Hybrid electrochemical sensor platform for capsaicin determination using coarsely stepped cyclic squarewave voltammetry.

A small, standalone electrochemical hybrid sensor platform, combining flexible electronics and screen-printed electrodes, is demonstrated in the determination of capsaicin through adsorptive stripping voltammetry. The sensing scheme was simplified to be compatible with a low-cost device. The simplification involved eliminating the need for additional modification of the electrode and employing a coarsely stepped squarewave voltammetry, a technique which is applicable with less sophisticated instrumentation. This architecture was found to be suitable for concentrations up to at least 5000 µM with a detection limit of 1.98 µM. The screen-printed carbon graphite electrodes were made reusable through an ethanol rinsing protocol. The effect of ethanol/buffer volumetric ratio in the test sample was shown to greatly influence the analytical data, and a fixed 10% (v/v) was chosen as a compromise between signal-to-noise ratio and not exceeding the solubility limit of the desired upper range.

Complement activation by candidate biomaterials of an implantable microfabricated medical device.

Implantable devices realized by microfabrication have introduced a new class of potential biomaterials whose properties would need to be assessed. Such devices include sensors for measuring biological substances like glucose. Thus, 14 different candidate materials intended for design of such a device were investigated with respect to their complement activation potential in human serum. The fluid-phase activation was measured by the products C4d, Bb, C3bc, and the terminal complement complex (TCC), whereas solid-phase activation was measured by deposition of TCC on the material surfaces. No fluid-phase activation was found for materials related to the capsule, carrier, or sealing. Fluid-phase activation was, however, triggered to a various extent in three of the four nanoporous membranes (cellulose, polyamide, and aluminium oxide), whereas polycarbonate was rendered inactive. Solid-phase activation discriminated more sensitively between all the materials, revealing that the capsule candidate polydimethylsiloxane and sealing candidate silicone 3140 were highly compatible, showing significantly lower TCC deposition than the negative control (p < 0.01). Three of the candidate materials were indifferent, whereas the remaining nine showed significantly higher deposition of TCC than the negative control (p < 0.01). In conclusion, complement activation, in particular when examined on the solid phase, discriminated well between the different candidate materials tested and could be used as a guide for the selection of the best-suited materials for further investigation and development of the device.

Activation of polymorphonuclear leukocytes by candidate biomaterials for an implantable glucose sensor.

BACKGROUND: Continuous monitoring of glucose by implantable microfabricated devices offers key advantages over current transcutaneous glucose sensors that limit usability due to their obtrusive nature and risk of infection. A successful sensory implant should be biocompatible and retain long-lasting function. Polymorphonuclear leukocytes (PMN) play a key role in the inflammatory system by releasing enzymes, cytokines, and reactive oxygen species, typically as a response to complement activation. The aim of this study was to perform an in vitro analysis of PMN activation as a marker for biocompatibility of materials and to evaluate the role of complement in the activation of PMN. METHODS: Fifteen candidate materials of an implantable glucose sensor were incubated in lepirudin-anticoagulated whole blood. The cluster of differentiation molecule 11b (CD11b) expression on PMN was analyzed with flow cytometry and the myeloperoxidase (MPO) concentration in plasma was analyzed with enzyme-linked immunosorbent assay. Complement activation was prevented by the C3 inhibitor compstatin or the C5 inhibitor eculizumab. RESULTS: Three of the biomaterials (cellulose ester, polyamide reverse osmosis membrane, and polyamide thin film membrane), all belonging to the membrane group, induced a substantial and significant increase in CD11b expression and MPO release. The changes were virtually identical for these two markers. Inhibition of complement with compstatin or eculizumab reduced the CD11b expression and MPO release dose dependently and in most cases back to baseline. The other 12 materials did not induce significant PMN activation. CONCLUSION: Three of the 15 candidate materials triggered PMN activation in a complement-dependent manner and should therefore be avoided for implementation in implantable microsensors.

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

In 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.

Implementation of radiotelemetry in a lab-in-a-pill format.

A miniaturised lab-in-a-pill device has been produced incorporating a temperature and pH sensor with wireless communication using the 433.92 MHz ISM band. The device has been designed in order to enable real time in situ measurements in the gastrointestinal (GI) tract, and accordingly, issues concerning the resolution and accuracy of the data, and the lifetime of the device have been considered. The sensors, which will measure two key parameters reflecting the physiological environment in the GI (as indicators for disease) were both controlled by an application specific integrated circuit (ASIC). The data were sampled at 10-bit resolution prior to communication off chip as a single interleaved data stream. This incorporated a power saving serial bitstream data compression algorithm that was found to extend the service lifetime of the pill by 70%. An integrated on-off keying (OOK) radio transmitter was used to send the signal to a local receiver (base station), prior to acquisition on a computer. A permanent magnet was also incorporated in the device to enable non-visual tracking of the system. We report on the implementation of this device, together with an initial study sampling from within the porcine GI tract, showing that measurements from the lab-on-a-pill, in situ, was within 90% of literature values.

