Introduction. Major trauma during military conflicts involve heavily contaminated open fractures. Staphylococcus aureus (S. aureus) commonly causes infection within a protective biofilm. Lactoferrin (Lf), a natural milk glycoprotein, chelates iron and releases bacteria from biofilms, complimenting antibiotics. This research developed a periprosthetic biofilm infection model in rodents to test an Lf based lavage/sustained local release formulation embedded in Stimulin beads. Method. Surgery was performed on adult rats and received systemic Flucloxacillin (Flu). The craniomedial tibia was exposed, drilled, then inoculated with S. aureus biofilm. A metal pin was placed within the medullary cavity and treatments conducted. Lf in lavage solutions: The defect was subject to 2× 50 mL lavage with 4 treatment groups (saline only, Lf only, Bactisure with Lf, Bactisure with saline). Lf embedded in Stimulin beads: 4 bead types were introduced (Stimulin only, Lf only, Flu only, Lf with Flu). At day 7, rats are processed for bioluminescent and X-ray imaging, and tibial explants/pins collected for bacterial enumeration (CFU). Results. Rats without treatments established a mean infection of 2×106 CFU/tibia. 4 treatment groups with a day 0, one-off lavage demonstrated >95% reduction in bacterial load 7 days post-op, with a reduction in CFU from 1×106/tibia down to 1×104/tibia. There was no statistically significant difference between each group (p = 0.55 with one way ANOVA). The stimulin bead experiments are ongoing and complete results will be obtained in the end of July. Conclusions. This research demonstrated a clinically relevant animal model of implanted metalware that establishes infection. No additional benefit was observed with a one-off, adjuvant Lf lavage during the initial decontamination of the surgical wound, compared with saline alone, and in combination with the antiseptic Bactisure. This animal model provides the foundation for future antibiofilm therapies

In joint prostheses where ultra-high molecular weight polyethylene (UHMWPE) is used as bearing material, efficacious treatments such as crosslinking, addition of vitamin E and the grafting of phospholipid polymer are known to improve wear resistance. Under severe conditions of various daily activities, however, friction and wear problems in such prostheses have not yet been completely solved. In contrast, extremely low friction and minimum wear have been maintained for a lifetime in healthy natural synovial joints containing articular cartilage with superior lubricity. Accordingly, joint prostheses containing artificial hydrogel cartilage with properties similar to those of articular cartilage are expected to show superior tribological functions. In establishing the function of artificial hydrogel cartilage as a novel material for joint prostheses, the tribological properties of hydrogel materials used and synergistic performance with synovia constituents are both important. In this study, the influence of synovia constituents on friction and wear in artificial hydrogels was examined in reciprocating test and compared with that for articular cartilage. As biocompatible artificial hydrogel cartilage materials, three poly(vinyl alcohol) (PVA) hydrogels were prepared using the repeated freeze-thawing (FT) method, the cast-drying (CD) method and hybrid method for CD on FT, which are physically crosslinked with hydrogen bonding but differ in terms of structure and mechanical properties. First the frictional behavior of the PVA hydrogels and articular cartilage as ellipsoidal specimens was examined in reciprocating tests against a glass plate with a sliding speed of 20 mm/s under constant continuous loading. As shown in Fig.1, the three hydrogels exhibited different frictional behaviors in a saline solution. It is noteworthy that the hybrid gel maintained very low friction until the end of test. The CD gel showed slightly higher friction and a gradual increase. Meanwhile, the FT gel showed initial medium friction and a gradual increase echoing the time-dependent behavior of natural articular cartilage. Based on these observations, focus was placed on FT gel and articular cartilage to examine how synovia constituents influence friction and wear in these hydrogel materials. In human body, lubricating constituents in synovial fluids such as hyaluronic acid, proteins, glycoproteins and phospholipids are considered to reduce the coefficient of friction in solid-to-solid interaction. Here, the effects of hyaluronic acid (HA, molecular weight: 9.2×10. 5. ), serum proteins and phospholipid were examined. Dipalmitoylphosphatidylcholine (DPPC) was used as a typical phospholipid. As indicated in Fig.2 for repeated reciprocating tests, addition of HA alone was effective particularly for PVA-FT hydrogel. The combination of HA and DPPC was more effective in reduction of friction. The simulated synovial fluid (composed of HA 0.5 wt%, DPPC 0.01 wt%, albumin(Alb) 1.4 wt% and gamma-globulin (g-glob) 0.7 wt%) exhibited both low friction and minimum wear. The rubbing surfaces of articular cartilage and FT gel after tests are shown in Fig.3. On the articular cartilage surface, gel-like surface layer existed. On the FT gel surface, the original texture was observed without damage. These results indicate the importance of synovia constituents for the clinical application of artificial hydrogel cartilage in joint prostheses

