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ArticleJune 12, 2015

3D Printed Microfluidic Device with Integrated Biosensors for Online Analysis of Subcutaneous Human Microdialysate
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Analytical Chemistry

Cite this: Anal. Chem. 2015, 87, 15, 7763–7770

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https://doi.org/10.1021/acs.analchem.5b01353

Published June 12, 2015

Abstract

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This work presents the design, fabrication, and characterization of a robust 3D printed microfluidic analysis system that integrates with FDA-approved clinical microdialysis probes for continuous monitoring of human tissue metabolite levels. The microfluidic device incorporates removable needle type integrated biosensors for glucose and lactate, which are optimized for high tissue concentrations, housed in novel 3D printed electrode holders. A soft compressible 3D printed elastomer at the base of the holder ensures a good seal with the microfluidic chip. Optimization of the channel size significantly improves the response time of the sensor. As a proof-of-concept study, our microfluidic device was coupled to lab-built wireless potentiostats and used to monitor real-time subcutaneous glucose and lactate levels in cyclists undergoing a training regime.

Subjects

Wearable sensors connected to body sensor networks (BSN) (1) that provide real-time information about the wearer’s health and fitness (2) are of great interest both academically and commercially. Developments of such platforms have mainly focused on sensors that measure physical vital signs (e.g. pulse rate, ECG). Biosensors targeting physiologically relevant analytes are more challenging but can provide important information about tissue health (3) and fitness, (4, 5) allowing, for example, athletes to tailor their training to their individual characteristics, enabling them to assess their training effectiveness, to make adjustments, and to track improvements in their performance.

Extensive research efforts have focused on the development of miniaturized on-body chemo/biosensors for the measurement of physiological analytes in different bodily fluids, such as interstitial fluid, (6, 7) sweat, (8, 9) tears, (10, 11) and saliva. (12, 13) Glucose and lactate are particularly attractive biomarkers to monitor as they provide information about tissue energy metabolism. Lactate, in particular, has received much interest for sports monitoring. During intense exercise, tissue oxygen levels are insufficient for aerobic metabolism to meet the energy demands of the body. Instead, anaerobic metabolism occurs to meet these increased energy demands, leading to elevated lactate levels. Lactate can therefore be used as a measure of how hard the body is working, allowing athletes to modulate their effort accordingly, in order to train the body to increase its efficiency in clearing excess lactate or to avoid causing damage by overtraining.

Commercially available blood lactate and glucose meters are used for sports applications. (14) Although blood measurements provide important information about global metabolite levels in the body, the use of finger-prick test strips has several limitations. The main limitation of discrete sampling is the lack of temporal resolution, with the result that it is not possible to observe dynamic changes in metabolite levels. In order to improve temporal resolution blood samples have to be taken regularly, resulting in constant interruptions during the activity period. In contrast, online microdialysis allows continuous monitoring of tissue metabolites, which, when coupled with an online analysis system, provides good temporal resolution, suitable for resolving dynamic changes. (15-17) The microdialysis probe consists of a semipermeable membrane that is perfused with a solution that matches the extracellular fluid. Formation of a concentration gradient across the membrane allows exchange of molecules between the probe and the tissue, creating a dialysate stream that can be analyzed for compounds of interest. Microdialysis has been used in a wide range of applications and is an attractive technology for human in vivo monitoring, as commercial FDA-approved probes are available. Microdialysis combined with online analysis systems has been used extensively to detect tissue health and ischemic events. (18-21) In particular, the lactate/glucose ratio has been shown to be an especially sensitive marker of tissue health, providing a clear indication as to whether tissue energy demands are being met. (16, 19, 22)

There is a natural synergy between microdialysis and microfluidic devices because high time resolution analysis of low volume flow rates requires very small internal volumes. (17, 20, 23) Conventionally, microfluidic devices have been made using methods such as PDMS-based soft lithography due to their ease of fabrication. PDMS chips have been used extensively for proof-of-concept analysis devices for mass spectrometry, (24) as well as for optical (23, 25) and electrochemical detection. (20, 26, 27) In all cases the analyzer is a large device placed on a bench near the experimental subject. In our current PDMS-needle biosensor system this requires >1 m of connection tubing between the probe and the PDMS chip, leading to a 25 min delay before analysis at 1 μL/min flow rate, as well as a broadened temporal response due to Taylor dispersion. (28) Furthermore, our current method for manually positioning the needle electrode biosensors inside the PDMS chamber is impractical for a wearable device as movement caused by exercise leads to repositioning of the biosensor inside the microfluidic channel leading to noise and decreased sensitivity. (27)

Fast responding wearable devices need to be small and robust and placed close to the microdialysis probe outlet. (29) For reliability, they require a robust low-volume connection to the probe and should ideally incorporate biosensors as easily replaceable modules, given the possibility of biosensor failure during high-value monitoring of athletes.

Recently, there has been great interest in the use of 3D printing for the fabrication of microfluidic devices. (30-34) This rapid prototyping methodology is particularly attractive as it enables one-step fabrication of a microfluidic platform. (35) It also enables dimensional control of the device, so that it can be integrated with commercially available components. (30) The versatility of this fabrication method allows for a flexible, modular-approach to device design with each part designed to meet exact requirements. It also allows for design modifications to be made quickly and easily so that device features can be adjusted iteratively, and their influence on the device performance can be evaluated. (30, 35) Erkal et al. recently reported on the fabrication of 3D printed microfluidic devices with integrated electrodes for electrochemical detection. (30) These devices were fabricated using commercial flangeless fitting nuts to house the electrodes, which integrated with microfabricated receiving ports.

Here, we show for the first time, the development of a 3D printed microfluidic device that integrates with FDA-approved clinical microdialysis probes and incorporates needle type biosensors and which can be used for continuous monitoring of human tissue metabolite levels. As a proof-of-concept, the device is employed for online monitoring of lactate and glucose tissue levels during cycling trials, providing a robust and reliable platform with potential use for wearable sensing technologies.

Experimental Section

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Reagents

Glucose oxidase (GOx) from Aspergillus niger and lactate oxidase (LOx) from Aerococcus viridians were purchased from Sekisui Diagnostics. Polyurethane (Texin 985) was obtained from Bayer. Other reagents were obtained from Sigma-Aldrich.

Electrode Fabrication

The biosensors used in this work are based on combined needle electrodes. (20, 36) Briefly, a 50 μm diameter polytetrafluoroethylene (PTFE) insulated platinum/iridium (90%:10%) wire (Advent Research Materials, UK) and a 50 μm polyester insulated silver wire were threaded through a 27G hypodermic needle. The insulation layer was removed from the ends of the wires using a small flame, to expose the metal. The ends of the two wires were each connected to an electrical wire using conductive silver epoxy glue (RS Components, UK). Epoxy resin (Robnor resins, CY1301 and HY1300) was used to fill the needle and to secure the wires in place. Once the epoxy resin was cured, the sharp tip of the needle was abraded using sandpaper (Buehler, UK), to just above the bevel of the needle, to create silver and platinum disc electrodes. The blunt needle was then polished sequentially with alumina slurries (1, 0.3, and 0.05 μm). Finally, in order to create the Ag|AgCl reference electrode, the tip of the needle was dipped into a potassium dichromate reference solution (BASi, US) for 3 s, and then into a solution of diluted 37% hydrochloric acid for 20 s, to remove the oxide layer from the working and auxiliary electrodes. Cyclic voltammetry was used to assess the working electrode surface.

Biosensor Fabrication

All biosensors were controlled using in-house potentiostats and a PowerLab 8/35, controlled by LabChart Pro (ADInstruments). Glucose and lactate biosensors were fabricated in several layers, as shown in Figure 1-B. Layer i: The working electrode was first coated with poly m-phenylenediamine (m-PD) using electropolymerization, to screen out potential interferences. Briefly, the combined needle electrode was placed in a 100 mM solution of m-phenylenediamine in 0.01 M PBS at pH 7.4. The potential was held at 0 V for 20 s, 0.7 V for 20 min for electropolymerization to occur, and then 0 V for 5 min. The electrode was gently rinsed with deionized water, and cyclic voltammetry was used to verify that the working electrode had been successfully coated. Layer ii: After successful electropolymerization of the screening layer, the electrodes were dipped into the enzyme solution (60 mg/mL LOx or GOx, 30 mg/mL bovine serum albumin, 60 mg/mL poly(ethylene glycol) diglycidyl ether, and 2% v/v glycerol in 0.01 M PBS, adapted from the method described by Vasylieva et al. (37, 38)). The needles were placed in an oven at 55 °C for 2 h. Layer iii: Following enzyme immobilization, biosensors were also coated with a polyurethane film in order to extend their dynamic range to include the higher lactate levels possible in exercising tissue and to minimize the effect of any flow variations, which could occur in a flow-cell, on biosensor response.

Fabrication of Microfluidic Platform

Two different 3D printers were used for printing of the microfluidic platform. The microfluidic chip was fabricated using a 3D printer ULTRA 3SP. This machine provides 100 μm resolution in the X- and Y-axis and between 25 and 100 μm resolution in the Z-axis, depending on the parameters set. However, the true resolution of the printer is given by the voxel dimension and the material employed during fabrication. Throughout the development of this work, the “ABS 3SP White” resist was used for printing of the microfluidic chip. ABS 3SP White allows printing of dimensionally and mechanically stable components, although due to shrinkage of the resist in the printing process smaller dimensions than those specified in the design of the microfluidic channel were observed. In general, a tolerance of about 100 μm needs to be considered during the design of the components. The microfluidic platform was designed with an L-shape, in which the inner microfluidic channel incorporates a 90° bend (Figure S1-A). As the microfluidic chip needs to integrate two separate needle biosensors, one for glucose and the other for lactate sensing, it was decided to insert the two needles into the microfluidic channel through two round openings printed on the top wall of the microchannel (Figure S1-C). This configuration ensures a tidy and compact packaging of the overall platform, as shown in Figure 1-j. However, it limits the minimum microchannel width that is achievable, as it has to fit the 27G needle (Ø = ca. 413 μm) biosensors. Three different sizes of microfluidic channels were printed and tested, which had different height and width dimensions, these were as follows: (1) 520 × 520 μm, (2) 750 × 550 μm, and (3) 1000 × 550 μm. Moreover, taking into account the material shrinkage, for channel (1) two slightly wider microfluidic chambers were designed at the two needle biosensor insertion locations (Figure S1-B) to avoid issues during placement of the biosensors.

Printing of the needle holders was performed using the Objet260 Connex 3D printer. The main advantage of using this printer compared to the ULTRA 3SP is the possibility to print rigid and soft material simultaneously on the same component. For instance, VeroWhitePlus (RGD835) and TangoBlack (FLX973) were employed for the printing of the rigid and soft parts, respectively. To fix the position of the needle biosensor inside the holder two grub screws M2.5 were also used. The rubbery part of the holder has a truncated cone shape to guarantee fluidic sealing and to avoid incorrect positioning of the biosensors inside the microfluidic channel. In fact, initial attempts using a cylindrical shape rubber part lead to incorrect mounting of the biosensor holder into the microfluidic chip due to XY expansion of the rubber when compressed.

Calibration and Characterization Studies

Glucose and lactate biosensors were both held at a constant potential of +0.7 V vs Ag|AgCl. The biosensors were calibrated inside the microfluidic chip using a calibration board, consisting of two LabSmith 20 μL programmable syringe pumps, one containing T1 perfusion solution and one containing a glucose/lactate standard. By mixing the flows, a multipoint calibration was carried out by varying the relative flow rates of the two pumps, while keeping the overall flow rate constant at 1 μL/min. This system was also used to measure the time response of the biosensors in the microfluidic chip, by switching between the two solutions and measuring the time taken for the sensors to reach a steady current. In vitro microdialysis experiments were conducted using an expired microdialysis probe (CMA70, MDialysis, 10 mm membrane length, 20 kDa molecular-weight cutoff), perfused with T1 solution (2.3 mM calcium chloride, 147 mM sodium chloride, and 4 mM potassium chloride) at 1 μL/min using a microdialysis pump (CMA107, MDialysis).

Cycling Protocol

For in vivo microdialysis experiments, all procedures were approved by the local ethics committee (NRES 10/H0808/124, protocol CRO1608), and probes were inserted percutaneously by a qualified clinician. The skin was cleaned with alcohol wipes, and an anesthetic cream (EMLA, APP Pharmaceuticals) was applied to the skin 45 min prior to probe insertion. An ice pack was also placed on the skin 5 min before probe insertion, to further numb the area. A sterile CMA63 microdialysis probe (Mdialysis, 10 mm membrane length, 20 kDa molecular-weight cutoff) was inserted subcutaneously, using the tunnelling needle and introducer supplied, and secured in place with 3M single coated conformable incise medical tape. The probe was perfused with sterile T1 perfusion solution (MDialysis) at 1 μL/min using a microdialysis pump (CMA107, MDialysis). Prior to beginning exercise, baseline dialysate levels of glucose and lactate were measured. The cycling protocol consisted of 3 levels of increasing intensity, followed by a 1 min sprint, and finally a warm-down phase, as shown in Figure 4-A. Dialysate glucose and lactate levels were also recorded during the recovery phase immediately after exercise.

Cycling trials were performed using a Wattbike (Wattbike, UK), that allows recording of pedal cadence (rpm) and heart rate using a wireless chest belt (Sunto dual chest belt). Data was despiked, (39) and the time delay between the microdialysis probe and the analysis system removed. Current measurements were converted into concentration values using pre-experiment calibrations.

