Project Grant R21DE033019

NOVEL INJECTABLE BIOMATERIALS FOR PERIODONTITIS - PROJECT SUMMARY ALMOST HALF OF AMERICANS OVER 30 YEARS OLD HAVE PERIODONTITIS, AND 9% HAVE SEVERE PERIODONTITIS, WHICH CAN LEAD TO BONE LOSS, LOSS OF TEETH AND OSSEOINTEGRATION FAILURE OF DENTAL IMPLANTS. CURRENT TREATMENTS FOR PERIODONTITIS, INCLUDING THE STANDARD SCALING AND ROOT PLANING COMBINED WITH SYSTEMIC OR LOCAL ADMINISTRATION OF ANTIBIOTICS, DO NOT EFFECTIVELY ADDRESS SAFETY CONCERNS, ADEQUATELY PREVENT PERIODONTAL BONE LOSS, OR REPAIR DAMAGED BONE STRUCTURES. TISSUE ENGINEERING USING STEM CELLS/GENES/PROTEINS, COMBINED WITH BIOMATERIALS, IS A PROMISING STRATEGY TO ADDRESS THE CHALLENGES IN PERIODONTAL BONE REGENERATION DESPITE THE NUMEROUS HURDLES THAT STILL REMAIN. OUR PRIMARY GOAL, IN COLLABORATION WITH DR. SHAOPING. ZHANG-A PERIODONTIST AT UNIVERSITY OF IOWA WITH EXTENSIVE EXPERTISE IN BOTH BASIC AND CLINICAL RESEARCH IN PERIODONTITIS-IS TO DEVELOP AN INNOVATIVE AND TRANSLATIONAL BIOMATERIALS-BASED STRATEGY TO PREVENT AND TREAT PERIODONTITIS-INDUCED BONE LOSS. PI SUN'S PILOT STUDY INDICATES THAT THE CELL-PERMEABLE METABOLITE AKG (DMAKG) SIGNIFICANTLY INHIBITS OSTEOCLASTOGENEIS AND INFLAMMATION AND PROMOTES OSTEOGENIC DIFFERENTIATION IN VITRO. A HYDROGEL-DELIVERED LOCAL DMAKG PROMOTES BONE REGENERATION IN AGED MICE, WHICH IS CHALLENGED BY CHRONIC INFLAMMATION. MOREOVER, WE DEVELOPED A NEW VANILLIN/BIOGLASS-BASED TECHNIQUE TO FABRICATE AN INJECTABLE CHITOSAN HYDROGEL (CVB) WITH POWERFUL ANTIMICROBIAL AND OSTEOGENIC ABILITIES. THUS, OUR CENTRAL HYPOTHESIS IS THAT AN INNOVATIVE, INJECTABLE, AND BIODEGRADABLE CHITOSAN HYDROGEL THAT LOCALLY RELEASES THE METABOLITE AKG CAN EFFECTIVELY PREVENT AND TREAT PERIODONTITIS- INDUCED BONE LOSS IN A CLINICALLY RELEVANT MOUSE MODEL BY SIMULTANEOUSLY REDUCING BACTERIAL INFECTION, INFLAMMATION, AND OSTEOCLASTOGENESIS WHILE PROMOTING OSTEOGENESIS. IN AIM 1, WE WILL DEVELOP A NOVEL INJECTABLE DMAKG-RELEASING CHITOSAN HYDROGEL THAT CAN REDUCE HARMFUL MICROBIAL COUNTS, INFLAMMATION, AND OSTEOCLASTOGENESIS WHILE IMPROVING OSTEOGENIC CAPABILITIES IN VITRO. IN AIM 2, WE WILL ESTABLISH THE EFFECTIVENESS OF A TREATMENT FOR PERIODONTITIS-INDUCED BONE LOSS USING A NOVEL CHITOSAN HYDROGEL-MEDIATED DMAKG RELEASE IN A MOUSE MODEL. AT THE COMPLETION OF THIS EXPLORATORY/DEVELOPMENTAL R21 PROJECT, WE WILL HAVE DEVELOPED A NOVEL PERIODONTITIS TREATMENT USING AN INJECTABLE CHITOSAN HYDROGEL THAT LOCALLY RELEASES THE METABOLITE AKG. OUR NOVEL STRATEGY WILL SIMULTANEOUSLY REDUCE 1) BACTERIA GROWTH, 2) CHRONIC INFLAMMATION, 3) OSTEOCLASTOGENESIS, AND 4) PROMOTE OSTEOGENESIS, WHICH ARE ALL IMPORTANT FOR EFFECTIVE TREATMENT OF PERIODONTITIS, BUT CURRENT TREATMENTS HAVE DIFFICULTY TARGETING THEM ALL. OUR ACELLULAR BIOMATERIALS AND METABOLITE- BASED STRATEGY FOR PERIODONTITIS TREATMENT HAS GREATER TRANSLATIONAL POTENTIAL THAN USING BIOLOGICAL MEDIATORS.