_{Ion-doped binary SiO2-CaO and ternary SiO2-CaO-P2O5 mesoporous bioactive glasses were synthesized and characterized to evaluate the influence of P2O5 in the glass network structure. Strontium, copper and cobalt oxides in a proportion of 0.8 mol% were selected as dopants because the osteogenic and angiogenic properties reported for these elements. Although the four glass compositions investigated presented analogous textural properties, TEM analysis revealed that the structure of those containing P2O5 exhibited an increased ordered mesoporosity. Furthermore, 29Si NMR revealed that the incorporation of P2O5 increased the network connectivity and that this compound captured the Sr2+, Cu2+ and Co2+ ions preventing themto behave as modifiers of the silica network. In addition, 31P NMR results revealed that the nature of the cation directly influences the  characteristics of the phosphate clusters. In this study, we have proven that phosphorous oxide entraps doping-metallic ions, granting these glasses with a greater mesopores order.}

_{Journal of Non-Crystalline Solids 455 (2017) 90–97}

_{A novel pH-sensitive nanocarrier based on mesoporous silica nanoparticles with self-immolative polymers blocking the pore openings is presented. Triggered release by acid pH is demonstrated, together with their in vitro biocompatibility and effective cell internalisation, which makes this new material a promising candidate for future applications in cancer treatment.}  

_{RSC Advances, 2017, 7, 132–136}

 _{Bone infection is a feared complication following surgery or trauma that remains as an extremely difficult disease to deal with. So far, the outcome of therapy could be improved with the design of 3D implants, which combine the merits of osseous regeneration and local multidrug therapy so as to avoid bacterial growth, drug resistance and the feared side effects. Herein, hierarchical 3D multidrug scaffolds based on nanocomposite bioceramic and polyvinyl alcohol (PVA) prepared by rapid prototyping with an external coating of gelatin-glutaraldehyde (Gel-Glu) have been fabricated. These 3D scaffolds contain hree antimicrobial agents (rifampin, levofloxacin and vancomycin), which have been localized in different compartments of the scaffold to obtain different release kinetics and more effective ombined therapy. Levofloxacin was loaded into the mesopores of nanocomposite bioceramic part, vancomycin was localized into PVA biopolymer part and rifampin was loaded in the external coating of Gel-Glu. The obtained results show an early and fast release of rifampin followed by sustained and prolonged release of vancomycin and levofloxacin, respectively, which are mainly governed by the progressive in vitro degradability rate of these scaffolds. This combined therapy is able to destroy Gram-positive and Gram-negative bacteria biofilms as well as inhibit the bacteria growth. In addition, these multifunctional scaffolds exhibit excellent bioactivity as well as good biocompatibility with complete cell colonization of preosteoblast in the entire surface, ensuring good bone regeneration. These findings suggest that these hierarchical 3D multidrug scaffolds are promising candidates as platforms for local bone infection therapy.}

_{Acta Biomaterialia 49 (2017) 113–126} 

_{The application of nanotechnology to medicine constitutes a major field of research nowadays. In particular, the use of mesoporous silica and carbon nanoparticles has attracted the attention of numerous researchers due to their unique properties, especially when applied to cancer treatment. Many strategies based on stimuli-responsive nanocarriers have been developed to control the drug release and avoid premature release. Here, we focus on the use of the subtle changes of pH between healthy and diseased areas along the body to trigger the release of the cargo. In this review, different approximations of pH-responsive systems are considered: those based on the use of the host-guest interactions between the nanocarriers and the drugs, those based on the hydrolysis of acid-labile bonds and those based on supramolecular structures acting as pore capping agents.}

_{Bioengineering 2017, 4(1), 3}

 _{Nanocarriers have emerged as a powerful alternative for cancer therapy. Indeed, they are promising candidates to tackle the acquired resistance of surviving cells against antiproliferative drugs – the so-called multidrug resistance (MDR) phenomenon – which has arisen as one of the major clinical issues of chemotherapy. Among nanocarriers, this review focuses on the recent approaches based on tailored mesoporous silica nanoparticles (MSNs) that could overcome this problem. Areas covered: Herein we summarize the current efforts developed to provide MSN-based nanosystems of enhanced dual therapeutic action against diseased cells. This can be accomplished by three main approaches: i) increasing nanosystems’ killing capability towards particular cells by enhancing both recognition and specificity; ii) increasing the apoptotic effect throughout co-delivery of several drugs; or iii) combining drug delivery with apoptosis induced by physical methods. Expert opinion: The development of multifunctional nanosystems able to exert the optimal therapeutic action through the minimal administration constitutes a major challenge in nanomedicine. Recent developments in advanced MSN-based platforms for drug delivery represent promising avenues in the management of MDR associated with cancer therapy. All strategies discussed in this manuscript demonstrate improvements against difficult-to-treat tumors.}

_{Expert Opin. Drug Del. 14 (2) 229-243   2017}

 _{The discovery and control of the biological roles mediated by nucleic acids have turned them into a powerful tool for the development of advanced biotechnological materials. Such is the importance of these gene-keeping biomacromolecules that even nanomaterials have succumbed to the claimed benefits of DNA and RNA. Currently, there could be found in the literature a practically intractable number of examples reporting the use of combination of nanoparticles with nucleic acids, so boundaries are demanded. Following this premise, this review will only cover the most recent and powerful strategies developed to exploit the possibilities of nucleic acids as biotechnological materials when in combination with mesoporous silica nanoparticles. The extensive research done on nucleic acids has significantly incremented the technological possibilities for those biomacromolecules, which could be employed in many different applications, where substrate or sequence recognition or modulation of biological pathways due to its coding role in living cells are the most promising. In the present review, the chosen counterpart, mesoporous silica nanoparticles, also with unique properties, became a reference material for drug delivery and biomedical applications due to their high biocompatibility and porous structure suitable for hosting and delivering small molecules. Although most of the reviews dealt with significant advances in the use of nucleic acid and mesoporous silica nanoparticles in biotechnological applications, a rational classification of these new generation hybrid materials is still uncovered. In this review, there will be covered promising strategies for the development of living cell and biological sensors, DNA-based molecular gates with targeting, transfection or silencing properties, which could provide a significant advance in current nanomedicine.}

_{Biomater. Sci., 2017, 5, 353–377}

 _{Osteoporosis is by far the most frequent metabolic disease affecting bone. Current clinical therapeutic treatments are not able to offer long-term solutions. Most of the clinically used antiosteoporotic drugs are administered systemically, which might lead to side effects in non-skeletal tissues. Therefore, to solve these disadvantages, researchers have turned to nanotechnologies and nanomaterials to create innovative and alternative treatments. One of the innovative approaches to enhance osteoporosis therapy and prevent potential adverse effects is the development of bonetargeting drug delivery technologies. It minimizes the systemic toxicity and also improves the pharmacokinetic profile and therapeutic efficacy of chemical drugs. This paper reviews the current available bone targeting drug delivery systems, focusing on nanoparticles, proposed for osteoporosis treatment. Bone targeting delivery systems is still in its infancy, thus, challenges are ahead of us, including the stability and the toxicity issues. Newly developed biomaterials and technologies with potential for safer and more effective drug delivery, require multidisciplinary collaboration between scientists from many different areas, such as chemistry, biology, engineering, medicine, etc, in order to facilitate their clinical applications.}

_{AIMS Bioengineering. 4(2), 259-274    2017}

_{The management of cancer in older aged people is becoming a common problem due to the aging of the population. There are many variables determining the complex situation that are interconnected. Some of them can be assessed, such as risk of mortality and risk of treatment complications, but many others are still unknown, such as the course of disease, the host-related factors that influence cancer aggressiveness, and the phenotype heralding risk of permanent treatment-related damage. This article presents a dynamic and personalized approach to older people with cancer based on our experience on aging, cancer, and their biological interactions. Also, novel treatments and management approaches to older individuals, based on their functional age and their social and emotional needs, are thoughtfully explored here.}

_{The Oncologist 2017;22:1–8}

_{Cancer-associated muscle dysfunction represents a deadly clinical problem, with ca. 80% mortality together with an increased toxicity from cancer treatment. . The normal bone remodeling might be disrupted by tumor cells that metastasize to bone in certain stages of cancer, which results in increased morbidity including muscle weakness. The reason for that muscle weakness might be attributed to the reduction on muscle mass or the reduction of muscle function. In fact, it has been demonstrated that in advanced cancers, it is probably caused by a combination of reductions, quantity and quality of muscle. This review focuses on the mechanisms that bone metastases promote skeletal muscle weakness}

_{(2017) Int J Cancer Oncol 4(1): 1- 5}

 _{The incidence and the mortality of cancer increase with age. This article explores the possibility of decreasing cancerrelated mortality in the aged with secondary prevention of cancer deaths that entails early diagnosis of cancer through the screening of asymptomatic older individuals. We establish that screening of asymptomatic individuals should be based on physiologic rather than chronologic age that may be estimated from a comprehensive geriatric assessment and possibly with the utilization of biologic markers of aging. It is reasonable to offer some form of screening for lung and colorectal cancer to individuals with a life expectancy of at least five years and screening for breast and prostate cancer to women and men respectively with a life expectancy of at least ten years. The ideal number of screening sessions and the ideal interval between screening sessions is unestablished. The aging of the population, the diversity of the older population, the development of new and more sensitive screening interventions, the discovery of new biologic markers of cancer and age represent the main challenges in studying the value of cancer screening in the aged. Probably the most reliable information may be obtained from rapid-learning databases in which information related to each person's physiologic age is included.Scientific Pages}

_{Geriatr Med 2017, 1(1):14-22}

_{The use of nanoparticles with the ability to transport drugs in a selective and controllable manner directly to diseased tissues and cells has improved the therapeutic arsenal for addressing unmet clinical situations. In recent years, a vast number of nanocarriers with inorganic, organic, hybrid and even biological nature have been developed especially for their application in the oncology field. The exponential growth in the field of nanomedicine would not have been possible without the also-rapid expansion of electron microscopy techniques, which allow a more precise observation of nanometric objects. The use of these techniques provides a better understanding of the key parameters which rule the nanoparticles’ synthesis and behavior. In this review, the recent advances made in the application of inorganic nanoparticles to clinical uses and the role which electron microscopy has played are presented.}

_{J. Mater. Chem. B, 2017, 5, 2714--2725}

_{A new platform constituted by engineered responsive nanoparticles transported by human mesenchymal stem cells is here presented as a proof of concept. Ultrasound-responsive mesoporous silica nanoparticles are coated with polyethylenimine to favor their effective uptake by decidua-derived mesenchymal stem cells. The responsive-release ability of the designed nanoparticles is confirmed, both in vial and in vivo. In addition, this capability is maintained inside the cells used as carriers. The migration capacity of the nanoparticle–cell platform towards mammary tumors is assessed in vitro. The efficacy of this platform for anticancer therapy is shown against mammary tumor cells by inducing the release of doxorubicin only when the cell vehicles are exposed to ultrasound.}

