ABSTRACT
Mesoporous bioactive glasses (MBGs) in the system SiO2-CaO-P2O5-Ga2O3 have been synthesized by the evaporation induced self-assembly method and subsequent impregnation with Ga cations. Two different compositions have been prepared and the local environment of Ga(III) has been characterized using 29Si, 71Ga and 31P NMR analysis, demonstrating that Ga(III) is efficiently incorporated as both, network former (GaO4 units) and network modifier (GaO6 units). In vitro bioactivity tests evidenced that Ga-containing MBGs retain their capability for nucleation and growth of an apatite-like layer in contact with a simulated body fluid with ion concentrations nearly equal to those of human blood plasma. Finally, in vitro cell culture tests evidenced that Ga incorporation results in a selective effect on osteoblasts and osteoclasts. Indeed, the presence of this element enhances the early differentiation towards osteoblast phenotype while disturbing osteoclastogenesis. Considering these results, Ga-doped MBGs might be proposed as bone substitutes, especially in osteoporosis scenarios. STATEMENT OF SIGNIFCANCE: Osteoporosis is the most prevalent bone disease affecting millions of patients every year. However, there is a lack of bone grafts specifically designed for the treatment of bone defects occurred because of osteoporotic fractures. The consequence is that osteoporotic bone defects are commonly treated with the same biomaterials intended for high quality bone tissue. In this work we have prepared mesoporous bioactive glasses doped with gallium, demonstrating osteoinductive capability by promoting the differentiation of pre-osteoblast toward osteoblasts and partial inhibition of osteoclastogenesis. Through a deep study of the local environment of gallium within the mesoporous matrix, this work shows that gallium release is not required to produce this effect on osteoblasts and osteoclasts. In this sense, the presence of this element at the surface of the mesoporous bioactive glasses would be enough to locally promote bone formation while reducing bone resorption.
Subject(s)
Bone Substitutes , Cell Differentiation/drug effects , Gallium , Glass/chemistry , Osteoblasts/metabolism , Osteoclasts/metabolism , Animals , Bone Substitutes/chemistry , Bone Substitutes/pharmacology , Cell Line , Gallium/chemistry , Gallium/pharmacology , Humans , Mice , Osteoblasts/cytology , Osteoclasts/cytologyABSTRACT
Autologous bone graft is considered as the gold standard in bone reconstructive surgery. However, the quantity of bone available is limited and the harvesting procedure requires a second surgical site resulting in severe complications. Due to these limits, scientists and clinicians have considered alternatives to autologous bone graft. Calcium phosphates (CaPs) biomaterials including biphasic calcium phosphate (BCP) ceramics have proven efficacy in numerous clinical indications. Their specific physico-chemical properties (HA/TCP ratio, dual porosity and subsequent interconnected architecture) control (regulate/condition) the progressive resorption and the bone substitution process. By describing the most significant biological responses reported in the last 30years, we review the main events that made their clinical success. We also discuss about their exciting future applications as osteoconductive scaffold for delivering various bioactive molecules or bone cells in bone tissue engineering and regenerative medicine. STATEMENT OF SIGNIFICANCE: Nowadays, BCPs are definitely considered as the gold standard of bone substitutes in bone reconstructive surgery. Among the numerous clinical studies in literature demonstrating the performance of BCP, Passuti et al. and Randsford et al. studies largely contributed to the emergence of the BCPs. It could be interesting to come back to the main events that made their success and could explain their large adhesion from scientists to clinicians. This paper aims to review the most significant biological responses reported in the last 30years, of these BCP-based materials. We also discuss about their exciting future applications as osteoconductive scaffold for delivering various bioactive molecules or bone cells in bone tissue engineering and regenerative medicine.