Results and Discussion

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3D Printed Microfluidic Device

The design of the 3D printed microfluidic device was driven by the need to make a reliable and simple connection between the microfluidic chip and the commercially available microdialysis probe through the use of the probe outlet holder (Figure 1-C item c). This simplifies the overall device architecture, as no extra connection tubing and adaptors are needed, additionally decreasing the overall dead volume of the system.

The design of the microfluidic device was inspired by the configuration used in the standard microdialysis setup (Figure 1-A), in which the microfluidic device slots into the probe outlet holder and replaces the microvial, as shown in Figure 1-D. To achieve this, the microfluidic chip (Figure 1-C item e) was designed and printed with a unique L-shape, the vertical arm for connection purposes and the horizontal arm for integration of the two needle biosensors. The vertical arm of the chip presents similar geometry to the microvial. For instance, the microfluidic inlet port was printed to incorporate the rubber insert (Figure 1-C item d) from the microvial, so as to take advantage of the easy and leak-free connection port. Moreover, this design offers flexibility for the device to be used in a diverse range of microdialysis applications, as it can be used with all clinical microdialysis probes, since they have the same type of outlet holder.

With regard to the horizontal section of the microfluidic device, a major challenge was to incorporate and secure the biosensors in the correct position inside the microfluidic channel, preventing any leaks. Initially, attempts were made to achieve this by threading the needle electrode through a commercially available 1/32″ one-piece fitting (2-56 UNC) and using this to secure the electrode in place inside the microfluidic chip. (30) Using this approach, the device dimensions were determined by the size of the fittings and as such were relatively large (over 1 mm). However, integrating the biosensor in this way did not provide a good seal with the microfluidic chip, causing leaks to occur. Erkal et al. showed that electrodes could be successfully integrated with 3D printed microfluidic devices using commercially available fittings; however, due to the small size of our sensor, a 1/32″ fitting was required. These threads were too small (2-56 UNC) to be printed and a thread tapping tool (M2.5) was used instead. Unfortunately this approach did not provide a satisfactory seal or good reproducibility. To overcome the issue of the previous method, custom-made electrode holders (Figure 1-C parts g and h) were also designed and 3D printed, which allow better control over the electrode placement inside the microfluidic channel.

The electrode holder was printed using the Objet260 Connex 3D printer, capable of printing both hard and soft plastics simultaneously on the same component. This enabled the bottom part of the holder to be printed using a soft and compressible plastic, ensuring a good seal between the holder and the microfluidic device, preventing potential leaks. The holders were designed so that the needle tip protruded from the end and the needle was secured in place using two grub screws. The needle position inside the holder could be varied depending on the length of the needle, as this can change after repeated polishing of the electrode (see supporting video 1).

This ensures that the needle tip is at a fixed distance from the end of the holder and hence in the correct position inside the microfluidic channel. The microfluidic platform was designed so that the holder could be guided into position; two pegs on the sides of the electrode holder inserted into guiding slots and locked into place, positioning the needle tip precisely inside the channel (see supporting video 2). Moreover, to facilitate the positioning of the electrode inside the microchannel an additional cross-sectional cut-out of the microfluidic device was printed. Using the cut-out component it was possible to visualize the electrode inside the channel under a microscope and to precisely secure the sensors inside the holders so that the tip of the biosensor was at the desired height inside the microchannel (Figure S2).

The use of 3D printing for fabrication of the device enabled a modular approach to be adopted, designing separate parts to be integrated together. Using this method each part of the device could be designed and optimized iteratively to meet its own individual requirements.

Figure 1. A. Standard microdialysis setup for discrete sampling. The probe (a) is perfused at a fixed low flow rate, and dialysate is collected into a microvial (b) at the probe outlet. *Right:* shows the microvial when connected to the probe outlet holder. B. Photograph of combined needle electrode based on a 27G hypodermic needle and schematic cross-section of the needle tip, showing the layers that make up the biosensor: *(i)* m-PD exclusion layer, *(ii)* substrate oxidase (SOx) entrapped in a hydrogel, and *(iii)* diffusion limiting polyurethane outer film. C. Exploded view of custom-made microfluidic device for continuous monitoring of dialysate, showing the multicomponent system. The microfluidic chip (e) connects to the probe outlet holder (c) in place of a microvial. The outlet holder needle enters the microvial rubber insert (d) at the inlet of the microfluidic chip. Glucose and lactate needle biosensors (f) are housed in custom-made electrode holders (g) that screw into the microfluidic chip, placing the biosensors in the middle of the microfluidic channel and providing a good seal between the holder and the microfluidic device. (h) shows a photograph of an electrode holder containing a needle biosensor. The black part at the base of the holder is made of soft, compressible plastic to ensure the holder makes a good seal with the microfluidic chip. D. The L-shaped design provides a tidy and compact overall system.

Biosensor Characterization Inside 3D Printed Microfluidic Chip

To investigate the effect of the microfluidic channel dimensions on the response time of the sensors, three different channel sizes were tested, as described in the Experimental Section. Figure 2-B shows the normalized current response of a glucose biosensor to a step change from 0 to 2 mM at 1 μL/min for the different channel sizes. In each case the sensor was positioned in the middle of the channel. Cross sections of each channel were measured using a microscope to determine the actual dimensions of each of the channels. The dimensions specified in the table in Figure 2-B refer to the measured dimensions.

Both glucose and lactate biosensors without the polyurethane (PU) outer film are fast responding (for a step change in well-stirred beaker T₉₀ glucose = 6.6 ± 3.9 s (n = 24), lactate = 5.1 ± 2.6 s (n = 30), data not shown). Addition of the PU film to extend the dynamic range (necessary for lactate biosensor) slows both sensors (as shown in Figure 2-A) and increases the variability in response as the PU thickness is difficult to control (for a step change T₉₀ glucose = 36.1 ± 19.6 s (n = 5), lactate = 22.8 ± 11.3 s (n = 21)). The same biosensor shows good reproducibility. For example, the sensors in Figure 2-A have T₉₀ glucose = 21.0 ± 0.6 s (n = 3) and lactate = 26.1 ± 1.4 s (n = 3). Laminar flow inside the connection tubing and microfluidic channel leads to broadening of the concentration change, due to Taylor dispersion. (28) In Figure 2-B we show that the time response of the sensor to a step change is reduced by decreasing the channel cross-sectional area. The T₉₀ values are summarized in Table 1 and are generally inversely proportional to cross-sectional area and hence proportional to linear flow rate. In the channel, glucose values are longer than lactate ones because the glucose biosensor was second in line and hence exposed to a greater channel volume. The fastest response time was observed in channel 1; therefore, these dimensions were chosen for the final device.

The horizontal section of the microfluidic chip is similar to the microfluidic device described by Erkal et al., which had an internal volume of 3.90 μL. Our microfluidic chip is broadly similar, but the internal volume up until the first biosensor is approximately 1.91 μL based on measured dimensions.

Metabolite levels in tissue vary between people and depend on a person’s metabolism and fitness during exercise, as well as on the particular tissue being sampled. (40) The system was calibrated online from 0 to 10 mM, at 1 μL/min to verify that it is capable of detecting physiologically relevant concentrations of glucose and lactate levels in the dialysate. Figure 3 shows typical current response vs concentration for the biosensors when placed in the microfluidic device. These data indicate that the biosensing system has good sensitivity to glucose and lactate, with clear current changes corresponding to increasing levels of substrate. The biosensors show a good dynamic range, suitable for physiological monitoring. The fact that sensitivities are similar for the glucose and lactate sensors (Figure 3) reflects the mass-transport limiting effects of the PU membrane.

As a further validation test, it was important to test the microfluidic device with a microdialysis probe in vitro. To mimic changes occurring in the tissue, the microdialysis probe was placed in a well-stirred beaker and subjected to changes in beaker lactate and glucose concentrations. The outlet holder of the microdialysis probe was connected to the microfluidic device, which continuously measured the glucose and lactate levels of the dialysate.

Figure 2. A. Normalized current response of a 50 μm disc glucose (red) and lactate (green) biosensor in a stirred beaker to a 2 mM concentration step (purple arrow). B. The graph shows the normalized current for a glucose biosensor to a step change from 0 to 2 mM at 1 μL/min in three different microfluidic channels. The measured channel sizes are shown in the table inset. The response time increases as the channel dimension increases.

Table 1. Effect of Channel Size on Response Time

channel dimensions H × W (μm)	glucose T₉₀ (s)	lactate T₉₀ (s)
375 × 508	208 ± 6.5	194 ± 15
410 × 615	267 ± 7.7	227 ± 7.0
421 × 971	398 ± 12.8	286 ± 6.9

As the biosensors are placed consecutively in the microfluidic chip, there is a 2 min delay between the lactate and glucose responses to the dialysate changes. There is also an additional delay to take into account between the changes occurring at the probe membrane and the analysis system due to the length of outlet tubing. Taking both factors into consideration, the total delay was found to be 13 min for the lactate biosensor, which was placed first in the direction of flow and 15 min for the glucose biosensor, which was placed second in the direction of flow. This delay is largely caused by the commercially available probe outlet tubing and, therefore, could be reduced further still if the extension on the probe outlet was shortened. Nevertheless, the delay time of the microfluidic device described here was substantially improved compared to our PDMS-based microfluidic device, which had a lag time of 25 min using the same flow rate (1 μL/min).

Online Subcutaneous Glucose and Lactate Measurement during Cycling Trials

In a proof-of-concept study to demonstrate the potential of this device for continuous monitoring applications the 3D printed microfluidic chip, housing glucose and lactate needle biosensors, was tested as a wearable device for online measurement of subcutaneous metabolite levels during cycling training in two cyclists.

Following probe insertion, the microfluidic device was connected to the probe outlet holder and secured to the lower back, as shown in Figure 4-A. The biosensors were connected to an in-house wireless potentiostat, housed inside a saddlebag attached to the bike seat. The wireless potentiostat used was relatively large (10.5 × 6.0 × 5.0 cm L × W × H) compared to the microfluidic device and is not yet small enough to be integrated into a fully wearable system. Current research within our groups is aimed at miniaturization of this device.

Figure 3. Typical calibration curves for 50 μm disc glucose and lactate biosensors in the microfluidic device at 1 μL/min. Mean ± standard deviation of measurement shown (n = 4). Points fitted with the Michaelis–Menten equation. Inset: Raw data for a typical 5-point lactate calibration from 0 to 4 mM in 1 mM steps.

A schematic of the cycling protocol is shown in Figure 4-B. Baseline glucose and lactate levels were measured in the dialysate, following probe insertion, prior to exercise. The exercise phase consisted of three levels of increasing intensity, followed by a short sprint and a period of warming down. Finally, dialysate glucose and lactate levels were monitored during the recovery period following exercise.

Initial levels after probe insertion were variable due to the trauma of insertion. Therefore, baseline levels were monitored for at least 30 min to allow time for the tissue to stabilize following probe insertion; typically this occurred 12 min after insertion. (21)

Results obtained from one of the cyclists during the exercise phase of the cycling protocol are presented in Figure 4-C, together with data recorded using the exercise bicycle, showing heart rate and rotations per minute (rpm), to quantify the exercise intensity. Initially, during phases ii and iii the heart rate signal was noisy as there was insufficient sweat to ensure good contact between the skin and the wireless chest belt electrodes. Prior to starting exercise, baseline glucose and lactate levels in the dialysate were 6.02 ± 1.08 mM and 1.81 ± 0.33 mM, respectively (mean ± standard deviation over 30 s time period). Measured subcutaneous glucose levels decreased with increasing exercise intensity, and local levels were driven down further still following exercise, even after 50 min of rest. In contrast, lactate levels increased with increasing exercise intensity, peaking immediately after the sprint, and gradually decreased once cycling had stopped. After 50 min of resting, dialysate glucose and lactate levels were 1.84 ± 0.05 mM and 1.67 ± 0.03 mM, respectively.

To guard against possible changes in probe recovery, a ratio of the two metabolites was also calculated. The lactate/glucose ratio increased with exercise and rose more steeply with increasing cycling intensity. Interestingly, the lactate/glucose ratio continued to increase considerably, even after exercise had stopped.

An overview of the dialysate glucose and lactate levels and the lactate/glucose ratio throughout the cycling protocol for two cyclists is shown in Figure 4-D. The overall trends in glucose and lactate levels are similar for the two cyclists, although the absolute concentrations appear quite different. This variability could be caused by changes in probe recovery or by differences in the fitness levels of the cyclists. In principle, level changes caused by differences in probe recovery would have been removed using ratios of analyte concentrations, such as the lactate/glucose ratio. (16) Such ratios are widely used for monitoring in the injured human brain (lactate/pyruvate) (41) and in muscle (lactate/pyruvate and lactate/glucose), (42) though this needs to be further investigated for subcutaneous tissue. Nevertheless, there are clear differences in the lactate/glucose ratio trend for the two cyclists.

