Expanding the Sensitivity of Lab-on-PCB Diagnostic Microsystems Via Inkjet Printed FETs

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Expanding the sensitivity of Lab-on-PCB diagnostic microsystems via inkjet printed FETs

Chapter 1: Biosensor

 

1.1 What is the biosensor

 The term sensor refers to any device that measures a physical quantity and converts it to electrical – in most cases – signal. For example, a thermocouple produces a temperature dependent voltage due to the thermoelectric effect and the output voltage level is assigned to a temperature level. However, in the case of mercury thermometer, it is a non-electronic sensor since it converts the measured temperature to dilatation of mercury upon a graduated scale. Sensor technology development signifies one of the most crucial parts in today’s scientific research and technological growth. Sensors flood people’s everyday life from piezoresistive in various electrical devices to wide range in automobiles.

A biosensor is an analytical device that is able to detect an analyte of either chemical or biological origin which is related to a biological response. This is achieved by implementing a biological component which is responsible for the interaction with the analyte and a transducer which is responsible for the transformation of this interaction to a signal that usually is electronic (e.g. current, potential) or another physical property like a colour change or a change of the optical density. The last part of the biosensor is the component that processes the electronic output signal in order to render it suitable for observable response by the human. It includes complex electronic circuits, like amplifiers and various types of converters. Its main purpose is to prepare the signal in order to be accepted by the next and final step: the display. The display is usually an electronic visual display (e.g. liquid crystal display) or other mean of demonstration (e.g. printed values or plots from a printer), understandable by human. A general scheme of the biosensor assembly is shown in Fig.1.1. It has to be noted that the intimate contact of the biological component with the transducer is the feature which distinguishes a biosensor from a burdensome bio-analytical system such as a bio-medical diagnostic laboratory which nevertheless, incorporates a variety of chemical sensors and biosensors. The following definition for the term biosensor is generally accepted: An electrochemical biosensor is a self-contained integrated device, which is capable of providing specific quantitative or semi-quantitative analytical information using a biological recognition element (biochemical receptor) which is retained in direct spatial contact with an electrochemical transduction element (Physical Chemistry and Analytical Chemistry Divisions of IUPAC 1999)1. Even though, this definition is referred to the electrochemical biosensor specifically, it was presumed that it can be applied to any type of biosensors2.

Figure 1.1: Principal scheme of a biosensor assembly: 1) Display 2) Signal processing module; 3) Transducer; 4) Biological recognition element; 5) Analyte.

 1.2 Characteristics of a biosensor

Biosensor specifications impose the technical and economic considerations that one has to examine in order to choose the appropriate sensor for a specific application. The majority of those specifications are listed below:

  • Accuracy

      Sensor accuracy is determined from the maximum measurement error. In practice, every electrical device introduces an error in their measurement.

  • Calibration

      Defining the transfer function of the sensor. It is usually conducted by comparing the output signal to another sensor for the same input stimulus. The second sensor is considered as reference and it has to be properly calibrated.

  • Linearity

      The degree that the graph of the output to input (transfer function) resembles a straight line. A sensor can be linear usually for a limited stimulus range.

  • Compatibility

      Compatibility describes to which extend the installation of the sensor in the system affects the output signal of the sensor.

  • Sensitivity

      The sensitivity of the sensor is defined as the slope of the output characteristic curve or, more generally, the minimum analyte concentration that will create a detectable output change. This can also be called as the limit of detection (LOD). In some sensors, the sensitivity is defined as the input parameter change required to produce a standardized output change. In others, it is defined as an output signal change for a given change in input parameter.

  • Sensitivity to other substances (selectivity)

      The sensitivity of a sensor to substances like admixtures or contaminants other than that which is designed for. It is the ability of the sensor to measure the analyte it is designed for in presence of other interfering factors. Selectivity is the main consideration when choosing bioreceptors.

  • Saturation

      Saturation is defined when the output signal of the biosensor does not change even when analyte concentration is further increased.

  • Drift

      Drift is the output signal change over time although the analyte concentration remains unchanged (Figure 1.2). Drift signal characterizes the sensor stability. It is highly affected by the affinity of the bioreceptor. Affinity is the degree of the binding between the analyte and the bioreceptor. Low affinity may lead to separation of the analyte from the receptor over time. Another factor that causes drift is the aging of the bioreceptor which may decrease its ability to bind robustly to the analyte.

Figure 1.2: The change with time of the output biosensor signal with stable analyte concentration.