Subject(s)
Bone Substitutes/chemistry , Ceramics/chemistry , Hydroxyapatites/chemistry , Animals , Bone Regeneration , Bone Transplantation , Drug Delivery Systems , Humans , Materials Testing , Osseointegration , Porosity , Regenerative Medicine , Tissue Engineering , Tissue Scaffolds/chemistryABSTRACT
Bisphosphonates (BPs) are the preferred class of antiresorptive agents used for the treatment of osteoporosis and bone metastases. Recently, an increasing number of clinical reports concerning osteonecrosis of the jaw and atypical fractures have suggested a link between prolonged use of BPs and these adverse bone events, which are exceptionally difficult to treat. Even though these side effects were mainly observed in patients with metastases, osteoporotic patients might become increasingly affected by these conditions with the increasing use of injectable BPs. Could these severe adverse bone events compromise the use of BPs? The development of these unfavorable conditions as a consequence of oversuppression of bone resorption could raise concern regarding the use of therapeutic strategies involving antiresorptive drugs.
Subject(s)
Bone Neoplasms/drug therapy , Diphosphonates/therapeutic use , Osteoporosis/drug therapy , Animals , Bisphosphonate-Associated Osteonecrosis of the Jaw/epidemiology , Bone Density Conservation Agents/adverse effects , Bone Density Conservation Agents/therapeutic use , Bone Neoplasms/secondary , Diphosphonates/adverse effects , Fractures, Bone/chemically induced , Fractures, Bone/epidemiology , Humans , Osteoporosis/pathology , Severity of Illness IndexABSTRACT
Staphylococcus aureus, a major responsible microorganism of osteomyelitis, represents a challenge to treat because of the poor penetration of antibiotics in bone and increasing minimum inhibitory concentrations (MICs) to glycopeptides. The calcium-deficient apatites (CDA), closer to the biological components found in bone and other calcified tissues, have osteoconductive properties. So, to process severe osseous infections, CDA can be used to deliver in the infectious site antibiotics like linezolid. The acute experimental osteomyelitis due to methicillin-resistant Staphylococcus aureus (MRSA) was induced in rabbit's femurs and surgery mimicking human procedures was performed at day three after inoculation. Animals were randomly assigned to treatment groups: L((IV)) [4-day linezolid IV infusion, human-equivalent dose of 10 mg/kg/12 h], L((CDA50%)) (100 mg CDA with linezolid 500 µg/mg) and L((CDA50%)) + L((IV)). Surviving bacteria were counted in bone marrow (BM) and bone (Bo) at day 3 (before treatment), day 7 (4-day treatment) or day 17 (14-day treatment). L(iv) was effective after a 4-day treatment with a log(10)CFU/g decrease of -2.63 ± 1.92 and -2.17 ± 1.58 in bone marrow and bone, respectively. CDA loaded with linezolid enhance the efficacy of the IV linezolid regimen by more than one log(10)CFU/g.
Subject(s)
Acetamides/administration & dosage , Anti-Bacterial Agents/administration & dosage , Apatites/administration & dosage , Drug Delivery Systems , Methicillin-Resistant Staphylococcus aureus/drug effects , Osteomyelitis/drug therapy , Oxazolidinones/administration & dosage , Staphylococcal Infections/drug therapy , Animals , Bone Marrow/microbiology , Bone and Bones/microbiology , Colony Count, Microbial , Disease Models, Animal , Female , Linezolid , Osteomyelitis/microbiology , Rabbits , Staphylococcal Infections/microbiology , Treatment OutcomeABSTRACT
Gallium (Ga) is a semi-metallic element that displays antitumor, antiresorptive, anti-inflammatory and immunosuppressive properties. Among all these properties, antitumor properties were the most extensively applied and have shown efficacy in treatment of Paget's disease, myeloma and hypercalcemia in cases of malignancy. By contrast, no clinical trials have been conducted in prevention and/or treatment of osteoporosis. In this article I focus on Ga effects on bone tissue and cells, as well as on molecular mechanisms governing Ga internalization into cells. Eventually, the potential of Ga as an antiosteoporotic agent is discussed.