In joint prostheses using ultra-high molecular weight polyethylene (UHMWPE) as bearing material, wear problems are not yet completely solved under severe conditions in various daily activities, although efficacious treatments such as crosslinking, addition of vitamin E and the grafting of phospholipid polymer improved the wear properties. In contrast, in healthy natural synovial joints possessing articular cartilage as biphasic bearing material lubricated with synovial fluid, minimal wear with extremely low friction has been maintained for a whole life. Therefore, the joint prosthesis with artificial hydrogel cartilage with similar properties to articular cartilage is expected to show superior tribological functions with very low friction and infinitesimal wear if the appropriate lubrication mechanism is actualized. In this study, the effectiveness of biphasic lubrication mechanism in hydrogel through significant load support by fluid phase is evaluated in finite element (FE) analysis for reciprocating motion. As biocompatible artificial hydrogel cartilage materials, two kinds of poly (vinyl alcohol) (PVA) hydrogels were prepared by the repeated freezing-thawing method and the cast-drying method, which are physically crosslinked with hydrogen bonding but different in structure and mechanical properties. To evaluate these time dependent behaviors of load-support ratio of fluid/solid phases and friction, two-dimensional biphasic FE analysis for cylindrical PVA hydrogel cartilage as 1.5 mm thick soft layer and radius of 5 mm was conducted under continuous loading of 0.2 N/mm by impermeable rigid plate in reciprocating motion in Fig. 1. The sliding speed is 4 mm/s for stroke of 8 mm at period of 4 s. A commercial package ABAQUS (6.8–4), which was appropriately evaluated for the biphasic FE analyses, was used in this study. The biphasic tissue was modeled by CPE4RP (four-node bilinear displacement and pore pressure, reduced integration with hour glass control) elements. The mechanical properties such as permeability, Young's modulus and Poisson ratio were estimated by curve fitting to stress relaxation behaviors in compression test. As indicated in Fig. 2, it is worth noting that the cast-drying PVA shows significant interstitial fluid pressurization compared with a repeated freezing-thawing PVA hydrogel at 292 s after start-up, where coefficient of friction for solid-to-solid was assumed as 0.2. Changes in friction for PVA hydrogels in reciprocating motion were estimated as shown in Fig. 3. In spite of high friction (0.2) for solid-to-solid, cast-drying PVA brought the gradual decreasing in friction, probably due to rising of load-support ratio by fluid phase from initial 74% to 80%. In human body, lubricating constituents in synovial fluids such as hyaluronic acid, proteins, glycoproteins and phospholipids can reduce the coefficient of friction for solid-to-solid. As suggested for low coefficient of friction for solid-to-solid as 0.01 in Fig. 3, rubbing friction is expected to be reduced to significantly low level. As described above, the effective biphasic lubrication can sustain low friction level and minimal wear in synergistic action with soft-elastohydrodynamic lubrication, hydration lubrication and boundary lubrication as a similar mechanism to natural cartilage in various daily activities. These results indicate the usefulness of artificial hydrogel cartilage for longer durability in joint prostheses for clinical application

Construction of a functional skeleton is accomplished through co-ordination of the developmental processes of chondrogenesis, osteogenesis, and synovial joint formation. Infants whose movement in utero is reduced or restricted and who subsequently suffer from joint dysplasia (including joint contractures) and thin hypo-mineralised bones, demonstrate that embryonic movement is crucial for appropriate skeletogenesis. This has been confirmed in mouse, chick, and zebrafish animal models, where reduced or eliminated movement consistently yields similar malformations and which provide the possibility of experimentation to uncover the precise disturbances and the mechanisms by which movement impacts molecular regulation. Molecular genetic studies have shown the important roles played by cell communication signalling pathways, namely Wnt, Hedgehog, and transforming growth factor-beta/bone morphogenetic protein. These pathways regulate cell behaviours such as proliferation and differentiation to control maturation of the skeletal elements, and are affected when movement is altered. Cell contacts to the extra-cellular matrix as well as the cytoskeleton offer a means of mechanotransduction which could integrate mechanical cues with genetic regulation. Indeed, expression of cytoskeletal genes has been shown to be affected by immobilisation. In addition to furthering our understanding of a fundamental aspect of cell control and differentiation during development, research in this area is applicable to the engineering of stable skeletal tissues from stem cells, which relies on an understanding of developmental mechanisms including genetic and physical criteria. A deeper understanding of how movement affects skeletogenesis therefore has broader implications for regenerative therapeutics for injury or disease, as well as for optimisation of physical therapy regimes for individuals affected by skeletal abnormalities.

Cite this article: Bone Joint Res 2015;4:105–116

Treatment for osteoarthritis (OA) has traditionally focused on joint replacement for end-stage disease. An increasing number of surgical and pharmaceutical strategies for disease prevention have now been proposed. However, these require the ability to identify OA at a stage when it is potentially reversible, and detect small changes in cartilage structure and function to enable treatment efficacy to be evaluated within an acceptable timeframe. This has not been possible using conventional imaging techniques but recent advances in musculoskeletal imaging have been significant. In this review we discuss the role of different imaging modalities in the diagnosis of the earliest changes of OA. The increasing number of MRI sequences that are able to non-invasively detect biochemical changes in cartilage that precede structural damage may offer a great advance in the diagnosis and treatment of this debilitating condition.

Cite this article: Bone Joint J 2013;95-B:738–46.