Biomedical sensors using optical ﬁbres

Rep. Prog. Phys.59 (1996) 1–28. Printed in the UK

Biomedical sensors using optical fibres

Anna Grazia Mignani† and Francesco Baldini‡Istituto di Ricerca sulle Onde Elettromagnetiche ‘Nello Carrara’, CNR Via Panciatichi 64, I-50127, Firenze, Italy

Abstract

Optical techniques developed for sensing purposes proved to be essential in many applicationfields, ranging from aerospace, industry, process control, to security, and also medicine.The capabilities of these sensors are generally enhanced when a bulk-optical configurationis replaced by optical fibre technology. In the past few years, research programmes andalso the market for fibre sensors have assumed a relevant role. This is undoubtedly due tothe growing interest in optoelectronics, but also to the very satisfactory performance andreliability that optical fibre sensors are now able to provide. This paper focuses on theadvantages that optical fibre sensors offer to the biomedical field, recalls the basic workingprinciples of sensing, and discusses some examples.

This review was received in July 1995

† E-mail address: [email protected]‡ E-mail address: [email protected]

0034-4885/96/010001+28$59.50c© 1996 IOP Publishing Ltd 1

2 A G Mignani and F Baldini

Contents

Page1. Introduction 32. The basic working principle of sensing 4

2.1. Architecture 42.2. Main problems 6

3. Sensors for physical parameters 63.1. Pressure 63.2. Temperature 83.3. Blood flow 93.4. Humidity 103.5. Cataract onset 103.6. Radiation dose 113.7. Biting force 12

4. Sensors for chemical parameters 124.1. Bile 124.2. pH 134.3. Oxygen 194.4. Carbon dioxide 214.5. Lipoproteins 214.6. Lipids 224.7. New aspects and perspectives of chemical sensors 22

5. Spectral sensors 236. Conclusions 24

Acknowledgments 25References 25

Biomedical sensors using optical fibres 3

1. Introduction

In the medical field, the opportunities offered by optical fibres have always beenadvantageously exploited. In fact, the use of optical fibres in medicine goes back to thesixties, when fibre bundles were successfully pioneered in endoscopy, both for illuminationand for imaging. Subsequently, cavitational laser surgery and therapy also benefited fromfibres, which proved to be the most flexible, and a low-attenuation delivery system insidethe ancillary channel of endoscopes, and inside the natural channels of the human body aswell. More recently, and especially since 1980, a great deal of research in optical fibreshas been dedicated to sensing, and again the medical field found good opportunities fordeveloping very promising sensors.

Two classes of clinical care procedures can be distinguished, in which conventionalmethods present some drawbacks:

• in vitro laboratory tests of blood or tissue samples, which means frequent sample-takings for continuous checking, thus placing the patient under stress. In addition,therapeutic intervention is delayed, and errors can also occur, due to sample handlingand photodegradation;

• in vivo measurements of many physical and chemical parameters performed by electricaldevices (thermocouples,CHEMFET, semiconductor or piezoelectric elements), which arefragile and expensive, and expose the patient to electrical connections.

Fibre optic sensors (FOSs) overcome some of these drawbacks, owing to the well knowninherent characteristics of optical fibres:

• geometrical versatility, such as miniaturization, flexibility, and lightness, which alloweasy insertion in catheters and needles, and hence highly localized measurements insideblood and tissues;

• suitable material, glass or plastic, which is study, non-toxic and biocompatible, and canbe used for continuous measurements;

• intrinsic safety for the patient, ensured by optical fibre dielectricity and by the low lightpower used for sensing purposes.

Furthermore, optical fibres present low attenuation, so that long fibre links can be used, ifthe electronics must be located far from the bedside; in this case, fibres must be cabled,so as to avoid handling problems. Another property is the absence of crosstalk betweenclose fibres, which suggests housing different sensors in the same catheter. In some casesa single electro-optic unit can be utilized for all the sensors, naturally with an appropriateillumination, detection and signal-processing scheme.

An overview of fibre optic sensors for biomedical applications is given, with particularattention to the sensors developed forin vivo monitoring, and to the advantages that thesesensors are able to offer in different fields of application such as cardiovascular and intensivecare, angiology, gastroenterology, ophthalmology, oncology, neurology, dermatology anddentistry.

Examples ofFOSs are reviewed according to a classification in three main classes:sensors for physical parameters, sensors for chemical parameters and ‘spectral’ sensors, forwhich spectral analysis is performed in order to know the state of health of a particularorgan or tissue.


2. The basic working principle of sensing

The working principle of FOSs is based on the modulation of the fibre-guided lightproduced in one of the optical properties (phase, intensity, wavelength, polarization state)by the parameter under investigation. The complexity of the electro-optical system, thetype of components selected, and thus cost of the sensor are related to the operatingprinciple.

The idealFOS for biomedical applications should possess the following characteristics:

• reliability,• automatic or semiautomatic operation for use by operators who have little or no technical

background,• low-cost installation and maintenance.

These requirements limit the selection of the sensor’s operating principle and imposelimitations to the complexity of the electro-optical system.FOSs for biomedical applicationsare mostly of the intensity modulation type, owing to the low cost of their components andthe simplicity of their architectures. They can be eitherintrinsic or extrinsic, according towhether the intensity modulation is produced by the fibre, which is sometimes modified, orby an external transducer connected to the fibre (figure 1).

Figure 1. Working principle of intensity-modulated fibre-optic sensor.

2.1. Architecture

A FOS of the intensity modulation type can be viewed as a compact electro-optical moduleconnected to the measuring probe by a multimode optical fibre (figure 2). The modulehouses source(s), detector(s), and all the electronics for signal processing.

The sources can be either lamps, lasers,LEDs, or laser diodes. Lamps and lasersrequire beam focus optics and holders for the fibre alignment. If a halogen lamp isused, interferential or dichroic filters may also be necessary when the sensor has a specificoperating wavelength.LEDs and laser diodes, the most compact, may be housed in specialreceptacles that are easily connected to the fibre by commercial connectors. The mostrecentLEDs and laser diodes offer a wide variety of wavelengths. Laser diodes have a highemission power and can, in many cases, replace costlier and bulkier lasers.

The detectors are normallyPIN-type photodiodes, which are also housed in properreceptacles, sometimes with filters to provide spectral response.

The electro-optical module provides modulation of the source and amplification of thedetected signals. An analogue/digital interface that connects the electronic section to a


Figure 2. Sketch of the instrumentation of a fibre-optic sensor.

PC can enhance system control and, in addition, is useful in calibration and in carryingout and recording measurements over long periods. For standard procedures that requireno subsequent modification, a preprogrammed microprocessor can be used in place ofa PC.

The optical fibre connection carries the light intensity from the source to the probe andreturns the intensity modulated by the measuring parameter to the detector. Generally, fibreshaving diameter larger than 100µm are used to maximize the source’s coupling efficiency.The fibres can be all silica (AS) or plastic silica (PCS), either bare or cabled, according toapplication.

