Biocompatibility of a lab-on-a-pill sensor in artificial gastrointestinal environments

n this paper, we present a radiotelemetry sensor, designed as a lab-in-a-pill, which incorporates a two-channel microfabricated sensor platform for real-time measurements of temperature and pH. These two parameters have potential application for use in remote biological sensing (for example they may be used as markers that reflect the physiological environment or as indicators for disease, within the gastrointestinal tract). We have investigated the effects of biofouling on these sensors, by exploring their response time and sensitivity in a model in vitro gastrointestinal system. The artificial gastric and intestinal solutions used represent a model both for fasting, as well as for the ingestion of food and subsequent digestion to gastrointestinal chyme. The results showed a decrease in pH sensitivity after exposure of the sensors for 3 h. The response time also increased from an initial measurement time of 10 s in pure GI juice, to ca. 25 s following the ingestion of food and 80 s in simulated chyme. These in vitro results indicate that changes in viscosity in our model gastrointestinal system had a pronounced effect on the unmodified sensor

Modelagem de um sistema de transferência transcutânea de energia adequado aos sistemas implantáveis de infusão contínua de insulina

Monografia (graduação)—Universidade de Brasília, Faculdade UnB Gama, Curso de Engenharia Eletrônica, 2014.A terapia utilizando bombas de infusão de insulina implantáveis é o método mais preciso e eficiente para o tratamento de pacientes portadores de Diabetes Mellitus Tipo 1, no entanto, questões como miniaturização, longetividade e biocompatibilidade dificultam a popularização do método. Em particular, o uso de baterias limitam a capacidade energética e aumentam o tamanho das bombas, além da alta toxicidade e riscos de superaquecimento associados. É investigada a viabilidade da integração de um sistema de transferência transcutânea de energia (TTE) às bombas de infusão de insulina implantáveis, com capacidade de fornecer energia elétrica sem fio através do tecido biológico humano. Serão investigados diversos esquemas de transdução e diferentes arquiteturas de sistemas de transmissão e recepção de energia, avaliando-as pela eficiência da potência transmitida e pela adequabilidade às bombas. Especificamente, este projeto é voltado aos sistemas TTE acoplados acusticamente e passíveis de integração com bombas de infusão de insulina, conferindoas autonomia energética para suprir demandas de até 72 mW. É apresentado um sistema com frequência de operação de 870 kHz capaz de energizar implantes subcutâneos localizados a uma distância de até 30 mm do transmissor. São propostos modelos computacionais, simulados utilizando ferramentas de desenho de circuitos eletrônicos, para a identificação da banda espectral de frequência, das dimensões físicas dos transdutores, dos mecanismos de casamento de impedância acústica, das topologias para geração e retificação de ondas sonoras recomendadas para se atingir a máxima transferência de potência possível. O sistema proposto demonstrou eficiência máxima de 30% capaz de suprir demandas de potência de até 72 mW. Os transdutores de transmissão e recepção utilizados foram cerâmicas piezoelétricas discoidais do tipo PZT-5A com 30 mm e 11 mm de diâmetro, respectivamente. As camadas de acoplamento acústico utilizadas foram a base gel condutivo para ultra-som com espessuras de até 2 mm. A constatação da exequibilidade de um sistema de transferência transcutânea de energia que seja adequado aos sistemas de infusão contínua de insulina constitui um passo fundamental para a construção de um sistema artificial definitivo de controle de glicose e que promete revolucionar a área de dispositivos médicos implantáveis.Therapy with implantable insulin pumps is the most precise and efficient method to treat patients afflicted by Diabetes Mellitus type 1, however, issues such as miniaturization, longevity and biocompatibility difficult the popularization of this method. Particularly, batteries have limited energy budget and increase the pumps size, and are also associated with high toxicity and overheating hazards. This end-of-course project evaluates the viability in integrating a transcutaneous energy transfer (TTE) system with implantable insulin pumps, conferring a capability of supplying, virtually, unlimited power through human biological tissue. Many transduction schemes and power transceiver systems will be investigated and evaluated by its efficiency in transmitting power. Especifically, this project is concerned with ultrasonic TTE based systems as the method for energizing implanted insulin pump devices at power levels up to 100 mW. It is proposed a continuous wave 870 kHz single frequency operation to power devices implanted up to 30 mm deep subcutaneously. The proposed approach is analyzed in detail, with design considerations provided to address issues such as recommended operating frequency range, transducers’ overall dimensions, acoustic link matching, acoustic waves generation and receiver’s rectifying electronics. Global optimization and design considerations for maximum power transfer are presented and verified by means of electronic circuits simulation. The proposed system demonstrated an overall peak power transfer efficiency of 30% at 72 mW output power. The transmitter and receiver transducers consisted of PZT-5A plane discs of 30 mm diameter and 11 mm respectively, with 2 mm thick acoustic matching layer made of couplant ultrasound gel. The verification of feasibility in integrating transcutaneous transfer energy systems with continuous insulin infusion systems is a crucial step towards a definitive closed-loop artificial glucose control system and it is promised to revolutionize the field of implantable medical devices

