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Abstract
Lens biomechanics has great potential for application in clinical diagnostics and treatment monitoring of presbyopia and cataracts. However, current approaches to lens elastography do not meet the desired safety or sensitivity for clinical application. In this regard, we propose a noncontact optical coherence elastography (OCE) method to facilitate quantitative in situ imaging of lens elasticity. Elastic waves induced by air-pulse stimulation on the limbus propagate to the lens and are then imaged using custom-built swept-source optical coherence tomography to obtain the elastic wave velocity and Young’s modulus. The proposed OCE method was first validated by comparing the results of in situ and in vitro measurements of porcine lenses. The results demonstrate that the Young’s modulus measured in situ was highly consistent with that measured in vitro and had an intraclass correlation coefficient of 0.988. We further investigated the elastic changes induced by cold storage and microwave heating. During 36-hour cold storage, the mean Young’s modulus gradually increased (from 5.62 ± 1.24 kPa to 11.40 ± 2.68 kPa, P < 0.0001, n = 9) along with the formation of nuclear opacities. 15-second microwave heating caused a greater increase in the mean Young’s modulus (from 6.86 ± 1.21 kPa to 25.96 ± 8.64 kPa, P < 0.0025, n = 6) without apparent cataract formation. Accordingly, this study reports the first air-pulse OCE measurements of in situ lenses, which quantified the loss of lens elasticity during simulated cataract development with good repeatability and sensitivity, thus enhancing the potential for adoption of lens biomechanics in the clinic.
© 2022 Optica Publishing Group under the terms of the Optica Open Access Publishing Agreement
Corrections
8 May 2023: A minor correction was made to the text.
1. Introduction
The crystalline lens, shaped like a biconvex oblate spheroid, provides approximately one-third the refractive power of the human eye and, in conjunction with the cornea, focuses images of the visual world onto the retina [1]. A crystalline lens is an elastic tissue for the purpose of accommodation, and it continues to grow throughout life with decreased elasticity and increased opacity as aging progresses [2–5]. By the age of 50, most people inevitably develop presbyopia together with a probable onset of age-related cataract [6,7]. Presbyopia, referred to as a decline in accommodative ability, is believed to be mainly occasioned by the loss of lens elasticity [8,9]. Recently, lens softeners have been investigated and suggested as agents for the pharmacological treatment of presbyopia [10–13]. The measurement of lens elasticity is necessary to assess the therapeutic effect of medicine. In cataracts, opacification of the lens is generally accompanied by lens hardening [14,15]. Phacoemulsification is the most commonly performed cataract surgery, where the optimal ultrasonic energy should adjust to lens elasticity (hardness) to improve the efficiency of the surgery and reduce injury to the lens capsule and corneal endothelium [14,16–20]. In this regard, in vivo quantitative elasticity measurement of the eye lens can provide a basis for assessing and understanding the elastic changes undergone by the crystalline lens and may aid in early diagnosis and clinical treatment to preserve the accommodation and transparency of the lens.
Brillouin microscopy [21–24], ultrasound elastography [25–27], and optical coherence elastography (OCE) [24,28–34] have been used for the noninvasive and in vivo assessment of lenticular mechanical properties. Nonetheless, Brillouin microscopy suffers from relatively long acquisition time, high light exposure intensity, and low sensitivity, whereas ultrasound elastography requires contact-based excitation, with relatively poor spatial resolution and contrast. Therefore, these cannot be applied in clinical ophthalmology.
On the other hand, OCE is a noninvasive measurement technique for elastography with significant potential for clinical application due to its micron-level axial resolution and high acquisition speed [35–39]. The tissue measured by OCE is excited to generate the elastic wave, and the propagation of the wave is tracked by the optical coherence tomography (OCT) system by detecting minute displacements in the tissue. The tissue elasticity has a quantitative relationship with wave velocity. Some studies used OCE to assess the biomechanical properties of the crystalline lens ex vivo, with the excitation methods of acoustic radiation force (ARF) [28–30,34] or air puff [24,31–33]. ARF-OCE was reported to actualize the first in vivo rabbit lens elasticity measurement, during which the eyeball was extruded out of the eye socket and immersed in sterile phosphate-buffered saline (PBS) to conduct the ARF in the eyeball [29]. ARF has almost exclusively been such a contact method [38] and would exert high ultrasound stresses on the tissue [40–42], making it difficult to apply in clinics. In contrast, air-pulse OCE can use suitable safe loading pressures (in the mPa range) to induce elastic waves on the eyes in a noncontact manner and has been widely used in biomechanical measurements of cornea [43–47]. In our previous study [48], we also demonstrated that an air-pulse OCE system is capable of in vivo measurement of the human iris by stimulating the limbus on the surface of the eye and transmitting the elastic wave through the cornea, sclera, ciliary body, and finally into the iris. Nevertheless, inducing elastic waves into the lens and imaging it by OCT is still a challenge owing to its complicated intraocular condition and relatively high transparency.