Conclusion

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We have demonstrated the first example of a 3D printed microfluidic device with integrated removable biosensors that joins directly to a clinical microdialysis probe for continuous human monitoring applications. Here we have demonstrated its capabilities as a wearable device for subcutaneous monitoring of tissue glucose and lactate levels in cyclists during exercise. The clear changes recorded in the local glucose and lactate levels indicate that this device could have huge potential for monitoring and evaluating athlete training effectiveness in real-time. Moreover, this miniaturized device also has potential for clinical microdialysis applications, such as bedside monitoring, as its wearable nature removes the need for long connection tubing, which usually leads to long lag times. Due to the dimensional control provided by 3D printing, it was possible to design the microfluidic device so that it could easily be integrated with commercially available microdialysis probes, making it suitable for numerous potential applications. Future work will focus on miniaturization of the wireless potentiostats to enable integration of the electronics within the wearable device. Due to the modular nature of the device, the platform can be expanded to include monitoring of other clinically relevant biomarkers, offering promise in a wide range of clinical and fitness applications.

Figure 4. A. Photograph of microfluidic device to measure tissue glucose and lactate levels in dialysate during the cycling protocol. Dialysate flowed into the microfluidic chip, housing the glucose and lactate biosensors, which were connected to wireless potentiostats, secured onto the bike. B. Experimental protocol. Tissue levels were monitored during an initial resting period (i), followed by cycling at 4 levels of increasing rpm (*ii-v*), a level of warming down (vi), and a final period of resting (*vii*). C. Dialysate glucose and lactate levels during the exercise phase of the cycling protocol. The bottom graph shows the glucose (red) and lactate (green) levels, the middle graph (black) shows the lactate/glucose ratio, and the top graph shows the rotations per minute (blue) and heart rate (purple) throughout the cycling protocol. Glucose and lactate traces have been despiked. (39) The dotted lines indicate the stages of varying cycling intensity: (ii) 55 rpm, (*iii*) 65 rpm, (iv) 75 rpm, (v) sprint, and (vi) 55 rpm. Data has been time-aligned, taking into account the time delay of the system. D. Histograms showing mean dialysate levels for two different cyclists during key points in cycling protocol. Labels correspond to stages described in the experimental protocol: (i) baseline (ii) midway through warm up, (*iii*) midway through medium intensity, (iv) midway through high intensity, (v) end of sprint, (vi) end of warm down, and (*vii*) after 50 min of recovery.

Supporting Information

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Additional information as noted in text (Figures S1–S3 and supporting videos 1 and 2). The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.analchem.5b01353. Data supporting this publication can be obtained on request from [email protected].

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Author Information

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Corresponding Author
- Martyn G. Boutelle - †Department of Bioengineering and ‡The Hamlyn Centre, Imperial College London, London SW7 2AZ, United Kingdom; School of Engineering and Materials Science, Queen Mary, University of London, Mile End Road, London E1 4NS, United Kingdom; Email: [email protected]
Authors
- Sally A. N. Gowers - †Department of Bioengineering and ‡The Hamlyn Centre, Imperial College London, London SW7 2AZ, United Kingdom; School of Engineering and Materials Science, Queen Mary, University of London, Mile End Road, London E1 4NS, United Kingdom
- Vincenzo F. Curto - †Department of Bioengineering and ‡The Hamlyn Centre, Imperial College London, London SW7 2AZ, United Kingdom; School of Engineering and Materials Science, Queen Mary, University of London, Mile End Road, London E1 4NS, United Kingdom
- Carlo A. Seneci - †Department of Bioengineering and ‡The Hamlyn Centre, Imperial College London, London SW7 2AZ, United Kingdom; School of Engineering and Materials Science, Queen Mary, University of London, Mile End Road, London E1 4NS, United Kingdom
- Chu Wang - †Department of Bioengineering and ‡The Hamlyn Centre, Imperial College London, London SW7 2AZ, United Kingdom; School of Engineering and Materials Science, Queen Mary, University of London, Mile End Road, London E1 4NS, United Kingdom
- Salzitsa Anastasova - School of Engineering and Materials Science, Queen Mary, University of London, Mile End Road, London E1 4NS, United Kingdom
- Pankaj Vadgama - School of Engineering and Materials Science, Queen Mary, University of London, Mile End Road, London E1 4NS, United Kingdom
- Guang-Zhong Yang - †Department of Bioengineering and ‡The Hamlyn Centre, Imperial College London, London SW7 2AZ, United Kingdom; School of Engineering and Materials Science, Queen Mary, University of London, Mile End Road, London E1 4NS, United Kingdom
Author Contributions
S.G. and V.F.C. contributed equally to this work.
Notes
The authors declare no competing financial interest.

Acknowledgment

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We thank the EPSRC (EP/H009744/1) and Wellcome Trust DOH (HICF-0510-080) for funding. We would like to thank Mr. Vassilios Kontojannis and Mr. Hani Marcus for their expertise in carrying out the microdialysis probe insertion. We are grateful to 3M for supplying the single coated conformable incise medical tape.

References

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This article references 42 other publications.

