BaTiO3-based piezoelectric wireless neuromodulation: From molecular mechanisms to clinical translation challenges.

Abstract

Neurological injuries remain difficult to treat due to the complex microenvironment and the limited intrinsic regenerative capacity of neural tissues. Recently, wireless neuromodulation based on piezoelectric nanomaterials, particularly barium titanate (BaTiO₃), has emerged as a promising alternative to conventional implantable electrical stimulation. Polar BaTiO₃ ceramics generally have higher piezoelectric charge coefficients than conventional Polyvinylidene Fluoride (PVDF) and Poly(vinylidene fluoride-co-trifluoroethylene) (P(VDF-TrFE)) films, are more resistant to degradation than ZnO, and are lead-free unlike Lead Zirconate Titanate (PZT), although their rigidity and potential persistence in tissue complicate soft-tissue integration and post-treatment clearance. This review systematically summarizes recent advances in BaTiO₃-enabled piezoelectric neuromodulation and further outline preclinical applications in pain management and metabolic regulation across multiple neurological disorders, including traumatic brain injury (TBI), spinal cord injury (SCI), peripheral nerve injury (PNI), and post-traumatic epilepsy (PTE). We subsequently analyze the underlying mechanisms for neural repair, highlighting modulation of voltage-gated ion channels (e.g., Ca²⁺ and Na⁺) to regulate neuronal excitability and stem cell differentiation, mitochondrial targeting to influence metabolism and immune polarization, and controlled intracellular ion release (e.g., Zn²⁺) to modulate gene transcription. To enhance electromechanical-biological coupling in vivo, interface engineering strategies for BaTiO₃ are also discussed, with emphasis on surface modification approaches such as polydopamine functionalization and integration with conductive hydrogels to improve biomechanical compatibility. Finally, key challenges for clinical translation, including the lack of standardized stimulation parameters, are addressed, providing insights for the development of next-generation neuromodulation-based therapies. STATEMENT OF SIGNIFICANCE: Neurological injuries and diseases represent some of the most formidable clinical challenges because neural tissues have limited regenerative capacity, whereas conventional wired electrical stimulation is invasive. Although BaTiO₃-based piezoelectric nanomaterials have emerged as important wireless transducers for neuromodulation, the field still lacks a systematic framework linking the fundamental electromechanical properties of BaTiO₃ to disease-relevant therapeutic mechanisms and barriers to clinical translation. This review provides a systematic, mechanism-oriented assessment of BaTiO₃-based wireless neuromodulation by outlining its crystallographic basis and multiscale structural engineering and examining how localized electrical potentials may modulate voltage-gated ion channels, the neuroimmune microenvironment, and stem-cell metabolism. Ultimately, we critically analyze the prominent bottlenecks impeding preclinical-to-clinical translation, involving long-term biosafety, biomechanical compatibility, manufacturing reproducibility, etc.