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(Journal of Nutrition. 2001;131:1596S-1604S.)
© 2001 The American Society for Nutritional Sciences

Supplement

Noninvasive and Minimally-Invasive Optical Monitoring Technologies1 ,2

Gerard L. Coté3

Biomedical Engineering Program, Texas A&M University, College Station, TX 77843-3120

3To whom correspondence should be addressed. E-mail: cote{at}tamu.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 Absorption spectroscopy
 Polarimetry
 Raman spectroscopy
 Fluorescence monitoring
 REFERENCES
 
With recent advancements in micro-fabrication and nano-fabrication techniques as well as advancements in the photonics industry, there is now the potential to develop less invasive portable sensors for monitoring micronutrients and other substances used to assess overall health. There have been many technology innovations in the central laboratory for these substances for overall health status but the primary motivation for the research and development of a portable field instrument has come from a diabetic patient and market-driven desire to minimally invasively or noninvasively monitor glucose concentrations in vivo. Such a sensor system has the potential to significantly improve the quality of life for the estimated 16 million diabetics in this country by making routine glucose measurements less painful and more convenient. In addition, there is a critical need for the development of less invasive portable technologies to assess micronutrient status (iron, vitamin A, iodine and folate), environmental hazards (lead) and for other disease-related substances, such as billirubin for infant jaundice. Currently, over 100 small companies and universities are working to develop improved monitoring devices, primarily for glucose, and optical methods are a big part of these efforts. In this article many of these potentially less invasive and portable optical sensing technologies, which are currently under investigation, will be reviewed including optical absorption spectroscopy, polarimetry, Raman spectroscopy and fluorescence.

KEY WORDS: • polarimetry • spectroscopy • fluorescence • micronutrients • glucose


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
Absorption spectroscopy
 Polarimetry
 Raman spectroscopy
 Fluorescence monitoring
 REFERENCES
 
A recent initiative, "Healthy People 2010," is a prevention agenda for the nation that developed through a broad consultation process, was built upon the best scientific information and was designed to measure programs over time (U.S. Department of Health and Human Services 2000Citation ). It is a statement of national health objectives designed to identify the most significant preventable threats to health and to establish national goals to reduce these threats. It has as its focus the achievement of two overarching goals: increase quality and years of healthy life and eliminate health disparities. As a part of this theme, there has been and continues to be several federal, state and local government as well as private sector initiatives to develop appropriate and sustainable technologies for overall health monitoring. For instance, there is a critical need for the development of technologies for the assessment of micronutrient status (iron, vitamin A, iodine and folate), for environmental hazards (lead) and for substances, such as glucose or billirubin, which are critical for various patient populations, including those with diabetes mellitus and infant jaundice.

In terms of micronutrient status, the World Bank estimates that 2 billion people worldwide are at risk from deficiencies in iron, vitamin A, iodine and folate and that 1 billion are actually ill or disabled by these deficiencies (U.S. Department of Health and Human Services, Centers for Disease Control and Prevention 2000Citation ). Iron deficiency is the most common nutritional deficiency in the world (DeMaeyer 1989Citation ), and it causes impairment in cognitive development as well as immune mechanisms. It is also associated with increased morbidity and mortality in children, and during pregnancy, iron deficiency increases perinatal risks for mothers and newborns and increases overall infant mortality (U.S. Department of Health and Human Services, Centers for Disease Control and Prevention 1998Citation ). Severe vitamin A deficiency is a leading cause of childhood blindness in the world, and even subclinical vitamin A deficiency is associated with increased severity of infection and higher rates of childhood morbidity and mortality (Sommer and West 1996Citation ). Iodine deficiency (IDD)4 is the single most common cause of preventable mental retardation and brain damage in the world (U.S. Department of Health and Human Services, Centers for Disease Control and Prevention 1999Citation , International Council for the Control of Iodine Deficiency Disorders 2000Citation ). It causes goiters and decreases the production of hormones vital to growth and development. Children with IDD can grow up stunted, apathetic, mentally retarded and incapable of normal movement, speech or hearing. IDD in pregnant women causes miscarriage, stillbirth and mentally retarded children. In addition to iodine deficiency, exposure to excess iodine can produce toxic responses including hyperthyroidism and hypothyroidism, thyroiditis, goiter, sensitivity reactions and acute responses (Zareba et al. 1995Citation , Standbury 1988Citation , Silva 1985Citation , Pennington 1990Citation , Woeber 1991Citation ). Interest in the role of adequate folate nutrition has grown in the last decade primarily because of the connection between folate intake and reduction of pregnancies with neural tube defects and the possible connection of occlusive vascular diseases in relation to the increased concentration of homocysteine in the circulation (Tamura 1998Citation , Medical Research Council 1991Citation , Boushey et al. 1995Citation ). In addition, other congenital abnormalities (heart defects, obstructive urinary tract abnormalities, limb defects, facial clefts and congenital hypertrophic pyloric stenosis) have been associated with improper maternal periconceptional folic acid consumption (Botto et al. 1996Citation , Czeizel, 1996Citation , Hayes et al. 1996Citation , Li et al. 1995Citation , Shaw et al. 1995aCitation , Shaw et al. 1995bCitation , Tolarova and Harris 1995Citation ). Overall, it is well known that deficiencies in these nutrients and, in general, micronutrient malnutrition as a whole is a severe problem in developing countries. However, the assessment of micronutrient status would have applicability in clinical laboratory and medical settings as well as rural and inner-city populations of the developing and developed world, including domestic programs in the United States, such as the Special Supplemental Nutrition Program for Women, Infants and Children. Given the above complications of micronutrient malnutrition and the existing need for monitoring at risk groups in the field, it is clear that the development, commercialization and application of innovative technologies that are rugged, portable, easy to operate and maintain, cost effective and sustainable is essential.

