Piezoelectric materials for tissue engineering and regenerative medicine: From fundamental principles to clinical...

Piezoelectric materials have emerged as promising electroactive biomaterials in regenerative medicine owing to their ability to convert mechanical forces into electrical signals and vice versa. These materials reproduce aspects of the body's native bioelectric microenvironment and influence key cellular processes, including adhesion, proliferation, migration, and differentiation. Clinically, piezoelectricity has been exploited, in dental implants, where electromechanical activity enhances osseointegration and long-term stability. This review provides a comprehensive overview of the principles of piezoelectricity, the major classes of piezoelectric materials, and recent advances in fabrication strategies such as electrospinning, additive manufacturing, and nanogenerators. Applications across bone, nerve, cartilage, skin, and cardiovascular tissues are critically examined, with emphasis on mechanosensitive ion channels, intracellular signalling pathways, and gene regulation. Safety concerns, including ion release from ceramic materials, and the emergence of biocompatible, lead-free alternatives are discussed alongside translational barriers related to scalability, regulatory approval, and device integration. The aim of this review is to provide a mechanistic and clinically oriented perspective that informs the design of next-generation piezoelectric materials. Finally, future directions in self-powered implants and piezoelectric catalysis are highlighted to support their clinical translation for tissue repair and regenerative therapies. STATEMENT OF SIGNIFICANCE: This review uniquely integrates the fundamental and translational aspects of piezoelectric biomaterials in regenerative medicine. We highlight how piezoelectric cues regulate cell behaviour through electrical stimulation, ion channel activation, particularly Ca²⁺ flux and downstream signalling pathways such as Wnt/GSK3β and PI3K/Akt. By linking these mechanisms to gene expression profiles and functional outcomes across bone, nerve, cartilage, cardiovascular, and skin tissues, this work provides a tissue-specific perspective that has not been comprehensively addressed before. Importantly, we emphasise the multifunctionality of piezoelectric scaffolds, showcasing their immunomodulatory, angiogenic, and biomechanical benefits. The review further bridges insights across chemistry, biology, materials science, and biofabrication, offering constructive guidance for designing next-generation, clinically translatable piezoelectric biomaterials.