The connection can be eithersingle fibre, in which case the fibre serves for bothlighting and detection, ortwo fibre, in which case one fibre serves for lighting and onefor detection. The single-fibre connection, which is evidently more compact and thusreduces probe dimensions, requires a device upstream of the fibre that separates the lightingand detection channels. However, the beam divider should always be characterized byintrinsic low losses and crosstalk to avoid covering up the measuring signal and alsoimpairing the signal-to-noise ratio. Often bi- or trifurcated fibre bundles are used, withrandom distribution of the fibres inside the bundle or with special distributions (linear,semicircles, concentric circles, etc). In such case, the source(s) and detector(s) are connectedto the branches of the bundle and the common termination is connected to the measuringprobe.

The optical architecture can be eitherall fibre or hybrid:

• In the all-fibre architecture, all the optical components connected to the fibre (X-, Y-,or star couplers,WDM, gratings, etc) are optical fibre based and the components areconnected simply and compactly with commercial type connectors;

• In the hybrid architecture, used when optical fibre components with less than satisfactorycharacteristics are available, the miniaturized optical components, such as lenses, filters,gratings, mirrors, etc, must be specially aligned and connected.


2.2. Main problems

The main problems regarding intensity modulationFOSs are:

Sensitivity to light propagation. A problem common to all intensity modulationFOSs issensitivity to propagation conditions. Since the information is contained in the intensity ofthe guided light, any modulation not correlated to the state of the measuring parameter upsetsthe measurement. For example, an incorrect interpretation can be caused by fluctuations inthe source or attenuations introduced by fibre curvatures. To solve this problem, a referencesystem must be used to compensate for the undesired intensity fluctuations, despite theincrease in system complexity and thus the cost it entails. Source intensity fluctuations canbe offset by normalizing the measurement signalS with a reference signalR proportionalto the source intensity. Other spurious fluctuations such as those produced by propagationaccidents can be offset by a lighting signal with two wavelengths, one of which is modulatedin intensity by the investigated parameter and the other of constant intensity. Since they bothtravel on the same fibre, their ratio provides a measurement devoid of propagation accidents.

Insufficient lighting power. The main problem determined by active and passive opticalcomponents is insufficient lighting power in theFOS. This depends somewhat on thepower emitted by the source, and also on the quantity and quality of the required passivecomponents. The requisites of the source, i.e. compactness, adequate power, and suitablewavelength, are not always fulfilled, especially when a source that is visible or beyond therange of typical telecommunication wavelengths is required. The requisites of the opticalcomponents are compactness and the capacity of each to perform several functions. Thenumber of passive components should be minimized by accurate assessment of systempower requirements.

Design and manufacturing specifications.The probes require accurate workmanshipand hand assembly and must be designed to produce a high back-transmitted signalsimultaneously with a fast response time. Major requisites are optimized housing,miniaturization, seal, and transducer stability. Particular attention must be devoted to therequisites of biocompatibility: i.e. the probe must not adversely affect the body nor must beadversely affected by it. The latter consideration should not be taken lightly; in fact, oftenwe think only about the dangerous effect that an invasive sensor can have on the humanbody, and do not consider that (especially in chemical sensors, where a chemistry is fixedat the end of the fibres) the local environment can notably impair sensor performance.

3. Sensors for physical parameters

The physical parameters of medical interest that have been successfully measured byFOSsare mainly pressure, temperature, blood flow, humidity, as well as cataract onset, radiationdose and biting force.

3.1. Pressure

Head trauma patients require continuous monitoring of intracranial pressure. During thepost-operative and drainage monitoring phases, it is essential to know, respectively, thesubdural and ventricular pressures, as well as the pressure waveform display. Non-optical


Figure 3. Fabry–Perot fibre-optic pressure sensor.

instruments make use of catheters tipped with miniaturized piezoresistive or capacitivetransducers, whose main drawbacks are long-term drifts, electrical-shock hazard, fragilityand costliness.FOSs, being relatively easy to manufacture and therefore inexpensive enoughto be disposable, overcome these drawbacks. In addition, they perform as well as or betterthan electric instrumentation. Main measurement requirements are: (i) a working rangefrom −50 to 300 mmHg; (ii) a sensitivity of at least 0.1 mmHg; (iii) an accuracy of at least1%; (iv) a flat frequency response up to 1 kHz. Among the many proposed pressureFOSs,two types fulfil the low-cost, high-performance requirements. One has a Fabry–Perot cavityat the fibre tip [1, 2]; the other has a small diaphragm in front of the fibre optic link [3–5].

The Fabry–Perot cavity for pressure sensing is a glass cube having a partially etchedface, covered by a pressure sensitive silicon diaphragm (figure 3). The pressure, deflectingthe diaphragm, alters the cavity depth and thus the optical cavity reflectance at a givenwavelength. If anLED source is used, the spectrally modulated reflected light can be splitinto two wavebands by a dichroic mirror. The ratio of the two signals provides a pressuremeasurement immune to the typical light level changes occurring inFOS systems. A sensorof this type, together with the complete intracranial pressure monitoring system, is currentlyavailable from the American company Innerspace [6].

The other pressure sensing approach, characterized by a diaphragm in front of the fibreoptic link, is based on the light intensity modulation of the reflected light caused by thepressure-induced position of the diaphragm. Two schemes can give immunity to falsefluctuations: (i) a dichroic coating on the diaphragm and the dual-wavelength referencingtechnique, and (ii) a dual-beam referencing using a second fibre optic path, which is joinedto the pressure measuring fibre link, but unaffected by pressure fluctuations. The low-costdisposableFOS manufactured by the American company Camino Labs [7], which uses abellow as a transducer, is interrogated by the intensity modulation technique with dual-beam referencing (figure 4) [8].


Figure 4. Fibre-optic pressure sensor based on a mechanical transducer.

3.2. Temperature

Fibre-optic thermometers are used when electrical insulation andEMI immunity are neces-sary [9]. The most relevant application involves tissue-heating control duringMW or RF

hyperthermia therapy for cancer treatment. For this application, conventional thermistorsor thermocouples can perturb the incident field and produce localized hot spots. Otherapplications of thermometry by fibre-optic sensors are the mapping of thermal distribu-tion in cancer phototherapy, patient monitoring during magnetic-resonance imaging, andcardiac-output monitoring by means of the thermodilution technique. The possibility ofsimultaneous monitoring with arrays of multiple sensors is also desirable. For these ap-plications, the restricted working range 35–45◦C is sufficient, with a sensitivity of at least0.1◦C. Because of the many applications, fibre-optic thermometers have been widely pro-posed, either using all-fibre mechanisms [10], and transducers undergoing intensity [11] orwavelength modulation [12, 13], or operating in the time domain [14].

