Quinoxaline, its derivatives and applications: A state of the art review.

Quinoxaline derivatives are an important class of heterocycle compounds, where N replaces some carbon atoms in the ring of naphthalene. Its molecular formula is C8H6N2, formed by the fusion of two aromatic rings, benzene and pyrazine. It is rare in natural state, but their synthesis is easy to perform. In this review the State of the Art will be presented, which includes a summary of the progress made over the past years in the knowledge of the structure and mechanism of the quinoxaline and quinoxaline derivatives, associated medical and biomedical value as well as industrial value. Modifying quinoxaline structure it is possible to obtain a wide variety of biomedical applications, namely antimicrobial activities and chronic and metabolic diseases treatment.

Quinoxaline, its derivatives and applications: a state of the art review

Quinoxaline derivatives are an important class of heterocycle compounds, where N replaces some carbon atoms in the ring of naphthalene. Its molecular formula is C8H6N2, formed by the fusion of two aromatic rings, benzene and pyrazine. It is rare in natural state, but their synthesis is easy to perform. In this review the State of the Art will be presented, which includes a summary of the progress made over the past years in the knowledge of the structure and mechanism of the quinoxaline and quinoxaline derivatives, associated medical and biomedical value as well as industrial value. Modifying quinoxaline structure it is possible to obtain a wide variety of biomedical applications, namely antimicrobial activities and chronic and metabolic diseases treatment.

Therapeutic applications of viscous and injectable poly(ortho esters).

Poly(ortho esters) (POE) are hydrophobic and bioerodible polymers that have been investigated for pharmaceutical use since the early 1970s. Among the four described generations of POE, the third (POE III) and fourth (POE IV) are promising viscous and injectable materials which have been investigated in numerous biomedical applications. POE III has been extensively studied for ophthalmic drug delivery, it presents an excellent biocompatibility and is currently being investigated as a vehicle for sustained drug delivery to treat diseases of the posterior segment of the eye. POE IV is distinguishable by a highly reproducible and controlled synthesis, a higher hydrophobicity, and an excellent biocompatibility. It is currently under development for a variety of applications, such as ocular delivery, periodontal disease treatment and applications in veterinary medicine. This review will also focus on new perspectives for this promising family of polymers, such as guided tissue regeneration, treatment of osteoarthritis, as well as peptide and protein delivery.

Development of Time - Frequency Techniques for Sonar Applications

Sonar signal processing comprises of a large number of signal processing algorithms for implementing functions such as Target Detection, Localisation, Classification, Tracking and Parameter estimation. Current implementations of these functions rely on conventional techniques largely based on Fourier Techniques, primarily meant for stationary signals. Interestingly enough, the signals received by the sonar sensors are often non-stationary and hence processing methods capable of handling the non-stationarity will definitely fare better than Fourier transform based methods.Time-frequency methods(TFMs) are known as one of the best DSP tools for nonstationary signal processing, with which one can analyze signals in time and frequency domains simultaneously. But, other than STFT, TFMs have been largely limited to academic research because of the complexity of the algorithms and the limitations of computing power. With the availability of fast processors, many applications of TFMs have been reported in the fields of speech and image processing and biomedical applications, but not many in sonar processing. A structured effort, to fill these lacunae by exploring the potential of TFMs in sonar applications, is the net outcome of this thesis. To this end, four TFMs have been explored in detail viz. Wavelet Transform, Fractional Fourier Transfonn, Wigner Ville Distribution and Ambiguity Function and their potential in implementing five major sonar functions has been demonstrated with very promising results. What has been conclusively brought out in this thesis, is that there is no "one best TFM" for all applications, but there is "one best TFM" for each application. Accordingly, the TFM has to be adapted and tailored in many ways in order to develop specific algorithms for each of the applications.

Novel production method of porous surface Ti samples for biomedical application

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Ab initio quantum mechanical investigation of structural and chemical-physical properties of selected minerals for minero-petrological, structural ceramic and biomaterial applications