Although there have been dramatic improvements in reducing lead in the environment, there are still nearly 1 million U.S. children with elevated blood lead levels. Lead poisoning is entirely preventable. However, this statistic underscores the need for the new lead-screening guidance recently released by the Centers for Disease Control and Prevention. These high levels of lead in the blood can cause irreversible damage to the health of children (U.S. Department of Health and Human Services, Centers for Disease Control and Prevention 2000Citation ). As stated in the Centers for Disease Control and Prevention National Center for Environmental Health Lead Prevention Program, lead poisoning affects virtually every system in the body and often occurs with no distinctive symptoms. Lead can damage a child’s central nervous system, kidneys and reproductive system and, at higher levels, can cause coma, convulsions and death. Finally, even low levels of lead are harmful and are associated with decreased intelligence, impaired neurobehavioral development, decreased stature and growth and impaired hearing acuity. Therefore, detection leading to the prevention of lead poisoning, particularly among children, is one of the many environmental health hazards that could benefit from more sophisticated monitoring technologies.

Noninvasive and minimally invasive monitoring technologies for the detection of billirubin and glucose for infant jaundice and diabetes mellitus patients have received the most attention from the private sector, primarily due to the large potential market for these devices. Six of every 10 newborns develop jaundice during the first week of life and, thus, nearly 60% of the 4 million infants born every year have some level of jaundice. Given a high level of serum bilirubin, hyperbilirubinemia or excessive jaundice occurs in a small number of infants and for very high levels it is possible for neurological problems to arise. Some early signs of problems due to elevated serum bilirubin may include hearing function abnormalities, and at higher levels, these may lead to severe brain damage (SpectRx Inc. 2000Citation ). Diabetes mellitus is a chronic systemic disease characterized by disorders in the metabolism of insulin, carbohydrate, fat and protein as well as the structure and function of blood vessels (Spencer 1981Citation ). This disease currently afflicts over 100 million people worldwide and nearly 14 million in the United States (National Institute of Diabetes and Digestive and Kidney Diseases 1994Citation ). In the United States, this disorder along with its associated complications is ranked as the seventh leading cause of death (Cotran et al. 1989Citation ). The goal of diabetes therapy is to approximate the 24-h blood glucose profile of a normal individual. To avoid the secondary complications of this disease (retinopathy, cardiovascular disease, etc.), it has been recommended that the patient monitor their glucose levels five or more times daily (National Institute of Diabetes and Digestive and Kidney Diseases 1993Citation ) but this is not achieved by most patients with the current finger-stick monitoring devices. The patient compliance for monitoring is low due to a number of factors including the pain associated with this approach, the possibility for infection and, in general, the inconvenience and cumbersome nature of the approach. To facilitate patient compliance for frequent monitoring of blood glucose, a noninvasive or minimally invasive glucose monitor would be highly beneficial.

Given the conditions described above, namely, micronutrient malnutrition, lead poisoning, infant jaundice and diabetes mellitus, it is clear that the development, commercialization and application of innovative technologies that are rugged, portable, easy to operate and maintain, cost effective and sustainable is essential. A few of the optical techniques (absorption spectroscopy, polarimetry, Raman spectroscopy and fluorescence) currently being investigated for monitoring these substances, with an emphasis toward glucose sensing, are the focus for the remainder of this article.


   Absorption spectroscopy
TOP
 ABSTRACT
 INTRODUCTION
 Absorption spectroscopy
Polarimetry
 Raman spectroscopy
 Fluorescence monitoring
 REFERENCES
 
Absorption spectroscopy has been shown to be useful as a noninvasive means of monitoring several substances in vitro, such as glucose, glutamine, glutamate, ammonia and lactic acid (Chung et al. 1996Citation , McShane and Coté 1998Citation , Small et al. 1993Citation ) as well as sugars and starches in the food industry (Lanza and Li 1984Citation ). Recently, many industries and universities are exploring this approach, in particular for in vivo glucose monitoring for diabetes, but also for bilirubin detection for infant jaundice and hemoglobin/hematocrit detection as a measure of iron deficiency.