Subject(s)
Bone Density Conservation Agents/pharmacology , Gallium/pharmacology , Animals , Bone Density Conservation Agents/therapeutic use , Gallium/therapeutic use , Humans , Osteoclasts/cytology , Osteoclasts/drug effects , Osteoclasts/physiology , Osteoporosis/drug therapyABSTRACT
There is a growing interest in bone tissue engineering for bone repair after traumatic, surgical or pathological injury, such as osteolytic tumor or osteoporosis. In this regard, calcium phosphate (CaP) bone substitutes have been used extensively as bone-targeting drug-delivery systems. This localized approach improves the osteogenic potential of bone substitutes by delivering bone growth factors, thus extending their biofunctionality to any pathological context, including infection, irradiation, tumor and osteoporosis. This review briefly describes the physical and chemical processes implicated in the preparation of drug-delivering CaPs. It also describes the impact of these processes on the intrinsic properties of CaPs, especially in terms of the drug-release profile. In addition, this review focuses on the potential influence of drugs on the resorption rate of CaPs. Interestingly, by modulating the resorption parameters of CaP biomaterials, it should be possible to control the release of bone-stimulating ions, such as inorganic phosphate, in the vicinity of bone cells. Finally, recent in vitro and in vivo evaluations are extensively reported.
Subject(s)
Bone Substitutes/chemistry , Bone Substitutes/metabolism , Calcium Phosphates/chemistry , Pharmaceutical Preparations/metabolism , Animals , Drug Delivery Systems , HumansABSTRACT
UNLABELLED: We measured bone texture parameters of excised human femurs with a new device (BMA™). We also measured bone mineral density by DXA and investigated the performance of these parameters in the prediction of failure load. Our results suggest that bone texture parameters improve failure load prediction when added to bone mineral density. INTRODUCTION: Bone mineral density (BMD) is a strong determinant of bone strength. However, nearly half of the fractures occur in patients with BMD which does not reach the osteoporotic threshold. In order to assess fracture risk properly, other factors are important to be taken into account such as clinical risk factors as well as macro- and microarchitecture of bone. Bone microarchitecture is usually assessed by high-resolution QCT, but this cannot be applied in routine clinical settings due to irradiation, cost and availability concerns. Texture analysis of bone has shown to be correlated to bone strength. METHODS: We used a new device to get digitized X-rays of 12 excised human femurs in order to measure bone texture parameters in three different regions of interest (ROIs). We investigated the performance of these parameters in the prediction of the failure load using biomechanical tests. Texture parameters measured were the fractal dimension (Hmean), the co-occurrence matrix, and the run length matrix. We also measured bone mineral density by DXA in the same ROIs as well as in standard DXA hip regions. RESULTS: The Spearman correlation coefficient between BMD and texture parameters measured in the same ROIs ranged from -0.05 (nonsignificant (NS)) to 0.57 (p = 0.003). There was no correlation between Hmean and co-occurrence matrix nor Hmean and run length matrix in the same ROI (r = -0.04 to 0.52, NS). Co-occurrence matrix and run length matrix in the same ROI were highly correlated (r = 0.90 to 0.99, p < 0.0001). Univariate analysis with the failure load revealed significant correlation only with BMD results, not texture parameters. Multiple regression analysis showed that the best predictors of failure load were BMD, Hmean, and run length matrix at the femoral neck, as well as age and sex, with an adjusted r (2) = 0.88. Added to femoral neck BMD, Hmean and run length matrix at the femoral neck (without the effect of age and sex) improved failure load prediction (compared to femoral neck BMD alone) from adjusted r (2) = 0.67 to adjusted r (2) = 0.84. CONCLUSION: Our results suggest that bone texture measurement improves failure load prediction when added to BMD.
