BACKGROUND

This disclosure pertains to a method for assessing changes in biomechanical properties of ocular and other tissues and for detecting and differentiating tissue stiffness using optical coherence elastography (OCE).

The changes in viscoelastic properties of the tissues are associated with onset and progression of different diseases. Therefore, it is important to assess and quantify tissue mechanical properties during disease progression and application of different therapeutic procedures.

For example, keratoconus is associated with localized reduced rigidity of the cornea, and the information of the corneal stiffness is useful to provide improved diagnosis and monitoring of this pathological status. Also, real-time in vivo measurement of the spatial elasticity distribution with microscopic scale in the cornea could lead to adaptive mechanical modeling of the individual corneal structure which is extremely important to prevent over-corrections, under-corrections and ectasia from refractive surgeries, such as LASIK, and to further optimize the laser ablation procedures.

Structurally degenerative diseases such as keratoconus can significantly alter the stiffness of the cornea, directly affecting the quality of vision. Keratoconus can pathologically decrease the stiffness of the cornea, leading to a loss in the quality of vision. Detecting changes in the biomechanical properties of ocular tissues, such as stiffness of the cornea, can aid in the diagnosis of these structurally degenerative diseases.

As another example, changes in mechanical properties of crystalline lens play an important role in the development of presbyopia, which is the progressive, age-related loss of accommodation of the eye. Results of ex-vivo studies have shown that the stiffness of crystalline lenses increases with age for animals and humans. The increase in lens stiffness is generally believed to be responsible for the progressive loss of the ability of the lens to change shape, leading to presbyopia. However, current understanding of the mechanical properties of the lens, its changes with age, and its role in presbyopia is limited, in part due to a lack of technology that allows measurements of the mechanical properties of the lens in situ and in vivo. The location of the crystalline lens inside the eye makes it challenging to measure its mechanical properties in vivo or in situ (i.e., inside the globe).

UV-induced collagen cross-linking (CXL) is an emerging treatment that effectively increases corneal stiffness and is applied clinically to treat keratoconus. The effectiveness of this treatment may be analyzed by measuring the corneal stiffness both before and after treatment. However, measured corneal stiffness is also influenced by intraocular pressure (TOP). Therefore, experimentally measured changes in corneal stiffness may be attributable to the effects of CXL, changes in TOP, or both. There is a possibility that a cornea, particularly after treatment with CXL, may still be structurally weakened by keratoconus, yet have a “normal” measured stiffness due to an elevated TOP. Current techniques are not able to measure the true IOP in vivo without consideration of the effect of the biomechanical properties of the cornea. Distinguishing corneas that have the same measured stiffness but are at different IOPs is still a challenge.

Elastography is an emerging technique that can map the local mechanical properties of tissues. Ultrasound elastography (USE) and magnetic resonance elastography (MRE) have experienced rapid development during the past few years as diagnostic tools. One common principle of these techniques is correlating tissue deformation caused by the external mechanical excitation to tissue elasticity. In previous studies, acoustic radiation force was applied to a microbubble created by laser-induced optical breakdown in the lens. The displacement of the microbubble was measured by ultrasound and used to evaluate lens elasticity. However, such approach is required to produce microbubbles within the lens. The basic feasibility of using Brillouin microscopy to measure the lens bulk modulus both in vitro and in vivo has been explored. Brillouin microscopy can be implemented using simple instrumentation, but it has a relatively slow acquisition time. There is also uncertainty on how to correlate Brillouin shift (modulus) to the classical mechanical description of the tissues (e.g. Young modulus). USE and MRE can assess mechanical properties of tissue but the relatively low spatial resolution of USE and MRE is still a critical limitation for certain applications, particularly for ocular tissues and also for measurements at the cellular level.

What is needed, therefore, is an improved, non-invasive and highly sensitive method to assess the mechanical properties of the ocular and other tissues with high resolution and sensitivity.

SUMMARY

The present disclosure relates generally to methods and systems for assessing the biomechanical properties of tissues non-invasively, to a method using optical coherence elastography (OCE) for detecting tissue stiffness, such as corneal or lens stiffness, and for differentiating samples having similar measured stiffness as a result of other influences, such as intraocular pressure (TOP). The methods described herein for tissue biomechanical quantification are demonstrated in the case of the cornea and crystalline lens but generally applicable for all soft and hard tissues in the body.

Optical coherence elastography (OCE) is capable of direct and high resolution assessment of mechanical properties of tissue and, therefore, overcomes the limitations of previously-used techniques. OCE employs high-resolution optical coherence tomography (OCT) to detect the sample deformation induced by an external force. In comparison to ultrasound elastography (USE) and magnetic resonance elastography (MRE), OCE is able to provide superior spatial imaging resolution, faster acquisition speed, and greater displacement sensitivity.

In one aspect, this disclosure relates to a method for quantifying biomechanical properties of a tissue, comprising: producing an external or internal force to stimulate localized deformation on a surface of the tissue; using an optical coherence tomography (OCT) or any other low-coherence interferometry subsystem to measure an induced displacement profile resulting from the localized deformation on the surface of the tissue; and quantifying the biomechanical properties of the tissue based on the analysis of the induced elastic wave (i.e. temporal or spatial displacement profile analysis) using an algorithm.

The present system combines a pulsed ultrasound system (or any other excitation methods such as air-puff, laser pulse, etc) capable of producing a force on the tissue surface and a phase-sensitive OCT system for measuring the tissue displacement caused by the force. The system allows for a non-invasive and highly sensitive method to assess the mechanical properties of the tissue in vivo.

The present noninvasive measurement method also uses phase-stabilized swept source optical coherence elastography (PhS-SSOCE) to distinguish between corneal stiffness attributable to disease or UV-induced collagen cross-linking (CXL) and IOP effects on measured corneal stiffness. Optical coherence elastography (OCE) is an emerging noninvasive technique used in recent years that can map the local biomechanical properties of tissue. Similar to ultrasound elastography (USE) and magnetic resonance elastography (MRE), OCE is usually comprised of an external loading component that produces displacements within the tissue. In OCE, imaging this tissue displacement is performed with optical coherence tomography (OCT), which has superior spatial resolution compared to USE and MRE. From the velocity of an induced elastic wave (EW), or stress-strain curve measured by OCE, tissue elasticity can be quantitatively estimated.

The present method compares the displacement amplitude attenuation, elastic wave speed, dispersion of the elastic waves, and natural frequency of the vibrations of a focused air-pulse induced elastic wave in corneal tissue. The damping speed of the displacement amplitudes at each measurement position along the wave propagation are compared for the different materials. This noninvasive method has the potential to detect the early stages of ocular diseases such as keratoconus or to be applied during CLX procedures by factoring in the effects of TOP on measured corneal stiffness.

FIG. 1shows a flow chart illustrating an example of a method encompassed by the present disclosure. Generally, in the first step of the method, an elastic wave is generated in two corneal tissue samples, preferably by a focused air pulse. The elastic wave is detected using PhS-SSOCE at different positions along the wave propagation. If the measured elasticity is different, then the two samples can be differentiated without additional measurement. If the measured elasticity is the same, or at least so close that additional measurement is warranted, then additional steps are taken. The wave displacement is normalized by dividing the amplitude at each measured position by the amplitude at the excitation position. Then, the attenuation of the normalized elastic wave displacement is compared. The sample that has the faster attenuation has a higher viscosity than the other sample, allowing for the samples to be differentiated.