The purpose of this thesis is the atomic-scale simulation of the crystal-chemical and physical (phonon, energetic) properties of some strategically important minerals for structural ceramics, biomedical and petrological applications. These properties affect the thermodynamic stability and rule the mineral-environment interface phenomena, with important economical, (bio)technological, petrological and environmental implications. The minerals of interest belong to the family of phyllosilicates (talc, pyrophyllite and muscovite) and apatite (OHAp), chosen for their importance in industrial and biomedical applications (structural ceramics) and petrophysics. In this thesis work we have applicated quantum mechanics methods, formulas and knowledge to the resolution of mineralogical problems ("Quantum Mineralogy”). The chosen theoretical approach is the Density Functional Theory (DFT), along with periodic boundary conditions to limit the portion of the mineral in analysis to the crystallographic cell and the hybrid functional B3LYP. The crystalline orbitals were simulated by linear combination of Gaussian functions (GTO). The dispersive forces, which are important for the structural determination of phyllosilicates and not properly con-sidered in pure DFT method, have been included by means of a semi-empirical correction. The phonon and the mechanical properties were also calculated. The equation of state, both in athermal conditions and in a wide temperature range, has been obtained by means of variations in the volume of the cell and quasi-harmonic approximation. Some thermo-chemical properties of the minerals (isochoric and isobaric thermal capacity) were calculated, because of their considerable applicative importance. For the first time three-dimensional charts related to these properties at different pressures and temperatures were provided. The hydroxylapatite has been studied from the standpoint of structural and phonon properties for its biotechnological role. In fact, biological apatite represents the inorganic phase of vertebrate hard tissues. Numerous carbonated (hydroxyl)apatite structures were modelled by QM to cover the broadest spectrum of possible biological structural variations to fulfil bioceramics applications.

Hyperbranched polyglycerols as building blocks for complex amphiphilic structures: synthesis, characterization and applications

Among hyperbranched polymers, polyglycerol is one of the most promising and commonly used macromolecules due to its biocompatibility and versatility. However, the synthesis of high molecular weight polyglycerols still involves many intricacies and has only been understood to a limited extent. Furthermore, only few complex structures like star or block copolymers incorporating polyglycerol have been realized so far. Particularly biocompatible block copolymers are considered promising candidates for biomedical applications.rnThe scope of this thesis was the enhancement of the synthetic process leading to polyglycerol derivatives which implies improved molecular weight control for a broad molecular weight range as well as the assembly of more complex structures like amphiphilic block copolymers. Further insight into the relation between reaction solvent, degree of deprotonation during the ring-opening multibranching polymerization of glycidol and the characteristics of the obtained polymers were achieved within the scope of this work. Based on these results, a novel concept for the preparation of hyperbranched polyglycerols with molecular weights up to 20,000 g/mol was developed, applying a two step synthesis pathway. Starting from a partially deprotonated TMP core, low molecular weight hb-PGs were prepared using the known synthetic protocol that has been established since the late 1990ies. In a subsequent reaction sequence, these well defined polymers were used as hyperbranched macroinitiator cores in order to obtain high molecular weight hb-PGs with remarkably low polydispersity (Mw/Mn < 1.8). Molecular weight control was shown to be excellent and undesired low molecular weight side products were absent. Furthermore, the technique of continuous spin fractionation has been discovered as an efficient method for polyglycerol work-up to remove quantitatively residual monomer- and oligomer traces from hb-PG compositions to result in samples with significantly reduced polydispersities. Based on these results the synthesis of amphiphilic block copolymers containing hydrophilic hyperbranched polyglycerol blocks and linear, apolar poly(propylene oxide) blocks has been significantly improved and augmented to hb-PG-b-l-PPO-b-hb-PG ABA block copolymers. The influence of different polyglycerol-based amphiphiles on the fibril formation was studied by Thioflavin T Fluorescence showing remarkable increasing lag times which is promising in order to enhance the stability of this protein. In addition the first synthesis of poly(glyceryl glycerols) (PGG), introducing a new solketyl glycidyl ether monomer (IGG) was shown. It was furthermore demonstrated that core-functional carbosilane wedges allow application in block copolymer synthesis. Bisglycidolized amine functional polymers were successfully employed as macroinitiators for glycidol polymerization. This resulted in the first example of amphiphilic hyperbranched-hyperbranched polymer structures. Finally, it has been shown that the previously reported synthetic pathway to carboxylated hyperbranched polyglycerol polyelectrolytes can also be applied for the amphiphilic linear-hyperbranched block copolymers. These novel biocompatible and highly amphiphilic polyelectrolytes offer great potential for further investigations. rnrn

Novel magnetic iron oxide nanoparticles coated with poly(ethylene imine)-g-poly(ethylene glycol) for potential biomedical application: synthesis, stability, cytotoxicity and MR imaging

