Controlled and localized antibiotics delivery using magnetic-responsive beads for synergistic treatment of orthopedic infection.

Antibiotic-loaded bone cement beads have been a reliable passive delivery system for the localized treatment of osteomyelitis; however, low, and unregulated drug release rates limit the ability of this system to maintain therapeutic concentrations. This problem is further amplified by drug-resistant pathogens that might invade or evolve under these conditions. Furthermore, currently available bone cements are incompatible with some antibiotics. The proposed device resembles conventional bone cement beads but contains an on-demand drug delivery magnetic sponge that provides actively controlled release of antibiotics. The slightly porous structure facilitates some drug diffusion while further drug release may be controlled remotely via magnetic actuation. Additionally, a combination of silver nitrate and gentamicin are used in the device as these agents are shown to display a synergistic antibacterial activity in vitro using checkerboard and time-kill assays. The device releases gentamicin and silver in both actuation and diffusion modes over 7 days. The in vitro bacterial studies demonstrate the efficacy of the released agents alone, and synergistically in combination, against Methicillin-resistant Staphylococcus aureus and Escherichia coli. The proposed device offers a facile fabrication process which allows control of the release profile by engineering hole configurations or manipulating magnetic field strength to provide the most effective therapy.

The Manufacture and Characterization of Silver Diammine Fluoride and Silver Salt Crosslinked Nanocrystalline Cellulose Films as Novel Antibacterial Materials.

There is an unmet need for biocompatible, anti-infective, and mechanically strong hydrogels. This study investigated the use of poly vinyl alcohol (PVA), polysaccharides, and nanocrystalline cellulose (CNC) to deliver silver in a controlled manner for possible use against oral or wound bacteria. Silver was included in solvent cast films as silver diammine fluoride (SDF) or as nitrate, sulphate, or acetate salts. Hydrogel formation was assessed by swelling determinations and silver release was measured using inductively coupled plasma methods. Antibacterial studies were performed using Gram-positive and negative bacteria turbidity assays. PVA formed homogenous, strong films with SDF and swelled gently (99% hydrolyzed) or vigorously with dissolution (88% hydrolyzed) and released silver slowly or quickly, respectively. CNC-SDF films swelled over a week and formed robust hydrogels whereas CNC alone (no silver) disintegrated after two days. SDF loaded CNC films released silver slowly over 9 days whereas films crosslinked with silver salts were less robust and swelled and released silver more quickly. All silver loaded films showed good antibacterial activity. CNC may be crosslinked with silver in the form of SDF (or any soluble silver salt) to form a robust hydrogel suitable for dental use such as for exposed periodontal debridement areas.

The Combined Use of Gentamicin and Silver Nitrate in Bone Cement for a Synergistic and Extended Antibiotic Action against Gram-Positive and Gram-Negative Bacteria.

Using bone cement as a carrier, gentamicin was for years the default drug to locally treat orthopedic infections but has lost favor due to increasing bacterial resistance to this drug. The objective of this study was to investigate the effect of combining gentamicin with silver nitrate in bone cement against S. aureus and P. aeruginosa. Antibacterial effects (CFU counts) of gentamicin and silver were initially studied followed by studies using subtherapeutic concentrations of each in combination. The release rates from cement were measured over 10 days and day 7 release samples were saved and analyzed for antibiotic activity. A strong synergistic effect of combining silver with gentamicin was found using both dissolved drugs and using day 7 bone cement release media for both Gram-positive and Gram-negative bacteria. The cement studies were extended to vancomycin and tobramycin, which are also used in bone cement, and similar synergistic effects were found for day 7 release media with P. aeruginosa but not S. aureus. These studies conclude that the combined use of low loadings of gentamicin and silver nitrate in bone cement may offer an economical and much improved synergistic method of providing anti-infective orthopedic treatments in the clinic.

Magnetically-actuated drug delivery device (MADDD) for minimally invasive treatment of prostate cancer: An in vivo animal pilot study.

BACKGROUND: The vast majority of prostate cancer presents clinically localized to the prostate without evidence of metastasis. Currently, there are several modalities available to treat this particular disease. Despite radical prostatectomy demonstrating a modest prostate cancer specific mortality benefit in the PIVOT trial, several novel modalities have emerged to treat localized prostate cancer in patients that are either not eligible for surgery or that prefer an alternative approach. METHODS: Athymic nude mice were subcutaneously inoculated with prostate cancer cells. The mice were divided into four cohorts, one cohort untreated, two cohorts received docetaxel (10 mg/kg) either subcutaneously (SC) or intravenously (IV) and the fourth cohort was treated using the magnetically-actuated docetaxel delivery device (MADDD), dispensing 1.5 µg of docetaxel per 30 min treatment session. Treatment in all three therapeutic arms (SC, IV, and MADDD) was administered once weekly for 6 weeks. Treatment efficacy was measured once a week according to tumor volume using ultrasound. In addition, calipers were used to assess tumor volume. RESULTS: Animals implanted with the device demonstrated no signs of distress or discomfort, neither local nor systemic symptoms of inflammation and infection. Using an independent sample t-test, the tumor growth rate of the treated tumors was significant when compared to the control. Post hoc Tukey HSD test results showed that the mean tumor growth rate of our device cohort was significantly lower than SC and control cohorts. Moreover, IV cohort showed slight reduction in mean tumor growth rates than the ones from the device cohort, however, there was no statistical significance in tumor growth rate between these two cohorts. Furthermore, immunohistochemistry demonstrated an increased cellular apoptosis in the MADDD treated tumors and a decreased proliferation when compared to the other cohorts. In addition, IV cohort showed increased treatment side effects (weight loss) when compared to the device cohort. Finally, MADDD showed minimal expression of CD45 comparable to the control cohort, suggesting no signs of chronic inflammation. CONCLUSIONS: In conclusion, this study showed for the first time that MADDD, clearly suppressed tumor growth in local prostate cancer tumors. This could potentially be a novel clinical treatment approach for localized prostate cancer.

A robust and refillable magnetic sponge capsule for remotely triggered drug release.

Numerous different delivery systems have been developed for local administration of drugs. However, their service lives generally depend on the payload depletion time and most of them are designed for one time use due to lack of drug replenishment abilities. To address this issue, a refillable magnetic porous polydimethylsiloxane (PDMS) capsule is proposed for remotely controlled drug delivery applications. An inner cavity is built in the sponge scaffold to provide space for drug storage and the refilling is accomplished by injecting drugs with a syringe. The rapid and reversible deformation of the magnetic porous structure under a magnetic field offers a controlled pumping force to push drugs out of the capsule. In this work, low molecular weight (methylene blue, MB, 320 g mol-1) and high molecular weight (bovine serum albumin, BSA, 67 000 g mol-1) molecules were used as model compounds to test and verify the operational principle. This proof-of-concept study has demonstrated the capability of the refillable porous capsule in controlled drug delivery under external magnetic stimuli.