Subject(s)
Femoral Fractures/physiopathology , Femur/physiopathology , Radiographic Image Interpretation, Computer-Assisted/instrumentation , Absorptiometry, Photon/methods , Aged , Aged, 80 and over , Bone Density/physiology , Female , Femoral Fractures/diagnostic imaging , Femur/diagnostic imaging , Femur Neck/diagnostic imaging , Femur Neck/physiopathology , Hip Fractures/diagnostic imaging , Hip Fractures/physiopathology , Humans , Male , Middle Aged , Predictive Value of Tests , Radiographic Image Interpretation, Computer-Assisted/methods , Stress, Mechanical , Weight-Bearing/physiologyABSTRACT
We had previously reported that gallium (Ga) inhibited both the differentiation and resorbing activity of osteoclasts in a dose-dependent manner. To provide new insights into Ga impact on osteoclastogenesis, we investigated here the molecular mechanisms of Ga action on osteoclastic differentiation of monocytes upon Rankl treatment. We first observed that Ga treatment inhibited the expression of Rankl-induced early differentiation marker genes, while the same treatment performed subsequently did not modify the expression of late differentiation marker genes. Focusing on the early stages of osteoclast differentiation, we observed that Ga considerably disturbed both the initial induction as well as the autoamplification step of Nfatc1 gene. We next demonstrated that Ga strongly up-regulated the expression of Traf6, p62 and Cyld genes, and we observed concomitantly an inhibition of IκB degradation and a blockade of NFκB nuclear translocation, which regulates the initial induction of Nfatc1 gene expression. In addition, Ga inhibited c-Fos gene expression, and subsequently the auto-amplification stage of Nfatc1 gene expression. Lastly, considering calcium signaling, we observed upon Ga treatment an inhibition of calcium-induced Creb phosphorylation, as well as a blockade of gadolinium-induced calcium entry through TRPV-5 calcium channels. We identify for the first time Traf6, p62, Cyld, IκB, NFκB, c-Fos, and the calcium-induced Creb phosphorylation as molecular targets of Ga, this tremendously impacting the expression of the master transcription factor Nfatc1. In addition, our results strongly suggest that the TRPV-5 calcium channel, which is located within the plasma membrane, is a target of Ga action on human osteoclast progenitor cells.
Subject(s)
Gallium/pharmacology , Monocytes/cytology , Monocytes/drug effects , Osteoclasts/cytology , Animals , Calcium Signaling/drug effects , Cell Differentiation/drug effects , Cells, Cultured , Cyclic AMP Response Element-Binding Protein/genetics , Cyclic AMP Response Element-Binding Protein/metabolism , Cytokines/genetics , Cytokines/metabolism , Gene Expression Regulation , Humans , Mice , NFATC Transcription Factors/genetics , NFATC Transcription Factors/metabolism , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism , RANK Ligand/genetics , RANK Ligand/metabolism , Real-Time Polymerase Chain ReactionABSTRACT
In this paper, we report X-ray diffraction investigations as well as Raman and solid-state (31)P and (23)Na magic angle spinning nuclear magnetic resonance (NMR) characterization of three series of calcium orthophosphates. The general formulae of the studied compounds are Ca(10.5-x/2)M(x)(PO(4))(7), where M=K or Na and x=0, 0.25, 0.50, 0.75, 1.0; and Ca(10)K(x)Na(1-x)(PO(4))(7), where x=0, 0.25, 0.5, 0.75, 1.0. These calcium orthophosphates are found to be isostructural with ß-tricalcium phosphate (ß-TCP, Ca(3)(PO(4))(2)) with the substitution of some calcium sites by potassium and/or sodium cations. The unit cell parameters vary continuously with the level of substitution, a characteristic of these solid solutions. The Raman spectra show the different vibrational bands of the phosphate groups PO(4), while the NMR chemical shifts are sensitive to the non-equivalent phosphorus and sodium ions present in these substituted samples. As both Raman and NMR spectroscopies are local probes, they offer tools to distinguish between these different phosphorus and phosphate groups, according to their structural site and local environment, especially the type of cation substituent. A convenient decomposition of the Raman and NMR spectra into Gaussian-Lorentzian components leads us to propose an assignment of the main observed bands of these substituted ß-TCPs.