The fibre optic thermometer commercialized by the American company Luxtron [15],one of the first developed for this purpose (figure 5), performs time-domain measurementsand stands out for technical performance and patient safety.UV light guided by the fibreis used to excite phosphors fixed at the fibre end and fluorescence decay-time is measured,which results temperature modulated and intrinsically down-lead insensitive as well. Othersensors based on a fibre Fabry–Perot (FFP) cavity coupled at the fibre tip [16, 17] andMID-IR

fibres used as pyrometers [18] are under development.

Figure 5. Luxtron 3000: an 8-channel fibre-optic temperature sensor.


3.3. Blood flow

Laser Doppler flowmetry is a powerful tool for vasomotion monitoring, and the use ofoptical fibres enhances the possibility of both invasive and contact measurements. Thebasic scheme of fibre-optic laser Doppler flowmetry is illustrated in figure 6. The lightof a He–Ne laser is guided by an optical fibre probe to the tissue or vascular networkbeing studied. The light is diffusely scattered and partially absorbed within the illuminatedvolume. Light hitting moving blood cells undergoes a slight Doppler shift. The bloodflow rate is derived by the spectrum-analysis of the back-scattered signal, which presents aflow-dependent Doppler-shifted frequency.

Various types of probes have been developed, either using a single fibre for illuminationand detection, or one fibre for illumination and two or three for detection [19]. An instrumentthat is widely used in the clinical practice is produced by the Swedish company Perimed(figure 7), which offers a wide selection of contact and endoscopic probes, with straightor angular tips, as well as with channels for liquid flushing [20]. Typical applications arein: (i) plastic and reconstructive surgery for monitoring flap quality; (ii) angiology for

Figure 6. Basic scheme of fibre-optic laser Doppler flowmetry.

Figure 7. PeriFlux PF3: the Perimed instrument for fibre-optic laser Doppler flowmetry.


locating atherosclerosis and occlusions; (iii) dermatology for testing several types of skinirritancies such as psoriasis, or produced by topical drugs or cosmetics; (iv) pharmacologyfor detecting vasoactive drugs and dose response. Endoscopic and needle probes are used forinvasive and deep measurements, for example in gastroenterology and in vascular surgery,respectively.

3.4. Humidity

A major requirement of intensive care is the continuous monitoring of breathing condition,i.e. the cough, sneeze, and breathing count. It should be possible to monitor from the nurses’station so patients can be kept under observation without a nurse being physically at theirbedsides. An optical fibre with a moisture-sensitive cladding has been developed for thispurpose. It is simple to use and has given good performance results. The cladding of thesensitive fibre-section is a plastic film doped with the umbelliferon dye, which is a moisture-sensitive fluorescent material underUV-pumping. The sensitive fibre-section is placed overthe patients mouth and laterally excited with a halogen lamp. Since the water vapour inhuman respiration exceeds that in the room, the patient’s expiration produces a fluorescentsignal which is detected by an electro-optical unit at the nurses’ station. This kind ofmonitoring is particularly useful in detecting abnormal breathing in bedridden patients [21].

Another very simple humidityFOS has been developed for the continuous monitoringof the respiratory rate. The sensor is based on the change of light reflection at the fibre endwhich is caused by a change in the condensed humidity from the airways during respiration.An optical fibre is simply clasped inside the nostril. During inspiration, the air is dry andcool, and there is maximum backreflected light. During expiration, a water film depositson the fibre and the backreflected light is reduced by about 50%, so that the respiration ratecan be monitored. Sensor output thus consists of a rhythmic signal, the frequency of whichrepresents the respiratory rate [22].

3.5. Cataract onset

A major ophthalmological application ofFOSs is the recognition of the onset of eye lensopacification, commonly known as cataracts. Since, in addition to ageing, cataracts can becaused by diseases such as hyperglycaemia or injury such as exposure to radiations, the earlydetection of a warning condition is essential in preventing and testing the new therapies thatare now becoming available. As opposed to current clinical diagnostic methods, which onlydetect cataracts when they are nearly irreversible, fibre-optic monitoring makes detectionpossible at onset, in time for reversal.

The eye lens is a water–protein system composed of water (≈ 65 weight percentage)and proteins (≈ 35 weight percentage). About 10% of the proteins, called the albuminoidfraction, are insoluble, while the remaining 90% of soluble proteins are divided intoα, β,andγ crystallins. Cataract onset is attributed to crystallin aggregation and can be recognizedby periodic measurement of the crystallin dimensions.

A powerful and versatile tool for measuring particle size distribution in fluid systemsis the Dynamic Light Scattering (DLS) technique. In this case, the Brownian motionof crystallins in the cytoplasm illuminated by a coherent light source produces temporalfluctuations in the scattered light. The measured intensity autocorrelation function showsan exponential decay, whose decay constant is related to the hydrodynamic radius of thescattering particles. Cataract onset is recognized byDLS measurement of theα-crystallinaggregation, since theα-crystallins are of greater molecular weight and size, and thus scatter


more light than theβ- andγ -crystallins.The non-invasive optical fibre probe is a stainless steel capillary (OD≈ 5 mm)

ending in a face plate which houses two monomode fibres sloped at a fixed angle withrespect to the capillary axis (figure 8). One of the fibres is coupled to a He–Ne laserused for illuminating the scattering region inside the eye lens. The other collects thebackward scattered light, which is measured by a photomultiplier and processed by adigital correlator. Intensity autocorrelation measurements show a nearly bimodal distributionof particle size, respectively corresponding toα-crystallins and their aggregation. Theprobe can be easily incorporated into conventional ophthalmological instruments such as anapplanation tonometer mount [23–25].

Figure 8. Assembly for cataract onset monitoring by optical fibres and Dynamic Light Scatteringmeasurements.

In addition to allowing prompt, non-invasive monitoring of cataract onset, optical fibresalso enhance the efficiency of theDLS technique. By providing a beam of small numericalaperture and dimensions, monomode fibres are able to produce an extremely small angle ofcoherence, and hence an optimal spatial coherence factor(≈ 0.9), which would be difficultto obtain with bulk optics systems [26].

3.6. Radiation dose

The success of radiotherapy is related to the on-line monitoring of the dose to whichthe tumour and the adjacent tissues are exposed. Conventional thermoluminescencedosimeters only provide off-line monitoring, since they determine the radiation exposureafter completing irradiation. A short length of heavy metal-doped optical fibre coupled toa radiation resistant fibre is an optimal system for the continuous monitoring of radiationdosage in both invasive and non-invasive applications. The light propagating in the dopedfibre section undergoes an intensity attenuation in the presence of radiation, since theattenuation is nearly linear to the radiation dose. Differential attenuation measurementcompensates for insensitivity due to cable and connector losses [27].


