Project Grant R21DE032503

DETERMINING THE EFFICACY OF A NOVEL APATITE-BASED ANTIMICROBIAL BONE SCAFFOLD FOR CRANIOFACIAL SURGICAL APPLICATIONS - PROJECT ABSTRACT / SUMMARY TRAUMATIC MUSCULOSKELETAL INJURIES COMMONLY INVOLVE MASSIVE BONE AND SOFT TISSUE DISRUPTIONS, WITH SUBSEQUENT INFECTION POSSIBLY DEVELOPING AS A FREQUENT COMPLICATION. THIS LEADS TO MULTIPLE SURGICAL DEBRIDEMENTS, WHICH FURTHER INCREASES THE SIZE OF THE DEFECT. SURGICAL DEBRIDEMENT IS NEEDED TO ACHIEVE A CLEAN WOUND REQUIRED FOR SUCCESSFUL BONY RECONSTRUCTION. THUS, ADDRESSING CRITICAL-SIZE BONE DEFECTS- WHICH CANNOT BE HEALED WITHOUT REPLACING THE LOST BONE WITH BONE GRAFT MATERIALS-IS OFTEN DELAYED UNTIL WOUND HOMEOSTASIS IS OBTAINED. SUCH DELAY MAY LEAD TO SECONDARY COMPLICATIONS AND LIFE-LONG DISABILITY. SELF-SOURCED OR AUTOGRAFT BONE IS THE "GOLD STANDARD" AMONG ALL GRAFT MATERIALS, BUT THE AMOUNT OF BONE SITES AVAILABLE IS LIMITED. THIS PRODUCES INSUFFICIENT GRAFT MATERIAL TO FILL CRITICAL-SIZE DEFECTS, AND SUCH HARVEST REQUIRES SECONDARY SURGICAL SITES. DECELLULARIZED AND STERILIZED CADAVERIC OR ALLOGRAFT BONE COMMONLY FAILS IN BACTERIALLY CONTAMINATED WOUND ENVIRONMENTS. ENGINEERED BONE SUBSTITUTES MAY PROVIDE A SOLUTION TO THIS DILEMMA IF THE CURRENT LIMITATIONS OF THESE MATERIALS CAN BE ADDRESSED, INCLUDING THEIR INABILITY TO MATCH THE MECHANICAL STRENGTH, POROSITY, AND BIOACTIVITY OF AUTOGRAFTS. IDEALLY, SUCH ENGINEERED BONE SCAFFOLDING MATERIALS SHOULD ALSO POSSESS ANTIMICROBIAL PROPERTIES. IN THE PAST, SCAFFOLD SURFACES HAVE BEEN COATED WITH ANTIMICROBIAL/BROAD-SPECTRUM ANTIBIOTICS, BUT THE RAPID RELEASE OR "BURST EFFECT" OF THESE COATINGS ONLY PROVIDES SHORT-TERM PROTECTION, AND SUDDEN HIGH ANTIBIOTIC LEVELS CAN BE TOXIC TO THE LOCAL CELLS NEEDED FOR HEALING. ONE OTHER OPTION COULD BE TO TAILOR BONE SCAFFOLDS WITH INTRINSIC ANTIMICROBIAL SURFACE PROPERTIES. THE BONE MATRIX CRYSTALLINE HYDROXYAPATITE (HA) IS KNOWN FOR ITS BIOCOMPATIBILITY, OSTEOGENIC PROPERTIES, AND BIO-ABSORBABILITY BUT LACKS MECHANICAL STRENGTH AND CONTROLLABLE RESORPTION PROPERTIES. TO IMPROVE THE MECHANICAL PROPERTIES OF HA, WE HAVE USED BOTH IONIC CHEMICAL SUBSTITUTION AND VARIATION IN TEMPERATURES TO SYNTHESIZE VARIOUS APATITE TYPES. OUR PRELIMINARY DATA REVEALED THAT FLUORIDE SUBSTITUTED APATITE (FLUORAPATITE (FA)), WHEN SINTERED ABOVE 11500C, PRODUCED IMPROVED MECHANICAL STRENGTHS, INCLUDING COMPRESSION STRENGTHS AND INCREASED BONE DEPOSITION IN AN IN VIVO MODEL. WE HAVE ALSO SHOWN THAT WHEN KNOWN ANTIMICROBIAL METALS ARE CO-DEPOSITED AND IMMOBILIZED WITHIN THE APATITE CRYSTALS DURING THE SYNTHESIS OF FA, SOME COMBINATION OF APATITES EXHIBITED IMPROVED ANTIMICROBIAL PROPERTIES WITHOUT PRODUCING CELL CYTOTOXICITY. THIS PROPOSAL IS DESIGNED TO TEST ONE SUCH APATITE, ZINC-DOPED FLUORAPATITE (ZN-FA). BASED ON OUR PRELIMINARY DATA, IT WAS HYPOTHESIZED THAT AN OPTIMIZED MOLAR PERCENT ZINC SUBSTITUTED POROUS FLUORAPATITE SCAFFOLDS WOULD HAVE THE POTENTIAL TO REGENERATE BONE TISSUE WITHIN BOTH STERILE AND INFECTED SITES. THIS HYPOTHESIS WILL BE TESTED USING THREE SPECIFIC AIMS. SPECIFIC AIM 1 IS DESIGNED TO FABRICATE AND TEST BOTH MECHANICAL AND ANTIMICROBIAL IN VITRO PROPERTIES OF VARIOUS MOLAR PERCENT ZN SUBSTITUTED FA, SPECIFIC AIMS 2 AND 3 WILL TEST THE EFFICACY OF AN OPTIMIZED MOLAR PERCENT ZINC SUBSTITUTED FA TO GENERATE BONE TISSUES IN CONTAMINATED AND CRITICAL-SIZE POCKETS, RESPECTIVELY.