Antibiotic-loaded calcium sulfate for local therapy: how intermolecular interactions control hydration, microstructure and drug uptake.

Systemic antibiotics often fail to maintain bactericidal levels at bone and implant-associated infection sites, motivating local antibiotic application. Calcium sulfate (CaSO4) carriers are practical and promising in this application. However, the role of antibiotic-carrier interactions in controlling hydration, microstructure, and drug release remains poorly understood. Using in situ time‑resolved powder X-ray diffraction (XRD), we investigate the hydration of CaSO4 loaded with tobramycin, vancomycin and ceftriaxone. Vancomycin- and ceftriaxone-loaded matrices show hydration kinetics similar to unloaded CaSO4, even though the respective interaction mechanisms are different, whereas tobramycin strongly delays the process, reducing the transformation rate by one order of magnitude. Observed by Scanning Electron Microscopy (SEM), the antibiotics induce very different crystallite sizes and morphologies based on specific dissolution, nucleation and growth behaviors. X-ray computed tomography (XCT) reveals larger pore sizes in tobramycin- and ceftriaxone-containing systems due to limited water transport to the sites of crystal nucleation and growth. Related, non-transformed CaSO4 was partially found. These observations on a macroscale are the result of specific dominant molecular interactions: electrostatic adsorption with hydrogen-bonding in the CaSO4-Tobramycin system, hydrogen bonding for CaSO4-Vancomycin, and calcium complexation for CaSO4-Ceftriaxone. This molecular-level understanding of drug-carrier interactions is necessary to regulate hydration kinetics and microstructure, supporting optimization of local antibiotic delivery systems to improve infection management in orthopaedic and trauma surgery. STATEMENT OF SIGNIFICANCE: Periprosthetic joint infections and fracture-related infections are major complications in orthopaedics. Systemic antibiotic administration may fail to achieve sufficient drug concentration at the infection site and expose patients to systemic toxicity. Local administration overcomes these limitations by delivering high levels of drugs directly to the infection site. CaSO4 is in use as drug carrier but its interaction with specific antibiotics is not fully understood. Our multiscale analytical approach using a combination of dynamic XRD studies and X-ray imaging methods for antibiotic-loading into CaSO4 for tobramycin, vancomycin and ceftriaxone allows us to discover the connection between molecular interactions, macroscopic morphological behavior and loading kinetics. This would enable us to design optimized antibiotic release for local drug administration.