骨水泥不同时相负载抗生素

背景：在人工关节置换中,骨水泥与何种抗生素配伍能起到有效预防和治疗置换后感染目前还存在争议。 目的：观察抗生素骨水泥中不同抗生素及不同混合方法对动物体内抗生素释放特性以及骨水泥力学性能的影响。 方法：36只大白兔随机抽签法分为6组,3个实验组在骨水泥固相与液相混合后分别加入2 g硫酸庆大霉素、1 g万古霉素、1.5 g头孢呋辛钠,制成负载抗生素的骨水泥,置于实验兔体内。3个对照组分别在40 g骨水泥固相与液相混合前加入2 g硫酸庆大霉素粉剂、1 g万古霉素粉剂、1.5 g头孢呋辛钠。 结果与结论：3种抗生素在兔体内持续平均释放时间均在31 d以上,骨水泥固相与液相混合后加入抗生素的3组抗生素洗提总量分别高于混合前加入抗生素的3组(P < 0.05),混合后加入万古霉素组的洗提总量高于其他各组(P < 0.05)。各组抗生素骨水泥的力学性能均优于ISO 5833国际标准,组间差异无显著性意义。提示抗生素能有效从骨水泥中释放,骨水泥中加入1.0~2.0 g抗生素不影响骨水泥的机械强度;万古霉素的洗提效果较好;骨水泥固相与液相混合后加入抗生素的混合方法更有利于抗生素的释出。     

The effect of porosity on drug release kinetics from vancomycin microsphere/calcium phosphate cement composites

The influence of porosity on release profiles of antibiotics from calcium phosphate composites was investigated to optimize the duration of treatment. We hypothesized, that by the encapsulation of vancomycin-HCl into biodegradable microspheres prior admixing to calcium phosphate bone cement, the influence of porosity of the cement matrix on vancomycin release could be reduced. Encapsulation of vancomycin into a biodegradable poly(lactic co-glycolic acid) copolymer (PLGA) was performed by spray drying; drug-loaded microparticles were added to calcium phosphate cement (CPC) at different powder to liquid ratios (P/L), resulting in different porosities of the cement composites. The effect of differences in P/L ratio on drug release kinetics was compared for both the direct addition of vancomycin-HCl to the cement liquid and for cement composites modified with vancomycin-HCl-loaded microspheres. Scanning electron microscopy (SEM) was used to visualize surface and cross section morphology of the different composites. Brunauer, Emmett, and Teller-plots (BET) was used to determine the specific surface area and pore size distribution of these matrices. It could be clearly shown, that variations in P/L ratio influenced both the porosity of cement and vancomycin release profiles. Antibiotic activity during release study was successfully measured using an agar diffusion assay. However, vancomycin-HCl encapsulation into PLGA polymer microspheres decreased porosity influence of cement on drug release while maintaining antibiotic activity of the embedded substance.     

In vitro evaluation of antibiotic release from and bacteria growth inhibition by antibiotic-loaded acrylic bone cement spacers

The antibiotic release from and the bacteria growth inhibition by antibiotic-loaded acrylic bone cement hip spacers were studied. The cement used was Palacos R, and it was loaded with either one antibiotic powder (gentamicin, vancomycin, teicoplanin, or synercid) [monoantibiotic case] or two antibiotic powders (gentamicin + vancomycin or gentamicin + teicoplanin) [biantibiotic case] and then tested against Staphylococcus epidermidis, Staphylococcus aureus, Enterococcus faecalis, and methicillin-resistant Staphylococcus aureus (MRSA). Antibiotic elution and bacteria growth were measured every 24 h simultaneously by fluorescence polarization immunoassay and photometrically, respectively. The gentamicin + vancomycin combination achieved the longest growth inhibition on S. epidermidis and MRSA (mean of 20 and 14 days, respectively). Gentamicin + teicoplanin-loaded spacers were capable of inhibiting growth on E. faecalis and S. aureus for the longest period (11 and 16 days, respectively). The highest concentrations of gentamicin and vancomycin could be assayed during the first 4 days. Teicoplanin concentrations could be detected only during the first 72 h, synercid was not detected at all, possibly because of the limitation of the detection technique used. A greater percentage of the gentamicin was released than of the vancomycin. The aminoglycosid-glycopeptid combination showed a synergistic effect on the release of gentamicin, but not on vancomycin or teicoplanin. Biantibiotic-impregnated hip spacers proved to be superior to monoantibiotic ones. Because of important differences between the conditions used for the present tests and the in vivo environment, any recommendation with regard to the use of monoantibiotic- and biantibiotic-loaded acrylic bone cement spacers must await the results of further investigations.     

