Transimpedance amplifier for early detection of breast cancer

Breast cancer is the most common type of cancer worldwide. The effectiveness of its treatment depends on early stage detection, as well as on the accuracy of its diagnosis. Recently, diagnosis techniques have been submitted to relevant breakthroughs with the upcoming of Magnetic Resonance Imaging, Ultrasound Sonograms and Positron Emission Tomography (PET) scans, among others. The work presented here is focused on studying the application of a PET system to a Positron Emission Mammography (PEM) system. A PET/PEM system works under the principle that a scintillating crystal will detect a gamma-ray pulse, originated at the cancerous cells, converting it into a correspondent visible light pulse. The latter must then be converted into an electrical current pulse by means of a Photo- -Sensitive Device (PSD). After the PSD there must be a Transimpedance Amplifier (TIA) in order to convert the current pulse into a suitable output voltage, in a time period lower than 40 ns. In this Thesis, the PSD considered is a Silicon Photo-Multiplier (SiPM). The usage of this recently developed type of PSD is impracticable with the conventional TIA topologies, as it will be proven. Therefore, the usage of the Regulated Common-Gate (RCG) topology will be studied in the design of the amplifier. There will be also presented two RCG variations, comprising a noise response improvement and differential operation of the circuit. The mentioned topology will also be tested in a Radio-Frequency front-end, showing the versatility of the RCG. A study comprising a low-voltage self-biasing feedback TIA will also be shown. The proposed circuits will be simulated with standard CMOS technology (UMC 130 nm), using a 1.2 V power supply. A power consumption of 0.34 mW with a signal-to-noise ratio of 43 dB was achieved.

A continuous solvent- and oil-free method to prepare injectable PEGylated fibrinogen cell-laden microparticles

Injectable biomaterials with in situ cross-linking reactions have been suggested to minimize the invasiveness associated with most implantation procedures. However, problems related with the rapid liquid-to-gel transition reaction can arise because it is difficult to predict the reliability of the reaction and its end products, as well as to mitigate cytotoxicity to the surrounding tissues. An alternative minimally invasive approach to deliver solid implants in vivo is based on injectable microparticles, which can be processed in vitro with high fidelity and reliability, while showing low cytotoxicity. Their delivery to the defect can be performed by injection through a small diameter syringe needle. We present a new methodology for the continuous, solvent- and oil-free production of photopolymerizable microparticles containing encapsulated human dermal fibroblasts. A precursor solution of cells in photo-reactive PEG-fibrinogen (PF) polymer was transported through a transparent injector exposed to light-irradiation before being atomized in a jet-in-air nozzle. Shear rheometry data provided the cross-linking kinetics of each PF/cell solution, which was then used to determine the amount of irradiation required to partially polymerize the mixture prior to atomization. The partially polymerized drops fell into a gelation bath for further polymerization. The system was capable of producing cell-laden microparticles with high cellular viability, with an average diameter of between 88.1 µm to 347.1 µm and a dispersity of between 1.1 and 2.4, depending on the parameters chosen.

Fucoidan-based particles for diabetes mellitus treatment

Marine organisms are rich in a variety of materials with potential use in Tissue Engineering and Regenerative Medicine. One important example is fucoidan, a sulfated polysaccharide extracted from the cell wall of brown seaweeds.  Fucoidan is composed by L-fucose, sulfate groups and glucuronic acid. It has important bioactive properties such as anti-oxidative, anticoagulant, anticancer and reducing the blood glucose (1). In this work, the biomedical potential of fucoidan-based materials as drug delivery system was assessed by processing modified fucoidan (MFu) into particles by photocrosslinking using superamphiphobic surfaces and visible light. Fucoidan was modified by methacrylation reaction using different concentrations of methacrylate anhydride, namely 8% v/v (MFu1) and 12% v/v (MFu2). Further, MFu particles with and without insulin (5% w/v) were produced by pipetting a solution of 5% MFu with triethanolamine and eosin-y onto a superamphiphobic surface and then photocrosslinking using visible light (2). The developed particles were characterized to assess their chemistry, morphology, swelling behavior, drug release, insulin content and encapsulation efficiency. Moreover, the viability assays of fibroblast L929 cells in contact with MFu particles showed good adhesion and proliferation up to 14 days. Furthermore, the therapeutic potential of these particles using human beta cells is currently under investigation. Results obtained so far suggest that modified fucoidan particles could be a good candidate for diabetes mellitus therapeutic approaches.  