3.7. Biting force

A FOS for dentistry measures biting force, which is an essential parameter in studyingdisturbances of the masticatory system and in the case of patients with osseointegratedimplants or dentures. Unlike conventional piezoelectric crystals, quartz crystals, and straingauges, which are unsuitable due to the high conductivity of the oral cavity, optical fibresare intrinsically safe.

The FOS is constituted by a mouthpiece made of two stainless steel plates with amicrobendingFOS placed in between. The optical fibre results squeezed in between twoplates inducing a periodic deformation in the fibre and giving a light intensity attenuationas the biting force increases. The system is managed by a personal computer with softwareproviding display, zeroing, and calibration. The dynamic range is 1–1000 N with a resolutionof 10 N, which is satisfactory for the application [28].

4. Sensors for chemical parameters

In fibre-optic chemical sensors the light transported by the fibre may be directly modulatedeither by the parameter being investigated (spectrophotometric sensors), or by a specialreagent connected to the fibre, whose optical properties vary with the variation in theconcentration of the parameter under study (transducer sensors). The probe is often calledoptrode, as it represents anoptical electrode. The main physical phenomena exploited forthe realization of chemical sensors are fluorescence and absorption, even if chemical opticalfibre sensors have been realized by exploiting other physical phenomena, such as chemicalluminescence, Raman scattering, evanescent-wave coupling, and plasmonic resonance.

4.1. Bile

The demand forFOSs for in vivo monitoring of foregut functional diseases is notablyon the increase. The first and, to-date, onlyFOS available on the market for such anarea of application is the Bilitec 2000 (manufactured by Prodotec, Firenze, Italy, andcommercialized by Synectics, Stockholm, Sweden), for the detection of enterogastric andnonacid gastroesophageal refluxes [29] which are considered to be contributing factorsto the development of several pathological conditions such as gastric ulcer, ‘chemical’gastritis, upper dyspeptic syndromes, and severe oesophagitis. Under certain conditions, theenterogastric reflux may also increase the risk of gastric cancer. Optical detection is basedon the optical properties of bile which is always present in such refluxes [30].

Basically, the Bilitec 2000 (figure 9) utilizes the light emitted atλ = 465 nm and570 nm (reference) by twoLEDs, and an optical fibre bundle that transports the light fromthe sources to the probe, (which is actually a miniaturized spectrophotometric cell whoseexternal diameter is 3 mm) and from the probe to the detector. The instrument evaluates thelogarithm of the ratio between the light intensities collected by the detection system. Since,according to the Lambert–Beer law, the difference in the logarithms measured in the sampleand in pure water is proportional to the bilirubin concentration, said difference is related tothe bile-containing reflux in the stomach and/or oesophagus. The method has been validatedon numerous patients by inserting the optical fibre bundle into the stomach or oesophagus viathe nasal cavity [31]. The sensitivity of the sensor is 2.5µmol/L (bilirubin concentration),and the working range is 0÷ 100µmol/L. This range fits well with the range which can beencountered in the stomach or in the oesophagus: even if the bilirubin concentration in purebile can be as high as 10 mmol/L, it is progressively diluted to its final concentration in


Figure 9. Bilitec 2000: the only instrument for the direct detection of gastric refluxes.

the refluxate by pancreatic enzymes, duodenal secretion and, lastly, by the gastric content.Clearly, the characteristics of the above mentioned sensor refer toin vitro tests; as forinvivo measurements, since the gastric content is inhomogeneous with both mucus and solidparticles suspended, although the absorbance values could numerically express the bilirubinconcentration, they can only make possible an approximate quantitative assessment of theoverall bile reflux concentration. In any case, the sensor is able to measure accurately thecontact time between the refluxate and the gastric and/or oesophageal mucosa.

4.2. pH

pH is a very important quantity; our knowledge of it, however, is strictly related to thediagnosis of the good working of many organs and parts of the human body. pH isgenerally detected by a chromophore which changes its optical spectrum as a functionof the pH; absorption-based indicators or fluorophores are used for this.

4.2.1. Blood pH. Real-time monitoring of pH in the blood should be always accompaniedby measurement of the oxygen and carbon dioxide partial pressures, pO2 and pCO2

respectively. Continuous and real-time knowledge of these parameters is of paramountimportance in operating rooms and intensive-care units, in order to determine the quantityof oxygen delivered to the tissues and the quality of the perfusion. Conventionally,these parameters are measured by benchtop blood-gas analysers on manually-withdrawnblood samples. In any case, significant changes may occur in blood samples after theirremoval from the body and before measurement is carried out by means of a blood-gasanalyser. Thanks to their ability to provide continuous monitoring,FOSs represent a welcome


Figure 10. Fibre-optic probe based on phenol-red dye for blood pH monitoring.

improvement in patient management.Invasive sensors must fulfil the following requirements: (i) they must be suitably

miniaturized so as not to slow down blood flow and thus give rise to clotting; (ii) they mustnot be thrombogenic; and (iii) they must be resistant to platelet and protein deposit. Sincedeposit resistance is primarily related to the sensor’s shape and to its chemical and physicalproperties, probes with smooth surfaces and coated with materials such as anticoagulants,and antiplatelet agents (e.g. heparin) are commonly used. It is apparent that these conditionsmust be satisfied not only by pH sensors, but by all sensors inserted in the circulatorysystem.

The first pH sensor was developed at NIH (Bethesda, Maryland) and made use ofphenol red as its acid-base indicator, covalently bound to polyacrylamide microspheres; suchmicrospheres are contained inside a cellulose dialysis tubing (internal diameter: 0.3 mm)connected to two plastic fibres (core diameter: 500µm). The probe was inserted into tissueor a blood vessel through a 22-gauge hypodermic needle (figure 10). The probe was testedin vivo on animals for the detection of extracellular acidosis during regional ischemia indog hearts [32], of transmural pH gradients in canine myocardial ischemia [33], and ofconjunctival pH [34].

The first intravascular sensor for the simultaneous and continuous monitoring of pH,pO2, and pCO2 uses three optical fibres (fibre diameter= 125 µm), and was developed byCDI-3M Health Care (Irvine CA, USA) on the basis of a system designed and tested by

Figure 11. Sketch of the fibre-optic probe for thein vivo simultaneous detection of pH, pO2,and pCO2 in human blood.


Gehrichet al [35]. The fibres are encapsulated in a polymer enclosure, that also containsa thermocouple embedded for temperature monitoring (figure 11). pH measurement iscarried out by means of a fluorophore, hydroxypyrene trisulphonic acid, covalently bondedto a cellulose matrix attached to the fibre tip. Both the acidic (λexc = 410 nm) and alkaline(λexc = 460 nm) excitation bands of the fluorophore are used, since their emission bands arecentred on the same wavelength (λem = 520 nm). The ratio of the fluorescence intensity forthe two excitations appears to be relatively insensitive to optical fluctuations. Measurementsof pO2 and pCO2 are described in the following sections.

