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Cylinders of biomimetic (nanocrystalline) calcium phosphate were loaded with gentamicin by four different methods: 1) dip-coating, 2) impregnation followed by cold-isostatic pressing, 3) co-precipitation followed by cold-isostatic pressing, and 4) coating of co-precipitated particles with a biodegradable polymer PDLLA (poly-D,L-lactide), followed by uniaxial pressing. The release kinetics were studied in vitro over 10 days. The incorporation by methods 2), 3) and 4) showed a significantly higher long-term release of active gentamicin than dip-coating, although there was an initial burst during the first two days with all four methods. With method 4), there was an increase of the released gentamicin after 7 days, and the long-term release was the highest of these four methods. The results are of considerable interest for the preparation of biodegradable bone implants which are loaded with biologically active substances.

Bei dem Implantatmaterial Cerabone® handelt es sich um eine Hydroxylapatitkeramik mit dem Hauptbestandteil Pentacalcium-hydroxid-[tris]phospat. Die Gewinnung des Implantates erfolgt durch die Präparation tierischer Knochen, die durch Temperaturprozesse in ihre keramische Form transformiert werden. Aufgrund des spongiösen Ausgangsmateriales besitzt Cerabone® ein interkonnektierendes makro- und mikroporöses Porensystem. Dieses liefert dem neuzubildenden Knochen eine strukturierte Leitschiene, in und um die ausgehend vom Lagerknochen neuer Knochen angelagert wird. Der durch die Herstellungsprozesse beibehaltene Aufbau der natürlichen Spongiosa wirkt sich besonders gut auf die mechanischen Eigenschaften des Implantates und das Einwachsverhalten des neuen Knochens nach der Implantation aus.

Summary In an experimental glioma model, using ethylnitrosourea induced and subsequently intracerebrally implanted tumours in BD-IX rats, the effectiveness of intratumoural application of methotrexate (MTX) by stereotactic implantation of polymethylmethacrylate (PMMA) pellets containing MTX, has been studied. Tumour volume 10 days after pellet implantation as well as survival rates of treated, untreated and control animals have been the criteria of the effect of treatment.

Low viscosity bone cement is expected to give improved long term fixation of prosthetic components by increased intrusion into cancellous bone. Fixation is more difficult to achieve after revision for infection because of the inferior quality of the bone. We have compared the amount of gentamicin released from high viscosity and low viscosity bone cements in 41 patients undergoing total hip replacement. The concentration of gentamicin in serum and the wound secretion, and the amount recovered from the urine, was about three times higher for low viscosity cement. A possible explanation for this is an increase in surface area of the cement body because of improved intrusion of cement into bone. The improved mechanical fixation and the high concentration of gentamicin of the bone cement interface favours the use of low viscosity cement, especially in revision for deep infection.

Summary Radical surgery in malignant bone tumors can either be limited by anatomical structures or seems inadequate in the palliative stabilization of bone metastases. Incomplete removal of the tumor and stabilization by compound osteosynthesis or endoprosthesis contains two problems: 1) the wide spread of malignant cells by manipulation in the tumor bearing area; 2) progressive destruction of bone due to remaining tumor. To overcome these problems we developed methotrexate bone cement (MTX-Palacos) with the aim to obtain high local concentrations of methotrexate in order to destroy remaining tumor cells and avoid systemic side effects. In vitro studies showed that methotrexate is released continuously from this cement without relevant changes of its biomechanical properties. Animal studies with transplanted osteosarcomas and mamma carcinomas in mice showed a considerable decrease of tumor growth when a plug of MTX-Palacos was inserted in the center of the tumor. Histological findings showed that in the surroundings of the plug the tumor was destroyed considerably contrary to normal bone cement which had no effect on the tumor at all. The results are discussed with regard to clinical application of MTX-Palacos.

A randomised, double-blind study was performed in two groups of 15 patients undergoing total hip replacements, using antibiotic-loaded acrylic cement containing 0.5 g and 1.0 g gentamicin base respectively per 40 g pack of powdered polymer. Postoperatively, the gentamicin levels in the blood, in the urine and in the wound drainage fluid were measured. In both groups of patients, the serum gentamicin concentrations were low whereas the wound drainage fluid contained highly effective antibacterial concentrations. Serum, urine and wound secretion levels showed approximately two-fold higher concentrations in the group of patients receiving the higher gentamicin load.

