Patent Application
20230129593
The present disclosure generally relates to the field of ophthalmology. More specifically, the present disclosure relates to quantifying and/or detecting biomechanics of ocular tissue, particularly, the cornea, by means of producing non-contact deformation in the ocular tissue.
Keratoconus is a form of ectasia, a progressive disease of the eye, resulting in localized thinning and reshaping of the cornea and localized change in corneal biomechanics. This can adversely affect vision, resulting in near-sightedness, astigmatism and light sensitivity. Keratoconus affects approximately 1% people.
For a number of reasons, from early diagnosis to prevention of post-LASIK ectasia, it is important to be able to biomechanically characterise ocular tissue, particularly, for screening biomechanical abnormality of the cornea.
Current approaches include the use of air-puff deformation imaging such as the Corvis ST (Oculus Optikgeräte GmbH, Wetzlar, Germany) to reconstruct parameters related to the biomechanics of the cornea. However, the use of such a device for screening purposes is commercially unfeasible.
Some other approaches involve the application of a variable force profile air puff or a contact device to the eye to estimate the force needed to flatten (applanate) the central cornea. This is an uncomfortable process (stimulation of the cornea normal to the corneal apex can be difficult), which may lead to problems in repeatability and interpretation of results. Also, calibration of the air puff and accurate information about the force applied to the cornea can be complicated.
Therefore, there is a need for a non-invasive approach for screening abnormality of ocular tissue (such as the cornea), which does not pose the above-mentioned drawbacks.
The present disclosure refers to a method and system for biomechanically characterising ocular tissue through deformation of the ocular tissue according to claims 1 and 14, respectively. Preferred embodiments of the method and system are defined in the dependent claims.
A first aspect of the present disclosure relates to a method for biomechanically characterising ocular tissue through deformation of the ocular tissue. The method comprises:
The present disclosure intends to solve the shortcomings of prior-art devices and methods by providing a method and a system for biomechanically characterising ocular tissue, such as corneal tissue, based on the response (frequency and amplitude) of the cornea to a dynamic stimulation using vibrography. The biomechanical characterisation may include obtaining biomechanical parameters -such as ocular tissue asymmetries, resonance frequencies or intraocular pressure IOP—which may be used inter alia for screening corneal abnormality, or for biomechanically assessing the effects of corneal collagen cross-linking.
According to the system of the present disclosure, a measuring device is combined with an acoustic excitation module which are mounted in coalignment for producing vibration of the ocular tissue; the measuring device is used to measure the displacement of the ocular tissue due to vibration at a plurality of locations of the ocular tissue. The measuring device can be an imaging device or other measuring device, such as a laser providing measurements of the up and down movement of the ocular tissue. The coalignment of the acoustic stimulation and the measuring channel (that is, the main axis of the measuring device, such as the optical axis when an imaging device is used as measuring device) allows for simultaneous stimulation and measurement of multiple points distributed throughout the surface of the ocular tissue, more particularly the corneal apex. This configuration greatly simplifies the analysis and interpretation of the observed ocular tissue frequency response at the multiple points in order to biomechanically characterise the ocular tissue. This configuration results in more accurate measurements and thus, the obtained biomechanical parameters are also more accurate. The frequency response can result in detecting resonance frequencies, which may serve as a biomarker for early detection of corneal/ocular abnormalities.
The acoustic stimulus can be an acoustic wave or any pressure stimulus, and it can be in the form of spatially-uniform, temporally modulated pressure, conveniently having a flat frequency profile. Advantageously, this results in a stronger pressure wave to be delivered to the ocular tissue.
The proposed solution has the advantages of being a low-cost solution, and also, precision of the coalignment between stimulation and measurement can be easily achieved thereby removing complications due to misalignment between stimulation and measurement. Vibration amplitudes can be in the orders of micrometres or nanometres, having the advantage that measurements are less straining in the patients' eye.
In some embodiments, the ocular tissue is excited over a large bandwidth of frequencies, and the frequency response and vibrational modes of the ocular tissue, which are dependent on the ocular tissue biomechanical properties, can be quantified as biomechanical parameters and further used to, probe changes in the cornea due to disease.
On the ocular surface, regional asymmetries are analysed within the excited resonance modes of the ocular tissue; deformation asymmetries can be analysed within a wave. Asymmetry can be calculated as the difference in the measured displacement of the ocular tissue between specific locations of the plurality of locations, such as at opposing points (for instance, at opposite meridians). For instance, the measured displacement is the corneal deformation amplitude at the resonance frequency at each point, on the corneal surface, under the pressure excitation.