Suivi de l’opération d’enrobage pour le développement d’une forme posologique facile à avaler pour des fins pédiatriques : étude du procédé et développement d’outils pour un suivi en temps réel

Malgré les mesures récentes des organismes de réglementation, il y a encore des lacunes dans la mise en œuvre de formulations adaptées à l'âge à l’intention de la population pédiatrique. Les différences au sein de cette population, conjuguées à la non-adhésion thérapeutique due au mauvais goût des médicaments, présentent de grands défis pour la formulation de médicaments pris par voie orale. Des formulations orales solides souples, comme les microsphères, ont été proposées comme solutions de rechange aux formulations déjà commercialisées, comme les comprimés ou les formes posologiques orales liquides. Les microsphères sont des systèmes matriciels dans lesquels le principe actif (PA) est dispersé. Le PA est donc subdivisé en plusieurs petites unités posologiques. De plus, les microsphères peuvent être enrobées afin de masquer le goût. La stratégie consiste à appliquer une barrière protectrice à la microsphère qui empêchera la libération du médicament dans la cavité buccale, tout en maintenant une libération immédiate dès que le produit médicamenteux atteint le site d’absorption, pour ainsi obtenir un profil neutre sur le plan du goût sans affecter la biodisponibilité du PA. Les lits d’air fluidisé avec : Wurster sont utilisés depuis plusieurs années dans l’industrie pharmaceutique pour enrober les petites particules, car ils produisent des particules uniformément enrobés. La nécessité d’acquérir une meilleure compréhension des procédés conventionnels utilisés dans l’industrie pharmaceutique est connue. Les organismes de réglementation favorisent l’utilisation des principes de qualité par la conception, ainsi que des nouvelles technologies, comme les outils de la technologie d’analyse des procédés (PAT), dans le but d’élaborer une stratégie pour transformer un procédé de fabrication qui se rapproche davantage d’une forme d’art en procédé basé sur des données scientifiques. La présente thèse porte spécifiquement sur cette question et plus particulièrement sur une meilleure compréhension de la relation entre la formulation de la solution d’enrobage et le procédé d’enrobage pour la dissolution du PA. Dans le cadre de ces travaux, un plan d’expérience D-optimal couplé à la mise en œuvre de trois outils PAT en ligne a permis d’identifier les paramètres critiques du procédé et les attributs critiques du matériau (formulation de la solution d’enrobage) qui influencent la libération in-vitro du PA au pH buccal. Le niveau de l’enrobage, le niveau de plastifiant, le débit, la température du lit et le durcissement sont les paramètres critiques identifiés pour une formation complète du film. La criticité de la morphologie de l’enrobage sur la dissolution dans la salive simulée est également démontrée. La performance en ligne de la spectroscopie Raman, de la spectroscopie proche infrarouge et de la mesure de la réflectance du faisceau focalisé, ainsi que les données du procédé et les attributs des matières premières sont évalués et comparés pour faire le suivi du procédé d’enrobage des microsphères. En recourant à une analyse multiblock partial least squares, il est démontré que la spectroscopie Raman a une performance supérieure pour assurer le suivi du procédé et obtenir ainsi un enrobage constant pour la membrane barrière à couche mince, essentielle à l'observance du patient.Abstract: Despite recent incentives provided by regulatory agencies there is still a gap in the implementation of age-appropriate formulations for the pediatric population. The differences within this population, coupled with the non-compliance due to poor taste, present great challenges for oral drug formulation. Flexible solid oral formulations, such as microspheres, have been proposed as alternatives to existing marketed formulations such as tablets or liquid oral dosage forms. Microspheres are matrix systems where the Active Pharmaceutical Ingredient (API) is dispersed. The API is thus subdivided into a plurality of small dosage units. Additionally, microspheres can be coated as a strategy to achieve taste masking. It consists in applying a protective barrier to the microsphere that will prevent the release of drug in the oral cavity, while maintaining an immediate release once the drug product reaches the absorption site, thereby achieving a taste neutral profile without adversely affect the bioavailabity of the API. To coat small particles Wurster fluid bed coaters have been used for many years in the pharmaceutical industry, as they produce uniformly coated particles. There is a recognized need to better understand conventional processes used within the pharmaceutical industry. The regulatory agencies have encouraged the employment of quality by design principles, together with new technologies, such as Process Analytical Technology (PAT) tools, with the aim of developing a strategy to transform, what is generally considered an art form, into sound science based processes. This thesis specifically concerns this issue by focusing on better understanding the relation between both coating formulation and coating process to dissolution of the API. In this work, a D-optimal design coupled with the implementation of three in-line PAT tools helped identify the critical process parameters and critical material attributes (coating formulation) influencing in-vitro API release at mouth pH. Coating level, plasticizer level, spray rate and product bed temperature and curing are the identified critical parameters for a complete film formation. The criticality of coating morphology on the dissolution in simulated saliva is also demonstrated. The in-line performance of Raman spectroscopy, near infrared spectroscopy and focused beam reflectance measurement, together with process data and raw material attribute is evaluated and compared to monitor the microsphere coating process. By resorting to multiblock partial least squares it is shown that Raman has superior performance to ensure consistent coating performance for thin film barrier membrane, essential to patient compliance

