Omar S. Khalil

Monitoring Blood Glucose Changes in Cutaneous Tissue by Temperature-modulated Localized Reflectance Measurements

BACKGROUND Most proposed noninvasive methods for glucose measurements do not consider the physiologic response of the body to changes in glucose concentration. Rather than consider the body as an inert matrix for the purpose of glucose measurement, we exploited the possibility that noninvasive measurements of glucose can be approached by investigating their effects on the skins thermo-optical response. METHODS Glucose concentrations in humans were correlated with temperature-modulated localized reflectance signals at wavelengths between 590 and 935 nm, which do not correspond to any near-infrared glucose absorption wavelengths. Optical signal was collected while skin temperature was modulated between 22 and 38 degrees C over 2 h to generate a periodic set of cutaneous vasoconstricting and vasodilating events, as well as a periodic change in skin light scattering. The method was tested in a series of modified meal tolerance tests involving carbohydrate-rich meals and no-meal or high-protein/no-carbohydrate meals. RESULTS The optical data correlated with glucose values. Changes in glucose concentrations resulting from a carbohydrate-rich meal were predicted with a model based on a carbohydrate-meal calibration run. For diabetic individuals, glucose concentrations were predicted with a standard error of prediction <1.5 mmol/L and a prediction correlation coefficient 0.73 in 80% of the cases. There were run-to-run differences in predicted glucose concentrations. Non-carbohydrate meals showed a high degree of scatter when predicted by a carbohydrate meal calibration model. CONCLUSIONS Blood glucose concentrations alter thermally modulated optical signals, presumably through physiologic and physical effects. Temperature changes drive cutaneous vascular and refractive index responses in a way that mimics the effect of changes in glucose concentration. Run-to-run differences are attributable to site-to-site structural differences.

Near-infrared thermo-optical response of the localized reflectance of intact diabetic and nondiabetic human skin.

We observed a difference in the thermal response of localized reflectance signal of human skin between type 2 diabetics and nondiabetics. We investigated the use of this thermo-optical behavior as the basis for a noninvasive method for the determination of the diabetic status of a subject. We used a two-site temperature differential method, which is predicated upon the measurement of localized reflectance from two areas on the surface of the skin. Each of these areas is subjected to a different thermal perturbation. The response of localized reflectance to temperature perturbation was measured and used in a classification algorithm. We used a discriminant function to classify subjects as diabetic or nondiabetic. In a prediction set of twenty-four noninvasive tests collected from six diabetic and six nondiabetic subjects, the sensitivity ranged between 73 and 100%, and the specificity ranged between 75 and 100%, depending on the thermal conditions and the probe-skin contact time. The difference in the thermo-optical response of the skin of the two groups is explained in terms of a difference in the response of cutaneous microcirculation, which is manifested as a difference in the near-infrared light absorption. Another factor is the difference in the temperature response of the scattering coefficient between the two groups, which may be caused by cutaneous structural differences induced by nonenzymatic glycation of skin protein fibers, and possibly by the difference in blood cell aggregation.

Calculated calibration models for glucose in cutaneous tissue from temperature modulation of localized reflectance measurements (Invited Paper)

We used a temperature controlled localized reflectance optical probe to test the effect of distance source detector distance, temperature and wavelength on the calibration of localized reflectance signals versus glucose concentration. Successful calibration models were established. The data suggests that the interplay of source-detector distances, wavelengths and temperature may lead to selecting a defined subcutaneous volume, where the signal can correlate better with glucose.

Temperature dependence of optical properties of in-vivo human skin

We examined the effect of temperature change on the diffuse reflectance of the skin. The optical probe consists of several optical fibers located at the center of a thermal electric device, which controls the temperature at the surface of the skin in contact. Measured light reflectance profile between 0.4-1.9 mm was fitted to a mathematical model obtained by Monte Carlo simulation, and absorption and scattering coefficients were estimated. The reduced scattering coefficient of the forearms consistently showed a positive relationship with temperature between 22 and 42 degree(s)C. This dependency was reversible without apparent delay. The same effect was observed on ex vivo pigskin. It is possible to explain the positive instantaneous dependency of scattering on temperature by the change of the refractive index of intercellular fluid. The scattering coefficient of the subcutaneous fat of pigskin showed a negative dependence on temperature. This negative dependency of scattering can be attributed to a phase change as a function of temperature. The absorption coefficient in vivo also increased with temperature from 22 to 42 degree(s)C. But the change was not immediately reversible after temperature reached 40 degree(s)C. This relationship was similar to the nonlinear increase in blood perfusion observed in laser Doppler measurements.

