Antibiotic delivery from bone-targeted mesoporous silica nanoparticles for the treatment of osteomyelitis caused by methicillin-resistant Staphylococcus aureus.

Osteomyelitis is a hard-to-treat infection of the bone and bone marrow that is mainly caused by Staphylococcus aureus, with an increasing incidence of methicillin-resistant S. aureus (MRSA). Owing to the aggressiveness of these bacteria in colonizing and destroying the bone, systemic antibiotic treatments fail to eradicate the infection. Instead, it normally entails surgery to remove the dead or infected bone. In this work, we report bone-targeted mesoporous silica nanoparticles for the treatment of osteomyelitis. The nanoparticles have been engineered with a functional gelatine/colistin coating able to hamper premature release from the mesopores while effectively disaggregating the bacterial biofilm. Because antibiotic resistance is a global emergency, we have designed two sets of identical nanoparticles, carrying each of them a clinically relevant antibiotic, that have demonstrated to have synergistic effect. The bone-targeted nanoparticles have been thoroughly evaluated in vitro and in vivo, obtaining a notable reduction of the amount of bacteria in the bone in just 24 h after only one dose, and paving the way for localized, nanoparticle-mediated treatment of MRSA-caused osteomyelitis. STATEMENT OF SIGNIFICANCE: In this work, we propose the use of bone-targeted mesoporous silica nanoparticles to address S. aureus-caused osteomyelitis that render synergistic therapeutic effect via multidrug delivery. Because the bacterial biofilm is responsible for an aggressive surgical approach and prolonged antibiotic treatment, the nanoparticles have been functionalized with a functional coating able to both disaggregate the biofilm, hamper premature antibiotic release and protect the intact bone. These engineered nanoparticles are able to effectively target bone tissue both in vitro and in vivo, showing high biocompatibility and elevated antibacterial effect.

Arabic gum plus colistin coated moxifloxacin-loaded nanoparticles for the treatment of bone infection caused by Escherichia coli.

Osteomyelitis is an inflammatory process of bone and bone marrow that may even lead to patient death. Even though this disease is mainly caused by Gram-positive organisms, the proportion of bone infections caused by Gram-negative bacteria, such as Escherichia coli, has significantly increased in recent years. In this work, mesoporous silica nanoparticles have been employed as platform to engineer a nanomedicine able to eradicate E. coli- related bone infections. For that purpose, the nanoparticles have been loaded with moxifloxacin and further functionalized with Arabic gum and colistin (AG+CO-coated MX-loaded MSNs). The nanosystem demonstrated high affinity toward E. coli biofilm matrix, thanks to AG coating, and marked antibacterial effect because of the bactericidal effect of moxifloxacin and the disaggregating effect of colistin. AG+CO-coated MX-loaded MSNs were able to eradicate the infection developed on a trabecular bone in vitro and showed pronounced antibacterial efficacy in vivo against an osteomyelitis provoked by E. coli. Furthermore, AG+CO-coated MX-loaded MSNs were shown to be essentially non-cytotoxic with only slight effect on cell proliferation and mild hepatotoxicity, which might be attributed to the nature of both antibiotics. In view of these results, these nanoparticles may be considered as a promising treatment for bone infections caused by enterobacteria, such as E. coli, and introduce a general strategy against bone infections based on the implementation of antibiotics with different but complementary activity into a single nanocarrier. STATEMENT OF SIGNIFICANCE: In this work, we propose a methodology to address E.coli bone infections by using moxifloxacin-loaded mesoporous silica nanoparticles coated with Arabic gum containing colistin (AG+CO-coated MX-loaded MSNs). The in vitro evaluation of this nanosystem demonstrated high affinity toward E. coli biofilm matrix thanks to the Arabic gum coating, a disaggregating and antibacterial effect of colistin, and a remarkable antibiofilm action because of the bactericidal ability of moxifloxacin and colistin. This anti-E. coli capacity of AG+CO-coated MX-loaded MSNs was brought out in an in vivo rabbit model of osteomyelitis where the nanosystem was able to eradicate more than 90% of the bacterial load within the infected bone.

Beneficial effects of manually assisted chiropractic adjusting instrument in a rabbit model of osteoarthritis.

