The disposable bandage soft contact lenses therapy and anterior segment optical coherence tomography for management of ocular graft-versus-host disease.

PURPOSE: To identify the ocular surface changes of ocular graft-versus-host disease (GVHD) using anterior segment optical coherence tomography (AS-OCT) and examine the efficacy of disposable bandage soft contact lens (BSCL) treatment in ocular GVHD patients. METHODS: This study is a prospective, Phase II clinical trial. Nineteen patients diagnosed with chronic GVHD based on the NIH criteria and ocular symptoms of NIH eye score 2 or greater were enrolled. Disposable BSCL was applied to the GVHD-affected eyes with topical antibiotic coverage. Ocular exams, eye symptom surveys, and AS-OCT were performed with signed informed consent. Patients were followed for one to three months. RESULTS: Thirty-eight eyes of 19 patients with ocular GVHD underwent BSCL treatment in this study. AS-OCT scans were done in 14 out of 19 patients. The mean best-corrected visual acuity at enrollment, 2-week, and 4-week visits was 0.180, 0.128, and 0.163 logMAR, respectively. Twenty-four out of 25 eyes (96 %) that initially presented with conjunctival inflammation, twenty-three out of 30 eyes (76.7 %) that initially presented with punctate epithelial erosion, and 8 out of 15 (53.3 %) eyes that initially presented with filamentous keratopathy showed improvement after wearing BSCL for 2 to 4 weeks. AS-OCT revealed corneal epithelial irregularity, abnormal meibomian gland orifice, and conjunctival hyperemia, in patients with ocular GVHD. CONCLUSIONS: BSCL treatment provided significant subjective and objective improvements in ocular GVHD patients. Meanwhile, we found that AS-OCT can be a promising diagnostic tool to characterize the ocular surface changes associated with ocular GVHD.

Impact of Ocular Chronic Graft-versus-Host Disease on Quality of Life.

Ocular involvement can be quite symptomatic in patients with chronic graft-versus-host disease (GVHD). The prevalence of and risk factors for ocular GVHD and its impact on quality of life (QOL) in patients with chronic GVHD were studied in a prospective, multicenter, longitudinal, observational study. This study enrolled 342 patients with 1483 follow-up visits after allogeneic hematopoietic cell transplantation. All patients in this analysis were diagnosed with chronic GVHD requiring systemic treatment and enrolled within 3 months of chronic GVHD diagnosis. The symptom burden of ocular GVHD was based on the degree of dry eye symptoms, frequency of artificial tear usage, and impact on activities of daily living. Patients' QOL was measured by self-administered questionnaires. Variables associated with ocular GVHD at enrollment and subsequent new-onset ocular GVHD and the associations with QOL were studied. Of the 284 chronic GVHD patients, 116 (41%) had ocular GVHD within 3 months of chronic GVHD diagnosis ("early ocular GVHD"). Late ocular GVHD (new onset > 3 months after chronic GVHD diagnosis) occurred in 64 patients. Overall cumulative incidence at 2 years was 57%. Female gender (P = .005), higher acute GVHD grade (P = .04), and higher prednisone dose at study entry (P = .04) were associated with early ocular GVHD. For patients who did not have ocular GVHD within 3 months of chronic GVHD diagnosis, presence of prior grades I to IV acute GVHD (HR 1.78, P = .04) was associated with shorter time to late ocular GVHD, whereas female donor-male recipient (HR .53, P = .05) was associated with longer time to late ocular GVHD onset. Using all visit data, patients with ocular GVHD had worse QOL, as measured by Functional Assessment of Cancer Therapy Bone Marrow Transplantation (P = .002), and greater chronic GVHD symptom burden, as measured by the Lee symptom overall score excluding the eye component (P < .001), compared with patients without ocular GVHD. In conclusion, this large, multicenter, prospective study shows that ocular GVHD affects 57% of patients within 2 years of chronic GVHD diagnosis. Women, patients on higher doses of prednisone at study entry, and those with a history of acute GVHD were at higher risk for ocular GVHD. Strong evidence suggests that ocular GVHD is associated with worse overall health-related QOL.

