Antibiotic Modification of Native Grafts: Improving Upon Nature's Scaffolds

Ketonis, Constantinos; Adams, Christopher S.; Barr, Stephanie; Aiyer, Amiethab; Shapiro, Irving M.; Parvızı, Javad; Hickok, Noreen J.

doi:10.1089/ten.tea.2009.0610

Cited by 20 publications

(22 citation statements)

References 31 publications

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“…While antibiotic integration into bone grafts has been proven successful, less work has been done to deliver an antibiotic and a growth factor together (either in series or parallel) (24,25). As a result of limiting the need for the antibiotic to travel systemically, there are higher antibiotic levels at the site of the wound and systemically safe levels, thus paving the way for resident osteoblasts to penetrate into the graft well before the offending bacteria are able to reach high confluence and form biofilms (38).…”

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confidence: 99%

Effect of Coadministration of Vancomycin and BMP-2 on Cocultured Staphylococcus aureus and W-20-17 Mouse Bone Marrow Stromal Cells In Vitro

Nguyen

Kim

Maloney

et al. 2012

Antimicrob Agents Chemother

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ABSTRACTIn this study, we aimed to establish anin vitrobacterium/bone cell coculture model system and to use this model for dose dependence studies of dual administration of antibiotics and growth factorsin vitro. We examined the effect of single or dual administration of the antibiotic vancomycin (VAN) at 0 to 16 μg/ml and bone morphogenetic protein-2 (BMP-2) at 0 or 100 ng/ml on both methicillin-sensitiveStaphylococcus aureusand mouse bone marrow stromal cells (W-20-17) under both mono- and coculture conditions. Cell metabolic activity, Live/Dead staining, double-stranded DNA (dsDNA) amounts, and alkaline phosphatase activity were measured to assess cell viability, proliferation, and differentiation. An interleukin-6 (IL-6) enzyme-linked immunosorbent assay (ELISA) kit was used to test the bone cell inflammation response in the presence of bacteria. Our results suggest that, when delivered together in coculture, VAN and BMP-2 maintain their primary functions as an antibiotic and a growth factor, respectively. Most interestingly, this dual-delivery type of approach has shown itself to be effective at lower concentrations of VAN than those required for an approach relying strictly on the antibiotic. It may be that BMP-2 enhances cell proliferation and differentiation before the cells become infected. In coculture, a dosage of VAN higher than that used for treatment in monoculture may be necessary to effectively inhibit growth ofStaphylococcus aureus. This could mean that the coculture environment may be limiting the efficacy of VAN, possibly by way of bacterial invasion of the bone cells. This report of a coculture study demonstrates a potential beneficial effect of the coadministration of antibiotics and growth factors compared to treatment with antibiotic alone.

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confidence: 99%

Effect of Coadministration of Vancomycin and BMP-2 on Cocultured Staphylococcus aureus and W-20-17 Mouse Bone Marrow Stromal Cells In Vitro

Nguyen

Kim

Maloney

et al. 2012

Antimicrob Agents Chemother

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“…When coupled to the allograft, the antibiotic was uniformly distributed over the bone surface and was stable (9). The VAN-allograft retained its antimicrobial activity and was able to retard bacterial colonization; moreover, the decrease in bacterial colonization was maintained over time.…”

Section: Discussionmentioning

confidence: 99%

“…1a). VAN was covalently coupled to cancellous/cortical human bone granules (0.5 to 2.0 mm, a gift of the Musculoskeletal Transplant Foundation [Edison, NJ]), as previously described (9). Briefly, the granules were washed, sonicated with distilled water (dH 2 O) until eluates were clear, and incubated in 12.5% EDTA at pH 7 and room temperature (RT) for 3 days with shaking.…”

Section: Methodsmentioning

confidence: 99%

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Vancomycin Bonded to Bone Grafts Prevents Bacterial Colonization

Ketonis

Barr

Adams

et al. 2011

Antimicrob Agents Chemother

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Infection is an important medical problem associated with the use of bone allografts. To retard bacterial colonization, we have recently reported on the modification of bone allografts with the antibiotic vancomycin (VAN). In this report, we examine the ability of this antibiotic-modified allograft to resist bacterial colonization and biofilm formation. When antibiotic was coupled to the allograft, a uniform distribution of the antibiotic was apparent. Following challenges with Staphylococcus aureus for 6 h, the covalently bonded VAN decreased colonization as a function of inoculum, ranging from 0.8 to 2.0 log 10 CFU. Furthermore, the VAN-modified surface resisted biofilm formation, even in topographical niches that provide a protected environment for bacterial adhesion. Attachment of the antibiotic to the allograft surface was robust, and the bonded VAN was stable whether incubated in aqueous media or in air, maintaining levels of 75 to 100% of initial levels over 60 days. While the VAN-modified allograft inhibited the Gram-positive S. aureus colonization, in keeping with VANs spectrum of activity, the VAN-modified allograft was readily colonized by the Gram-negative Escherichia coli. Finally, initial toxicity measures indicated that the VAN-modified allograft did not influence osteoblast colonization or viability. Since the covalently tethered antibiotic is stable, is active, retains its specificity, and does not exhibit toxicity, it is concluded that this modified allograft holds great promise for decreasing bone graft-associated infections.

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“…Before completing this section of the review it should be acknowledged that bonding VAN to an aminopropylated surface by solid phase peptide synthesis is a very useful general chemical procedure. We have used it to bond a number of antibiotics to metals and the technology can be readily applied to other bioactive molecules (Chen and Wickstrom, 2010;Ketonis et al, 2010).…”

Section: Synthesis Of a Tethered Antibiotic Surfacementioning

confidence: 99%

Molecular engineering of an orthopaedic implant: from bench to bedside

Shapiro

Hickok²,

Parvızı³

et al. 2012

eCM

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The use of metallic implants has revolutionised the practice of orthopaedic surgery. While the safety and biocompatibility of these devices are excellent, a small percentage becomes infected. These infections are due to the formation of a biofilm that harbours bacteria encased in a complex extracellular matrix. The matrix serves as a barrier to immune surveillance as well as limiting the biocidal effects of systemic and local antibiotics. The objective of the review is to describe a novel approach to controlling implant infection using an antibiotic that is linked to titanium through a self-assembled monolayer of siloxy amines. We show that the hybrid-engineered surface is stable, biocompatible and resists colonisation by bacterial species most commonly associated with implant-related infections. Studies with rodent bone infection models suggest that the engineered titanium surface prevents bone infection. Results of a very recent investigation utilising a sheep model of infection indicate that the titanium-tethered antibiotic controls infection without compromising bone formation and remodelling. From all of these perspectives, the tethered antibiotic holds promise of providing a novel and practical approach to reducing implant-associated infections.

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Antibiotic Modification of Native Grafts: Improving Upon Nature's Scaffolds

Cited by 20 publications

References 31 publications

Effect of Coadministration of Vancomycin and BMP-2 on Cocultured Staphylococcus aureus and W-20-17 Mouse Bone Marrow Stromal Cells In Vitro

Effect of Coadministration of Vancomycin and BMP-2 on Cocultured Staphylococcus aureus and W-20-17 Mouse Bone Marrow Stromal Cells In Vitro

Vancomycin Bonded to Bone Grafts Prevents Bacterial Colonization

Molecular engineering of an orthopaedic implant: from bench to bedside

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