Osteoarthritis (OA) is a degenerative disease characterized by injury of all joint tissues. Our previous study showed that in experimental osteoporosis, chiropractic manipulation (CM) exerts protective effects on bone. We here assessed whether CM might ameliorate OA by improving subchondral bone sclerosis, cartilage integrity and synovitis. Male New-Zealand rabbits underwent knee surgery to induce OA by anterior cruciate ligament injury. CM was performed using the chiropractic instrument ActivatorV 3 times/week for 8 weeks as follows: force 2 setting was applied to the tibial tubercle of the rabbit right hind limb (TM-OA), whereas the corresponding left hind limb received a false manipulation (FM-OA) consisting of ActivatorV firing in the air and slightly touching the tibial tubercle. After sacrifice, subchondral bone integrity was assessed in the tibiae by microCT and histology. Cartilage damage and synovitis were estimated by Mankin's and Krenn's scores, respectively, and histological techniques. Bone mineral density and content in both cortical and trabecular compartments of subchondral bone decreased in OA rabbits compared to controls, but partially reversed in the TM-OA group. Trabecular bone parameters in the latter group also showed a significant improvement compared to FM-OA group. Moreover RANKL, OPG, ALP and TRAP protein expression in subchondral bone significantly decreased in TM-OA rabbits with respect to FM-OA group. CM was associated with lower Mankin's and Krenn's scores and macrophage infiltrate together with a decreased protein expression of pro-inflammatory, fibrotic and angiogenic factors, in TM-OA rabbits with respect to FM-OA. Our results suggest that CM may mitigate OA progression by improving subchondral bone as well as cartilage and synovial membrane status.

Functionalization of sol-gel coatings with organophosphorus compounds for prosthetic devices.

Sol-gel coatings are proposed as surface treatments for titanium-based materials to promote the osseointegration of prosthetic devices with the host. As precursors of sol-gel synthesis, two silanes were selected: 3-methacryloxypropyltrimethoxy silane and 2 tetramethyl orthosilane. Sol-gel synthesis was functionalized with the addition of two different organophosphorus compounds, namely, tris(trimethylsilyl) phosphite and tris(trimethylsilyl) phosphate. Depending on the organophosphorus compound, phosphorus was incorporated into the sol-gel network by different mechanisms: organophosphate was incorporated following a hydrolysis/polycondensation reaction with the precursors of synthesis (two organopolysiloxanes), whereas organophosphite was introduced into the network through transformation of trivalent phosphorus to pentavalent phosphorus following a Michaelis-Arbuzov reaction and subsequent reaction of hydrolysis/polycondensation. When compared to the control coating, which has good adhesion coating-substrate, only the addition of the organophosphite ensured good adhesion without altering synthesis. The resulting coating modified with organophosphite was subjected to cellular study and the concentration of this compound was varied to reach the highest enhancement of proliferation. It was demonstrated that by increasing the amount of organophosphite cell proliferation increased. Inspection of the surfaces of the coatings revealed that by increasing the quantity of organophosphite, adhesion to the substrate was compromised. Thus, an intermediate quantity of organophosphite was considered the most suitable for application on metallic prosthetic devices.

Chondrocyte enlargement is a marker of osteoarthritis severity.

OBJECTIVE: We aimed to assess whether an increase in chondrocyte size might be a feature of the articular cartilage (AC) hypertrophic-like phenotype both in experimental and in human osteoarthritis (OA). The anatomical location of these enlarged cells in the cartilage layers was also evaluated. METHODS: Experimental OA was carried out in female rabbits alone or in combination with osteoporosis (OPOA). The rabbits were subjected to destabilization knee surgery to develop OA. Osteoporosis was induced with ovariectomy and methylprednisolone administration. Human OA samples obtained from knee replacement surgery were also studied. Cartilage lesions and chondrocyte size were assessed in AC sections. Immunostaining of type-X collagen and metalloproteinase-13 were used as markers of the AC hypertrophic transformation. Both the cell size and the gene expression of type-X collagen were further analyzed in primary murine chondrocyte cultures. RESULTS: Compared to healthy AC, chondrocyte size was increased both in experimental and in human OA, in correlation with the severity of cartilage damage. No differences in chondrocyte size were found between deeper or more superficial regions of AC. In cell cultures, accretion of hypertrophic markers and cell enlargement were found to occur synchronized. CONCLUSIONS: We observed an enhancement in the mean size of chondrocytes at the OA cartilage, which showed correlation with cartilage damage, both in human and in experimental OA. The enlarged chondrocytes were homogeneously distributed throughout the AC. Our results suggest that chondrocyte size could be a reliable measure of disease progression, of potential use in the histopathological assessment of OA cartilage.