Bandage Soft Contact Lenses for Ocular Graft-versus-Host Disease.

To examine safety and efficacy of bandage soft contact lenses (BSCLs) for ocular chronic graft-versus host disease (GVHD), we conducted a phase II clinical trial. Extended-wear BSCLs were applied under daily topical antibiotic prophylaxis. Patients completed standardized symptom questionnaires at enrollment and at 2 weeks, 4 weeks, and 3 months afterward. Ophthalmologic assessment was performed at enrollment, at 2 weeks, and afterward as medically needed. Assessments at follow-up were compared with baseline by paired t-test. Nineteen patients with ocular GVHD who remained symptomatic despite conventional treatments were studied. The mean Lee eye subscale score was 75.4 at enrollment and improved significantly to 63.2 at 2 weeks (P = .01), to 61.8 at 4 weeks (P = .005), and to 56.3 at 3 months (P = .02). The ocular surface disease index score and 11-point eye symptom ratings also improved significantly. According to the Lee eye subscale, clinically meaningful improvement was observed in 9 patients (47%) at 2 weeks, in 11 patients (58%) at 4 weeks, and in 9 patients (47%) at 3 months. Visual acuity improved significantly at 2 weeks compared with enrollment values. Based on slit lamp exam at 2 weeks, punctate epithelial erosions improved in 58% of the patients, showed stability in 16%, and worsened in 5%. No corneal ulceration or ocular infection occurred. BSCLs are a widely available, safe, and effective treatment option that improves manifestations of ocular GVHD in approximately 50% of patients. This study was registered at www.clinicaltrials.gov as NCT01616056.

Non-contact acoustic micro-tapping optical coherence elastography for quantification of corneal anisotropic elasticity: in vivo rabbit study.

PURPOSE: To demonstrate accurate measurement of corneal elastic moduli in vivo with non-contact and non-invasive optical coherence elastography. METHODS: Elastic properties (in-plane Young's modulus E and both in-plane, u, and out-of-plane, G, shear moduli) of rabbit cornea were quantified in vivo using non-contact dynamic Acoustic micro-Tapping Optical Coherence Elastography (AuT-OCE). The IOP-dependence of measured mechanical properties was explored in extracted whole globes following in vivo measurement. A nearly-incompressible transverse isotropic (NITI) model was used to reconstruct moduli from AuT-OCE data. Independently, cornea elastic moduli were also measured ex vivo with traditional, destructive mechanical tests (tensile extensometry and shear rheometry). RESULTS: Our study demonstrates strong anisotropy of corneal elasticity in rabbits. The in-plane Young's modulus, computer as E=3u, was in the range of 20-44 MPa, whereas the out-of-plane shear modulus was in the range of 34-261 kPa. Both pressure-dependent ex vivo OCE and destructive mechanical tests performed on the same samples within an hour of euthanasia strongly support the results of AuT-OCE measurements. CONCLUSIONS: Non-contact AuT-OCE can non-invasively quantify cornea anisotropic elastic properties in vivo. TRANSLATIONAL RELEVANCE: As OCT is broadly accepted in Ophthalmology, these results suggest the potential for rapid translation of AuT-OCE into clinical practice. In addition, AuT-OCE can likely improve diagnostic criteria of ectatic corneal diseases, leading to early diagnosis, reduced complications, customized surgical treatment, and personalized biomechanical models of the eye.

Possible depth-resolved reconstruction of shear moduli in the cornea following collagen crosslinking (CXL) with optical coherence tomography and elastography.

