Multifunctional pH sensitive 3D scaffolds for treatment and prevention of bone infection.

Multifunctional-therapeutic three-dimensional (3D) scaffolds have been prepared. These biomaterials are able to destroy the S. aureus bacterial biofilm and to allow bone regeneration at the same time. The present study is focused on the design of pH sensitive 3D hierarchical meso-macroporous 3D scaffolds based on MGHA nanocomposite formed by a mesostructured glassy network with embedded hydroxyapatite nanoparticles, whose mesopores have been loaded with levofloxacin (Levo) as antibacterial agent. These 3D platforms exhibit controlled and pH-dependent Levo release, sustained over time at physiological pH (7.4) and notably increased at infection pH (6.7 and 5.5), which is due to the different interaction rate between diverse Levo species and the silica matrix. These 3D systems are able to inhibit the S. aureus growth and to destroy the bacterial biofilm without cytotoxic effects on human osteoblasts and allowing an adequate colonization and differentiation of preosteoblastic cells on their surface. These findings suggest promising applications of these hierarchical MGHA nanocomposite 3D scaffolds for the treatment and prevention of bone infection. STATEMENT OF SIGNIFICANCE: Multifunctional 3D nanocomposite scaffolds with the ability for loading and sustained delivery of an antimicrobial agent, to eliminate and prevent bone infection and at the same time to contribute to bone regeneration process without cytotoxic effects on the surrounding tissue has been proposed. These 3D scaffolds exhibit a sustained levofloxacin delivery at physiological pH (pH 7.4), which increasing notably when pH decreases to characteristic values of bone infection process (pH 6.7 and pH 5.5). In vitro competitive assays between preosteoblastic and bacteria onto the 3D scaffold surface demonstrated an adequate osteoblast colonization in entire scaffold surface together with the ability to eliminate bacteria contamination.

Mesoporous silica nanoparticles as a new carrier methodology in the controlled release of the active components in a polypill.

Polypill is a medication designed for preventing heart attacks through a combination of drugs. Current formulations contain blood pressure-lowering drugs and others, such statins or acetylsalicylic acid. These drugs exhibit different physical chemical features, and consequently different release kinetics. Therefore, the concentration in plasma of some of them after the release process can be out of the therapeutic range. This paper investigates a new methodology for the control dosage of a polypill recently reported containing hydrochlorothiazide, amlodipine, losartan and simvastatin in a 12.5/2.5/25/40 weight ratio. The procedure is based on mesoporous silica nanoparticles (MSN) with MCM-41 structure (MSN-41) used as carrier, aimed to control release of the four drugs included in the polypill. In vitro release data were obtained by HPLC and the curves adjusted with a kinetic model. To explain the release results, a molecular model was built to determine the drug-matrix interactions, and quantum mechanical calculations were performed to obtain the electrostatic properties of each drug. Amlodipine, losartan and simvastatin were released from the polypill-MSN-41 system in a controlled way. This would be a favourable behavior when used clinically because avoid too quick pressure decrease. However, the diuretic hydrochlorothiazide was quickly released from our system in the first minutes, as is needed in hypertensive urgencies. In addition, an increase in the stability of amlodipine and hydrochlorothiazide occurred in the polypill-MSN-41 system. Therefore, the new way of polypill dosage proposed can result in a safer and effective treatment.

Osteostatin-loaded onto mesoporous ceramics improves the early phase of bone regeneration in a rabbit osteopenia model.

Parathyroid hormone-related protein (PTHrP) is an important modulator of bone formation. Recently, we reported that PTHrP (107-111) (osteostatin) coating onto mesoporous ceramics confers osteogenic activity to these materials. Bone repair is dramatically compromised in osteopenia/osteoporosis. Thus, we examined the efficacy of unmodified and organically modified SBA15 ceramics loaded with osteostatin in promoting bone repair in an osteoporotic rabbit model. Osteoporosis was induced in New Zealand rabbits by methylprednisolone administration, and healthy rabbits were used as controls. Tested materials were implanted into a femoral cavitary defect, and animals were sacrificed at 2 weeks post-implantation. At this time, implants were encapsulated by a variable layer of fibrotic tissue with no evidence of inflammation. Similarly to observations in normal rabbits, both types of osteostatin-loaded bioceramics induced tissue regeneration associated with increased staining for PCNA, Runx2, osteopontin, and/or vascular endothelial growth factor in osteoporotic rabbits. Our present findings demonstrate that these osteostatin-bearing bioceramics increase the early repair response not only in normal bone but also in osteoporotic bone after a local injury.

The osteoinductive properties of mesoporous silicate coated with osteostatin in a rabbit femur cavity defect model.

Parathyroid hormone-related protein (PTHrP) is an important regulator of bone formation and remodeling. Our recent findings demonstrate that PTHrP (107-111) (osteostatin) loaded onto silica-based ordered mesoporous SBA15 materials exhibit osteogenic features in osteoblastic cell cultures. We aimed here to elucidate whether these peptide-coated materials might be suitable for promoting bone repair following a cavitary defect in the rabbit femur. Histological examination revealed the absence of significant inflammation or bone resorption within the time of study (4 and 8 weeks) after implantation. At 8 weeks, the peptide-unloaded materials were still separated from the bone marrow by a fibrous cap, which was greatly diminished by the presence of the PTHrP peptide. By using µCT analysis, new bone formation was evident at different distances from the implants, mainly for the latter peptide-loaded biomaterials. This was confirmed by performing immunostaining for different osteoblast markers. Our findings demonstrate that these PTHrP (107-111)-loaded bioceramics significantly improve local bone induction, as compared to that observed with the unloaded material.

Bacterial adherence to SiO2-based multifunctional bioceramics.

The bacterial adherence onto different multifunctional silica-based bioceramics has been evaluated. Staphylococcus aureus and Staphylococcus epidermidis were chosen, as they cause the majority of the implant-related infections in this field. Two SiO2 mesoporous materials (MCM-41, SBA-15), an ordered SiO2-CaO-P2O5 mesoporous glass (OMG), and a biphasic magnetic bioceramic (BMB), were incubated with S. aureus and S. epidermidis for 90 min, and subsequently sonicated to quantify the number of adhered bacteria on each material. It was found that S. aureus and S. epidermidis (10(8) CFU/mL) adhered significantly less to BMB samples when compared to MCM-41, SBA-15, or OMG. However, when the material pores accessible for bacteria in each material were taken into account, the lowest bacterial adherence was found in MCM-41, and the highest in SBA-15. The results show that bacterial adherence is higher on mesoporous bioceramics, although this higher microbial attachment is mainly due to the intergranular porosity and grain size morphology rather than to the mesoporous structure.