Biocompatability of hydroxyapatite composite as a local drug delivery system

PURPOSE. To investigate the biocompatibility of hydroxyapatite composite (hydroxyapatite, plaster of Paris, and chitosan) impregnated with gentamicin, fosfomycin, imipenem, or amphotericin B. METHODS. The interactions of the extract from each drug against osteoblast were tested using the methylthiotetrazole test. RESULTS. Extracts from all drugs showed good biocompatibility at concentrations varying from 10 microgram/ml to 1000 microgram/ml. Imipenem and amphotericin B at a concentration of 1000 microgram/ml had a significantly higher percentage of cell viability than the control group. No morphological change of osteoblast was observed in all drug tests at any concentrations. CONCLUSION. The hydroxyapatite composite had a good biocompatibility for carrying gentamicin, fosfomycin, imipenem, or amphotericin B.     

The efficacy of a hydroxyapatite composite as a biodegradable antibiotic delivery system

Local biodegradable carriers have been studied for use as a skeletal drug delivery system. This study investigated the efficacy of a local biodegradable composite composed of hydroxyapatite, plaster of Paris, and chitosan impregnated with antibiotics to treat methicillin-resistant Staphylococcus aureus. The composite, impregnated with vancomycin, fosfomycin, or sodium fusidate was tested for its sustained elution characteristics during 3 months and compared with similarly impregnated polymethylmethacrylate using the modified disc diffusion technique. Physicochemical properties using scanning electron microscopy and xray diffraction analysis of each preparation also were analyzed. Vancomycin and fosfomycin incorporated into the hydroxyapatite composite inhibited the organism for 3 months, whereas sodium fusidate was effective only for 3 weeks. Vancomycin and fosfomycin loaded into the hydroxyapatite composite had a significantly better inhibitive effect than when loaded in polymethylmethacrylate, whereas sodium fusidate loaded in polymethylmethacrylate showed a significantly better inhibitive effect than when loaded in the hydroxyapatite composite. Scanning electron microscopy and xray diffraction analysis elucidated the patterns of each drug release profile. The local hydroxyapatite composite is a promising local biodegradable delivery system for vancomycin and fosfomycin, whereas PMMA is a better carrier for sodium fusidate in treating methicillin-resistant staphylococcus aureus osteomyelitis.     

Calcium hydroxyapatite ceramic implants in bone tumour surgery. A long-term follow-up study

We reviewed the results of 51 patients with benign bone tumours treated by curettage and implantation of calcium hydroxyapatite ceramic (CHA). The mean follow-up was 11.4 years (10 to 15.5). Post-operative fractures occurred in two patients and three had local recurrences; three had slightly limited movement of the adjacent joint and one had mild osteoarthritis. There were no allergic or neoplastic complications. In all cases, radiographs showed that the CHA was well incorporated into the host bone. Statistical analysis showed that absorption of the implanted CHA was greater in males (odds ratio, 6.2; 95% CI, 1.6 to 23.7) and younger patients (odds ratio, 0.6 for increase in age of 10 years; 95% CI, 0.91 to 0.99). However, the implanted CHA was not completely absorbed in any patient. We conclude that CHA is a useful and safe bone substitute for the treatment of benign bone tumours.     

Calcium sulphate as a drug delivery system in a deep diabetic foot infection

Treating diabetic foot infection is costly, time consuming and challenging for the patient and clinician alike. It requires a multidisciplinary approach to provide a favourable outcome but all too often results in amputation.We present a patient with Type 2 diabetes who attended clinic with a limb threatening foot infection complicated by osteomyelitis and requiring emergency surgery and antibiotic administration.Our patient underwent surgery by means of an incision and drainage procedure with local antibiotic administration to augment systemic antibiotics. The wound was packed with calcium sulphate (Stimulan^® Biocomposites Ltd.) impregnated with gentamicin and vancomycin to enable high antibiotic concentrations at the site of infection. The patient made a full recovery at four months requiring only minimal bone excision to maintain a functional foot.This case demonstrates an alternative route for antibiotic administration to overcome some of the limitations of systemic administration including penetration at the site of infection, systemic toxicity, prolonged hospital admission and cost. This route of administration is being increasingly used as an alternative to systemic antibiotics at our centre.     

Attenuation of the acute-phase response in thermally injured rats by cholesterol-containing cationic liposomes used as a delivery system for gene therapy.