Corneal collagen crosslinking (CXL) is commonly used to prevent or treat keratoconus. Although changes in corneal stiffness induced by CXL surgery can be monitored with non-contact dynamic optical coherence elastography (OCE) by tracking mechanical wave propagation, depth dependent changes are still unclear if the cornea is not crosslinked through the whole depth. Here, phase-decorrelation measurements on optical coherence tomography (OCT) structural images are combined with acoustic micro-tapping (A$\mu$T) OCE to explore possible reconstruction of depth-dependent stiffness within crosslinked corneas in an ex vivo human cornea sample. Experimental OCT images are analyzed to define the penetration depth of CXL into the cornea. In a representative ex vivo human cornea sample, crosslinking depth varied from $\sim 100\mu m$ in the periphery to $\sim 150\mu m$ in the cornea center and exhibited a sharp in-depth transition between crosslinked and untreated areas. This information was used in an analytical two-layer guided wave propagation model to quantify the stiffness of the treated layer. We also discuss how the elastic moduli of partially CXL-treated cornea layers reflect the effective engineering stiffness of the entire cornea to properly quantify corneal deformation.

Noncontact Acoustic Micro-Tapping Optical Coherence Elastography for Quantification of Corneal Anisotropic Elasticity: In Vivo Rabbit Study.

Purpose: The purpose of this study was to demonstrate accurate measurement of corneal elastic moduli in vivo with noncontact and noninvasive optical coherence elastography. Methods: Elastic properties (in-plane Young's modulus, E, and both in-plane, µ, and out-of-plane, G, shear moduli) of rabbit cornea were quantified in vivo using noncontact dynamic acoustic micro-tapping optical coherence elastography (AµT-OCE). The intraocular pressure (IOP)-dependence of measured mechanical properties was explored in extracted whole globes following in vivo measurement. A nearly incompressible transverse isotropic (NITI) model was used to reconstruct moduli from AµT-OCE data. Independently, cornea elastic moduli were also measured ex vivo with traditional, destructive mechanical tests (tensile extensometry and shear rheometry). Results: Our study demonstrates strong anisotropy of corneal elasticity in rabbits. The in-plane Young's modulus, computed as E = 3µ, was in the range of 20 MPa to 44 MPa, whereas the out-of-plane shear modulus was in the range of 34 kPa to 261 kPa. Both pressure-dependent ex vivo OCE and destructive mechanical tests performed on the same samples within an hour of euthanasia strongly support the results of AµT-OCE measurements. Conclusions: Noncontact AµT-OCE can noninvasively quantify cornea anisotropic elastic properties in vivo. Translational Relevance: As optical coherence tomography (OCT) is broadly accepted in ophthalmology, these results suggest the potential for rapid translation of AµT-OCE into clinical practice. In addition, AµT-OCE can likely improve diagnostic criteria of ectatic corneal diseases, leading to early diagnosis, reduced complications, customized surgical treatment, and personalized biomechanical models of the eye.

Possible depth-resolved reconstruction of shear moduli in the cornea following collagen crosslinking (CXL) with optical coherence tomography and elastography.

Corneal collagen crosslinking (CXL) is commonly used to prevent or treat keratoconus. Although changes in corneal stiffness induced by CXL surgery can be monitored with non-contact dynamic optical coherence elastography (OCE) by tracking mechanical wave propagation, depth dependent changes are still unclear if the cornea is not crosslinked through the whole depth. Here, phase-decorrelation measurements on optical coherence tomography (OCT) structural images are combined with acoustic micro-tapping (AµT) OCE to explore possible reconstruction of depth-dependent stiffness within crosslinked corneas in an ex vivo human cornea sample. Experimental OCT images are analyzed to define the penetration depth of CXL into the cornea. In a representative ex vivo human cornea sample, crosslinking depth varied from ∼100 µm in the periphery to ∼150 µm in the cornea center and exhibited a sharp in-depth transition between crosslinked and untreated areas. This information was used in an analytical two-layer guided wave propagation model to quantify the stiffness of the treated layer. We also discuss how the elastic moduli of partially CXL-treated cornea layers reflect the effective engineering stiffness of the entire cornea to properly quantify corneal deformation.

Acoustic Micro-Tapping Optical Coherence Elastography to Quantify Corneal Collagen Cross-Linking: An Ex Vivo Human Study.