The optoelectronic system consists of three modules, one for each sensor. A Xenonlamp (operating at 20 Hz), suitably filtered, provides illumination for the three modules.The light from the source is focused through aGRIN lens onto a prism beam-splitter andis coupled by means of a fibre to the sensor tip, while the deflected light is collected by areference detector for source control. The returning fluorescence is deflected by the prismbeam-splitter onto the signal detector through a filter selecting the fluorescence light. Amicroprocessor processes all the detected signals, giving the read-out of the three measurandson a monitor. The described probe (OD= 0.6 mm) has been testedin vivo on animals[36, 37], exhibiting satisfactory correlation with data obtainedex vivo from electrochemicalblood gas analysers.

In clinical trials on volunteers in intensive care and on surgical patients, among theproblems that have emerged with the use of intravascular optical fibre sensors are: (i) theformation of a thrombus around the sensor tip which alters the value of all the analytes and(ii) the so-called ‘wall effect’ which primarily affects the oxygen count since, if the fibre tiptouches the arterial wall, it measures the oxygen in the tissue, which is lower than arterialblood oxygen.

These problems are clearly avoided in a system working in an extracorporeal bloodcircuit, developed by CDI-3M and available on the market since 1984. Figure 12 shows theconnection between the fibre link and the blood circuit. A disposable probe, which makesuse of the same chemistry as the intravascular optrode previously described, is inserted online in the blood circuit on one side and connected to the fibre bundle on the other. The

Figure 12. Exploded view of the optrode of the CDI-3M blood-gas analyser for extracorporealanalysis.


system is currently serving in open-heart measurements; more than 10 000 disposable probesare produced by CDI-3M monthly.

Figure 13. Intravascular probe with bent fibre and side-window sample chamber.

Other intravascular-probe systems have been proposed by Abbott (Mountain View, CA)[38] and by Optex Biomedical (Woodlands, TX) [39], as the structure of the probe is similarto the CDI one previously described, i.e. three different multimode fibres, each of which isassociated with the specific chemistry and charged with the detection of a single measurand.In the Optex Biomedical approach, the configuration is somewhat different: each single fibreis bent, and a side-window sample chamber is built up to contain the appropriate chemistry(figure 13). The use of plastic fibres ensures that the bundle will not break during insertion,routine patient manipulations and removal. There are basically three advantages in this lat-eral configuration: (i) the real optrode does not suffer any mechanical stress during insertionthrough the arterial catheter, (ii) there exists the possibility of avoiding the ‘wall effect’ byrotating the probe into areas where the blood flow is good, and (iii) there is an increasedsensing-element washability in the presence of a thrombus or other fouling phenomena.

A different approach, recently proposed but still not testedin vivo [40], makes possiblesimultaneous multi-analyte detection with a single bundle of imaging fibres (1500 individual10 µm fibres with an overall diameter of 400µm). Spatial discrimination is obtained bycreating, at the distal end of the bundle, separate portions with different indicating chemistryobtained by means of the photopolymerization process. The same optoelectronic system isused for both photodeposition and detection (figure 14). The white light from a mercuryXenon lamp suitably collimated passes through a dichroic filter, is removed during thephotodeposition and is replaced by a pinhole, followed by a microscope objective. Byadjusting the pinhole size and objective magnification, it is possible to illuminate a givenportion of the fibre bundle distal end which is then dipped into a polymerization solutioncontaining the appropriate fluorophore (fluorescein for pH and pCO2 and a rutheniumcomplex for pO2). Photopolymerization allows the immobilization of the fluorophore onlyin the illuminated region. Detection of the return fluorescent signal is performed by usingappropriate excitation and emission filters for the different sensing spots, and aCCD camera.An image-process approach is necessary in order to discriminate between the responsescoming from the different sensitive spots.


Figure 14. Multianalyte detection with an imaging fibre bundle: scheme of the optoelectronicsystem used for both optrode photodeposition and detection.

4.2.2. Gastric and oesophageal pH.The gastric and oesophageal pH is an important pa-rameter for the study of the human foregut. Monitoring gastric pH for long periods (for ex-ample, 24 hours) serves to analyse the physiological pattern of acidity, provides informationregarding changes in the course of a peptic ulcer, and makes it possible to assess the effectof gastric antisecretory drugs. In the oesophagus gastrooesophageal reflux, which causes apH decrease in the oesophagus content from pH 7 to pH 2, can determine oesophagitis withpossible strictures and Barrett’s oesophagus, which is considered a preneoplastic lesion.In addition, in measuring the bile-containing reflux, the bile and pH should be measuredsimultaneously, since the accuracy of bile measurements decreases by about 30% for pH< 3.5 due to a shift in the bilirubin absorption peak to lower wavelengths [41].

Current practice is to insert a miniaturized glass electrode mounted on a flexible catheterinto the stomach or oesophagus through the nostrils, an impractical system due to the size andrigidity of the glass electrode, as well as to the possibility of electromagnetic interference.FOSs eliminate these drawbacks, although the broad range of interest (from 1 to 8 pH units)requires the use of more than one chromophore, which thus complicates the optrode designand construction. Most likely this is why almost all the fibre-optic pH sensors developedfor biomedical applications have been proposed for blood pH detection, and why only afew have been proposed for the detection of gastric or oesophageal pH [42, 43, 44].

The first sensor proposed for this application made use of two fluorophores, fluoresceinand eosin, immobilized in fibrous particles of amino-ethyl cellulose fixed on polyester foil.The sensor, characterized by a satisfactory response time (about 20 s), was only testedinvitro. First in vivo measurements have been performed only very recently [45, 46], but noneof the proposed systems appears completely satisfactory.

John Peterson proposed a sensor based on two absorbance dyes, meta-cresol purple andbromophenol blue, bound to polyacrylamide microspheres. The configuration of the probeis similar to the one for blood pH measurement previously described (figure 10): the dyedparticles are enclosed in 300µm inside diameter cellulosic-dialysis tubing, attached to a250µm diameter acrylic optical fibre. The fibre is connected to a laboratory optical systemarrangement consisting of a lamp coupled to filters, aCCD spectrometer and a personal


computer. The sensor was tested on samples of human gastric fluid, and was also testedin vivo by inserting the optical probe into the stomach of a dog. The accuracy, betterthan 0.1 pH units, satisfies clinical requirements, but the response time is much too long,between 1 and 6 minutes depending on the pH step; such a long response time wouldprevent detection of any rapid change of pH, and makes the sensor useless for the detectionof gastro-oesophageal reflux in which pH changes are very often extremely rapid (less than1 minute).