Development of a biodegradable bone cement for craniofacial applications

This study investigated the formulation of a two-component biodegradable bone cement comprising the unsaturated linear polyester macromer poly(propylene fumarate) (PPF) and crosslinked PPF microparticles for use in craniofacial bone repair applications. A full factorial design was employed to evaluate the effects of formulation parameters such as particle weight percentage, particle size, and accelerator concentration on the setting and mechanical properties of crosslinked composites. It was found that the addition of crosslinked microparticles to PPF macromer significantly reduced the temperature rise upon crosslinking from 100.3°C ± 21.6°C to 102.7°C ± 49.3°C for formulations without microparticles to 28.0°C ± 2.0°C to 65.3°C ± 17.5°C for formulations with microparticles. The main effects of increasing the particle weight percentage from 25 to 50% were to significantly increase the compressive modulus by 37.7 ± 16.3 MPa, increase the compressive strength by 2.2 ± 0.5 MPa, decrease the maximum temperature by 9.5°C ± 3.7°C, and increase the setting time by 0.7 ± 0.3 min. Additionally, the main effects of increasing the particle size range from 0-150 μm to 150-300 μm were to significantly increase the compressive modulus by 31.2 ± 16.3 MPa and the compressive strength by 1.3 ± 0.5 MPa. However, the particle size range did not have a significant effect on the maximum temperature and setting time. Overall, the composites tested in this study were found to have properties suitable for further consideration in craniofacial bone repair applications.     

New bioactive glass-ceramic: synthesis and application in PMMA bone cement composites

In present study, a new composition of glass-ceramic was synthesized based on the Na2O-CaO-SiO2-P2O5 glass system. Heat treatment of glass powder was carried out in 2 stages: 600 °C as the nucleation temperature and different temperature on crystallization at 850, 950 and 1000 °C. The glass-ceramic heat-treated at 950 °C was selected as bioactive filler in commercial PMMA bone cement; (PALACOS? LV) due to its ability to form 2 high crystallization phases in comparison with 850 and 1000 °C. The results of this newly glass-ceramic filled PMMA bone cement at 0-16 wt% of filler loading were compared with those of hydroxyapatite (HA). The effect of different filler loading on the setting properties was evaluated. The peak temperature during the polymerization of bone cement decreased when the liquid to powder (L/P) ratio was reduced. The setting time, however, did not show any trend when filler loading was increased. In contrast, dough time was observed to decrease with increased filler loading. Apatite morphology was observed on the surface of the glass-ceramic and selected cement after bioactivity test.     

Pore distribution and material properties of bone cement cured at different temperatures

Implant heating has been advocated as a means to alter the porosity of the bone cement/implant interface; however, little is known about the influence on cement properties. This study investigates the mechanical properties and pore distribution of 10 commercially available cements cured in molds at 20, 37, 40 and 50 °C. Although each cement reacted differently to the curing environments, the most prevalent trend was increased mechanical properties when cured at 50 °C vs. room temperature. Pores were shown to gather near the surface of cooler molds and near the center in warmer molds for all cement brands. Pore size was also influenced. Small pores were more often present in cements cured at cooler temperatures, with higher-temperature molds producing more large pores. The mechanical properties of all cements were above the minimum regulatory standards. This work shows the influence of curing temperature on cement properties and porosity characteristics, and supports the practice of heating cemented implants to influence interfacial porosity.     

In vitro elution characteristics of antibiotic laden BoneSource™, hydroxyapatite bone cement

A calcium phosphate – hydroxyapatite (HA) bone cement was loaded with varying concentrations of tobramycin and vancomycin and the elution properties of these antibiotics were evaluated. Nine groups of antibiotic loaded cement cylinders (N?=?6 in each group) were prepared and placed in saline for 28?days. Elution rates of tobramycin and vancomycin from the HA cement were evaluated at high, medium, and low doses of incorporated antibiotic. Tobramycin elution rates did not vary according to dose (0.36, 0.18, and 0.09g). Vancomycin elution rates were also not significantly affected by dose (0.1?, 0.05?, and 0.025?g). The combination of tobramycin and vancomycin increased the elution rate of vancomycin for the medium and low dose of tobramycin. The dose of tobramycin did not affect its elution rate from the cement in the combined groups. Importantly, the concentration of antibiotic eluent stayed above the minimum inhibitory concentration for the entire 28?days for all groups except the medium and low dose of vancomycin alone. Overall, elution rates of both tobramycin and vancomycin in the calcium phosphate-HA cement were comparable to those from polymethylmethacryltate beads in vitro.     

