Objectives

Preclinical data showed poly(methyl methacrylate) (PMMA) loaded with microsilver to be effective against a variety of bacteria. The purpose of this study was to assess patient safety of PMMA spacers with microsilver in prosthetic hip infections in a prospective cohort study.

Objectives

Osteoporosis and osteomalacia lead to increased fracture risk. Previous studies documented dysregulated osteoblast and osteoclast activity, leading to a high-turnover phenotype, reduced bone mass and low bone mineral content. Osteocytes, the most abundant bone cell type, are involved in bone metabolism by enabling cell to cell interaction. Osteocytes presence and viability are crucial for bone tissue homeostasis and mechanical integrity. Osseo-integration and implant degradation are the main problems in developing biomaterials for systemically diseased bone. This study examines osteocyte localisation, morphology and on the implant surface and at the implant bone interface. Furthermore, the study investigates ECM proteins regulation correlated to osteocytes and mechanical competence in an ovariectomised rat model with a critical size metaphyseal defect.

Background

Multiple Myeloma is a hematological malignancy of terminally differentiated plasma cells associated with increased osteoclast activity and decreased osteoblast functions. Systemic antiproliferative treatment includes proteasome inhibitors such as bortezomib, a clinical potent antimyeloma agent. Local delivery of biological active molecules via biomaterial composite implants to the site of the lesion has been shown to be beneficial for bone and implant-associated infections. In anticancer treatment local delivery of anticancer agents to the neoplasia via biomaterial carriers has never been reported before. The purpose of the current is to present the concepts and the first in vivo results for proteasome inhibitor composite biomaterials for local delivery of bortezomib to proliferative multiple myeloma bone lesions including concentration measurements at different anatomical regions in a rat model.

Summary Statement

Magnesium has a number of qualities suitable for bioresorbable metallic implants. However, high corrosion rate and formation of hydrogen gas can compromise its performance. Combining magnesium with calcium phosphate improves magnesium's biocompatibility by decreasing gas formation and increasing bone remodeling.

The introduction of new treatments needs to be both clinically effective and cost effective. Clinicians tend to be unaware of the importance of the latter, and how health economic assessments are undertaken, especially in a public health system where the inclusion of funded treatments is made on a national basis. The purpose of this study was to determine the cost savings from a societal perspective in the use of recombinant human Bone Morphogenetic Protein -2 (rhBMP-2) in grade III A and B open tibia fractures treated with a locked intramedullary nail and soft-tissue management in the UK, Germany, and France. Healthcare system (direct healthcare costs) and costs for productivity losses (indirect health-care costs) were calculated using the raw data from the Bone Morphogenetic Protein Evaluation Group in Surgery for Tibial Trauma “BESTT study”. Return-to-work time for estimation of productivity losses was assumed to correspond with the time of fracture healing. For calculation of secondary interventions costs and productivity losses the respective 2007/08 national tariffs for surgical procedures and average national wages for the UK, Germany, and France were used. From a societal perspective, overall savings per case of €7911 for the UK, €9270 for Germany, and €9291 were calculated. Those savings largely offset the upfront price of rhBMP-2 of €2266(£1,790) in the UK, €2970 in Germany, and €2950 in France. Total net savings can be estimated to be €9.6 million for the UK, €14.5 million for Germany, and €11.4 million for France. For all three countries reduced productivity losses are the key driver for the overall savings. In summary, despite the apparent high direct cost of rhBMP-2 in grade III A and B open tibia fractures, at a national level there are net cost-savings from a societal perspective for all three countries.

Gentamicin was described with negative effects on bone formation. Arginin-Glycin-Aspartat (RGD) sequences play a key role in the adhesion of osteoblasts and have proven to improve implant integration. We have already shown a significant reduction in infection rates by a combined gentamicin-hydroxyapatite (HA) and gentamicin-RGD-hydroxyapatite coating in a rabbit infection model for cementless joint prostheses.

The purpose of the study was to assess whether the gentamicin-HA coating had a negative effect on the implant integration and new bone formation, compared to pure HA coating, and whether this could be enhanced by additional gentamicin-RGD-HA coating.

There were 5 study groups (8 animals per group) with 5 different stainless steel K-wires: uncoated, HA coated, gentamicin-HA, RGD-coated, gentamicin-RGD-HA coated. A 2.0 mm K-wire with one type of coating was introduced into the intramedullary canal of the tibia. The tibiae were harvested after 12 weeks and standardised longitudinal and transverse sections were performed to study new bone formation around the implant and implant bone contact. New bone formation and osseointegration of the implant surface was assessed using histomorphometrical methods by computerised semi-quantitative analysis and histological methods.

