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ABSTRACTIntroductionNano-based systems have received a lot of attention owing to their particular properties and, hence, have been proposed for a wide variety of biomedical applications. These nanosystems could be potentially employed for diagnosis and therapy of different medical issues. Although these nanomaterials are designed for specific tasks, interactions, and transformations when administered to the human body affect their performance and behavior. In this regard, bacteria and other cells have been presented as alternative nanocarriers. These microorganisms can be genetically modified and customized for a more specific therapeutic action and, in combination with nanomaterials, can lead to bio-hybrids with a unique potential for biomedical purposes.Areas coveredLiterature regarding bacteria and cells employed in combination with nanomaterials for biomedical applications is revised and discussed in this review. The potential as well as the limitations of these novel bio-hybrid systems are evaluated. Several examples are presented to show the performance of these alternative nanocarriers.Expert opinionBio-hybrid systems have shown their potential as alternative nanocarriers as they contribute to better performance than traditional nano-based systems. Nevertheless, their limitations must be studied, and advantages and drawbacks assessed before their application to medicine.

The several biological barriers that nanoparticles might encounter when administered to a patient constitute the major bottleneck of nanoparticle-mediated tumor drug delivery, preventing their successful translation into the clinic and reducing their therapeutic profile. In this work, mesoporous silica nanoparticles have been employed as a platform to engineer a versatile nanomedicine able to address such barriers, achieving (a) excessive premature drug release control, (b) accumulation in tumor tissues, (c) selective internalization in tumoral cells, and (d) endosomal escape. The nanoparticles have been decorated with a self-immolative redox-responsive linker to prevent excessive premature release, to which a versatile and polyvalent peptide that is able to recognize tumoral cells and induce the delivery of the nanoparticles to the cytoplasm via endosomal escape has been grafted. The excellent biological performance of the carrier has been demonstrated using 2D and 3D in vitrocell cultures and a tumor-bearing chicken embryo model, demonstrating in all cases high biocompatibility and cytotoxic effect, efficient endosomal escape and tumor penetration, and accumulation in tumors grown on the chorioallantoic membrane of chicken embryos.

In this work, two types of mesoporous carbon particles with different morphology, size, and pore structure have been functionalized with a self-immolative polymer sensitive to changes in pH and tested as drug nanocarriers. It is shown that their textural properties allow significantly higher loading capacity compared to typical mesoporous silica nanoparticles. In vial release experiments of a model Ru dye at pH 7.4 and 5 confirm the pH-responsiveness of the hybrid systems, showing that only small amounts of the cargo are released at physiological pH, whereas at slightly acidic pH (e.g., that of lysosomes), self-immolation takes place and a significant amount of the cargo is released. Cytotoxicity studies using human osteosarcoma cells show that the hybrid nanocarriers are not cytotoxic by themselves but induce significant cell growth inhibition when loaded with a chemotherapeutic drug such as doxorubicin. In preparation of an in vivo application, in vial responsiveness of the hybrid system to short-term pH-triggering is confirmed. The consecutive in vivo study shows no substantial cargo release over a period of 96 h under physiological pH conditions. Short-term exposure to acidic pH releases an experimental fluorescent cargo during and continuously after the triggering period over 72 h.

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.The combination of ultrasound with nanoparticles enables the development of different types of therapeutic strategies. In this work, we aim to provide an overview of the main types of inducible responses that have been reported in the literature in this context, divided in: inducing drug release, producing ultrasound-derived biological effects, modifying nanoparticle biodistribution and developing theranostic agents.

ABSTRACTIntroduction: Stimuli-responsive nanomaterials for cancer therapy have attracted much interest recently due to their potential for improving the current standard of care. Different types of inorganic nanoparticles are widely employed for the development of these strategies, but in some cases safety concerns hinder their clinical translation. This review aims to provide an overview of the challenges that inorganic nanoparticles face regarding their stability, toxicity, and biodegradability, as well as the strategies that have been proposed to overcome them.Areas covered: The available information about the in vitroand in vivobiocompatibility, as well as the biodegradability of the following nanoparticles, is presented and discussed: superparamagnetic iron oxide nanoparticles, gold nanoparticles, graphene and mesoporous nanoparticles made of silicon or silicon oxide. The toxicology of inorganic nanoparticles is greatly affected by many physicochemical parameters, and their surface modification emerges as the main intervention to improve their biocompatibility and tailor their performance for specific biomedical applications.Expert opinion: Even though many different studies have been performed regarding the biological behavior of inorganic nanoparticles, long-term in vivodata is still scarce, limiting our capacity to evaluate the proposed nanomaterials for clinical use. The role of biodegradability in different therapeutic contexts is also discussed.