Properties of an injectable low modulus PMMA bone cement for osteoporotic bone

The use of polymethylmethacrylate (PMMA) cement to reinforce fragile or broken vertebral bodies (vertebroplasty) leads to extensive bone stiffening. Fractures in the adjacent vertebrae may be the consequence of this procedure. PMMA with a reduced Young's modulus may be more suitable. The goal of this study was to produce and characterize stiffness adapted PMMA bone cements. Porous PMMA bone cements were produced by combining PMMA with various volume fractions of an aqueous sodium hyaluronate solution. Porosity, Young's modulus, yield strength, polymerization temperature, setting time, viscosity, injectability, and monomer release of those porous cements were investigated. Samples presented pores with diameters in the range of 25-260 microm and porosity up to 56%. Young's modulus and yield strength decreased from 930 to 50 MPa and from 39 to 1.3 MPa between 0 and 56% porosity, respectively. The polymerization temperature decreased from 68 degrees C (0%, regular cement) to 41 degrees C for cement having 30% aqueous fraction. Setting time decreased from 1020 s (0%, regular cement) to 720 s for the 30% composition. Viscosity of the 30% composition (145 Pa s) was higher than the ones received from regular cement and the 45% composition (100-125 Pa s). The monomer release was in the range of 4-10 mg/mL for all porosities; showing no higher release for the porous materials. The generation of pores using an aqueous gel seems to be a promising method to make the PMMA cement more compliant and lower its mechanical properties to values close to those of cancellous bone.     

Silica sol-gel for the controlled release of antibiotics. I. Synthesis, characterization, and in vitro release

Room temperature processed silica sol-gel (xerogel) was investigated as a novel controlled release carrier of antibiotics (vancomycin). Xerogel characteristics, in vitro release properties, and bactericidal efficacy of the released antibiotic were determined. The xerogel/vancomycin composite showed a long-term sustained release (up to 6 weeks). In addition, bactericidal efficacy of released vancomycin was retained. The kinetics of release and the amount released were dose dependent. The initial, first-order release was followed by a near-zero-order release. The time to transition from the first- to zero-order release increased with vancomycin load (from 2 to 3 weeks with load increase from 2.2 to 11.1 mg/g). Regardless of the load, about 70% of the original vancomycin content was released by the transitional point, and the cumulative release after 6 weeks of immersion was about 90%. This study, combined with other reports documenting biocompatibility and controlled resorbability of the xerogel/drug composite in vivo, suggests that silica xerogel is a promising controlled release material for the treatment of bone infections.     

Theoretical prediction and experimental determination of the effect of mold characteristics on temperature and monomer conversion fraction profiles during polymerization of a PMMA-based bone cement

The present work is concerned with applications of a kinetic model for free-radical polymerization of a polymethylmethacrylate-based bone cement. Autocatalytic behavior at the first part of the reaction as well as a diffusion control phenomenon near vitrification are described by the model. Comparison of theoretical computations with experimental measurements for the temperature evolution during batch casting demonstrated the capacity of the proposed model to represent the kinetic behavior of the polymerization reaction. Temperature evolution and monomer conversion were simulated for the cure of the cement in molds made of different materials. The maximum monomer conversion fraction was markedly influenced by the physical properties of the mold material. The unreacted monomer acts as a plasticizer that influences the mechanical behavior of the cement. Hence, the same cement formulation cured in molds of different materials may result in different mechanical response because of the differences in the amounts of residual monomer. Standardization of the mold type to prepare specimens for the mechanical characterization of bone cements is recommended. Theoretical prediction of temperature evolution during hip replacement indicated that for cement thickness lower than 6 mm the peak temperature at the bone-cement interface was below the limit stated for thermal injury (50 degrees C for more than 1 min). The use of thin cement layers is recommended to diminish the risk of thermal injury; however, it is accompanied by an increase in the amount of unreacted monomer present in the cured material.     