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Journal of diabetes science and technology (2007), 1 (5), 617-23 ISSN:.
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Purpose: To examine muscle and blood metabolites during soccer match play and relate it to possible changes in sprint performance. Methods: Thirty-one Danish fourth division players took part in three friendly games. Blood samples were collected frequently during the game, and muscle biopsies were taken before and after the game as well as immediately after an intense period in each half. The players performed five 30-m sprints interspersed by 25-s recovery periods before the game and immediately after each half (N = 11) or after an intense exercise period in each half (N = 20). Results: Muscle lactate was 15.9 ± 1.9 and 16.9 ± 2.3 mmol·kg d.w. during the first and second halves, resp., with blood lactate being 6.0 ± 0.4 and 5.0 ± 0.4 mM, resp. Muscle lactate was not correlated with blood lactate (r = 0.06-0.25, P >0.05). Muscle glycogen decreased (P < 0.05) from 449 ± 23 to 255 ± 22 mmol·kg d.w. during the game, with 47 ± 7% of the muscle fibers being completely or almost empty of glycogen after the game. Blood glucose remained elevated during the game, whereas plasma FFA increased (P < 0.05) from 0.45 ± 0.05 to 1.37 ± 0.23 mM. Mean sprint time was unaltered after the first half, but longer (P < 0.05) after the game (2.8 ± 0.7%) as well as after intense periods in the first (1.6 ± 0.6%) and second halves (3.6 ± 0.5%). The decline in sprint performance during the game was not correlated with muscle lactate, muscle pH, or total glycogen content. Conclusion: Sprint performance is reduced both temporarily during a game and at the end of a soccer game. The latter finding may be explained by low glycogen levels in individual muscle fibers. Blood lactate is a poor indicator of muscle lactate during soccer match play.
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Watson Christopher J; Venton B Jill; Kennedy Robert T
Analytical chemistry (2006), 78 (5), 1391-9 ISSN:0003-2700.
The brain contains a vast network of neurons that connect with each other at specialized junctions called synapses.A synapse consists of a presynaptic terminal (the "sending"neuron) and a postsynaptic bouton (the "receiving" neuron)that are separated by a gap of 5-50 nm (Figure 1). Chemicals released into this synaptic gap interact with receptors on the postsynaptic neuron. This leads to intracellular changes in the postsynaptic neuron-for example, an altered membrane potential or gene expression. The chemical signal is terminated by transporter proteins that transfer transmitter molecules across the membrane to the intracellular space (a process known as "reuptake")or enzymes that degrade the transmitter in the vicinity of the synapse (Figure 1). This classical view of neurotransmission might be considered point-to-point or"wired" communication because neurons communicate only with neurons to which they are specifically connected. In addition,neurotransmitters can activate receptors at more distant sites either by escaping the synapse or by being directly released into extrasynaptic space. This longer-range communication has been called "volume" transmission (1, S1; S references can be found in Supporting Information). All brain functions, from controlling movement to emotions, involve these two forms of chemical communication. Analytical chemistry has an important role to play in developing our understanding of the brain by providing tools for identification and measurement of the many chemicals involved in neurotransmission.
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Schultz, Kristin N.; Kennedy, Robert T.
Annual Review of Analytical Chemistry (2008), 1 (), 627-661CODEN: ARACFU; ISSN:1936-1327. (Annual Reviews Inc.)
A review. Monitoring changes in chem. concns. over time in complex environments is typically performed using sensors and spectroscopic techniques. Another approach is to couple sampling methods, such as microdialysis, with chromatog., electrophoretic, or enzymic assays. Recent advances of such coupling have enabled improvements in temporal resoln., multianalyte capability, and automation. In a sampling and anal. method, the temporal resoln. is set by the mass sensitivity of the anal. method, anal. time, and zone dispersion during sampling. Coupling methods with high speed and mass sensitivity to microdialysis sampling help to reduce some of these contributions to yield methods with temporal resoln. of seconds. These advances have been primarily used in monitoring neurotransmitters in vivo. This review covers the problems assocd. with chem. monitoring in the brain, recent advances in using microdialysis for time-resolved in vivo measurements, sample applications, and other potential applications of the technol. such as detg. reaction kinetics and process monitoring.
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Analytica Chimica Acta (2009), 651 (1), 1-14CODEN: ACACAM; ISSN:0003-2670. (Elsevier B.V.)
A review. Microdialysis (MD) is a sampling technique that can be employed to monitor biol. events both in vivo and in vitro. When it is coupled to an anal. system, microdialysis can provide near real-time information on the time-dependent concn. changes of analytes in the extracellular space or other aq. environments. Online systems for the anal. of microdialysis samples enable fast, selective and sensitive anal. while preserving the temporal information. Anal. methods employed for online anal. include liq. chromatog. (LC), capillary (CE) and microchip electrophoresis and flow-through biosensor devices. This review article provides an overview of microdialysis sampling and online anal. systems with emphasis on in vivo anal. Factors that affect the frequency of anal. and, hence, the temporal resoln. of these systems are also discussed.
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Rogers, M. L.; Brennan, P. A.; Leong, C. L.; Gowers, S. A. N.; Aldridge, T.; Mellor, T. K.; Boutelle, M. G.
Analytical and Bioanalytical Chemistry (2013), 405 (11), 3881-3888CODEN: ABCNBP; ISSN:1618-2642. (Springer)
We describe an enzyme-based electroanal. system for real-time anal. of a clin. microdialysis sampling stream during surgery. Free flap tissue transfer is used widely in reconstructive surgery after resection of tumors or in other situations such as following major trauma. However, there is a risk of flap failure, due to thrombosis in the flap pedicle, leading to tissue ischemia. Conventional clin. assessment is particularly difficult in such buried' flaps where access to the tissue is limited. Rapid sampling microdialysis (rsMD) is an enzyme-based electrochem. detection method, which is particularly suited to monitoring metab. This online flow injection system analyses a dialyzate flow stream from an implanted microdialysis probe every 30 s for levels of glucose and lactate. Here, we report its first use in the monitoring of free flap reconstructive surgery, from flap detachment to re-vascularisation and overnight in the intensive care unit. The on-set of ischemia by both arterial clamping and failure of venous drainage was seen as an increase in lactate and decrease in glucose levels. Glucose levels returned to normal within 10 min of successful arterial anastomosis, while lactate took longer to clear. The use of the lactate/glucose ratio provides a clear predictor of ischemia on-set and subsequent recovery, as it is insensitive to changes in blood flow such as those caused by topical vasodilators, like papaverine. The use of storage tubing to preserve the time course of dialyzate, when tech. difficulties arise, until offline anal. can occur, is also shown. The potential use of rsMD in free flap surgery and tissue monitoring is highly promising.
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Rogers, M. L.; Feuerstein, D.; Leong, C. L.; Takagaki, M.; Niu, X.; Graf, R.; Boutelle, M. G. ACS Chem. Neurosci. 2013, 4, 799– 807
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Continuous Online Microdialysis Using Microfluidic Sensors: Dynamic Neurometabolic Changes during Spreading Depolarization
Rogers, Michelle L.; Feuerstein, Delphine; Leong, Chi Leng; Takagaki, Masatoshi; Niu, Xize; Graf, Rudolf; Boutelle, Martyn G.
ACS Chemical Neuroscience (2013), 4 (5), 799-807CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)
Microfluidic glucose biosensors and potassium ion selective electrodes were used in an in vivo study to measure the neurochem. effects of spreading depolarizations (SD), which have been shown to be detrimental to the injured human brain. A microdialysis probe implanted in the cortex of rats was connected to a microfluidic PDMS chip contg. the sensors. The dialyzate was also analyzed using our gold std., rapid sampling microdialysis (rsMD). The glucose biosensor performance was validated against rsMD with excellent results. The glucose biosensors successfully monitored concn. changes, in response to SD wave induction, in the range of 10-400 μM with a second time-resoln. The data show that during a SD wave, there is a time delay of 62 ± 24.8 s (n = 4) between the onset of the increase in potassium and the decrease in glucose. This delay can be for the first time demonstrated, thanks to the high-temporal resoln. of the microfluidic sensors sampling from a single tissue site (the microdialysis probe), and it indicates that the decrease in glucose is due to the high demand of energy required for repolarization.
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Deeba S; Corcoles E P; Hanna G B; Hanna B G; Pareskevas P; Aziz O; Boutelle M G; Darzi A
Diseases of the colon and rectum (2008), 51 (9), 1408-13 ISSN:.
PURPOSE: Intestinal ischemia is a major cause of anastomotic leak and death and remains a clinical challenge as the physician relies on several nonspecific signs, biologic markers, and radiologic studies to make the diagnosis. This study used rapid sampling online microdialysis to evaluate the biochemical changes occurring in a segment of human bowel during and after resection, and assessed for the feasibility and reproducibility of this technique in monitoring intestinal ischemia. METHODS: A custom made, rapid sampling online microdialysis analyzer was used to monitor the changes in the bowel wall of specimens being resected intraoperatively. Two patients were recruited for the pilot study to optimize the analyzer and seven patients undergoing colonic resections were recruited for the data collection and analysis. RESULTS: The concentration of glucose in the extracellular bowel wall fluid decreased transiently after division of individual feeding arteries followed by a rebound increase in the concentration back to baseline concentrations. After completion of resection, glucose concentrations continued to decrease while lactate concentrations increased constantly. CONCLUSION: Rapid sampling microdialysis was feasible in the clinical environment. These results suggest that tissue responds to ischemic insult by mobilizing glucose stores which later decrease again, whereas lactate concentrations constantly increased.
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Detection of postoperative intestinal ischemia in small bowel transplants
Birke-Sorensen Hanne
Journal of transplantation (2012), 2012 (), 970630 ISSN:.
Small bowel transplantation is acknowledged as auto- and allotransplantation. In both instances, there is up to a 4%-10% risk of postoperative ischemia, and as the small bowel is extremely susceptible to ischemia, the timely diagnosis of ischemia is important. The location of the transplant, whether it is buried in the abdominal cavity or in the neck region, increases the challenge, as monitoring becomes more difficult and the consequences of neglect more dangerous. All methods for the early detection of postoperative ischemia in small bowel transplants are described together with the requirements of the ideal monitoring method. A small bowel transplant can be inspected directly or indirectly; the blood flow can be monitored by Doppler or by photoplethysmography, and the consequences of the blood flow can be monitored. The ideal monitoring method should be reliable, fast, minimally invasive, safe, objective, easy, cheap, and comfortable. No monitoring methods today fulfill the criteria of the ideal monitoring method, and evidence-based guidelines regarding postoperative monitoring cannot be made. The choice of whether to implement monitoring of ischemia-and if so, which method to choose-has to be made by the individual surgeon or center.
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Dispersion of soluble matter in solvent flowing slowly through a tube
Taylor, Geoffrey
Proceedings of the Royal Society of London, Series A: Mathematical, Physical and Engineering Sciences (1953), 219 (), 186-203CODEN: PRLAAZ; ISSN:1364-5021.
When a sol. substance is introduced into a fluid flowing slowly through a small-bore tube it spreads out under the combined action of mol. diffusion and the variation of velocity over the cross section. It is shown analytically that the distribution of concn. produced in this way is centered on a point which moves with the mean speed of flow and is symmetrical about it in spite of the asymmetry of the flow. The dispersion along the tube is governed by a virtual coeff. of diffusivity which can be calcd. from observed distributions of concn. Since the analysis relates the longitudinal diffusivity to the coeff. of mol. diffusion, observations of concn. along a tube provide a new method for measuring diffusion coeffs. The coeff. so obtained was found, with KMnO4, to agree with that measured in other ways. The dispersion in steady flow is due to the combined action of convection parallel to the axis and mol. diffusion in the radial direction. It is of interest to consider, first, dispersion by convection alone, and then to introduce the effect of mol. diffusion. The results may be useful to physiologists who may wish to know how a sol. salt is dispersed in a blood vessel, but they may also be useful to physicists who wish to measure mol. diffusion coeffs. The exptl. technique used for KMnO4 is described in detail, and results are compared with earlier measurements.
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Lunte, S. M.; Nandi, P.; Regel, A.; Grigsby, R.; Hulvey, M. K.; Scott, D.; Naylor, E.; Gabbert, S.; Johnson, D. In 14th International Conference on Miniaturized Systems for Chemistry and Life Sciences; 2010; pp 1535– 1537.
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Erkal, J. L.; Selimovic, A.; Gross, B. C.; Lockwood, S. Y.; Walton, E. L.; McNamara, S.; Martin, R. S.; Spence, D. M. Lab Chip 2014, 14, 2023– 2032
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3D printed microfluidic devices with integrated versatile and reusable electrodes
Erkal, Jayda L.; Selimovic, Asmira; Gross, Bethany C.; Lockwood, Sarah Y.; Walton, Eric L.; McNamara, Stephen; Martin, R. Scott; Spence, Dana M.
Lab on a Chip (2014), 14 (12), 2023-2032CODEN: LCAHAM; ISSN:1473-0189. (Royal Society of Chemistry)
We report two 3D printed devices that can be used for electrochem. detection. In both cases, the electrode is housed in com. available, polymer-based fittings so that the various electrode materials (platinum, platinum black, carbon, gold, silver) can be easily added to a threaded receiving port printed on the device; this enables a module-like approach to the exptl. design, where the electrodes are removable and can be easily repolished for reuse after exposure to biol. samples. The first printed device represents a microfluidic platform with a 500 × 500 μm channel and a threaded receiving port to allow integration of either polyetheretherketone (PEEK) nut-encased glassy carbon or platinum black (Pt-black) electrodes for dopamine and nitric oxide (NO) detection, resp. The embedded 1 mm glassy carbon electrode had a limit of detection (LOD) of 500 nM for dopamine and a linear response (R2 = 0.99) for concns. between 25-500 μM. When the glassy carbon electrode was coated with 0.05% Nafion, significant exclusion of nitrite was obsd. when compared to signal obtained from equimolar injections of dopamine. When using flow injection anal. with a Pt/Pt-black electrode and stds. derived from NO gas, a linear correlation (R2 = 0.99) over a wide range of concns. (7.6-190 μM) was obtained, with the LOD for NO being 1 μM. The second application showcases a 3D printed fluidic device that allows collection of the biol. relevant analyte ATP (ATP) while simultaneously measuring the release stimulus (reduced oxygen concn.). The hypoxic sample (4.8 ± 0.5 ppm oxygen) released 2.4 ± 0.4 times more ATP than the normoxic sample (8.4 ± 0.6 ppm oxygen). Importantly, the results reported here verify the reproducible and transferable nature of using 3D printing as a fabrication technique, as devices and electrodes were moved between labs multiple times during completion of the study.
