title: 3D scaffold with effective multidrug sequential release against bacteria biofilm.
abstract: Bone infection is a feared complication following surgery or trauma that remains as an extremely difficult disease to deal with. So far, the outcome of therapy could be improved with the design of 3D implants, which combine the merits of osseous regeneration and local multidrug therapy so as to avoid bacterial growth, drug resistance and the feared side effects. Herein, hierarchical 3D multidrug scaffolds based on nanocomposite bioceramic and polyvinyl alcohol (PVA) prepared by rapid prototyping with an external coating of gelatin-glutaraldehyde (Gel-Glu) have been fabricated. These 3D scaffolds contain three antimicrobial agents (rifampin, levofloxacin and vancomycin), which have been localized in different compartments of the scaffold to obtain different release kinetics and more effective combined therapy. Levofloxacin was loaded into the mesopores of nanocomposite bioceramic part, vancomycin was localized into PVA biopolymer part and rifampin was loaded in the external coating of Gel-Glu. The obtained results show an early and fast release of rifampin followed by sustained and prolonged release of vancomycin and levofloxacin, respectively, which are mainly governed by the progressive in vitro degradability rate of these scaffolds. This combined therapy is able to destroy Gram-positive and Gram-negative bacteria biofilms as well as inhibit the bacteria growth. In addition, these multifunctional scaffolds exhibit excellent bioactivity as well as good biocompatibility with complete cell colonization of preosteoblast in the entire surface, ensuring good bone regeneration. These findings suggest that these hierarchical 3D multidrug scaffolds are promising candidates as platforms for local bone infection therapy.
  
  
  
  The present study is focused in finding an adequate therapeutic solution for the treatment of bone infection based on 3D multifunctional scaffolds, which combines the merits of osseous regeneration and local multidrug delivery. These 3D multidrug scaffolds, containing rifampin, levofloxacin and vancomycin, localized in different compartments to achieve different release kinetics. These 3D multidrug scaffolds displays an early and fast release of rifampin followed by sustained and prolonged release of vancomycin and levofloxacin, which are able to destroy Staphylococcus and Escherichia biofilms as well as inhibit bacteria growth in very short time periods. This new combined therapy approach involving the sequential delivery of antibiofilms with antibiotics constitutes an excellent and promising alternative for bone infection treatment.
authors.affiliation: Dpto. Química Inorgánica y Bioinorgánica, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria Hospital 12 de Octubre i+12, Plaza Ramón y Cajal s/n, 28040 Madrid, Spain.
authors.forename: Rafaela
authors.initials: R
authors.lastname: García-Alvarez
authors.affiliation: Dpto. Química Inorgánica y Bioinorgánica, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria Hospital 12 de Octubre i+12, Plaza Ramón y Cajal s/n, 28040 Madrid, Spain; CIBER de Bioingeniería, Biomateriales y Nanomedicina, CIBER-BBN, Madrid, Spain. Electronic address: ibarba@ucm.es.
authors.forename: Isabel
authors.initials: I
authors.lastname: Izquierdo-Barba
authors.affiliation: Dpto. Química Inorgánica y Bioinorgánica, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria Hospital 12 de Octubre i+12, Plaza Ramón y Cajal s/n, 28040 Madrid, Spain; CIBER de Bioingeniería, Biomateriales y Nanomedicina, CIBER-BBN, Madrid, Spain. Electronic address: vallet@ucm.es.
authors.forename: María
authors.initials: M
authors.lastname: Vallet-Regí
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects; D018441:Biofilms / Q000187:drug effects*; D001826:Body Fluids / Q000737:chemistry; D002113:Calcification, Physiologic / Q000187:drug effects; D002460:Cell Line; D065546:Drug Liberation; D007700:Kinetics; D064704:Levofloxacin / Q000494:pharmacology; D051379:Mice; D008826:Microbial Sensitivity Tests; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000648:ultrastructure; D012293:Rifampin / Q000494:pharmacology; D054457:Tissue Scaffolds / Q000737:chemistry*; D014640:Vancomycin / Q000494:pharmacology; D014961:X-Ray Diffraction
chemical_list: D000900:Anti-Bacterial Agents; D064704:Levofloxacin; D014640:Vancomycin; D012293:Rifampin
keywords: Biofilm; Combined therapy; Gram-negative bacteria; Gram-positive bacteria; Multidrug 3D scaffold; Sequential antimicrobial delivery