Bone cement, used to fix prostheses into the bone, must be sterilized prior to implantation. Two sterilization techniques, γ and β radiation, were investigated, examining the influence upon molecular weight, static and dynamic mechanical characteristics and rheological properties. A number of experimental cements were studied prepared from methylmethacrylate (MMA) co-polymers, either single powders or powder blends, mixed with MMA monomer. It was found that with both γ and β radiation, there was a decrease in molecular weight of all powders, including a MMA/styrene co-polymer, in relation to the radiation dose. This fall in molecular weight resulted in a drop in tensile strength, Young’s modulus and strain to failure of all cements tested. However, the deterioration in mechanical strength was highlighted by the dynamic testing. Fatigue lives of cements after testing in tension–tension, at 2 Hz under load control and irradiated with 25 kGy γ radiation, displayed significant decreases. This result indicated the utmost importance of conducting such tests upon experimental bone cements prior to in vivo use. The rheological time profiles of curing cements were also found to be influenced by 25 kGy γ radiation, with a reduction of complex viscosity after sterilization.

Comparing several antibiotics and different bone cements, the mixture of Palacos® R (polymethylmethacrylate, PMMA) with gentamicin proved to be the most suitable one as far as a high and sustained release of the antibiotic from the artificial resin is concerned. A continuous leaching of gentamicin was observed for more than 5 years. Gentamicin proved to be stable in Palacos R for the whole period of time.The release of 12 antibiotics from Palaes R was evaluated in vitro. Four other bone cements were included in this ttudy as well, in order to evaluate the leaching of gentamicin from these materials. the combination Gentamicin-Palacos R (GP) showed a 2-3 fold higher and much more prolonged release than did the other mixtures. From this investigation, which also included studies of commercially available antibiotic bone cement mixtures, it is quite obvious that there exist distinct differences in the various bone cements as well as in the various antibiotics as regards their qualification for use in alloarthroplasty.Pharmacokinetic studies in patients after implantation of GP showed low gentamicin concentrations in serum (on average 1.8μg/ml) and urine. However, in wound exudate, derived directly from the vicinity of the implanted cement, gentamicin concentrations up to 150μg/ml were observed. Also in tissue samples from the vicinity of the implant, high concentrations were measurable for a long period of time (up to 5 1/2 years).

Gentamicin incorporated in beads of polymethylmethacrylate has been shown capable of being released over a period of several months in concentrations sufficiently high to control most pathogens. The therapeutic efficacy of such beads has been demonstrated in a model of osteomyelitis of the femur in the dog. Good tolerance has been shown, both in the animal model and in tissue cultures. In forty-one patients with infection of either bone or soft tissue, mainly of the lower limb, the findings were similar. The concentrations in serum and urine were low, which excludes side-effects. The insertion of gentamicin-PMMA beads may prove to be a valuable new form of local antibiotic therapy.

Zusammenfassung: Cefazedon — ein neues halbsynthetisches Cephalosporinderivat — wurde in vitro, im Tierexperiment und in pharmakokinetischen Studien bei Patienten untersucht. Eine gute antibakterielle Wirksamkeit wurde gegenber zahlreichen von Patienten mit chronischen Knocheninfektionen frisch isolierten Bakterienstmmen gefunden. Im Tierexperiment kam es nach Injektion einer Staphylokokken-Suspension in die Femurmarkhhle von Hunden unter der Cefazedontherapie zu einer deutlichen Senkung der Keimzahl. Bei Patienten mit TEP-Operationen wurden in verschiedenen infektionsgefhrdeten Geweben und im Wundsekret hohe, ber der MHK der tiologisch wichtigen Erreger liegende Cefazedonkonzentrationen gemessen.

Zusammenfassung: Gentamycin-PMMA (PMMA = Polymethylmethacrylat) -Kugeln stellen eine neue Therapieform fr die Behandlung chronischer Knocheninfektionen dar. In vitro wurde die auf dem Wege einer Diffusion erfolgende Freisetzung von Gentamycin aus PMMA bestimmt. Aus einer Kugel werden anfangs pro Tag 200–400 g, um den 20. Tag 30–40 g und am 40. Tag noch etwa 10 g Gentamycin-Base pro ml Elutionsflssigkeit freigesetzt. Die experimentelle berprfung der therapeutischen Wirksamkeit dieses Behandlungsprinzips erfolgte an einem Osteomyelitismodell am Hund. Die Infektion der Femur-Markhhle mit einem Staph.-aureus-Stamm fhrte innerhalb von 6 Wochen zu ausgedehnten osteomyelitischen Vernderungen. Unter der Therapie mit Gentamycin-PMMA-Kugeln, die in die Markhhle implantiert wurden, gingen die periostitischen Auflagerungen zurck und die osteolytischen Vernderungen an der Kortikalis verschwanden. Nach 6 Monaten war die Infektion klinisch, bakteriologisch und histologisch abgeheilt. Bei pharmakokinetischen Untersuchungen an Hunden wurden in Serum und Urin nur geringe Gentamycin-Konzentrationen nachgewiesen. Gentamycin-Bestimmungen in den die Kugeln umgebenden Geweben wurden ber 4 Monate durchgefhrt. Noch nach dieser Zeit konnten ca. 5 g Gentamycin pro g Gewebe gemessen werden. Die Vertrglichkeit der Gentamycin-PMMA-Kugeln war sehr gut. Die Kugeln im Hundefemur wurden von einer dnnen Bindegewebshlle umgeben, und in die Hohlrume zwischen den Kugeln wuchs innerhalb von 4–6 Monaten Spongiosa ein. In der Zellkultur wuchsen Kaninchennierenfibroblasten auf Gentamycin-PMMA ebenso gut wie in den blichen Zellkulturschlchen.