Another sensor makes use of two dyes, bromophenol blue (BPB) and thymol blue (TB),to cover the range of interest. The chromophores, immobilized on controlled pore glass,are fixed at the end of plastic optical fibres: the distal end of the fibres is heated and theCPGs form a very thin pH-sensitive layer on the tip of the fibres. Figure 15 shows a sketchof the probe: four fibres are used (two for each chromophore) and a Teflon reflector wasplaced in front of the fibres. A small fine steel wire was used in order to have a bettercoupling of the modulated light. An optoelectronic unit, similar to that used for bilimetricmonitoring, has been developed: it consists of two similar channels, separately connectedwith the fibres carryingTB andBPB for the detection of pH in the range 1÷ 3.5 and in therange 3.5÷ 7.5, respectively. The use of light-emitting diodes as sources and of an internalmicroprocessor has made it possible to construct a truly portable sensor.In vitro accuracywas 0.05 pH units. On the other hand thein vivo accuracy is still not satisfactory sincein some cases, a step of some tenths of pH is present between the response of the opticalsensor and the pH electrode.

Figure 15. Sketch of the optical probe forin vivo gastric pH monitoring.

4.2.3. Tissue pH. Twin-fibre probes are generally used forin vivo mapping of normaland tumoural areas by means of pH measurements, since malignant tumours induce adecrease in the pH of the interstitial fluid and depression caused by the administrationof glucose. Dual-wavelength fluorometry using optical fibres provides a new diagnostictool for highly-localized measurements. A nontoxic pH-dependent indicator (fluoresceinderivatives) is injected in the tissues to be analysed, and the twin-fibre probe illuminatesthe tissue and measures the fluorescence intensities at 465 and 490 nm. The ratio of thesefluorescence intensities is related to the pH of the tissue, thus providing normal-neoplastictissue-mapping [47, 48].


4.3. Oxygen

Together with pH, oxygen is surely the chemical parameter most investigated forin vivoapplications, as its knowledge and continuous monitoring are very important in many fields,such as those of circulatory and respiratory gas analysis.

4.3.1. Blood oxygen. As outlined previously, a knowledge of the oxygen content in blood isessential in order to know how the cardiovascular and cardiopulmonary systems work. Thismeasurement can be performed either spectroscopically by exploiting the optical propertiesof haemoglobin, the oxygen-carrying pigment of erythrocytes, or by using an appropriatefluorophore, the fluorescence of which is quenched by oxygen.

Spectroscopic analysis.Oxygen saturation, i.e. the amount of oxygen carried by thehaemoglobin (Hb) in the erythrocytes in relation to its maximum capacity, was the firstquantity measured withFOSs [49]. This parameter is measured optically by exploiting thedifferent absorption spectra of the Hb and the oxyhaemoglobin (OxyHb) in the visible/nearinfrared region.

Numerous artery and vein insertion models are now commercially available, for examplethe instruments made by Oximetric Inc., Mountain View, CA; BTI, Boulder, CO; AbbottCritical Care, Mountain View, CA. In the simpler version, reflected or absorbed light iscollected at two different wavelengths and the oxygen saturation is calculated via the ratiotechnique on the basis of the isobestic regions of Hb and OxyHb absorption. On the otherhand, the presence of other haemoglobin derivates, such as carboxyhaemoglobin, carbonmonoxide haemoglobin, methemoglobin and sulphaemoglobin, makes preferable the use ofmultiple wavelengths or of the whole spectrum, which allow their discrimination [50–51].

Non-invasive optical oximeters, which calculate oxygen saturation via the lighttransmitted through the earlobes, toes, or fingertips have also been developed, primarilyfor neonatal care [52]. In this case, particular attention has to be paid to differentiatingbetween the light absorption due to arterial blood and that due to all other tissues and bloodin the light path. This implies the use of multiple wavelengths, such as the eight wavelengthHewlett Packard ear oximeter [53].

Such a drawback can be avoided by using a pulse oximeter. This original approachis based on the assumption that a change in the light absorbed by tissue during systoleis caused primarily by the arterial blood. By an appropriate choice of two wavelengths,it is possible to measure non-invasively the oxygen saturation by analysing the pulsatile,rather than the absolute transmitted or reflected, light intensity [54–56]. The detectionof blood absorbance fluctuations that are synchronous with systolic heart contractions iscalled photoplethysmography. One application is in dentistry where, by means of a pulseoximeter, it is possible to obtain information on whether the pulp is vital or necrotic: thetooth is squeezed between the termination of an optical fibre bundle and two reflectiveprisms, to illuminate the tooth and to collect the light transmitted through it. The ratiobetween the recordedAC (at 0.5 Hz) andDC components of the detected signal at 570 nmconstitutes the sensor output, i.e. the tooth plethysmogram. Vitality is indicated by arhythmic plethysmogram; necrosis, by a random plethysmogram [57]. In another dental-pulpvitalometer, the oxygen saturation content of dental blood is obtained by an optical-fibreprobe placed in contact with the tooth that performs reflectance measurements at 660 nmand 850 nm. The signal ratio is processed together with a non-optical plethysmogramsignal from one of the patient’s fingers, which is used as a reference in determining thetooth’s blood pulse. The resultant tooth plethysmogram also contains information on oxygen


saturation, thereby allowing pulp vitality to be assessed [58].Spectrophotometric measurements performed directly on the skin tissue and on the organ

surface provide essential information on the microcirculation in tissue and skin and on themetabolism of an organ, respectively [59]. For example, on-line monitoring of the oxygensupply in peripheral organs has considerable importance. It is apparent that a perfect andadequate perfusion of all the organism is basic to the safety of the patient. In the presenceof pathological changes in the oxygen transport chain, the organism, by itself, decreasesthe perfusion in peripheral organs (e.g. skin, skeletal muscles, gut) in favour of centralorgans such as the brain and the heart (centralization). This mechanism is one of the mosteffective and important ones during different shock forms. Spectra from biological tissuesare able to detect the beginning of centralization before any external, physical and moredangerous symptoms become visible. On the other hand, during the early stages of shock,such an alteration of oxygen transport does not occur homogeneously on the tissue surface:therefore, only fibre optics offer a sufficient spatial resolution for immediate detection. Aspecial algorithm is generally used, since the spectra of the Hb and its derivatives areunevenly distributed in a highly scattering medium, and thus are notably altered.

With the spectrophotometer analyser developed by BGT (Uberlingen, Germany)[60], important parameters such as intracapillary haemoglobin oxygenation, intracapillaryhaemoglobin concentration, local oxygen uptake rate, local capillary blood flow, changesin subcellular particle sizes, and capillary wall permeability (via the injection of exogenousdyes) can be measured in real time. Light from a Xenon arc lamp illuminates the tissue viaa bifurcated fibre bundle. The back-scattered light, filtered by a monochromator, impinges aphotomultiplier connected to a computer that records the spectra resulting from the biologicaltissue. Thanks to the use of fibres, only small volumes of tissue are investigated, thus makingpossible the resolution of spatial heterogeneities. The instrument is able to record spectraof high quality even in moving organs.

