Project Summary/Abstract The last decade has seen a shift in the philosophy of dental care towards prevention and minimal-invasive restorative approaches, promoting tissue repair by remineralization as a key element of dental treatments. Remineralization of enamel, which is 95% mineral, is an accepted phenomenon with established mechanisms relying mainly on fluoride release. Those mechanisms, however, do not apply to dentin, as they do not produce intrafibrillar mineral as demonstrated in our preliminary studies. Dentin is a collagenous tissue, similar to bone, and requires apatite mineral to form inside collagen fibrils (intrafibrillar) for mechanical reinforcement. We have shown that the “Polymer-Induced Liquid Precursor” (PILP) approach is suitable and effective to reintroduce mineral into collagen in vitro restoring the mechanical properties of the tissue, which is critical for its function. PILP-treatments performed on demineralized specimens recovered their mechanical properties at 50 to 100% of normal tissue value when evaluated by nanoindentation and 4-point bending tests, respectively. We have identified two proteins, osteopontin (OPN-10) and phosvitin (PV) in addition to synthetic poly-aspartic acid (pAsp), among a larger set of possible systems, reported in the literature, that reintroduce oriented apatite crystallites in the interstices of collagen-I fibrils in dentin matrices. Based on this concept, we propose to develop PILP-releasing materials and procedures that can be applied to dentin caries and be integrated with a restorative treatment facilitating long-term collagen remineralization leading to a restoration of tissue function, ultimately extending the life-time of the tooth and thus reducing the incidents of pulp exposure and endodontic treatment or tooth loss due to caries. The proposed reparative procedures will interfere with the current standard of care for caries management in dentistry that stresses excessive tissue removal. Instead this approach will promote repair, regeneration and conservation of the natural tissue. Dentin's function is primarily mechanical as it supports the stiff enamel in the mastication process. That function is lost when bacterial acid dissolves and removes apatite from collagen fibrils. PILP-mineralization is thus far the only known method to restore this function in vitro in artificial lesions. We consider this approach a regenerative approach as it rebuilds a weight-bearing tissue which would otherwise not contribute to the mastication process. Here we propose to test the standard PILP-mineralization method as well as novel cement formulations that are comprised of PILP-components for their potential to repair natural caries lesions in vitro as a further step towards translation of the PILP-mineralization concept into a clinical setting.