As mentioned above, hyperbilirubinemia is a serious condition affecting many neonates. The hyperbilirubinemic infant presents a yellow skin color, and optical reflectance spectroscopy is used to enable continuous quantitative noninvasive monitoring of the bilirubin levels. Natural variations in skin pigmentation, erythema, water content (edema) and skin layer thickness have frustrated early monitors but through the early work of Jacques et al. (Saidi et al. 1989Citation , Saidi et al. 1990Citation ) on computer simulations of light propagation in a multilayered skin model and the commercial development by scientists at SpectRx, an infrared (IR)-based absorption monitoring device and algorithm for reliable quantification of bilirubin despite variations in skin optics are now commercially available (SpectRx Inc. 2000Citation ).

Iron status can be assessed through several laboratory tests. Because each test assesses a different aspect of iron metabolism, results of one test may not always agree with results of other tests. Hematological tests based on characteristics of red blood cells (i.e., hemoglobin concentration, hematocrit, mean cell volume and red blood cell distribution width) are generally more available and less expensive than are biochemical tests. However, biochemical tests (i.e., erythrocyte protoporphyrin concentration, serum ferritin concentration and transferrin saturation) detect earlier changes in iron status (U.S. Department of Health and Human Services, Centers for Disease Control and Prevention 1998Citation ). Although all of these tests can be used to assess iron status, no single test is accepted for diagnosing iron deficiency (U.S. Department of Health and Human Services, Centers for Disease Control and Prevention 1998Citation , Yip 1989Citation ), and most of these tests are still performed on blood samples in the central laboratory. Only through the work of Groner et al. (1999Citation ) and recently commercialized by Cytometrics as the Hemoscan 1000 (Cytometrics Inc. 2000Citation ) has a noninvasive optical approach become available that has the potential to monitor hemoglobin and hematocrit as an indicator of iron deficiency in a clinical or field setting. The approach is based on imaging the near-infrared (NIR) absorption spectral peaks of hemoglobin but using a polarized light input and has been referred to as orthogonal polarization spectral (OPS) imaging. This is a novel method for obtaining and analyzing images from reflected light. OPS imaging works by creating a virtual light source behind the object that is being observed by removing the surface scattering of light. In human mucosal tissue (such as tissues inside the mouth), OPS-imaging technology allows the capture of detailed high-contrast video images of the microcirculation, similar to what can be observed using a special research instrument called an intravital microscope. The images are striking but the key to this technology becoming truly useful as a field device for blood monitoring is in the software development to provide quantifiable data.

For glucose detection, the NIR region of the wavelength spectrum has been the primary region of interest. The advantage of the NIR wavelength region of the optical spectrum is that the spectra are not affected by water to the same degree as the midinfrared region allowing for path lengths of 1 mm to 1 cm to be used (Coté 1997Citation , McNichols and Coté 2000Citation ). The NIR region (700–2500 nm) exhibits absorptions due to low energy electronic vibrations (700–1000 nm), as well as overtones of molecular bond stretching and combination bands (1000–2500 nm). These bands result from interactions between different bonds (-CH, -OH, -NH) to the same atom. Typically, only the first, second and third overtones of a molecular vibration are detectable. Only at high concentrations of the chemical species are these overtones qualitatively detectable with the intensity dropping off rapidly as overtone order increases. The NIR absorption bands are also influenced by temperature and hydrogen bonding effects and can overlap significantly. Thus, unlike mid-IR spectroscopy, NIR spectroscopy is purely empirical and not particularly suited for qualitative work. However, using multivariate statistical techniques on NIR spectrum does allow for quantitative analysis. The theory and application of these methods to spectroscopic data have been thoroughly reviewed by this and other investigators (Haaland 1990Citation , Martens and Naes 1989Citation , McClure 1984Citation ).

Heise and co-workers (1989Citation ) were one of the initial groups to propose the use of multivariate techniques on mid-IR spectra for blood glucose determination. Later studies (Animas Corporation 2000Citation , Arnold and Small 1990Citation , Burmeister and Arnold 1999Citation , Chung et al. 1996Citation , Gabriely et al. 1999Citation , Haaland et al. 1992Citation , Hazen et al. 1994Citation , Heinemann and Schmelzeisen-Redeker 1998Citation , Heise et al. 1998Citation , Marbach et al. 1993Citation , Pan et al. 1996Citation , Robinson et al. 1992Citation , Samann et al. 2000Citation , Small et al. 1993Citation ) have concentrated on using NIR spectroscopy coupled with multivariate techniques on glucose-doped aqueous solution, whole blood, and in vivo across the finger of patients. The reported differences in the actual versus predicted concentrations varied by 0.14 mmol/L in aqueous solution (Hazen et al. 1994Citation ), 1.67–2.78 mmol/L in blood and plasma (Animas Corporation 2000Citation , Haaland et al. 1992Citation , Small et al. 1993Citation ), and 1.11–3.06 mmol/L in vivo (Animas Corporation 2000Citation , Gabriely et al. 1999Citation , Heise et al. 1998Citation , Marbach et al. 1993Citation , Robinson et al. 1992Citation , Samann et al. 2000Citation ).