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 half-life 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.

ABSTRACTIntroductionMesoporous 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 coveredThis 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 opinionThe 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 vivoevaluation; furthermore, preclinical in vivostudies need to be standardized to demonstrate the MSNs clinical translation potential.

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.

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 vitroresults 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.

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.

ABSTRACTIntroduction: 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.

When exposed to body fluids, mesoporous bioactive glasses (MBGs) of the CaO–SiO2–P2O5system 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–/PO43–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 cross-polarization 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.

ABSTRACTIntroduction: 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.

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.

Bacterial antimicrobial resistance is posed to become a major hazard to global health in the 21st century. An aggravating issue is the stalled antibiotic research pipeline, which requires the development of new therapeutic strategies to combat antibiotic-resistant infections. Nanotechnology has entered into this scenario bringing up the opportunity to use nanocarriers capable of transporting and delivering antimicrobials to the target site, overcoming bacterial resistant barriers. Among them, mesoporous silica nanoparticles (MSNs) are receiving growing attention due to their unique features, including large drug loading capacity, biocompatibility, tunable pore sizes and volumes, and functionalizable silanol-rich surface. This perspective article outlines the recent research advances in the design and development of organically modified MSNs to fight bacterial infections. First, a brief introduction to the different mechanisms of bacterial resistance is presented. Then, we review the recent scientific approaches to engineer multifunctional MSNs conceived as an assembly of inorganic and organic building blocks, against bacterial resistance. These elements include specific ligands to target planktonic bacteria, intracellular bacteria, or bacterial biofilm; stimuli-responsive entities to prevent antimicrobial cargo release before arriving at the target; imaging agents for diagnosis; additional constituents for synergistic combination antimicrobial therapies; and aims to improve the therapeutic outcomes. Finally, this manuscript addresses the current challenges and future perspectives on this hot research area.

A bone-mineral-mimicking layer of hydroxycarbonate apatite (HCA) forms at the surface of a bioactive glass on its contact with body fluids. We report a solid-state 29Si nuclear magnetic resonance (NMR) spectroscopy study of the surface reactions preceding the HCA formation at three CaO–SiO2–(P2O5) mesoporous bioactive glasses (MBGs) with distinct compositions, surface areas, and mesoporous arrangements, during their immersion in simulated body fluid (SBF) out to 30 days. The evolution of the various populations of coexisting silicate species associated with the bulk and surface portions of the pore-walls were monitored. The MBGs revealed drastically different surface alterations between the scenarios of low (0.6 g/L) and high (20 g/L) MBG concentrations in the SBF: for the low MBG dose, which is expected to be more relevant for in vivoconditions, all MBGs follow a “universal” dissolution mechanism beyond ≈24 h of SBF soaking, regardless of their precise compositions and textural properties. The only essential difference among the specimens occurs during the first hour of soaking when their variable Ca2+reservoirs are depleted. In contrast, for high MBG concentrations, the surface reactions and their associated silicate network degradation retard for Ca-poor MBGs, whereas the reactions are completely quenched for Ca-rich compositions. These findings rationalize previously reported discrepancies in the correlation between the HCA formation and the MBG composition for distinct concentrations during SBF testing, and simplify future MBG design by identifying which compositional and textural factors are relevant for a rapid and substantial HCA formation in vitro.

Since 2001, when our research group proposed for the first time MCM-41 as a drug release system, the scientific community has demonstrated a growing interest in mesoporous silica nanoparticles (MSNs) for their revolutionary potential in nanomedicine. Among the diverse pathologies that can be treated with MSNs, cancer has received increasing attention. MSNs can be loaded with large amounts of therapeutic cargoes and once intravenously administrated preferentially accumulate in solid tumours viathe enhanced permeation and retention (EPR) effect. Herein we report the recent developments achieved by our research group as a pioneer in this field, highlighting: the design of sophisticated MSNs as stimuli-responsive drug delivery systems to release the entrapped cargo upon exposure to a given stimulus while preventing the premature release of highly cytotoxic drugs before reaching the target; transporting non-toxic prodrugs and the enzyme responsible for its conversion into cytotoxic agents into the same MSNs; improving the selectivity and cellular uptake by cancer cells by active targeting of MSNs; increasing the penetration of MSNs within the tumour mass, which is one of the major challenges in the use of NPs to treat solid tumours.