Optrode analysis. The disadvantage of utilizing haemoglobin as an indirect indicator forthe measurement of oxygen is its full saturation at≈ 100 Torr: this fact prevents, forexample, the use of this method in the case of the respiration of gas mixtures with an O2

content larger than 20% as routinely used in anaesthesia. Therefore the use of a chemicaltransducer becomes necessary in some cases.

The first optrode-based oxygen sensor was described by John Peterson, and makes useof a fluorophore, perylene-dibutyrate, the fluorescence of which is efficiently quenched byoxygen [61]. The dye, adsorbed on amberlite resin beads, was fixed at the distal end oftwo plastic optical fibres with a hydrophobic membrane permeable to oxygen. The probedescribed was testedin vivo for the measurement of the arterial pO2 level in dog eyes [62].

Other optrodes have been developed and testedin vivo, all of them using a fluorophore,the fluorescence of which is quenched by oxygen. In the intravascular sensor developedby CDI, previously described, a specially synthesized fluorophore, a modified decacyclene(λexc = 385 nm,λem = 515 nm), is combined with a second reference-fluorophore thatis insensitive to oxygen, and is incorporated into a hydrophobic silicon membrane that ispermeable to oxygen.

A new type of non-invasive sensor has been proposed to measure the local oxygenuptake through the skin. The direct measurement of the oxygen flow on the skin surfaceprovides information regarding the oxygen flow inside the tissue, which can help physiciansto diagnose circulatory disturbances and their consequences. Two optrodes, which makeuse of a ruthenium complex, measure the difference in oxygen pressure across a membrane


placed in contact with the skin.In vivo tests performed on the left lower forearm of apatient gave good results [63].

4.3.2. Respiratory oxygen.A knowledge of the concentration of oxygen, as well as ofmany other gases, in exhalation analysis is very important, since it may provide importantinformation on the correct metabolism of the human body. An optrode for the simultaneousdetection of oxygen and carbon dioxide, potentially suitable for respiratory gas analysis,has recently been proposed [64–65]. It makes use of two fluorescent dyes dissolved in avery thin layer (1–3µm) of a plasticized hydrophobic polymer which is fixed at the distalend of optical fibres. A wavelength discrimination by appropriate interference filters makespossible the simultaneous monitoring of O2 and CO2, as the emission wavelengths of thetwo fluorophores are sufficiently separated.

4.4. Carbon dioxide

As for oxygen, the measurement of CO2 is capable of providing important information inregard to the working of the circulatory and respiratory systems. Its detection is based onthe detection of the pH of a carbonate solution, since its acidity depends on the quantity ofCO2 dissolved therein. Therefore, all optrodes developed for blood CO2 make use of thesame dye utilized for blood pH detection, fixed at the end of the fibre and covered by ahydrophobic membrane permeable to CO2. In the intravascular CDI system the fluorophore,hydroxypyrene trisulphonic acid (the same one used in the pH optrode), is dissolved ina bicarbonate buffer solution which is encapsulated in a hydrophobic silicon membranepermeable to CO2 and attached to the fibre tip.

4.5. Lipoproteins

A knowledge of the lipoprotein content in the blood is of paramount importance, asthis protein is the carrier of cholesterol. Epidemiological studies have indicated thata reduction in blood cholesterol levels significantly reduces the risk of atherosclerosis,ischemia, myocardial infarction, and death. On the other hand, it has been well demonstratedthat measuring the total cholesterol in the blood is not sufficient for predicting the risk ofcardiovascular diseases; but a knowledge of the type of lipoproteins, which can be differentin size, density and lipid and apolipoprotein composition is essential. For example, high-density lipoproteins, the second largest carriers of plasma cholesterol, have been recognizedas being able to remove cholesterol from tissue and, consequently, of being capable ofcarrying on a protective action against arterial disease.

The use of optical fibres allows anin vivo investigation of arterial lesions. Fluorescencespectroscopy with optical fibres makes the imaging of the intimal surfaces of arteriespossible. On the other hand, interferences from the whole blood make preferable the useof near-IR wavelengths in which such interferences are noticeably reduced. Collectionof the many whole near-IR spectra from one location at a time has recently allowedthe chemical analysis of arterial lesions in living tissues, with the aid of an appropriateprocessing of the data based on a new experimental clustering technique that uses a parallelvector algorithm [66]. Such anin vivo qualitative (recognition of the different types oflipoproteins) and quantitative (concentration evaluation) analysis appears fundamental bothfor monitoring changes in arterial wall composition and for testing important new hypothesesof lesion formation, growth, and regression.


4.6. Lipids

One of the major dermatological requirements is knowing the condition of the skin, whichcan be roughly determined by monitoring the skin’s hydration state and, more precisely, bydetermining lipid content. The latter parameter is of special importance in studies of acne.An inexpensive fibre-optic refractometer has been developed for both tasks.

The sensor comprises a plastic fibre with a short section stripped of its cladding, whereit is bent into a U-shape. With the U-shaped tip on the skin, the skin surface acts as thefibre cladding. Since the skin surface is not perfectly smooth, some gaps are created aroundthe fibre core. At probe contact, the gaps are filled with air, but during the time the probeis in contact with the skin, they fill up with skin moisture. Consequently, sensor outputdecreases with time, at a rate dependent on the hydration state. The skin moisture contentis obtained in relation to pre-fixed threshold values [67].

It has been noted that, the higher the lipid contents, the higher the light reflection, thusreducing sensor output. This disturbance has been used for estimating lipid quantity, throughcomparisons of sensor outputs relative to defatted and unprepared skin. By comparing thisdifference with pre-fixed values, the lipid content has been successfully monitored, with theexperimental results in good agreement with those obtained using a traditional gravimetrictechnique [68].

4.7. New aspects and perspectives of chemical sensors

Almost all the chemical sensors described above were testedin vivo or are being tested. Asalready pointed out, some of them are available on the market, and are capable of providingsatisfactory answers to clinicians’ requirements while others are still at an experimentalstage.

A recent survey has made evident the main areas in whichin vivo chemical sensorswould be helpful [69], as can be seen from table 1, which reports the results of this survey.The number in parentheses for each analyte is the number of physicians who answered thesurvey.

Table 1. Main clinical problems and related analytes for which a continuousin vivo monitoringshould be performed.

Clinical problem Analyte

Diabetes mellitus glucose (24), K+ (3), ketones (2), insulin (2), lactate (1), pH(1)

Vital function monitoring in O2 (15), CO2 (10), pH (8), haemoglobin (3), K+ (2), glucoseintensive care/anaesthetics/ (2), electrolytes (unclassified) (1), gases (unclassified) (1),prolonged surgery Na+ (1), osmolality (1), lactate (1)renal failure/monitoring dialysis urea (4), creatinine (2), K+ (2), atrial natriuretic peptide (1),

pH(1)

Some of the required analytes are already being monitored on-line withFOSs, and havebeen described here. OtherFOSs have been proposed and seem promising, although nonehas as yet undergonein vivo testing (glucose, potassium, urea, lactate).