Gd2O3: Eu Nanoparticle-Based Poly(vinylidene fluoride) Composites for Indirect X-ray Detection

Polymer based scintillator composites have been fabricated by combining poly(vinylidene fluoride) (PVDF) and Gd2O3:Eu nanoparticles (50nm). PVDF has been used since it is a flexible and stable binder matrix and highly resistance to thermal and light deterioration. Gd2O3:Eu has been selected as scintillator material due to its wide band gap, high density and suitable visible light yield. The structural, mechanical, thermal and electrical characteristics of the composites were studied as a function of filler content, together with their performance as scintillator material. The introduction of Gd2O3:Eu nanoparticles into the PVDF matrix does not influence the morphology of the polymer or the degree of crystallinity. On the other hand, an increase of the Young´s modulus with respect to PVDF matrix is observed for filler contents of 0.1-0.75 wt.%. The introduction of Gd2O3:Eu into the PVDF matrix increases dielectric constant and DC electrical conductivity as well as the visible light yield in the nanocomposite, being this increase dependent upon Gd2O3:Eu content and X-ray input power. In this way, Gd2O3:Eu/PVDF composites shows suitable characteristics to be used as X-ray radiation transducers, in particular for large area applications.

Electronic structure and optical signatures of semiconducting transition metal dichalcogenide nanosheets

CONSPECTUS: Two-dimensional (2D) crystals derived from transition metal dichalcogenides (TMDs) are intriguing materials that offer a unique platform to study fundamental physical phenomena as well as to explore development of novel devices. Semiconducting group 6 TMDs such as MoS2 and WSe2 are known for their large optical absorption coefficient and their potential for high efficiency photovoltaics and photodetectors. Monolayer sheets of these compounds are flexible, stretchable, and soft semiconductors with a direct band gap in contrast to their well-known bulk crystals that are rigid and hard indirect gap semiconductors. Recent intense research has been motivated by the distinct electrical, optical, and mechanical properties of these TMD crystals in the ultimate thickness regime. As a semiconductor with a band gap in the visible to near-IR frequencies, these 2D MX2 materials (M = Mo, W; X = S, Se) exhibit distinct excitonic absorption and emission features. In this Account, we discuss how optical spectroscopy of these materials allows investigation of their electronic properties and the relaxation dynamics of excitons. We first discuss the basic electronic structure of 2D TMDs highlighting the key features of the dispersion relation. With the help of theoretical calculations, we further discuss how photoluminescence energy of direct and indirect excitons provide a guide to understanding the evolution of the electronic structure as a function of the number of layers. We also highlight the behavior of the two competing conduction valleys and their role in the optical processes. Intercalation of group 6 TMDs by alkali metals results in the structural phase transformation with corresponding semiconductor-to-metal transition. Monolayer TMDs obtained by intercalation-assisted exfoliation retains the metastable metallic phase. Mild annealing, however, destabilizes the metastable phase and gradually restores the original semiconducting phase. Interestingly, the semiconducting 2H phase, metallic 1T phase, and a charge-density-wave-like 1T' phase can coexist within a single crystalline monolayer sheet. We further discuss the electronic properties of the restacked films of chemically exfoliated MoS2. Finally, we focus on the strong optical absorption and related exciton relaxation in monolayer and bilayer MX2. Monolayer MX2 absorbs as much as 30% of incident photons in the blue region of the visible light despite being atomically thin. This giant absorption is attributed to nesting of the conduction and valence bands, which leads to diversion of optical conductivity. We describe how the relaxation pathway of excitons depends strongly on the excitation energy. Excitation at the band nesting region is of unique significance because it leads to relaxation of electrons and holes with opposite momentum and spontaneous formation of indirect excitons.

Novas funcionalidades para dispositivos médicos invasivos com imagem

Tese de Doutoramento em Engenharia Eletrónica e de Computadores.