HYPOTHESIS: Cholesterol-containing cationic liposomes alone modulate the acute-phase response and cytokine expression in thermally injured rats and are an effective delivery system for gene therapy in trauma. SETTING: Laboratory. INTERVENTION: Fifty-six adult male Sprague-Dawley rats with a full-thickness scald burn covering 60% of total body surface area were randomly divided into 2 groups to receive either intravenous injections of cholesterol-containing cationic liposomes or saline (control). MAIN OUTCOME MEASURES: Body weights, muscle and liver dry-wet weights, serum levels of constitutive hepatic proteins, acute-phase protein levels, and cytokine levels were determined at 1, 2, 5, and 7 days after thermal injury. RESULTS: Rats receiving cholesterol-containing cationic liposomes had less body weight loss, increased serum transferrin levels, and decreased serum alpha1-acid glycoprotein levels when compared with controls (P<.05). Serum interleukin 1beta and tumor necrosis factor alpha levels were decreased in rats receiving liposomes at 1 and 2 days after burn compared with controls (P<.05). CONCLUSIONS: These results suggest that cholesterol-containing cationic liposomes alone may have a beneficial effect in modulating the hypermetabolic response after burn injury by decreasing type 1 acute-phase proteins and the expression of the proinflammatory cytokines interleukin 1beta and tumor necrosis factor alpha. Therefore, cholesterol-containing cationic liposomes appear to be suitable as a delivery system for gene therapy in trauma.     

Calcium absorption from a new calcium delivery system (CCM)

Absorption of calcium from a highly soluble form of calcium, a mixed calcium citrate-malate^* salt (CCM), was tested against calcium carbonate and milk in both rats and humans. The rat method estimated absorption from the 6-day retention of an oral tracer, and the human method employed the standard double-isotope procedure. CCM was given both as a dry powder and in an organe juice beverage. In two experiments in rats calcium from CCM was absorbed at least as well as, if not better than from calcium carbonate or milk. In two separate experiments in humans, calcium from CCM was absorbed significantly better than from calcium carbonate or milk. We conclude that CCM exhibits excellent bioavailability and that this formulation is a useful addition to the forms of calcium now available either for direct supplementation or for food fortification.     

Fixation of hip prostheses by hydroxyapatite ceramic coatings.

We report the histological findings in post-mortem specimens obtained ten days, 17 days and seven weeks after implantation of hydroxyapatite-coated femoral components of hip arthroplasties. There was early deposition of woven bone on the hydroxyapatite ceramic, identical to that deposited on surviving cancellous trabeculae. The space between these deposits became bridged from both sides by new trabeculae, and there was no evidence of an inflammatory reaction or of fibrous tissue formation. The use of an hydroxyapatite coating seems to allow early, sound, secondary fixation of implants.     

Infection following the use of porous hydroxyapatite ceramic as a bone defect filler in articular fractures

Summary This article is a preliminary report focussed on infection after implantation of porous hydroxyapatite (Endobon®) as a bone defect filler. Eighteen adults received Endobon® implants for cancellous bone defects after trauma, tumoral excision or for arthrodesis. Four patients exhibited osteoarthritis. Infections required debridementand removal of osteosynthesis material and implants. Relevant infectious organisms were Staphylococcus and Enterobacteria. The incidence of postoperative infection, the nature of the organisms and indications are discussed. Further investigations are required in order to understand the causes of infection and undertake their prophylaxis.     

Slow release of anticancer drugs from porous calcium hydroxyapatite ceramic.

We have developed a new delivery system for sustained release of an anticancer drug (cis-platinum) by enclosure into blocks of porous calcium hydroxyapatite ceramic. The slow release of this drug from this system was confirmed in in vitro experiments. When this system was implanted into normal back muscle, or the tibia, sustained release of cis-platinum was observed during a 12-week period after implantation. The diffusion rate of cis-platinum into blood and other organs (liver, kidney, brain) was less than 10% of that at the implanted site. This delivery system placed into experimental tumors of mice also showed a uniform release of anticancer drug for more than 3 months. Inhibition of tumor growth was more marked after local implantation of this system than after intraperitoneal administration of cis-platinum. These results indicate that this new approach to a drug delivery system may well have an important role in cancer chemotherapy. In bone tumors it is attractive because the mechanical strength of calcium hydroxyapatite ceramic permits partial surgical excision and replacement of the bone defect at the same time.     