_{Nanoscale, 2017, 9, 5528–5537}

 _{Matrix degradation has a major impact on the release kinetics of drug delivery systems. Regarding ordered mesoporous silica materials for biomedical applications, their dissolution is an important parameter that should be taken into consideration. In this paper, we review the main factors that govern the mesoporous silica dissolution in physiological environments. We also provide the necessary knowledge to researchers in the area for tuning the dissolution rate of those matrices, so the degradation could be controlled and the material behaviour optimised.}

_{J. Mater. Sci. (2017) 52:8761-8771}

_{The application of mesoporous bioactive glasses (MBGs) containing controllable amount of different ions, with the aim to impart antibacterial activity, as well as stimulation of osteogenesis and angiogenesis, is attracting an increasing interest. In this contribution, in order to endow nano-sized MBG with additional biological functions, the framework of a binary SiO2-CaO mesoporous glass was modified with different concentrations of copper ions (2 and 5% mol.), through a one-pot ultrasound-assisted sol-gel procedure. The Cu-containing MBG (2% mol.) showed high exposed surface area (550 m2 g
1), uniform mesoporous channels (2.6 nm), remarkable in vitro bioactive behaviour and sustained release of Cu2+ ions. Cu-MBG nanoparticles and their ionic dissolution extracts exhibited antibacterial effect against three different bacteria strains, E. coli, S. aureus, S. epidermidis, and the ability to inhibit and disperse the biofilm produced by S. epidermidis. The obtained results suggest that the developed material, which combines in single multifunctional agent excellent bioactivity and antimicrobial ability, offers promising opportunities for the prevention of infectious diseases and the effective treatment of bone defects.}

_{Acta Biomaterialia 55 (2017) 493–504}

 _{The selective transportation of therapeutic agents to tumoral cells is usually achieved by their conjugation with targeting moieties able to recognize these cells. Unfortunately, simple and static targeting systems usually show a lack in selectivity. Herein, a double sequential encrypted targeting system is proposed as a stimuli-responsive targeting analogue for selectivity enhancement. The system is able to recognize diseased bone tissue in the first place, and once there, a hidden secondary targeting group is activated by the presence of an enzyme overproduced in the malignant tissue (cathepsin K), thereby triggering the recognition of diseased cells. Transporting the cell targeting agent in a hidden conformation that contains a high selective tissular primary targeting, could avoid not only its binding to similar cell receptors but also the apparition of the binding-site barrier effect, which can enhance the penetration of the therapeutic agent within the affected zone. This strategy could be applied not only to conjugate drugs but also to drug-loaded nanocarriers to improve the efficiency for bone cancer treatments.}

_{Chem. Eur. J. 2017, 23, 7174 – 7179}

_{When exposed to body fluids, mesoporous bioactive glasses (MBGs) of the CaO−SiO2−P2O5 system develop a bone-bonding surface layer that initially consists of amorphous calcium phosphate (ACP), which transforms into
hydroxy-carbonate apatite (HCA) with a very similar composition as bone/dentin mineral. Information from various 1H-based solid-state nuclear magnetic resonance (NMR) experiments was combined to elucidate the evolution of the
proton speciations both at the MBG surface and within each ACP/HCA constituent of the biomimetic phosphate layer formed when each of three MBGs with distinct Ca, Si, and P contents was immersed in a simulated body fluid (SBF) for variable periods between 15 min and 30 days. Directly excited magic-angle-spinning (MAS) 1H NMR spectra mainly reflect the MBG component, whose surface is rich in water and silanol (SiOH) moieties. Double-quantum−single-quantum correlation 1H NMR experimentation at fast MAS revealed their interatomic proximities. The comparatively minor H species of each ACP and HCA component were probed selectively by heteronuclear 1H−31P NMR experimentation. The initially prevailing ACP phase comprises H2O and “nonapatitic” HPO42−/PO4 3− groups, whereas for prolonged MBG soaking over days, a well-progressed ACP → HCA transformation was evidenced by a dominating O1H resonance from HCA. We show that 1H-detected 1H → 31P crosspolarization NMR is markedly more sensitive than utilizing powder X-ray diffraction or 31P NMR for detecting the onset of HCA formation, notably so for P-bearing (M)BGs. In relation to the long-standing controversy as to whether bone mineral comprises ACP and/or forms via an ACP precursor, we discuss a recently accepted structural core−shell picture of both synthetic and biological HCA, highlighting the close relationship between the disordered surface layer and ACP.}

_{J. Phys. Chem. C 2017, 121, 13223−13238}

 _{Novel materials, based on Mesoporous Bioactive Glasses (MBGs) in the ternary system SiO2-CaO-P2O5, decorated with (3-aminopropyl)triethoxysilane (APTES) and subsequently with amino acid Lysine (Lys), by post-grafting method on the external surface of the glasses (named MBG-NH2 and MBG-Lys), are reported. The surface functionalization with organic groups did not damage the mesoporous network and their structural and textural properties were also preserved despite the high solubility of MBG atrices. The incorporation of Lys confers a zwitterionic nature to these MBG materials due to the presence of adjacent amine and carboxylic groups in the external surface. At physiologic pH, this coexistence of basic amine and carboxilic acid groups from anchored Lys provided zero surface charge named zwitterionic effect. This behaviour could give rise to potential applications of antibacterial adhesion. Therefore, in order to assess the influence of zwitterionic nature in in vitro bacterial adhesion, studies were carried out with  taphylococcus aureus. It was demonstrated that the efficient interaction of these zwitterionic pairs onto the MBG surfaces reduced bacterial adhesion up to 99.9% compared to bare MBGs. In order to test the suitability of zwitterionic MBGs materials as bone grafts, their cytocompatibility was investigated in vitro with MC3T3-E1 preosteoblasts. These findings suggested that the proposed surface functionalization strategy provided MBG materials with notable antibacterial adhesion properties, hence making these materials promising candidates for local bone infection therapy.}

_{Acta Biomaterialia 57 (2017) 472–486}

_{The development of targeted nanocarriers able to be selectively internalized within tumor cells, and therefore to deliver anti-tumor drugs specifically to diseased cells, constitutes one of the most important goals in nano-oncology. Herein, the development of Janus mesoporous silica particles asymmetrically decorated with two targeting moieties, one of them selective for folate membrane cell receptors (folic acid) and the other one able to bind to mitochondria membrane (triphenylphosphine, TPP), is described in order to achieve sequential cell to organelle vectorization. The asymmetric decoration of each side of the particle allows fine control in the targeting attachment process in comparison with the use of symmetric nanocarriers. The presence of folic acid induces a higher increase in particle accumulation inside tumor cells, and once there, these nanocarriers are guided close to mitochondria by the action of the TPP moiety. This strategy can be applied for improving the therapeutic efficacy of current nanomedicines.}

_{ACS Appl. Mater. Interfaces 2017, 9, 26697−26706}

_{Diabetes mellitus (DM) induces bone deterioration, while mechanical stimulation promotes osteocyte-driven bone formation. We aimed to evaluate the interaction of acute exposure (24 h) to high glucose (HG) with both the pro-survival effect conferred to osteocytic MLO-Y4 cells and osteoblastic MC3T3-E1 cells by mechanical stimulation and the interaction of these cells with osteoclast precursor RAW264.7 cells. We found that 24 h of HG (25 mM) preexposure prevented both cell survival and ERK and β-catenin nuclear translocation upon mechanical stimulation by fluid flow (FF) (10 min) in both MLO-Y4 and MC3T3-E1 cells. However, migration of RAW 264.7 cells was inhibited by MLO-Y4 cell-conditioned medium (CM), but not by MC3T3-E1 cell-CM, with HG or FF. This inhibitory effect was associated with consistent changes in VEGF, RANTES, MIP-1α, MIP-1β MCP-1, and GM-CSF in MLO-Y4 cell-CM. RAW264.7 proliferation was inhibited by MLO-Y4CMunder static orHGconditions, but it increased by FF-CM with or without HG. In addition, both FF and HG abrogated the capacity of RAW 264.7 cells to differentiate into osteoclasts, but in a different manner. Thus, HG-CM in static condition allowed formation of osteoclast-like cells, which were unable to resorb hydroxyapatite. In contrast, FF-CM prevented osteoclastogenesis even in HG condition. Moreover, HG did not affect basal RANKL or IL-6 secretion or their inhibition induced by FF in MLO-Y4cells. In conclusion, this in vitro study demonstrates thatHGexerts disparate effects on osteocyte mechanotransduction, and provides a novel mechanism by which DM disturbs skeletal metabolism through altered osteocyte-osteoclast communication.}

_{J Cell Physiol. 2017;232:3611–3621}

 _{This paper proposes a facile strategy for the zwitterionization of bioceramics that is based on the direct incorporation of L-lysine amino acid via the "-amino group onto mesoporous MCM-41 materials. Fourier transform infrared (FTIR) studies of lysine-grafted MCM-41 (MCM-LYS) simultaneously showed bands at 3080 and 1540 cm1 and bands at 1625 and 1415 cm1 corresponding to -NH3+/COO pairs, which demonstrate the incorporation of the amino acid on the material surface keeping its zwitterionic character. Both elemental and thermogravimetric analyses showed that the amount of grafted lysine was 8 wt. % based on the bioceramic total weight. Moreover, MCM-LYS exhibited a reduction of adhesion of S. aureus and E. coli bacteria in 33% and 50%, respectively at physiological pH, as compared with pristine MCM-41. Biofilm studies onto surfaces showed that lysine functionalization elicited a reduction of the area covered by S. aureus biofilm from 42% to only 5% (88%). This research shows a simple and effective approach to chemically modify bioceramics using single amino acids that provides zwitterionic functionality, which is useful to develop new biomaterials that are able to resist bacterial adhesion.}

_{Bioengineering 2017, 4, 80}

_{Titulo:       Handbook of Sol-Gel Science and Technology. 2nd Ed.Capítulo:  Sol-Gel Silica-Based Biomaterials and Bone Tissue Regeneration.Autor:       M. Vallet-Regí, A. Salinas.Editores:   L. Klein, M. Aparicio, Mario, A. JitianuEditorial:  The Springer. 2017, ISBN 978-3-319-32100-4}

_{Titulo:   Handbook of Solid State Chemistry - Volume 4 Nano and Hybrid Materials.Capítulo: Materials for tissue engineeringAutores: M. Vallet-Regí, A.J.  SalinasEditores:  R. Dronskowski, S. Kikkawa, A. SteinEditorial: Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, 2017.   ISBN: 978-3-527-32587-0.}

_{Titulo: Comprehensive Biomaterials II, 2nd EditionAutores: Montserrat Colilla and María Vallet-RegíCapítulo: Ordered Mesoporous Silica Materials.Editor: Paul Ducheyne Kevin Healy Dietmar E. Hutmacher David W. Grainger C. James KirkpatrickEditorial: Elsevier 2017. ISBN- 9780081006917.}