Subject(s)
Calcium Phosphates/chemistry , Potassium/chemistry , Sodium/chemistry , Magnetic Resonance Spectroscopy , Spectrum Analysis, Raman , X-Ray DiffractionABSTRACT
Calcium phosphate substitutes drug delivery systems are well known substances used in minor bone void-filling to release their therapeutic agent in situ. Few studies associating anaesthetics and analgesics have been performed to date. The aim of this work was to study the association of the analgesic, morphine, and the local anaesthetic, lidocaine, with a calcium deficient apatite matrix. Three types of biomaterials i.e. powders, granules and blocks, were prepared by isostatic compression, wet granulation and a combination of the two, evaluated and compared. The chemical structure of the associated therapeutic agent was studied and the characteristics of the drug delivery systems were appraised in terms of drug release. The integrity of the lidocaine hydrochloride structure, as determined by RMN (1)H, was confirmed regardless of the formulation technique used (isostatic compression or wet granulation). However, analyses of morphine hydrochloride by RMN (1)H revealed slight structural modifications. The association and formulation techniques that were used made it possible to obtain an in vitro release time varying from 1 to 4 days for lidocaine hydrochloride and from 1 to 3 days for morphine hydrochloride.
Subject(s)
Biocompatible Materials/chemistry , Biocompatible Materials/metabolism , Calcium Phosphates/chemistry , Lidocaine/administration & dosage , Morphine/administration & dosage , Anesthetics, Local/administration & dosage , Anesthetics, Local/pharmacokinetics , Chemistry, Pharmaceutical/methods , Compressive Strength/physiology , Drug Carriers/analysis , Drug Carriers/chemistry , Drug Carriers/metabolism , Drug Compounding , Drug Delivery Systems , In Vitro Techniques , Lidocaine/pharmacokinetics , Morphine/pharmacokinetics , Nuclear Magnetic Resonance, Biomolecular , Powders , X-Ray DiffractionABSTRACT
The present study investigates the development of controlled drug delivery devices by association of bisphosphonates (BPs) with calcium-deficient apatite (CDA) to obtain a prolonged drug delivery. In a first part, we studied the microencapsulation of methylene bisphosphonic acid, our model of BPs, in biodegradable PLGA by the double emulsion (w/o/w) solvent evaporation/extraction process. Secondly, we associated BPs, either in a free form or microencapsulated, with calcium phosphate biomaterials. The association of free BPs with CDA was performed by isostatic compression at 80 MPa and we tested the interest of adding a binder, HPMC, in the formulation to reinforce the association. In parallel, microparticles were associated with calcium-deficient apatite, either by simple mixture or by isostatic compression. To compare the different formulations, in vitro dissolution studies were performed. All the formulations tested appear to be efficient to produce BPs loaded biomaterials able to deliver the drug slowly and at a constant rate. The slowest release rate (2.7% in 14 days) was obtained with the blend of microencapsulated BPs with CDA.
Subject(s)
Diphosphonates/metabolism , Drug Delivery Systems , Apatites , Biocompatible Materials/chemistry , Calcium Phosphates/chemistry , Chemistry, Pharmaceutical , Dosage Forms , Drug Administration Routes , Drug Compounding , Lactic Acid , Physiological Phenomena , Polyglycolic Acid , Polylactic Acid-Polyglycolic Acid CopolymerABSTRACT
The antimicrobial activities of calcium-deficient apatite loaded with different concentrations (25, 100, and 500 microg/mg) of vancomycin as a filling biomaterial were evaluated in a methicillin-resistant Staphylococcus aureus (MRSA) rabbit acute osteomyelitis model. Bacterial counts in bone, bone marrow, and joint fluid samples treated with forms of the apatite were compared to those in tissue samples receiving a constant intravenous vancomycin infusion after 4 days. This study demonstrates that using a calcium-deficient apatite loaded with vancomycin dramatically decreases the bacterial counts in bone and marrow.
