Motivation
The term macular pigment (MP) is a collective term for three carotenoids, of purely dietary origin, found at the central part of the ocular fundus. Its role in ocular function is thought to be twofold: first, acting as an optical filter, protecting the photoreceptors from the phototoxic effects of high-energy blue light, and, second, as an anti-oxidant, quenching free radicals in the retina. Studies have shown correlation between the macular pigment optical density (MPOD) and age-related macular degeneration, one of the leading cause of blindness in the western world. Therefore, MP can act as an early warning sign for the disease. Finally, due to its relation to diet and other lifestyle parameters, such as smoking, obesity, etc it can be used as a general biomarker of how healthy one’s lifestyle is.
Despite the potential importance of the MP, it has not yet been part of the standard eye exam. The reason for that is that there are currently only a small number of instruments that can measure it and they are bulky and expensive, not accurate and time consuming. In this project, we developed an optical system that uses an innovating method, based on
- the illumination of the ocular fundus with dual-wavelength, structured light using LED sources.
- the collection of the reflected signal with a high-speed and high-sensitivity photodetector.
- the processing of the harvested signal using analysis in the frequency domain.
This new technique allowed the development of an optical system, built specifically for the measurement of MPOD. The use of LEDs, a single photodetector and low-cost optics allows for the construction of an overall low-cost instrument that can carry out the measurement accurately and within a few seconds.
During the project, a compact version of the laboratory prototype was designed and built. The optics and the electronic parts of the system were redesigned. A user-friendly graphical user interface was developed in order for the instrument to be easily used by clinicians with very short training. A first validation of the clinical use of the instrument on a cohort of healthy subjects was carried out successfully in a clinical environment and the results were presented at conferences. In parallel, we worked on the development of a hand-held, stand-alone instrument featuring a raspberry-Pi and an on-board touch screen that could further reduce the portability, usability and significantly lower the cost of the instrument, making it apt for wider use.
Currently, there is only a handful of instruments used to measure MPOD. There are two methods to measure MPOD in vivo: one phychophysical, where the subject’s input is required during the measurement and the optical, where no input is required by the subject. Both methods use the spatial and spectral properties of the macular pigment and the ocular fundus.
There are several different psychophysical techniques used for the measurement of MPOD, but the most used one is based on Heterochromatic Flicker Photometry (HFP). In this technique the subject is presented with a series of flickering light fields and the subject’s task it to determine where the flickering becomes minimum or vanished completely. There are a number of commercial devices such as the MPSII (Elektron Eye Technology, Cambridge, UK) or the MPS 9000 (Tinsley Ophthalmic Instruments, Redhill, Surrey, UK). The technique is repeatable but makes a number of assumptions that can often lead to wrongly estimating the value of MPOD. Furthermore, the test itself is not easy for all subjects and can also be time consuming.
Optical methods illuminate the fundus with light of different wavelengths and analyse the reflected (or re-emitted in some methods) light from the fundus. These methods include reflectometry, autofluorescence and Raman spectroscopy. Currently, the only commercial instrument using this method is the fundus camera Visucam 200 (Carl Zeiss Meditec AG, Jena, Germany), which offers a module for the measurement of macular pigment. The instrument provides a quick measurement, yet it is not considered to be fully proven, the instrument is bulky and expensive, and therefore it is not considered apt for wide clinical use for MPOD measurements.
There is no golden standard in the measurement of MPOD, although it has been in the spotlight of research for more than two decades.
Methods
The project involved the development of an optical instrument for the in-vivo, quick, reliable and accurate measurement of MPOD. The instrument is based on the reflectometry method where light is delivered on the retina and the reflected light is captured by a light sensor, typically a camera. In the prototype instrument, LED sources of specific spectral, spatial and temporal properties were used and the reflected signal was captured using a high-speed, high-sensitivity photodetector. The instrument features a number of innovative elements:
- a specific spatial distribution of the source allowing to encode the spatial information in the illumination.
- the use of a photodetector to capture the reflected signal.
- the temporal modulation of the sources that allowed the analysis of the recorded signal in the frequency domain, hence the method was named Frequency Imaging (FI).