_{Titulo:   Bioactive glasses, 2nd Edition.Capítulo: Use of bioactive glasses as bone substitutes in orthopedics and traumatologyAutores: A.J. Salinas. M. Vallet-Regi, J. Heikkila  Editores:  Heimo YlanenEditorial: Elsevier, 2017. ISBN-978-0-08-100936-9}

 _{A novel singlet-oxygen sensitive drug delivery nanocarrier able to release its cargo after exposure to visible (Vis) light from a common lamp is presented. This nanodevice is based on mesoporous silica nanoparticles (MSN) decorated with porphyrin-caps grafted via reactive oxygen species (ROS)-cleavable linkages.In the presence of Vis light porphyrin-nanocaps produce singlet oxygen molecules that break the sensitive-linker, which triggers pore uncapping and therefore allows the release of the entrapped cargo (topotecan, TOP). This new system takes advantage of the non-toxicity and greater penetration capacity of Vis radiation and a double antitumor effect due to the drug release and the ROS production. In vitrotests with HOS osteosarcoma cancer cells reveal that TOP is able to be released in a controlled fashion inside the tumor cells. This research work constitutes a proof of concept that opens up promising expectations in the search for new alternatives for the treatment of cancer.}

_{Nanoscale, 2017, 9, 15967–15973}

_{Silica mesoporous nanomaterials have been proved to have meaningful application in biotechnology and biomedicine. Particularly, mesoporous bioactive glasses are recently gaining importance thanks to their bone regenerative properties. Moreover, the mesoporous nature of these materials makes them suitable for drug delivery applications, opening new lines in the field of bone therapies. In this work, we have developed innovative nanodevices based on the implementation of adenosine triphosphate (ATP) and e-poly-llysine molecular gates using a mesoporous bioglass as an inorganic support. The systems have been previously proved to work properly with a fluorescence probe and subsequently with an antibiotic (levofloxacin) and an antitumoral drug (doxorubicin). The bioactivity of the preparedmaterials has also been tested, giving promising results. Finally, in vitro cell culture studies have been carried out; demonstrating that this gated devices can provide useful approaches for bone cancer and bone infection treatments.}

_{Acta Biomaterialia 50 (2017) 114–126}

_{Nanotechnology has provided new tools for addressing unmet clinical situations, especially in the oncology field. The development of smart nanocarriers able to deliver chemotherapeutic agents specifically to the diseased cells and to release them in a controlled way has offered a paramount advantage over conventional therapy. Areas covered: Among the different types of nanoparticle that can be employed for this purpose, inorganic porous materials have received significant attention in the last decade due to their unique properties such as high loading capacity, chemical and physical robustness, low toxicity and easy and cheap production in the laboratory. This review discuss the recent advances performed in the application of porous inorganic and metal-organic materials for antitumoral therapy, paying special attention to the application of mesoporous silica, porous silicon and metal-organic nanoparticles. Expert opinion: The use of porous inorganic nanoparticles as drug carriers for cancer therapy has the potential to improve the life expectancy of the patients affected by this disease. However, much work is needed to overcome their drawbacks, which are aggravated by their hard nature, exploiting the advantages offered by highly the ordered pore network of these materials.}

_{Expert Opin. Drug Del. 14, 783-796   2017}

 _{This manuscript reports an effective new alternative for the management of bone infection by the development of an antibiotic nanocarrier able to penetrate bacterial biofilm, thus enhancing antimicrobial effectiveness. This nanosystem, also denoted as “nanoantibiotic”, consists in mesoporous silica nanoparticles (MSNs) loaded with an antimicrobial agent (levofloxacin, LEVO) and externally functionalized with N-(2-aminoethyl)-3-aminopropyltrimethoxysilane (DAMO) as targeting agent. This amine functionalization provides MSNs of positive charges, which improves the affinity towards the negatively charged bacteria wall and biofilm. Physical and chemical properties of the nanoantibiotic were studied using different characterization techniques, including Xray diffraction (XRD), transmission electron microscopy (TEM), N2 adsorption porosimetry, elemental chemical analysis, dynamic light scattering (DLS), zeta ( )-potential and solid-state nuclear magnetic resonance (NMR). “In vial” LEVO release profiles and the in vitro antimicrobial effectiveness of the different released doses were investigated. The efficacy of the nanoantibiotic against a S. aureus biofilm was also determined, showing the practically total destruction of the biofilm due to the high penetration ability of the developed nanosystem. These findings open up promising expectations in the field of bone infection treatment.}

_{Biomed. Glasses 2018; 4:1–12}

_{A novel multifunction al nanodevice based in doxorubicin (DOX)-loaded mesoporous silica nanoparticles (MSNs) as nanoplatforms for the assembly of different building blocks has been developed for bone cancer treatment. These building blocks consists of: i) a polyacrylic acid (PAA) capping layer grafted to MSNs via an acid-cleavable acetal linker, to minimize premature cargo release and provide the nanosystem of pH-responsive drug delivery ability; and ii) a targeting ligand, the plant lectin concanavalin A (ConA), able to selectively recognize, bind and internalize owing to certain cell-surface glycans, such as sialic acids (SA), overexpressed in given tumor cells. This multifunctional nanosystem exhibits a noticeable higher internalization degree into human osteosarcoma cells (HOS), overexpressing SA, compared to healthy preosteoblast cells (MC3T3-E1). Moreover, the results indicate that small DOX loading (2.5 mg mL
1) leads to almost 100% of osteosarcoma cell death in comparison with healthy bone cells, which significantly preserve their viability. Besides, this nanodevice has a cytotoxicity on tumor cells 8-fold higher than that caused by the free drug. These findings demonstrate that the synergistic combination of different building blocks into a unique nanoplatform increases antitumor effectiveness and decreases toxicity towards normal cells. This line of attack opens up new insights in targeted bone cancer therapy.}

_{Acta Biomaterialia 65 (2018) 393–404}

_{This manuscript reviews the recent progress on mesoporous silica nanoparticles as drug delivery systems. Their intrinsic structural, textural and chemical features permit to design versatile multifunctional nanosystems with the capability to target the diseased tissue and release the cargo on demand upon exposition to internal or external stimuli. The degradation rate of these nanocarriers in diverse physiological fluids is overviewed obeying their significance for their potential translation towards clinical applications. To conclude, the balance between the benefits and downsides of this revolutionary nanotechnological tool is also discussed.}

_{Molecules 2018, 23, 47}

_{This work aims to provide an effective and novel solution for the treatment of infection by using nanovehicles loaded with antibiotics capable of penetrating the bacterial wall, thus increasing the antimicrobial effectiveness. These nanosystems, named ‘‘nanoantibiotics”, are composed of mesoporous silica nanoparticles (MSNs), which act as nanocarriers of an antimicrobial agent (levofloxacin, LEVO) localized inside the mesopores. To provide the nanosystem of bacterial membrane interaction capability, a polycationic dendrimer, concretely the poly(propyleneimine) dendrimer of third generation (G3), was covalently grafted to the external surface of the LEVO-loaded MSNs. After physicochemical characterization of this nanoantibiotic, the release kinetics of LEVO and the antimicrobial efficacy of each released dosage were evaluated. Besides, internalization studies of the MSNs functionalized with the G3 dendrimer were carried out, showing a high penetrability throughout Gram-negative bacterial membranes. This work evidences that the synergistic combination of polycationic dendrimers as bacterial membrane permeabilization agents with LEVO-loaded MSNs triggers an efficient antimicrobial effect on Gramnegative bacterial biofilm. These positive results open up very promising expectations for their potential application in new infection therapies.}

_{Acta Biomaterialia 68 (2018) 261–271}

_{Beneficial effects in bone cell growth and antibacterial action are currently attributed to Ga3+ ions. Thus, they can be used to upgrade mesoporous bioactive glasses (MBGs), investigated for tissue engineering, whenever they released therapeutic amounts of gallium ions to the surrounding medium. Three gallium-enriched MBGs with composition (in mol %) xSiO2–yCaO–zP2O5–5Ga2O3, being x = 70, y = 15, z = 10 for Ga_1; x = 80, y = 12, z = 3 for Ga_2; and x = 80, y = 15, z = 0 for Ga_3, were investigated and compared with the gallium-free 80SiO2–15CaO–5P2O5 MBG (B). 29Si and 31P MAS NMR analyses indicated that Ga3+ acts as network modifier in the glass regions with higher polymerization degree and as network former in the zones with high concentration of classical modifiers (Ca2+ ions). Ga_1 and Ga_2 exhibited a quick in vitro bioactive response because they were coated by an apatite-like layer after 1 and 3 days in simulated body fluid. Although we have not conducted biological tests in this paper (cells or bacteria), Ga_1 released high but non-cytotoxic amounts of Ga3+ ions in Todd Hewitt Broth culture medium that were 140 times higher than the IC90 of Pseudomonas aeruginosa bacteria, demonstrating its potential for tissue engineering applications.}

_{Materials 2018, 11, 367}

_{Biomedical application of nanoparticles is largely associated to their fate in biological media which, in turn, is related to their surface properties. Surface functionalization plays a key role in determining biodegradation, cytotoxicity and biodistribution through interactions which may be mediated by the macromolecules occurring in biological media. A typical example is given by several proteins which lead to the formation of coated nanoparticles referred as protein corona. In this work we focus on mesoporous silica nanoparticles which, due to their intrinsic textural features, show potential as carriers for sustained drug release. Mesoporous silica nanoparticles functionalized by different biopolymers such as hyaluronic acid and chitosan were synthesized and characterized through small angle X-rays scattering, thermal analysis, and infrared spectroscopy. Biopolymercoated mesoporous silica nanoparticles were used to investigate the interaction with bovine serum albumin, and to point out the role of different biopolymer coating. Gold-conjugated-bovine serum albumin was used to gain evidence on the occurrence of surface bound proteins enabling direct observation by transmission electron microscopy. Our findings provide insights on how different biopolymers affect the formation of a protein corona around functionalized mesoporous silica nanoparticles.}