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Kitson, P. J.; Rosnes, M. H.; Sans, V.; Dragone, V.; Cronin, L. Lab Chip 2012, 12, 3267
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Configurable 3D-Printed millifluidic and microfluidic lab on a chip reactionware devices
Kitson, Philip J.; Rosnes, Mali H.; Sans, Victor; Dragone, Vincenza; Cronin, Leroy
Lab on a Chip (2012), 12 (18), 3267-3271CODEN: LCAHAM; ISSN:1473-0189. (Royal Society of Chemistry)
We utilize 3D design and 3D printing techniques to fabricate a no. of miniaturized fluidic 'reactionware' devices for chem. syntheses in just a few hours, using inexpensive materials producing reliable and robust reactors. Both two and three inlet reactors could be assembled, as well as one-inlet devices with reactant silos' allowing the introduction of reactants during the fabrication process of the device. To demonstrate the utility and versatility of these devices org. (reductive amination and alkylation reactions), inorg. (large polyoxometalate synthesis) and materials (gold nanoparticle synthesis) processes were efficiently carried out in the printed devices.
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Fabrication of Versatile Channel Flow Cells for Quantitative Electroanalysis Using Prototyping
Snowden, Michael E.; King, Philip H.; Covington, James A.; MacPherson, Julie V.; Unwin, Patrick R.
Analytical Chemistry (Washington, DC, United States) (2010), 82 (8), 3124-3131CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
Here the authors demonstrate the use of microstereolithog. (MSL), a 3D direct manufg. technique, as a viable method to produce small-scale microfluidic components for electrochem. flow detection. The flow cell is assembled simply by resting the microfabricated component on the electrode of interest and securing with thread!. This configuration allows the use of a wide range of electrode materials. Also, the approach eliminates the need for addnl. sealing methods, such as adhesives, waxes, and screws, which were previously deployed. It removes any issues assocd. with compression of the cell chamber. MSL allows a redn. of the dimensions of the channel geometry (and the resultant component) and, compared to most previously produced devices, it offers a high degree of flexibility in the design, reduced manuf. time, and high reliability. Importantly, the polymer used does not distort so that the cell maintains well-defined geometrical dimensions after assembly. For the studies herein the channel dimensions were 3 mm wide, 3.5 mm long, and 192 or 250 μm high. The channel flow cell dimensions were chosen to ensure that the substrate electrodes experienced laminar flow conditions, even with vol. flow rates of up to 64 mL min-1 (the limit of the pumping system). The steady-state transport-limited current response, for the oxidn. of ferrocenylmethyltrimethylammonium hexafluorophosphate (FcTMA+), at Au and polycryst. B doped diamond (pBDD) band electrodes was in agreement with the Levich equation and/or finite element simulations of mass transport. Probably this method of creating and using channel flow electrodes offers a wide range of new applications from electroanal. to electrocatalysis.
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Anderson, K. B.; Lockwood, S. Y.; Martin, R. S.; Spence, D. M. Anal. Chem. 2013, 85, 5622– 5626
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A 3D Printed Fluidic Device that Enables Integrated Features
Anderson, Kari B.; Lockwood, Sarah Y.; Martin, R. Scott; Spence, Dana M.
Analytical Chemistry (Washington, DC, United States) (2013), 85 (12), 5622-5626CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
Fluidic devices fabricated using conventional soft lithog. are well suited as prototyping methods. Three-dimensional (3D) printing, commonly used for producing design prototypes in industry, allows for one step prodn. of devices. 3D printers build a device layer by layer based on 3D computer models. Here, a reusable, high throughput, 3D printed fluidic device was created that enables flow and incorporates a membrane above a channel in order to study drug transport and affect cells. The device contains 8 parallel channels, 3 mm wide by 1.5 mm deep, connected to a syringe pump through std., threaded fittings. The device was also printed to allow integration with com. available membrane inserts whose bottoms are constructed of a porous polycarbonate membrane; this insert enables mol. transport to occur from the channel to above the well. When concns. of various antibiotics (levofloxacin and linezolid) are pumped through the channels, approx. 18-21% of the drug migrates through the porous membrane, providing evidence that this device will be useful for studies where drug effects on cells are investigated. Finally, we show that mammalian cells cultured on this membrane can be affected by reagents flowing through the channels. Specifically, saponin was used to compromise cell membranes, and a fluorescent label was used to monitor the extent, resulting in a 4-fold increase in fluorescence for saponin treated cells.
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Waldbaur, A.; Rapp, H.; Länge, K.; Rapp, B. E. Anal. Methods 2011, 3, 2681
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Let there be chip-towards rapid prototyping of microfluidic devices: one-step manufacturing processes
Waldbaur, Ansgar; Rapp, Holger; Laenge, Kerstin; Rapp, Bastian E.
Analytical Methods (2011), 3 (12), 2681-2716CODEN: AMNEGX; ISSN:1759-9679. (Royal Society of Chemistry)
A review. Microfluidics is an evolving scientific field with immense com. potential: anal. applications, such as biochem. assay development, biochem. anal. and biosensors as well as chem. synthesis applications essentially require microfluidics for sample handling, treatment or readout. A no. of techniques are available to create microfluidic structures today. On industrial scale replication techniques such as injection molding are the gold std. whereas academic research mostly focuses on replication by casting of soft elastomers such as polydimethylsiloxane (PDMS). Both of these techniques require the creation of a replication master thus creating the microfluidic structure only in the second process step-they can therefore be termed two-(or multi-)step manufg. techniques. However, very often the no. of pieces to be created of one specific microfluidic design is low, sometimes even as low as one. This raises the question if two-step manufg. is an appropriate choice, particularly if short concept-to-chip times are required. In this case one-step manufg. techniques that allow the direct creation of microfluidic structures from digital three-dimensional models are preferable. For these processes the no. of parts per design is low (sometimes as low as one), but quick adaptation is possible by simply changing digital data. Suitable techniques include, among others, maskless or mask based stereolithog., fused deposition molding and 3D printing. This work intends to discuss the potential and application examples of such processes with a detailed view on applicable materials. It will also point out the advantages and the disadvantages of the resp. technique. Furthermore this paper also includes a discussion about non-conventional manufg. equipment and community projects that can be used in the prodn. of microfluidic devices.
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Patel, B. A.; Rogers, M.; Wieder, T.; O’Hare, D.; Boutelle, M. G. Biosens. Bioelectron. 2011, 26, 2890– 2896
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Viggiano, A.; Marinesco, S.; Pain, F.; Meiller, A.; Gurden, H. J. Neurosci. Methods 2012, 206, 1– 6
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Reconstruction of field excitatory post-synaptic potentials in the dentate gyrus from amperometric biosensor signals
Viggiano Alessandro; Marinesco Stephane; Pain Frederic; Meiller Anne; Gurden Hirac
Journal of neuroscience methods (2012), 206 (1), 1-6 ISSN:.
A new feasible and reproducible method to reconstruct local field potentials from amperometric biosensor signals is presented. It is based on the least-square fit of the current response of the biosensor electrode to a voltage step by the use of two time constants. After determination of the electrode impedance, Fast Fourier Transform (FFT) and Inverse FFT are performed to convert the recorded amperometric signals into voltage and trace the local field potentials using a resistor-capacitor circuit-based model. We applied this method to reconstruct field evoked potentials from currents recorded by a lactate biosensor in the rat dentate gyrus after stimulation of the perforant pathway in vivo. Initial slope of the reconstructed field excitatory postsynaptic potentials was used in order to demonstrate long term potentiation induced by high frequency stimulation of the perforant path. Our results show that reconstructing evoked potentials from amperometric recordings is a reliable method to obtain in vivo electrophysiological and amperometric information simultaneously from the same electrode in order to understand how chemical compounds vary with and modulate the dynamics of brain activity.
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Vasylieva, N.; Barnych, B.; Meiller, A.; Maucler, C.; Pollegioni, L.; Lin, J.-S.; Barbier, D.; Marinesco, S. Biosens. Bioelectron 2011, 26, 3993– 4000
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Covalent enzyme immobilization by poly(ethylene glycol) diglycidyl ether (PEGDE) for microelectrode biosensor preparation
Vasylieva, Natalia; Barnych, Bogdan; Meiller, Anne; Maucler, Caroline; Pollegioni, Loredano; Lin, Jian-Sheng; Barbier, Daniel; Marinesco, Stephane
Biosensors & Bioelectronics (2011), 26 (10), 3993-4000CODEN: BBIOE4; ISSN:0956-5663. (Elsevier B.V.)
Poly(ethylene glycol) diglycidyl ether (PEGDE) is widely used as an additive for crosslinking polymers bearing amine, hydroxyl, or carboxyl groups. However, the idea of using PEGDE alone for immobilizing proteins on biosensors has never been thoroughly explored. We report the successful fabrication of microelectrode biosensors based on glucose oxidase, D-amino acid oxidase, and glutamate oxidase immobilized using PEGDE. We found that biosensors made with PEGDE exhibited high sensitivity and a response time on the order of seconds, which is sufficient for observing biol. processes in vivo. The enzymic activity on these biosensors was highly stable over several months when they were stored at 4 °C, and over at least 3 d at 37 °C. Glucose microelectrode biosensors implanted in the central nervous system of anesthetized rats reliably monitored changes in brain glucose levels induced by sequential administration of insulin and glucose. PEGDE provides a simple, low cost, non-toxic alternative for the prepn. of in vivo microelectrode biosensors.
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Feuerstein, D.; Parker, K. H.; Boutelle, M. G. Anal. Chem. 2009, 81, 4987– 4994
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Heinonen, I.; Kalliokoski, K. K.; Hannukainen, J. C.; Duncker, D. J.; Nuutila, P.; Knuuti, J. Physiology (Bethesda) 2014, 29, 421– 436
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Organ-specific physiological responses to acute physical exercise and long-term training in humans
Heinonen Ilkka; Kalliokoski Kari K; Hannukainen Jarna C; Knuuti Juhani; Duncker Dirk J; Nuutila Pirjo
Physiology (Bethesda, Md.) (2014), 29 (6), 421-36 ISSN:.
Virtually all tissues in the human body rely on aerobic metabolism for energy production and are therefore critically dependent on continuous supply of oxygen. Oxygen is provided by blood flow, and, in essence, changes in organ perfusion are also closely associated with alterations in tissue metabolism. In response to acute exercise, blood flow is markedly increased in contracting skeletal muscles and myocardium, but perfusion in other organs (brain and bone) is only slightly enhanced or is even reduced (visceral organs). Despite largely unchanged metabolism and perfusion, repeated exposures to altered hemodynamics and hormonal milieu produced by acute exercise, long-term exercise training appears to be capable of inducing effects also in tissues other than muscles that may yield health benefits. However, the physiological adaptations and driving-force mechanisms in organs such as brain, liver, pancreas, gut, bone, and adipose tissue, remain largely obscure in humans. Along these lines, this review integrates current information on physiological responses to acute exercise and to long-term physical training in major metabolically active human organs. Knowledge is mostly provided based on the state-of-the-art, noninvasive human imaging studies, and directions for future novel research are proposed throughout the review.
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Timofeev, I.; Carpenter, K. L. H.; Nortje, J.; Al-Rawi, P. G.; O’Connell, M. T.; Czosnyka, M.; Smielewski, P.; Pickard, J. D.; Menon, D. K.; Kirkpatrick, P. J.; Gupta, A. K.; Hutchinson, P. J. Brain 2011, 134, 484– 494
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Kristensen, D. L.; Ladefoged, S. A; Sloth, E.; Aagaard, R.; Birke-Sørensen, H. Br. J. Oral Maxillofac. Surg. 2013, 51, 117– 122
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Microdialysis: characterisation of haematomas in myocutaneous flaps by use of biochemical agents
Kristensen Danja Lykke; Ladefoged Soren A; Sloth Erik; Aagaard Rasmus; Birke-Sorensen Hanne
The British journal of oral & maxillofacial surgery (2013), 51 (2), 117-22 ISSN:.
Metabolic markers are measured by microdialysis to detect postoperative ischaemia after reconstructive surgery with myocutaneous flaps. If a haematoma develops around the microdialysis catheter, it can result in misinterpretation of the measurements. The aim of the present study was to investigate whether a haematoma in a flap can be identified and dissociated from ischaemia, or a well-perfused flap, by a characteristic chemical profile. In 7 pigs, the pedicled rectus abdominal muscle flap was mobilised on both sides. A haematoma was made in each flap and two microdialysis catheters were placed, one in the haematoma, and the other in normal tissue. One flap was made ischaemic by ligation of the pedicle. For 6 hours, the metabolism was monitored by measurement every half-an-hour of the concentrations of glucose, lactate, pyruvate, and glycerol from all 4 catheters. After 3 hours of monitoring, intravenous glucose was given as a challenge test to identify ischaemia. The non-ischaemic flap could be differentiated from the ischaemic flap by low glucose, and high lactate, concentrations. It was possible to identify a catheter surrounded by a haematoma in ischaemic as well as non-ischaemic muscle from a low or decreasing concentration of glucose together with a low concentration of lactate. All four sites could be completely dissociated when the concentrations of glucose and lactate were evaluated and combined with the lactate:glucose ratio and a flow chart. The challenge test was useful for differentiating between haematomas in ischaemic and non-ischaemic tissue.
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Analytical Chemistry

