimicry of human trauma but lack fundamental biological equivalence.

We evaluated how physical simulation masks critical interspecies divergences. Following PRISMA guidelines, we systematically searched PubMed and Web of Science (2000-2024) to assess preclinical model utilization frequencies and synthesized evidence across distinct pathophysiological pillars to evaluate cross-species biological mismatches.

Our analysis reveals profound spatiotemporal dissonances across three pillars: (i) immunodynamics, where the delayed inflammatory resolution in mice misaligns with human chronobiology; (ii) lesion architecture, distinguishing rodent cystic cavitation from the fibrotic scarring characteristic of human pathology; and (iii) neural circuitry, contrasting indirect rodent corticospinal projections with the direct cortico-motoneuronal connections essential for human dexterity. To address this, we propose a mechanistic fidelity matching framework. This paradigm shifts from indiscriminate single-model validation to a problem-driven matrix, selecting models based on their specific biological fidelity to targeted mechanisms-utilizing mice for scar modulation, rats for cystic repair, and nonhuman primates for fine sensorimotor recovery.

Restoring translational credibility requires replacing the pursuit of a universal model with a hierarchical, cross-species validation pipeline anchored in objective, mechanism-coupled readouts.