Glucose is surely the analyte most in demand, because its control is of vital importancein diabetic patients, and a glucose sensor is an integral part of an artificial pancreas with itscontrolled insulin release. Patients affected by diabetes mellitus need a monitoring of bloodglucose levels during the whole day; but so far, no continuous sensor is available, obliging


patients to self-monitoring of their blood glucose by periodic sampling and to the use ofchemistry reagent strips. Different approaches with fibre-optics have been presented, but atthe moment some problems for theirin vivo utilization still exist.

Reversible competitive binding of glucose with fluorescence labelled-dextran for sugarbinding sites of a lectin, concanavalin A [70–71], has been proposed. The probe consistsof an appropriate hollow fibre, coupled to fibre-optics, capable of preventing the exit ofreagents, but permeable to glucose (selection made on the basis of the molecular weight).Problems still open are the lifetime of the probe and the response time. Another approachmakes use of glucose oxidase, an enzyme that catalyzes the oxidation of glucose; byexploiting the enzymatic reaction, it is possible to indirectly monitor glucose levels withthe measurement of oxygen [72] or pH [73]. Although sensitive and for some aspectssatisfactory (for example, fast response time), this approach seems even more appropriatefor laboratory diagnostics than forin vivo sensing, mainly due to the deterioration of thechemicals utilized, which strongly limits the lifetime of the probes.

An interesting technique is the exploitation of properties of the glucose as an optically-active substance, and therefore one capable of inducing a rotation of linearly-polarized light.The amount of rotation, detected by measuring the phase shift of the output voltage of thesignal detector, can be related to the glucose concentration. Although at the moment itis not used with optical fibres, this optical method seems very promising and has alreadybeen tested for the non-invasive monitoring of the aqueous humour of the eye [74–75]. Theadvantage of this plain spectrophotometric technique is apparent and enormous: detectionof the analyte is made without chemical reactions; consequently, fouling problems causedby the biological medium are avoided, and the problem of the lifetime of the probe iseliminated.

Identical advantages are presented byIR-spectroscopy. The advent ofIR-transmittingfibres provides the possibility of ‘seeing’, by means of fibre-optics, the rotational/vibrationalbands which univocally characterize each molecule. The use in biomedicine of infra-red spectroscopy coupled with the use ofIR fibres for in vivo monitoring is now takingits first steps, but preliminary tests are very encouraging.In vitro spectral analysis ofhuman blood serum performed withIR-transmitting non-toxic silver halide fibres connectedto anFTIR spectrometer, has recently been proposed [76], making possible the simultaneousmonitoring of cholesterol, urea, total protein, uric acid and calcium. Continuous monitoringof respiratory gases could be performedin situ by couplingIR-fibres with tunable diode laserspectroscopy (TDLS). TDLS has recently been applied with good results for the determinationof trace gases such as CO, CO2, NH3, CH4, NO in the exhalation of both humans andanimals [77].

5. Spectral sensors

FOSs are also used inin vivo applications for checking the optical properties of organswithout the measurements being related to the detection of any definite chemical/physicalparameters.

Spectral analysis of tissue can provide important information on its health. Fibre-ringcatheters are used for the spectral-autofluorescence analysis of tissues during endoscopy.Tissue autofluorescence, excited by an He–Ne laser, is spectrally analysed in the 660–850 nm range. The differences in spectral distribution between normal, cancerous, andnecrotic tissues allow for real-time diagnostics, without the necessity for biopsy. Stomach,bronchial, and lung tissues have been diagnosed by fibre catheters that combine coherentfibre bundles with custom bundles optimized for fluorescence measurements [78].


MID-IR fibre-based systems have been tested forin vitro tissue spectra measurements,with evanescent fibre probes coupled to Fourier Transform spectrometers. Such systemshave demonstrated the possibility of recognizing differences in normal and malignant tissuespectra (kidney, stomach, lungs) [79] and their suitability for diagnosing atherosclerosis [80].

In dermatological applications, the erythema meter (figure 16) aids in quantifyingerythema in allergy and irritancy testing, as well as in measuringUV-induced erythema.Skin colour is mostly the result of blood quantity and melanin content, the reflectanceof which modulations range between 520–580 nm and 500–700 nm, respectively. Skincolour measurements are performed by a fibre-optic bundle coupled with a dual-wavelengthreflectometer, which measures the ratio of skin reflectance at 555 nm, modulated by bloodquantity, to 660 nm, melanin sensitive but not influenced by blood quantity and hence usedas a reference. The sensor head (OD≈ 5 mm) can be equipped with two mechanicalcomponents for 45◦ and 0◦ no-contact measurements [81, 82].

Figure 16. Fibre-optic erythema meter.

In dentistry, tooth-colour matching is a constant problem in restorative dentistry. Themany disadvantages of the conventionally-used method, which is based on the visualcomparison of natural tooth colour with standard colours, can be overcome by using afibre-optic reflectance spectrometer. Originally developed for tissue diagnosis, this sensorcan be a great help in selecting the material that best replicates the appearance of naturalteeth. A slender, flexiblePMMA fibre-optic bundle is used to illuminate a portion of the toothwith white light, and guides the tooth’s reflected light to a portable grating spectrometer.The reflectance spectrometer can also be used for diagnosing gingiva by means of bentprobe heads inserted in the patient’s oral cavity [83].

6. Conclusions

The FOSs described above have given good results inin vivo testing. Some of these arealready commercially available, while others are being developed in response to demandsfrom the medical profession and encouraging market studies.

The utilization of FOSs is increasing continuously, and this fact makes it feasible toimagine their more and more widespread diffusion forin vivo monitoring. The possibilityof FOSs, in some cases already exploited [2, 35, 40, 84, 85], of monitoring several parameters


with a single instrument makes them still more competitive in comparison with the othertechniques and is continuously encouraged by physicians, who greatly appreciate thepossibility of having a multitest portable unit with low-cost disposable probes, that canbe easily managed by both doctors and patients.

Acknowledgments

The authors are grateful to Professor Annamaria Scheggi for her many helpful discussionsand constructive suggestions. Thanks are also due to Dr Klaus Frank, BGT,Uberlingen,Germany; Professor Harri Kopola of the University of Oulu, Oulu, Finland; Dr GordonMitchell of Future Focus, Woodinville, WA; Dr John Peterson of the National Institutes ofHealth, Bethesda, MD; Dr Mei Sun of Luxtron, Santa Clara, CA; and, lastly, to ProfessorTakashi Takeo of the Nagoya Municipal Industrial Research Institute, Nagoya, Japan, forproviding illustrative material.

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Biomedical sensors using optical ﬁbres

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