Magnetically Assisted Capsule Endoscopy: A Viable Alternative to Conventional Flexible Endoscopy of the Stomach?

INTRODUCTION: Oesophagogastroduodenoscopy is the investigation of choice to identify mucosal lesions of the upper gastrointestinal tract, but it is poorly tolerated by patients. A simple non-invasive technique to image the upper gastrointestinal tract, which could be made widely available, would be beneficial to patients. Capsule endoscopy is well tolerated by patients but the stomach has proved difficult to visualise accurately with capsule technology due to its’ capacious nature and mucosal folds, which can obscure pathology. MiroCam Navi (Intromedic Ltd, Seoul, Korea) is a capsule endoscope containing a small amount of magnetic material which has been made available with a handheld magnet which might allow a degree of control. This body of work aims to address whether this new technology could be a feasible alternative to conventional flexible endoscopy of the stomach. METHODS: Four studies were conducted to test this research question. The first explores the feasibility of magnetically assisted capsule endoscopy of the stomach and operator learning curve in an ex vivo porcine model. This was followed by a randomised, blinded trial comparing magnetically assisted capsule endoscopy to conventional flexible endoscopy in ex vivo porcine stomach models. Subsequently a prospective, single centre randomised controlled trial in humans examined whether magnetically assisted capsule endoscopy could enhance conventional small bowel capsule endoscopy by reducing gastric transit time. Finally a blinded comparison of diagnostic yield of magnetically assisted capsule endoscopy compared to oesophagogastroduodenoscopy was performed in patients with recurrent or refractory iron deficiency anaemia. RESULTS: In the first study all stomach tags were identified in 87.2% of examinations and a learning curve was demonstrated (mean examination times for the first 23 and second 23 procedures 10.28 and 6.26 minutes respectively (p<0.001). In the second study the difference in sensitivities between oesophagogastroduodenoscopy and conventional flexible endoscopy for detecting beads within an ex vivo porcine stomach model was 1.11 (95% CI 0.06, 28.26) proving magnetically assisted capsule endoscopy to be non-inferior to flexible endoscopy. In the first human study, although there was no significant difference in gastric transit time or capsule endoscopy completion rate between the two groups (p=0.12 and p=0.39 respectively), the time to first pyloric image was significantly shorter in the intervention group (p=0.03) suggesting that magnetic control hastens capsular transit to the gastric antrum but cannot impact upon duodenal passage. In the last study, a total of 38 pathological findings were identified in this comparative study of magnetically assisted capsule endoscopy and conventional endoscopy. Of these, 16 were detected at both procedures, while flexible endoscopy identified 14 additional lesions not seen at magnetically assisted capsule endoscopy and magnetically assisted capsule endoscopy detected 8 abnormalities not seen by oesophagogastroduodenoscopy. No adverse events occurred in either of the human trials. Finally magnetically steerable capsule endoscopy induced less procedural pain, discomfort and distress than oesophagogastroduodenoscopy (p=0.0009, p=0.001 and p=0.006 respectively). CONCLUSION: Magnetically assisted capsule endoscopy is safe, well tolerated and a viable alternative to conventional endoscopy. Further research to develop and improve this new procedure is recommended

