Project Summary Dental caries is a major health concern in most industrialized countries, in which most children, young and older adults have experienced the disease at least once in their lifetime. In recent study (2019) on the impact of oral diseases on global public health, untreated caries figures as the most prevalent and consequential amongst all oral conditions, affecting more than 3 billion people worldwide, with strong detrimental effect on quality of life and high costs for individuals, families, and society. Moreover, caries disease is unequally distributed in populations with a significant socioeconomic gradient. Although dental caries is essentially a preventable condition, its prevalence has barely diminished over the last 40 years. While a definitive approach to prevent and manage dental caries has yet to be found, restorative biomaterials and techniques remain as the only existing resources for rehabilitation of the caries-affected tooth. The primary goal of restorative dentistry is to repair tooth damaged structures by replacing them with synthetic materials aiming at the re-establishment of tooth aesthetics and function. Current restorative procedures fully depend on effective micromechanical interactions between resin methacrylates and nanostructured organic macromolecules of dentin (mainly collagen), the bulkiest substrate of tooth demanding substantial repair in dental rehabilitation schemes. As quoted by several dental material scientists, infiltration of resin methacrylates within partially demineralized dentin is a type of on-demand tissue engineering. Nonetheless, creating durable resin-based fillings is still a significant challenge in adhesive dentistry. The NIDCR 2009-2013 strategic plan on tooth-colored resin restorations reported that the average replacement time of these restorations is only 5.7 years. The major reason for replacement of such restorations has been attributed to enzymatic degradation of the resin-dentin bonded interface, which ultimately facilitates recurrent caries. Estimated costs to replace defective resin fillings are in the order of about five billion dollars per year in the US alone. The overall goal of this proposal is to use modified natural biomaterials to address this matter. This study will develop hybrid hydrogels by means the functionalization of extracellular matrix (ECM) of demineralized dentin with acrylamides to produce resin dental adhesives that are less vulnerable to undergo hydrolytic degradation. In addition, this proposal will pioneer a dental adhesive that is truly biomimetic for endogenous dentin and, as such, will have the capacity not only repair dental caries lesions, but to regenerate dentin better than current methacrylate dental adhesives. This program will offer excellent training opportunities for graduate and professional students, thus providing scientific support to the next generation of clinicians. Furthermore, while this technology intends primarily advance dent...