Magnetic iron oxide nanoparticles have found application as contrast agents for magnetic resonance imaging (MRI) and as switchable drug delivery vehicles. Their stabilization as colloidal carriers remains a challenge. The potential of poly(ethylene imine)-g-poly(ethylene glycol) (PEGPEI) as stabilizer for iron oxide (γ-Fe₂O₃) nanoparticles was studied in comparison to branched poly(ethylene imine) (PEI). Carrier systems consisting of γ-Fe₂O₃-PEI and γ-Fe₂O₃-PEGPEI were prepared and characterized regarding their physicochemical properties including magnetic resonance relaxometry. Colloidal stability of the formulations was tested in several media and cytotoxic effects in adenocarcinomic epithelial cells were investigated. Synthesized γ-Fe₂O₃ cores showed superparamagnetism and high degree of crystallinity. Diameters of polymer-coated nanoparticles γ-Fe₂O₃-PEI and γ-Fe₂O₃-PEGPEI were found to be 38.7 ± 1.0 nm and 40.4 ± 1.6 nm, respectively. No aggregation tendency was observable for γ-Fe₂O₃-PEGPEI over 12 h even in high ionic strength media. Furthermore, IC₅₀ values were significantly increased by more than 10-fold when compared to γ-Fe₂O₃-PEI. Formulations exhibited r₂ relaxivities of high numerical value, namely around 160 mM⁻¹ s⁻¹. In summary, novel carrier systems composed of γ-Fe₂O₃-PEGPEI meet key quality requirements rendering them promising for biomedical applications, e.g. as MRI contrast agents.

Boron nitride nanotubes : synthesis, characterization, functionalization, and potential applications

Boron nitride nanotubes (BNNTs) are structurally similar to carbon nanotubes (CNTs), but exhibit completely different physical and chemical properties. Thus, BNNTs with various interesting properties may be complementary to CNTs and provide an alternative perspective to be useful in different applications. However, synthesis of high quality of BNNTs is still challenging. Hence, the major goals of this research work focus on the fundamental study of synthesis, characterizations, functionalization, and explorations of potential applications. In this work, we have established a new growth vapor trapping (GVT) approach to produce high quality and quantity BNNTs on a Si substrate, by using a conventional tube furnace. This chemical vapor deposition (CVD) approach was conducted at a growth temperature of 1200 °C. As compared to other known approaches, our GVT technique is much simpler in experimental setup and requires relatively lower growth temperatures. The as-grown BNNTs are fully characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), electron energy loss spectroscopy (EELS), Energy Filtered Mapping, Raman spectroscopy, Fourier Transform Infra Red spectroscopy (FTIR), UV-Visible (UV-vis) absorption spectroscopy, etc. Following this success, the growth of BNNTs is now as convenient as growing CNTs and ZnO nanowires. Some important parameters have been identified to produce high-quality BNNTs on Si substrates. Furthermore, we have identified a series of effective catalysts for patterned growth of BNNTs at desirable or pre-defined locations. This catalytic CVD technique is achieved based on our finding that MgO, Ni or Fe are the good catalysts for the growth of BNNTs. The success of patterned growth not only explains the role of catalysts in the formation of BNNTs, this technique will also become technologically important for future device fabrication of BNNTs. Following our success in controlled growth of BNNTs on substrates, we have discovered the superhydrophobic behavior of these partially vertically aligned BNNTs. Since BNNTs are chemically inert, resistive to oxidation up to ~1000°C, and transparent to UV-visible light, our discovery suggests that BNNTs could be useful as self-cleaning, insulating and protective coatings under rigorous chemical and thermal conditions. We have also established various approaches to functionalize BNNTs with polymeric molecules and carbon coatings. First, we showed that BNNTs can be functionalized by mPEG-DSPE (Polyethylene glycol-1,2-distearoyl-sn-glycero-3-phosphoethanolamine), a bio-compatible polymer that helps disperse and dissolve BNNTs in water solution. Furthermore, well-dispersed BNNTs in water can be cut from its original length of >10µm to(>20hrs). This success is an essential step to implement BNNTs in biomedical applications. On the other hand, we have also succeeded to functionalize BNNTs with various conjugated polymers. This success enables the dispersion of BNNTs in organic solvents instead of water. Our approaches are useful for applications of BNNTs in high-strength composites. In addition, we have also functionalized BNNTs with carbon decoration. This was performed by introducing methane (CH4) gas into the growth process of BNNT. Graphitic carbon coatings can be deposited on the side wall of BNNTs with thicknesses ranging from 2 to 5 nm. This success can modulate the conductivity of pure BNNTs from insulating to weakly electrically conductive. Finally, efforts were devoted to explore the application of the wide bandgap BNNTs in solar-blind deep UV (DUV) photo-detectors. We found that photoelectric current generated by the DUV light was dominated in the microelectrodes of our devices. The contribution of photocurrent from BNNTs is not significant if there is any. Implication from these preliminary experiments and potential future work are discussed.

