ABSTRACT
Most drug delivery systems as treatment modalities for osteomyelitis have not been evaluated for resistant infections. Tigecycline (TG) is an antimicrobial agent that could be used in the treatment of multi-drug-resistant orthopedic infections. The objective of this in vitro study has been to determine what dosage of TG causes changes in the morphology and number of osteoblasts. We have also investigated whether nanoparticulate tigecycline-loaded calcium-phosphate/poly-DL-lactide-co-glycolide is biocompatible and whether it could release bioactive TG in a controlled manner during the observation time. The cytotoxicity was tested by analyzing the release of lactate dehydrogenase from dead osteoblasts to the medium. Staphylococcus aureus was used to verify the antibacterial effect of the multifunctional drug delivery system. At concentrations as achieved by local application, TG caused high toxic effect and impaired the normal osteoblastic morphology. The nanoparticulate multifunctional drug delivery system showed good compatibility and antibacterial effect during the observation time and thus appears to be suitable for the treatment of osteomyelitis caused by multi-drug-resistant microbes.
Subject(s)
Anti-Bacterial Agents/administration & dosage , Calcium Phosphates/chemistry , Delayed-Action Preparations/chemistry , Minocycline/analogs & derivatives , Nanostructures/chemistry , Polyglactin 910/chemistry , 3T3 Cells , Animals , Anti-Bacterial Agents/pharmacology , Cell Survival/drug effects , Humans , Mice , Minocycline/administration & dosage , Minocycline/pharmacology , Osteoblasts/cytology , Osteoblasts/drug effects , Staphylococcal Infections/drug therapy , Staphylococcus aureus/drug effects , TigecyclineABSTRACT
The purpose of the study presented in this paper has been to examine the possibility of the synthesis of a new nanoparticulate system for controlled and systemic drug delivery with double effect. In the first step, a drug is released from bioresorbable polymer; in the second stage, after resorption of the polymer, non-bioresorbable calcium phosphate remains the chief part of the particle and takes the role of a filler, filling a bone defect. The obtained tigecycline-loaded calcium-phosphate(CP)/poly(DL-lactide-co-glycolide)(PLGA) nanoparticles contain calcium phosphate coated with bioresorbable polymer. The composite was analyzed by FT-IR, XRD and AFM methods. The average particle size of the nanocomposite ranges between 65 and 95 nm. Release profiles of tigecycline were obtained by UV-VIS spectroscopy in physiological solution at 37 degrees C. Experimental results were analyzed using Peppas and Weibull mathematical models. Based on kinetic parameters, tigecycline release was defined as non-Fickian transport. The cytotoxicity of the nanocomposite was examined on standard cell lines of MC3T3-E1, in vitro. The obtained low values of lactate dehydrogenase (LDH) activity (under 37%) indicate low cytotoxicity level. The behaviour of the composite under real-life conditions was analyzed through implantation of the nanocomposite into living organisms, in vivo. The system with the lowest tigecycline content proved to be an adequate system for local and controlled release. Having in mind the registered antibiotics concentration in other tissues, delivery systems with a higher tigecycline content show both local and systemic effects.
Subject(s)
Calcium Phosphates/chemistry , Drug Delivery Systems , Lactic Acid/chemistry , Minocycline/analogs & derivatives , Nanostructures/chemistry , Polyglycolic Acid/chemistry , Animals , Anti-Bacterial Agents/pharmacokinetics , Cells, Cultured , Coated Materials, Biocompatible/chemical synthesis , Coated Materials, Biocompatible/chemistry , Coated Materials, Biocompatible/pharmacokinetics , Drug Carriers , Drug Implants , Humans , Materials Testing , Minocycline/pharmacokinetics , Models, Biological , Particle Size , Polylactic Acid-Polyglycolic Acid Copolymer , Rats , TigecyclineABSTRACT
Reconstruction of bone defects is one of the major therapeutic goals in various clinical fields. Bone replacement materials must satisfy a number of criteria. Biological criteria are biocompatibility, controlled biodegradability, and osteoconductive or even osteogenic potential. The material should have a three-dimensional structure with an interconnected pore system so as to permit cell growth and transport of substances. The surface must permit cell adhesion and proliferation. Composite biomaterials have enormous potential for natural bone tissue reparation, filling and augmentation. Calcium hydroxyapatite/polymer composite biomaterials belong to this group of composites and, because of their osteoconductive and biocompatible properties, can be successfully implemented within bone tissue reparations. In this study, possible differences between BCP/DLPLG, pure BCP, and Bio-Oss materials were examined in vitro. During overnight incubations, fibroblast and fibroblast-like cells (L929, MRC5) were able to adhere, spread, and remain viable on BCP, BCP/PLGA, and Bio-Oss discs, as was evidenced by using light- and LVSEM-microscopy. Inhibiting influence over the cell growth is more pronounced in the cases of BCP usage on both cell lines--41.29% for L929 and 43.08% for MRC-5 cells. MRC-5 cells are, within the given experimental conditions, less sensitive on inhibiting effects for the materials BCP/PLGA and Bio-Oss (10.13% and 10.76%, respectively) than for the L929 cell lines (23.02% and 15.44%, respectively).