A new ultrasound-responsive system based on mesoporous silica nanoparticles was developed for biomedical applications, grafting a copolymer on their surface that acts as gatekeeper of the pores. The nanoparticles can be loaded with a cargo at low temperature (4 °C), taking advantage of the open conformation that the polymer presents under these conditions. Then, at 37 °C the copolymer collapses closing the pore entrances and allowing the nanoparticles to carry the drugs at physiological temperature without premature release, which is of great importance when dealing with cytotoxic drugs in cancer treatments. Upon ultrasound irradiation, the sensitive polymer changes its hydrophobicity and, therefore, its conformation toward coil-like opening the gates and releasing the cargo. These hybrid nanoparticles have been shown to be noncytotoxic and can be internalized into LNCaP cells retaining their ultrasound-responsive capability in the cytoplasm of the cells. Moreover, doxorubicin-loaded hybrid MSNs were incubated with LNCaP cells to show their capacity to induce cell death only when the nanoparticles had been exposed to ultrasound. This work demonstrates that our hybrid-MSNs can be triggered by remote stimuli, which is of capital importance for future applications in drug delivery and cancer therapy.

Poor penetration of drug delivery nanocarriers within dense extracellular matrices constitutes one of the main liabilities of current nanomedicines. The conjugation of proteolytic enzymes on the nanoparticle surface constitutes an attractive alternative. However, the scarce resistance of these enzymes against the action of proteases or other aggressive agents present in the bloodstream strongly limits their application. Herein, a novel nanodevice able to transport proteolytic enzymes coated with an engineered pH-responsive polymeric is presented. This degradable coat protects the housed enzymes against proteolytic attack at the same time that it triggers their release under mild acidic conditions, usually present in many tumoral tissues. These enzyme nanocapsules have been attached on the surface of mesoporous silica nanoparticles, as nanocarrier model, showing a significatively higher penetration of the nanoparticles within 3D collagen matrices which housed human osteosarcoma cells (HOS). This strategy can improve the therapeutic efficacy of the current nanomedicines, allowing a more homogeneous and deeper distribution of the therapeutic nanosystems in cancerous tissues.

Introduction:Mesoporous silica nanoparticles (MSNPs) are one of the most promising inorganic drug delivery systems (DDSs). The design and development of tumour-targeted MSNPs with stimuli-responsive drug release capability aim at enhancing the efficiency and minimising the side effects of anti-tumour drugs for cancer therapy.Areas covered:This review provides an overview of the scientific advances in MSNPs for tumour-targeted stimuli-responsive drug delivery. The key factors that govern the passive accumulation of MSNPs within solid tumours such as size, shape and surface functionalisation are roughly described. The different active targeting strategies for the specific retention and uptake of MSNPs by tumour cells are also outlined. The approaches developed so far for the synthesis of smart MSNPs capable of releasing the trapped drugs in response to internal or external stimuli and their applications are reviewed. Critical considerations in the use of MSNPs for the treatment of cancer treatment are discussed. The future prospects and key factors concerning the clinical application of MSNPs are considered throughout the manuscript.Expert opinion:MSNPs are promising nanocarriers to efficiently transport and site-specifically deliver highly toxic drugs, such as chemotherapeutic agents for cancer treatment. However, there are certain issues that should be overcome to improve the suitability of MSNPs for clinical applications. Increasing the penetration capability of MSNPs within tumour tissues, providing them of appropriate colloidal stability in physiological fluids and ensuring that their active targeting capability and stimuli-responsive performance are preserved in complex biological media are of foremost significance. Few in vivoevaluation tests of MSNPs have been reported and much research effort into this field is mandatory to be able to move from bench to bedside.