Colloidal Nano-apatite Particles with Active Luminescent and Magentic Properties for Biotechnology Applications

Colloidal Nano-apatite Particles with Active Luminescent and Magentic Properties for Biotechnology Applications. The synthesis of functional nano-materials is a burgeoning field that has produced remarkable and consistent breakthroughs over the last two decades. Individual particles have become smaller and shown potential for well defined functionality. However, there are still unresolved problems, a primary one being the loss of functionality and novelty due to uncontrolled aggregation driven by surface energy considerations. As such the first design criteria to harness the true potential of nanoparticles is to prevent unwanted agglomeration by: (1) improving, and, if possible, (2) controlling aggregation behavior. This requires specific knowledge of the chemistry of the immediate locale of the intended application; especially for biologically relevant applications. The latter criterion is also application driven but should be considered, generally, to diversify the range of functional properties that can be achieved. We have now reason to believe that such a novel system with multifunctional capabilities can be synthesized rather conveniently and have far reaching impact in biotechnology and other applications in the near future. We are presently experimenting with the syntheses of spheroidal, metal-doped, colloidal apatite nano-particles (~10 nm) for several potential biomedical applications.

Adsorption of biomedical coating molecules, amino acids, and short peptides on magnetite (110)

Superparamagnetic iron oxide nanoparticles for biomedical applications are usually coated with organic molecules to form a steric barrier against agglomeration. The stability of these coatings is well established in the synthesis medium but is more difficult to assess in physiological environment. To obtain a first theoretical estimate of their stability in such an environment, we perform density functional theory calculations of the adsorption of water, polyvinyl alcohol (PVA) and polyethylene glycol (PEG) coating molecules, as well as the monomer and dimer of glycine as a prototype short peptide, on the (110) surface of magnetite (Fe3O4) in vacuo. Our results show that PVA binds significantly stronger to the surface than both PEG and glycine, while the difference between the latter two is quite small. Depending on the coverage, the wateradsorption strength is intermediate between PVA and glycine. Due to its strongly interacting OH side groups, PVA is likely to remain bound to the surface in the presence of short peptides. This stability will have to be further assessed by molecular dynamics in the solvated state for which the present work forms the basis.

Research lines in Hyperthermia at the Bioinstrumentation Laboratory of the Centre for Biomedical Technology

The Bioinstrumentation Laboratory belongs to the Centre for Biomedical Technology (CTB) of the Technical University of Madrid and its main objective is to provide the scientific community with devices and techniques for the characterization of micro and nanostructures and consequently finding their best biomedical applications. Hyperthermia (greek word for “overheating”) is defined as the phenomenon that occurs when a body is exposed to an energy generating source that can produce a rise in temperature (42-45ºC) for a given time [1]. Specifically, the aim of the hyperthermia methods used in The Bioinstrumentation Laboratory is the development of thermal therapies, some of these using different kinds of nanoparticles, to kill cancer cells and reduce the damage on healthy tissues. The optical hyperthermia is based on noble metal nanoparticles and laser irradiation. This kind of nanoparticles has an immense potential associated to the development of therapies for cancer on account of their Surface Plasmon Resonance (SPR) enhanced light scattering and absorption. In a short period of time, the absorbed light is converted into localized heat, so we can take advantage of these characteristics to heat up tumor cells in order to obtain the cellular death [2]. In this case, the laboratory has an optical hyperthermia device based on a continuous wave laser used to kill glioblastoma cell lines (1321N1) in the presence of gold nanorods (Figure 1a). The wavelength of the laser light is 808 nm because the penetration of the light in the tissue is deeper in the Near Infrared Region. The first optical hyperthermia results show that the laser irradiation produces cellular death in the experimental samples of glioblastoma cell lines using gold nanorods but is not able to decrease the cellular viability of cancer cells in samples without the suitable nanorods (Figure 1b) [3]. The generation of magnetic hyperthermia is performed through changes of the magnetic induction in magnetic nanoparticles (MNPs) that are embedded in viscous medium. The Figure 2 shows a schematic design of the AC induction hyperthermia device in magnetic fluids. The equipment has been manufactured at The Bioinstrumentation Laboratory. The first block implies two steps: the signal selection with frequency manipulation option from 9 KHz to 2MHz, and a linear output up to 1500W. The second block is where magnetic field is generated ( 5mm, 10 turns). Finally, the third block is a software control where the user can establish initial parameters, and also shows the temperature response of MNPs due to the magnetic field applied [4-8]. The Bioinstrumentation Laboratory in collaboration with the Mexican company MRI-DT have recently implemented a new research line on Nuclear Magnetic Resonance Hyperthermia, which is sustained on the patent US 7,423,429B2 owned by this company. This investigation is based on the use of clinical MRI equipment not only for diagnosis but for therapy [9]. This idea consists of two main facts: Magnetic Resonance Imaging can cause focal heating [10], and the differentiation in resonant frequency between healthy and cancer cells [11]. To produce only heating in cancer cells when the whole body is irradiated, it is necessary to determine the specific resonant frequency of the target, using the information contained in the spectra of the area of interest. Then, special RF pulse sequence is applied to produce fast excitation and relaxation mechanism that generates temperature increase of the tumor, causing cellular death or metabolism malfunction that stops cellular division