Much of the early work in the NIR has used transmission spectroscopy and in nearly all of these proof-of-concept studies, large and relatively expensive bench-top machines have been used such as the Fourier transform infrared-based instruments and grating spectrometer instruments. The assumption has been that the main signal, or transmission loss, across the 0.75- to 2.5-µm range has been due to light absorption by glucose or the other chemicals. In the region above 1.35 µm, in particular above 2 µm, this does seem to be true because the water subtracted absorption spectrum shows the broad peaks due to overtones and combinations of the various molecules (Fig. 1Citation ). However, for glucose measurement in the very NIR region below 1.35 µm, results (Kohl and Cope 1994Citation , Maier et al. 1994Citation ) indicate that the major signal for the physiologic glucose range may be due more to refractive index variations and, hence, scattering changes of glucose or other physiologic effects related to glucose rather than to glucose absorption alone. Whether the signal is due to a fundamental absorption or scatter, as mentioned, in the NIR region the light can penetrate deeper into a sample, thus, allowing the use of much larger path lengths without signal loss. In addition, in an effort to eliminate the need for expensive laboratory table-top machines and to maintain high accuracy in the approach for a portable unit, this group has investigated the use of wavelength selection algorithms to determine the minimum number of wavelengths required in such a device (McShane et al. 1999Citation , Spiegelman et al. 1998Citation ). Using these wavelength selection routines, the number of wavelengths required has been reduced. Furthermore, inexpensive reliable semiconductor radiation sources and detectors are now becoming available, primarily because of the optical communications industry, making NIR spectroscopy an affordable instrumentation option and potentially viable noninvasive sensing technique.



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  		Figure 1. NIR absorption spectra of water-subtracted glucose, lactate, ammonia, glutamate and glutamine at nearly saturated concentrations. The three absorption bands due to glucose are clearly visible in this part of the spectral range and although it is difficult to visualize each component in the mixture, the advances in statistical processing using partial least squares is able to pull out this information.

 
Several companies have begun to produce smaller semiportable NIR glucose-monitoring devices (Day 1996Citation , Sabatini 1996Citation ) but, unlike the in vitro studies, have had limited success in producing repeatable and quantifiable results in vivo. The lack of repeatability of the NIR signal in vivo both within and especially between patients is a major concern. The signal variations in most instances are not fully understood or accounted for in the system. The primary known drawbacks to taking this technology from an in vitro to an in vivo monitoring device include the path length variability when going from a fixed test cell to pliable tissue, temperature variability when going from a controlled, incubator, environment to a peripheral site such as the finger or earlobe, other chemical substances (protein, urea, cholesterol, alcohols, etc.) that have overlapping spectra and may vary in ways not accommodated by the calibration spectral data, and the pulsatile nature of the blood, which affects both path length and the concentration of the chemical. In addition to repeatability, the specificity, in particular in the NIR region from 0.7 to 1.35 µm, is questionable because for physiologic concentrations (0–33 mmol/L), using glucose in water, there is little quantifiable change in the absorption of the spectral output due to glucose alone. In contrast, human studies undertaken by other groups (Marbach et al. 1993Citation , Robinson et al. 1992Citation ) show a good correlation with varying glucose concentration. This correlation may be a physiologic effect related to the increase of glucose, such as the interaction with hemoglobin, a known strong absorber in this region, or the effects of scattering in the turbid media, or possibly a time-dependent artifact. Thus, good correlation in vivo, if based on time-dependent artifacts (as may be seen using a simple oral glucose tolerance test), may not be repeatable and these must be avoided with good randomized experimental designs. Finally, the optical properties of tissues vary widely in the NIR region, and they must be analyzed within and between patients.


   Polarimetry
TOP
 ABSTRACT
 INTRODUCTION
 Absorption spectroscopy
 Polarimetry
Raman spectroscopy
 Fluorescence monitoring
 REFERENCES
 
The basis of this optical approach is that the linear polarization vector of light will rotate when the light is passed through a substance and that the rotation measured is proportional to the concentration of the substance being monitored. This rotation is due to a difference in the indices of refraction nL and nR for left and right circularly polarized light passing through a solution containing the molecule. It occurs by virtue of the molecule’s chirality or handedness, by which we mean the molecule has at least one center about which its mirror image cannot be superimposed upon itself. A variety of both polarimeters, adapted to the examination of all chiral substances and saccharimeters designed solely for polarizing sugars, have been developed. Glucose in the body is dextrorotatory (rotates light in the right-handed direction with concentration). In addition to the concentration of the chiral material, the amount of rotation of linear vector of the polarized light also depends on the thickness of the layer traversed by the light, the wavelength of the light used for the measurement, the temperature and the pH of the solvent. Historically, polarimetric measurements have been generally obtained under a set of standard conditions. The path length typically used as a standard in polarimetry is 10 cm for liquids, the wavelength is usually that of the green mercury line (5461 Angstroms) and the temperature is 20°C. If the layer thickness in decimeters (0.1 m) is L, the concentration of solute in grams per 0.1 L of solution is C, {alpha} is the observed rotation in degrees, and {alpha} is the specific rotation or rotation under standard conditions, which is unique for all chiral molecules, then

(1)

In the above equation the specific rotation [{alpha}] of a molecule is dependent upon temperature, wavelength and the pH of the solvent. Of these three, the wavelength of the light has the dominant effect on the specific rotation as shown in Figure 2Citation . This fact could potentially be used to distinguish chiral rotation of the molecule of interest from other confounding molecules as well as chiral rotation from birefringence due to the tissue.



