Wound Geometry Determines Whether Aligned-Fiber Scaffolds Accelerate or Impede Diabetic Wound Healing: A Biased Random Walk Analysis.

Aligned-fiber scaffolds for wound healing show inconsistent clinical outcomes, sometimes dramatically accelerating wound healing, other times providing no benefit or even impeding closure. This unpredictability has prevented widespread adoption despite compelling biological rationale. We resolved this by demonstrating that healing outcomes depend on geometric relationships between wound shape and fiber orientation, not material properties alone. Using a biased random-walk model calibrated to streptozotocin-induced diabetic rat wound data, recapitulating the migration-limited healing characteristic of chronic diabetic wounds, we show that identical scaffolds can either accelerate healing or provide no benefit depending solely on orientation relative to wound geometry. Cells migrate 50% faster along fibers, but are impeded perpendicular to them, creating a trade-off that depends on wound shape. Model predictions across diverse geometries generate an optimal healing landscape, with elongated wounds showing 30% variation in closure rates depending on alignment angle. Results explain conflicting literature reports in the context of diabetic wound repair and provide a proof-of-concept framework for the rational selection of scaffold architecture in this specific setting.