Sustained release of antibiotics from injectable and thermally responsive polypeptide depots

Biodegradable polymeric scaffolds are of interest for delivering antibiotics to local sites of infection in orthopaedic applications, such as bone and diarthrodial joints. The objective of this study was to develop a biodegradable scaffold with ease of drug loading in aqueous solution, while providing for drug depot delivery via syringe injection. Elastin-like polypeptides (ELPs) were used for this application, biopolymers of repeating pentapeptide sequences that were thermally triggered to undergo in situ depot formation at body temperature. ELPs were modified to enable loading with the antibiotics, cefazolin, and vancomycin, followed by induction of the phase transition in vitro. Cefazolin and vancomycin concentrations were monitored, as well as bioactivity of the released antibiotics, to test an ability of the ELP depot to provide for prolonged release of bioactive drugs. Further tests of formulation viscosity were conducted to test suitability as an injectable drug carrier. Results demonstrate sustained release of therapeutic concentrations of bioactive antibiotics by the ELP, with first-order time constants for drug release of approximately 25 h for cefazolin and approximately 500 h for vancomycin. These findings illustrate that an injectable, in situ forming ELP depot can provide for sustained release of antibiotics with an effect that varies across antibiotic formulation. ELPs have important advantages for drug delivery, as they are known to be biocompatible, biodegradable, and elicit no known immune response. These benefits suggest distinct advantages over currently used carriers for antibiotic drug delivery in orthopedic applications.     

Hyperosmolality in the plasma modulates behavioral thermoregulation in mice: the quantitative and multilateral assessment using a new experimental system

We evaluated the effect of plasma hyperosmolality on behavioral thermoregulation in mice, using a new experimental system. The system consisted of Plexiglas box (dimensions: 50×12×19 cm) with five computer-controlled Peltier boards (dimensions: 10×10 cm) at the bottom. Experiments were conducted in two different settings of the system. An operant behavior setting: each board was first set to 39°C, and the right-end board was changed to 20°C for 1 min when a mouse moved to a specific position. A temperature mosaic setting: each board was randomly set to 15°C, 22°C, 28°C, 35°C, or 39°C with a 6-min interval, but each board temperature was different from the others at a given time point. Mice were injected subcutaneous (s.c.) isotonic or hypertonic saline (154 mM (IS group) or 2,500 mM (HS group), 10 ml/kg body wt), and exposed to either setting for 90 min. In the operant setting, the HS group showed fewer operant behavior counts than the IS group (11±5 and 25±4 counts, respectively; P<0.05) with greater increase in body temperature (1.6±0.4°C vs. 0.0±0.2°C, respectively; P<0.05). In the mosaic setting, the HS group selected the board temperature of 35°C more frequently than the other temperatures (P<0.05) with the same increase in body temperature. These results may suggest that plasma hyperosmolality modulates behavioral thermoregulatory response to heat and induce regulated hyperthermia.     

Vancomycin release behaviour from amorphous calcium polyphosphate matrices intended for osteomyelitis treatment

Calcium polyphosphate (CPP) antibiotic delivery matrices were prepared using a unique processing technique involving the exposure of antibiotic-loaded CPP pastes to high humidity for 0, 5, or 24 h. After the designated gelling period, samples were dried for a minimum of 24 h. At several time points out to 130 h, the elution medium was monitored for vancomycin, Ca2+ ion and ortho and poly phosphate release levels. Vancomycin activity was also assessed after 1, 24 and 130 h, while solution 31P-NMR was used to monitor changes in chain length within a 24 hr gelled VCM disc throughout the elution process. The gelling and drying process significantly reduced the rate of vancomycin release during the initial 2-4 h of elution, while extending the effective antibiotic release period by an additional 80 h. The mild conditions associated with matrix fabrication readily allowed for vancomycin incorporation within an environment that did not disrupt antibiotic activity. Throughout the elution process, all sample groups experienced considerable swelling followed by some apparent bulk erosion. Phosphate chain lysis was clearly observed by the end of the elution period. Generally, no strong or consistent correlation existed between matrix degradation and antibiotic release for the treatment groups investigated. An ability to delay antibiotic release using CPPs in conjunction with this protocol supports further investigations into the potential of this matrix as a localized drug delivery system.     