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  		Figure 2. Change in specific rotation of the molecule of interest as a function of wavelength of the light is known as optical rotatory dispersion. This change can potentially be used to distinguish various chiral molecules in the presence of each other as well as distinguish optical rotation from birefringence. Note that you can get nearly double the rotational change as you go from green at 532 nm to the red at 670 nm.

 
For polarimetry to be used as a noninvasive technique for any chiral molecule and in particular for blood glucose monitoring, the signal must be able to pass from the source, through the body and to a detector without total depolarization of the beam. Because the skin possesses high scattering coefficients, maintaining polarization information in a beam passing through a thick piece of tissue (i.e., 1 cm), which includes skin, would not be feasible. Tissue thicknesses of < 4 mm, which include skin, may potentially be used, but the polarimetric sensing device must be able to measure millidegree rotations in the presence of > 95% depolarization of the light due to scattering from the tissue. As an alternative to transmitting light through the skin, several investigators have suggested the eye, as depicted in Figure 3Citation , as a site for detection of in vivo glucose concentrations (Cameron et al. 2000Citation , Cameron and Coté 1996Citation , Coté et al. 1992Citation , Goetz 1992Citation , Gough 1982Citation , King et al. 1994Citation , March et al. 1982Citation , Rabinovitch et al. 1982Citation ). For instance, an observed rotation of ~4.562 millidegrees per optical pass can be expected for a normal blood glucose level of 5.55 mmol/L (100 mg/100 mL), given a specific rotation of glucose at a wavelength of 633 nm of 45.62°/(dm g/ml) and thickness of 1 cm. A path length on the order of 1 cm is considered, because this is the approximate width of the average anterior chamber of a human eye.



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  		Figure 3. Polarimetric sensing is potentially better facilitated using a beam path through the anterior chamber of the eye as shown, because this is a clear optical media with a reasonable path length (1 cm), which, unlike skin, does not depolarize the light beam (McNichols and Coté 2000Citation ).

 
The first optical glucose-sensing approach using polarization rotation of light through the eye was described by March and co-workers (March et al. 1982Citation , Rabinovitch et al. 1982Citation ). The approach used a single wavelength amplitude-based technique. In this work, it was found that the glucose concentration in the aqueous humor was two orders of magnitude higher than any other optically active substances for the rhesus monkey animal model. In addition, limited data were taken to show that the measurement of glucose concentration of the aqueous humor of the eye correlated well with blood glucose levels, with a minor time delay (on the order of minutes), in rabbit models. Coté et al. (1992Citation ) developed an open-loop phase technique to increase the signal-to-noise ratio of the sensor and theoretically account for potential noise sources anticipated in the in vivo system. Goetz (1992Citation ) presented results showing millidegree accuracy in vitro, comparable to 0.28 mmol/L (5 mg/dl) of glucose, using a closed-loop approach similar to that of March et al. (1982Citation ). King et al. (1994Citation ) developed a closed-loop system using a Pockels cell, which, when used with a multiwavelength light source, could potentially compensate for birefringence of the polarized light due to the cornea and interference due to other optically active components. Cameron and co-workers (Cameron et al. 2000Citation , Cameron and Coté 1996Citation ) developed a digital feedback approach, which increased the robustness and repeatability of previous polarimetric systems and demonstrated measurement of glucose in aqueous cell culture media (Coté and Cameron 1997Citation ). An article by Chou et al. (1998Citation ) implied that the time lag between blood and aqueous humor was on the order of 30 min; however, a more careful study by Cameron et al. (2000Citation ) showed the time lag to be < 5 min comparable to the original work of March and co-workers (March et al. 1982Citation , Rabinovitch et al. 1982Citation ).

The key technological problem to be overcome before this approach is viable for glucose monitoring in the eye is the confounding rotation due to corneal birefringence and the variation in this rotation with eye motion artifact. As shown in Equation 1 , the rotation is directly proportional to the path length and, thus, it is critical that this length be determined or at least kept constant for each individual subject regardless of the sensing site. This can potentially be overcome in two ways. The first is to use multiple polarization states (linear polarization at ± 45 degrees and left and right circular polarization) to separate birefringence from chiral rotation as described by the full Jones or Mueller matrix theory (McNichols and Coté 1998Citation ). Finally, there is the possibility that multiple wavelengths could be used because the rotation due to glucose will vary with wavelength differently than the birefringence.


   Raman spectroscopy
TOP
 ABSTRACT
 INTRODUCTION
 Absorption spectroscopy
 Polarimetry
 Raman spectroscopy
Fluorescence monitoring
 REFERENCES
 
Raman spectroscopy has become a powerful tool for studying a variety of biological molecules including proteins, enzymes and immunoglobulins, nucleic acids, nucleoproteins, lipids and biological membranes, and carbohydrates (Carey 1982Citation , Tu 1982Citation ). However, because of its potential applicability to biological problems, specifically biochemical sensing, Raman spectroscopy is now being studied as a potential noninvasive monitoring approach (Berger et al. 1997Citation , Goetz et al. 1995Citation , Lambert et al. 1998Citation , Tarr 1991Citation , Wang et al. 1993Citation , Wicksted et al. 1994Citation ). The optical technology and use of multivariate statistical techniques (Berger et al. 1997Citation , Goetz et al. 1995Citation , Lambert et al. 1998Citation ) have only recently advanced to the point that near real-time and quantifiable glucose measurements using Raman spectroscopy is realizable (Coté 1997Citation ).

