Introduction: To date, there is no evidence that conventional remineralization techniques using calcium and phosphate ioncontaining media will completely remineralize carious lesions in regions where remnant apatite seed crystallites are absent. Conversely, guided tissue remineralization using biomimetic analogs of dentin matrix proteins is successful in remineralizing thin layers of completely demineralized dentin. The hypothesis: Conventional remineralization strategy depends on epitaxial growth over existing apatite crystallites. If there are no or few crystallites, there will be no remineralization. Guided tissue remineralization uses biomimetic analogs of dentin matrix proteins to introduce sequestered amorphous calcium phosphate nanoprecursors into the internal water compartments of collagen fibrils. Attachment of templating analogs of matrix phosphoproteins to the collagen fibrils further guided the nucleation and growth of apatite crystallites within the fibril. Such a strategy is independent of apatite seed crystallites. Our hypothesis is that 250-300 microns thick artificial carious lesions can be completely remineralized in vitro by guide tissue remineralization but not by conventional remineralization techniques. Evaluation of the hypothesis: Validation of the hypothesis will address the critical barrier to progress in remineralization of cariesaffected dentin and shift existing paradigms by providing a novel method of remineralization based on a nanotechnology-based bottom- up approach. This will also generate important information to support the translation of the proof-of-concept biomimetic strategy into a clinically-relevant delivery system for remineralizing cariesaffected dentin created by micro-organisms in the oral cavity. © 2010 Dai L, et al.