In this study, we designed an OCE system with a micro air-pulse excitation unit to measure lens elasticity in intact porcine eyeballs (in situ) that closely reflected lenticular in vivo conditions. Moreover, we performed both in situ and in vitro OCE measurements of porcine lens lenses for comparison to evaluate the repeatability and reliability. We then measured the in situ elasticity changes in the lenses during the formation of cold cataracts and investigated the microwave effect on lens elasticity in porcine eyes. To the best of our knowledge, this is the first study to accomplish in situ measurement of lens elasticity in intact eyeballs based on the air-pulse OCE method.
2. Materials and methods
2.1 OCE experimental setup
The OCE system comprised a custom-built phase-resolved swept-source optical coherence tomography (Phs-SSOCT) and a micro air-pulse excitation unit (Fig. 1).
In the Phs-SSOCT system, the broadband swept-source laser (Axsun Technologies, Billerica, MA) was characterized by a center wavelength of 1050 nm, a bandwidth of 100 nm and a scan repetition rate of 100 kHz. A 90/10 fiber coupler was configured to separate the output light, of which 10% was introduced into the fiber Bragg grating which reflects the light as an A-scan acquisition trigger of the data acquisition card to stabilize the phase of light source. With the axial resolution of 4.5 µm and imaging depth of 3.8 mm, the anterior lens can be imaged in situ as Fig. 2(a).
Fig. 2. Data processing steps. (a) The OCT structural image of in situ lens. The red line demarcated the anterior surface of lens, while the blue line determined the lower boundary at a depth of 1∼2 mm. The region between the two lines was selected for ROI. (b) Phase shift of the ROI at different times after the trigger. (c) The spatial–temporal displacement map. (d) The displacement of different locations as a function of time. (e) The time-displacement curve with a best-line fit.
To generate impulse excitation force at a certain frequency, a microliter dispensing solenoid valve (The Lee Company, Connecticut, USA), was drived by a function generator. For well-targeted tissue excitation, a 0.85 mm inner diameter nozzle, with an adjustable pointing angle of 45∼60°, was set to point at a distance of 1∼2 cm towards the limbus. Herein, the air supply pressure was 0.15 MPa, providing an excitation force of 1.73 mN on eye surface [46], which was much smaller than the Corvis ST [49] or Ocular Response Analyzer (ORA) [50]. Owing to the structural continuity of eye tissue, elastic waves, arising from the excitation point in the limbus, can travel to the crystalline lens via the ciliary body and zonule, as shown in the schematic diagram of wave propagation (Fig. 1). For in vitro lenses, OCE measurements were performed using direct air pulse on the surface of the lenses.
2.2 Data acquisition and processing
The synchronization of PhS-SSOCT and air-pulse excitation unit has been described in detail in our previous study [45]. In brief, the PhS-SSOCT scan worked an M-B-mode protocol. M-scan, included 500 A-lines acquired at the same location, and 250 positions, which covering a range of 6.5 mm in the central anterior lens, were detected in the B-scan mode. The air puff was activated at the 100th A-line in each M-scan.