The phenomenon of Raman scattering is observed when monochromatic radiation is incident upon optically transparent (negligible absorption) media. In addition to the transmitted light, a portion of the radiation is scattered. Most of the light that is scattered is elastically scattered at the same wavelength; however, some of the incident light of frequency wo exhibits inelastic scatter with frequency shifts ± wm, which is associated with transitions between rotational, vibrational and electronic levels (Long 1977Citation ). In general, the intensity and polarization of the scattered radiation are dependent upon the position of observation relative to the incident energy. Most studies use the Stokes type of scattering bands, which correspond to the wo-wm scattering. Therefore, the Raman bands of interest are shifted to longer wavelengths relative to the excitation wavelength. An example of this is depicted in Figure 4Citation (Goetz 1999Citation ) for water-subtracted glucose. Note that the background sample autofluorescence has also been removed.



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  		Figure 4. Typical Stokes Raman spectrum is shown for glucose as a vibrational intensity versus shift in wave numbers from the 514-nm excitation wavelength. The water background has been subtracted and the background sample autofluorescence has also been removed for this nearly saturated glucose concentration (Goetz 1999Citation ).

 
As with IR spectroscopic techniques, Raman spectra can be used to identify molecules because these spectra are characteristic of variations in the molecular polarizability and dipole moments. Raman spectroscopy can be considered as complementary to absorption spectroscopy because neither technique alone can resolve all of the energy states of a molecule; in fact, for certain molecules, some energy levels may not be resolved by either technique. Due to the anharmonic oscillator model for dipoles, overtone frequencies exist in addition to fundamental vibrations. It is an advantage of Raman spectroscopy that the overtones are much weaker than are the fundamental tones, thus, contributing to simpler spectra compared with absorption spectroscopy.

One advantage to using Raman spectroscopy in biological investigations is that the Raman spectrum of water is weak, which, unlike IR spectroscopy, only minimally interferes with the spectrum of the solute, and, thus, the spectrum can be obtained from aqueous solutions. However, the Raman signal is also weak and only recently, with the replacement of slow photomultiplier tubes with faster charged coupled device arrays as well as the manufacture of higher power NIR laser diodes, has the technology become available to allow researchers to consider the possibility of distinguishing tissue types and quantifying blood chemicals in near real time (Coté 1997Citation ). In current investigations (Berger et al. 1997Citation , Goetz et al. 1995Citation , Lambert et al. 1998Citation , Tarr 1991Citation , Wang et al. 1993Citation , Wicksted et al. 1994Citation ), the eye has been suggested as a site for glucose concentration measurements using Raman spectroscopy. The reason for this selection is to minimize the high fluorescence background, which is incurred in heavily vascularized tissue, due to the high concentration of proteins and other fluorescent components. Investigators have applied statistical methods such as partial least squares for estimation of biochemical concentrations from Raman spectra (Berger et al. 1997Citation , Goetz et al. 1995Citation , Lambert et al. 1998Citation ). These statistical methods combined with more affordable instrumentation give Raman the potential to also be a viable noninvasive glucose sensor.

There are disadvantages to using the eye for Raman spectroscopy studies, with the primary concern being the laser excitation powers. The power must be kept low to prevent injury, but this significantly reduces the signal-to-noise ratio. In addition, in other tissues, especially those with blood, a large background fluorescence overwhelms the Raman signal. Instrumentation to excite in the NIR wavelength range has also been proposed to overcome this problem because the fluorescence component falls off with increasing wavelength. Excitation in the NIR region also offers longer wavelengths, which pass through larger tissue samples with lower absorption and scatter than other spectral regions such as visible or ultraviolet. However, in addition to fluorescence falling off with wavelength, the Raman signal also falls off to the fourth power as wavelength increases. Thus, there is a tradeoff between minimizing fluorescence and maintaining the Raman signal. In addition, like IR and NIR absorption, to quantifiably determine the inherently low concentrations of glucose in vivo one also must account for the presence of different chemicals that yield overlapping Raman signals (Coté 1997Citation ).


