Local and Sustained Delivery of Rifampicin from a Bioactive Ceramic Carrier Treats Bone Infection in Rat Tibia

Abstract

Next-generation treatment strategies to treat osteomyelitis with complete eradication of pathogen at the bone nidus and prevention of emergence of drug resistance is a real challenge in orthopedics. Conventional treatment strategies including long-term adherence of patients to systemic antibiotic delivery, local delivery using nondegradable vehicles, and surgical debridement are not completely effective in achieving successful results. In this study, a broad-spectrum antibiotic, rifampicin (RFP), was incorporated into a biphasic nanohydroxyapatite (nHAP)/calcium sulfate ceramic carrier (NC) system. In vivo release and distribution of rifampicin was evaluated for a period of one month by implanting NC and NC + RFP in a subcutaneous pouch in a rat model. We detected the RFP in bone and implanted NC scaffolds even after day 28 and the concentration was still higher than the minimal inhibitory concentration of RFP when it was implanted with NC in an abdominal subcutaneous pouch. Moreover, we also observed the accumulation of RFP in bone and NC when administered orally, showing strong binding between RFP and nHAP. Additionally, we generated an osteomyelitis bone infection model in the rat tibia using Staphylococcus aureus as an infective agent to evaluate the antibacterial and osteogenic efficiency of RFP containing NC as a delivery system. S. aureus mediated implant infection is a major problem in orthopedics. The results suggested that NC loaded with RFP could eradicate the pathogen completely in the bone nidus. Further, defect healing and bone formation were also evaluated by micro-CT and histological analysis demonstrating proper trabecular-type bone formation at the debridement site and complete healing of the defect when NC + RFP was implanted. Our findings provide an insight into the use of an nHAP based ceramic matrix as a carrier of rifampicin to eradicate the bone infection and simultaneously promote bone healing at the bone nidus.

Bioceramic-based scaffolds with antibacterial function for bone tissue engineering: A review

“…For example, the researchers of ref. [ 56 ] designed a nanohydroxyapatite-based scaffold adopted as the drug carrier to treat bone implant-associated infection by local and sustained delivery of rifampicin. Based on in vivo and in vitro antibacterial and osteogenetic experiments, this work demonstrated that the nanohydroxyapatite-based bioceramic scaffolds, as a carrier of rifampicin, could eliminate bacterial infection while simultaneously promoting bone repair and regeneration.…”

Recent Advances in the Evaluation of Antimicrobial Materials for Resolution of Orthopedic Implant-Associated Infections In Vivo

“…Prior to incorporating antimicrobial orthopedic biomaterials in implant-associated infection in vivo models, the properties of the materials can be first evaluated in in vivo models without tibial or femoral implants (e.g., materials can be placed into dorsal subcutaneous pouches). 37,41,59,83,87,135,144,148,161 To detect the presence and concentration of eluted antibiotics from the implanted biomaterial, blood can be collected both throughout the experiment and terminally in conjunction with hard and soft tissues surrounding the material. 83,[142][143][144]161,196,197 The antibiotic can then be extracted from the serum and tissues, and high performance liquid chromatography (HPLC) and liquid chromatography− mass spectrometry (LC-MS) can be used to quantify the systemic and local concentration of the antibiotics.…”

“…37,41,59,83,87,135,144,148,161 To detect the presence and concentration of eluted antibiotics from the implanted biomaterial, blood can be collected both throughout the experiment and terminally in conjunction with hard and soft tissues surrounding the material. 83,[142][143][144]161,196,197 The antibiotic can then be extracted from the serum and tissues, and high performance liquid chromatography (HPLC) and liquid chromatography− mass spectrometry (LC-MS) can be used to quantify the systemic and local concentration of the antibiotics. 83,[142][143][144]161,196,197 Following euthanasia, residual drug remaining entrapped in the implanted material can be extracted and evaluated for its concentration and antimicrobial activity in the zone of inhibition assays.…”

Exosome-Functionalized Ceramic Bone Substitute Promotes Critical-Sized Bone Defect Repair in Rats

“…In the present work, we have explored the uptake of purified exosomes by MSCs, their cell differentiation, and regenerative potential. To evaluate their regenerative potential, purified exosomes were delivered locally at a bone injury site using a biphasic (calcium sulfate–nano-hydroxyapatite) nanocement (NC), which is a biocompatible bone void filler. ,, NC + gentamicin (NCG) was functionalized with exosomes isolated either from MSCs cultured in normal (NCG + EX) or osteogenic media (NCG + OMEX) or from osteoblast (Saos-2) cells (NCG + OEX) . Effects of different exosomes types on bone formation were analyzed by micro-computer tomography (microCT) and histological analysis of bone samples 8 weeks post-implantation.…”