There were no significant differences between the HA and the gentamicin-HA group although new bone formation and implant bone contact were always higher for the pure HA coating. Additional RGD coating on the gentamicin-RGD-HA coating did not show significant improvement of bone formation and implant integration compared to gentamicin-HA. There was a very similar histological appearance of new bone formation between all groups with very low frequency of giant cells, indicating good biocompatibility.

Gentamicin-HA coating did not have significant negative effects on bone formation and bone implant contact, compared to pure HA coating. In combination with the excellent ability to reduce infection rates, gentamicin-HA coating may have a high interest in cement-less arthroplasty.

Introduction: Similar local infection prophylaxis as in cemented total joint by antibiotic-loaded bone cement has not been possible yet for cementless prostheses. In this study, a gentamicin-coating which can be brought additionally onto standard hydroxyapatite (HA) coatings of cementless prostheses is presented. It was tested whether this gentamicin-coating can reduce infection rates in a rabbit infection model with Staphylococcus aureus compared to compared to standard-HA coating. Furthermore, the biocompatibility of this gentamicin coating was investigated.

Materials and Methods: Staphylococcus aureus with a dose of 10(7) CFUs was inoculated into the intramedullary canal of the tibia of 30 rabbits followed by the implantation of standard hydroxyapatite (HA) K-wires, K-wires coated with a HA--gentamicin combination, and K-wires coated with a HA-RGD-gentamicin combination, respectively. The animals were sacrificed after 28 days and clinical, histological and microbiological assessment on the bone and on the removed K-wire itself by agar plating and DNA-pulse field gel electrophoresis were carried out to detect infection. Infection was defined as positive culture growth from the bone and/or cement samples. In another study with 40 rabbits biocompatibility of the two gentamicin-coating types was assessed after an implantation time of 12 weeks and compared to pure HA-coating and uncoated implants.

Results: Infection rates were 88% (7 of 8 animals) for the standard HA, 0% (0 of 9 animals) for the HA-gentamicin and 0% (0 of 10 animals) for the HA-RGD-gentamicin group. There was a statistically highly significant reduction of infection rates by both gentamicin-coating types compared to standard HA-coating (p < 0.001). The animals that were identified to have positive culture growth corresponded to the animals that showed clinical signs of infection. An excellent correlation between agar plating testing results of the K-wires and of the bone samples was found. Detailed histology showed cortical lysis, abcess and sequester formation in the infected animals. There were no major differences in the biocompatibility between the different groups. There were only a few giant cells and regions of bone marrow necrosis in the gentamicin-groups which was comparable to the control implants. There was a very similar histologic appearance of the gentamicin coatings and the standard HA coating.

Conclusion: Both gentamicin-coating types showed significant improvement of infection prophylaxis compared to standard HA coating. Furthermore, both gentamicin coating types revealed good biocompatibility after 12 weeks. Therefore, HA-gentamicin and HA-RGD-gentamicin coatings could help to reduce infection rates in cementless arthroplasty in all day clinical use

Introduction: The addition of recombinant human bone morphogenetic protein-2 (rhBMP-2) showed significant reduction of secondary intervention, fracture healing time and infection rates compared with intramedullary nailing alone in open tibia fractures. However, the upfront price of approx. 3000 € is a barrier to its regular use. The goal of the study was to determine potential cost savings and cost-effectiveness of rhBMP-2 in grade III open tibia fractures from the perspective of the UK National Health Service (NHS) and the German Health Care System and to derive conclusions for other European health care systems.

Materials and Methods: Clinical data from a previously published randomised controlled study with 450 patients (“BESTT study”) were used to generate total treatment costs for each patient for the control and the 1.5 mg/ml BMP-2 group based on the current German-DRG and the NHS for UK. The analysis was performed from a health care system and a societal perspective for a one year time horizon. Furthermore, assessment of the cost-effectiveness of BMP-2 was done by utility analysis.

Results: The use of BMP-2 for grade III open tibia fractures is leading to cost savings of 3183 € per case and, therefore, to net savings for the German health care system. The main driver for cost savings is faster fracture healing with faster resumption of work and reduced expenses for sickness leave payments. For the UK rhBMP-2 is a cost-effective strategy with a cost-effectiveness ratio of approx. £11,000/QALY which is well below the standard £30,000 benchmark for the NHS. From a societal perspective, rhBMP-2 is a cost-saving treatment.

