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CONTENTS
Volume 2, Number 3, September 2015
 

Abstract
Silver-based systems activated by low intensity direct current continue to be investigated as an alternative antimicrobial for infection prophylaxis and treatment. However there has been limited research on the quantitative characterization of the antimicrobial efficacy of such systems. The objective of this study was to develop a semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model providing the quantitative relationship between the critical system parameters and the degree of antimicrobial efficacy. First, time-kill curves were experimentally established for a strain of Staphylococcus aureus in a nutrientrich fluid environment over 48 hours. Based on these curves, a modified PK/PD model was developed with two components: a growing silver-susceptible bacterial population and a depreciating bactericidal process. The test of goodness-of-fit showed that the model was robust and had good predictability (R2>0.7). The model demonstrated that the current intensity was positively correlated to the initial killing rate and the bactericidal fatigue rate of the system while the anode surface area was negatively correlated to the fatigue rate. The model also allowed the determination of the effective range of these two parameters within which the system has significant antimicrobial efficacy. In conclusion, the modified PK/PD model successfully described bacterial growth and killing kinetics when the bacteria were exposed to the electrically activated silver-titanium implant system. This modeling approach as well as the model itself can also potentially contribute to the development of optimal design strategies for other similar antimicrobial systems.

Key Words
Pharmacokinetic/Pharmacodynamic model; antimicrobial efficacy; orthopaedic implants; silver oligodynamic iontophoresis; low intensity direct current; parameter characterization; time-kill curves

Address
Zhuo Tan, Rohan A. Shirwaiker: Edward P. Fitts Department of Industrial and Systems Engineering, North Carolina State University, Raleigh, NC 27695, USA

Zhuo Tan, Rohan A. Shirwaiker: Medical Implants and Tissue Engineering (MITE) Lab, North Carolina State University,
Raleigh, NC 27695, USA

Paul E. Orndorff: Department of Population Health and Pathobiology, North Carolina State University,
Raleigh, NC 27607, USA

Rohan A. Shirwaiker: UNC-NCSU Joint Department of Biomedical Engineering, Raleigh, NC 27695, USA

Abstract
Successful integration of cementless femoral stems using porous surfaces relies on effective periimplant bone healing to secure the bone-implant interface. The initial stages of the healing process involve protein adsorption, fibrin clot formation and cell osteoconduction onto the implant surface. Modelling this process in vitro, the current work considered the effect of fibrin deposition on the responses of human mesenchymal stromal cells cultured on ferritic fibre networks intended for magneto-mechanical actuation of in-growing bone tissue. The underlying hypothesis for the study was that fibrin deposition would support early stromal cell attachment and physiological functions within the optimal regions for strain transmission to the cells in the fibre networks. Highly porous fibre networks composed of 444 ferritic stainless steel were selected due to their ability to support human osteoblasts and mesenchymal stromal cells without inducing untoward inflammatory responses in vitro. Cell attachment, proliferation, metabolic activity, differentiation and penetration into the ferritic fibre networks were examined for one week. For all fibrin-containing samples, cells were observed on and between the metal fibres, supported by the deposited fibrin, while cells on fibrin-free fibre networks (control surface) attached only onto fibre surfaces and junctions. Initial cell attachment, measured by analysis of deoxyribonucleic acid, increased significantly with increasing fibrinogen concentration within the physiological range. Despite higher cell numbers on fibrin-containing samples, similar metabolic activities to control surfaces were observed, which significantly increased for all samples over the duration of the study. It is concluded that fibrin deposition can support the early attachment of viable mesenchymal stromal cells within the inter-fibre spaces of fibre networks intended for magnetomechanical strain transduction to in-growing cells.