  • Resolution

      Resolution is the minimum measureable variation in sensor’s input.

  • Repeatability

      Repeatability concerns the output signal variation under the same identical input signal. The repeatability is affected by the accuracy of the transducer part.

  • Noise

      Noise is a random change in output signal. If noise level is comparable to the output signal, then the stimulus in input cannot be perceived. Noise depends on device sensitivity over other than the measured stimulus parameters (Figure 1.3).

Figure 1.3: Noise signal in the output.

 1.3 Historical background of biosensor

It is broadly accepted that the first “real” biosensor was developed by L. C. Clark and C. Lyons. Clark first suggested the oxygen probe for sensing oxygen in the blood (1956)3. This oxygen sensor was modified to accommodate “enzyme transducers as membrane enclosed sandwiches” by adding the enzyme Glucose Oxidase over the oxygen probe4(Fig.1.4). The enzyme catalysed the oxidation of glucose to gluconic acid. Thus, the addition of glucose led to a proportional decrease of oxygen content in the vicinity of the oxygen probe. Later, a similar device was presented by Updike and Hicks who immobilized the same enzyme on a polyacrylamide gel onto a surface of a Pt oxygen electrode5 (1967).

Figure 1.4: Schematic of the first biosensor developed by Clark and Lyons2.

In 1963, Guilbault described a biosensor with immobilized enzymes (cholinesterase) between 2 Pt electrodes for early detection of nerve agents in the atmosphere6. Besides this, Guilbault along with Montalvo invented the first potentiometric enzyme biosensor to detect urea in urine using immobilized urease (1969)7. The second-generation biosensor was introduced in 1986 by Hill et al8. The difference to the first generation was the improved electrical signal that is generated by the reaction between the biological component and the analyte. This was accomplished by using ferrocene as a mediator before the transducer element. This device was marketed by Medisense as the Glucose pen. Finally, the third-generation biosensor was presented by Adam Heller in the 1990s9 by coupling the enzyme directly to the electrode, thus neither direct involvement of a reaction product (1st generation) nor a mediator (2nd generation) is required. A more detailed historical overview is illustrated in table 1.1.

Table 1.1: Keystones in the biosensor history

1962-1967

The first biosensor – modified oxygen probe for glucose detection4,5

1963-1969

Immobilized enzymes biosensor6, first potentiometric enzyme biosensor for urea determination7

1970-1972

Ion-selective field effect transistor (ISFET) to quantify the ion composition around nerve tissues10

1971

Organon International launched the first home pregnancy test11

1975

The first potentiometric  immunosensor12

1976

The first amperometric immunosensor for assaying human immunoglobulin G (IgG)13

1980

ISFET combination with an enzyme for penicillin sensing14

1980

Fibre-optic biosensor for alcohol detection15

1983

Surface plasmon resonance (SPR) techniques are described16

1983

The first biosensor based on the quartz crystal micro- balance (QCM)17

1986

Second-generation biosensor is introduced8

1990

Third-generation biosensor is introduced9

1990

SPR-based biosensor by Pharmacia Biacore18

1992

Handheld blood biosensor by i-STAT18

1.4 Applications of biosensors, impact and future prospects

Biosensors are an interdisciplinary technology as it requires the synergy of multiple research fields: micro and nano-technology, biology, bio-technology, pharmacy, chemistry, physics and so on. Since all of these disciplines are involved, it is not surprising that they are used in numerous applications, as Fig. 1.5 shows. Biosensors are used for the detection of elevated glucose level in blood in diabetic patients19, for detection of tumours20, of pathogens21 and toxins22 in living organisms. Biosensors can also be used for monitoring the quality of products in the food industry23. They are also used to sense pathogens and other critical substances for health like heavy metals in the environment24. Finally, military defence systems incorporate biosensors to identify biological materials that are used for biological warfare, like Bacillus anthracis and hepatitis C viruses25. The last two applications can be defined as ‘long-term monitoring’ sensing tools as they are used continuously for long periods of time in stand-by mode to alert when the level of the analyte exceeds a particular concentration in the medium. The other aforementioned applications can be labelled as ‘single shots’ sensing tools as they are mostly used for a single set of measurements and for this reason they are usually characterised by low cost and disposability18.

