Electrochemical multi sensors for biomedical applications

Abstract

[spa] El diagnóstico médico es uno de los campos que han obtenido más ventajas de la capacidad de los electrodos selectivos de iones (ESI) para la detección de iones, ya que los cambios en la concentración de estos elementos están directamente relacionados con diferentes enfermedades. La detección de isquemia es una de las favorecidas por estos sensores. La isquemia es una disminución del suministro de sangre a un órgano y se requiere una detección rápida y precisa. Los métodos de detección in situ en el tejido de los órganos conllevan una detección temprana de la isquemia y el estómago es uno de los órganos más importantes en la detección de Ischemia. Sin embargo, el bajo pH del jugo gástrico del estómago hace difícil la fabricación de sensores de estado sólido con ESI estables y funcionales, principalmente debido a la interferencia de aniones y al problema de la adhesión entre la membrana ESI y la superficie del electrodo. En esta tesis, se han diseñado y fabricado electrodos selección de iones de pH y potasio ESI de estado sólido basados en la potenciometría y sensores de bioimpedancia y se han integrado en una matriz en miniatura para su aplicación en la cirugía endoscópica para la detección de isquemia in vivo en el interior del estómago. El conjunto de sensores se integró con éxito en endoscopio comercial y se inserto en el interior del estómago de un cerdo. El flujo de sangre de cierta área del estómago se interrumpió mediante la ligación o pinzamiento de los vasos sanguineos y la pared del órgano. Los pasos de isquemia y reperfusión fueron detectados con éxito con los sensores de potasio y de pH. Estos resultados también indican que se puede obtener información sobre el daño en el tejido hipóxico recogido con esta matriz. Los sensores de pH de sólido desarrollados permiten la detección pH bajos de 0,7 a 2,5, que es el único ejemplo en la literatura de detección de pH tan bajos con este tipo de sensores y por lo tanto hacen que sea este sensor de un dispositivo único para la detección de isquemia en el estómago.

[eng] In this thesis, pH and potassium all-solid-state ISE based on potentiometry and bioimpedance sensors were designed, fabricated and integrated in a miniaturized array for its application in endoscopic surgery for in vivo ischemia detection inside the stomach. To achieve this goal, the developed array withstood the low pH and corrosive condition in the gastric juice of the stomach, by modifying the surface with a conductive Ag/AgCl ink containing hydrophilic and hydrophobic groups. That creates a stable and robust candidate for low pH applications. However, these sensors have to demonstrate besides stability, high sensitivity, and selectivity. For this purpose, different ionophores specific to a single ion were tested. Octadecyl isonicotinate was the one that shown better results as pH ionophore and valinomycin, bis [(benzo-15-crown-4)-4-ylmethyl] pimelate for potassium detection. All these ionophores were embedded in PVC polymer membrane containing also plasticizers such as 2-nitrophenyl octyl ether, bis (1-butylpentyl) adipate (BBPA) and liphophilic anionic additives such as potassium tetrakis (4-chlorophenyl) borate (KTpClPB). The specific compositions of membranes to detect potassium or pH were optimized for the better performance of the sensors. pH ISE sensor shows a nernstian behavior (-54,38 mV/pH) at low pH and a nearly nernstian behavior at physiological pH (-34,899 mV/pH). Bioimpedance sensor was tested and optimized in vitro with different solutions of ions concentration to mimic ischemia detection and with different kinds of tissues from different nature. For this purpose, chicken fat and breast tissues were taken as a model for mimicking non-ischemic and ischemic states respectively. The effect of electrodes insulation as well as the pressure applied on the tissue was studied. The dependence of the impedance response with different pressure applied to the sensor was overcome by applying magnetic field attachment. The sensor array was modified with ring magnets which were attracted by an external magnet, giving stable and reliable signal discarding mechanical motion. The shape and size of the sensor array were designed for being adapted to the commercially available gastroendoscopes. Round shaped cylinder of 7 mm diameter was fabricated with 12 electrodes pin of 600 µm diameter, containing 3 RE, 3 pH and 2 potassium all-solid-state sensors and 4 electrodes in a row for impedance measurements. The sensor array was successfully integrated in commercial endoscope and inserted inside the pig stomach. The blood flow of certain area of the stomach was interrupted by ligating or crossclamping vessels and organ wall. Ischemia and reperfusion steps were sensed successfully with potassium and pH sensors. These results also indicate that information about hypoxic tissue damage can be collected with this array. Ischemia was also sensed on small intestine tissue by opening the abdominal part of the body and getting the sensor array in contact with the intestine. By crossclamping of mesenteric artery by tourniquets and scissors, ischemic and reperfusion states were controlled. Results proved that ischemia and reperfusion can be monitored by our integrated sensor array. As a conclusion, a novel all-solid-state potentiometric, miniaturized, low cost and mass producible pH, potassium all-solid-state ISE and impedance sensors integrated in an array was successfully fabricated for detecting ischemia inside the stomach by means of endoscopic techniques and also on small intestine. This array was tested in vitro and vivo giving reproducible and reliable results. The developed all-solid-state pH sensors permit low pH sensing from 0.7-2.5, which is the only example in the literature that allows so low pH detection, and so make this sensor a unique device for stomach detection.