Piezoelectric scaffolds: Mediating tendon regeneration by activation of piezosensitive receptors
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Tendon disease caused by trauma, illness or age-related degeneration constitutes an unmet clinical need. Tendon repair using different pharmacological and engineering strategies based on both synthetic and biological grafts has failed to restore native tendon function. Advancement in regenerative medicine and integrative physicomechanical approaches has enabled the development of electrically and mechanically active scaffolds that can recapitulate closer the native tendon tissue physical properties. In particular, electromechanical coupling (piezoelectricity) is present in all living beings and provides a basis for sense, thoughts and the mechanisms of tissue regeneration. Critically, the piezoelectric properties of musculoskeletal tissue have been recently measured at the molecular, fibrillar and tissue level and are mainly attributed to collagen type I - a fibrous protein abundant in mammals. This thesis is concerned with the study of the effect of piezoelectricity on biological processes such as cellular differentiation, cell growth, and cytoskeleton rearrangement to improve the functionality of tendon engineered substitutes. Initially, piezoelectric nanocomposites were fabricated and displayed superior piezoelectric performance while enhancing tendon cell adhesion. Following the identification of optimal mechanical stimulation conditions, piezoelectric scaffolds showed the ability to negate the phenotypic drift and dedifferentiation of tendon cells in vitro. This system was assessed in vivo in clinically relevant full-thickness rat Achilles tendon injury model undergoing treadmill running. The effect of treadmill running was first evaluated and showed to enhance tendon regeneration. Piezoelectric scaffolds, in combination with treadmill running, proved to be able to speed the functional recovery of injured tendons through the activation of piezosensitive receptors at both 4 and 8 weeks. Analysis of the tissue with custom-made protein microarrays revealed that in addition to the modulation of tenogenic TGF-β/BMP signalling pathways, there was also activation of piezosensitive receptors TRP and Piezo family members. While changes in organisation and maturation of collagen I were not significant between piezoelectric and non-piezoelectric systems, changes in the ectopic bone formation were observed. Piezoelectric scaffolds were able to promote bone formation while maintaining also enhanced tenogenic potential indicative of the strong regenerative potential of piezoelectric scaffolds. Overall, the system shows promise for the treatment of tendon injuries in which regeneration of tendon is required.
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