Nano-graphene oxide (GO) has attracted great interest in nanomedicine due to its own intrinsic properties and its possible biomedical applications such as drug delivery, tissue engineering and hyperthermia cancer therapy. However, the toxicity of GO nanosheets is not yet well-known and it is necessary to understand its entry mechanisms into mammalian cells in order to avoid cell damage and human toxicity. In the present study, the cellular uptake of pegylated GO nanosheets of ca. 100 nm labeled with fluorescein isothiocyanate (FITC-PEG-GOs) has been evaluated in the presence of eight inhibitors (colchicine, wortmannin, amiloride, cytochalasin B, cytochalasin D, genistein, phenylarsine oxide and chlorpromazine) that specifically affect different endocytosis mechanisms. Three cell types were chosen for this study: human Saos-2 osteoblasts, human HepG2 hepatocytes and murine RAW-264.7 macrophages. The results show that different mechanisms take part in FITC-PEG-GOs uptake, depending on the characteristics of each cell type. However, macropinocytosis seems to be a general internalization process in the three cell lines analyzed. Besides macropinocytosis, FITC-PEG-GOs can enter through pathways dependent on microtubules in Saos-2 osteoblasts, and through clathrin-dependent mechanisms in HepG2 hepatocytes and RAW-264.7 macrophages. HepG2 cells can also phagocytize FITC-PEG-GOs. These findings help to understand the interactions at the interface of GO nanosheets and mammalian cells and must be considered in further studies focused on their use for biomedical applications.

Mesoporous silica nanoparticles (MSNPs) are receiving growing attention by the scientific community for their groundbreaking potential in nanomedicine. It is possible to load huge amounts of cargo into the mesopore voids and capping the pore entrances with different nanogates. Different internal or external stimuli can provoke the nanocap removal and trigger the departure of the cargo, which permits the design of stimuli-responsive drug delivery nanodevices. It is also feasible to combine the multifunctionality of MSNPs with the wide range of applications of magnetic nanoparticles (mNPs), giving rise to advanced smart nanosystems whose features and functionality can be tailored attending to specific clinical needs. This review describes the possible combinations of MSNPs, stimuli-responsive nanocaps and mNPs and the current scientific challenges aimed at accelerating the progression from bench to bedside.

Biomimetics takes advantage of natural strategies for the solution of technological problems, including the proper design of biomaterials. Living bone exhibits a hierarchical porosity with both giant and nanometric pores which must be reproduced for the design of biomaterials for hard tissue repair. Bioactive and degradable bioceramics are a good alternative for the manufacture of scaffolds. Tissue engineering approaches to improve bone regeneration include strategies supporting endogenous osteoblast adhesion, proliferation (osteoconduction), osteoinduction by growth factors, and osteoprogenitors. Understanding the natural ossification mechanisms and the role of biomolecules involved in this process is a requirement for the design of bone tissue scaffolds. Mesoporous bioactive ceramics, namely mesoporous silica and templated glasses with nanometric pores to host growth factors, conformed into 3D scaffolds with micrometric porosity by rapid prototyping, are a good option for bone regeneration. In this regard, biomolecules such as well characterized bone morphogenetic proteins and others under current research, such as osteostatin and osteoprogenitors, are promising strategies in bone tissue engineering applications. Future developments in biomaterials will come in both micro- and nano- scales, and molecular and cell biology approaches will provide suitable solutions to the demanding needs of these compounds.

By exploiting 1H and 31P magic-angle spinning nuclear magnetic resonance (NMR) spectroscopy, we explore the proton and orthophosphate environments in biomimetic amorphous calcium phosphate (ACP) and hydroxy-apatite (HA), as grown in vitro at the surface of a 10CaO–85SiO2–5P2O5mesoporous bioactive glass (MBG) in either a simulated body fluid or buffered water. Transmission electron microscopy confirmed the presence of a calcium phosphate layer comprising nanocrystalline HA. Two-dimensional 1H–31P heteronuclear correlation NMR established predominantly 1H2O↔31PO43–and O1H↔31PO43–contacts in the amorphous and crystalline component, respectively, of the MBG surface-layer; these two pairs exhibit distinctly different 1H→31P cross-polarization dynamics, revealing a twice as large squared effective 1H–31P dipolar coupling constant in ACP compared with HA. These respective observations are mirrored in synthetic (well-crystalline) HA, and the amorphous calcium orthophosphate (CaP) clusters that are present in the pristine MBG pore walls: besides highlighting very similar local 1H and 31P environments in synthetic and biomimetic HA, our findings evidence closely related NMR characteristics, and thereby similar local structures, of the CaP clusters in the pristine MBG relative to biomimetic ACP.

