Strong bone cement loaded with antibiotics could be used to treat bone infections

Strong bone cement loaded with antibiotics could be used to treat bone infections

Every year 700,000 people die from antibiotic resistance. Unfortunately, a growing global population is creating increasing resistance to established antibiotic treatments -; A threat that has been met with inadequate funding and dwindling inspiration as commercial incentives to develop new antibiotics have diminished. A new study by researchers at Brigham and Women's Hospital, a founding member of the Mass General Brigham Health System, addresses this growing problem in antibiotic development with a novel, interdisciplinary approach to building a robust, computer-generated library of antibiotics and identifying an effective antibiotic for targeted use in a Bone cement matrix. This approach could potentially be used to treat bone infections, a common complication following orthopedic surgery. Their results were published in Nature Biomedical Engineering.

“Currently, the Food and Drug Administration (FDA) has only approved bone cements loaded with antibiotics that were not originally designed for bone tissue,” said Hae Lin Jang, PhD, co-director of the Brigham’s Center for Engineered Therapeutics and principal investigator of the Laboratory for the Development of Advanced Biomaterials and Biotechnologies. "In addition to being non-bone tissue specific, resistance to these antibiotics has emerged. We need to develop a new generation of antibiotics optimized to meet this emerging need."

This increasing battle against antibiotic resistance has merged with a similarly increasing aging population, which now requires more orthopedic procedures than ever before. Common procedures such as knee and hip replacements can lead to bacterial infections such as staph, which are currently treated with systemic antibiotics. Systemic exposure to antibiotics does not precisely target the infection; Therefore, enormous doses are required, leading to the unintended consequences of drug resistance and destruction of beneficial microbiota. To address this growing problem, researchers at Brigham's Department of Medicine and the Department of Orthopedic Surgery worked to develop a locally delivered and effective combination of antibiotics and bone cement.

To construct a new antibiotic for specific local delivery via a bone cement matrix, polymethyl methacrylate (PMMA) bone cement was used -; the recognized FDA gold standard. The team shortlisted molecules for antibiotic design and screened for drug-sensitive and drug-resistant bacteria in a preclinical model. Finally, the team compared clinically used PMMA bone cement and the new antibiotic-loaded PMMA bone cement using a prophylactic and an established staphylococcal-infected tibial injury model.

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Researchers identified the dual-action antibiotic VCD-077 and examined its activity and effectiveness in cells and in animal models. VCD-077 not only demonstrated the desired drug release kinetics without compromising the stability of the PMMA bone cement, but also demonstrated high efficacy against a broad spectrum of drug-resistant bacterial strains and slowed the development of future resistance. In fact, VCD-077-loaded PMMA bone cement demonstrated greater efficacy than all currently used antibiotic-loaded bone cements against staphylococcal bone infections in a rat model.

Before clinical use, the team must address two major limitations: potential differences between the rat model studied and humans and necessary toxicity studies. But researchers note that the future is bright for tissue-specific, localized treatments such as a minimally invasive injection of antibiotic-laced bone cement. Focusing on tissue specificity from the development stage and drug-device interaction can help develop treatments that work precisely without maintaining drug resistance. Additionally, the team's novel use of computing to find molecules and optimize antibiotic design was a major success, suggesting the potential for computer programming and AI technology to streamline drug development.

The future lies in combining artificial intelligence and drug discovery to make the development of new antibiotics more efficient and cost-effective than ever before. Interdisciplinarity in our approach and specificity in our drug development will truly create a new medical technology paradigm.”

Shiladitya Sengupta, PhD, co-corresponding author, co-director of Brigham’s Center for Engineered Therapeutics

Jang said, "The treatment may become more complicated and the bacteria may become more sophisticated, but we biomedical engineers are also becoming more sophisticated."

Source:

Brigham and Women's Hospital

Reference:

Ghosh, S., et al. (2022) An effective antibiotic-loaded bone cement implant against staphylococcal bone infections. Nature Biomedical Engineering. doi.org/10.1038/s41551-022-00950-x.

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