_{Chemical Engineering Journal 340 (2018) 42–50}

_{Mesoporous silica nanoparticles (MSNPs) have many potential applications in biomedical fields. However, when MSNPs are exposed to plasma, protein adsorption leads to opsonization and decreases blood circulation time. A new multifunctional nanodevice based on polyethylenimine (PEI) coated core-shell Fe3O4@SiO2 MSNPs with a zwitterionic 2-methacryloyloxyethyl phosphorylcholine (MPC) surface was designed to minimize unspecific protein adhesion. Particle size measurements demonstrated an excellent non-fouling capacity in solutions containing Bovine Serum Albumin (BSA) and Fetal Bovine Serum (FBS) plasma proteins. The system was used in this study to co-deliver two different cargos: siRNA and daunorubicin. Anti-TWIST siRNA plays critical role in modulating knockdown of TWIST and sensitizing cells to chemotherapeutics such as daunorubicin for ovarian cancer therapy. The drug was released in response to externally controlled oscillating magnetic fields (OMF). siRNA (siGFP) silenced expression of green fluorescence protein (GFP) in Ovcar8 cancer cells, demonstrating the incorporation of core shell MSNPs into cells and siGFP delivery. The synergistic effect of the co-release of anti-TWIST-siRNA loaded in the PEI and daunorubicin loaded in NPs’ pores caused increased cytotoxicity in Ovcar8 of up to 50% from both zwitteronic and non-zwitteronic NPs. The system is the first example of silencing by antihttps TWITS-siRNA/daunorubicin co-delivered using zwitterionic core-shell nanoparticles with low-fouling adsorption. This engineered multifunctional approach may provide therapeutic potential for the treatment of currently incurable ovarian cancer.}

_{Chemical Engineering Journal 340 (2018) 114–124}

_{In 2005, our group described for the first time the structural characterization at the atomic scale of bioactive glasses and the influence of the glasses’ nanostructure in their reactivity in simulated body fluids. In that study, two bioactive sol-gel glasses with composition 80%SiO2–20%CaO and 80%SiO2–17%CaO–3%P2O5 (in mol-%) were characterized by High-Resolution Transmission Electron Microscopy (HRTEM). Such characterization revealed unknown features of the glasses’ structure at the local scale that allowed the understanding of their different in vitro behaviors as a  consequence of the presence or absence of P2O5. Since then, the nanostructure of numerous bioactive glasses, including melt-prepared, sol-gel derived, and mesoporous glasses, was investigated by HRTEM, Nuclear Magnetic Resonance (NMR) spectroscopy, Molecular Dynamics (MD) simulations, and other experimental techniques. These studies have shown that although glasses are amorphous solids, a certain type of short distance order, which greatly influences the in vitro and in vivo reactivity, is always present. This paper reviews the most significant advances in the understanding of bioactive glasses that took place in the last years as a result of the growing knowledge of the glasses’ nanostructure.}

_{Materials 2018, 11, 415}

_{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 hierachical MGHA nanocomposite 3D scaffolds for the treatment and prevention of bone infection.}

_{Acta Biomaterialia 65 (2018) 450–461}

_{The use of cells with migratory properties towards different pathological sites holds great promise in the development of future therapeutics [1,2]. Some of these cell types can exert some positive effect on the development of a variety of diseases [3]. Furthermore, these effects could be improved by also transporting some drug of interest within the migrating cells [4]. However, the number of different drugs that can be
introduced within the vehicle cells without compromising their viability or migratory behavior is very low. For this reason, the introduction of drug-loaded nanoparticles appears as an interesting strategy to increase the amount of drug that the cells can carry, allowing us to also ensure the retention of the active molecule inside the cell during its journey in the bloodstream.}

 _{Insights Stem Cells. 4, (1), 1-2 (2018)}

_{A novel smart hierarchical ultrasound-responsive mesoporous silica nanocarrier for cancer therapy is presented here. This dynamic nanosystem has been designed to display different surface characteristics during its journey towards tumor cells. Initially, the anticancer-loaded nanocarriers are shielded with a polyethylene glycol layer. Upon exposure to high frequency ultrasound, the polymer shell detaches from the nanoparticles, exposing a positively charged surface. This favors the internalization in human osteosarcoma cells, where the release of topotecan takes place, drastically enhancing the cytotoxic effect.}

_{Nanoscale, 2018, 10, 6402–6408}

PATENT

_{Inventors (p.o. of signature): María Vallet Regí, Rocio Villegas Díaz, Alejandro Baeza García, Pablo Luis Ortiz Romero, José Luis Pablos Álvarez, Alicia Usategui Corral
Title: Nanocapsules with controlled degradation for sustained collagenase release in clinical applications
Patent No.: EP18382005.9.
Entity: UCM (60%) Foundation for Biomedical Research of the 12 de Octubre Hospital (40%).
Date of publication. 09/01/2018.}

PATENT

_{Inventors (p.o. of signature): María Vallet Regí, Alejandro Baeza García, Gonzálo Villaverde Cantizano, Rafael Castillo Romero, Manuel Ramírez Orellana, Gustavo Melen Frajlich, África González Murillo, Arantzazu Alfranca González
Title: Ligands for enhanced imaging and drug delivery to neuroblastoma cells
Patent No.: EP18382207.1
Entity: UCM (50%) Hospital Infantil Univ. Niño Jesús (37.5%) Hospital Univ. The Princess (12.5%).
Date of publication. 26/03/2018.}

_{In the last two decades, zinc oxide (ZnO) semiconductor Quantum dots (QDs) have been shown to have fantastic luminescent properties, which together with their low-c ost, low-toxicity and biocompatibility have turned these nanomaterials into one of the main candidates for bio-imaging. The discovery of other desirable traits such as their ability to produce destructive reactive oxygen species (ROS), high catalytic efficiency, strong adsorption capability and high isoelectric point, also make them promising nanomaterials for therapeutic and diagnostic functions. Herein, we review the recent progress on the use of ZnO based nanoplatforms in drug delivery and theranostic in several diseases such as bacterial infection and cancer.}

_{Nanomaterials 2018, 8, 268}

_{The high density of the extracellular matrix in solid tumors is an important obstacle to nanocarriers for reaching deep tumor regions and has severely limited the efficacy of administrated nanotherapeutics. The use of proteolytic enzymes prior to nanoparticle administration or directly attached to the nanocarrier surface has been proposed to enhance their penetration, but the low in vivo stability of these macromolecules compromises their efficacy and strongly limits their application. Herein, we have designed a multifunctional nanocarrier able to transport cytotoxic drugs to deep areas of solid tumors and once there, to be engulfed by tumoral cells causing their destruction. This system is based on mesoporous silica nanocarriers encapsulated within supported lipid bilayers (SLBs). The SLB avoids premature release of the housed drug while providing high colloidal stability and an easy to functionalize surface. The tumor penetration property is provided by attachment of engineered polymeric nanocapsules that transport and controllably unveil and release the proteolytic enzymes that in turn digest the extracellular matrix, facilitating the nanocarrier diffusion through the matrix. Additionally, targeting properties were endowed by conjugating an antibody specific to the investigated tumoral cells to enhance binding, internalization, and drug delivery. This multifunctional design improves the therapeutic efficacy of the transported drug as a consequence of its more homogeneous distribution throughout the tumoral tissue.}

_{Chem. Mater. 2018, 30, 112−120}

_{The use of therapeutic proteins plays a fundamental role in the treatment of numerous diseases. The low physico-chemical stability of proteins in physiological conditions put their function at risk in the human body until they reach their target. Moreover, several proteins are unable to cross the cell membrane. All these facts strongly hinder their therapeutic effect. Nanomedicine has emerged as a powerful tool which can provide solutions to solve these limitations and improve the efficacy of treatments based on protein administration. This review discusses the advantages and limitations of different types of strategies employed for protein delivery, such as PEGylation, transport within liposomes or inorganic nanoparticles or their in situ encapsulation.}

_{Molecules 2018, 23, 1008}

_{Mesoporous silica nanoparticles have been reported as suitable drug carriers, but their successful delivery to target tissues following systemic administration remains a challenge. In the present work, ultrasound-induced inertial cavitation was evaluated as a mechanism to promote their extravasation in a flow-through tissue-mimicking agarose phantom. Two different ultrasound frequencies, 0.5 or 1.6 MHz, with pressures in the range 0.5–4 MPa were used to drive cavitation activity which was detected in real time. The optimal ultrasound conditions identified were employed to deliver dye-loaded nanoparticles as a model for drug-loaded nanocarriers, with the level of extravasation evaluated by fluorescence microscopy. The same nanoparticles were then co-injected with submicrometric polymeric cavitation nuclei as a means to promote cavitation activity and decrease the required in-situ acoustic pressure required to attain extravasation. The overall cavitation energy and penetration of the combination was compared to mesoporous silica nanoparticles alone. The results of the present work suggest that combining mesoporous silica nanocarriers and submcrometric cavitation nuclei may help enhance the extravasation of the nanocarrier, thus enabling subsequent sustained drug release to happen from those particles already embedded in the tumour tissue.}

_{Chemical Engineering Journal 340 (2018) 2–8}

_{Self-immolative chemistry is based on the cascade of disassembling reactions triggered by the adequate stimulation and leading to the sequential release of the smaller constituent elements. This review will focus on the possibilities that this type of chemistry offers to nanomedicine research, which is an area where the stimuli responsive behavior is always targeted. There are some examples on the use of self-immolative chemistry for prodrugs or nanoparticles for drug delivery, but there is still an exciting land of opportunities waiting to be explored. This review aims at revising what has been done so far, but, most importantly, it aims at inspiring new research of self-immolative chemistry on nanomedicine.}

_{Chemical Engineering Journal 340 (2018) 24–31}

_{In this study, we present an innovation in the tumor treatment in vivo mediated by magnetic mesoporous silica nanoparticles. This device was built with iron oxide magnetic nanoparticles embedded in a mesoporous silica matrix and coated with an engineered thermoresponsive polymer. The magnetic nanoparticles act as internal heating sources under an alternating magnetic field (AMF) that increase the temperature of the surroundings, provoking the polymer transition and consequently the release of a drug trapped inside the silica pores. By a synergic effect between the intracellular hyperthermia and chemotherapy triggered by AMF application, significant tumor growth inhibition was achieved in 48 h after treatment. Furthermore, the small magnetic loading used in the experiments indicates that the treatment is carried out without a global temperature rise of the tissue, which avoids the problem of the necessity to employ large amounts of magnetic cores, as is common in current magnetic hyperthermia.}

_{ACS Appl. Mater. Interfaces 2018, 10, 12518−12525}

_{The implementation of nanoparticles as nanomedicines requires sophisticated surface modifications to reduce the immune response and enhance recognition abilities. Mesoporous silica nanoparticles present extraordinary host–guest abilities and facile surface functionalization. These two factors make them ideal candidates for the development of novel drug-delivery systems, at the expense of increasing structural complexity. With this idea in mind, a system composed of triggerable and tunable silica nanoparticles was developed for application as drug-delivery nanocarriers. Diels–Alder cycloaddition adducts were chosen as thermal-responsive units that permitted the binding of gold nanocaps able to block the pores and allow the incorporation of targeting fragments. The capping efficiency was tested under different thermal conditions to give outstanding efficiencies within the physiological range and mild temperatures,as well as enhanced release under pulsing heating cycles, which showed the best release profiles.}