Purpose: To evaluate changes in the anisotropic elastic properties of ex vivo human cornea treated with ultraviolet cross-linking (CXL) using noncontact acoustic micro-tapping optical coherence elastography (AµT-OCE). Design: Acoustic micro-tapping OCE was performed on normal and CXL human donor cornea in an ex vivo laboratory study. Subjects: Normal human donor cornea (n = 22) divided into 4 subgroups. All samples were stored in optisol. Methods: Elastic properties (in-plane Young's, E, and out-of-plane, G, shear modulus) of normal and ultraviolet CXL-treated human corneas were quantified using noncontact AµT-OCE. A nearly incompressible transverse isotropic model was used to reconstruct moduli from AµT-OCE data. Independently, cornea elastic moduli were also measured with destructive mechanical tests (tensile extensometry and shear rheometry). Main Outcome Measures: Corneal elastic moduli (in-plane Young's modulus, E, in-plane, µ, and out-of-plane, G, shear moduli) can be evaluated in both normal and CXL treated tissues, as well as monitored during the CXL procedure using noncontact AµT-OCE. Results: Cross-linking induced a significant increase in both in-plane and out-of-plane elastic moduli in human cornea. The statistical mean in the paired study (presurgery and postsurgery, n = 7) of the in-plane Young's modulus, E = 3 µ , increased from 19 MPa to 43 MPa, while the out-of-plane shear modulus, G, increased from 188 kPa to 673 kPa. Mechanical tests in a separate subgroup support CXL-induced cornea moduli changes and generally agree with noncontact AµT-OCE measurements. Conclusions: The human cornea is a highly anisotropic material where in-plane mechanical properties are very different from those out-of-plane. Noncontact AµT-OCE can measure changes in the anisotropic elastic properties in human cornea as a result of ultraviolet CXL.

Histological study of graft failure in AlphaCor transplantation.

To report clinical and histopathologic findings in a case of a failed AlphaCor artificial cornea explanted due to corneal stromal melting. We describe the case of a 77-year-old man who received multiple penetrating keratoplasties (PKPs) and subsequent placement of an AlphaCor artificial cornea. Examination showed total corneal infiltration as well as an AlphaCor that was partially dehisced from the host cornea. After explantation, the implant and adjacent host tissue underwent hematoxylin and eosin staining and high-resolution scanning electron microscopy (HR-SEM). Histopathologic analysis of the specimens revealed infiltration of the skirt pores by reactive corneal fibroblasts. Although the AlphaCor implant is an established method of treating multiple failed PKPs, in this case, HR-SEM imaging strongly suggests that the strength of the interface between the implant and corneal tissue is highly dependent on collagen deposition between the pores found in the implant skirt. Collagen deposition then increases the mechanical strength of the cornea-skirt interface.

Delineating Corneal Elastic Anisotropy in a Porcine Model Using Noncontact OCT Elastography and Ex Vivo Mechanical Tests.

