Soutenance de thèse de Shangaya Touraivane

Dentinogenesis Imperfecta (DI) is a rare genetic disorder (1 in 6,000–8,000 births) that alters the structure and mechanical properties of dentin. Caused by variants in COL1A1/COL1A2 or DSPP, the disease increases tooth fragility. Patients commonly experience fractures, excessive wear, and enamel detachment that exposes the underlying dentin. DI is therefore a highly debilitating oral disorder that often necessitates extraction and prosthetic replacement of affected teeth. Despite its clinical impact, the pathophysiology of DI remains incompletely understood. In particular, the mechanisms through which genetic mutations lead to structural defects and increased dentin fragility remain poorly defined. This work investigates how molecular-level collagen damage associated with a COL1A2 variant propagates across hierarchical scales to alter dentin structure, composition, and mechanical behavior, ultimately contributing to tissue fragility. 
        
        To address this question, we performed a multimodal, multiscale investigation of DI dentin carrying a COL1A2 (c.982G>A (p.Gly328Ser)) variant. We found that DI was associated with a marked increase in molecular-level collagen damage (i.e., denaturation). Collagen denaturation coincided with major disruptions in the spatial organization of the organic matrix, including the emergence of large regions devoid of non-denatured collagen. These regions were spatially associated with pronounced mineralization heterogeneities. As a result, dentin morphology was profoundly altered: dentinal tubules were occluded by mineral deposits, and extensive hypermineralized regions were observed. Two distinct types of hypermineralized structures were identified: (i) oblong features aligned with dentinal tubules, devoid of non-denatured collagen and containing nested tubules, which we named comets; and (ii) concentric bands running parallel to the dentin–enamel junction (DEJ). These alterations extended across scales, culminating with a macroscale increase in dentin mineralization.
        The microscale mechanical properties of dentin were significantly affected by these morphological changes. Hypermineralized regions were harder and more brittle, and cracks propagated preferentially through them. Notably, a hypermineralized band located beneath the DEJ may contribute to enamel detachment. At the macroscale, DI dentin exhibited increased stiffness but reduced hardness despite its higher mineral content. To further characterize the mechanical consequences of DI, we developed a complete workflow for microscale toughness testing of focused ion beam–milled chevron-notched micro-cantilevers. We also performed macroscale 3-point bending toughness tests on aged dentin and conducted correlation analyses to evaluate the respective contributions of collagen denaturation and mineralization to dentin fragility.
        
        Together, these findings provide multiscale evidence that collagen damage associated with the studied variant is linked to coupled alterations in the organic matrix, mineral phase, and porous network of dentin, all of which are critical determinants of mechanical performance. Our data suggest that the brittleness of DI dentin arises, at least in part, from microscale heterogeneities in collagen organization and mineral distribution. More broadly, this work represents a step toward establishing a mechanistic framework describing how collagen-related variants generate molecular-level defects that propagate across scales to compromise dentin integrity. Such a framework is essential for advancing our understanding of both healthy and pathological dentin and may ultimately support the development of more effective treatments for affected patients and fuel the general understanding of architectured materials.

Composition du jury :

• Jean-Marc ALLAIN - Professeur à Ecole Polytechnique. Examinateur
• Aurélien GOURRIER - Directeur de recherche à Université Grenoble Alpes. Rapporteur
• Davide RUFFONI - Associate professor à Université de Liège. Rapporteur
• Denis AUBRY - Professeur émérite à CentraleSupélec. Examinateur
• Kathryn GRANDFIELD - Professor à McMaster University. Examinatrice