Continuous wave ultrasound enhances vancomycin release and antimicrobial efficacy of antibiotic-loaded acrylic bone cement in vitro and in vivo

Although antibiotic-loaded bone cement (ALBC) is used as a drug delivery vehicle to decrease infection rates, the varied clinical effect of the antibiotic release remains controversial. The objective of this study is to investigate the enhancement of continuous wave ultrasound (CWU) on vancomycin release and antimicrobial efficacy of ALBC in vitro and in vivo. We measured vancomycin concentrations after a 0.5-h exposure of CWU. The results showed that CWU increased the drug elution by 2.57-27.44% when compared with the controls in vitro. Ultrasonic intensity and vancomycin load both had a significant effect on the cumulative drug elution at 10.5 h, with a significant interaction between each other. We also implanted ALBC specimens into hip joints of sixteen New Zealand White female rabbits after inoculations of Staphylococcus aureus around primary implants for 30 days. Vancomycin concentrations in the hip cavity and urinary elimination of vancomycin were both measured after intermittent exposures of CWU. The results showed that CWU increased local Tmax by 47.6 microg/mL and urinary elimination of vancomycin by 109.56 microg, but failed to prolong local T>MIC. On day 30 after the implantation, assessment in clinical performance, radiology, bacteriology, and histology all showed a tendency of decreased bacterial vitality and relieved inflammation in the infected hip treated by CWU. This study suggested that CWU could effectively enhance vancomycin release and antimicrobial efficacy of ALBC, which may be of clinical significance for treating prosthesis-related infections.     

In vitro development and stability of tolerance to cloxacillin and vancomycin inStaphylococcus aureus

The stability of tolerance ofStaphylococcus aureus during subculturing at 37°C and development of this property after repeated exposure to cloxacillin or vancomycin were investigated in vitro. Four of five tolerant strains lost this property during repeated subculturing at 37°C for 50 days. Conversely, tolerance emerged in two of four nontolerant strains after repeated cycles of exposure to 25 µg of cloxacillin/ml or 10 µg of vancomycin/ml alternating with growth in antibiotic-free medium. Previous in vivo exposure to cloxacillin did not enhance the development of tolerance in vitro. MICs of both cloxacillin and vancomycin did not change significantly during this procedure. Whether the conversion of nontolerant strains to the tolerant state can also occur during antibiotic exposure in treatment of patients remains to be determined.     

Effectiveness of hydroxyapatite-vancomycin bone cement in the treatment of Staphylococcus aureus induced chronic osteomyelitis

In the field of local application of antimicrobials, a number of novel drugs and/or new drug delivery systems have been developed in recent years. The present study aimed to investigate hydroxyapatite cement (HAC) as a carrier for vancomycin in the treatment of chronic osteomyelitis due to Staphylococcus aureus strains with various mechanisms of resistance. The release of vancomycin from standard test cylinders was determined in vitro and the efficacy of the delivery system was measured in vivo using a rabbit model of chronic osteomyelitis. First, powdered HAC was mixed with vancomycin at 80, 160 and 240 mg/g. After hardening, formed cylinders were eluted in phosphate buffer and antibiotic release was measured by agar diffusion. High levels of release (1512+/-318 to 1937+/-336 microg/ml) were obtained for 12 to 20 days depending on the dosage of vancomycin. Additionally, bone infection was induced in the tibia of 30 New Zealand white rabbits by injecting either a methicillin-resistant S. aureus strain (MRSA) or a S. aureus strain with a small colony variant (SCV) phenotype. After 3 weeks (chronic infection), all animals were treated by debridement. Moreover, group 1 (challenged with SCVs) and group 2 (challenged with MRSA) were treated by filling the marrow with HAC alone, whereas in groups 3 (SCVs) and 4 (MRSA) the marrow was filled with HAC/vancomycin (160 mg/g). After 6 weeks all animals were sacrificed. At 3 weeks, pathogens were detected in 24 of 30 animals. All swabs of the control groups, positive for S. aureus on day 21, were also positive on day 42 and S. aureus strains recovered were shown to be clonal to the strains used for induction of osteomyelitis. By contrast, no growth was found in the treatment group following 7 days of incubation in BHI bouillon. HAC/vancomycin-treated animals showed no histological evidence of infection on day 42. In the other groups, different stages of chronic osteomyelitis were found histologically. No local or systemic side effects due to HAC or vancomycin were seen. HAC is an effective carrier material for antibiotic compounds even in refractory infections due to MRSA or S. aureus SCVs.     