Calcium sulfate used as bone graft substitute in acetabular fracture fixation

The purpose of this study was to determine the natural history of calcium sulfate pellets implanted during acetabular fracture surgery. The study group consisted of patients sustaining an acetabular fracture with intraarticular comminution or marginal impaction or both in whom calcium sulfate pellets were implanted in lieu of autologous bone graft. Between 1997 and 1999, 32 fractures were treated. Followup adequate to delineate pellet outcome, including radiographs and computed tomography, was obtained in 31 patients. Evaluation of plain radiographs showed that the calcium sulfate pellets became undifferentiated from the surrounding bone at an average of 7 weeks postoperatively. In no case was a residual bony deficit seen. Computed tomography analysis showed that in 22 patients, the pellets essentially had been (> 90%) replaced by bone and in four patients, the majority (> 50%-90%) of the pellets had been replaced by bone. However, in five patients, less than 50% of the pellets had been replaced by bone, including one showing no bony replacement. The common finding in patients with an extensive residual deficit was direct communication of the pellets with the joint space shown on the postoperative computed tomography scan. Patients with the best results had complete containment of the pellets within bone. Therefore, it seems that implanted calcium sulfate pellets in contact with joint synovial fluid are at risk for resorption without significant bony response. If calcium sulfate pellets are to be implanted in a periarticular location, complete bony containment is desirable. Evaluation of the periacetabular bony response requires computed tomography scans, as plain radiographs are inadequate for this purpose.     

Osteoconduction in large macroporous hydroxyapatite ceramic implants: evidence for a complementary integration and disintegration mechanism

Large, cylindrical implants of a porous calcium phosphate ceramic (“hydroxyapatite” starting material, HAC) were used to replace far greater than critical-sized sections of the midshaft of sheep tibiae and retrieved at 2 and 9 months; external fixation was used in the first 5 months. Excellent clinical function of these implants was reported in a previous study. The material retrieved was embedded in PMMA, and blocks were sectioned and surfaces were polished and carbon coated prior to study using digital backscattered electron (BSE) imaging. Detailed scanning electron microscopy study of the pattern of osseointegration of the implanted material at early (2 months) and late (9 months) timepoints revealed a previously unrecognized pattern of integration/disintegration of this implant material in tandem with bone growth. We conclude that bone adaptation to the HAC leads to its fracture and that the newly generated surfaces are equally osteoconductive. This leads to a self-propagating, self-annealing system in which defects in the HAC are mended by intercalation of bone.     

Hydroxyapatite crystals as a local delivery system for cisplatin: adsorption and release of cisplatin in vitro.

This study describes the characteristics of the in vitro binding and release of the anti-tumor drug cisplatin by slurries of synthetic hydroxyapatite crystals carried out in aqueous media. The adsorption of cisplatin by slurries of hydroxyapatite and its release were found to depend significantly on the ionic composition of the aqueous media used. At a constant pH of 7.4, significantly more cisplatin is adsorbed by the hydroxyapatite crystals in the slurry from a chloride-free phosphate buffered solution or a Tris buffered solution than from a buffered phosphate solution containing chloride ions. The amount of hydroxyapatite-bound cisplatin desorbed into solution was also progressively increased as a function of the increasing concentration of chloride in the equilibrating solution. Very little hydroxyapatite-bound cisplatin was released from the crystals in either a Tris or phosphate buffer. These results suggest that it is the hydrated derivatives of cisplatin which are involved in the adsorption of cisplatin by hydroxyapatite crystals. The adsorption data can be expressed as a Freundlich isotherm from which the association constant can be calculated. The rate of release of cisplatin bound to crystals of hydroxyapatite is relatively slow even at the maximum concentration of chloride ions in the phosphate buffer. Approximately 33% of the total cisplatin bound to the crystals of hydroxyapatite was released after 4.25 days. An additional 15% of the remaining cisplatin bound to the hydroxyapatite cyrstals was released after an additional equilibration with fresh buffer for two weeks (58% of the total cisplatin originally bound). These findings suggest that cisplatin bound to slurries of hydroxyapatite crystals may be useful in the local treatment of malignant tumors.     

Development of a biodegradable antibiotic delivery system.

