Expanding indications for corneal cross-linking.

PURPOSE OF REVIEW: The aim of this study was to summarize the recent developments in corneal cross-linking (CXL) and its indications, including corneal ectasias, refractive surgery and infectious keratitis. RECENT FINDINGS: Advances in CXL technology, such as the use of higher-intensity LED ultraviolet (UV) light sources and a better understanding of the UV-riboflavin photochemical reaction, have enabled safer and more effective methods of cross-linking thin and ultra-thin corneas, and more effective accelerated transepithelial/'epi-on' CXL procedures that are beginning to supplant the Dresden protocol as the 'gold standard' CXL method. CXL is also being used in combination with laser surgery, not only to expand the patient base who can receive refractive surgery, but also to help rehabilitate vision in patients with ectasia. CXL, and CXL combined with photorefractive keratectomy (PRK), can result in corneal flattening of 1-2 D, and corneal regularization of 4-5 D, respectively. Finally, photoactivated chromophore for keratitis-corneal cross-linking (PACK-CXL) has been shown to be an effective therapy for infectious keratitis, both alone, and in combination with antimicrobial drugs. SUMMARY: CXL has evolved from a single technique to treat a single corneal ectasia, keratoconus, to several techniques with several indications, spanning a spectrum of corneal ectasias, as well as visual rehabilitation, refractive procedures and infectious keratitis treatment.

Repeated application of riboflavin during corneal cross-linking does not improve the biomechanical stiffening effect ex vivo.

PURPOSE: To evaluate whether repeated application of riboflavin during corneal cross-linking (CXL) has an impact on the corneal biomechanical strength in ex-vivo porcine corneas. DESIGN: Laboratory investigation. METHODS: Sixty-six porcine corneas with intact epithelium were divided into three groups and analyzed. All corneas were pre-soaked with an iso-osmolar solution of 0.1% riboflavin in a phosphate-buffered saline (PBS) solution ("riboflavin solution"). Then, the corneas in Groups 1 and 2 were irradiated with a standard epi-off CXL (S-CXL) UV-A irradiation protocol (3 mW/cm2 for 30 min); while the corneas in Group 3 were not irradiated and served as control. During irradiation, Group 1 (CXL-PBS-Ribo) received repeated riboflavin solution application while corneas in Group 2 (CXL-PBS) received only repeated iso-osmolar PBS solution. Immediately after the procedure, 5-mm wide corneal strips were prepared, and elastic modulus was calculated to characterize biomechanical properties. RESULTS: Significant differences in stress-strain extensiometry were found between two cross-linked groups with control group (P = 0.005 and 0.002, respectively). No significant difference was observed in the normalized stiffening effect between Groups 1 and 2 (P = 0.715). CONCLUSIONS: The repeated application of riboflavin solution during UV-A irradiation does not affect the corneal biomechanical properties achieved with standard epi-off CXL. Riboflavin application during CXL may be omitted without altering the biomechanical stiffening induced by the procedure.

Developing Affordable, Portable and Simplistic Diagnostic Sensors to Improve Access to Care.

Ophthalmology is a highly technical specialty, especially in the area of diagnostic equipment. While the field is innovative, the access to cutting-edge technology is limited with reference to the global population. A significant way to improve overall healthcare is to understand the needs and possibilities of all possible consumers when developing sophisticated and accurate medical devices. The Smartphone-based Keratograph (SBK), is an example of a new project that uses real world feedback, addresses an unmet medical need, and implements commercially available components to create a device that is affordable, portable and simplistic to operate. The long-term goal of the SBK is to collect data from users for supervised machine-learning. This machine-learning aspect will ultimately aid in the development of an artificial intelligence device to enable even earlier detection of keratoconus, especially in children and adolescents. Again, the ultimate goal of any medical device should be to improve patient care, and to make a significant improvement on vision healthcare for the global population, providing access to this technology is essential.

Perichondrial Attached Diced Cartilage (PADC), a Novel Graft Material for Nasal Augmentation: 10 Years of Experience.

BACKGROUND: Achieving dorsal augmentation with onlay grafts presents several challenges. Visibility and warping of grafted cartilages can ruin an otherwise successful operation. A shortage of septal cartilage and rib donor site morbidity compound the problems associated with this procedure. OBJECTIVES: The aim of this study was to find an autologous material for dorsal nasal augmentation that does not disperse upon implementation. This material also should have minimal resorption, resist warping, and not require a wrapping membrane. METHODS: In 30 patients, concha cartilage of the ear with attached perichondrium and fascia were removed. The concha cartilage was diced while it was attached to the posterior soft tissue. The purpose was to develop graft material for dorsal augmentation. RESULTS: In an average of 19.56 months follow-up, no sign of resorption, infection, inflammation, volume loss, or displacement of the grafted material was observed. Aesthetically the results were acceptable and most of the patients were satisfied with the outcome. CONCLUSIONS: Perichondrial attached diced cartilage is a new material for the rhinoplasty surgeon to apply in different onlay nasal augmentation procedures in the unduly reduced nasal dorsum. This technique transforms uneven, peculiarly shaped concha cartilage into a flexible, versatile, and durable material. The donor site is in the surgical field and easy to access.