The phase shift information of the region of interest (ROI) on the OCT image which was manually selected [Fig. 2(a)], was abstracted based on the phase-resolved color doppler algorithm [51]. The phase shift signal, as shown in Fig. 2(b), was projected in the axial direction to generate a spatial-temporal phase map [Fig. 2(c)]. And then the displacement of each location as a function of time was obtained as shown in Fig. 2(d). The time-distance displacement curve indicating the propagation of wave was extracted and was linear fitted to calculate the group velocity (Cg) of the elastic wave [Fig. 2(e)]. Herein, Cg is equal to the Scholte wave speed (Csch) which is considered to propagate at the interface between elastic and liquid medium [52]. As the case of in situ lens, the shear wave velocity (Cs) can be derived from Csch as follows [35,36]:
The crystalline lens was regarded as the isotropic homogeneous elastic material, with a density (ρ) of 1183 kg/m3 and a Poisson’s ratio (ν) of 0.5 [5,53]. Thus, according to the relation between Young’s modulus and shear wave velocity, in situ Cg can be employed to obtain Young’s modulus (E) by the following equation [35,36]:
Whereas for in vitro lens, the detected Cg is equal to the Rayleigh wave speed (Cr) which is considered to propagate at the boundary of an elastic solid interfacing with air [52]. Cs can be derived as follows:
Therefore, Young’s modulus of in vitro lens can be calculated by the following equation:
2.3 Sample treatments and measurements
Porcine eyeballs were purchased from a local abattoir and taken to the laboratory for initial OCE measurements within 12 hours after eye enucleation. The fresh porcine eyes were then immersed in 1× phosphate buffered saline (PBS) and refrigerated at 4 °C for cold storage. All OCE experiments that followed were performed within 72 hours. For the sharpest images of the eye lens, porcine eyes with corneal rupture or opacity were excluded. Moreover, to test the reliability of the OCE measurements in situ, eight porcine eyes were firstly measured via OCE (in situ), and then the lenses were abstracted and measured again (in vitro).
As reported by previous research, low-temperature incubation is a proven way to induce a cold cataract in the nucleus of lens [32,54–56], while short-term heat can reasonably be used to mimic the changes known to occur with age, i.e., presbyopia and cataracts [2,6,57,58]. This research takes advantage of the elasticity changes of lenses in porcine eyes undergoing cold storage and/or microwave heat to validate the capacity of OCE. In this regard, another nine porcine eyes were tested at an interval of 12 hours during 36-hour cold storage, and six were tested before and after a 15-second heat treatment in a 700-watt microwave oven. During OCE measurements, intact porcine eyeballs or abstracted porcine lenses were placed in dry culture dishes, and 1× PBS was occasionally dropped onto their surfaces to keep them moist. Each sample was tested three times, and the average value was adopted. Meanwhile, we monitored the formation of cataracts via OCT imaging. To clarify and highlight the opacification in the lens, OCT images were adjusted linearly for brightness and contrast using ImageJ software.
2.4 Statistical analysis
All statistical analysis was done in SPSS 22 and GraphPad Prism 9 software. Intraclass correlation coefficient (ICC) was used to characterize the repeatability of the measurements. Simple linear regression was carried out to estimate the correlation between the in-situ and in-vitro measurements of the porcine lenses. While one-way analysis of variance (ANOVA) was performed to evaluate the treatment effect on lens elasticity, paired t test was performed for further comparison of the differences before and after different treatments. For all statistical tests, the significance level was set at a P < 0.05.
3. Results
3.1 Reliability evaluation
The elastic wave speed values measured in situ and in vitro for the porcine lenses (n = 8) are shown in Fig. 3(a). Among these samples, the in situ and in vitro OCE-measured values ranged from 0.97 ± 0.02 m/s to 2.61 ± 0.09 m/s and from 1.19 ± 0.08 m/s to 2.47 ± 0.11 m/s, respectively. Good consistency was observed between in situ and in vitro measurements of the same porcine lenses for all samples. We further performed simple linear regression analysis for the Young’s moduli of the lenses, as shown in Fig. 3(b), which demonstrated a significant (P < 0.0001) positive correlation between in situ and in vitro measurements. The ICC of the measured group velocities and Young's moduli of all in situ lenses were 0.990 (95% CI, 0.967 to 0.998; P < 0.001) and 0.988 (95% CI, 0.962 to 0.997; P < 0.001), respectively, indicating great repeatability.
Fig. 3. (a) Comparisons between group velocities measured in situ and in vitro. Error bars represent within-sample standard deviation in the three repeated measurements. (b) Correlation between the in situ and in vitro estimated Young’s moduli of the porcine lenses. Each black dot simultaneously corresponds to an in situ and in vitro measured value of each lens. Simple linear regression was used to analyze the relationship. The slope is plotted as the red line along with the correlation coefficient and statistical significance of the slope noted in the legend. The two dotted lines demarcate 95% confidence intervals.
3.2 Effect of cold storage on lens elasticity
The structure and elasticity of in situ lenses (n = 9) were measured before the 4-°C refrigeration and at 12, 24, and 36 hours by OCT and OCE, respectively. Figure 4 shows the OCT structural images of a porcine lens in situ at four time points. With the increase in refrigeration time, aggregated scattering structures gradually developed and became apparent in the nucleus. Every sample underwent this nuclear opacification during cold storage.
Fig. 4. Representative OCT structural images of in situ lens at different points of time during 36-hour cold storage. (a) 0 hours; (b) 12 hours; (c) 24 hours; (d) 36 hours.