Antibiotic beads have been used as a drug delivery system for the treatment of various surgical infections. In this study, the copolymer 50:50 poly(DL-lactide):co-glycolide was mixed with vancomycin powder and hot compressing molded at 55 degrees C to form five types of biodegradable antibiotic beads. The beads were placed in 1 mL of phosphate buffered saline and incubated at 37 degrees C. The phosphate buffered saline was changed daily, and the removed buffer solutions were stored at -70 degrees C until the antibiotic concentration in each sample was determined by high performance liquid chromatography system assay. The concentration of vancomycin in each sample was well above the breakpoint sensitivity concentration (the antibiotic concentration at the transition point between bacterial killing and resistance to the antibiotic) for more than 32 days. The release was most marked during the first 48 hours. All copolymer 50:50 poly(DI lactide):co-glycolide biodegradable beads released high concentrations of the antibiotics in vitro for the time needed to treat bone infections (4 to 6 weeks). The diameter of the sample inhibition zone ranged from 6.5 mm to 10 mm, and the relative activity of vancomycin ranged from 12.5% to 100%. Copolymers with low heat of formation temperatures are required for making a controlled release system to prevent antibiotic decomposition, which occurs when using the hot compressing molded method. The rate and duration of release from the antibiotic beads can be adjusted by varying the diameter of the beads. This offers a convenient method to adjust the release rate to meet the specific antibiotic requirements for different patients.     

The possible use of coralline hydroxyapatite as a bone implant.

Hydroxyapatite developed from sea coral has been utilized as a bone implant. The primary application at this time is in maxillofacial surgery along with experimental use in orthopedic surgery. The acceptance of this implant in bone and by the body has been found to be excellent without signs of rejection or increase in the incidence of infection. Advantages of this material over autogenous and allogenic bone grafts will be discussed along with its potential application to podiatric surgery.     

A biodegradable delivery system for antibiotics and recombinant human bone morphogenetic protein-2: A potential treatment for infected bone defects.

To produce an osteogenic and bacteriocidal biomaterial for the treatment of infected nonunions or bone defects, a synthetic degradable block copolymer of poly-D,L-lactic acid segments with randomly inserted p-dioxanone and polyethylene glycol (PLA-DX-PEG) segments was mixed with recombinant human BMP-2 (rhBMP-2) and antibiotics at high concentration. We then examined the in vitro elution profile of an antibiotic (teicoplanin) from the polymer, the effects of antibiotics on the bone-inducing capacity of rhBMP-2 or on ectopic new bone formation induced by the rhBMP, and the ability of the polymer to repair bone in a rat cranial defect model. Approximately 40% of teicoplanin was released within the first 24 h, with the remaining amount released steadily over 21 days with no loss of antibacterial activity. The polymer had disappeared by degradation in the phosphate buffered saline (pH 7.4) at the end of the incubation period. The in vivo performance of pellets with antibiotics and rhBMP-2 revealed no significant change in bone yield within the ossicles after 3 weeks. Also, antibiotics had no inhibitory effect on the ability of rhBMP2 to repair cranial defects. Indeed, when the defect was filled by a polymer disc loaded with rhBMP-2 with or without teicoplanin, the defect was repaired by new bone, and normal anatomy was restored within 6 weeks. In conclusion, the PLA/DX/PEG polymer appears to work as effectively for antibiotics as it does for rhBMP-2. Additionally, the biological activity of rhBMP-2 was retained irrespective of the presence of antibiotics.     

An alternative aerosol delivery system for amiloride.

BACKGROUND--The advent of novel treatments such as aerosolized amiloride are potentially useful additions to the therapeutic options available for the treatment of cystic fibrosis. Unfortunately, amiloride and other aerosolized drugs such as antibiotics are generally administered via jet nebulisers which are time consuming to use, and thus limit the acceptance and efficacy of these forms of treatment. In vitro experiments were performed in order to determine whether amiloride could be administered in dry powder form using a Turbohaler. METHODS--Amiloride was micronised and loaded into 200 micrograms Turbohalers. The dose delivered per actuation and particle size distribution of the generated aerosol were assessed using a flow of 60 l/min through the Turbohaler. The dose of amiloride delivered was measured by collecting the aerosol on a filter and the quantity of drug was assayed by an ultraviolet spectrophotometric method. The particle size distribution was assessed using a Malvern MasterSizer laser particle sizer and compared with that generated by a commercially available 200 micrograms budesonide Turbohaler. RESULTS--The mean (SD) dose delivered per actuation was 246.3 (40.4) micrograms. The volume median diameter of the amiloride aerosol was 3.80 (0.68) micron compared with 3.07 (1.47) microns for budesonide. CONCLUSIONS--These results suggest that therapeutic doses of micronised amiloride could be delivered effectively and conveniently as a dry powder aerosol using a Turbohaler.     