Empleo de óptica adaptativa y fluorescencia en un oftalmoscopio laser de barrido para el registro de células

Estudio elaborado a partir de una estancia en la Universidad de Rochester, Estados Unidos, de octubre del 2006 a enero del 2007. La estancia realizada en la Universidad de Rochester estuvo orientada al aprendizaje en profundidad del oftalmoscopio láser de barrido. El oftalmoscopio láser de barrido emplea una técnica confocal con la finalidad de visualizar diferentes estructuras retinianas en seres vivos. El instrumento diseñado y desarrollado en el Centro de Ciencias de la Visión incorpora un sistema de óptica adaptativa y fluorescencia. La óptica adaptativa aplicada en este oftalmoscopio tiene como objetivo corregir las aberraciones existentes en el ojo y así permitir observar detalles de la retina que de otra forma se verían emborronados. De esta forma se consigue alcanzar valores de resolución muy cercanos a los impuestos por difracción. Por otro lado el uso de fluorescencia tiene por objetivo el permitir la visualización de células y estructuras que, de no ser teñidas, son transparentes a la luz y visible. Esta técnica se ha estado utilizando principalmente en primates y ratas, aunque actualmente también se están llevando a cabo medidas de células de epitelio pigmentario en seres humanos ya que el pigmento contenido en estas células permite la aplicación de la fluorescencia sin necesidad de utilizar tinción.

Arabidopsis NPH1: a flavoprotein with the properties of a photoreceptor for phototropism.

The NPH1 gene of Arabidopsis thaliana encodes a 120-kilodalton serine-threonine protein kinase hypothesized to function as a photoreceptor for phototropism. When expressed in insect cells, the NPH1 protein is phosphorylated in response to blue light irradiation. The biochemical and photochemical properties of the photosensitive protein reflect those of the native protein in microsomal membranes. Recombinant NPH1 noncovalently binds flavin mononucleotide, a likely chromophore for light-dependent autophosphorylation. The fluorescence excitation spectrum of the recombinant protein is similar to the action spectrum for phototropism, consistent with the conclusion that NPH1 is an autophosphorylating flavoprotein photoreceptor mediating phototropic responses in higher plants.

Photodamage to Oxygen Evolving Complex - An Initial Event in Photoinhibition of Photosystem II.

Photosystem II (PSII) of oxygenic photosynthesis is susceptible to photoinhibition. Photoinhibition is defined as light induced damage resulting in turnover of the D1 protein subunit of the reaction center of PSII. Both visible and ultraviolet (UV) light cause photoinhibition. Photoinhibition induced by UV light damages the oxygen evolving complex (OEC) via absorption of UV photons by the Mn ion(s) of OEC. Under visible light, most of the earlier hypotheses assume that photoinhibition occurs when the rate of photon absorption by PSII antenna exceeds the use of the absorbed energy in photosynthesis. However, photoinhibition occurs at all light intensities with the same efficiency per photon. The aim of my thesis work was to build a model of photoinhibition that fits the experimental features of photoinhibition. I studied the role of electron transfer reactions of PSII in photoinhibition and found that changing the electron transfer rate had only minor influence on photoinhibition if light intensity was kept constant. Furthermore, quenching of antenna excitations protected less efficiently than it would protect if antenna chlorophylls were the only photoreceptors of photoinhibition. To identify photoreceptors of photoinhibition, I measured the action spectrum of photoinhibition. The action spectrum showed resemblance to the absorption spectra of Mn model compounds suggesting that the Mn cluster of OEC acts as a photoreceptor of photoinhibition under visible light, too. The role of Mn in photoinhibition was further supported by experiments showing that during photoinhibition OEC is damaged before electron transfer activity at the acceptor side of PSII is lost. Mn enzymes were found to be photosensitive under visible and UV light indicating that Mn-containing compounds, including OEC, are capable of functioning as photosensitizers both in visible and UV light. The experimental results above led to the Mn hypothesis of the mechanism of continuous-light-induced photoinhibition. According to the Mn hypothesis, excitation of Mn of OEC results in inhibition of electron donation from OEC to the oxidized primary donor P680+ both under UV and visible light. P680 is oxidized by photons absorbed by chlorophyll, and if not reduced by OEC, P680+ may cause harmful oxidation of other PSII components. Photoinhibition was also induced with intense laser pulses and it was found that the photoinhibitory efficiency increased in proportion to the square of pulse intensity suggesting that laser-pulse-induced photoinhibition is a two-photon reaction. I further developed the Mn hypothesis suggesting that the initial event in photoinhibition under both continuous and pulsed light is the same: Mn excitation that leads to the inhibition of electron donation from OEC to P680+. Under laser-pulse-illumination, another Mn-mediated inhibitory photoreaction occurs within the duration of the same pulse, whereas under continuous light, secondary damage is chlorophyll mediated. A mathematical model based on the Mn hypothesis was found to explain photoinhibition under continuous light, under flash illumination and under the combination of these two.