Key Words
human mesenchymal stromal cells; fibrin; fibre networks; ferritic stainless steel; porous coatings

Address
Rose L. Spear, Antonia Symeonidou, Athina E. Markaki: Department of Engineering, University of Cambridge, Trumpington Street, Cambridge, CB2 1PZ, UK

Jeremy N. Skepper: Department of Physiology, University of Cambridge, Downing Street, Cambridge, CB2 3DY, UK

Roger A. Brooks: Division of Trauma & Orthopaedic Surgery, Addenbrooke

Abstract
Treatment of polymicrobial infected musculoskeletal defects continues to be a challenge in orthopaedics. This research investigated single and dual-delivery of two antibiotics, vancomycin and amikacin, targeting different classes of microorganism from a biodegradable calcium sulfate-chitosan-nHA microsphere composite scaffold. The addition of chitosan-nHA was included to provide additional structure for cellular attachment and as a secondary drug-loading device. All scaffolds exhibited an initial burst of antibiotics, but groups containing chitosan reduced the burst for amikacin at 1hr by 50%, and vancomycin by 14-25% over the first 2 days. Extended elution was present in groups containing chitosan; amikacin was above MIC (2-4 µg/mL, Pseudomonas aeruginosa) for 7-42 days and vancomycin was above MIC (0.5-1 µg/mL Staphylococcus aureus) for 42 days. The antibiotic activity of the eluates was tested against S. aureus and P. aeruginosa. The elution from the dual-loaded scaffold was most effective against S. aureus (bacteriostatic 34 days and bactericidal 27 days), compared to vancomycin-loaded scaffolds (bacteriostatic and bactericidal 14 days). The dual- and amikacin-loaded scaffolds were effective against P. aeruginosa, but eluates exhibited very short antibacterial properties; only 24 hours bacteriostatic and 1-5 hours bactericidal activity. For all groups, vancomycin recovery was near 100% whereas the amikacin recovery was 41%. In conclusion, in the presence of chitosan-nHA microspheres, the dual-antibiotic loaded scaffold was able to sustain an extended vancomycin elution longer than individually loaded scaffolds. The composite scaffold shows promise as a dual-drug delivery system for infected orthopaedic wounds and overcomes some deficits of other dual-delivery systems by extending the antibiotic release.

Key Words
drug delivery; biodegradable scaffolds; chitosan; calcium sulfate; bone regeneration

Address
Heather A. Doty, Jessica A. Jennings, Warren O. Haggard and Joel D. Bumgardner: Joint Program in Biomedical Engineering, University of Memphis and University of Tennessee Health
Science Center, 330 Engineering Technology Building, Memphis, Tennessee 38152, USA

Harry S. Courtney: Veterans Affairs Medical Center and Department of Medicine, University of Tennessee Health Science
Center, Memphis, Tennessee 38104, USA

Abstract
In obstetrics, cardiotocography is a procedure to record the fetal heartbeat and the uterine contractions usually during the last trimester of pregnancy. It helps to monitor patterns associated with the fetal activity and to detect the pathologies. In this paper, random forest classifier is used to classify normal, suspicious and pathological patterns based on the features extracted from the cardiotocograms. The results showed that random forest classifier can detect these classes successfully with overall classification accuracy of 93.6%. Moreover, important features are identified to reduce the feature space. It is found that using seven important features, similar classification accuracy can be achieved by random forest classifier (93.3%).

Key Words
cardiotocography; fetal heart rate; random forest classifier; uterine contractions; biomedical data classification

Address
Muhammad Arif: Department of Computer Science, College of Computer and Information systems, Umm-Alqura University, KSA

Abstract
Titanium (Ti) based alloys are widely used in biomedical implants due to their low density, excellent corrosion resistance and good biocompatibilities. In recent years, growing interest in sever plastic deformation (SPD) has stimulated research and development on the techniques to attain refining of the grain size to the submicrometer or even nanometer level. The mechanical and wear properties determining the application of Ti in medicine may be improved via SPD. High pressure torsion (HPT) technique is one of the approaches available for improving the mechanical and wear properties of biomedical Ti materials. Accordingly, this article is designed to examine most recent state of the art scientific works related to the developments in mechanical properties and wear resistance of biomedical Ti materials processed by HPT. A comprehensive review in this area is systematically presented.

Key Words
titanium; biomedical applications; mechanical properties; wear; HPT

Address
Mechanical Engineering Department, Faculty of Engineering, Kufa University, Najaf, Iraq


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