Influence of lactose addition to gentamicin-loaded acrylic bone cement on the kinetics of release of the antibiotic and the cement properties

The purpose of this study was to characterize a poly(methyl methacrylate) bone cement that was loaded with the antibiotic gentamicin sulphate (GS) and lactose, which served to modulate the release of GS from cement specimens. The release of GS when the cement specimens were immersed in phosphate-buffered saline at 37 °C was determined spectrophotometrically. The microstructure, porosity, density, tensile properties and flexural properties of the cements were determined before and after release of GS. A kinetics model of the release of GS from the cement that involved a coupled mechanism based on dissolution/diffusion processes and an initial burst effect was proposed. Dissolution assay results showed that drug elution was controlled by a diffusion mechanism which can be modulated by lactose addition. Density values and mechanical properties (tensile strength, flexural strength, elastic modulus and fracture toughness) were reduced by the increased porosity resulting from lactose addition, but maintained acceptable values for the structural functions of bone cement. The present results suggest that lactose-modified, gentamicin-loaded acrylic bone cements are potential candidates for use in various orthopaedic and dental applications.     

Characterization of chromosomal damage accumulated in freeze-dried mouse spermatozoa preserved under ambient and heat stress conditions

Structural chromosome aberrations and DNA damage generated in freeze-dried mouse spermatozoa were investigated. Freeze-dried sperm samples were preserved at 4, 25 and 50°C for short duration (1 day to 2 months) and at 25°C for long duration (2 years). The spermatozoa were injected into mouse oocytes to analyse the chromosomes of the zygotes at the first cleavage metaphase. Chromosome break of the chromosome-type aberrations was the most common type of structural chromosome aberrations observed in all freeze-dried samples. The frequency of chromatid exchanges rapidly increased in freeze-dried spermatozoa preserved at 50°C for 1-5 days. The frequency of chromatid-type aberrations (break and exchange) gradually increased in freeze-dried spermatozoa preserved at 25°C for up to 2 months. Alkaline comet assay revealed significant migration of damaged DNA accumulated in freeze-dried spermatozoa preserved at 50°C for 3 days and 25°C for 2 years. However, no DNA damage was detected using the same sperm samples by neutral comet assay, which can detect mostly DNA double-strand breaks in cellular DNA. These results suggest that DNA single-strand breaks were accumulated in freeze-dried spermatozoa preserved under ambient or heat conditions, and then chromatid-type aberrations, especially the chromatid exchanges, were formed via post-replication repair system in zygotes.     

Doxycycline sustained release from brushite cements for the treatment of periodontal diseases

Doxycycline (DOXY) is a wide spectrum antibiotic used in the treatment of dental, periodontal, and bone infections. Brushite cements are calcium phosphate biomaterials especially interesting for bone regeneration processes. In this work, we describe the preparation of a brushite cement containing DOXY and the drug release from the cement. DOXY solutions were mixed with the cement powder and after a 50% burst release in the first 12 h, a slow and controlled release was achieved over 3.5 days. The release of DOXY hyclate was controlled by both, diffusion and Ca(2+) interaction. Formation of DOXY-Ca(2+) chelates was detected in the cement structure using solid state fluorescence. The brushite cement loaded with DOXY hyclate had antibacterial activity against periodontal pathogens: Actinobacillus actinomycetemcomitans, Porphyromonas gingivalis, and Bacteroides frosthytus. This new biomaterial may be helpful for the treatment of periodontal diseases.     

High-strength resorbable brushite bone cement with controlled drug-releasing capabilities

Brushite cements differ from apatite-forming compositions by consuming a lot of water in their setting reaction whereas apatite-forming cements consume little or no water at all. Only such cement systems that consume water during setting can theoretically produce near-zero porosity ceramics. This study aimed to produce such a brushite ceramic and investigated whether near elimination of porosity would prevent a burst release profile of incorporated antibiotics that is common to prior calcium phosphate cement delivery matrices. Through adjustment of the powder technological properties of the powder reactants, that is particle size and particle size distribution, and by adjusting citric acid concentration of the liquid phase to 800mM, a relative porosity of as low as 11% of the brushite cement matrix could be achieved (a 60% reduction compared to previous studies), resulting in a wet unprecompacted compressive strength of 52MPa (representing a more than 100% increase to previously reported results) with a workable setting time of 4.5min of the cement paste. Up to 2wt.% of vancomycin and ciprofloxacin could be incorporated into the cement system without loss of wet compressive strength. It was found that drug release rates could be controlled by the adjustable relative porosity of the cement system and burst release could be minimized and an almost linear release achieved, but the solubility of the antibiotic (vancomycin>ciprofloxacin) appeared also to be a crucial factor.