Optical-geometrical effects on the photoluminescence spectra of Si nanocrystals embedded in SiO2

We demonstrate that thickness, optical constants, and details of the multilayer stack, together with the detection setting, strongly influence the photoluminescence spectra of Si nanocrystals embedded in SiO2. Due to multiple reflections of the visible light against the opaque silicon substrate, an interference pattern is built inside the oxide layer, which is responsible for the modifications in the measured spectra. This interference effect is complicated by the depth dependence of (i) the intensity of the excitation laser and (ii) the concentration of the emitting nanocrystals. These variations can give rise to apparent features in the recorded spectra, such as peak shifts, satellite shoulders, and even splittings, which can be mistaken as intrinsic material features. Thus, they can give rise to an erroneous attribution of optical bands or estimate of the average particle size, while they are only optical-geometrical artifacts. We have analyzed these effects as a function of material composition (Si excess fraction) and thickness, and also evaluated how the geometry of the detection setup affects the measurements. To correct the experimental photoluminescence spectra and extract the true spectral shape of the emission from Si nanocrystals, we have developed an algorithm based on a modulation function, which depends on both the multilayer sequence and the experimental configuration. This procedure can be easily extended to other heterogeneous systems.

Drug targeting strategies for photodynamic therapy.

In human pathologies, therapeutic treatments are often limited by the lack of selectivity of drugs and their elevated effective concentrations. Targeting these agents to a defined tissue could enhance their selectivity and then diminish their side effects when compared to drugs that accumulate in the entire body. Targeting could also improve treatment efficiency by allowing a localized high concentration of the agents. Based on the different behaviors and patterns of expression between diseased and normal cells, strategies for targeting can be explored. For example, receptors, proteases or trans-membrane carriers could be different or differently expressed. Many therapeutic procedures rely on this fact, including photodynamic therapy (PDT). PDT is already used in the treatment of some cancers, of inflammatory diseases and others diseases such as age-related macular degeneration or acne. PDT relies on the activation of a photosensitizer (PS) by visible light which results in the production of cytotoxic reactive oxygen species. In PDT, the general distribution of PS to the whole body leads to generalized photosensitization and poor acceptance of treatments by patients. One way to avoid these effects is to improve the targeting of PSs to diseased tissues using modification of PS with peptides or proteins that will target specific receptors or enzymes. PSs could also be functionalized with non-proteic ligands such as organometalics to achieve targeted and/or combined therapies. Alternatively, PSs could be encapsulated in nanoparticles bearing targeting agents which will decrease concentration of free circulating PS and improve photodynamic efficiency. These different approaches will be discussed in the present review with an emphasis on the use of peptides and proteins.

Thrombin-sensitive photodynamic agents: a novel strategy for selective synovectomy in rheumatoid arthritis.

Protease-sensitive macromolecular prodrugs have attracted interest for bio-responsive drug delivery to sites with up-regulated proteolytic activities such as inflammatory or cancerous lesions. Here we report the development of a novel polymeric photosensitizer prodrug (T-PS) to target thrombin, a protease up-regulated in synovial tissues of rheumatoid arthritis (RA) patients, for minimally invasive photodynamic synovectomy. In T-PS, multiple photosensitizer units are tethered to a polymeric backbone via short, thrombin-cleavable peptide linkers. Photoactivity of the prodrug is efficiently impaired due to energy transfer between neighbouring photosensitizer units. T-PS activation by exogenous and endogenous thrombin induced an increase in fluorescence emission by a factor of 16 after in vitro digestion and a selective fluorescence enhancement in arthritic lesions in vivo, in a collagen-induced arthritis mouse model. In vitro studies on primary human synoviocytes showed a phototoxic effect only after enzymatic digestion of the prodrug and light irradiation, thus demonstrating the functionality of T-PS induced PDT. The developed photosensitizer prodrugs combine the passive targeting capacity of macromolecular drug delivery systems with site-selective photosensitizer release and activation. They illuminate lesions with pathologically enhanced proteolytic activity and induce cell death, subsequent to irradiation.