The interdisciplinary form that characterises biosensors is a significant factor that affects the career of early-stage researchers in the biosensors field. This approach urges scientists and engineers involved in this field to think out of the box in order to overcome the challenges that originate from the diverse professional backgrounds. This essential scientific interaction leads to a rapid progress in all the involved disciplines. It is not coincidental that many biosensing related technologies have found the way from the lab to the production line in the last two decades. Numerous companies have also been formed rendering biosensors a part of our daily life and not a niche product. In general, biosensors have contributed to the improvement of healthcare, homeland security, agriculture, pharmacology and food safety, thus the quality of living for a substantial proportion of people has been enhanced.

Figure 1.5: Biosensors applications18.

Nevertheless, there are still several challenges to overcome. Demand for cost-effective devices with ease of use is ever-growing, especially in underdeveloped countries with limited healthcare resources where drugs to cure certain diseases may exist but there is a deficiency in diagnostic facilities. Lab-on-Chip (LoC) is a novel technology that promises cost reduction due to the miniaturization of the implemented technology. LoC is a device that incorporates several laboratory processes on a single substrate that has a dimension of millimetres or a few square centimetres. Apart from the reduced manufacturing cost, there are benefits like low user’s cost due to the ease of operation that does not require expensive staff training, reduction of human error and faster response and diagnosis times since everything is done automatically on a confined space. It can handle fluids of very small volume (picolitres) transferring them across the chip’s surface for analytical processes such as pumping, mixing, filtering and sorting. The delivery of the fluids to the specific sites on the chip is handled by microfluidics: a set of micro-channels etched or molded into a material (glass, silicon or polymers). The microfluidic channels are connected to the outside macro-world via inputs and outlets pierced through the chip and connected to suitable tubing. The integration and parallelization benefits that microfluidic technology offers are summarized in Fig. 1.6.

Figure 1.6: Two step production of a multiple emulsion using a) conventional batch emulsification, b) microfluidics26.

Hence, LoC is the technology that has at its disposal strong characteristics which can advance the Point of care testing (POCT):

Although, it is a well-proven laboratory technology, few products have managed to achieve a widespread commercial use, with the most well-known being the at home pregnancy test kit. tha pw gia pcb kai inkjet print ligo, otan tha milisw gia auta me letpomereies argotera tha ta sindesw tha ta sindesw me autin tin paragrafo

Ending phraseThus, cost-effective scalable techniques have to be further explored to overcome the described LoC bottleneck. Suggested methods to face this challenge will be examined during this research degree and will be discussed in the following chapters.

1.5 Classification of biosensors

Μtas, poc microfluidic, GIA Future tha pw gia meiwsi costous-lab on chip, mass production, reachable from everyone, cost effective scalable techniques has to be found to overcome the LoC bottleneck kai kati geniko apo evtygin, use of nanomaterials (koita pedro)

Erwtisi: pws tha sindesw to diagnostic microsystems tou titlou me to dna detection p tha kanw egw   (apantisi: first point of research will be dna…)

classification by transducer and biological component

ΜΕΤΑ ΝΑ πω για κατηγοριες, ειδικα θα αναπτυξω τους biofet (des katigories sto evtugyn)

References: (ieee style)

[1] D. Thevenot, K. Tóth, R. Durst and G. Wilson, “Electrochemical Biosensors: Recommended Definitions and Classification”, Pure and Applied Chemistry, vol. 71, no. 12, pp. 2333-2348, 1999.

[2] G. Evtugyn, Biosensors. Kazan: Springer-Verlag Berlin An, 2016.

[3] L. Clark, “Monitor and control of blood and tissue oxygenation”, Transactions – American Society for Artificial Internal Organs, vol. 2, no. 1, pp41-48, 1956.

[4] L. Clark and C. Lyons, “Electrode systems for continuous monitoring in cardiovascular surgery”, Annals of the New York Academy of Sciences, vol. 102, no. 1, pp. 29-45, 1962.

[5] S. Updike and G. Hicks, “The Enzyme Electrode”, Nature, vol. 214, no. 5092, pp. 986-988, 1967.

[6] G. Guilbault, D. Kramer and P. Cannon, “Electrical Determination of Organophosphorous Compounds.”, Analytical Chemistry, vol. 34, no. 11, pp. 1437-1439, 1962.

[7] G. Guilbault and J. Montalvo, “An Improved Urea Specific Enzyme Electrode”, Analytical Letters, vol. 2, no. 5, pp. 283-293, 1969.