Resistance measurements indicate the presence of magnetoresistance in the La0.5Sr0.5MnO2.5brownmillerite related compound. An 80 % of magnetoresistance is found at 75 K. In spite of the partial break‐up occurring at the 3D network of octahedra sharing corners, characteristic of the full oxygen content perovskite phase, the oxygen deficient compound exhibits complex magnetic and electric properties. Such behavior can be explained on the basis of ferromagnetic and metallic clusters randomly distributed at the octahedral layers separated from each other by an insulating antiferromagnetic matrix. AC susceptibility measurements suggest spin glass behavior at low temperature as a consequence of the competition between different magnetic interactions.

Mesoporous silica nanoparticles can be modified to perform on-demand stimuli-responsive dosing of therapeutic molecules. The silica network was loaded with iron oxide superparamagnetic nanocrystals, providing the potential to perform targeting and magnetic resonance imaging. Single-stranded DNA was immobilized onto the material surface. The complementary DNA sequence was then attached to magnetic nanoparticles. The present work demonstrates that DNA/magnetic nanoparticle conjugates are able to cap the pores of the magnetic silica particles upon hybridization of both DNA strands. Progressive double-stranded DNA melting as a result of temperature increase gave rise to uncapping and the subsequent release of a mesopore-filled model drug, fluorescein. The reversibility of DNA linkage results in an “on−off” release mechanism. Moreover, the magnetic component of the whole system allows reaching hyperthermic temperatures (42−47 °C) under an alternating magnetic field. This feature leaves open the possibility of a remotely triggered drug delivery. Furthermore, due to its capacity to increase the temperature of the surrounding media, this multifunctional device could play an important role in the development of advanced drug delivery systems for thermochemotherapy against cancer.

An array of magic-angle spinning (MAS) nuclear magnetic resonance (NMR) spectroscopy experiments is applied to explore the surface reactions of a mesoporous bioactive glass (MBG) of composition Ca0.10Si0.85P0.04O1.90when subjected to a simulated body fluid (SBF) for variable intervals. Powder X-ray diffraction and 31P NMR techniques are employed to quantitatively monitor the formation of an initially amorphous calcium phosphate surface layer and its subsequent crystallization into hydroxycarbonate apatite (HCA). Prior to the onset of HCA formation, 1H → 29Si cross-polarization (CP) NMR evidence dissolution of calcium ions; a slightly increased connectivity of the speciation of silicate ions is observed at the MBG surface over 1 week of SBF exposure. The incorporation of carbonate and sodium ions into the bioactive orthophosphate surface layer is explored by 1H → 13C CPMAS and 23Na NMR, respectively. We discuss similarities and distinctions in composition−bioactivity relationships established for traditional melt-prepared bioglasses compared to MBGs. The high bioactivity of phosphorus-bearing MBGs is rationalized to stem from an acceleration of their surface reactions due to presence of amorphous calcium orthophosphate clusters of the MBG pore wall.

Mesoporous bioactive glasses (MBGs) associated with an anti‐osteoporotic drug (ipriflavone) have been prepared. With this aim, MBGs were functionalised with different organic groups by following a post‐grafting method, thus retaining the mesoporous network of the bioactive substrates. Drug‐delivery tests were carried out by using ipriflavone as a hydrophobic model drug. Our results revealed that by means of the proper functionalisation, most of the drug is retained in the mesoporous network. By tailoring the hydrophobicity of the surface with functional groups, the drug–material link can be tuned, thereby ensuring the long‐term delivery of ipriflavone. In vitro bioactive tests demonstrate that these systems exhibit the same excellent behaviour of non‐functionalised MBGs. The possibility to add a bone resorption inhibitor such as ipriflavone to highly bioactive materials confirms functionalised MBGs as very promising bone‐tissue regeneration systems.

Research interest in silica-based ordered mesoporous materials (SMMs) as drug delivery systems has grown drastically in the last few years owing to the great versatility and stability of these mesoporous matrices. This review aims to resume the work carried out in this area so far and the possible applications in biomedical technologies. The different SMMs can be designed and tailored using different chemical strategies according to the drug and clinical necessity. The available channels of SMMs that can be used to store drugs can be opened and closed by different systems, in the so-called stimuli-responsive release devices. These systems could improve the therapeutic efficacy compared with conventional sustained release systems. SMMs offer such a great versatility that can be used both for oral and for local drug delivery, with huge possible applications in different clinical areas.