   Fluorescence monitoring
TOP
 ABSTRACT
 INTRODUCTION
 Absorption spectroscopy
 Polarimetry
 Raman spectroscopy
 Fluorescence monitoring
REFERENCES
 
Several reports of fluorescence-based detection and assays have also appeared in the literature for a variety of chemicals including folate (Day and Gregory 1981Citation , Gregory et al. 1984Citation , Vahteristo et al. 1996Citation ), retinal binding protein for vitamin A status (Craft et al. 2000Citation , Craft 2000Citation ) and glucose. The fluorescence approach is different from the other optical approaches described in that it requires the sample be in contact with the sensor and, thus, cannot be developed as a totally noninvasive technology but rather requires fluid extraction or an implant. For folate and vitamin A, the fluorescence approaches have been used in the central laboratory as a process that includes high performance liquid chromatography, and only recently have technologies for monitoring the vitamin A and glucose levels been investigated for development into a field instrument (Ballerstadt and Schultz 1997Citation , Craft 2000Citation , Mansouri and Schultz 1984Citation , McShane et al. 2000Citation , Meadows and Schultz 1993Citation , Lakowicz and Maliwal 1993Citation , Rosenzweig and Kopelman 1996Citation , Russell et al. 1999Citation , Schaffar and Wolfbeis 1990Citation , Schultz et al. 1982Citation , Tolosa et al. 1997Citation ).

A number of novel fluorescence-based techniques for glucose sensing have been presented. Unlike many of the noninvasive optical approaches being investigated, because the fluorescent glucose-sensing approaches have to be in contact with the sample, they have the advantage of being highly specific to the glucose. Because of the high sensitivity and specificity, research groups (McDonald and Kopelman 1998Citation , Rolinski et al. 2000Citation ) are also looking into this technology for monitoring interstitial fluid that is extracted from the skin (Klonoff 1998Citation ). The sensitivity of fluorescence is necessary because this fluid has a glucose concentration range that is orders of magnitude smaller (micromolar) than that of blood glucose. Those fluorescent approaches that seem to have demonstrated the most promise generally fall into two categories: the glucose oxidase (GOX)-based sensors and the affinity-binding sensors (McNichols and Coté 2000Citation ). In the first category, the sensors use the electroenzymatic oxidation of glucose by GOX to generate an optically detectable glucose-dependent signal. Several methods for optically detecting the products of this reaction and, hence, the concentration of glucose driving the reaction have been devised (McNichols and Coté 2000Citation , Rosenzweig and Kopelman 1996Citation , Schaffar and Wolfbeis 1990Citation ). All of these approaches have been explored with short-term use in mind because they all use indwelling fiber optic probes. The primary drawback to GOX-based sensors is that their response depends not only on glucose concentration, but also on local oxygen tension (McNichols and Coté 2000Citation ).

The affinity-based sensors do not depend on local oxygen; however, many of the earlier affinity-binding techniques were investigated for short-term use because they required indwelling probes (Ballerstadt and Schultz 1997Citation , Mansouri and Schultz 1984Citation , Meadows and Schultz 1993Citation , Lakowicz and Maliwal 1993Citation , Schultz et al. 1982Citation ). The most prominent fluorescence approaches have exploited the concanavalin A (Con A) affinity for polysaccharides. In initial work by Shultz and co-workers (Mansouri and Schultz 1984Citation , Schultz et al. 1982Citation ), immobilized Con A was used as a receptor for competing species of fluorescein isothiocyanate (FITC)-labeled dextran and glucose. Increased concentrations of glucose displace FITC-dextran from Con A sites, thus, increasing the concentration and fluorescence intensity of FITC-dextran in the visible field. In more recent work, this group and others (Ballerstadt and Schultz 1993Citation , Russell et al. 1999Citation , McShane et al. 2000Citation ) have exploited the phenomenon of fluorescence resonance energy transfer (FRET), whereby an acceptor in close proximity to a fluorescent donor can induce fluorescence quenching in the latter as shown in Figure 5Citation . In most of the reported literature, glucose detection based upon FRET was between FITC-bound dextran and tetramethylrhodamine isothiocyanate (TRITC)-bound Con A. Meadows and Schultz (1993Citation ) showed that when TRITC-Con A is added to a solution of FITC-dextran, the binding of the dextran to the Con A results in the required molecular proximity (54 Å) for FRET-based quenching to occur. Mansouri and Schultz (1984Citation ) reported that glucose concentrations could be measured in aqueous solutions by a proportional change in FITC fluorescence. The technique was both very specific to glucose and sensitive to glucose concentration, without interference from other constituents frequently found in blood plasma. An indwelling fiber optic probe incorporating this chemistry was successfully tested in a canine model (Mansouri and Schultz 1984Citation ).



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  		Figure 5. Pictorial depiction of the phenomenon of FRET. A, The excitation and emission spectra for both the FITC and TRITC fluorephores are shown and, as depicted, the emission spectra of FITC overlaps with the excitation of TRITC. B, Cartoon characters for the glucose, TRITC-labeled Con A and FITC-labeled dextran. C, This shows the no glucose case in which the FITC-labeled dextran is bound to the TRITC-labeled Con A so that the two fluorephores are in close proximity, thus producing a quenching of the FITC emission peak. D, In the presence of glucose the FITC-labeled dextran is displaced, is no longer in close proximity to the TRITC-labeled Con A, and, therefore, the emission peak of FITC would rise.