Cite this: Anal. Chem. 2015, 87, 15, 7763–7770

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https://doi.org/10.1021/acs.analchem.5b01353

Published June 12, 2015

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Abstract
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Figure 1
Figure 1. A. Standard microdialysis setup for discrete sampling. The probe (a) is perfused at a fixed low flow rate, and dialysate is collected into a microvial (b) at the probe outlet. Right: shows the microvial when connected to the probe outlet holder. B. Photograph of combined needle electrode based on a 27G hypodermic needle and schematic cross-section of the needle tip, showing the layers that make up the biosensor: (i) m-PD exclusion layer, (ii) substrate oxidase (SOx) entrapped in a hydrogel, and (iii) diffusion limiting polyurethane outer film. C. Exploded view of custom-made microfluidic device for continuous monitoring of dialysate, showing the multicomponent system. The microfluidic chip (e) connects to the probe outlet holder (c) in place of a microvial. The outlet holder needle enters the microvial rubber insert (d) at the inlet of the microfluidic chip. Glucose and lactate needle biosensors (f) are housed in custom-made electrode holders (g) that screw into the microfluidic chip, placing the biosensors in the middle of the microfluidic channel and providing a good seal between the holder and the microfluidic device. (h) shows a photograph of an electrode holder containing a needle biosensor. The black part at the base of the holder is made of soft, compressible plastic to ensure the holder makes a good seal with the microfluidic chip. D. The L-shaped design provides a tidy and compact overall system.
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Figure 2
Figure 2. A. Normalized current response of a 50 μm disc glucose (red) and lactate (green) biosensor in a stirred beaker to a 2 mM concentration step (purple arrow). B. The graph shows the normalized current for a glucose biosensor to a step change from 0 to 2 mM at 1 μL/min in three different microfluidic channels. The measured channel sizes are shown in the table inset. The response time increases as the channel dimension increases.
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Figure 3
Figure 3. Typical calibration curves for 50 μm disc glucose and lactate biosensors in the microfluidic device at 1 μL/min. Mean ± standard deviation of measurement shown (n = 4). Points fitted with the Michaelis–Menten equation. Inset: Raw data for a typical 5-point lactate calibration from 0 to 4 mM in 1 mM steps.
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Figure 4
Figure 4. A. Photograph of microfluidic device to measure tissue glucose and lactate levels in dialysate during the cycling protocol. Dialysate flowed into the microfluidic chip, housing the glucose and lactate biosensors, which were connected to wireless potentiostats, secured onto the bike. B. Experimental protocol. Tissue levels were monitored during an initial resting period (i), followed by cycling at 4 levels of increasing rpm (ii-v), a level of warming down (vi), and a final period of resting (vii). C. Dialysate glucose and lactate levels during the exercise phase of the cycling protocol. The bottom graph shows the glucose (red) and lactate (green) levels, the middle graph (black) shows the lactate/glucose ratio, and the top graph shows the rotations per minute (blue) and heart rate (purple) throughout the cycling protocol. Glucose and lactate traces have been despiked. (39) The dotted lines indicate the stages of varying cycling intensity: (ii) 55 rpm, (iii) 65 rpm, (iv) 75 rpm, (v) sprint, and (vi) 55 rpm. Data has been time-aligned, taking into account the time delay of the system. D. Histograms showing mean dialysate levels for two different cyclists during key points in cycling protocol. Labels correspond to stages described in the experimental protocol: (i) baseline (ii) midway through warm up, (iii) midway through medium intensity, (iv) midway through high intensity, (v) end of sprint, (vi) end of warm down, and (vii) after 50 min of recovery.
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  3
  Real-time clinical monitoring of biomolecules
  Rogers, Michelle L.; Boutelle, Martyn G.
  Annual Review of Analytical Chemistry (2013), 6 (), 427-453CODEN: ARACFU; ISSN:1936-1327. (Annual Reviews)
  A review. Continuous monitoring of clin. biomarkers offers the exciting possibility of new therapies that use biomarker levels to guide treatment in real time. This review explores recent progress toward this goal. We initially consider measurements in body fluids by a range of anal. methods. We then discuss direct tissue measurements performed by implanted sensors; sampling techniques, including microdialysis and ultrafiltration; and noninvasive methods. A future directions section considers anal. methods at the cusp of clin. use.
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4. 4
  Diamond, D.; Coyle, S.; Scarmagnani, S.; Hayes, J. Chem. Rev. 2008, 108, 652– 679
  There is no corresponding record for this reference.
5. 5
  Windmiller, J. R.; Wang, J. Electroanalysis 2013, 25, 29– 46
  5
  Wearable Electrochemical Sensors and Biosensors: A Review
  Windmiller, Joshua Ray; Wang, Joseph
  Electroanalysis (2013), 25 (1), 29-46CODEN: ELANEU; ISSN:1040-0397. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A review. This article reviews recent advances and developments in the field of wearable sensors with emphasis on a subclass of these devices that are able to perform highly-sensitive electrochem. anal. Recent insights into novel fabrication methodologies and electrochem. techniques have resulted in the demonstration of chem. sensors able to augment conventional phys. measurements (i.e. heart rate, EEG, ECG, etc.), thereby providing added dimensions of rich, anal. information to the wearer in a timely manner. Wearable electrochem. sensors have been integrated onto both textile materials and directly on the epidermis for various monitoring applications owing to their unique ability to process chem. analytes in a non-invasive and non-obtrusive fashion. In this manner, multi-analyte detection can easily be performed, in real time, in order to ascertain the overall physiol. health of the wearer or to identify potential offenders in their environment. Of profound importance is the development of an understanding of the impact of mech. strain on textile- and epidermal (tattoo)-based sensors and their failure mechanisms as well as the compatibility of the substrate employed in the fabrication process. We conclude this review with a retrospective outlook of the field and identify potential implications of this new sensing paradigm in the healthcare, fitness, security, and environmental monitoring domains. With continued innovation and detailed attention to core challenges, it is expected that wearable electrochem. sensors will play a pivotal role in the emergent body sensor networks arena.
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6. 6
  Woderer, S.; Henninger, N.; Garthe, C. D.; Kloetzer, H. M.; Hajnsek, M.; Kamecke, U.; Gretz, N.; Kraenzlin, B.; Pill, J. Anal. Chim. Acta 2007, 581, 7– 12
  There is no corresponding record for this reference.
7. 7
  Facchinetti, A.; Sparacino, G.; Cobelli, C. J. Diabetes Sci. Technol. 2007, 1, 617– 623
  7
  Reconstruction of glucose in plasma from interstitial fluid continuous glucose monitoring data: role of sensor calibration
  Facchinetti Andrea; Sparacino Giovanni; Cobelli Claudio
  Journal of diabetes science and technology (2007), 1 (5), 617-23 ISSN:.
  BACKGROUND: Continuous glucose monitoring (CGM) sensors measure glucose concentration in the interstitial fluid (ISF). Equilibration between plasma and ISF glucose is not instantaneous. Therefore, ISF and plasma glucose concentrations exhibit different dynamic patterns, particularly during rapid changes. The purpose of this work was to investigate how well plasma glucose can be reconstructed from ISF CGM data. METHODS: Six diabetic volunteers were monitored for 2 days using the TheraSense FreeStyle Navigator (Abbott Diabetes Care, Alameda, CA), a minimally invasive device that, on the basis of an initial calibration procedure (hereafter referred to as standard calibration), returns ISF glucose concentration. Simultaneously, plasma glucose concentration was also measured every 15 minutes. First we identified, in each subject, the linear time-invariant (LTI) two-compartment model of plasma-interstitium kinetics. Then, a nonparametric regularization deconvolution method was used to reconstruct plasma from ISF glucose. RESULTS: Deconvoluted profiles were always closer to plasma glucose than ISF ones. However, the quality of the reconstruction is unsatisfactory. Some visible discrepancies between average plasma and ISF time series suggest problems either in the applicability of the LTI model of plasma-interstitium kinetics to normal life conditions or in the standard calibration with which ISF glucose is determined from the sensor internal readings. Assuming that the LTI model of plasma-interstitium kinetics is correct, we focused on the influence of calibration and we employed a recently proposed method to recalibrate ISF data. CONCLUSIONS: After the recalibration step, the relative error in reconstructing plasma glucose was reduced significantly. Results also demonstrate that further margins of improvement of plasma glucose reconstruction are possible by developing more sophisticated recalibration procedures.
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8. 8
  Curto, V. F.; Fay, C.; Coyle, S.; Byrne, R.; O’Toole, C.; Barry, C.; Hughes, S.; Moyna, N.; Diamond, D.; Benito-Lopez, F. Sens. Actuators, B Chem. 2012, 171–172, 1327– 1334
  8
  Real-time sweat pH monitoring based on a wearable chemical barcode micro-fluidic platform incorporating ionic liquids
  Curto, Vincenzo F.; Fay, Cormac; Coyle, Shirley; Byrne, Robert; O'Toole, Corinne; Barry, Caroline; Hughes, Sarah; Moyna, Niall; Diamond, Dermot; Benito-Lopez, Fernando
  Sensors and Actuators, B: Chemical (2012), 171-172 (), 1327-1334CODEN: SABCEB; ISSN:0925-4005. (Elsevier B.V.)
  This work presents the fabrication, characterization and the performance of a wearable, robust, flexible and disposable chem. barcode device based on a micro-fluidic platform that incorporates ionic liq. polymer gels (ionogels). The device has been applied to the monitoring of the pH of sweat in real time during an exercise period. The device is an ideal wearable sensor for measuring the pH of sweat since it does not contain any electronic part for fluidic handle or pH detection and because it can be directly incorporated into clothing, head- or wristbands, which are in continuous contact with the skin. In addn., due to the micro-fluidic structure, fresh sweat is continuously passing through the sensing area providing the capability to perform continuous real time anal. The approach presented here ensures immediate feedback regarding sweat compn. Sweat anal. is attractive for monitoring purposes as it can provide physiol. information directly relevant to the health and performance of the wearer without the need for an invasive sampling approach.
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9. 9
  Jia, W.; Bandodkar, A. J.; Valde, G.; Windmiller, J. R.; Yang, Z.; Ram, J.; Chan, G.; Wang, J. Anal. Chem. 2013, 85, 6553– 6560
  9
  Electrochemical Tattoo Biosensors for Real-Time Noninvasive Lactate Monitoring in Human Perspiration
  Jia, Wenzhao; Bandodkar, Amay J.; Valdes-Ramirez, Gabriela; Windmiller, Joshua R.; Yang, Zhanjun; Ramirez, Julian; Chan, Garrett; Wang, Joseph
  Analytical Chemistry (Washington, DC, United States) (2013), 85 (14), 6553-6560CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
  The present work describes the first example of real-time noninvasive lactate sensing in human perspiration during exercise events using a flexible printed temporary-transfer tattoo electrochem. biosensor that conforms to the wearer's skin. The new skin-worn enzymic biosensor exhibits chem. selectivity toward lactate with linearity up to 20 mM and demonstrates resiliency against continuous mech. deformation expected from epidermal wear. The device was applied successfully to human subjects for real-time continuous monitoring of sweat lactate dynamics during prolonged cycling exercise. The resulting temporal lactate profiles reflect changes in the prodn. of sweat lactate upon varying the exercise intensity. Such skin-worn metabolite biosensors could lead to useful insights into phys. performance and overall physiol. status, hence offering considerable promise for diverse sport, military, and biomedical applications.
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10. 10
  Kabilan, S.; Ph, D.; Lowe, C. Diabetes Technol. Ther. 2006, 8, 89– 93
  10
  Initial clinical testing of a holographic non-invasive contact lens glucose sensor
  Domschke, Angelika; March, Wayne F.; Kabilan, Satyamoorthy; Lowe, Christopher
  Diabetes Technology & Therapeutics (2006), 8 (1), 89-93CODEN: DTTHFH; ISSN:1520-9156. (Mary Ann Liebert, Inc.)
  Introduction: the purpose of the present study was to det. the effectiveness of a new holog. contact lens glucose sensor for the non-invasive monitoring of blood glucose. Methods: one fasting normal subject was given an oral challenge consisting of 44 g of glucose. The contact lens hologram signal and fingerstick blood glucose were measured over a 26- min period. Results: the contact lens hologram signal appeared to track blood glucose well. The contact lens was comfortable and well tolerated. Conclusion: the holog. contact lens glucose sensor shows promise as a non-invasive home glucose monitor.
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11. 11
  Iguchi, S.; Kudo, H.; Saito, T.; Ogawa, M.; Saito, H.; Otsuka, K.; Funakubo, A.; Mitsubayashi, K. Biomed. Microdevices 2007, 9, 603– 609
  There is no corresponding record for this reference.
12. 12
  Yoda, K.; Shimazaki, K.; Ueda, Y.; Ann, N. Y. Acad. Sci. 1998, 864, 600– 604
  12
  Analysis of glycolysis relevant compounds in saliva by microbiosensors
  Yoda, Kentaro; Shimazaki, Kouji; Ueda, Yuichiro
  Annals of the New York Academy of Sciences (1998), 864 (Enzyme Engineering XIV), 600-604CODEN: ANYAA9; ISSN:0077-8923. (New York Academy of Sciences)
  Microbiosensors for glucose and lactate were constructed and applied for the detn. of glucose and lactate in saliva and blood samples taken before and after anaerobic exercise.
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13. 13
  Mannoor, M. S.; Tao, H.; Clayton, J. D.; Sengupta, A.; Kaplan, D. L.; Naik, R. R.; Verma, N.; Omenetto, F. G.; McAlpine, M. C. Graphene-based wireless bacteria detection on tooth enamel Nat. Commun. 2012, 3, 763
  13
  Graphene-based wireless bacteria detection on tooth enamel
  Mannoor Manu S; Tao Hu; Clayton Jefferson D; Sengupta Amartya; Kaplan David L; Naik Rajesh R; Verma Naveen; Omenetto Fiorenzo G; McAlpine Michael C
  Nature communications (2012), 3 (), 763 ISSN:.
  Direct interfacing of nanosensors onto biomaterials could impact health quality monitoring and adaptive threat detection. Graphene is capable of highly sensitive analyte detection due to its nanoscale nature. Here we show that graphene can be printed onto water-soluble silk. This in turn permits intimate biotransfer of graphene nanosensors onto biomaterials, including tooth enamel. The result is a fully biointerfaced sensing platform, which can be tuned to detect target analytes. For example, via self-assembly of antimicrobial peptides onto graphene, we show bioselective detection of bacteria at single-cell levels. Incorporation of a resonant coil eliminates the need for onboard power and external connections. Combining these elements yields two-tiered interfacing of peptide-graphene nanosensors with biomaterials. In particular, we demonstrate integration onto a tooth for remote monitoring of respiration and bacteria detection in saliva. Overall, this strategy of interfacing graphene nanosensors with biomaterials represents a versatile approach for ubiquitous detection of biochemical targets.
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14. 14
  Krustrup, P.; Mohr, M.; Steensberg, A.; Bencke, J.; Kjaer, M.; Bangsbo, J. Med. Sci. Sports Exercise 2006, 38, 1165– 1174
  14
  Muscle and Blood Metabolites during a Soccer Game: Implications for Sprint Performance
  Krustrup, Peter; Mohr, Magni; Steensberg, Adam; Bencke, Jesper; Kjaer, Michael; Bangsbo, Jens
  Medicine & Science in Sports & Exercise (2006), 38 (6), 1165-1174CODEN: MSPEDA; ISSN:0195-9131. (Lippincott Williams & Wilkins)