Neutron diffraction and X‐ray absorption near‐edge structure (XANES) studies have been performed in La0.5Ca0.5MnO2.5, La0.5Sr0.5MnO2.5and Nd0.5Sr0.5MnO2.5oxygen‐deficient perovskite compounds obtained by topotactic reduction. They all exhibit a brownmillerite structure with G‐type antiferromagnetic ordering. Mn2+, Mn3+and Mn4+coexist at the octahedral sites, whereas only Mn2+is placed in the tetrahedral positions. A magnetic moment of 1.6 μBhas been detected at the tetrahedral layers, which can be explained by assuming Mn2+is in a low‐spin configuration.

Background: Research on the development of bioceramics as controlled delivery systems of biologically active molecules for bone implant technologies exhibits two distinct approaches: i) drug delivery to treat bone infection, inflammation or bone diseases; and ii) release of osteogenic agents that promote bone tissue regeneration, such as peptides, proteins and growth factors. Objective/methods: This is a review of the literature and patents on recently developed bioceramics for drug delivery systems in bone tissue regeneration. A critical overview concerning the conventional sol-gel glasses, as well as the last trends in silica-based mesoporous materials, is provided. Results/conclusion: Supramolecular chemistry has allowed major advances in the biomedical field, as a very precise control in the drug-load capacity, drug-release kinetics, together with an enhanced bone-forming capability, are achieved.

A new kind of magnetic thermoseed for bone tissue engineering has been synthesized. The materials used are specially designed to restore bone tissue after tumor extirpation, because they exhibit bioactive behavior and the ability to act as thermoseeds for cancer treatment using hyperthermia. The L929 cell line of mouse fibroblasts has been used in a wide biocompatibility study concerning cell proliferation and morphology studies, mitochondrial function determination, lactate dehydrogenase measurement, and flow cytometry studies, including cell cycle analysis, cell size and complexity, and intracellular reactive oxygen species content. The results presented in this work indicate that these bioactive magnetic materials are highly biocompatible and show greater cell response for thermoseeds with a higher magnetic phase content. There were no significant alterations detected in the cell cycle, and the interaction between fibroblasts and the different mixtures did not induce significant apoptosis.

Research on mesoporous materials for biomedical purposes has experienced an outstanding increase during recent years. Since 2001, when MCM-41 was first proposed as drug-delivery system, silica-based materials, such as SBA-15 or MCM-48, and some metal–organic frameworks have been discussed as drug carriers and controlled-release systems. Mesoporous materials are intended for both systemic-delivery systems and implantable local-delivery devices. The latter application provides very promising possibilities in the field of bone-tissue repair because of the excellent behavior of these materials as bioceramics. This Minireview deals with the advances in this field by the control of the textural parameters, surface functionalization, and the synthesis of sophisticated stimuli-response systems.

Die Erforschung mesoporöser Materialien für biomedizinische Anwendungen hat während der letzten Jahre außerordentlich zugenommen. Seit 2001 erstmals MCM-41 als Wirkstoff-Transportsystem vorgeschlagen wurde, wurden Materialien auf Siliciumdioxid-Basis, wie SBA-15 oder MCM-48, und einige metall-organische Gerüste als Wirkstoffträger und Systeme für die kontrollierte Freisetzung diskutiert. Mesoporöse Materialien werden sowohl für den systemischen Transport als auch für implantierbare lokale Abgabeeinheiten in Betracht gezogen. Die zweite Anwendung birgt vielversprechende Möglichkeiten für den Aufbau von Knochengewebe, weil mesoporöse Materialien ein sehr gutes Verhalten als Biokeramiken zeigen. Dieser Kurzaufsatz behandelt die Fortschritte auf diesem Gebiet durch Steuerung der Strukturparameter, Oberflächenfunktionalisierung und Synthese hoch entwickelter stimuliresponsiver Systeme.

Bioceramics are those ceramics designed to be implanted into the human body. In the last fifty years these materials experienced an enormous evolution. Initially, the objective was bio–inertness, that is a minimum interaction with the living organism. These bioceramics are nowadays called first generation. The second generation bioceramics started to be widely investigated in the 1980s with the goal of a positive interaction with living tissues. This group collects bioactive and resorbable bioceramics. At the beginning of the 21stCentury it is clear that the medical paradigm of tissue substitution must be replaced with tissue regeneration. Bioceramics must be supplemented with cells and biologically active molecules. The investigation in third generation bioceramics has just started. In this article, a description of the main second generation ceramics and new advanced ceramics currently under our investigation aimed to be used as scaffolds and templates in third generation biomaterials is presented.