_{Chem. Eur. J. 2018, 24, 6992 – 7001}

_{Nanographene oxide (nGO)-mediated hyperthermia has been increasingly investigated as a localized, minimally invasive anticancer therapeutic approach. Near InfraRed (NIR) light irradiation for inducing hyperthermia is particularly attractive, because biological systems mostly lack chromophores that absorb in this spectral window, facilitating the selective heating and destruction of cells which have internalized the NIR absorbingnanomaterials. However, little is known about biological effects accompanying nGO-mediated hyperthermia at cellular and molecular levels. In this work, well-characterized pegylated nGO sheets with a hydrodynamic size of 300 nm were incubated with human Saos-2 osteosarcoma cells for 24 h and their internalization verified by flow cytometry and confocal microscopy. No effect on cell viability was observed after nGO uptake by Saos-2 cells. However, a proliferation delay was observed due to the presence of nGO sheets in the cytoplasm. 1 H NMR metabolomics was employed to screen for changes in the metabolic profile of cells, as this could help to improve understanding of cellular responses to nanomaterials and provide new endpoint markers of effect. Cells internalizing nGO sheets showed noticeable changes in several metabolites compared to control cells, including decreased levels of several amino acids, taurine and creatine and increased levels of phosphocholine and uridine/adenosine nucleotides. After NIR irradiation, cells showed decreases in glutamate and uridine nucleotides, together with increases in glycerophosphocholine and adenosine monophosphate. Overall, this study has shown that the cellular metabolome sensitively responded to nGO exposure and nGO-mediated hyperthermia and that NMR metabolomics is a powerful tool to investigate treatment responses}

_{Materials Science & Engineering C 91 (2018) 340–348}

_{The development of nanomachines able to operate at the nanoscale, performing complex tasks such as drug delivery, precision surgery, or cell detection, constitutes one of the most important challenges in nanotechnology. The principles that rule the nanoscale are completely different from the ones which govern the macroscopic world and, therefore, the collaboration of scientists with expertise in different fields is required for the effective fabrication of these tiny machines. In this review, the most recent advances carried out in the synthesis and application of nanomachines for diagnosis applications will be presented in order to provide a picture of their potential in the detection of important biomolecules or pathogens in a selective and controlled manner.}

_{Int. J. Mol. Sci. 2018, 19, 1579}

_{A mesoporous bioactive glass (MBG) of molar composition 75SiO2-20CaO-5P2O5 (MBG-75S) has been synthetized as a potential bioceramic for bone regeneration purposes. X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), nitrogen adsorption studies and transmission electron microscopy (TEM) demonstrated that MBG-75S possess a highly ordered mesoporous structure with high surface area and porosity, which would explain the high ionic exchange rate (mainly calcium and silicon soluble species) with the surrounded media. MBG-75S showed high biocompatibility in contact with Saos-2 osteoblast-like cells. Concentrations up to 1 mg/ml did not lead to significant alterations on either morphology or cell cycle. Regarding the effects on osteoclasts, MBG-75S allowed the differentiation of RAW-264.7 macrophages into osteoclast-like cells but exhibiting a decreased resorptive activity. These results point out that MBG-75S does not inhibit osteoclastogenesis but reduces the osteoclast boneresorbing capability. Finally, in vitro studies focused on the innate immune response, evidenced that MBG-75S allows the proliferation of macrophages without inducing their polarization towards the M1 pro-inflammatory phenotype. This in vitro behavior is indicative that MBG-75S would just induce the required innate immune response without further inflammatory complications under in vivo conditions. The overall behavior respect to osteoblasts, osteoclasts and macrophages, makes this MBG a very interesting candidate for bone grafting applications in osteoporotic patients.}

_{Journal of Colloid and Interface Science 528 (2018) 309–320}

_{Nanocarriers for cancer therapy have been extensively studied, but there is still some research that must be addressed in order to achieve their safe application. In this field, hyperthermia thermal treatments mediated by the use of responsive nanomaterials are not different, and researchers have carried out many attempts to overcome their drawbacks due to the valuable potential of these techniques. Here, an overview is presented of nanodevices based on magnetic- and photoresponsive nanocrystals that respond to magnetic fields and/or near-infrared stimuli for cancer therapies. Special attention is given to the synergic effect that can be achieved with nanoscale heating in combination with chemotherapy through drug-delivery devices to effectively kill cancer cells. In this way, the nanoparticles act as heating sources or “hot spots,” which can trigger cellular responses in the absence of a global temperature rise, making the tumor cells more sensitive to chemotherapeutics. The fabrication of optical and magnetic drug-delivery devices, the heating mechanisms, and their applications in tumor treatment are also summarized}

_{Small Methods2018, 1800007}

_{Mesoporous silica nanoparticles (MSNs) were functionalized with amino groups (MSN-NH2) and thenwith hyaluronic acid, a biocompatible biopolymer which can be recognized by CD44 receptors in tumorcells, to obtain a targeting drug delivery system. To this purpose, three hyaluronic acid samples differ-ing for the molecular weight, namely HAS(8–15 kDa), HAM(30–50 kDa) and HAL(90–130 kDa), wereused. The MSN-HAS, MSN-HAM, and MSN-HALmaterials were characterized through zeta potential anddynamic light scattering measurements at pH = 7.4 and T = 37◦C to simulate physiological conditions.While zeta potential showed an increasing negative value with the increase of the HA chain length, ananomalous value of the hydrodynamic diameter was observed for MSN-HAL, which was smaller than thatof MSN-HASand MSN-HAMsamples. The cellular uptake of MSN-HA samples on HeLa cells at 37◦C wasstudied by optical and electron microscopy. HA chain length affected significantly the cellular uptakethat occurred at a higher extent for MSN-NH2and MSN-HASthan for MSN-HAMand MSN-HALsamples.Cellular uptake experiments carried out at 4◦C showed that the internalization process was inhibitedfor MSN-HA samples but not for MSN-NH2. This suggests the occurrence of two different mechanismsof internalization. For MSN-NH2the uptake is mainly driven by the attractive electrostatic interactionwith membrane phospholipids, while MSN-HA internalization involves CD44 receptors overexpressedin HeLa cells.}

_{Colloids and Surfaces B: Biointerfaces 168 (2018) 50–59}

_{In this work we present the synthesis, characterization and in vitro biological evaluation of PEGylated and actively-targeted ultrasound-responsive hybrid mesoporous silica nanoparticles. This work covers the development of the chemical strategies necessary to afford a modular nanocarrier starting from a proof-of-concept material presented in previous work. This functional ultrasound-responsive material can be adapted to different specific pathological conditions by carefully choosing the appropriate targeting moieties. The new ultrasound responsive material is able to target HeLa cells when conjugated with biotin or an RGD peptide. Ultrasound-responsive cytotoxicity towards cancer cells of doxorubicin-loaded nanoparticles is demonstrated in an in vitrocytotoxicity assay.}

_{J. Mater. Chem. B, 2018, 6, 2785-2794}

_{Calcium phosphate (CaP) based hybrid materials have been synthesized through a precipitation method in aqueous medium in the presence of the anionic surfactant sodium dodecylbenzene sulfonate (SDBS) as structure directing agent. Parameters of synthesis, such as Ca/P molar ratio, surfactant concentration and initial pH, have been investigated trying to get mesostructured CaP phases. A lamellar-like hybrid mesophase consisting in several wavy layers of apatite or apatitebrushite nanoplates was successfully obtained. Materials have been characterized by several physico-chemical techniques. A potential application of these lamellar calcium phosphate based hybrids can be as matrixes in drug delivery systems with the possibility of loading hydrophobic drugs in the organic interlayers. To evaluate their potential as biomaterials, the biocompatibility of two hybrids has been studied in vitro with human Saos-2 osteoblasts. Cell assays showed that, upon the appropriate synthesis and stabilization conditions, a biocompatible CaP and SDBS mesolamellar hybrid can be prepared.}

_{ChemistrySelect 2018, 3, 6880 – 6891}

_{Fibrosis is a common lesion in different pathologic diseases and defined by the excessive accumulation of collagen. Different approaches have been used to treat different conditions characterized by fibrosis. The FDA and EMA approved the use of collagenase to treat palmar fibromatosis (Dupuytren’s contracture). The EMA approved additionally its use in severe Peyronie’s disease, but it has been used off label in other conditions [1,2]. The approved treatment includes up to three (in palmar fibromatosis) or up to eight (in
penile fibromatosis) injections followed by finger extension or penile modeling procedures, typically causing severe pain. Frequent single injections are adequate to treat palmar fibromatosis [3]. The need to repeatedly inject doses of this enzyme can be due to the labile nature of collagenase, which exhibits a complete activity loss after a short period of time. This study presents a novel strategy to manage this enzyme based on the synthesis of polymeric nanocapsules that contain collagenase encapsulated within their matrix. These nanocapsules have been engineered for achieving a gradual release of the encapsulated enzyme for a longer time, which can be up to ten days. The efficacy of these nanocapsules has been tested in a murine model of local dermal fibrosis, and the results demonstrate a reduction in fibrosis greater than that with the injection of free enzyme; this type of treatment showed a significant improvement compared to conventional therapy of free collagenase.}

_{Acta Biomaterialia 74 (2018) 430–438}

_{In the last few years mesoporous silica nanoparticles (MSNs) have gained the attention of the nanomedicine research community, especially for the potential treatment of cancer. Although this topic has been reviewed before, periodic updates on such a hot topic are necessary due to the dynamic character of this field. The reasons that make MSNs so attractive for designing controlled drug delivery systems lie beneath their physico-chemical stability, easy functionalisation, low toxicity and their great loading capacity of many different types of therapeutic agents. The present brief overview tries to cover some of the recent findings on stimuli-responsive mesoporous silica nanocarriers together with the efforts to design targeted nanosystems using that platform. The versatility of those smart nanocarriers has promoted them as very promising candidates to be used in the clinic in the near future to overcome some of the pitfalls of conventional medicine.}

_{Journal of Materials Science: Materials in Medicine (2018) 29:65}

_{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.}

_{Acta Biomaterialia 76 (2018) 333–343}

_{Mesoporous Bioactive Glasses (MBGs) are a family of bioceramics widely investigated for their putative clinical use as scaffolds for bone regeneration. Their outstanding textural properties allow for high bioactivity when compared with other bioactive materials. Moreover, their great pore volumes allow these glasses to be loaded with a wide range of biomolecules to stimulate new bone formation. In this study, an MBG with a composition, in mol%, of 80% SiO2–15% CaO–5% P2O5 (Blank, BL) was compared with two analogous glasses containing 4% and 5% of ZnO (4ZN and 5ZN) before and after impregnation with osteostatin, a C-terminal peptide from a parathyroid hormone-related protein (PTHrP107-111). Zn2+ ions were included in the glass for their bone growth stimulator properties, whereas osteostatin was added for its osteogenic properties. Glasses were characterized, and their cytocompatibility investigated, in pre-osteoblastic MC3T3-E1 cell cultures. The simultaneous additions of osteostatin and Zn2+ions provoked enhanced MC3T3-E1 cell viability and a higher differentiation capacity, compared with either raw BL or MBGs supplemented only with osteostatin or Zn2+. These in vitro results show that osteostatin enhances the osteogenic effect of Zn2+-enriched glasses, suggesting the potential of this combined approach in bone tissue engineering applications.}