Differences in thermal optical response between intact diabetic and nondiabetic human skin

We observed a difference in the thermal response of localized reflectance signal of human skin between type-2 diabetic and non-diabetic volunteers. We investigated the use of this thermo-optical behavior as a basis for a non-invasive method for the determination of the diabetic status of a subject. We used a two-site temperature differential method, which is predicated upon the measurement of localized reflectance from two areas on the surface of the skin, each of these areas is subjected to a different thermal perturbation. The response of skin localized reflectance to temperature was measured and used in a classification algorithm. We used a discriminant function to classify subjects as diabetics or non-diabetics. In a prediction set of 24 non-invasive tests collected from 6 diabetics and 6 non-diabetics, the sensitivity ranged between 73% and 100%, and the specificity ranged between 75% and 100%, depending on the thermal conditions and probe-skin contact time. The difference in thermo-optical response of the skin of the two groups may be explained in terms of difference in response of cutaneous microcirculation to temperature, which is manifested as a difference in the near infrared light absorption and scattering. Another factor is the difference in the temperature response of the scattering coefficient between the two groups, which may be caused by cutaneous structural differences induced by non-enzymatic glycation of skin protein fibers, and/or by the difference in blood cell aggregation.

Non-invasive determination of concentration of compounds in strongly absorbing biological tissue

We describe a non-invasive method for the determination of optical parameters of highly scattering media, such as biological tissue. An advantage of this method is that it does not rely on diffusion theory, thus it is applicable to strongly absorbing media and at small source-detector separations. Monte Carlo simulations and phantom measurements are used to illustrate the achievable accuracy of the system. The method was applied to non-invasive in- vivo tracking of haemoglobin concentration in biological tissue. The results correlated well to clinically determined Hb concentrations.

Noise contribution to the correlation between temperature-induced localized reflectance of diabetic skin and blood glucose.

We used the effect of temperature on the localized reflectance of human skin to assess the role of noise sources on the correlation between temperature-induced fractional change in optical density of human skin (DeltaOD(T)) and blood glucose concentration [BG]. Two temperature-controlled optical probes at 30 degrees C contacted the skin, one was then cooled by -10 degrees C; the other was heated by +10 degrees C. DeltaOD(T) upon cooling or heating was correlated with capillary [BG] of diabetic volunteers over a period of three days. Calibration models in the first two days were used to predict [BG] in the third day. We examined the conditions where the correlation coefficient (R2) for predicting [BG] in a third day ranked higher than R2 values resulting from fitting permutations of randomized [BG] to the same DeltaOD(T) values. It was possible to establish a four-term linear regression correlation between DeltaOD(T) upon cooling and [BG] with a correlation coefficient higher than that of an established noise threshold in diabetic patients that were mostly females with less than 20 years of diabetes duration. The ability to predict [BG] values with a correlation coefficient above biological and body-interface noise varied between the cases of cooling and heating.

Longitudinal 3-week tracking of blood glucose concentration from thermo-optical response measurements on human skin

We designed a dual-sensor instrument for measuring optical signals from the arms of human volunteers. The instrument had two temperature-controlled localized reflectance optical probes. Each probe had one illumination fiber and four detection fibers at different source-detector distances. The two probes were maintained at 30 °C. Thirty seconds after contact with the skin one was heated and the other was cooled at the same rate. The effect of heating and cooling on the signal was measured and correlated with blood glucose concentration. The measurements were performed 3 to 5 times a day for each volunteer over the span of three weeks. The data points from the first two weeks were used to establish a calibration model for each volunteer, which was used to predict glucose values from the third week optical data. Successftil calibration was possible for two of the three volunteers.