The measured elastic wave velocities and the corresponding Young’s moduli of the in situ lenses for different cold storage times are shown in Fig. 5. The averaged elastic-wave velocity in the initial state was 1.06 ± 0.12 m/s, and it was 1.14 ± 0.08 m/s, 1.21 ± 0.14 m/s, and 1.50 ± 0.18 m/s for 12-, 24-, and 36-hour cold storage, respectively. ANOVA revealed a statistically significant difference in the group velocities for different cold-storage times [F (2.429, 19.43) = 29.69, P < 0.0001]. The corresponding averaged Young’s moduli were 5.62 ± 1.24 kPa, 6.49 ± 0.92 kPa, 7.38 ± 1.74 kPa, and 11.40 ± 2.68 kPa at the four time points. Paired t-test suggests that there was more than 30% increase (P < 0.0358) in the Young’s moduli during 24-hour cold storage, compared with the initial state. After 36 hours, the Young’s moduli increased by approximately 100% (P < 0.0001).
Fig. 5. Elastic changes of in situ lenses (n = 9) during 36-hour cold storage. (a) OCE-measured group velocities at an interval of 12 hours; (b) The corresponding Young’s moduli. Box and whiskers plots illustrate the median (central line), interquartile range (box) and 10–90% range (whiskers).
3.3 Effect of microwave heating on lens elasticity
The variations in the structure and elasticity of the in situ lenses (n = 6) before and after the 15-second microwave heating are demonstrated in Fig. 6 and Fig. 7, respectively. As we identified by visual observation and OCT imaging, opacification was not induced in the lenses after such brief microwave heating. The average group velocities of all lenses before and after microwave treatment were 1.17 ± 0.09 m/s and 2.19 ± 0.39 m/s, respectively. Paired t-test shows that there was a significant increase in Young’s moduli (from 6.86 ± 1.21 kPa to 25.96 ± 8.64 kPa, P < 0.0025, > 250% increase) of all porcine lenses after microwave treatment.
Fig. 6. Representative OCT structural images of in situ lens. (a) Before microwave treatment; (b) After microwave treatment.
Fig. 7. Microwave effect on in situ lenses (n = 6) elasticity. (a) Group velocity for each lens before and after microwave treatment; (b) The corresponding Young’s modulus.
4. Discussion and conclusions
Unlike the easily accessible cornea in the surface layer of the eyeball, the crystalline lens is located behind the cornea and iris, surrounded by the aqueous humor, and its periphery is tied to the ciliary body by the ciliary zonule. Most conventional mechanical methods exert force on the sample in a direct-contact manner and hence cannot be employed for in vivo measurement of lens biomechanics. ARF-OCE is the only reported technology for in vivo OCE measurements performed on a rabbit lens [29]. However, ARF is delivered by an ultrasound transducer acoustically coupled to the cornea and exerts stress upon the eyeball, leading to a change in eye shape and intraocular pressure. Compared to ARF-OCE, air-puff tonometry is widely used in ophthalmology with sufficient safety, and air pulse-based OCE with minor stress and short duration is believed to be the most promising modality for ocular detection. However, air-pulse excitation of the inner eyeball tissue such as the lens is challenging. In this paper, we describe an air-pulse OCE system that induces transient and minute air-puff excitations on the corneal limbus. Elastic waves are generated and then propagated to the surface of the lens via the ciliary muscle and zonule. The propagation path is inessential here, because the detected wave velocity of the lens is independent of the wave source and the propagation path before reaching the target region, based on the principle of OCE measurement. In addition, the corneal limbus is less sensitive to external force compared to the central cornea, and the patient will not experience much discomfort thus. Therefore, air-pulse OCE has considerable potential for application in in vivo elasticity assessment of human-eye lenses in the clinic.
The good repeatability as well as the good agreement between the in situ and in vitro OCE measurements of porcine lenses demonstrated the reliability of air-pulse OCE for in situ lens elasticity assessment. The Young’s moduli measured in situ ranged from 4.64 to 33.90 kPa, in agreement with previous reports [24,30–34]. In consideration of the complex intraocular environment underwent by in situ lens, the influence of intraocular pressure (IOP) and the elastic wave on the cornea on detected wave velocity on in situ lens needs to be clarified. Other groups have measured the cornea and lens elasticities simultaneously based on ARF-induced surface wave [29,30], and it’s noted that with the increasing IOP, the corneal wave velocity presented an obvious ascending trend, while the lenticular wave velocity almost remained stable. These results indicated that the wave velocity in the in situ lens is not sensitive to IOP in comparison to the change of measured velocity in cornea. It also indicated that the propagation of corneal wave induced by the same stimulation has negligible influence on OCE measurement of underlying lens. Additionally, we measured the in vitro lens, which eliminates the interrupt from the cornea, after the in situ measurement for the same lens. The good consistence between them as shown in Fig. 3 also strongly verified this conclusion.