The calculated asymmetry can be used for screening a biomechanical abnormality of ocular tissue. A location of the biomechanical abnormality can be obtained based on the map of asymmetry of the frequency response of the ocular tissue displacement.
The acoustic waves incident on the ocular tissue are produced by an acoustic excitation module (such as a speaker, voice coil etc.) which is being fed an oscillating voltage signal.
The acoustic excitation module can exhibit a resonance effect, so the amplitude of the stimulation varies greatly across frequencies. In certain embodiments, the method further comprises characterising the frequency response of the acoustic stimulus. This characterisation of the acoustic excitation module can be measured by mounting a microphone in front of the acoustic excitation module, usually near the sample; the microphone can be placed at the distance at which the ocular tissue would be placed.
In certain embodiments, the method further comprises pre-compensation, wherein the voltage signal passed to speaker is adjusted to ensure the signal produced by the speaker has a constant amplitude at all frequencies.
In some embodiments, in order to correct the measured corneal frequency response for the acoustic excitation module which has not been pre-compensated, the frequency response of the ocular tissue can be post-compensated, where the observed frequency response of the ocular tissue is adjusted according to the acoustic stimulus response.
In some embodiments the ocular tissue is the cornea, which allows for screening corneal biomechanical abnormality; but it could also be the sclera.
In some embodiments, the method further comprises obtaining intraocular pressure of the ocular tissue from a resonance mode analysis of the vibration of the ocular tissue independently from biomechanics.
The above method in any of its embodiments can be carried out using optical coherence tomography. In any of the previous embodiments, the measuring device can be an optical coherence tomography imaging system.
According to another aspect, the disclosure refers to a method for screening a biomechanical abnormality of ocular tissue through deformation of the ocular tissue, the method comprising:
In another aspect of the disclosure, a system for biomechanically characterising ocular tissue is presented. The system comprising:
The present disclosure provides a system that measures localised asymmetries in the corneal vibrational frequency response (resonance modes) by means of acoustic excitation collinear with the imaging system.
The different aspects and embodiments defined in the foregoing can be combined with one another, as long as they are compatible with each other.
Additional advantages and features of the method and system presented herein will become apparent from the detail description that follows and will be particularly pointed out in the appended claims.
To complete the description, a set of drawings is provided. Said drawings form an integral part of the description and illustrate embodiments of the method and system here disclosed, which should not be interpreted in a restricting fashion, but just as an example of how they can be carried out. The drawings comprise the following figures:
The following description is not to be taken in a limiting sense but is given solely for the purpose of describing the broad principles of the disclosed method and system. Different embodiments will be described by way of example with reference to the above-mentioned drawings.
The present disclosure proposes the use of vibrography to determine the presence of corneal abnormality. Vibrography is the process of mechanically stimulating an object at a given frequency or range of frequencies and observing its physical displacement response.
The speaker 20 has a hole 22 in its centre (the hole is not visible in this
The ssOCT 10 provides light beam(s) 11 which pass through an objective lens 30, which focuses the beams 12 through the speaker 20 and onto the cornea C. The light beams 11, 12 are reflected from the sample back to the ssOCT 10.
The objective lens 30 may be part of the ssOCT 10 itself instead of being a separate component.
As shown in
The ssOCT 10 employs a polygon scanner swept laser in the spectral range from 1.23 to 1.34 μm with a typical sweep rate of 45 kHz and an optical power of less than 10 mW on the sample. The axial resolution of the system is 15 μm, and the axial field of view is 7.8 mm.
The speaker 20 is fed by an oscillating voltage signal produced by a function generator 25, to produce acoustic waves 21 which are directed onto the cornea C. The oscillating voltage signal has a flat bandwidth. The function generator generates a frequency sweep from 0 to 1000 Hz with a peak-to-peak signal of 10 V with no dc voltage. The sweep duration was 1 s.
The hole and/or transparent region 22 has to be large enough in diameter to allow a light beam or multiple light beams (for the single and multi-beam setups shown in
Beams are focused on the sample and so the objective lens 30 used needs to have a focal length which is larger than the depth of the speaker 20 and also reach the sample to be imaged.
In either configuration, the acoustic waves produced from the speaker in response to the voltage signal supplied by the computer/function generator are incident on the sample, in this case, the cornea C. The distance between speaker 20 and cornea C is 5-10 mm. These acoustic waves induce some motion, typically in the form of vibration, of the sample which is detected by the ssOCT from the reflected light beams.
In order that these acoustic waves have the same bandwidth as the voltage signal and also have a flat bandwidth, they are subjected to a pre-compensation process, in order to compensate for the effect of the own frequency response of the speaker.