Thermogravimetry, X-ray and electron diffraction and high resolution electron microscopy show that the reduction process from perovskite La0.5Ca0.5MnO3 to brownmilleriteLa0.5Ca0.5MnO2.5 is a reversible topotactic process. Two series of monophasic La0.5Ca0.5MnO3–δ oxygen-deficient perovskites were stabilized in the 0 ≤ δ ≤ 0.12 range, either from reduction of La0.5Ca0.5MnO3 or oxidation of La0.5Ca0.5MnO2.5. Soft X-ray absorption spectroscopy shows that Mn oxidation states differ as a function of the synthetic pathway. Temperature dependence of the magnetization as a function of anionic vacancies concentration at constant doping level are reported together with the evolution of high-resolution O K-edge and Mn L-edge spectra. Our results show dramatic changes in the magnetic behaviour due to the stabilization of different Mn oxidation states.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

The topotactic reduction of La0.5Sr0.5MnO3leads to ordering of the anionic vacancies in the La0.5Sr0.5MnO2.5composition. The isolated material, which is isostructural with Sr2Fe2O5, crystallises in the brownmillerite structural type with unit cell parameters a=0.54117(3), b=1.67608(12), c=0.54004(3) nm and space group Ibm2. Its microstructural characterisation by means of electron diffraction and high‐resolution electron microscopy suggests a complex microstructure arising from the coherent intergrowth of different brownmillerite‐type domains that show short‐range ordering at the A sub‐lattice. The layer structure of La0.5Sr0.5MnO2.5leads to a double magnetic behaviour where a ferromagnetic two‐dimensional component is present.

Organic-inorganic hybrid materials containing amino functional groups were prepared as monoliths and their in vitro bioactivity and degradation were investigated using a simulated body fluid (SBF). The amino-polyorganosiloxane hybrids were obtained via sol-gel starting from N-(2-aminoethyl)-3-aminopropyltrimethoxysilane (DAMO). With the addition of -methacryloxypropyl-trimethoxysilane (MPS), hydrolytically stable and flexible polyorganosiloxane networks were obtained. To induce bioactivity, we added calcium to the hybrids as a calcium salt during the synthesis. A nanocrystalline apatite-like phase was formed on the hybrid surfaces after being soaked in SBF. The bioactivity and degradability of calcium-containing hybrids increased as the DAMO:MPS molar ratio increased, because the molar ratio affects both the functional groups and the charge of the hybrid surfaces, as well as the rate of Ca2release to the SBF solution. Zeta-potential () measurements revealed that at physiological pH, the net surface charge of the bioactive hybrids was negative because of a Si-O-group density higher than that of protonated amino groups (NH3and NH2). These new materials are a promising alternative in bone tissue regeneration because of their tailored in vitro bioactivity and degradability and the presence of amino groups that are able to interact with biological entities.

Abstract: The improvement of bioactive glasses is one of the most important subjects in the field of hard tissue replacement. More than 30 years after being discovered by Prof. Hench, bioactive glasses still attract the attention of many researchers all over the World. With this article we want to pay homage to Prof. Hench by means of reviewing the main contribution of our research team to the field initiated by him in 1969. Our efforts, aimed to go further in the understanding of sol-gel glasses bioactivity as well as to improve the mechanical properties of bioactive materials, are explained.

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Chemistry, materials science and medicine are research areas that converge in the field of drug delivery systems and tissue engineering. This paper tries to introduce an example of such an interaction, aimed at solving health issues within the world of biomaterials. Ordered mesoporous materials can be loaded with different organic molecules that would be released afterwards, in a controlled fashion, inside a living body. These materials can also react with the body fluids giving rise to carbonated nanoapatite particles as the products of such a chemical interaction; these particles, equivalent to biological apatites, enable the regeneration of bone tissue.

Mesoporous silica SBA-15 was prepared to evaluate its effectiveness as a matrix for the controlled delivery of macrolide-type antibiotics. Two types of material were used to evaluate the delivery: calcined samples and samples functionalized with octyltrimethoxysilane and octadecyltrimethoxysilane. The samples were charged with the macrolide antibiotic erythromycin and the release assays were carried out in vitro. It has been observed that the release rate decreases as the population of hydrophobic –CH2moieties in the host increases.