_{Nanomaterials 2018, 8, 592}

_{Certain biomaterials are capable of inducing the secretion of Vascular Endothelial Growth Factor (VEGF) from cells exposed to their biochemical influence, which plays a vital role in stimulating angiogenesis. Looking for this capacity, in this study three porous glasses were synthesized and characterized. Glass compositions (in mol-%) were: 60SiO2–(36-2x)CaO–4P2O5–xCuO–xSrO with x=0, 1 or 2.5, respectively, for B60, CuSr-1 or CuSr-2.5 glasses. Cu2+ and Sr2+ ions were added because of the reported biological capabilities of Cu2+ as angiogenic stimulator and Sr2+ as osteogenic stimulator. The objective of this study was to determine the concentration of the glass particles that, being out of the cytotoxic range, could increase VEGF secretion. The viability of cultivated bone marrow stromal cells (ST-2) was assessed. The samples were examined with light microscopy (LM) after the histochemical staining for haematoxylin and eosin (HE). The biological activity of glasses was evaluated in terms of the influence of the Cu2+ and Sr2+ ions on the cells. The dissolution products of CuSr-1 and CuSr-2.5 produced the highest secretion of VEGF from ST-2 cells after 48 h of incubation. The combination of Cu2+ and Sr2+ lays the foundation for engineering a bioactive glass than can lead to vascularized, functional bone tissue when used in bone regeneration applications.}

_{Journal of Non-Crystalline Solids 500 (2018) 217–224}

 _{The poor penetration of drug nanocarriers within tumor tissues is one of the most critical factors which limit their effectiveness. Nanomedicine has developed different strategies in order to overcome this important hurdle. Some of these strategies are based on the degradation of the highly dense extracellular matrix (ECM) which is usually present in many solid tumors. In this sense, one of the most promising approaches consists in the nanoparticle decoration with proteolytic enzymes able to digest the ECM favoring its penetration. Other strategy is based on the capacity of ultrasounds to induce cavitation which propels the nanocarriers to deep areas into the tumor. Both strategies have demonstrated significant improvement in the penetration of nanocarriers in malignant tissues, enhancing their effectivity.}

_{Material Sci & Eng Int J 2018, 2(1): 00028}

 _{We report the use of bis-catecholic polymers as candidates for obtaining effective, tunable gatekeeping coatings for mesoporous silica nanoparticles (MSNs) intended for drug release applications. In monomers, catechol rings act as adhesive moieties and reactive sites for polymerization, together with middle linkers which may be chosen to tune the physicochemical properties of the resulting coating. Stable and low-toxicity coatings (pNDGA and pBHZ) were prepared from two biscatechols of different polarity (NDGA and BHZ) on MSN carriers previously loaded with rhodamine B (RhB) as a model payload, by means of a previously reported synthetic methodology and without any previous surface modification. Coating robustness and payload content were shown to depend significantly on the workup protocol. The release profiles in a model physiological PBS buffer of coated systems (RhB@MSN@pNDGA and RhB@MSN@pBHZ) showed marked differences in the “gatekeeping” behavior of each coating, which correlated qualitatively with the chemical nature of their respective linker moieties. While the uncoated system (RhB@MSN) lost its payload almost completely after 2 days, release from RhB@MSN@pNDGA was virtually negligible, likely due to the low polarity of the parent bis-catechol (NDGA). As opposed to these extremes, RhB@MSN@pBHZ presented the most promising behavior, showing an intermediate release of 50% of the payload in the same period of time.}

_{ACS Appl. Mater. Interfaces 2018, 10, 7661−7669}

_{Mesoporous nanospheres in the system SiO2-CaO (NanoMBGs) with a hollow core surrounded by a radial arrangement  of mesopores were characterized, labeled with FITC (FITC-NanoMBGs) and loaded with ipriflavone (NanoMBG-IPs) in order to evaluate their incorporation and their effects on both osteoblasts and osteoclasts simultaneously and maintaining the communication with each other in coculture. The influence of these nanospheres on macrophage polarization towards pro-inflammatory M1 or reparative M2 phenotypes was also evaluated in basal and stimulated conditions through the expression of CD80 (as M1 marker) and CD206 (as M2 marker) by flow cytometry and confocal microscopy. NanoMBGs did not induce the macrophage polarization towards the M1 pro-inflammatory phenotype, favoring the M2 reparative phenotype and increasing the macrophage response capability against stimuli as LPS and IL-4. NanoMBG-IPs induced a significant decrease of osteoclast proliferation and resorption activity after 7 days in coculture with osteoblasts, without affecting osteoblast proliferation and viability. Drug release test demonstrated that only a fraction of the payload is released by diffusion, whereas the rest of the drug remains within the hollow core after 7 days, thus ensuring the local long-term pharmacological treatment beyond the initial fast IP release. All these data ensure an appropriate immune response to these nanospheres and the potential application of NanoMBG-IPs as local drug delivery system in osteoporotic patients.}

_{European Journal of Pharmaceutics and Biopharmaceutics 133 (2018) 258–268}

_{Despite the claim that encapsulation of drugs improves the therapeutic profile of free drugs, there are still important limitations in drug delivery. With respect to cancer treatment, two promising implementations are combination therapy and targeted devices, which are aimed at increasing the drug effect either by achieving higher cell death rates or by discriminating between cell populations. However, for the time being, the scope of combining both approaches is unknown. To advance this knowledge, a two-drug-delivery system with dual cell-organelle targeting based on mesoporous silica nanoparticles, which are known to be able to host drugs within their pores, has been designed. In vitro results show a synergistic effect and high efficacy, demonstrating that the combination of dual therapy and targeting could still advance the development of drug-delivery nanodevices against difficult-to-treat cancers.}

_{Bioconjugate Chem. 2018, 29, 3677−3685}

_{Zwitterionization of biomaterials has been heightened to a potent tool to develop biocompatible materials that are able to inhibit bacterial and non-specific proteins adhesion. This constitutes a major progress in the biomedical field. This manuscript overviews the main functionalization strategies that have been reported up to date to design and develop these advanced biomaterials. On this regard, the recent research efforts that were dedicated to provide their surface of zwitterionic nature are summarized by classifying biomaterials in two main groups. First, we centre on biomaterials in clinical use, concretely bioceramics, and metallic implants. Finally, we revise emerging nanostructured biomaterials, which are receiving growing attention due to their multifunctionality and versatility mainly in the local drug delivery and bone tissue regeneration scenarios.}

_{Medicines 2018, 5, 125}

_{Mesoporous silica materials (MSM) have a great surface area and a high pore volume,meaning that they consequently have a large loading capacity, and have been demonstrated to be unique candidates for the treatment of different pathologies, including bacterial infection. In this text, we review the multiple ways of action in which MSM can be used to fight bacterial infection, including early detection, drug release, targeting bacteria or biofilm, antifouling surfaces, and adjuvant capacity. This review focus mainly on those that act as a drug delivery system, and therefore that have an essential characteristic, which is their great loading capacity. Since MSM have advantages in all stages of combatting bacterial infection; its prevention, detection and finally in its treatment, we can venture to talk about them as the “nightmare of bacteria”.}

_{Pharmaceutics 2018, 10, 279}

_{In this work, we evaluate the tissue response and tolerance to a designed 3D porous scaffold composed of nanocrystalline carbonate-hydroxyapatite and agarose as a preliminary step in bone repair and regeneration. These scaffolds  were subcutaneously implanted into rats, which were sacrificed at different times. CD4þ, CD8þ and ED1þ cells were evaluated as measurements of inflammatory reaction and tolerance. We observed some inflammatory response early after subcutaneous implantation. The 3D interconnected porosity increased scaffold integration via the formation of granulation tissue and the generation of a fibrous capsule around the scaffold. The capsule is initially formed by collagen which progressively invades the scaffold, creating a network that supports the settlement of connective tissue and generating a compact structure. The timing of the appearance of CD4þ and CD8þ cell populations is in agreement with the resolved inflammatory response. The appearance of macrophage activity evidences a slow and gradual degradation activity. Degradation started with the agarose component of the scaffold, but the nano-apatite was kept intact for up to 30 days. Therefore, this apatite/agarose scaffold showed a high capacity for integration by a connective network that stabilizes the scaffold and results in slow nano-apatite degradation. The fundamental properties of the scaffold would provide mechanical support and facilitate bone mobilization, which is of great importance in the masticatory system or large bones.}

_{J. Biomater. Appl.2018, Vol. 33(5) 741–752}

_{Trojan-horse strategy for cancer therapy employing tumor-tropic mesenchymal stem cells transfected with a non-viral nanovector is here presented. In this sense, ultrasound-responsive mesoporous silica nanoparticles were coated with a polycation (using two different molecular weights), providing them with gene transfection capabilities that were evaluated using two different plasmids. First, the expression of Green Fluorescent Protein was analyzed in Decidua-derived Mesenchymal Stem Cells after incubation with the silica nanoparticles. The most successful nanoparticle was then employed to induce the expression of two suicide genes: cytosine deaminase and uracil phosphoribosyl transferase, which allow the
cells to convert a non-toxic pro-drug (5-fluorocytosine) into a toxic drug (5-Fluorouridine monophosphate). The effect of the production of the toxic final product was also evaluated in a cancer cell line (NMU cells) co-cultured with the transfected vehicle cells, Decidua-derived Mesenchymal Stem Cells.}

_{Acta Biomaterialia 83 (2019) 372–378}

_{The osteogenic and angiogenic responses to metal macroporous scaffolds coated with silicon substituted hydroxyapatite (SiHA) and decorated with vascular endothelial growth factor (VEGF) have been evaluated in vitro and in vivo. Ti6Al4V-ELI scaffolds were prepared by electron beam melting and subsequently
coated with Ca10(PO4)5.6(SiO4)0.4(OH)1.6 following a dip coating method. In vitro studies demonstrated that SiHA stimulates the proliferation of MC3T3-E1 pre-osteoblastic cells, whereas the adsorption of VEGF stimulates the proliferation of EC2 mature endothelial cells. In vivo studies were carried out in an osteoporotic sheep model, evidencing that only the simultaneous presence of both components led to a significant increase of new tissue formation in osteoporotic bone.}