[Home versus inpatient therapy for deep venous thrombosis. A cost-comparative analysis]. / Tratamiento domiciliario de la trombosis venosa profunda. Comparación de costes con la hospitalización convencional.

AIMS: To compare the home-care management of deep vein thromboses (DVT) by a Home Care Unit (HCU) respect to conventional inpatient treatment. METHODS: Twenty-one patients with a doppler-ecography diagnosis of DVT were managed by the HCU during 2002. In 7 out 13 a concomitant diagnosis of pulmonary embolism (PE) was made by lung scan. Median age was 81 years, 52% were women and all, except one case, showed severe medical concomitant conditions. All patients received low-weight molecular heparin, followed by oral anticoagulants in 3 patients. No patients died and only one was hospitalized briefly due to a poor thrombosis-related pain control. Costs of this patient were added to those of HCU. A comparison was made between ambulatory and hospitalary costs for EP and DVT. Pharmacological treatment costs were calculated for a 10-days period. RESULTS: The length of inhospital stay was 1 day for HCU vs. 8 days (DVT) and 13 days (EP). There was a estimated cost-saving of 1680 per patient. CONCLUSIONS: The management of DVT in patients with serious conditions, can be accomplished safely and in a cost-saving manner by a Home Care Unit.

Tratamiento domiciliario de la trombosis venosa profunda. Comparación de costes con la hospitalización convencional / Home versus inpatient therapy for deep venous thrombosis. A cost-comparative analysis

Objetivos: Comparar los costes del tratamiento ambulatorio por una Unidad de Hospitalización a Domicilio (HADO) frente a la hospitalización convencional en el tratamiento agudo de la trombosis venosa profunda (TVP) y embolismo pulmonar (EP). Métodos: Durante el año 2002 se trataron 21 pacientes con TVP en la Unidad de HADO. La mediana de edad fue de 81 años, 11 fueron mujeres (52%) y, excepto uno, todos los pacientes presentaban importante comorbilidad. El diagnóstico se realizó en el hospital por ecografía-doppler. En 13 casos se realizó además una gammagrafía pulmonar, objetivándose EP concomitante en 7 pacientes. El tratamiento se realizó mediante heparinas de bajo peso molecular (HBPM) seguidas de anticoagulantes orales en 3 pacientes. No hubo complicaciones excepto un caso que requirió un ingreso breve debido al pobre control sintomático de la TVP y cuyos costes se imputaron a HADO. El estudio comparativo de costes se realizó con respecto a pacientes con TVP (grupo de diagnóstico relacionado, GDR 131) y EP ingresados (GDR: 78). El coste farmacológico para pacientes de HADO se calculó para 10 días. Resultados: La estancia media hospitalaria de los pacientes ingresados fue de 8,1 días en TVP y 13,1 en TEP frente a 1 día en los pacientes en HADO. El ahorro de costes en HADO para el tratamiento agudo fue estimado en 1.680 € por paciente. Conclusiones: El tratamiento ambulatorio mediante una unidad de HADO de pacientes con TVP (y TEP seleccionados) resultó una estrategia segura, eficaz y coste-efectiva

Aims: To compare the home-care management of deep vein thromboses (DVT) by a Home Care Unit (HCU) respect to conventional inpatient treatment. Methods: Twenty-one patients with a doppler-ecography diagnosis of DVT were managed by the HCU during 2002. In 7 out 13 a concomitant diagnosis of pulmonary embolism (PE) was made by lung scan. Median age was 81 years, 52% were women and all, except one case, showed severe medical concomitant conditions. All patients received low-weight molecular heparin, followed by oral anticoagulants in 3 patients. No patients died and only one was hopitalized briefly due to a poor thrombosis-related pain control. Costs of this patient were added to those of HCU. A comparison was made between ambulatory and hospitalary costs for EP and DVT. Pharmacological treatment costs were calculated for a 10-days period. Results: The length of inhospital stay was 1 day for HCU vs. 8 days (DVT) and 13 days (EP). There was a estimated cost-saving of 1680 € per patient. Conclusions: The management of DVT in patients with serious conditions, can be accomplished safely and in a cost–saving manner by a Home Care Unit