PROJECT SUMMARY The prevalence of diabetes has rapidly risen during the last decades at an alarming rate, and more than 54.9 million Americans (15.3% of the population) are predicted to suffer from diabetes by 2030. Diabetic patients are highly susceptible to bone infections (osteomyelitis) and have poor bone regeneration capacity, placing them at a risk of amputations that dramatically impacts the quality of life. Even though osteomyelitis is one of the oldest diseases in human history, the existing medical approach to treat infected bone still has serious limitations while encountering new challenges. The effectiveness of the current treatment approach of debridement of the bone followed by antibiotics application is critically limited by (a) the formation of strongly assembled bacteria (biofilm) that are difficult to remove, (b) evolution of bacterial resistance to existing antibiotics, and (3) non-degradability of polymethylmethacrylate (PMMA) bone cement, which is used to locally deliver antibiotics but requires additional surgery to remove it afterward and is bioinert with potential toxicity of unreacted monomers. Therefore, there is a significant unmet medical need for the development of a next-generation antibiotic and an advanced antibiotic delivering system that can effectively cure the infection and improve the recovery of bone tissue. To solve this important problem, in this project, we aim to develop an innovative drug-device combination based on a novel dual-targeting antibiotic that can effectively retard bacteria resistance and an advanced biodegradable nanostructured bone cement that can induce a sustained release of antibiotics and enhance bone regeneration. We propose (1) to use whitlockite (WH) nanoparticles to develop a next-generation biodegradable bone cement, leveraging the excellent bone regeneration capacity and biodegradability of WH nanoparticles. WH also has a highly functionalized surface and can form nanostructured cement that can provide a large binding site for antibiotics; (2) to rationally develop next-generation antibiotics to have enhanced bactericidal capacity and compatible with our new degradable bone cement via computer-aided design and multiple screening processes. This is a significant advance from currently used antibiotics, which were originally never developed for bone infection or delivery from bone cement. We have already demonstrated that our preliminary model of dual-action antibiotics can significantly retard the evolution of bacterial resistance and is effective against biofilms; and (3) to validate the therapeutic efficacy of our dual-targeting antibiotic-impregnated WH bone cement in a diabetic osteomyelitis model in vivo by evaluating bone regeneration rate and conducting a comprehensive toxicological test. We envisage that this project will generate the first rationally designed antibiotic-delivering biodegradable cement that can treat biofilms, overcome drug resistance and regenerate the bone, thereby addressing a major clinical need. This research will also be beneficial for inhibiting infections in general orthopedic surgeries and thus, can lead to a paradigm shift in the treatment of bone infection.

PROJECT NARRATIVE Patients with diabetes are at increased risk of developing osteomyelitis or severe chronic bone infection, a debilitating condition characterized by bone loss often resulting in amputations, which poses a significant health burden. Current medical approaches for treating diabetic bone infection (osteomyelitis) are limited by (a) biofilm formation, (b) development of bacterial resistance, and (c) use of nondegradable antibiotic-delivering bone cements, which require additional removal surgery and show potential toxicity. To solve this important problem, we aim to develop an innovative drug-device combination based on rational engineering of the next-generation antibiotic that can retard resistance and an injectable nanostructured bone cement that can effectively deliver antibiotics, gradually degrade, and regenerate bone tissue.