Subject(s)
Apatites/chemistry , Calcium/chemistry , Methicillin-Resistant Staphylococcus aureus/drug effects , Osteomyelitis/drug therapy , Staphylococcal Infections/drug therapy , Vancomycin/pharmacology , Vancomycin/therapeutic use , Animals , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/therapeutic use , Bone Marrow/microbiology , Bone and Bones/microbiology , Drug Delivery Systems , Female , Osteomyelitis/microbiology , Rabbits , Staphylococcal Infections/microbiology , Vancomycin/administration & dosageABSTRACT
The fixation of an orthopedic implant depends strongly upon its initial stability. Peri-implant bone may resorb shortly after the surgery. This resorption is directly followed by new bone formation and implants fixation strengthening, the so-called secondary fixation. If the initial stability is not reached, the resorption continues and the implant fixation weakens, which leads to implant loosening. Studies with rats and dogs have shown that a solution to prevent peri-implant resorption is to deliver bisphosphonate from the implant surface. The aims of the study were, first, to develop a model of bone remodeling around an implant delivering bisphosphonate, second, to predict the bisphosphonate dose that would induce the maximal peri-implant bone density, and third to verify in vivo that peri-implant bone density is maximal with the calculated dose. The model consists of a bone remodeling equation and a drug diffusion equation. The change in bone density is driven by a mechanical stimulus and a drug stimulus. The drug stimulus function and the other numerical parameters were identified from experimental data. The model predicted that a dose of 0.3 microg of zoledronate on the implant would induce a maximal bone density. Implants with 0.3 microg of zoledronate were then implanted in rat femurs for 3, 6 and 9 weeks. We measured that peri-implant bone density was 4% greater with the calculated dose compared to the dose empirically described as best. The approach presented in this paper could be used in the design and analysis processes of experiments in local delivery of drug such as bisphosphonate.
Subject(s)
Bone Density/physiology , Bone Remodeling/physiology , Diphosphonates/pharmacology , Femur , Imidazoles/pharmacology , Prostheses and Implants , Animals , Bone Density/drug effects , Bone Density Conservation Agents , Bone Remodeling/drug effects , Female , Models, Biological , Rats , Rats, Wistar , Zoledronic AcidABSTRACT
The purpose of this study was to assess the effects of high doses of ionising radiation on the histology and healing of bone in an experimental model of 12 inbred rats. Ten of the rats had external irradiation of a single dose of 30 or 45 Gy on the hind limbs, which is equivalent to 2 or 3 times the routine doses used for treatment in humans. Three weeks later, two bony defects were created on their left sides, and the animals were killed 12 or 18 weeks after irradiation. Decalcified bony specimens were studied with light microscopy for qualitative analysis. Thirty Gy irradiation induced medullar oedema or fibro-oedema and normal or fibrous healing of the defects. Forty-five Gy induced medullar oedema or fibro-oedema and depletion in bone marrow. In addition, pathological healing of the defects was obvious and characterised by oedema, fibrosis, and necrosis. In this study high doses of ionising radiation modified the histology of bone, particularly into fibro-oedema, and delayed healing. This new animal model could be used to evaluate the capacities of tissue-engineered materials to repair bony defects after irradiation and osteoradionecrosis.
Subject(s)
Bone and Bones/radiation effects , Disease Models, Animal , Radiation Dosage , Tissue Engineering , Animals , Bone Diseases/physiopathology , Bone Marrow/pathology , Bone Marrow/radiation effects , Bone Marrow Diseases/etiology , Bone Marrow Diseases/pathology , Bone and Bones/pathology , Edema/etiology , Edema/pathology , Female , Femur/pathology , Femur/radiation effects , Fibrosis , Osteoradionecrosis/etiology , Osteoradionecrosis/pathology , Radiation, Ionizing , Random Allocation , Rats , Rats, Inbred Lew , Tibia/pathology , Tibia/radiation effects , Time Factors , Wound Healing/radiation effectsABSTRACT
Calcium phosphate biomaterials such as calcium deficient apatite (CDA) have been contemplated as carrier for delivery of bisphosphonate in bone tissues. In the present work, we have investigated the in vitro biological properties of Zoledronate-loaded CDA. CDA was loaded with zoledronate according to a previously described coating process. 31P MAS NMR spectra demonstrated the effective loading of zoledronate onto CDA. Using 14C labeled zoledronate, we then demonstrated the in vitro release of zoledronate from CDA. In a first set of experiments, we confirmed that Zoledronate reduced the number of TRAP-, vitronectin receptor-, and F-actin ring-positive cells as well as the resorption activity of osteoclasts obtained from a total rabbit bone cell culture. Interestingly, Zoledronate-loaded CDA and its extractive solutions decreased the osteoclastic resorption. Finally, zoledronate-loaded CDA did not affect the viability and alkaline phosphatase activity of primary osteoblastic cells. These data demonstrate that CDA is effective for loading and release of zoledronate. The released zoledronate inhibited osteoclastic resorption without affecting osteoblasts. Our findings therefore suggest that such a drug delivery system would allow an increase in the efficiency of bisphosphonates by being locally available. Further experiments are now required to evaluate the in vivo antiresorptive activity of this concept.