[8] K. Di Gleria, M. Green, H. Hill and C. McNeil, “Homogeneous ferrocene-mediated amperometric immunoassay”, Analytical Chemistry, vol. 58, no. 6, pp. 1203-1205, 1986.

[9] C. McNeil, D. Athey and W. On Ho, “Direct electron transfer bioelectronic interfaces: application to clinical analysis”, Biosensors and Bioelectronics, vol. 10, no. 1-2, pp. 75-83, 1995.

[10] P. Bergveld, “Development, Operation, and Application of the Ion-Sensitive Field-Effect Transistor as a Tool for Electrophysiology”, IEEE Transactions on Biomedical Engineering, vol. -19, no. 5, pp. 342-351, 1972.

[11] C. Romm, “Why the Home Pregnancy Test Was Revolutionary”, The Atlantic, 2018. [Online]. Available: https://www.theatlantic.com/health/archive/2015/06/history-home-pregnancy-test/396077/. [Accessed: 15- Nov- 2018].

[12] J. Janata, “An immunoelectrode”, Chemischer Informationsdienst, vol. 6, no. 30, p. no-no, 1975.

[13] M. Aizawa, A. Morioka, H. Matsuoka, S. Suzuki, Y. Nagamura, R. Shino-Hara and I. Ishiguro, “An enzyme immunosensor for IgG”, Journal of Solid-Phase Biochemistry, vol. 1, pp. 319–328, 1976.

[14] S. Caras and J. Janata, “Field effect transistor sensitive to penicillin”, Analytical Chemistry, vol. 52, no. 12, pp. 1935-1937, 1980.

[15] K. Volkl, N. Opitz and D. Lobbers, “Continuous measurement of concentrations of alcohol using a fluorescence-photometric enzymatic method”, Fresenius’ Zeitschrift fr Analytische Chemie, vol. 301, no. 2, pp. 162-163, 1980.

[16] B. Liedberg, C. Nylander and I. Lunström, “Surface plasmon resonance for gas detection and biosensing”, Sensors and Actuators, vol. 4, pp. 299-304, 1983.

[17] G. Guilbault, “Determination of formaldehyde with an enzyme-coated piezoelectric crystal detector”, Analytical Chemistry, vol. 55, no. 11, pp. 1682-1684, 1983.

[18] N. Bhalla, P. Jolly, N. Formisano and P. Estrela, “Introduction to biosensors”, Essays In Biochemistry, vol. 60, no. 1, pp. 1-8, 2016.

 [19] “About Abbott Diabetes Care | FreeStyle Glucose Meters”, Freestylediabetes.co.uk, 2018. [Online]. Available: https://freestylediabetes.co.uk/about-us. [Accessed: 11- Nov- 2018].

[20] P. Jolly, N. Formisano and P. Estrela, “DNA aptamer-based detection of prostate cancer”, Chemical Papers, vol. 69, no. 1, 2015.

[21] R. Singh, M. Mukherjee, G. Sumana, R. Gupta, S. Sood and B. Malhotra, “Biosensors for pathogen detection: A smart approach towards clinical diagnosis”, Sensors and Actuators B: Chemical, vol. 197, pp. 385-404, 2014.

[22] L. Sutarlie, S. Ow and X. Su, “Nanomaterials-based biosensors for detection of microorganisms and microbial toxins”, Biotechnology Journal, vol. 12, no. 4, 2016.

[23] T. Sharma, R. Ramanathan, R. Rakwal, G. Agrawal and V. Bansal, “Moving forward in plant food safety and security through NanoBioSensors: Adopt or adapt biomedical technologies?”, PROTEOMICS, vol. 15, no. 10, pp. 1680-1692, 2015.

[24] J. Tamayo, A. Humphris, A. Malloy and M. Miles, “Chemical sensors and biosensors in liquid environment based on microcantilevers with amplified quality factor”, Ultramicroscopy, vol. 86, no. 1-2, pp. 167-173, 2001.

[25] R. Edelstein, C. Tamanaha, P. Sheehan, M. Miller, D. Baselt, L. Whitman and R. Colton, “The BARC biosensor applied to the detection of biological warfare agents”, Biosensors and Bioelectronics, vol. 14, no. 10-11, pp. 805-813, 2000.

[26] P. Clegg, J. Tavacoli and P. Wilde, “One-step production of multiple emulsions: microfluidic, polymer-stabilized and particle-stabilized approaches”, Soft Matter, vol. 12, no. 4, pp. 998-1008, 2016.

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