The most significant demand for biomaterials has emerged as a consequence of the need to provide clinical treatment to a large number of patients. The search for potential solutions produces a large demand for materials suitable for bone repair or replacement. Calcium phosphates, bio-glasses, bio-glass ceramics and ordered silica mesoporous materials, among other types of materials, will be reviewed and studied from the point of view of their potential applications as replacement materials in bone repair and regeneration, as potential substrates in tissue engineering, and also as drug delivery systems. An overview on the present achievements, but also on the “missing links” will be presented.

The bioactivity behaviour of SBA-15, MCM-48, MCM-41 mesoporous materials, is revisited in this paper. The influence of their different textural and structural properties on apatite formation is outlined and strategies to modify their kinetics are proven and discussed. On the basis of the experimental data showing the feasibility of control of the bioactivity kinetics on mesoporous materials, together with their controlled drug release abilities, new possibilities for tissue engineering developments are proposed.

Silicon substituted hydroxyapatites SiHA are among the most interesting bioceramics in the field of bioactive bone implants. Silicon incorporation into the apatite structure results in materials with comparable biocompatibility and mechanical properties, but with improved bioactive behaviour. The higher bioactivity promotes the reaction between bone and implant, leading to excellent osteointegration and ensuring the implant success. The improved properties of SiHA compared to pure HA have been demonstrated by both in vitroand in vivotests. In this feature article, the main synthesis methods and results are reviewed for different SiHA. Finally, the role of Si is considered from the point of view of materials science at the crystallographic, micro structural and surface chemistry levels.

A sol-gel dipping method has been utilised to deposit SiO2-CaO films onto Ti6Al4V alloy substrates. These layers were prepared by the dip-coating technique from a series of precursor solutions with different concentrations of glassy xSiO2-(1 − x)CaO (x = 0.8 mol) diluted with absolute ethanol. The characterisation of the films by a variety of techniques reveals differences in the textural properties and in the films’ thicknesses depending on the sol concentration in the precursor solution. Concentrated precursor solutions yield porous layers with a higher thickness and surface roughness than those obtained from the dilute ones. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

Bioactive glasses react chemically with the body fluids. The reaction product is an apatite, which, with the intervention of biological drivers, assists the generation of bone matrix and bone growth. The main application of these bioactive glasses in the clinical field is the filling of osseous cavities, manufacture of small parts for middle ear bone replacement and maxilofacial reconstruction and dental applications. Thanks to advances in related medical technologies, bioactive glasses are now undergoing a new stage of development, resulting in different mechanical properties, drug delivery capabilities, bioactive coating of metallic implants, protein and/or cell activation for tissue regeneration and tissue engineering, and are also finding use in biomimetics, nanotechnology, production of hybrid organic-inorganic materials and as bioactivity accelerators of mineral apatites or as bioactivity inductors of magnetic materials for hyperthermia treatment of osseous tumours. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

This work analyses the textural evolution, characterised by N₂ adsorption and Hg porosimetry, of tin oxide (SnO₂) obtained by spray pyrolysis (300–900 °C) and subjected to thermal treatments at 600 and 800 °C. The so-obtained materials have also been characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM) and energy dispersive spectroscopy (EDS); resistance measurements were made on annealed pellets of these materials. After the thermal treatment, samples obtained at lower pyrolysis temperatures (300–500 °C) undergo a complete collapse of their original structure: the initial hollow spheres transform into polyhedral crystals of the same order of magnitude. On the other hand, those obtained at higher temperatures (700–900 °C) maintain the original morphology, although the initial smooth surface becomes wrinkled due to the increase of the crystals size as a consequence of the sintering process.

In order to test the influence of ceramic morphology and particle size on the behaviour of the ceramic/polymer/drug composite α-Al2O3 /poly(l-lactic acid)/poly(methyl methacrylate)/ibuprofen (α-Al2O3 /PLLA/PMMA/IB) containing the antiinflammatory drug ibuprofen, have been studied. We have used α-alumina synthesised by two preparation methods which provide different morphologies and particle sizes. The influence of these parameters on the ibuprofen release process after the immersion of composites in a buffered solution at pH=7.4 at 37 °C was analysed. The results obtained show that drug release is facilitated in the samples which have smaller particle size, with spherical morphology and a homogeneous size distribution of α-alumina.