Conclusions: BMP-2 leads to net savings in grade III open tibia fractures in Germany which can be expected for other European countries where sickness payments are provided by health care insurers. For countries like UK where sickness are provided by third parties BMP-2 is a cost-effective treatment strategy from a health care system perspective and a cost-saving treatment from a societal perspective.

These studies are indicative of the potential utility of resorbable and nonresorbable inorganic materials as bone graft substitutes. Bone transplants and bone substitute materials are necessary in +/−10% of all skeletal reconstructive operations. The higher osteogenic potential of autografts compared to allogenic transplants is undisputed, but restricted by limited availability and necessity of secondary operations.

Commercial bone graft materials show variety of compositions and properties, many very different from those of autologous bone. Physicochemical properties of these materials were compared using x-ray diffraction, scanning and transmission electron microscopy. Biological reactivity of different materials was also compared in histological evaluations in animal models. Experimental and clinical studies have been encouraging, especially in metaphyseal defects.

Bone substituting the artificial material should be able to bear weight and, if possible, be lamellar bone. Since fundamental examinations of osteoinduction and affiliated isolation of growth factors (Urist 1965), extensive scientific research on growth factors contained in bone matrix has been performed. Proteins of the TGF-β family play a key role in regulation of bone regeneration. In past years, alkaline fibroblast growth factor has raised increased interest among researchers. Its presence implies that it plays an important role in the development of bone substance. One best known effect is significant augmentation of microangiogenesis, which could be demonstrated among others in experimental wound healing investigations. Further experimental examinations showed significant increase of callus formation in rats and miniature pigs, in which FGF had been injected into the fracture site.

Current bone substitute materials are only to be used in clearly defined indications, as they do not currently meet the biological or mechanical properties of autogenous bone. Our knowledge is grounded on various experimental models, which are not always comparable. Therefore many aspects have to be considered as a working understanding.

Infections in total joint arthroplasty, particularly with multiresistant bacteria, are a serious problem. A new nanoparticulate silver cement had previously shown good biocompatibility combined with good in vitro antimicrobial activity against multiresistant bacteria.

The purpose of the current study was to evaluate the antibacterial activity of nanoparticulate silver cement against biofilm-building methicillin-resistant S. aureus (MRSA) in a rabbit model and to compare it to that of gentamicin-loaded cement.

Gentamicin cement or nanoparticulate silver bone cement was injected into the proximal half of one femur in 10 animals, respectively. Before hardening of the cement 10⁷ or 10⁸ colony forming units of MRSA with high gentamicin resistance were inoculated at the cement bone interface in 5 rabbits of each group. The animals were euthanized after 14 days and both the cement adjacent bone and the cement itself were studied using microbiological and histological methods. Infection was defined as positive culture growth from the bone and/or cement samples.

Infections rates were 100% for the gentamicin group (10 of 10 animals had infection) and 30% for the NanoSilver group (3 of 10 animals). Thus, nanoparticulate silver bone cement significantly reduced infection rates by 70%.

Nanoparticulate silver cement exhibited good antimicrobial activity in the prophylaxis of cement-related infections with MRSA and is therefore a promising alternative in total joint arthroplasty.

Introduction: Deep periprosthetic infections are infrequent but devastating situations in total joint arthroplasty. During the last years the total number and the percentage of total joint infections with multiresistant bacteria has increased. The aim of this study was to investigate the antimicrobial activity of a new bone cement loaded with nanoparticulate silver against bacteria with different antibiotic resistance.

Material and Methods: An in vitro proliferation test was used to test antimicrobial properties of 1% nanoparticulate silver bone cement, gentamicin-loaded, tobramycin-loaded and plain bone cement. This in vitro testing method consisted of two incubation steps. During the first step the tested bacteria could adhere to the bone cement surface. In the second step bacteria either seeded out of vital daughter cells in case of no antimicrobial effect of the cement or were killed by the antibacterial properties of the cement. Seeding out of daughter cells was detected by a microplate reading system resulting in specific time proliferation curves. Several staphylococci and gram-negative strains with different resistance profiles against methicillin, tobramycin, and gentamicin were tested including MRSA and MRSE.

Results: 1% nanoparticulate silver bone cement showed bactericidal effect against all tested strains, including MRSA and MRSE. Gentamicin and tobramycin cement was not effective against bacteria with high resistance level against the respective antibiotic. Plain bone cement was not effective against any strain.

Conclusion: 1% nanoparticulate silver bone cement exhibited excellent antibacterial properties that could not be reached by gentamicin or tobramycin-loaded cement. Good activity against MRSA could also already be shown in a first animal trial. If further in vivo investigations confirm these promising results nanoparticulate silver bone cement is a new alternative for prophylaxis in total joint arthroplasty.