Project Grant R56DE032903

PEPTIDE ENABLED TUNABLE RESTORATIVE INTERFACE - PROJECT SUMMARY AMONG U.S. CHILDREN, CARIES IS THE SINGLE MOST COMMON CHRONIC DISEASE AND ONE OF THE MOST COMMON UNMET HEALTH CARE NEEDS. UNDERSERVED AND SPECIAL NEEDS PATIENT POPULATIONS HAVE A HIGHER CARIES BURDEN, I.E., UNTREATED DENTAL CARIES IS A MAJOR HEALTH PROBLEM FOR CHILDREN WITH DEVELOPMENTAL DISABILITIES. TREATING CARIOUS LESIONS CONVENTIONALLY REQUIRES SURGICAL REMOVAL OF DISEASED TOOTH STRUCTURE USING HIGH-SPEED DRILLS AND THE ACCOMPANYING EXTENSIVE DENTAL RESTORATIVE TREATMENT FOR YOUNG CHILDREN OR PERSONS WITH SPECIAL NEEDS MAY REQUIRE GENERAL ANESTHESIA OR DEEP SEDATION, STEPS WHICH REQUIRE REFERRING THE CHILD TO A DENTAL SPECIALIST AND CONCORDANT HIGH HOSPITALIZATION COSTS. UNTREATED EARLY CHILDHOOD CARIES (ECC) SPREADS MORE RAPIDLY COMPARED TO ADULT TEETH AND DEVELOPS BOTH SHORT- AND LONG-TERM SIGNIFICANT HEALTH ISSUES. THE ONLY NONINVASIVE, EFFICACIOUS TREATMENT OPTION IN THE U.S. FOR ARRESTING CARIES IS SILVER DIAMINE FLUORIDE (SDF). SDF WAS APPROVED BY THE FDA IN 2014 AND GRANTED A BREAKTHROUGH THERAPY DESIGNATION FOR TREATING CARIES IN CHILDREN. HOWEVER, PERMANENT BLACK STAINING OF SDF-TREATED CARIES LESIONS LIMITED THE ACCEPTABILITY AND ADOPTION OF THIS TREATMENT. BESIDES, THE NEW INTERFACE FORMED AT THE SDF SITE RAISED CONCERNS REGARDING REDUCED BONDING OF COMPOSITE MATERIALS COMMONLY USED TO MASK THE STAINING. RECENT STUDIES ON SDF TREATMENT INDICATED THE FORMATION OF SILVER COMPLEXES FILLING THE CAVITIES AND PENETRATING DENTIN TUBULES. THIS PROPOSAL ADDRESSES THE URGENT CLINICAL NEED FOR NONINVASIVE TREATMENT FOR CARIES IN CHILDREN AND PERSONS WITH SPECIAL NEEDS BY DEVELOPING A SILVER TARGETING BIOMIMETIC INTERFACE THAT WORKS SYNERGISTICALLY WITH SDF TO ARREST CARIES AND REMINERALIZE THE TOOTH WHILE REDUCING SILVER OXIDATION WHICH LEADS TO BLACK STAINING. WE HYPOTHESIZE THAT POLYMERIZABLE PEPTIDES TARGETING SILVER COMPOUNDS AND ACTING AS REMINERALIZATION AGENTS WILL SLOW SILVER OXIDATION, PROMOTE TOOTH REMINERALIZATION, ENHANCE PROPERTIES OF SDF-TOOTH INTERFACE AND ARREST CARIES. RECENT FINDINGS FROM OUR LAB SUPPORT THIS HYPOTHESIS AND OFFER SIGNIFICANT PROMISE FOR MEETING THIS URGENT NEED. FIRST, WE ENGINEERED BIFUNCTIONAL PEPTIDES CONTAINING A SILVER-BINDING DOMAIN (AGBP) THAT SELF ASSEMBLES AND MEDIATES REMINERALIZATION AT THE SDF TREATED CARIOUS LESION. SECOND, WE DEVELOPED A POLYMERIZABLE AGBP BY TETHERING IT TO METHACRYLIC ACID FOR USE AS A PEPTIDE- MONOMER IN DENTIN ADHESIVE. THIRD, WE DEMONSTRATED THAT SELF-ASSEMBLY OF THE AGBP-MONOMER AT THE SDF TREATED INTERFACE SIGNIFICANTLY REDUCES THE SILVER OXIDATION PROCESS. BUILDING ON OUR PROGRESS, THE PROPOSAL EXPLOITS: AIM 1) ENGINEERED PEPTIDES TO IMPROVE INTERFACE PROPERTIES BY PREFERENTIALLY INTERACTING WITH SILVER COMPLEXES AND REMINERALIZING THE SDF-TREATED LESIONS; AIM 2) POLYMERIZED PEPTIDE-POLYMER RESINS TO REDUCE THE AG OXIDATION PROCESS AND PROVIDE DURABLE BONDING WITH SDF; AIM 3) CO-TREATMENT WITH SDF AND PEPTIDE-POLYMER RESINS TO PROVIDE MORE-DURABLE, MECHANICALLY ROBUST INTERFACIAL BONDS COMPARED TO SDF TREATMENT ALONE. THE PROPOSED APPLICATION HAS THE POTENTIAL TO DIRECTLY IMPACT ORAL HEALTH DISPARITIES BY ARRESTING CARIES, REMINERALIZING THE TOOTH, AND REDUCING THE STIGMATIZING SIDE EFFECT OF BLACK STAINING ASSOCIATED WITH SDF TREATMENT ALONE.