  Purpose: To examine muscle and blood metabolites during soccer match play and relate it to possible changes in sprint performance. Methods: Thirty-one Danish fourth division players took part in three friendly games. Blood samples were collected frequently during the game, and muscle biopsies were taken before and after the game as well as immediately after an intense period in each half. The players performed five 30-m sprints interspersed by 25-s recovery periods before the game and immediately after each half (N = 11) or after an intense exercise period in each half (N = 20). Results: Muscle lactate was 15.9 ± 1.9 and 16.9 ± 2.3 mmol·kg d.w. during the first and second halves, resp., with blood lactate being 6.0 ± 0.4 and 5.0 ± 0.4 mM, resp. Muscle lactate was not correlated with blood lactate (r = 0.06-0.25, P >0.05). Muscle glycogen decreased (P < 0.05) from 449 ± 23 to 255 ± 22 mmol·kg d.w. during the game, with 47 ± 7% of the muscle fibers being completely or almost empty of glycogen after the game. Blood glucose remained elevated during the game, whereas plasma FFA increased (P < 0.05) from 0.45 ± 0.05 to 1.37 ± 0.23 mM. Mean sprint time was unaltered after the first half, but longer (P < 0.05) after the game (2.8 ± 0.7%) as well as after intense periods in the first (1.6 ± 0.6%) and second halves (3.6 ± 0.5%). The decline in sprint performance during the game was not correlated with muscle lactate, muscle pH, or total glycogen content. Conclusion: Sprint performance is reduced both temporarily during a game and at the end of a soccer game. The latter finding may be explained by low glycogen levels in individual muscle fibers. Blood lactate is a poor indicator of muscle lactate during soccer match play.
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15. 15
  Watson, C. J.; Venton, B. J.; Kennedy, R. T. Anal. Chem. 2006, 78, 1391– 1399
  15
  In vivo measurements of neurotransmitters by microdialysis sampling
  Watson Christopher J; Venton B Jill; Kennedy Robert T
  Analytical chemistry (2006), 78 (5), 1391-9 ISSN:0003-2700.
  The brain contains a vast network of neurons that connect with each other at specialized junctions called synapses.A synapse consists of a presynaptic terminal (the "sending"neuron) and a postsynaptic bouton (the "receiving" neuron)that are separated by a gap of 5-50 nm (Figure 1). Chemicals released into this synaptic gap interact with receptors on the postsynaptic neuron. This leads to intracellular changes in the postsynaptic neuron-for example, an altered membrane potential or gene expression. The chemical signal is terminated by transporter proteins that transfer transmitter molecules across the membrane to the intracellular space (a process known as "reuptake")or enzymes that degrade the transmitter in the vicinity of the synapse (Figure 1). This classical view of neurotransmission might be considered point-to-point or"wired" communication because neurons communicate only with neurons to which they are specifically connected. In addition,neurotransmitters can activate receptors at more distant sites either by escaping the synapse or by being directly released into extrasynaptic space. This longer-range communication has been called "volume" transmission (1, S1; S references can be found in Supporting Information). All brain functions, from controlling movement to emotions, involve these two forms of chemical communication. Analytical chemistry has an important role to play in developing our understanding of the brain by providing tools for identification and measurement of the many chemicals involved in neurotransmission.
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16. 16
  Parkin, M. C.; Hopwood, S. E.; Boutelle, M. G.; Strong, A. J. TrAC, Trends Anal. Chem. 2003, 22, 487– 497
  There is no corresponding record for this reference.
17. 17
  Schultz, K. N.; Kennedy, R. T. Annu. Rev. Anal. Chem. 2008, 1, 627– 661
  17
  Time-resolved microdialysis for in vivo neurochemical measurements and other applications
  Schultz, Kristin N.; Kennedy, Robert T.
  Annual Review of Analytical Chemistry (2008), 1 (), 627-661CODEN: ARACFU; ISSN:1936-1327. (Annual Reviews Inc.)
  A review. Monitoring changes in chem. concns. over time in complex environments is typically performed using sensors and spectroscopic techniques. Another approach is to couple sampling methods, such as microdialysis, with chromatog., electrophoretic, or enzymic assays. Recent advances of such coupling have enabled improvements in temporal resoln., multianalyte capability, and automation. In a sampling and anal. method, the temporal resoln. is set by the mass sensitivity of the anal. method, anal. time, and zone dispersion during sampling. Coupling methods with high speed and mass sensitivity to microdialysis sampling help to reduce some of these contributions to yield methods with temporal resoln. of seconds. These advances have been primarily used in monitoring neurotransmitters in vivo. This review covers the problems assocd. with chem. monitoring in the brain, recent advances in using microdialysis for time-resolved in vivo measurements, sample applications, and other potential applications of the technol. such as detg. reaction kinetics and process monitoring.
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18. 18
  Nandi, P.; Lunte, S. M. Anal. Chim. Acta 2009, 651, 1– 14
  18
  Recent trends in microdialysis sampling integrated with conventional and microanalytical systems for monitoring biological events: A review
  Nandi, Pradyot; Lunte, Susan M.
  Analytica Chimica Acta (2009), 651 (1), 1-14CODEN: ACACAM; ISSN:0003-2670. (Elsevier B.V.)
  A review. Microdialysis (MD) is a sampling technique that can be employed to monitor biol. events both in vivo and in vitro. When it is coupled to an anal. system, microdialysis can provide near real-time information on the time-dependent concn. changes of analytes in the extracellular space or other aq. environments. Online systems for the anal. of microdialysis samples enable fast, selective and sensitive anal. while preserving the temporal information. Anal. methods employed for online anal. include liq. chromatog. (LC), capillary (CE) and microchip electrophoresis and flow-through biosensor devices. This review article provides an overview of microdialysis sampling and online anal. systems with emphasis on in vivo anal. Factors that affect the frequency of anal. and, hence, the temporal resoln. of these systems are also discussed.
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19. 19
  Rogers, M. L.; Brennan, P. A.; Leong, C. L.; Gowers, S. A. N.; Aldridge, T.; Mellor, T. K.; Boutelle, M. G. Anal. Bioanal. Chem. 2013, 405, 3881– 3888
  19
  Online rapid sampling microdialysis (rsMD) using enzyme-based electroanalysis for dynamic detection of ischaemia during free flap reconstructive surgery
  Rogers, M. L.; Brennan, P. A.; Leong, C. L.; Gowers, S. A. N.; Aldridge, T.; Mellor, T. K.; Boutelle, M. G.
  Analytical and Bioanalytical Chemistry (2013), 405 (11), 3881-3888CODEN: ABCNBP; ISSN:1618-2642. (Springer)
  We describe an enzyme-based electroanal. system for real-time anal. of a clin. microdialysis sampling stream during surgery. Free flap tissue transfer is used widely in reconstructive surgery after resection of tumors or in other situations such as following major trauma. However, there is a risk of flap failure, due to thrombosis in the flap pedicle, leading to tissue ischemia. Conventional clin. assessment is particularly difficult in such buried' flaps where access to the tissue is limited. Rapid sampling microdialysis (rsMD) is an enzyme-based electrochem. detection method, which is particularly suited to monitoring metab. This online flow injection system analyses a dialyzate flow stream from an implanted microdialysis probe every 30 s for levels of glucose and lactate. Here, we report its first use in the monitoring of free flap reconstructive surgery, from flap detachment to re-vascularisation and overnight in the intensive care unit. The on-set of ischemia by both arterial clamping and failure of venous drainage was seen as an increase in lactate and decrease in glucose levels. Glucose levels returned to normal within 10 min of successful arterial anastomosis, while lactate took longer to clear. The use of the lactate/glucose ratio provides a clear predictor of ischemia on-set and subsequent recovery, as it is insensitive to changes in blood flow such as those caused by topical vasodilators, like papaverine. The use of storage tubing to preserve the time course of dialyzate, when tech. difficulties arise, until offline anal. can occur, is also shown. The potential use of rsMD in free flap surgery and tissue monitoring is highly promising.
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20. 20
  Rogers, M. L.; Feuerstein, D.; Leong, C. L.; Takagaki, M.; Niu, X.; Graf, R.; Boutelle, M. G. ACS Chem. Neurosci. 2013, 4, 799– 807
  20
  Continuous Online Microdialysis Using Microfluidic Sensors: Dynamic Neurometabolic Changes during Spreading Depolarization
  Rogers, Michelle L.; Feuerstein, Delphine; Leong, Chi Leng; Takagaki, Masatoshi; Niu, Xize; Graf, Rudolf; Boutelle, Martyn G.
  ACS Chemical Neuroscience (2013), 4 (5), 799-807CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)
  Microfluidic glucose biosensors and potassium ion selective electrodes were used in an in vivo study to measure the neurochem. effects of spreading depolarizations (SD), which have been shown to be detrimental to the injured human brain. A microdialysis probe implanted in the cortex of rats was connected to a microfluidic PDMS chip contg. the sensors. The dialyzate was also analyzed using our gold std., rapid sampling microdialysis (rsMD). The glucose biosensor performance was validated against rsMD with excellent results. The glucose biosensors successfully monitored concn. changes, in response to SD wave induction, in the range of 10-400 μM with a second time-resoln. The data show that during a SD wave, there is a time delay of 62 ± 24.8 s (n = 4) between the onset of the increase in potassium and the decrease in glucose. This delay can be for the first time demonstrated, thanks to the high-temporal resoln. of the microfluidic sensors sampling from a single tissue site (the microdialysis probe), and it indicates that the decrease in glucose is due to the high demand of energy required for repolarization.
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21. 21
  Deeba, S.; Corcoles, E. P.; Hanna, G. B.; Hanna, B. G.; Pareskevas, P.; Aziz, O.; Boutelle, M. G.; Darzi, A. Dis. Colon Rectum 2008, 51, 1408– 1413
  21
  Use of rapid sampling microdialysis for intraoperative monitoring of bowel ischemia
  Deeba S; Corcoles E P; Hanna G B; Hanna B G; Pareskevas P; Aziz O; Boutelle M G; Darzi A
  Diseases of the colon and rectum (2008), 51 (9), 1408-13 ISSN:.
  PURPOSE: Intestinal ischemia is a major cause of anastomotic leak and death and remains a clinical challenge as the physician relies on several nonspecific signs, biologic markers, and radiologic studies to make the diagnosis. This study used rapid sampling online microdialysis to evaluate the biochemical changes occurring in a segment of human bowel during and after resection, and assessed for the feasibility and reproducibility of this technique in monitoring intestinal ischemia. METHODS: A custom made, rapid sampling online microdialysis analyzer was used to monitor the changes in the bowel wall of specimens being resected intraoperatively. Two patients were recruited for the pilot study to optimize the analyzer and seven patients undergoing colonic resections were recruited for the data collection and analysis. RESULTS: The concentration of glucose in the extracellular bowel wall fluid decreased transiently after division of individual feeding arteries followed by a rebound increase in the concentration back to baseline concentrations. After completion of resection, glucose concentrations continued to decrease while lactate concentrations increased constantly. CONCLUSION: Rapid sampling microdialysis was feasible in the clinical environment. These results suggest that tissue responds to ischemic insult by mobilizing glucose stores which later decrease again, whereas lactate concentrations constantly increased.
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22. 22
  Birke-Sorensen, H. J. Transplant. 2012, 2012, 970630
  22
  Detection of postoperative intestinal ischemia in small bowel transplants
  Birke-Sorensen Hanne
  Journal of transplantation (2012), 2012 (), 970630 ISSN:.
  Small bowel transplantation is acknowledged as auto- and allotransplantation. In both instances, there is up to a 4%-10% risk of postoperative ischemia, and as the small bowel is extremely susceptible to ischemia, the timely diagnosis of ischemia is important. The location of the transplant, whether it is buried in the abdominal cavity or in the neck region, increases the challenge, as monitoring becomes more difficult and the consequences of neglect more dangerous. All methods for the early detection of postoperative ischemia in small bowel transplants are described together with the requirements of the ideal monitoring method. A small bowel transplant can be inspected directly or indirectly; the blood flow can be monitored by Doppler or by photoplethysmography, and the consequences of the blood flow can be monitored. The ideal monitoring method should be reliable, fast, minimally invasive, safe, objective, easy, cheap, and comfortable. No monitoring methods today fulfill the criteria of the ideal monitoring method, and evidence-based guidelines regarding postoperative monitoring cannot be made. The choice of whether to implement monitoring of ischemia-and if so, which method to choose-has to be made by the individual surgeon or center.
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23. 23
  Wang, M.; Roman, G. T.; Schultz, K.; Jennings, C.; Kennedy, R. T. Anal. Chem. 2008, 80, 5607– 5615
  There is no corresponding record for this reference.
24. 24
  Sun, S.; Slaney, T. R.; Kennedy, R. T. Anal. Chem. 2012, 84, 5794– 5800
  There is no corresponding record for this reference.
25. 25
  Nandi, P.; Desai, D. P.; Lunte, S. M. Electrophoresis 2010, 31, 1414– 1422
  There is no corresponding record for this reference.
26. 26
  Lucca, B. G.; Lunte, S. M.; Tomazelli Coltro, W. K.; Ferreira, V. S. Electrophoresis 2014, 35, 3363– 3370
  There is no corresponding record for this reference.
27. 27
  Rogers, M.; Leong, C.; Niu, X.; de Mello, A.; Parker, K. H.; Boutelle, M. G. Phys. Chem. Chem. Phys. 2011, 13, 5298– 5303
  There is no corresponding record for this reference.
28. 28
  Taylor, G. Proc. R. Soc. London, Ser. A 1953, 219, 186– 203
  28
  Dispersion of soluble matter in solvent flowing slowly through a tube
  Taylor, Geoffrey
  Proceedings of the Royal Society of London, Series A: Mathematical, Physical and Engineering Sciences (1953), 219 (), 186-203CODEN: PRLAAZ; ISSN:1364-5021.
  When a sol. substance is introduced into a fluid flowing slowly through a small-bore tube it spreads out under the combined action of mol. diffusion and the variation of velocity over the cross section. It is shown analytically that the distribution of concn. produced in this way is centered on a point which moves with the mean speed of flow and is symmetrical about it in spite of the asymmetry of the flow. The dispersion along the tube is governed by a virtual coeff. of diffusivity which can be calcd. from observed distributions of concn. Since the analysis relates the longitudinal diffusivity to the coeff. of mol. diffusion, observations of concn. along a tube provide a new method for measuring diffusion coeffs. The coeff. so obtained was found, with KMnO4, to agree with that measured in other ways. The dispersion in steady flow is due to the combined action of convection parallel to the axis and mol. diffusion in the radial direction. It is of interest to consider, first, dispersion by convection alone, and then to introduce the effect of mol. diffusion. The results may be useful to physiologists who may wish to know how a sol. salt is dispersed in a blood vessel, but they may also be useful to physicists who wish to measure mol. diffusion coeffs. The exptl. technique used for KMnO4 is described in detail, and results are compared with earlier measurements.
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29. 29
  Lunte, S. M.; Nandi, P.; Regel, A.; Grigsby, R.; Hulvey, M. K.; Scott, D.; Naylor, E.; Gabbert, S.; Johnson, D. In 14th International Conference on Miniaturized Systems for Chemistry and Life Sciences; 2010; pp 1535– 1537.
  There is no corresponding record for this reference.
30. 30
  Erkal, J. L.; Selimovic, A.; Gross, B. C.; Lockwood, S. Y.; Walton, E. L.; McNamara, S.; Martin, R. S.; Spence, D. M. Lab Chip 2014, 14, 2023– 2032
  30
  3D printed microfluidic devices with integrated versatile and reusable electrodes
  Erkal, Jayda L.; Selimovic, Asmira; Gross, Bethany C.; Lockwood, Sarah Y.; Walton, Eric L.; McNamara, Stephen; Martin, R. Scott; Spence, Dana M.
  Lab on a Chip (2014), 14 (12), 2023-2032CODEN: LCAHAM; ISSN:1473-0189. (Royal Society of Chemistry)