_{Acta Biomaterialia 83 (2019) 456–466}

_{The design of drug delivery systems needs to consider biocompatibility and host body recognition for an adequate actuation. In this work, mesoporous silica nanoparticles (MSNs) surfaces were successfully modified with two silane molecules to provide mixed-charge brushes (-NH3
/-PO3 €) and well evaluated in terms of surface properties, low-fouling capability and cell uptake in comparison to PEGylated MSNs. The modification process consists in the simultaneous direct-grafting of hydrolysable short chain amino (aminopropyl silanetriol, APST) and phosphonate-based (trihydroxy-silyl-propyl-methyl-phospho nate, THSPMP) silane molecules able to provide a pseudo-zwitterionic nature under physiological pH conditions. Results confirmed that both mixed-charge pseudo-zwitterionic MSNs (ZMSN) and PEG-MSN display a significant reduction of serum protein adhesion and macrophages uptake with respect to pristine MSNs. In the case of ZMSNs, this reduction is up to a 70–90% for protein adsorption and c.a. 60% for cellular uptake. This pseudo-zwitterionic modification has been focused on the aim of local treatment of bacterial infections through the synergistic effect between the inherent antimicrobial effect of mixed-charge system and the levofloxacin antibiotic release profile. These findings open promising future expectations for the effective treatment of bacterial infections through the use of mixed-charge pseudo-zwitterionic MSNs furtive to macrophages and with antimicrobial properties.}

_{Acta Biomaterialia 84 (2019) 317–327}

_{3D porous scaffolds based on agarose and nanocrystalline apatite, two structural components that act as a temporary mineralized extracellular matrix, were prepared by the GELPOR3D method. This shaping technology allows the introduction of thermally-labile molecules within the scaffolds during the fabrication procedure. An angiogenic protein, Vascular Endothelial Growth Factor, and an antibiotic, cephalexin, loaded in mesoporous silica nanoparticles, were included to design multifunctional scaffolds for bone reconstruction. The dual release of both molecules showed a marked increase in the number of blood vessels on embryonic day 14 in chicken embryos grown ex ovo, while, at the same time providing an antibiotic local concentration capable of inhibiting Staphylococcus aureus bacterial growth. In this sense, different release patterns, monitored by UV-spectroscopy, could be tailored as a function of the cephalexin loading strategy, either releasing all the loaded cephalexin in the first 4 h or less than 50% after 24 h. The scaffold surface was characterized by a high hydrophilicity, with contact angles between 50
 and 63
, which enabled the adhesion and proliferation of preosteoblastic cells.}

_{Acta Biomaterialia 86 (2019) 441–449}

_{The rise and development of nanotechnology has enabled the creation of a wide number
of systems with new and advantageous features to treat cancer. However, in many cases, the lone
application of these new nanotherapeutics has proven not to be enough to achieve acceptable
therapeutic efficacies. Hence, to avoid these limitations, the scientific community has embarked on
the development of single formulations capable of combining functionalities. Among all possible
components, silica—either solid or mesoporous—has become of importance as connecting and
coating material for these new-generation therapeutic nanodevices. In the present review, the most recent examples of fully inorganic silica-based functional composites are visited, paying particular attention to those with potential biomedical applicability. Additionally, some highlights will be given with respect to their possible biosafety issues based on their chemical composition.}

_{Int. J. Mol. Sci. 2019, 20, 929}

_{Nanotechnology, which has already revolutionised many technological areas, is expected to transform life sciences. In this sense, nanomedicine could address some of the most important limitations of conventional medicine. In general, nanomedicine includes three major objectives: (1) trap and protect a great amount of therapeutic agents; (2) carry them to the specific site of disease avoiding any leakage; and (3) release on-demand high local concentrations of therapeutic agents. This feature article will make special emphasis on mesoporous silica nanoparticles that release their therapeutic cargo in response to ultrasound.}

_{Chem. Commun., 2019, 55, 2731--2740}

_{Theselectivedeliveryof therapeuticandimagingagentsto tumoralcellshas beenpostulatedas one of the mostimportantchallengesin the nanomedicinefield.Meta-iodo-benzilguanidine(MIBG)is widelyusedfor the diagnosisofneuroblastoma(NB)due to its strongaffinityfor the norepi-nephrinetransporter(NET),usuallyoverexpressedon themembraneof malignantcells.Herein,afamilyof novelY-shapedscaffoldshas beensynthesized, whichhave structuralanaloguesof MIBGcovalentlyattachedat eachend of the Y-structure.The cellularuptakecapacityof thesedouble-target-ing ligandshas beenevaluatedin vitroand in vivo,yieldingonespecificY-shapedstructurethat is ableto be engulfedby themalignantcells,and accumulatesin the tumoraltissue,atsignificantlyhigherlevelsthanthe structurecontainingonlyone singletargetingagent.ThisY-shapedligandcan provideapowerfultool for the currenttreatmentand diagnosisof thisdisease.}

_{Angew.Chem.2019,131,3099–3104}

_{An approach for safely delivering AgNPs to cancer cells and the evaluation of the affected cellular mechanism are presented. The use of mesoporous silica nanoparticles (MSNs) as nanovehicles decorated with transferrin (Tf, targeting agent) provides a nanoplatform for the nucleation and immobilization of AgNPs (MSNs-Tf-AgNPs). We performed the physico-chemical characterization of the nanosystems and evaluated their therapeutic potential using bioanalytical strategies to estimate the efficiency of the targeting, the degree of cellular internalization in two cell lines with different TfR expression, and the cytotoxic effects of the delivered AgNPs. In addition, cellular localization of the nanosystems in cells has been evaluated by a transmission electron microscopy analysis of ultrathin sections of human hepatocarcinoma (HepG2) cells exposed to MSNs-Tf-AgNPs. The in vitro assays demonstrate that only the nanosystem functionalized with Tf is able to transport the AgNPs inside the cells which overexpress transferrin receptors. Therefore, this novel nanosystem is able to deliver AgNPs specifically to cancer cells overexpressing Tf receptors and offers the possibility of a targeted therapy using reduced doses of silver nanoparticles as cytotoxic agents. Then, a quantitative proteomic experiment validated through the analysis of gene expression has been performed to identify the molecular mechanisms of action associated with the chemotherapeutic potential of the MSNs-Tf-AgNP nanocarriers.}

_{Nanoscale, 2019, 11, 4531–4545}

_{In this paper we aim to analyse the behaviour of ZnO nanocrystals (ZnO NCs), prepared with a new synthetic approach and not embedded in any composite matrix, for bone implant applications in vitro. In particular, we have developed a novel, fast and reproducible microwave-assisted synthesis, to obtain highly-crystalline, round-shaped ZnO NCs of 20 nm in diameter as an extremely-stable colloidal solution in ethanol. The nanocrystals were also partially chemically functionalized by anchoring amino-propyl groups to the ZnO surface (ZnO–NH2 NCs). Thus, the role of both ZnO NC concentration and surface chemistry were tested in terms of biocompatibility towards pre-osteoblast cells, promotion of cell proliferation and differentiation, and also in terms of antimicrobial activity against Gram positive and negative bacteria, such as Escherichia coli and Staphylococcus aureus, respectively. The results suggest that ZnO–NH2 NCs is the most promising
candidate to solve infectious disease in bone implants and at the same time promote bone tissue proliferation, even at high concentrations. Although further investigations are needed to clarify the mechanism underlying the inhibition of biofilm formation and to investigate the role of the ZnO–NH2 NCs in in vivo assays, we demonstrated that fine and reproducible control over the chemical and structural parameters in ZnO nanomaterials can open up new horizons in the use of functionalized ZnO NCs as a highly biocompatible and osteoinductive nanoantibiotic agent for bone tissue engineering.}

_{RSC Adv., 2019, 9, 11312–11321}

_{Since the second half of the 20th century, bioceramics are used for bone repair and regeneration. Inspired by bones and teeth, and aimed at mimicking their structure and composition, several artificial bioceramics were developed for biomedical applications. And nowadays, in the 21st century, with the increasing prominence of nanoscience and nanotechnology, certain bioceramics are being used to build smart drug delivery systems, among other applications. This minireview will mainly describe both tendencies through the research work carried out by the research team of María Vallet-Regí.}

_{Pure Appl. Chem. 2019; 91(4): 687–706}

_{Macroporous scaffolds made of a SiO2-CaO-P2O5mesoporous bioactive glass (MBG) ande-polycaprolactone (PCL) have been prepared by robocasting. These scaffolds showed an excellentin vitrobiocompatibility in contact with osteoblast like cells (Saos 2) and osteoclasts derived fromRAW 264.7 macrophages.In vivostudies were carried out by implantation into cavitary defects drilledin osteoporotic sheep. The scaffolds evidenced excellent bone regeneration properties, promoting newbone formation at both the peripheral and the inner parts of the scaffolds, thick trabeculae, high vascu-larization and high presence of osteoblasts and osteoclasts. In order to evaluate the effects of the localrelease of an antiosteoporotic drug, 1% (%wt) of zoledronic acid was incorporated to the scaffolds. Thescaffolds loaded with zoledronic acid induced apoptosis in Saos 2 cells, impeded osteoclast differentiationin a time dependent manner and inhibited bone healing, promoting an intense inflammatory response inosteoporotic sheep.}

_{Acta Biomaterialia 90 (2019) 393–402}

_{Osteoporosis is the most common disease involving bone degeneration. Current clinical treatments are not able to offer a satisfying curative effect, so the development of effective treatments is desired. Gene silencing through siRNA delivery has gained great attention as a potential treatment in bone diseases. SOST gene inhibits the Wnt signaling pathway reducing osteoblast differentiation. Consequently, silencing SOST genes with a specific siRNA could be a potential option to treat osteoporosis. Generally, siRNAs have a very short halflife and poor transfection capacity, so an effective carrier is needed. In particular, mesoporous silica nanoparticles (MSNs) have attracted great attention for intracellular delivery of nucleic acids. We took advantage of their high loading capacity to further load the pores with osteostatin, an osteogenic peptide. In this study, we developed a system based on MSNs coated with poly(ethylenimine), which can effectively deliver SOST siRNA and osteostatin inside cells, with the consequent augmentation of osteogenic markers with a synergistic effect. This established the potential utility of MSNs to co-deliver both biomolecules to promote bone formation, this being a potential alternative to treat osteoporosis.}

_{ACS Nano 2019, 13, 5451−5464}

 _{Introduction: Mesoporous silica nanoparticles (MSNs) are outstanding nanoplatforms for drug delivery. Herein, the most recent advances to turn MSN-based carriers into minimal side effect drug delivery agents are covered. Areas covered: This review summarizes the scientific advances dealing with MSNs for targeted and stimuli-responsive drug delivery since 2015. Delivery aspects to diseased tissues together with approaches to obtain smart MSNs able to respond to internal or external stimuli and their applications are here described. Special emphasis is done on the combination of two or more stimuli on the same nanoplatform and on combined drug therapy. Expert opinion: The use of MSNs in nanomedicine is a promising research field because they are outstanding platforms for treating different pathologies. This is possible thanks to their structural, chemical, physical and biological properties. However, there are certain issues that should be overcome to improve the suitability of MSNs for clinical applications. All materials must be properly characterized prior to their in vivo evaluation; furthermore, preclinical in vivo studies need to be standardized to demonstrate the MSNs clinical translation potential.}

