Correlative Multimodal Framework Reveals Supramolecular Chirality Loss Preceding Fibrillar Rarefaction in Dermal...

Early-stage remodeling of collagen-rich tissues is commonly inferred from fibrillar thinning and loss of connectivity, yet the structural change that initiates this process has remained unclear. Here, we show that early collagen remodeling is first expressed as a loss of supramolecular chirality coherence, rather than a reduction in collagen density or network integrity. By correlating molecular-scale chiral order with mesoscale fibrillar organization across three independent adult skin sample donors (Samples 1-3, referred to as S1-S3), we identify an abrupt collapse of chirality coherence despite preserved collagen mass and coverage. Only at some stages do fibrillar fragmentation and directional reorganization become apparent, accompanied by a reduction in nonlinear optical response. These findings establish supramolecular chirality coherence as an early-failing order parameter in collagen assemblies and reveal a previously unrecognized precursor to dermal remodeling. More broadly, this work provides a framework for detecting incipient failure in hierarchical chiral biomaterials before macroscopic degradation becomes evident.