Subject(s)
Biocompatible Materials/metabolism , Bone Density Conservation Agents/metabolism , Bone Resorption/metabolism , Calcium Phosphates/metabolism , Diphosphonates/metabolism , Imidazoles/metabolism , Osteoclasts/metabolism , Animals , Apatites/chemistry , Biocompatible Materials/chemistry , Calcium Phosphates/chemistry , Cells, Cultured , Drug Carriers/chemistry , Drug Carriers/metabolism , Drug Delivery Systems , Materials Testing , Osteoblasts/cytology , Osteoblasts/metabolism , Osteoclasts/cytology , Rabbits , Zoledronic AcidABSTRACT
It is a clinical challenge to obtain a sufficient orthopaedic implant fixation in weak osteoporotic bone. When the primary implant fixation is poor, micromotions occur at the bone-implant interface, activating osteoclasts, which leads to implant loosening. Bisphosphonate can be used to prevent the osteoclastic response, but when administered systemically its bioavailability is low and the time it takes for the drug to reach the periprosthetic bone may be a limiting factor. Recent data has shown that delivering bisphosphonate locally from the implant surface could be an interesting solution. Local bisphosphonate delivery increased periprosthetic bone density, which leads to a stronger implant fixation, as demonstrated in rats by the increased implant pullout force. The aim of the present study was to verify the positive effect on periprosthetic bone remodelling of local bisphosphonate delivery in an osteoporotic sheep model. Four implants coated with zoledronate and two control implants were inserted in the femoral condyle of ovariectomized sheep for 4 weeks. The bone at the implant surface was 50% higher in the zoledronate-group compared to control group. This effect was significant up to a distance of 400mum from the implant surface. The presented results are similar to what was observed in the osteoporotic rat model, which suggest that the concept of releasing zoledronate locally from the implant to increase the implant fixation is not species specific. The results of this trial study support the claim that local zoledronate could increase the fixation of an implant in weak bone.
Subject(s)
Bone Density Conservation Agents/pharmacology , Bone Density/drug effects , Bone and Bones/drug effects , Diphosphonates/pharmacology , Implants, Experimental , Osteoporosis/drug therapy , Osteoporosis/surgery , Animals , Bone Density/physiology , Bone Density Conservation Agents/therapeutic use , Bone and Bones/metabolism , Bone and Bones/surgery , Diphosphonates/therapeutic use , Disease Models, Animal , Drug Delivery Systems/instrumentation , Drug Delivery Systems/methods , Female , Femur/drug effects , Femur/metabolism , Femur/surgery , Imidazoles/pharmacology , Imidazoles/therapeutic use , Osteoporosis/metabolism , Osteoporosis/physiopathology , Pilot Projects , Sheep , Treatment Outcome , Zoledronic AcidABSTRACT
Interconnection, one of the main structural features of macroporous calcium-phosphate ceramics, contributes to the biological and physicochemical properties of bone substitutes. As no satisfactory method exists for evaluating this feature, analysis was performed to determine the permeability, tortuosity, and equivalent diameter of interconnecting channels, that is the parameters that appear to be representative of the way pores are linked. The testing of two ceramics with similar porosity levels revealed important differences in all three interconnection parameters. One ceramic showed poor permeability, corresponding to a small equivalent diameter for interconnecting channels in conjunction with a high tortuosity factor, while the other displayed high permeability, a large diameter for interconnecting channels, and a low tortuosity factor. The methodology used, which can be applied to the quantification of interconnection in all calcium-phosphate ceramics, constitutes the first step in a complete study of the role of this feature in cellular colonization of the ceramic, matrix dissolution, and drug release from the calcium-phosphate matrix.