Purpose: To compare noncontact acoustic microtapping (AµT) OCT elastography (OCE) with destructive mechanical tests to confirm corneal elastic anisotropy. Design: Ex vivo laboratory study with noncontact AµT-OCE followed by mechanical rheometry and extensometry. Participants: Inflated cornea of whole-globe porcine eyes (n = 9). Methods: A noncontact AµT transducer was used to launch propagating mechanical waves in the cornea that were imaged with phase-sensitive OCT at physiologically relevant controlled pressures. Reconstruction of both Young's modulus (E) and out-of-plane shear modulus (G) in the cornea from experimental data was performed using a nearly incompressible transversely isotropic (NITI) medium material model assuming spatial isotropy of corneal tensile properties. Corneal samples were excised and parallel plate rheometry was performed to measure shear modulus, G. Corneal samples were then subjected to strip extensometry to measure the Young's modulus, E. Main Outcome Measures: Strong corneal anisotropy was confirmed with both AµT-OCE and mechanical tests, with the Young's (E) and shear (G) moduli differing by more than an order of magnitude. These results show that AµT-OCE can quantify both moduli simultaneously with a noncontact, noninvasive, clinically translatable technique. Results: Mean of the OCE measured moduli were E = 12 ± 5 MPa and G = 31 ± 11 kPa at 5 mmHg and E = 20 ± 9 MPa and G = 61 ± 29 kPa at 20 mmHg. Tensile testing yielded a mean Young's modulus of 1 MPa - 20 MPa over a strain range of 1% to 7%. Shear storage and loss modulus (G'/G'') measured with rheometry was approximately 82/13 ± 12/4 kPa at 0.2 Hz and 133/29 ± 16/3 kPa at 16 Hz (0.1% strain). Conclusions: The cornea is confirmed to be a strongly anisotropic elastic material that cannot be characterized with a single elastic modulus. The NITI model is the simplest one that accounts for the cornea's incompressibility and in-plane distribution of lamellae. AµT-OCE has been shown to be the only reported noncontact, noninvasive method to measure both elastic moduli. Submillimeter spatial resolution and near real-time operation can be achieved. Quantifying corneal elasticity in vivo will enable significant innovation in ophthalmology, helping to develop personalized biomechanical models of the eye that can predict response to ophthalmic interventions.

Nearly-incompressible transverse isotropy (NITI) of cornea elasticity: model and experiments with acoustic micro-tapping OCE.

The cornea provides the largest refractive power for the human visual system. Its stiffness, along with intraocular pressure (IOP), are linked to several pathologies, including keratoconus and glaucoma. Although mechanical tests can quantify corneal elasticity ex vivo, they cannot be used clinically. Dynamic optical coherence elastography (OCE), which launches and tracks shear waves to estimate stiffness, provides an attractive non-contact probe of corneal elasticity. To date, however, OCE studies report corneal moduli around tens of kPa, orders-of-magnitude less than those (few MPa) obtained by tensile/inflation testing. This large discrepancy impedes OCE's clinical adoption. Based on corneal microstructure, we introduce and fully characterize a nearly-incompressible transversely isotropic (NITI) model depicting corneal biomechanics. We show that the cornea must be described by at least two shear moduli, contrary to current single-modulus models, decoupling tensile and shear responses. We measure both as a function of IOP in ex vivo porcine cornea, obtaining values consistent with both tensile and shear tests. At pressures above 30 mmHg, the model begins to fail, consistent with non-linear changes in cornea at high IOP.

Modified conjunctival flap as a primary procedure for nontraumatic acute corneal perforation.

OBJECTIVE: Appropriate management of nontraumatic acute corneal perforation is always a challenge even with the many advances in surgical materials and techniques. We reported the outcomes of a case series of acute corneal perforation repair using a newly modified conjunctival flap with amniotic membrane transplant (AMT), fibrin glue, and a bandage soft contact lens (BCL). MATERIALS AND METHODS: A total of 13 consecutive referral cases with nontraumatic acute corneal perforation at the University of Washington were reviewed. All open globes were repaired by a combined surgery with a modified conjunctival flap, AMT, fibrin glue, and BCL. Visual acuity, a slit lamp examination, and the patient-reported pain level were collected preoperatively and postoperatively. Subsequent corneal surgeries to improve visual function were also reviewed. RESULTS: All ocular surfaces of the 13 eyes were stable at postoperative follow-up. Eleven of the 13 patients had the same or worse visual acuity 1 week postoperatively. Nine of the 13 patients achieved better vision 6 months postoperatively. None of the patients developed perioperative or postoperative complications. Five patients with good visual potential underwent further corneal surgeries, including Boston keratoprosthesis and penetrating keratoplasty. The average referral distance was 217 miles and the median number of follow-up visits within 6 months was 4. CONCLUSIONS: The combination of a modified conjunctival flap, AMT, fibrin glue, and a BCL could provide a temporary method to stabilize and secure the integrity of the globe as well as the ocular surface after a nontraumatic acute corneal perforation. This approach allows easy follow-up and preserves the eye for future corneal surgery under optimal conditions.