  We report two 3D printed devices that can be used for electrochem. detection. In both cases, the electrode is housed in com. available, polymer-based fittings so that the various electrode materials (platinum, platinum black, carbon, gold, silver) can be easily added to a threaded receiving port printed on the device; this enables a module-like approach to the exptl. design, where the electrodes are removable and can be easily repolished for reuse after exposure to biol. samples. The first printed device represents a microfluidic platform with a 500 × 500 μm channel and a threaded receiving port to allow integration of either polyetheretherketone (PEEK) nut-encased glassy carbon or platinum black (Pt-black) electrodes for dopamine and nitric oxide (NO) detection, resp. The embedded 1 mm glassy carbon electrode had a limit of detection (LOD) of 500 nM for dopamine and a linear response (R2 = 0.99) for concns. between 25-500 μM. When the glassy carbon electrode was coated with 0.05% Nafion, significant exclusion of nitrite was obsd. when compared to signal obtained from equimolar injections of dopamine. When using flow injection anal. with a Pt/Pt-black electrode and stds. derived from NO gas, a linear correlation (R2 = 0.99) over a wide range of concns. (7.6-190 μM) was obtained, with the LOD for NO being 1 μM. The second application showcases a 3D printed fluidic device that allows collection of the biol. relevant analyte ATP (ATP) while simultaneously measuring the release stimulus (reduced oxygen concn.). The hypoxic sample (4.8 ± 0.5 ppm oxygen) released 2.4 ± 0.4 times more ATP than the normoxic sample (8.4 ± 0.6 ppm oxygen). Importantly, the results reported here verify the reproducible and transferable nature of using 3D printing as a fabrication technique, as devices and electrodes were moved between labs multiple times during completion of the study.
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31. 31
  Kitson, P. J.; Rosnes, M. H.; Sans, V.; Dragone, V.; Cronin, L. Lab Chip 2012, 12, 3267
  31
  Configurable 3D-Printed millifluidic and microfluidic lab on a chip reactionware devices
  Kitson, Philip J.; Rosnes, Mali H.; Sans, Victor; Dragone, Vincenza; Cronin, Leroy
  Lab on a Chip (2012), 12 (18), 3267-3271CODEN: LCAHAM; ISSN:1473-0189. (Royal Society of Chemistry)
  We utilize 3D design and 3D printing techniques to fabricate a no. of miniaturized fluidic 'reactionware' devices for chem. syntheses in just a few hours, using inexpensive materials producing reliable and robust reactors. Both two and three inlet reactors could be assembled, as well as one-inlet devices with reactant silos' allowing the introduction of reactants during the fabrication process of the device. To demonstrate the utility and versatility of these devices org. (reductive amination and alkylation reactions), inorg. (large polyoxometalate synthesis) and materials (gold nanoparticle synthesis) processes were efficiently carried out in the printed devices.
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32. 32
  Therriault, D.; White, S. R.; Lewis, J. A. Nat. Mater. 2003, 2, 265– 271
  There is no corresponding record for this reference.
33. 33
  Snowden, M. E.; King, P. H.; Covington, J. a; Macpherson, J. V.; Unwin, P. R. Anal. Chem. 2010, 82, 3124– 3131
  33
  Fabrication of Versatile Channel Flow Cells for Quantitative Electroanalysis Using Prototyping
  Snowden, Michael E.; King, Philip H.; Covington, James A.; MacPherson, Julie V.; Unwin, Patrick R.
  Analytical Chemistry (Washington, DC, United States) (2010), 82 (8), 3124-3131CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
  Here the authors demonstrate the use of microstereolithog. (MSL), a 3D direct manufg. technique, as a viable method to produce small-scale microfluidic components for electrochem. flow detection. The flow cell is assembled simply by resting the microfabricated component on the electrode of interest and securing with thread!. This configuration allows the use of a wide range of electrode materials. Also, the approach eliminates the need for addnl. sealing methods, such as adhesives, waxes, and screws, which were previously deployed. It removes any issues assocd. with compression of the cell chamber. MSL allows a redn. of the dimensions of the channel geometry (and the resultant component) and, compared to most previously produced devices, it offers a high degree of flexibility in the design, reduced manuf. time, and high reliability. Importantly, the polymer used does not distort so that the cell maintains well-defined geometrical dimensions after assembly. For the studies herein the channel dimensions were 3 mm wide, 3.5 mm long, and 192 or 250 μm high. The channel flow cell dimensions were chosen to ensure that the substrate electrodes experienced laminar flow conditions, even with vol. flow rates of up to 64 mL min-1 (the limit of the pumping system). The steady-state transport-limited current response, for the oxidn. of ferrocenylmethyltrimethylammonium hexafluorophosphate (FcTMA+), at Au and polycryst. B doped diamond (pBDD) band electrodes was in agreement with the Levich equation and/or finite element simulations of mass transport. Probably this method of creating and using channel flow electrodes offers a wide range of new applications from electroanal. to electrocatalysis.
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34. 34
  Anderson, K. B.; Lockwood, S. Y.; Martin, R. S.; Spence, D. M. Anal. Chem. 2013, 85, 5622– 5626
  34
  A 3D Printed Fluidic Device that Enables Integrated Features
  Anderson, Kari B.; Lockwood, Sarah Y.; Martin, R. Scott; Spence, Dana M.
  Analytical Chemistry (Washington, DC, United States) (2013), 85 (12), 5622-5626CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
  Fluidic devices fabricated using conventional soft lithog. are well suited as prototyping methods. Three-dimensional (3D) printing, commonly used for producing design prototypes in industry, allows for one step prodn. of devices. 3D printers build a device layer by layer based on 3D computer models. Here, a reusable, high throughput, 3D printed fluidic device was created that enables flow and incorporates a membrane above a channel in order to study drug transport and affect cells. The device contains 8 parallel channels, 3 mm wide by 1.5 mm deep, connected to a syringe pump through std., threaded fittings. The device was also printed to allow integration with com. available membrane inserts whose bottoms are constructed of a porous polycarbonate membrane; this insert enables mol. transport to occur from the channel to above the well. When concns. of various antibiotics (levofloxacin and linezolid) are pumped through the channels, approx. 18-21% of the drug migrates through the porous membrane, providing evidence that this device will be useful for studies where drug effects on cells are investigated. Finally, we show that mammalian cells cultured on this membrane can be affected by reagents flowing through the channels. Specifically, saponin was used to compromise cell membranes, and a fluorescent label was used to monitor the extent, resulting in a 4-fold increase in fluorescence for saponin treated cells.
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35. 35
  Waldbaur, A.; Rapp, H.; Länge, K.; Rapp, B. E. Anal. Methods 2011, 3, 2681
  35
  Let there be chip-towards rapid prototyping of microfluidic devices: one-step manufacturing processes
  Waldbaur, Ansgar; Rapp, Holger; Laenge, Kerstin; Rapp, Bastian E.
  Analytical Methods (2011), 3 (12), 2681-2716CODEN: AMNEGX; ISSN:1759-9679. (Royal Society of Chemistry)
  A review. Microfluidics is an evolving scientific field with immense com. potential: anal. applications, such as biochem. assay development, biochem. anal. and biosensors as well as chem. synthesis applications essentially require microfluidics for sample handling, treatment or readout. A no. of techniques are available to create microfluidic structures today. On industrial scale replication techniques such as injection molding are the gold std. whereas academic research mostly focuses on replication by casting of soft elastomers such as polydimethylsiloxane (PDMS). Both of these techniques require the creation of a replication master thus creating the microfluidic structure only in the second process step-they can therefore be termed two-(or multi-)step manufg. techniques. However, very often the no. of pieces to be created of one specific microfluidic design is low, sometimes even as low as one. This raises the question if two-step manufg. is an appropriate choice, particularly if short concept-to-chip times are required. In this case one-step manufg. techniques that allow the direct creation of microfluidic structures from digital three-dimensional models are preferable. For these processes the no. of parts per design is low (sometimes as low as one), but quick adaptation is possible by simply changing digital data. Suitable techniques include, among others, maskless or mask based stereolithog., fused deposition molding and 3D printing. This work intends to discuss the potential and application examples of such processes with a detailed view on applicable materials. It will also point out the advantages and the disadvantages of the resp. technique. Furthermore this paper also includes a discussion about non-conventional manufg. equipment and community projects that can be used in the prodn. of microfluidic devices.
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36. 36
  Patel, B. A.; Rogers, M.; Wieder, T.; O’Hare, D.; Boutelle, M. G. Biosens. Bioelectron. 2011, 26, 2890– 2896
  There is no corresponding record for this reference.
37. 37
  Viggiano, A.; Marinesco, S.; Pain, F.; Meiller, A.; Gurden, H. J. Neurosci. Methods 2012, 206, 1– 6
  37
  Reconstruction of field excitatory post-synaptic potentials in the dentate gyrus from amperometric biosensor signals
  Viggiano Alessandro; Marinesco Stephane; Pain Frederic; Meiller Anne; Gurden Hirac
  Journal of neuroscience methods (2012), 206 (1), 1-6 ISSN:.
  A new feasible and reproducible method to reconstruct local field potentials from amperometric biosensor signals is presented. It is based on the least-square fit of the current response of the biosensor electrode to a voltage step by the use of two time constants. After determination of the electrode impedance, Fast Fourier Transform (FFT) and Inverse FFT are performed to convert the recorded amperometric signals into voltage and trace the local field potentials using a resistor-capacitor circuit-based model. We applied this method to reconstruct field evoked potentials from currents recorded by a lactate biosensor in the rat dentate gyrus after stimulation of the perforant pathway in vivo. Initial slope of the reconstructed field excitatory postsynaptic potentials was used in order to demonstrate long term potentiation induced by high frequency stimulation of the perforant path. Our results show that reconstructing evoked potentials from amperometric recordings is a reliable method to obtain in vivo electrophysiological and amperometric information simultaneously from the same electrode in order to understand how chemical compounds vary with and modulate the dynamics of brain activity.
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38. 38
  Vasylieva, N.; Barnych, B.; Meiller, A.; Maucler, C.; Pollegioni, L.; Lin, J.-S.; Barbier, D.; Marinesco, S. Biosens. Bioelectron 2011, 26, 3993– 4000
  38
  Covalent enzyme immobilization by poly(ethylene glycol) diglycidyl ether (PEGDE) for microelectrode biosensor preparation
  Vasylieva, Natalia; Barnych, Bogdan; Meiller, Anne; Maucler, Caroline; Pollegioni, Loredano; Lin, Jian-Sheng; Barbier, Daniel; Marinesco, Stephane
  Biosensors & Bioelectronics (2011), 26 (10), 3993-4000CODEN: BBIOE4; ISSN:0956-5663. (Elsevier B.V.)
  Poly(ethylene glycol) diglycidyl ether (PEGDE) is widely used as an additive for crosslinking polymers bearing amine, hydroxyl, or carboxyl groups. However, the idea of using PEGDE alone for immobilizing proteins on biosensors has never been thoroughly explored. We report the successful fabrication of microelectrode biosensors based on glucose oxidase, D-amino acid oxidase, and glutamate oxidase immobilized using PEGDE. We found that biosensors made with PEGDE exhibited high sensitivity and a response time on the order of seconds, which is sufficient for observing biol. processes in vivo. The enzymic activity on these biosensors was highly stable over several months when they were stored at 4 °C, and over at least 3 d at 37 °C. Glucose microelectrode biosensors implanted in the central nervous system of anesthetized rats reliably monitored changes in brain glucose levels induced by sequential administration of insulin and glucose. PEGDE provides a simple, low cost, non-toxic alternative for the prepn. of in vivo microelectrode biosensors.
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39. 39
  Feuerstein, D.; Parker, K. H.; Boutelle, M. G. Anal. Chem. 2009, 81, 4987– 4994
  There is no corresponding record for this reference.
40. 40
  Heinonen, I.; Kalliokoski, K. K.; Hannukainen, J. C.; Duncker, D. J.; Nuutila, P.; Knuuti, J. Physiology (Bethesda) 2014, 29, 421– 436
  40
  Organ-specific physiological responses to acute physical exercise and long-term training in humans
  Heinonen Ilkka; Kalliokoski Kari K; Hannukainen Jarna C; Knuuti Juhani; Duncker Dirk J; Nuutila Pirjo
  Physiology (Bethesda, Md.) (2014), 29 (6), 421-36 ISSN:.
  Virtually all tissues in the human body rely on aerobic metabolism for energy production and are therefore critically dependent on continuous supply of oxygen. Oxygen is provided by blood flow, and, in essence, changes in organ perfusion are also closely associated with alterations in tissue metabolism. In response to acute exercise, blood flow is markedly increased in contracting skeletal muscles and myocardium, but perfusion in other organs (brain and bone) is only slightly enhanced or is even reduced (visceral organs). Despite largely unchanged metabolism and perfusion, repeated exposures to altered hemodynamics and hormonal milieu produced by acute exercise, long-term exercise training appears to be capable of inducing effects also in tissues other than muscles that may yield health benefits. However, the physiological adaptations and driving-force mechanisms in organs such as brain, liver, pancreas, gut, bone, and adipose tissue, remain largely obscure in humans. Along these lines, this review integrates current information on physiological responses to acute exercise and to long-term physical training in major metabolically active human organs. Knowledge is mostly provided based on the state-of-the-art, noninvasive human imaging studies, and directions for future novel research are proposed throughout the review.
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41. 41
  Timofeev, I.; Carpenter, K. L. H.; Nortje, J.; Al-Rawi, P. G.; O’Connell, M. T.; Czosnyka, M.; Smielewski, P.; Pickard, J. D.; Menon, D. K.; Kirkpatrick, P. J.; Gupta, A. K.; Hutchinson, P. J. Brain 2011, 134, 484– 494
  There is no corresponding record for this reference.
42. 42
  Kristensen, D. L.; Ladefoged, S. A; Sloth, E.; Aagaard, R.; Birke-Sørensen, H. Br. J. Oral Maxillofac. Surg. 2013, 51, 117– 122
  42
  Microdialysis: characterisation of haematomas in myocutaneous flaps by use of biochemical agents
  Kristensen Danja Lykke; Ladefoged Soren A; Sloth Erik; Aagaard Rasmus; Birke-Sorensen Hanne
  The British journal of oral & maxillofacial surgery (2013), 51 (2), 117-22 ISSN:.
  Metabolic markers are measured by microdialysis to detect postoperative ischaemia after reconstructive surgery with myocutaneous flaps. If a haematoma develops around the microdialysis catheter, it can result in misinterpretation of the measurements. The aim of the present study was to investigate whether a haematoma in a flap can be identified and dissociated from ischaemia, or a well-perfused flap, by a characteristic chemical profile. In 7 pigs, the pedicled rectus abdominal muscle flap was mobilised on both sides. A haematoma was made in each flap and two microdialysis catheters were placed, one in the haematoma, and the other in normal tissue. One flap was made ischaemic by ligation of the pedicle. For 6 hours, the metabolism was monitored by measurement every half-an-hour of the concentrations of glucose, lactate, pyruvate, and glycerol from all 4 catheters. After 3 hours of monitoring, intravenous glucose was given as a challenge test to identify ischaemia. The non-ischaemic flap could be differentiated from the ischaemic flap by low glucose, and high lactate, concentrations. It was possible to identify a catheter surrounded by a haematoma in ischaemic as well as non-ischaemic muscle from a low or decreasing concentration of glucose together with a low concentration of lactate. All four sites could be completely dissociated when the concentrations of glucose and lactate were evaluated and combined with the lactate:glucose ratio and a flow chart. The challenge test was useful for differentiating between haematomas in ischaemic and non-ischaemic tissue.
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Additional information as noted in text (Figures S1–S3 and supporting videos 1 and 2). The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.analchem.5b01353. Data supporting this publication can be obtained on request from [email protected].
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3D Printed Microfluidic Device with Integrated Biosensors for Online Analysis of Subcutaneous Human MicrodialysateClick to copy article linkArticle link copied!

Analytical Chemistry

Abstract

Experimental Section

Reagents

Electrode Fabrication

Biosensor Fabrication

Fabrication of Microfluidic Platform

Calibration and Characterization Studies

Cycling Protocol

Results and Discussion

3D Printed Microfluidic Device

Figure 1

Biosensor Characterization Inside 3D Printed Microfluidic Chip

Figure 2

Online Subcutaneous Glucose and Lactate Measurement during Cycling Trials

Figure 3

Conclusion

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3D Printed Microfluidic Device with Integrated Biosensors for Online Analysis of Subcutaneous Human Microdialysate
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