_{Expert Opin. Drug. Deliv.. 16 (4), 415-439     2019}

_{The purpose of this work was the assembly of multicomponent nano-bioconjugates based on mesoporous silica nanoparticles (MSNs), proteins (bovine serum albumin, BSA, or lysozyme, LYZ), and gold nanoparticles (GNPs). These nanobioconjugates may find applications in nanomedicine as theranostic devices. Indeed, MSNs can act as drug carriers, proteins stabilize MSNs within the bloodstream, or may have therapeutic or targeting functions. Finally, GNPs can either be used as contrast agents for imaging or for photothermal therapy. Here, amino-functionalized MSNs (MSN−NH2) were synthesized and characterized through various techniques (small angle X-rays scattering TEM, N2 adsorption/desorption isotherms, and thermogravimetric analysis (TGA)). BSA or lysozyme were then grafted on the external surface of MSN−NH2 to obtain MSN−BSA and MSN−LYZ bioconjugates, respectively. Protein immobilization on MSNs surface was confirmed by Fourier transform infrared spectroscopy, ζ-potential measurements, and TGA, which also allowed the estimation of protein loading. The MSN−protein samples were then dispersed in a GNP solution to obtain MSN−protein−GNPs nano-bioconjugates. Transmission electron microscopy (TEM) analysis showed the occurrence of GNPs on the MSN−protein surface, whereas almost no GNPs occurred in the protein-free control samples. Fluorescence and Raman spectroscopies suggested that proteins−GNP interactions involve tryptophan residues.}

_{ACS Omega 2019, 4, 11044−11052}

_{The ability of bacteria to form biofilms hinders any conventional treatment for chronic infections and hasserious socio-economic implications. For this purpose, a nanocarrier capable of overcoming the barrier ofthe mucopolysaccharide matrix of the biofilm and releasing its loaded-antibiotic within this matrixwould be desirable. Herein, we developed a new nanosystem based on levofloxacin (LEVO)-loaded meso-porous silica nanoparticles (MSN) decorated with the lectin concanavalin A (ConA). The presence of ConApromotes the internalization of this nanosystem into the biofilm matrix, which increases the antimicro-bial efficacy of the antibiotic hosted within the mesopores. This nanodevice is envisioned as a promisingalternative to conventional treatments for infection by improving the antimicrobial efficacy and reducingside effects.}

_{Acta Biomaterialia 96 (2019) 547–556}

_{Based on an already tested laboratory procedure, a new magnetron sputtering methodology to simultaneously coat two-sides of large area implants (up to ~15 cm2) with Ti nanocolumns in industrial reactors has been developed. By analyzing the required growth conditions in a laboratory setup, a new geometry and methodology have been proposed and tested in a semi-industrial scale reactor. A bone plate (DePuy Synthes) and a pseudo-rectangular bone plate extracted from a patient were coated following the new methodology, obtaining that their osteoblast proliferation efficiency and antibacterial functionality were equivalent to the coatings grown in the laboratory reactor on small areas. In particular, two kinds of experiments were performed: Analysis of bacterial adhesion and biofilm formation, and osteoblasts–bacteria competitive in vitro growth scenarios. In all these cases, the coatings show an opposite behavior toward osteoblast and bacterial proliferation, demonstrating that the proposed methodology represents a valid approach for industrial production and practical application of nanostructured titanium coatings.}

_{Nanomaterials 2019, 9, 1217; doi:10.3390/nano9091217}

_{Both the prevalence of antibiotic resistance and the increased biofilm-associated infections
are boosting the demand for new advanced and more eective treatment for such infections. In this sense, nanotechnology oers a ground-breaking platform for addressing this challenge. This review shows the current progress in the field of antimicrobial inorganic-based nanomaterials and their activity against bacteria and bacterial biofilm. Herein, nanomaterials preventing the bacteria adhesion and nanomaterials treating the infection once formed are presented through a classification based on their functionality. To fight infection, nanoparticles with inherent antibacterial activity and nanoparticles acting as nanovehicles are described, emphasizing the design of the carrier nanosystems with properties targeting the bacteria and the biofilm.}

_{Int. J. Mol. Sci. 2019, 20, 3806}

_{A very small number of biomaterials investigated for bone regeneration were reported as able to prevent the oxidative stress. In this study beads based on alginate hydrogel and mesoporous glasses (MG) containing different amounts of cerium oxides (Ce3+/Ce4+) exhibiting antioxidant properties were investigated as a good approach to mimic the action of antioxidant enzymes in our organism. The effect of cerium contents on the bioactivity and biocompatibility of beads were investigated. Moreover, the potential capability of Ce-containing MG to prevent the oxidative stress caused by the activity of reactive oxygen species (ROS) was here investigated for the first time. The increment of cerium oxide from 1.2, to 3.6 and 5.3 mol% decreases the surface area and porosity of MG and increases the catalase mimetic activity after 168 h. Swelling tests in different cell culture media (D- and α-MEM) demonstrated the rehydration capability of beads. The presence of beads with the highest Ce-contents (3.6 and 5.3%) improved the proliferation of pre-osteoblastic cells MC3T3-C1 cells. However, the cell differentiation decreased when increased the cerium content. Lactate dehydrogenase assays showed beads are cytocompatible materials. Moreover, oxidative stress tests with H2O2 showed a better response related to cell viability and the elimination of oxidant species when increased cerium content. Beads of glasses with 1.2 and 3.6% of CeO2 are excellent candidates as bioactive scaffolds for bone regeneration capable of counteract the oxidative stress.}

_{Materials Science & Engineering C 105 (2019) 109971}

_{The poor delivery of nanoparticles to target cancer cells hinders their success in the clinical setting. In this work, an alternative target readily available for circulating nanoparticles has been selected to elimi- nate the need for nanoparticle penetration in the tissue: the tumor blood vessels. A tumor endothelium- targeted nanoparticle (employing an RGD-containing peptide) capable of co-delivering two anti-vascular drugs (one anti-angiogenic drug and one vascular disruption agent) is here presented. Furthermore, the nanodevice presents two additional anti-vascular capabilities upon activation by Near-Infrared light: pro- voking local hyperthermia (by gold nanorods in the system) and generating toxic reactive oxygen species (by the presence of a photosensitizer). RGD-targeting is shown to increase uptake by HUVEC cells, and while the nanoparticles are shown not to be toxic for these cells, upon Near-Infrared irradiation their almost complete killing is achieved. The combination of all four therapeutic modalities is then evalu- ated in an ex ovo fibrosarcoma xenograft model, which shows a significant reduction in the number of blood vessels irrigating the xenografts when the nanoparticles are present, as well as the destruction of the existing blood vessels upon irradiation. These results suggest that the combination of different anti- vascular therapeutic strategies in a single nanocarrier appears promising and should be further explored in the future.}

_{Acta Biomaterialia 101 (2020) 459–468}

_{Silicon-substituted hydroxyapatite (SiHA) macroporous scaffolds have been prepared by robocasting. In order to optimize their bone regeneration properties, we have manufactured these scaffolds presenting different microstructures: nanocrystalline and crystalline. Moreover, their surfaces have been decorated with vascular endothelial growth factor (VEGF) to evaluate the potential coupling between vasculariza- tion and bone regeneration. In vitro cell culture tests evidence that nanocrystalline SiHA hinders pre- osteblast proliferation, whereas the presence of VEGF enhances the biological functions of both endothe- lial cells and pre-osteoblasts. The bone regeneration capability has been evaluated using an osteoporotic sheep model. In vivo observations strongly correlate with in vitro cell culture tests. Those scaffolds made of nanocrystalline SiHA were colonized by fibrous tissue, promoted inflammatory response and fostered osteoclast recruitment. These observations discard nanocystalline SiHA as a suitable material for bone re- generation purposes. On the contrary, those scaffolds made of crystalline SiHA and decorated with VEGF exhibited bone regeneration properties, with high ossification degree, thicker trabeculae and higher pres- ence of osteoblasts and blood vessels. Considering these results, macroporous scaffolds made of SiHA and decorated with VEGF are suitable bone grafts for regeneration purposes, even in adverse pathological scenarios such as osteoporosis.}

_{Acta Biomaterialia 101 (2020) 544–553}

_{Hypothesis:
The treatment of bone fractures still represents a challenging clinical issue when complications due to impaired bone remodelling (i.e. osteoporosis) or infections occur. These clinical needs still require a radical improvement of the existing therapeutic approach through the design of advanced biomaterials combining the ability to promote bone regeneration with anti-adhesive properties able to minimise unspecific biomolecules adsorption and bacterial adhesion. Strontium-containing mesoporous bioactive glasses (Sr-MBG), which are able to exert a pro-osteogenic effect by releasing Sr2+ ions, have been successfully functionalised to provide mixed-charge (ANH3 /ACOO€) surface groups with anti-adhesive abilities.
Experiments:
Sr-MBG have been post-synthesis modified by co-grafting hydrolysable short chain silanes containing amino (aminopropylsilanetriol) and carboxylate (carboxyethylsilanetriol) moieties to achieve a zwitterionic zero-charge surface. The final system was then characterised in terms of textural-structural properties, bioactivity, cytotoxicity, pro-osteogenic and anti-adhesive capabilities.}

_{Journal of Colloid and Interface Science 563 (2020) 92–103}

_{In recent years, nanomedicine has emerged at the forefront of nanotechnology, generating great expectations in the biomedical field. Researchers are developing novel nanoparticles for both diagnostic applications using imaging technology and treatment purposes through drug delivery technologies. Among all the available nanoparticles, inorganic mesoporous silica nanoparticles are the newcomers to the field, contributing with their unique and superlative properties. A brief overview of the most recent progress in the synthesis of mesoporous silica nanoparticles and their use as drug delivery nanocarriers is provided. The latest trends in this type of nanoparticles and their use in modern medicine are discussed, highlighting the significant impact that this technology might have in the near future.}

_{Adv. Funct. Mater.2020, 30, 1902634}

_{Ultrasound has attracted much attention in recent years as an external stimulus capable of activating different types of nanomaterials for therapeutic application. One of the characteristics that makes ultrasound an especially appealing triggering stimulus for nanomedicine is its capacity to be non-invasively applied in a focused manner at deep regions of the body. Combining ultrasound with nanoparticles, different biological effects can be achieved. In this work, an overview of the four main types of inducible responses will be provided: inducing drug release, producing ultrasound-derived biological effects, modifying nanoparticle biodistribution and developing theranostic agents. Several examples of each one of these applications are presented here to illustrate the key concepts underlying recent developments in the discipline.}

_{Bull. Chem. Soc. Jpn. 2020, 93, 220–229}