 
Lakowicz and co-workers (Lakowicz and Maliwal 1993Citation , Tolosa et al. 1997Citation ) have developed similar fluorescent assays for glucose, based on phase-modulation fluorimetry and Con A-dextran moieties. Similar to the work of Schultz and colleagues, the investigations were conducted in an aqueous solution. The authors used fluorescence lifetime techniques and FRET to indirectly measure glucose concentrations. They have more recently devised a similar sensor in which ruthenium-Con A and maltose-insulin-malachite green are used as the reagents. Increased glucose concentration causes an increase in both fluorescence intensity and fluorescence lifetime of the ruthenium dye (McNichols and Coté 2000Citation ). Although they suggested using a polymeric acceptor to shield the glucose sensor behind a glucose-permeable barrier, to date most of the research involving fluorescence detection of glucose has been limited to aqueous solutions and has not addressed the in vivo issue of encapsulating the assay chemistry (Russell et al. 1999Citation ).

Our group has previously reported on results from one such encapsulation system, consisting of alginate-poly-L-lysine spheres that encapsulated glucose-sensitive, fluorescently labeled macromolecules (Russell et al. 1998Citation ). Similarly, constructed microcapsules have been demonstrated to be highly permeable to water and low-molecular-weight compounds (Tanaka et al. 1984Citation ). Fluorescence intensity of FITC emission from these spheres was shown to be glucose responsive, but the dextran displacement due to competitive glucose binding was not reversible within a reasonable timescale. In addition, the microcapsules experienced leakage of TRITC-succinyl-Con A and FITC-dextran (the extent of which was dependent upon the molecular weight of the poly-L-lysine used), and they lacked structural rigidity once the interior alginate had diffused out of the microcapsule.

Most recently, this group has reported the use of poly(ethylene glycol) (PEG) particles to encapsulate the FRET assay (Russell et al. 1999Citation ). This polymer has been reported to have numerous properties beneficial for use in vivo and may potentially overcome many of the drawbacks of the alginate/poly-L-lysine system. A highly water-soluble hydrogel is formed upon cross-linking. PEG-based polymers have previously been evaluated for in vivo use as protein drug delivery devices, for postoperative adhesion prevention and for biocompatible membranes over electrochemical sensors (Pathak et al. 1992Citation , Sawhney et al. 1994Citation , West and Hubbell 1995Citation ). PEG-based coatings were reported to improve the biocompatibility of implanted glucose sensors, without being glucose mass-transfer limiting (Quinn et al. 1995Citation ). The stability and solubility of numerous proteins are reportedly increased upon conjugation to PEG (Delgado et al. 1992Citation ). Con A has been conjugated to monomethoxy PEG-5000 while retaining its sugar-binding abilities (Mattiasson and Ling 1980Citation ). In our work (Russell et al. 1999Citation ) it was reported that it is possible to create a microparticle-based fluorescent glucose assay system potentially suitable for subcutaneous implantation and the optimization of the glucose response through control of the Con A to dextran ratio within the gel.

Overall, the advantage of fluorescence sensors is that they can be made highly sensitive and highly specific to the analyte of interest and eliminate many of the potential interferences common with other techniques. However, to obtain that specificity they suffer the serious drawback that in all cases exogenous chemicals are required, which must be introduced to the body or sample. Additionally, long-term studies are required to assess the extent to which these chemicals may be susceptible to degradation over time via consumption, photo-bleaching or denaturation (McNichols and Coté 2000Citation ).

The field of advanced optical approaches for biomedical applications, and, in particular, technology aimed at noninvasive and minimally invasive monitoring, is still in its infancy. Many of the technologies described above are at the early bench-top preprototype stage. Indeed, the production of a less invasive glucose monitor is still elusive; however, more and more of these noninvasive optical technologies, including those for hemoglobin, hematocrit and now bilirubin are making it through clinical trials and into the marketplace. Overall, due to the extreme interest by the government, private industry and general population in the development of smaller, more portable, less invasive devices, optical sensing promises to be an exciting area of development for many years to come.


   FOOTNOTES
 
1 Presented at the symposium "Non- or Minimally-Invasive Technologies for Monitoring Health and Nutritional Status in Mothers and Young Children" held August 7–8, 2000 at the Children’s Nutrition Research Center, Baylor College of Medicine, Houston, TX. This symposium was sponsored by Baylor College of Medicine Office of Analysis, Nutrition and Evaluation of the Food and Nutrition Service of the U.S. Department of Agriculture. The proceedings of this symposium are published as a supplement to The Journal of Nutrition. Guest editors for the supplement publication were Dennis M. Bier, Baylor College of Medicine, Houston, TX and D’Ann Finley, University of California, Davis, CA. Back

2 Supported by the National Science Foundation (Grant BES-9908439), National Aeronautics and Space Administration (Grant NCC8-169) and the Advanced Research Program of the Texas Higher Education Coordinating Board. Back

4 Abbreviations used: IDD, iodine deficiency; IR, infrared; NIR, near infrared; OPS, orthogonal polarization spectral; GOX, glucose oxidase; Con A, concanavalin A; FITC, fluorescein isothiocyanate; FRET, fluorescence resonance energy transfer; TRITC, tetramethylrhodamine isothiocyanate; PEG, poly(ethylene glycol). Back


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 Absorption spectroscopy
 Polarimetry
 Raman spectroscopy
 Fluorescence monitoring
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