With the combined osteosynthesis of pathological fractures in association with tumors and/or metastases in mind, E. Merck (Darmstadt, FRG) developed a bone cement containing a cytostatic agent, methotrexate-Palacos flow y (MTX-Pf). The animal-experimental study presented here investigates the tolerability of MTX-Pf in the femurs of rabbits with lateral comparison. In these investigations we used both the concentration of 0.63% MTX, as is currently used in standard clinical surgery, as well as a much higher concentration of 2.5% MTX. The histological sections were investigated using microradiographic methods and provided no indication of any significant differences between the femora with the MTX-Pf implantation and those into which standard Palacos flow y had been implanted.

The in vitro release of vancomycin, teicoplanin, gentamicin and clindamycin from biodegradable calcium sulphate (CaSO(4)) carrier beads is described. All antibiotics showed prolonged release from the carrier beads, which was elevated during the first 24 h, with peak levels exceeding 2500 microg/bead. Doubling the antibiotic load of the beads revealed a more prolonged elution and a two-fold increase in antibiotic release. Local carrier-associated antibiotic treatment with CaSO(4) beads may prove to be effective in the management of chronic bone infections.

Zusammenfassung: Bei Patienten mit Knocheninfektionen wurden nach Implantation von Gentamycin-PMMA-Kugeln die Gentamycin-Konzentrationen in Serum, Urin und Wundsekret bestimmt. Im Serum war Gentamycin nur fr wenige Tage nach der Kugelimplantation in Konzentrationen von maximal 0,5 g/ml nachweisbar. Damit sind toxische Nebenwirkungen auszuschlieen. Im Urin von Patienten konnte Gentamycin noch mehrere Monate nach der Operation gemessen werden: ein Beweis fr die andauernde Freisetzung aus den implantierten Kugeln. Hohe, aber je nach klinischen Bedingungen stark schwankende Gentamycin-Konzentrationen von 14 bis 215 g/ml wurden im Wundsekret gefunden, das unmittelbar dem Operationsgebiet entstammte. Diese Konzentrationen lagen weit ber der MHK und MBK der tiologisch bedeutenden Erreger.

The pressing of bone cement into the medullary space of the femur causes acute presure increases. The consequence is a marrow and fat intravasation leading to mechanical blocking of the microcirculation in the lung, which also entails the transfer of thromboplastic substances. A ventricular obstruction of the outflow is possible. As a prophylactic measure, pressure compensation within the medullary space by means of drainage and suction is recommended, as is the application of the natural proteinase inhibitor aprotinin to prevent a fall in the platelet count. Durch das Einpressen von Knochenzement in den Markraum des Oberschenkelknochens, kommt es zu akuten Drucksteigerungen. Die Folge ist eine Mark- und Fettintravasation, welche zu einer mechanischen Blockade der Mikrozirkulation in der Lunge führt. Ebenso kommt es auch zum Übertritt von thromboplastischen Substanzen. Eine rechtsventrikuläre Ausflußblockade, die zum akuten Cor pulmonale führen kann, ist möglich. Als prophylaktische Maßnahme, Druckausgleich im Markraum durch Drainage und Sog, sowie die Anwendung eines natürlichen Proteinaseninhibitors Aprotinin zur Hemmung des Thrombocytensturzes wird empfohlen.

Summary The gentamicin concentrations in serum, urine, and wound secretions following implantation of gentamicin-PMMA beads in osteomyelitic cavities were determined. The effectiveneB of the local antibiotic therapy is demonstrated in experimental osteomyelitis in dogs. The operative procedure is explained and shown in cases of chronic osteomyelitis, infected pseudoarthroses, and infected osteosyntheses.

Summary Gentamicin concentrations in serum, urine, and wound secretion were determined in patients with bone and soft tIssue infections after implantation of gentamicin-PMMA beads. The release of gentamicin in high concentrations permits effective local antibiotic therapy in indications such as chronic osteomyelitis, infected osteosyntheses, infected, pseudoarthroses, subphrenic absceBes, and other soft tIssue infections. Before implantation of the gentamicin-PMMA beads, radical removal of all necroses and foreign bodies in absolutely neceBary.