Sulpun kuvantaminen painelajittelussa

Painelajittelussa sellusta poistetaan epäpuhtauksia. Painelajittimien suunnittelussa on tärkeää ymmärtää lajittimessa tapahtuvia ilmiöitä. Työn tavoitteena oli kehittää kuvaamiseen perustuva mittausjärjestelmä kuitujen liikkeiden mittaamista varten. Mittauksen kohteena ovat sellusulpun kuitujen ja epäpuhtauksien nopeudet. Kuvaamisessa käytetyllä kaksoisvalotuksella pystytään mittaamaan kuitujen ja roskien nopeuksia. Nopeuksien mittaamiseen kuvista kehitettiin järjestelmä ja tutkittiin mahdollisuutta automatisoida mittaaminen. Yksittäisten kuitujen havaitsemiseen sellumassasta käytettiin optisella kirkasteella kirkastettuja kuituja ja UV-valoa. Kuituja värjättiin myös mustiksi ja kuvattiin näkyvällä valolla. Kaksoisvalotukseen käytettiin kahta stroboskooppia. Prosessin kuvaamisessa käytettiin ulkoisella herätteellä ohjattavaa kameraa. Kuvan tuomiseen kameralle ja kohteen valaistukseen käytettiin boroskooppia. Saatujen kuvien käsittelyä ja nopeuksien mittausta varten tehtiin tietokoneohjelma. Käytetyn boroskoopin valovoima ei ollut riittävä kuvausten suorittamiseen, mutta muilta osin laitteisto havaittiin toimivaksi. Kuitujen ja roskien nopeuksia pystyttiin laskemaan ohjelmalla kuvista, joita otettiin ilman boroskooppia. Mittaustiedon hankinnan automatisointi näyttää mahdolliselta tekemällä muutoksia kuvauslaitteistoon.

Suodatuskalvon puhdistaminen UV-valolla tai ultraäänellä aktivoidulla titaanidioksidilla

Kalvotekniikan suurin ongelma on edelleen kalvon likaantuminen, jonka tuloksena kalvon erotuskyky voi muuttua ja liuoksen vuo kalvon läpi pientyä huomattavasti. Kalvotekniikan teollisissa sovelluksissa kalvojen puhdistus on yksi tärkeimmistä pääkohdista, sillä se määrittää kalvon käyttöikää ja käyttötehokkuutta. Yleisimmin käytetyn kemiallisen pesun tuloksena muodostuu hävitettävä pesuliuos, joka sisältää sekä kemikaaleja, että kalvosta poistetun lian. Työssä on tutkittu kalvon puhdistusta ultravioletti-valo- tai ultraäänikäsittelyssä titaanidioksidin läsnäollessa. Menetelmien mahdollisina etuina ovat kalvosta poistetun lian hajotus harmittomiksi komponenteiksi ja mahdollisesti kalvon pienempi kuluminen pesussa. Työn kirjallisuusosassa on käsitelty orgaanisten ja epäorgaanisten aineiden hajottamista ultraviolettivalon tai ultraäänikäsittelyn avulla titaanidioksidin läsnäollessa sekä olosuhteiden vaikutusta menetelmien tehokkuuteen. Tämän lisäksi työssä on keskitytty polymeerikalvojen UV-valo- ja ultraäänikäsittelykestävyyteen. Kokeellisessa osassa on tutkittu UV-valo- ja ultraäänikäsittelyjen sopivuutta liatun PVDF-kalvon puhdistukseen titaanidioksidin läsnäollessa. Tavoitteena oli liatun kalvon permeabiliteetin palautus puhtaan kalvon tasolle käsittelyn avulla. Kalvon kestävyyttä on myös tutkittu. Tämän työn perusteella tutkittuja menetelmiä ei voida soveltaa tarkistettavan PVDF-kalvon puhdistukseen, ainakaan testeissä käytetyissä olosuhteissa, sillä kalvon ominaisuudet muuttuvat käsittelyissä.

Inativação fotodinâmica de microrganismos

Photodynamic Therapy uses photosensitive dyes and visible light that, combined in the presence of oxygen, produce cytotoxic species that cause tumor death. Microorganisms such as bacteria, fungi, yeasts and viruses (including HIV) can also be inactivated by visible light after treatment with an appropriate photosensitizer as an alternative low cost treatment for localized infections, viral lesions such as acnes, and fungical skin lesions for example. Besides, Photodynamic Inactivation can be used for sterilization of blood and its subproducts for clinical use, in the treatment of drinking water as well as in antimicrobial detoxification of foods.