Firstly (step S1), a voltage signal is synthesized using signal processing programming, with a predefined amplitude, frequency bandwidth and flat frequency response. The voltage signal is produced from the computer or function generator 25 (step S2) and applied to the speaker 20 via an audio jack, USB, cables or similar (step S3) for producing acoustic waves (step S3). The acoustic waves are produced from the speaker in response to the voltage signal (step S4) and impinge on the sample to be measured (step S5).
The acoustic waves produced have the same bandwidth as the voltage signal, but a different frequency response. This is due to the nature of the speaker 20 which has a frequency response of its own.
There are several methods for characterising the speaker: measurement of diaphragm movement using OCT; measurement of impedance of speaker and measurement of sound produced by the speaker using a microphone. The former two methods are indirect measurements of the acoustic stimulation produced by the speaker. In the present case, the frequency response of the speaker is characterised and compensated using a microphone. The advantage is that it characterises the acoustic stimulation produced by the speaker directly, and can be examined at a position very similar to the location of the cornea during measurement.
This frequency response of the speaker can be pre-compensated for using a microphone as explained in the following paragraphs. It is to be noted that the frequency response of the microphone is observed to be flat, and thus, compensation for the response of the microphone is considered unnecessary.
A microphone (not shown in the drawings) with a known, flat frequency response in the frequency range of interested is placed in front of the speaker, as near as possible to where the sample is placed. The acoustic signal from the speaker is recorded by the microphone (step S6) and shown in
A Fast Fourier Transform (FFT) is performed on this recorded acoustic signal which reveals the frequency response/content of the acoustic waves at the position where the microphone is, and so, representative of the position of the sample (step S7). This frequency response is shown in
After this process, the acoustic signal produced by the speaker is pre-compensated and has a flat frequency response at the position of the microphone/sample, as shown in
For the acoustic waves to be impinged onto the sample, two stimulation regimes can be considered: a frequency sweep regime in which each frequency is probed individually and sequentially, and a sinc regime where a range of frequencies are probed simultaneously using a sinc pulse.
In the frequency sweep regime, the frequencies of interest are scanned individually and sequentially. Each frequency is sampled at the same amplitude for the same length of time. While this regime has the advantage of a higher amplitude at a given frequency, the Fourier Transform of the signal produces Fresnel ripples which can complicate the interpretation of the resultant corneal response. The frequency sweep signal is shown in
In the sinc regime, all frequencies of interest are sampled simultaneously using a sinc pulse. While this signal can probe all frequencies more quickly, the pressure amplitude at a given frequency is lower than in the frequency sweep regime, for the same input voltage dynamic range. The sinc signal is shown in
Another possibility for compensating the frequency response of the speaker is to post-compensate for it in the processing of the observed corneal frequency. In this case, the frequency response of the speaker is also characterised using a microphone (as in the pre-compensation process). As shown in
The frequency response of the speaker can be used to apply post-compensation as follows: the corneal movement signal frequency response, measured with the ss-OCT is divided by the frequency response of the speaker. The effect of this technique can be seen from the post-compensated corneal frequency response (cf.
Post-compensation can be used in correcting the measured corneal response for the speaker response; however, information about the absolute movement of the cornea under stimulation is lost under this post-compensation process. This loss of information does not happen when using pre-compensation, and the signal passed to the speaker is adapted to ensure the amplitude of the acoustic stimulation remains constant at all frequencies (a flat signal across the frequency range of interest is generated).
Freshly enucleated porcine eyes were obtained from a slaughterhouse (Matadero Justino Gutiérrez, Laguna de Duero, Valladolid, Spain) prior to scalding, and used within 48 hours post-mortem. The eye globes were mounted and excited by an acoustic frequency sweep from 0 to 1000 Hz, while OCT motion mode (M-mode) scans, i.e. depth scans at a fixed lateral position, evolving over time, were collected at or around the corneal apex.
In these tests, acoustic stimulation using a frequency sweep is used to stimulate the cornea. Corneal resonance frequencies were investigated under the following conditions:
In the first test, measurements are carried out on the porcine eye in nominal conditions (i.e. de-epithelialized cornea at a constant IOP of 15 mmHg), and the frequency response was measured at the apex (comparable with the middle panel of
In the second test, measurements are carried out at nine different locations on the cornea of a porcine, also in nominal conditions (i.e. de-epithelialized cornea at constant IOP). Similar frequency responses are observed at all nine locations (see
In the third test, the variation in corneal frequency response with intraocular pressure is investigated. For a single porcine eye, the IOP is varied from 15 mmHg to 30 mmHg in increments of 3 mmHg and the corneal frequency response measured at each IOP value. With increasing IOP, a decrease in resonance amplitude and a frequency shift to more positive values is observed.