CDAPubMed: a browser extension to retrieve EHR-based biomedical literature

Over the last few decades, the ever-increasing output of scientific publications has led to new challenges to keep up to date with the literature. In the biomedical area, this growth has introduced new requirements for professionals, e.g., physicians, who have to locate the exact papers that they need for their clinical and research work amongst a huge number of publications. Against this backdrop, novel information retrieval methods are even more necessary. While web search engines are widespread in many areas, facilitating access to all kinds of information, additional tools are required to automatically link information retrieved from these engines to specific biomedical applications. In the case of clinical environments, this also means considering aspects such as patient data security and confidentiality or structured contents, e.g., electronic health records (EHRs). In this scenario, we have developed a new tool to facilitate query building to retrieve scientific literature related to EHRs. Results: We have developed CDAPubMed, an open-source web browser extension to integrate EHR features in biomedical literature retrieval approaches. Clinical users can use CDAPubMed to: (i) load patient clinical documents, i.e., EHRs based on the Health Level 7-Clinical Document Architecture Standard (HL7-CDA), (ii) identify relevant terms for scientific literature search in these documents, i.e., Medical Subject Headings (MeSH), automatically driven by the CDAPubMed configuration, which advanced users can optimize to adapt to each specific situation, and (iii) generate and launch literature search queries to a major search engine, i.e., PubMed, to retrieve citations related to the EHR under examination. Conclusions: CDAPubMed is a platform-independent tool designed to facilitate literature searching using keywords contained in specific EHRs. CDAPubMed is visually integrated, as an extension of a widespread web browser, within the standard PubMed interface. It has been tested on a public dataset of HL7-CDA documents, returning significantly fewer citations since queries are focused on characteristics identified within the EHR. For instance, compared with more than 200,000 citations retrieved by breast neoplasm, fewer than ten citations were retrieved when ten patient features were added using CDAPubMed. This is an open source tool that can be freely used for non-profit purposes and integrated with other existing systems.

Hypercoiling and hydrophobically associating polymers : interfacial synthesis, surface properties and pharmaceutical applications

The objective of the work described was to identify and synthesize a range of biodegradable hypercoiling or hydrophobically associating polymers to mimic natural apoproteins, such as those found in lung surfactant or plasma apolipoproteins. Stirred interfacial polymerization was used to synthesize potentially biodegradable aromatic polyamides (Mw of 12,000-26,000) based on L-Iysine, L-Iysine ethyl ester, L-ornithine and DL-diaminopropionic acid, by reaction with isophthaloyl chloride. A similar technique was used to synthesize aliphatic polyamides based on L-Iysine ethyl ester and either adipoyl chloride or glutaryl chloride resulting in the synthesis of poly(lysine ethyl ester adipamide) [PLETESA] or poly(lysine ethyl ester glutaramide) (Mw of 126,000 and 26,000, respectively). PLETESA was found to be soluble in both polar and non-polar solvents and the hydrophobic/hydrophilic balance could be modified by partial saponification (66-75%) of the ethyl ester side chains. Surface or interfacial tension/pH profiles were used to assess the conformation of both the poly(isophthalamides) and partially saponified PLETESA in aqueous solution. The results demonstrated that a loss of charge from the polymer was accompanied by an initial fall in surface activity, followed by a rise in activity, and ultimately, by polymer precipitation. These observations were explained by a collapse of the polymer chains into non-surface active intramolecular coils, followed by a transition to an amphipathic conformation, and finally to a collapsed hydrophobe. 2-Dimensional NMR analysis of polymer conformation in polar and non-polar solvents revealed intramolecular associations between the hydrophobic groups within partially saponified PLETESA. Unsaponified PLETESA appeared to form a coiled structure in polar solvents where the ethyl ester side chains were contained within the polymer coil. The implications of the secondary structure of PLETESA and potential biomedical applications are discussed.