The advantage of using a photodetector is two-fold: on the one hand the high-sensitivity compared to the traditional camera allowed fast, low-noise measurements with minimal retinal exposure to light, limiting the actual measurement to less than 200ms. A measurement below 200ms is faster that the pupil reflex, and therefore there is no need for medically induced pupil dilation. The latter means that the measurement does not need to be performed by an ophthalmologist but, in most places, but non-medical health care professionals. Furthermore, since the analysis of the recorded is done in the frequency domain, the instrument is not affected by ambient light, leading to a more reliable measurement. The optical design and was such that the instrument was easy to construct and align, and reduce its cost, making large scale production possible.
The instrument was based on a laboratory prototype and an associated patented method. The main focus of the project was to redesign the laboratory instrument and adapt the associated method, to be apt for clinical use and a potential scale up. As such, the first step of the project was to redesign the electronics of the instrument and more specifically the illumination (LEDs sources and drivers) and the imaging (photodetector and driver) electronics. Also, the optics were redesigned, focusing in reducing the form factor and the complexity of the instrument, and hence, the cost, without sacrificing its performance. The redesigned instrument was built on an optical breadboard. Furthermore, a user-friendly graphical user interface (GUI) was developed; the GUI was built so that it would be used by a person not involved in the development of the instrument and with limited knowledge of the method details. Subsequently a set of measurements was carried out on a healthy cohort of 51 volunteers to test the prototype instrument outside the laboratory environment. The measurements were carried out by a non-specialist, after a short training in the use of the instrument. The results were presented at the Association for Research in Vision and Ophthalmology (ARVO) meeting 2020.
Parallelly to the development of breadboard version of the instrument, a fully portable, stand-alone instrument was designed, and a first prototype is being developed. The instrument has the same principle of operation but it uses custom electronics to carry out the measurement and the processing of the signal. Furthermore, the optical design was refined to further reduce the instrument’s form factor, towards a handheld instrument. A single-board computer (raspberry Pi) is used to fully control the instrument, featuring a mini TFT touch screen. A pupil tracking algorithm was developed and used in the mini-instrument, in order to assist with the alignment of the subject during the measurement. The mini-instrument was presented at the ARVO – Imaging the Eye conference 2020. A series of outreach actions were carried out during the project. The focus audience of the actions at this stage of the project was ophthalmologists and optometrists. A mini lecture was given at the Athens Eye Hospital in Greece, one of Greece’s leading clinics in ophthalmology, presenting the main principle of operation of the instrument, measurement details, as well as the current status in the macular pigment research. An invited lecture on the topic was also given at the South-Eastern European Ophthalomological Society meeting in Pristina in June 2019.
Future of the project
The project was based on a laboratory prototype instrument built on an optical table at the Laboratorio de Optica at the Universidad de Murcia. The method was experimentally tested in the lab, presented at conferences, published in a scientific journal and the technology was patented (TRL1-3). During the project, the prototype was further developed in order to be more suitable for clinical use and preliminary tests were carried out at the partner (AEH) in a clinical environment on a cohort of healthy subjects (TRL4-5) . In parallel, a handheld instrument is being developed that would significantly reduce the cost and the complexity. The next step would be to produce a small number of prototype devices and send them to clinical partners at different locations. The clinical partners will carry out large scale measurements on volunteers and examine how various optical parameters and specific ocular pathologies can affect the measurements (e.g. very high myopia, cataract). Also, a large cohort of healthy volunteers will be measured to establish a baseline value for MPOD. Development of the handheld, stand-alone version of the instrument will continue during the next phase and will be tested by the clinical partners and further refined using their feedback. Other potential applications of the developed method will also be explored during this phase (eg. retinal oximetry). Furthermore, preliminary work will be done to subsequently certify the instrument as a medical device, following the EU medical device regulation. Finally, an in-depth market analysis will be carried out, in order to determine the appropriate markets to initially launch the instrument. This will also examine legal matters on the use of the instrument by non-ophthalmologists (eg. optometrists or nutrionists).