Robust numerical phase stabilization for long-range swept-source optical coherence tomography.

A novel phase stabilization technique is demonstrated with significant improvement in the phase stability of a micro-electromechanical (MEMS) vertical cavity surface-emitting laser (VCSEL) based swept-source optical coherence tomography (SS-OCT) system. Without any requirements of hardware modifications, the new fully numerical phase stabilization technique features high tolerance to acquisition jitter, and significantly reduced budget in computational effort. We demonstrate that when measured with biological tissue, this technique enables a phase sensitivity of 89 mrad in highly scattering tissue, with image ranging distance of up to 12.5 mm at A-line scan rate of 100.3 kHz. We further compare the performances delivered by the phase-stabilization approach with conventional numerical approach for accuracy and computational efficiency. Imaging result of complex signal-based optical coherence tomography angiography (OCTA) and Doppler OCTA indicate that the proposed phase stabilization technique is robust, and efficient in improving the image contrast-to-noise ratio and extending OCTA depth range. The proposed technique can be universally applied to improve phase-stability in generic SS-OCT with different scale of scan rates without a need for special treatment.

Optical coherence elastography in ophthalmology.

Optical coherence elastography (OCE) can provide clinically valuable information based on local measurements of tissue stiffness. Improved light sources and scanning methods in optical coherence tomography (OCT) have led to rapid growth in systems for high-resolution, quantitative elastography using imaged displacements and strains within soft tissue to infer local mechanical properties. We describe in some detail the physical processes underlying tissue mechanical response based on static and dynamic displacement methods. Namely, the assumptions commonly used to interpret displacement and strain measurements in terms of tissue elasticity for static OCE and propagating wave modes in dynamic OCE are discussed with the ultimate focus on OCT system design for ophthalmic applications. Practical OCT motion-tracking methods used to map tissue elasticity are also presented to fully describe technical developments in OCE, particularly noting those focused on the anterior segment of the eye. Clinical issues and future directions are discussed in the hope that OCE techniques will rapidly move forward to translational studies and clinical applications.

Strategies to improve phase-stability of ultrafast swept source optical coherence tomography for single shot imaging of transient mechanical waves at 16 kHz frame rate.

We present single-shot phase-sensitive imaging of propagating mechanical waves within tissue, enabled by an ultrafast optical coherence tomography (OCT) system powered by a 1.628 MHz Fourier domain mode-locked (FDML) swept laser source. We propose a practical strategy for phase-sensitive measurement by comparing the phases between adjacent OCT B-scans, where the B-scan contains a number of A-scans equaling an integer number of FDML buffers. With this approach, we show that micro-strain fields can be mapped with ∼3.0 nm sensitivity at ∼16 000 fps. The system's capabilities are demonstrated on porcine cornea by imaging mechanical wave propagation launched by a pulsed UV laser beam, promising non-contact, real-time, and high-resolution optical coherence elastography.

Acoustic micro-tapping for non-contact 4D imaging of tissue elasticity.

Elastography plays a key role in characterizing soft media such as biological tissue. Although this technology has found widespread use in both clinical diagnostics and basic science research, nearly all methods require direct physical contact with the object of interest and can even be invasive. For a number of applications, such as diagnostic measurements on the anterior segment of the eye, physical contact is not desired and may even be prohibited. Here we present a fundamentally new approach to dynamic elastography using non-contact mechanical stimulation of soft media with precise spatial and temporal shaping. We call it acoustic micro-tapping (AµT) because it employs focused, air-coupled ultrasound to induce significant mechanical displacement at the boundary of a soft material using reflection-based radiation force. Combining it with high-speed, four-dimensional (three space dimensions plus time) phase-sensitive optical coherence tomography creates a non-contact tool for high-resolution and quantitative dynamic elastography of soft tissue at near real-time imaging rates. The overall approach is demonstrated in ex-vivo porcine cornea.