Subject(s)
Biocompatible Materials/chemistry , Calcium Phosphates/chemistry , Ceramics/chemistry , Algorithms , Biocompatible Materials/chemical synthesis , Calcium Phosphates/chemical synthesis , Ceramics/chemical synthesis , Diffusion , Iodides/chemistry , Mercury/chemistry , Models, Chemical , Permeability , Porosity , Spectrometry, Mass, Electrospray IonizationABSTRACT
The aim of the present study was to assess the efficacy of a ready-to-use injectable bone substitute on the prevention of alveolar ridge resorption after tooth extraction. Maxillary and mandibular premolars were extracted from 3 Beagle dogs with preservation of alveolar bone. Thereafter, distal sockets were filled with an injectable bone substitute (IBS), obtained by combining a polymer solution and granules of a biphasic calcium phosphate (BCP) ceramic. As a control, the mesial sockets were left unfilled. After a 3 months healing period, specimens were removed and prepared for histomorphometric evaluation with image analysis. Histomorphometric study allowed to measure the mean and the maximal heights of alveolar crest modifications. Results always showed an alveolar bone resorption in unfilled sockets. Resorption in filled maxillary sites was significantly lower than in control sites. Interestingly, an alveolar ridge augmentation was measured in mandibular filled sockets including 30% of newly-formed bone. It was concluded that an injectable bone substitute composed of a polymeric carrier and calcium phosphate can significantly increase alveolar ridge preservation after tooth extraction.
Subject(s)
Alveolar Process/physiology , Bone Resorption/prevention & control , Bone Substitutes/administration & dosage , Tooth Extraction , Wound Healing/physiology , Animals , Bone Resorption/physiopathology , Dogs , InjectionsABSTRACT
Despite total hip replacement (THR) gives generally satisfactory results, the quality of outcome in young patients is markedly decreased compared to the average THR outcome. For this population, pharmacological treatment with bisphosphonate would be beneficial to decrease the peri-implant osteolysis. However, as this population does not necessarily suffer from osteoporosis, a nonsystemic treatment would be preferable. Zoledronate was then grafted to hydroxyapatite (HA) coating of titanium implants. The implants were inserted in rat condyles with various zoledronate concentrations. A positive concentration-dependent effect was observed on the peri-implant bone density and on different histomorphometric parameters. Importantly for the outcome of the implants, the mechanical fixation was increased by the local presence of zoledronate. The obtained results open the way of an easy transformation of currently existing HA-coated implants by grafting bisphosphonate onto the coating in order to increase their service life in the patients.
Subject(s)
Calcium Phosphates/administration & dosage , Diphosphonates/administration & dosage , Imidazoles/administration & dosage , Osseointegration , Animals , Drug Delivery Systems , Female , Microscopy, Electron, Scanning , Prostheses and Implants , Rats , Rats, Wistar , Titanium , Zoledronic AcidABSTRACT
The present study investigates vancomycin microencapsulation in biodegradable PLAGA microparticles. To optimize encapsulation efficiency by the double emulsion (w/o/w) solvent evaporation/extraction process, two parameters were studied: surfactant (Span 80) rate and external aqueous phase saturation. In vitro dissolution studies, laser granulometry and scanning electron microscopy were performed to characterize the microparticles. The best results were obtained by stabilizing the first emulsion with 0.5% Span 80 and saturating the external phase with sodium chloride. Such parameters allowed a 95% drug encapsulation efficiency. This process yielded round microparticles with a mean diameter of approximately 170 microm and presenting a smooth surface without any pores. Moreover, this formulation induces a sustained drug release at a constant rate over a period of 10 days. Such materials could be associated with biphasic calcium phosphate granules to form an antibiotic-loaded injectable bone substitute offering a long-term activity in situ.