A programmable microsystem using system-on-chip for real-time biotelemetry.

A telemetry microsystem, including multiple sensors, integrated instrumentation and a wireless interface has been implemented. We have employed a methodology akin to that for System-on-Chip microelectronics to design an integrated circuit instrument containing several "intellectual property" blocks that will enable convenient reuse of modules in future projects. The present system was optimized for low-power and included mixed-signal sensor circuits, a programmable digital system, a feedback clock control loop and RF circuits integrated on a 5 mm x 5 mm silicon chip using a 0.6 microm, 3.3 V CMOS process. Undesirable signal coupling between circuit components has been investigated and current injection into sensitive instrumentation nodes was minimized by careful floor-planning. The chip, the sensors, a magnetic induction-based transmitter and two silver oxide cells were packaged into a 36 mm x 12 mm capsule format. A base station was built in order to retrieve the data from the microsystem in real-time. The base station was designed to be adaptive and timing tolerant since the microsystem design was simplified to reduce power consumption and size. The telemetry system was found to have a packet error rate of 10(-3) using an asynchronous simplex link. Trials in animal carcasses were carried out to show that the transmitter was as effective as a conventional RF device whilst consuming less power.

Implementation of multichannel sensors for remote biomedical measurements in a microsystems format.

A novel microelectronic "pill" has been developed for in situ studies of the gastro-intestinal tract, combining microsensors and integrated circuits with system-level integration technology. The measurement parameters include real-time remote recording of temperature, pH, conductivity, and dissolved oxygen. The unit comprises an outer biocompatible capsule encasing four microsensors, a control chip, a discrete component radio transmitter, and two silver oxide cells (the latter providing an operating time of 40 h at the rated power consumption of 12.1 mW). The sensors were fabricated on two separate silicon chips located at the front end of the capsule. The robust nature of the pill makes it adaptable for use in a variety of environments related to biomedical and industrial applications.

Micromachined nanocalorimetric sensor for ultra-low-volume cell-based assays.

Current strategies for cell-based screening generally focus on the development of highly specific assays, which require an understanding of the nature of the signaling molecules and cellular pathways involved. In contrast, changes in temperature of cells provides a measure of altered cellular metabolism that is not stimulus specific and hence could have widespread applications in cell-based screening of receptor agonists and antagonists, as well as in the assessment of toxicity of new lead compounds. Consequently, we have developed a micromachined nanocalorimetric biological sensor using a small number of isolated living cells integrated within a subnanoliter format, which is capable of detecting 13 nW of generated power from the cells, upon exposure to a chemical or pharmaceutical stimulus. The sensor comprises a 10-junction gold and nickel thermopile, integrated on a silicon chip which was back-etched to span a 800-nm-thick membrane of silicon nitride. The thin-film membrane, which supported the sensing junctions of the thermoelectric transducer, gave the system a temperature resolution of 0.125 mK, a low heat capacity of 1.2 nJ mK(-1), and a rapid (unfiltered) response time of 12 ms. The application of the system in ultra-low-volume cell-based assays could provide a rapid endogenous screen. It offers important additional advantages over existing methods in that it is generic in nature, it does not require the use of recombinant cell lines or of detailed assay development, and finally, it can enable the use of primary cell lines or tissue biopsies.

A suspended membrane nanocalorimeter for ultralow volume bioanalysis.

A nanocalorimetric suspended membrane sensor for pL volumes of aqueous media was fabricated by bulk silicon micromachining using anisotropic wet etching and photo and electron beam lithographic techniques. A high-temperature sensitivity of 125 microK and a rapid unfiltered time constant of 12 ms have been achieved by integrating a miniaturized reaction vessel of 0.7-nL volume on a 800-nm-thick and 300 x 300- microm2-large silicon nitride membrane, thermally insulated from the surrounding bulk silicon. The combination of a ten-junction gold and nickel thermoelectric sensor with an integrated ultralow noise preamplifier has enabled the resolution of 15-nW power in a single measurement, a result confirmed by electrical calibration. The combination of a high sensitivity and rapid response time is a consequence of miniaturization. The choice of gold and nickel as sensor material provided the maximum thermal sensitivity in the context of ease of fabrication and cost. The nanocalorimetric sensor has the potential for integration in an ultralow-volume high-density array format for the characterization of processes in which there is an exchange of heat.