Assessment of the mechanical forces applied during eye rubbing.

BACKGROUND: To determine the average amount of mechanical forces applied to the lids of keratoconus patients during eye rubbing. METHODS: Fifty-seven patients (41 male, 16 female, average age 34.8 years) with a clinically and topographically diagnosed keratoconus and a history of eye rubbing were prospectively asked to perform their individual eye rubbing movement on a high-precision balance. The type of eye-rubbing movement and the force applied, represented in newtons (N), were recorded and analyzed. RESULTS: We detected three different types of eye rubbing. Rubbing with the fingertip was most frequent (51%), followed by rubbing with the knuckle (44%) and rubbing with the fingernail (6%). Each type of eye rubbing showed different average forces, with knuckle type eye rubbing applying significantly more force (9.6 ± 6.3 N) on the lids than fingertip (4.3 ± 3.1 N) and fingernail (2.6 ± 3.3 N) types (p < 0,001 and p = 0,016, respectively). CONCLUSIONS: There were major variations in the force exerted on the lids, depending on the type of eye rubbing employed. This data will help determine the forces that need to be applied in future experimental eye rubbing models.

Anthropometric Analysis of the Human Skull for Developmental Left-Sided Asymmetry, New Finding.

BACKGROUND: Facial and cranial asymmetry is common in bilateral vertebrates, particularly human beings. Through years of injecting fillers and performing face-lift operation on patients, we began to observe that more fillers were required on the right side to reach symmetry and also more loose skin and soft tissue was observed on the right side in the majority of patients (Fig. 5). Here, we conducted an analytical study to comprehensively measure human skulls in order to observe and quantify this difference. METHODS: We collected forty-one natural skulls available from five medical schools of Tehran province in Iran. Standard photography was conducted from the front, lateral, and superior views. Measurements and statistics were completed using Image J software (National Institutes of Health) for exact comparison of fixed-point distances on the samples. RESULTS: Comparison of right and left dimensions on the skulls revealed several fixed asymmetries. The most significant differences were measurements around the orbit. The distance between the upper orbit point and zygion (zy), zygion to sub-nasal, and orbital areas were significantly larger on the left side. Measuring the anterior gonion-pogonion distance showed a wider mandibular body on the left side. We did not find any considerable differences between any other left-sided and right-sided skull dimensions. CONCLUSIONS: Asymmetry of the face and body is a general rule in human anatomy, but correlation and consistency of this asymmetry between the left and right sides is a novel finding based on our measurements. Our findings showed that the orbit was significantly bigger in width, height, and surface area on the left side. We also quantified a narrower mandible on the right side. We hope these findings can be translated to aesthetic surgery practice to make the plastic surgeon and patient more familiar with the patient's specific anatomy in order to better predict, plan, and successfully implement aesthetic procedures such as injecting fillers or doing peri-orbital procedures. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Lower Lateral Cartilage Cephalic Malposition: An Over-Diagnosed Entity.

BACKGROUND: Lower lateral cartilage malposition is represented by anterior convexity of the lower lateral cartilage (LLC) dome with posterior pinch, as defined by Sheen and Constantian. This anatomic variation consists of cephalic, or upward and inward, rotation of lateral crura, particularly in bulbous tip patients. In most cases, "bulbous pinch" LLC is positioned toward the medial canthus, not laterally, so it is referred to as cephalic displacement. Accordingly, it is recommended to caudally displace cartilage in the majority of rhinoplasty cases in which variation is seen. OBJECTIVES: The purpose of this paper is to measure the exact angle of lateral crura with fixed reference points on the face. METHODS: We drew and marked LLC contours and vertical/horizontal lines in 40 consecutive rhinoplasty cases. We then divided them into two groups: (1) bulbous pinch and (2) flat LLCs. The right- and left-sided LLC angles to midline and horizontal lines were measured and compared to assess whether there was any significant difference between the two subgroups. RESULTS: There was no significant difference between the angles of LLC rotation in the bulbous and flat LLCs groups, measured both vertically and horizontally. CONCLUSION: Based on our findings, although cephalic malposition of LLCs may be present in some patients but in the majority of cases the etiology of nasal lateral wall pinching is not cephalic displacement of lateral crura but most probably is due, rather, to severe convexity of the posterior and lateral crura. According to our findings, cephalic malposition is an uncommon anatomic variation of LLCs that has been reported at high frequency (60-70% of their rhinoplasty cases). This finding may help to correct this deformity into a normal anatomic configuration. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Corneal biomechanics - a review.

