Optical Non-Invasive Glucose Monitoring Using Aqueous Humor: A Review

Abstract

This review explores optical technologies for non-invasive glucose monitoring (NIGM) using aqueous humor (AH) as media, addressing the limitations of traditional invasive methods in diabetes management. It analyzes key techniques such as Raman spectroscopy, polarimetry, and mid- and near-infrared spectral methods, highlighting their respective challenges, alongside emerging hybrid approaches like photoacoustic spectroscopy and optical coherence tomography. Crucially, the practical realization of these optical methods for portable NIGM hinges on advanced instrumentation. Therefore, this review also details progress in compact NIR spectrometers. While conventional systems often lack suitability, significant advancements in on-chip technologies-including miniaturized dispersive spectrometers and various on-chip Fourier transform systems (e.g., spatial heterodyne, stationary wave integral, and temporally modulated FT systems)-utilizing integration platforms like SOI and SiN are promising. Such innovations offer the potential for high spectral resolution, large bandwidth, and miniaturization, which are essential for developing practical AH-based NIGM systems to improve diabetes care.

Keywords: Raman spectroscopy; glucose biosensor; infrared; non-invasive; optics; polarization; spectrometer; spectroscopy.

Figure 1

Aqueous humor drainage in healthy eyes through the trabecular meshwork pathway (blue arrows) and uveoscleral pathway (pink arrows) is demonstrated. Adapted with permission [28]. Copyright 2023, ScienceDirect.

Figure 2

(A) Jablonski energy diagram illustrating the transitions involved during infrared absorption, Rayleigh, Raman Stokes, anti-Stokes, and resonance Raman scattering as reported by Geraldes. Adapted with permission [44]. Copyright 2020, MDPI. (B) Molecular interaction with light. Adapted from Ref. [45].

Figure 3

Raman spectra of D-glucose solutions at 22 and 50% (w/w) concentration. Adapted with permission [46]. Copyright 1980, ScienceDirect.

Figure 4

Laser light delivery probe for favorable collection of the Raman photons at 90° scattering geometry scanning the anterior chamber of the eye (ground plane vision). The laser beam inside the anterior chamber is delivered perpendicularly to the optical axis of the eye for safety reasons and Raman signal optimization. Adapted with permission [54]. Copyright 2006, John Wiley and Sons.

Figure 5

(A) Photo of the folded SERS-disk-mounted implant. (B) Photo of the implant inserted inside the anterior chamber of an ex vivo rabbit eye. (C) Schematic illustration of the glucose measurement made using the SERS implant inside the anterior chamber of an ex vivo rabbit eye. (D) Clarke-error-grid analysis of the glucose measurements using our Raman-mode-constraining approach in ex vivo rabbit eyes. All the data measured by the implanted sensor were located in region A of the Clarke error grid, which is labeled as red dots. Adapted with permission [55]. Copyright 2018, American Chemical Society.

Figure 6

(A) Schematic of mμSORS system. mμSORS setup (top). (B) CEG of predictions from the PLS regression model in the cross-validation. Adapted with permission [43]. Copyright 2025, Springer Nature.

Figure 7

An example of plane-polarized light. Adapted from Ref. [56].

Figure 8

(A) Typical setup for polarimetric in vivo measurements. (B) Scheme of artificial eye. (C) Laboratory setup. Adapted with permission [65]. Copyright 2004, Springer Nature.

Figure 9

Optical access to the human eye. (A) Tangential path (solid beam path). The dashed beam-path indicates the first possible entrance condition. (B) New scheme applying Brewster reflection off the lens. (C) Diagram of the glucose sensor. (D) Measurement of the rotation of light polarization for different known glucose samples. Each measurement was repeated 50 times for statistical accuracy. The vertical error bars show the standard deviation of each measurement. The correlation coefficient of the linear regression amounts to R² = 0.986. Adapted with permission [66]. Copyright 2004, SPIE.

Figure 10

(A) The polarimetric experimental setup employed for the sensing glucose concentration in the eye. DAQ, data acquisition; GPIB, general purpose interface bus. (B) The coupling of the glucose-sensing optical signal through the aqueous humor of a NZW rabbit. (C) Clarke error grid showing 41 points, with 93% in region A and the remainder in region B. The reference concentrations are from a handheld glucometer (One Touch Ultra, Lifescan Inc., Milpitas, CA, USA), except for circled points. Circled points additionally have YSI-measured concentrations as reference (red points) and show the predicted values are closer to the YSI measurements than the handheld meter. Adapted with permission [67]. Copyright 2011, Sage.

Figure 11

(A) Schematic of a Sagnac interferometer, where light from counterpropagating paths is combined. For a stationary interferometer with no sample, the optical paths are identical. Optical rotation, however, introduces an optical path difference between the counterpropagating beams. The modulating retarder, which continuously changes the optical rotation from 0 to 360 deg, produces a cosinusoidal interference signal at the detector. An additional optical rotation from the eye results in a phase difference between the reference and sample signals. (B) The optical path of the sample and reference beam. Adapted from [69].

Figure 12

Schematic of a traditional dispersive spectrometer. Adapted from [84].

Figure 13

(A) A basic quantum dot spectrometer is composed of a set of CQD absorptive filters and a light detector. (B) Instead of measuring the light intensities using one detector and one filter at a time, the CQD spectrometer measures the set of intensities in parallel by using an array detector, with each detecting element dedicated to one CQD filter, all of which are integrated into a CQD filter array. Adapted with permission [85]. Copyright 2015, Springer Nature.

Figure 14

Schematic of a Fourier transform spectrometer. Adapted from Ref. [87].

Figure 15

Schematic of planar waveguide on-chip SHS formed by an array of imbalanced MZIs. Adapted with permission [91]. Copyright 2021, John Wiley and Sons.

Figure 16

Schematic of grating-assisted SWIFTS. Adapted with permission [93]. Copyright 2017, Optica Publication Group.

Figure 17

(A) Conceptual schematic of the proposed ultra-broadband spectrometer featuring multiple stages of micro-ring resonators on a single bus. The inset shows the mode field distribution on the bus waveguide. (B) Photograph of the miniaturized near-infrared spectrometric sensor. The insets show the optical sampling interfaces for measuring reflection and transmission spectra, respectively. MCU, microcontroller unit. DAC, digital-to-analog converter. (C) Fiber collimator of the spectrometer. (D) The stage for the cuvette and fiber collimator. Adapted with permission [97]. Copyright 2024, Springer Nature.