In this study, cold storage at 4 °C was utilized to establish the cataract model in situ. As the cold storage time increased, nuclear opacification occurred and became more apparent after 36 hours. Meanwhile, the OCE results showed an overall increasing trend of lens stiffness along with a gradual formation of cold cataracts. Over the 24-hour cold storage, the average Young’s modulus increased by approximately 2 kPa with statistical significance, whereas after 36-hour cold storage, the Young’s modulus increased by approximately 6 kPa compared to the initial state. As illustrated in Fig. 4, the opacification by cold cataracts mainly occurred in the lens nucleus, while the anterior subcapsular region of the lens with a thickness of 1 to 2 mm appeared to remain transparent. This was consistent with previous literature reports [32,54,55] and was similar to the common clinical type of age-related nuclear cataracts [59,60]. As the Scholte wave propagated along the anterior surface of the lens, the anterior subcapsular region was selected to collect the phase information [Fig. 2(a)], and the Scholte wave speed was extracted to provide a global assessment of lens elasticity. Although the selected anterior subcapsular region was still clear after cold treatment, our experiment successfully detected changes in lens elasticity. This indicates that the appearance of opacification cannot be used as a criterion for assessing lens stiffness in nuclear cataracts.
Short-time heating is another method used to induce lens hardening by reproducing age-related changes in the proteins of the lens fiber cells [2,6,57]. Previous studies have mostly employed microwave heating to induce cataracts [58,61,62]. In our microwave experiment, a shorter heating time and lower power (15-second heating in a non-preheated 700-watt microwave oven) were chosen in comparison with the literature [62]. Under these experimental conditions, the biomechanical properties of the lens changed significantly in relation to the OCE results before the formation of cataracts (Fig. 4). This observation can be used to explain the occurrence of presbyopia, which may be an early symptom of age-related cataracts. An ex vivo dynamic mechanical analysis reported that the hardness of a normal lens increased from approximately 2 kPa to 40 kPa in the process of presbyopia, which was numerically similar to the microwave-induced lens hardening in our study [15].
Additionally, it is worth noting that the microwave-induced increase in the Young’s moduli was much larger than that induced by 36-hour cold storage. This might be occasioned by the possible different underlying mechanisms of cataract formation, i.e., the change in biomechanical properties caused by microwave treatment mainly occurs in the subcapsular lenticular region, which is consistent with the selected OCE region. Our results indicate that the progression of lens opacification and lens elasticity is asynchronous in cataracts with different formative mechanisms. This phenomenon was also observed in a clinical case of diabetic cataracts, where younger patients with diabetes may develop a mature cataract within a short period, but the lens tends to be not as hard [14]. A lower cumulative-energy composite parameter is more suitable for phacoemulsification cataract surgery in patients with diabetes owing to the relatively low lens stiffness [18]. P. Heyworth et al. reported that only 56% of the variation in hardness could be explained in terms of age and the degree of nuclear sclerosis as evaluated by color and opalescence [16]. Therefore, current cataract grading systems depending on observation of color and opalescence are not sufficiently accurate for lens hardness classifications [20]. Hence, a reliable and objective approach is necessary to estimate hardness when selecting patients for cataract surgery and to determine the appropriate phacoemulsification strategy [14,16–20,63].
In summary, we report the first air-pulse OCE measurements of in situ lenses, which allow for quantification of in situ lens elasticity in a noncontact manner with high sensitivity. Further, we verified the increased Young's modulus of the lens in the intact eyeball as a function of cold storage and microwave heating. To successfully translate into clinical applications, our future studies will update the system to achieve a faster acquisition speed. With good reliability and feasibility, the system showed great potential to promote in vivo research on lens biomechanics and improve clinical management of presbyopia and cataracts.
Funding
National Natural Science Foundation of China (62275201); Joint Funds of the National Natural Science Foundation of China (U22A20312).
Disclosures
The authors declare that there are no conflicts of interest related to this article.
Data availability
Data underlying the results presented in this paper are not publicly available at this time but may be obtained from the authors upon reasonable request.
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