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Designer Dual Therapy Nanolayered Implant Coatings Eradicate Biofilms and Accelerate Bone Tissue Repair.

ABSTRACT: Infections associated with orthopedic implants cause increased morbidity and significant healthcare cost. A prolonged and expensive two-stage procedure requiring two surgical steps and a 6-8 week period of joint immobilization exists as today's gold standard for the revision arthroplasty of an infected prosthesis. Because infection is much more common in implant replacement surgeries, these issues greatly impact long-term patient care for a continually growing part of the population. Here, we demonstrate that a single-stage revision using prostheses coated with self-assembled, hydrolytically degradable multilayers that sequentially deliver the antibiotic (gentamicin) and the osteoinductive growth factor (BMP-2) in a time-staggered manner enables both eradication of established biofilms and complete and rapid bone tissue repair around the implant in rats with induced osteomyelitis. The nanolayered construct allows precise independent control of release kinetics and loading for each therapeutic agent in an infected implant environment. Antibiotics contained in top layers can be tuned to provide a rapid release at early times sufficient to eliminate infection, followed by sustained release for several weeks, and the underlying BMP-2 component enables a long-term sustained release of BMP-2, which induced more significant and mechanically competent bone formation than a short-term burst release. The successful growth factor-mediated osteointegration of the multilayered implants with the host tissue improved bone-implant interfacial strength 15-fold when compared with the uncoated one. These findings demonstrate the potential of this layered release strategy to introduce a durable next-generation implant solution, ultimately an important step forward to future large animal models toward the clinic.

SUBMITTER: Min J

PROVIDER: S-EPMC6501197 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Designer Dual Therapy Nanolayered Implant Coatings Eradicate Biofilms and Accelerate Bone Tissue Repair.

Min Jouha J Choi Ki Young KY Dreaden Erik C EC Padera Robert F RF Braatz Richard D RD Spector Myron M Hammond Paula T PT

ACS nano 20160302 4

Infections associated with orthopedic implants cause increased morbidity and significant healthcare cost. A prolonged and expensive two-stage procedure requiring two surgical steps and a 6-8 week period of joint immobilization exists as today's gold standard for the revision arthroplasty of an infected prosthesis. Because infection is much more common in implant replacement surgeries, these issues greatly impact long-term patient care for a continually growing part of the population. Here, we de ...[more]

PMID: 26923427

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Project description:Background: Bacterial biofilms cause chronic orthopaedic infections. Surgical debridement to remove biofilm can be ineffective without adjuvant local antimicrobials because undetected biofilm fragments may remain in the wound and reestablish the infection if untreated. However, the concentrations and duration of antimicrobial exposure necessary to eradicate bacteria from clinical biofilms remain largely undefined. In this study, we determined the minimum biofilm eradication concentration (MBEC) of tobramycin and vancomycin for bacterial biofilms grown on bone and muscle in vitro. Methods: Biofilms of pathogens found in musculoskeletal infections (S. aureus, S. epidermidis, E. faecalis, P. aeruginosa, and E. coli) were established for 72 hr on rabbit muscle and bone specimens in vitro and characterized by SEM imaging and CFU counts. Biofilm-covered tissue specimens were exposed to serial log2 dilutions (4000-31.25 µg/mL) of tobramycin, vancomycin, or a 1:1 combination of both drugs for 6, 24, or 72 hr. Tissues were subcultured following antimicrobial exposure to determine bacterial survival. The breakpoint concentration with no surviving bacteria was defined as the MBEC for each pathogen-antimicrobial-exposure time combination. Results: All tested pathogens formed biofilm on tissue. Tobramycin/vancomycin (1:1) was the most effective antimicrobial regimen with MBEC on muscle (10/10 pathogens) or bone (7/10 pathogens) generally in the range of 100-750 µg/mL with 24 or 72 hr exposure. MBEC decreased with exposure time for 53.3% of biofilms between 6 and 24 hr, 53.3% of biofilms between 24 and 72 hr, and for 76.7% of biofilms between 6 and 72 hr. MBECs on bone were significantly higher than corresponding MBECs on muscle tissue (p < 0.05). In most cases, tissue MBECs were lower compared to previously published MBECs for the same pathogens on polystyrene tissue-culture plates. Conclusions: The majority of MBECs for orthopaedic infections on bone and muscle are on the order of 100-750 µg/mL of vancomycin+tobramycin when sustained for at least 24 hr, which may be clinically achievable using high-dose antimicrobial-loaded bone cement (ALBC).

Project description:BackgroundA pivotal determinant for the success of tissue regeneration lies in the establishment of sufficient vasculature. Utilizing autologous tissue grafts from donors offers the dual advantage of mitigating the risk of disease transmission and circumventing the necessity for post-transplant immunosuppression, rendering it an exemplary vascularization strategy. Among the various potential autologous donors, adipose tissue emerges as a particularly auspicious source, being both widely available and compositionally rich. Notably, adipose-derived microvascular fragments (ad-MVFs) are a promising candidate for vascularization. ad-MVFs can be isolated from adipose tissue in a short period of time and show high vascularized capacity. In this study, we extracted ad-MVFs from adipose tissue and utilized their strong angiogenic ability to accelerate bone repair by promoting vascularization.Methodsad-MVFs were extracted from the rat epididymis using enzymatic hydrolysis. To preserve the integrity of the blood vessels, gelatin methacryloyl (GelMA) hydrogel was chosen as the carrier for ad-MVFs in three-dimensional (3D) culture. The ad-MVFs were cultured directly on the well plates for two-dimensional (2D) culture as a control. The morphology of ad-MVFs was observed under both 2D and 3D cultures, and the release levels of vascular endothelial growth factor (VEGF) and bone morphogenetic protein 2 (BMP-2) were assessed under both culture conditions. In vitro studies investigated the impact of ad-MVFs/GelMA hydrogel on the toxicity, osteoblastic activity, and mineralization of rat bone marrow mesenchymal stem cells (rBMSCs), along with the examination of osteogenic gene and protein expression. In vivo experiments involved implanting the ad-MVFs/GelMA hydrogel into critical-size skull defects in rats, and its osteogenic ability was evaluated through radiographic and histological methods.Resultsad-MVFs were successfully isolated from rat adipose tissue. When cultured under 2D conditions, ad-MVFs exhibited a gradual disintegration and loss of their original vascular morphology. Compared with 2D culture, ad-MVFs can not only maintain the original vascular morphology, but also connect into a network in hydrogel under 3D culture condition. Moreover, the release levels of VEGF and BMP-2 were significantly higher than those in 2D culture. Moreover, the ad-MVFs/GelMA hydrogel exhibited superior osteoinductive activity. After implanting into the skull defect of rats, the ad-MVFs/GelMA hydrogel showed obvious effects for angiogenesis and osteogenesis.The translational potential of this articleThe utilization of autologous adipose tissue as a donor presents a more direct route toward clinical translation. Anticipated future clinical applications envision the transformation of discarded adipose tissue into a valuable resource for personalized tissue repair, thereby realizing a paradigm shift in the utilization of this abundant biological material.

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Designer Dual Therapy Nanolayered Implant Coatings Eradicate Biofilms and Accelerate Bone Tissue Repair.

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Designer Dual Therapy Nanolayered Implant Coatings Eradicate Biofilms and Accelerate Bone Tissue Repair.

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