Development and reliability of a direct access sensor using flip chip on flex technology with anisotropic conductive adhesive

Technological developments in biomedical microsystems are opening up new opportunities to improve healthcare procedures. Swallowable diagnostic sensing capsules are an example of these. In none of the diagnostic sensing capsules, is the sensor’s first level packaging achieved via Flip Chip Over Hole (FCOH) method using Anisotropic Conductive Adhesive (ACA). In a capsule application with direct access sensor (DAS), ACA not only provides the electrical interconnection but simultaneously seals the interconnect area and the underlying electronics. The development showed that the ACA FCOH was a viable option for the DAS interconnection. Adequate adhesive formed a strong joint that withstood a shear stress of 120N/mm2 and a compressive stress of 6N required to secure the final sensor assembly in place before encapsulation. Electrical characterization of the ACA joint in a fluid environment showed that the ACA was saturated with moisture and that the ions in the solution actively contributed to the leakage current, characterized by the varying rate of change of conductance. Long term hygrothermal aging of the ACA joint showed that a thermal strain of 0.004 and a hygroscopic strain of 0.0052 were present and resulted in a fatigue like process. In-vitro tests showed that high temperature and acidity had a deleterious effect of the ACA and its joint. It also showed that the ACA contact joints positioned at around or over 1mm would survive the gastrointestinal (GI) fluids and would be able to provide a reliable contact during the entire 72hr of the GI transit time. A final capsule demonstrator was achieved by successfully integrating the DAS, the battery and the final foldable circuitry into a glycerine capsule. Final capsule soak tests suggested that the silicone encapsulated system could survive the 72hr gut transition

Ultra-thin and flexible CMOS technology: ISFET-based microsystem for biomedical applications

A new paradigm of silicon technology is the ultra-thin chip (UTC) technology and the emerging applications. Very thin integrated circuits (ICs) with through-silicon vias (TSVs) will allow the stacking and interconnection of multiple dies in a compact format allowing a migration towards three-dimensional ICs (3D-ICs). Also, extremely thin and therefore mechanically bendable silicon chips in conjunction with the emerging thin-film and organic semiconductor technologies will enhance the performance and functionality of large-area flexible electronic systems. However, UTC technology requires special attention related to the circuit design, fabrication, dicing and handling of ultra-thin chips as they have different physical properties compared to their bulky counterparts. Also, transistors and other active devices on UTCs experiencing variable bending stresses will suffer from the piezoresistive effect of silicon substrate which results in a shift of their operating point and therefore, an additional aspect should be considered during circuit design. This thesis tries to address some of these challenges related to UTC technology by focusing initially on modelling of transistors on mechanically bendable Si-UTCs. The developed behavioural models are a combination of mathematical equations and extracted parameters from BSIM4 and BSIM6 modified by a set of equations describing the bending-induced stresses on silicon. The transistor models are written in Verilog-A and compiled in Cadence Virtuoso environment where they were simulated at different bending conditions. To complement this, the verification of these models through experimental results is also presented. Two chips were designed using a 180 nm CMOS technology. The first chip includes nMOS and pMOS transistors with fixed channel width and two different channel lengths and two different channel orientations (0° and 90°) with respect to the wafer crystal orientation. The second chip includes inverter logic gates with different transistor sizes and orientations, as in the previous chip. Both chips were thinned down to ∼20m using dicing-before-grinding (DBG) prior to electrical characterisation at different bending conditions. Furthermore, this thesis presents the first reported fully integrated CMOS-based ISFET microsystem on UTC technology. The design of the integrated CMOS-based ISFET chip with 512 integrated on-chip ISFET sensors along with their read-out and digitisation scheme is presented. The integrated circuits (ICs) are thinned down to ∼30m and the bulky, as well as thinned ICs, are electrically and electrochemically characterised. Also, the thesis presents the first reported mechanically bendable CMOS-based ISFET device demonstrating that mechanical deformation of the die can result in drift compensation through the exploitation of the piezoresistive nature of silicon. Finally, this thesis presents the studies towards the development of on-chip reference electrodes and biodegradable and ultra-thin biosensors for the detection of neurotransmitters such as dopamine and serotonin