A bioabsorbable delivery system for antibiotic treatment of osteomyelitis. The use of lactic acid oligomer as a carrier

We prepared a composite of D,L-lactic acid oligomer and dideoxykanamycin B for use as a biodegradable antibiotic delivery system with sustained effect. The composite was implanted in the distal portion of the rabbit femur, and the effective concentration of the antibiotic was measured in the cortex, the cancellous bone, and the bone marrow. In all bone tissues around the implant, the concentration of antibiotic exceeded the minimum inhibitory concentration for the common causative organisms of osteomyelitis for six weeks. Most of the implant material had been absorbed and the bone marrow had been repaired to a nearly normal state within nine weeks of implantation. The implant caused no systemic side effects, and it is likely to prove clinically useful as a drug delivery system for treating chronic osteomyelitis.     

Hydroxyapatite ceramic as a bone substitute

Summary We have used hydroxyapatite ceramic as a bone substitute for grafting in extensive bone replacement. Hydroxyapatite is composed of calcium phosphate and is incorporated into bone as a physiological mineral. It is not antigenic, carcinogenic or osteogenic. The material used in this study differs from other hydroxyapatite ceramics in that it is an interconnected porous system. Between 1981 and 1986 we used this material on forty five occasions in 44 patients. It was combined with autologous cancellous bone graft in 38 cases and used alone in a further seven. It was usually employed to fill defects after removal of bone cysts and for long fusions in patients with scoliosis. It was also used to fill bone defects after trauma, for non-union in the lumbosacral area, for anterior vertebral fusions, in limb sparing operations for malignant bone tumours, and in exchange operations after failed joint endoprostheses. We have not seen incompatibility or rejection of the implanted material. The rate of post-operative infection was higher than usual due to the selection of patients, but did not appear to be connected with the use of hydroxyapatite ceramic. We were able to review 36 patients up to sixty months after operation. The results are encouraging with no difference in progress compared with patients in whom simple autologous bone grafts had been used.

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Résumé Présentation des possibilités d'utilisation d'une céramique synthétique à base d'hydroxyapatite pour remplacement osseux en orthopédie. Ce matériau est une céramique de phosphate de calcium inactive sur le plan antigènique, ni cancérigène, ni ostéogène, qui, en raison de ses propriétés biodynamiques est intégrée à l'os de façon physiologique. Elle diffère des autres céramiques poreuses à base d'hydroxyapatite par son système poreux interconnecté. Cette céramique a été implantée dans notre clinique 45 fois sur 44 malades, entre 1981 et 1986. Dans 38 cas l'implantation a été effectuée en combinaison avec une greffe osseuse autologue, dans 7 cas le matériau a été utilisé seul. Les indications principales ont été les pertes de substance osseuse après résection de kystes bénins et les arthrodèses étendues pour scoliose. Le matériau a été aussi utilisé pour des défects osseux traumatiques, des pseudarthroses lombo-sacrées, des arthrodèses vertébrales antérieures, des résections avec conservation des extrémités lors de tumeurs malignes, des changements de prothèses ainsi que pour combler des pertes de substance après prise de greffe. On n'a dans aucun cas remarqué d'incompatibilité ou de rejet de la céramique implantée. Le pourcentage d'infection post-opératoire a été de 8,9% (4 cas), sans corrélation apparente avec l'utilisation de cette céramique. L'examen de 36 malades après implantation de céramique à l'hydroxyapatite avec un recul atteignant 60 mois, a montré des résultats tout à fait satisfaisants. Il ne semble pas y avoir de différence avec les patients chez qui on a utilisé des greffes autologues simples.

     

Squeaking as a cause for revision of a composite ceramic cup

Squeaking in total hip arthroplasty (THA) has been observed only in hard-on-hard bearings, such as ceramic-on-ceramic or metal-on-metal. We report the case of a patient with a squeaking THA who had undergone multiple femoral head revisions combined with a composite ceramic cup (polyurethane, ceramic). Squeaking started 6 years postoperatively and acetabular revision was necessary to resolve the issue. Secondary deformation of the inlay resulted in clamping of the femoral head and increased friction. This should be considered when assessing and advising patients with squeaking THA when composite ceramic components are involved.