A multiscale pathoanatomical atlas guides the design of functionally graded, anatomically intelligent implants for chronic osteomyelitis.

Chronic osteomyelitis remains a formidable clinical challenge because conventional biomaterials, which are designed for spatially uniform defects, cannot match the hierarchical, compartmentalized progression of deep bone infection. Using a clinically relevant rabbit femoral osteomyelitis model, we construct a multiscale pathoanatomical atlas of S. aureus infection, revealing a coherent disease cascade: medullary colonization, invasion of the immunoprivileged osteocyte lacuno-canalicular system (OLCS), region-specific bone destruction, and ultimate formation of a biomechanically incompetent sequestrum. Guided explicitly by this anatomical blueprint, we design and computationally optimize a dual-component bioactive material system that mirrors and counteracts the infection hierarchy. This dual-component implant integrates a 3D-printed, load-bearing macro-scaffold for mechanical stabilization and bone regeneration with infiltrative microspheres capable of penetrating trabecular microdomains and releasing antimicrobials within the marrow and cortical compartments, directly targeting bacterial reservoirs. In vivo validation demonstrates that this system enables simultaneous eradication of deep-seated infection, resolution of chronic inflammation, and restoration of structurally competent bone. Collectively, this work establishes imaging-resolved anatomical mapping as a generative framework for bioactive material design and provides a strategy that may be adapted for developing spatially adaptive therapeutic systems against complex tissue infections.