In the fourth test (see
As shown in these tests and results, there is significant sensitivity of the resonance modes to changes in biomechanical parameters of the cornea; this can be used, for instance, in differentiating keratoconic and healthy eyes, and for the evaluation, and also for tracking of riboflavin/UV-A cornea collagen crosslinking treatment for keratoconus.
Corneal abnormality can be determined based on comparison of the frequency response amplitudes at a plurality of points across the cornea. Finite element analysis models have been completed to demonstrate the principle. Specifically, nonlinear hyper-elastic finite element models of porcine eyes were built and subjected to a modulated pressure, equal to the pressure used in the above tests. The frequency response was determined by monitoring corneal surface displacement at a plurality of points over time then using Fast Fourier transformation (FFT) analysis to determine the frequency peaks. Resonance frequency and amplitudes were determined across corneal meridians for homogeneous biomechanical corneas and for corneas with local biomechanical variations.
By paying attention to the vibrations of points across the whole corneal surface, the results showed that including a keratoconic cone in the models led to significant asymmetry in resonance amplitude and some limited effect on the resonance frequency. In order to eliminate the asymmetry effect resulting from the fact that the orbital geometry is not rotationally symmetric, the asymmetry of the healthy eye models was subtracted from the asymmetry of the keratoconic eye models.
In these analyses, a distinct asymmetry is noted in the amplitude of the frequency response when a keratoconus area (called cone in clinical practice despite its edge not being circular or regular) is included in the cornea models. The corneal frequency response is monitored at a plurality of points, preferably around the corneal apex, and corneal abnormality can be detected from the asymmetry of behaviour at these points.
According to the present disclosure, frequency domain analysis is used to generate a distinctive peak amplitude variation (imbalance) map over a multitude/plurality of corneal locations over its surface, referenced by subtraction between opposing points equidistant from the apex at their peak response frequency. Then, through this map, the weak areas of the corneal surface are identified as they record higher imbalance values than the healthy areas. Through this amplitude map, the distorted area (cone location) can be detected even if the geometrical deformation is still limited.
These finite element analyses show the localisation of mechanically weakened locations of the cornea by means of corneal amplitude variation at the peak response frequency. Current cone location investigative tools for a corneal affected by a biomechanical disease (like keratoconus) rely on corneal topography or pachymetry, hence they only detect the distortion when it becomes geometrically quantifiable.
The present disclosure also proposes the use of vibrography to determine intraocular pressure IOP. A range of finite element analysis models have been completed to demonstrate the principle. The results suggest that the IOP can be estimated using the frequency response of the apical node in both healthy and abnormal cases. Interestingly, changing the material properties of the cornea did not lead to notable changes in the detected amplitude or the resonance frequency for the same IOP. Hence, IOP can be estimated without a significant effect of corneal stiffness, which is an advantage the frequency-based analysis has over commonly used tonometry devices in which it is hard to measure IOP without being influenced by corneal stiffness.
Using vibrography, IOP can be estimated without a significant effect of corneal stiffness, which is an advantage the frequency-based analysis has over the normal tonometry devices in which it is hard to measure the IOP without being influenced by the corneal stiffness. In vivo tests on porcine eyes show a similar trend in corneal response with change in IOP.
For both the experimental results and the finite element simulations, resonance frequencies were defined at the positions of peak amplitudes. In the present example, both showed resonance frequencies of 370 Hz. An increase of 15 mmHg in lap resulted in a decrease of the resonance amplitude of up to 1.24±0.61 μm and a frequency shift of up to 22.7±9.3 Hz. Biomechanical changes produced by crosslinking led to a decrease in amplitude of 2.19±0.78 μm, without significant frequency shifts. The simulations supported these trends but showed up to 13 Hz higher frequency shifts with IOP increase. Additionally, simulations showed that localized biomechanical changes could be detected by examining asymmetries of the resonance amplitude across opposite corneal meridians. IOP and biomechanics could be decoupled, due to differential dependencies of amplitude and resonance frequency on IOP and biomechanics.
In this text, the term “comprises” and its derivations (such as “comprising”, etc.) should not be understood in an excluding sense, that is, these terms should not be interpreted as excluding the possibility that what is described and defined may include further elements, steps, etc.
On the other hand, the disclosure is obviously not limited to the specific embodiment(s) described herein, but also encompasses any variations that may be considered by any person skilled in the art (for example, as regards the choice of materials, dimensions, components, configuration, etc.), within the general scope of the disclosure as defined in the claims.
| Number | Date | Country | Kind |
|---|---|---|---|
| 20382178.0 | Mar 2020 | EP | regional |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2021/056280 | 3/11/2021 | WO |