PURPOSE: In recent years, the interest in corneal biomechanics has strongly increased. The material properties of the cornea determine its shape and therefore play an important role in corneal ectasia and related pathologies. This review addresses the molecular origin of biomechanical properties, models for their description, methods for their characterisation, techniques for their modification, and computational simulation approaches. RECENT FINDINGS: Recent research has focused on developing non-contact techniques to measure the biomechanical properties in vivo, on determining structural and molecular abnormalities in pathological corneas, on developing and optimising techniques to reinforce the corneal tissue and on the computational simulation of surgical interventions. SUMMARY: A better understanding of corneal biomechanics will help to improve current refractive surgeries, allow an earlier diagnosis of ectatic disorders and a better quantification of treatments aiming at reinforcing the corneal tissue.

Effects of riboflavin, calcium-phosphate layer and adhesive system on stress-strain behavior of demineralized dentin.

PURPOSE: To evaluate if three dentin treatments improved mechanical properties of demineralized dentin. METHODS: Dentin slices were demineralized and treated with a universal adhesive, Scotchbond Universal (SBU), a cross-linker, Riboflavin (RF), and a calcium phosphate-based product, Teethmate (TM). The groups (n= 8 per group) were: Group 1: SBU, Group 2: RF + SBU, Group 3: RF + TM + SBU. Tensile tests were performed; stress/strain curves and E modulus were calculated. Differences between groups were assessed by one-way ANOVA and Duncan post hoc test. RESULTS: At high strains, no significant differences in E moduli were observed between dentin specimens treated only with SBU and those treated with RF + SBU. A significantly higher E modulus was observed in dentin specimens treated with RF + TM + SBU. In the presence of an adhesive system, crosslinking collagen with RF and TM addition significantly improved mechanical properties of dentin. CLINICAL SIGNIFICANCE: Restitution of mineral content into dentin, in addition to collagen strengthening, may significantly improve mechanical properties of previously demineralized dentin, when covered by an adhesive system in a reasonable clinical timeframe.

Five-Year Safety and Performance Results from the Argus II Retinal Prosthesis System Clinical Trial.

PURPOSE: The Argus II Retinal Prosthesis System (Second Sight Medical Products, Inc, Sylmar, CA) was developed to restore some vision to patients blind as a result of retinitis pigmentosa (RP) or outer retinal degeneration. A clinical trial was initiated in 2006 to study the long-term safety and efficacy of the Argus II System in patients with bare or no light perception resulting from end-stage RP. DESIGN: Prospective, multicenter, single-arm clinical trial. Within-patient controls included the nonimplanted fellow eye and patients' native residual vision compared with their vision with the Argus II. PARTICIPANTS: Thirty participants in 10 centers in the United States and Europe. METHODS: The worse-seeing eye of blind patients was implanted with the Argus II. Patients wore glasses mounted with a small camera and a video processor that converted images into stimulation patterns sent to the electrode array on the retina. MAIN OUTCOME MEASURES: The primary outcome measures were safety (the number, seriousness, and relatedness of adverse events) and visual function, as measured by 3 computer-based, objective tests. Secondary measures included functional vision performance on objectively scored real-world tasks. RESULTS: Twenty-four of 30 patients remained implanted with functioning Argus II Systems at 5 years after implantation. Only 1 additional serious adverse event was experienced after the 3-year time point. Patients performed significantly better with the Argus II on than off on all visual function tests and functional vision tasks. CONCLUSIONS: The 5-year results of the Argus II trial support the long-term safety profile and benefit of the Argus II System for patients blind as a result of RP. The Argus II is the first and only retinal implant to have market approval in the European Economic Area, the United States, and Canada.

Penetration depth of corneal cross-linking with riboflavin and UV-A (CXL) in horses and rabbits.

OBJECTIVE: CXL penetration depth is an important variable influencing clinical treatment effect and safety. The purposes of this study were to determine the penetration depth of CXL in rabbit and equine corneas in epithelium-on and epithelium-off procedures and to assess an ex vivo fluorescent biomarker staining assay for objective assessment of CXL penetration depth. PROCEDURES: CXL treatment was performed according to a standardized protocol on 21 and 17 rabbit eyes and on 12 and 10 equine eyes with and without debridement, respectively. Control corneas were treated similarly, but not exposed to CXL. Hemicorneas were stained with either phalloidin and DAPI to visualize intracellular F-actin and nuclei, or with hematoxylin and eosin. Loss of actin staining was measured and compared between groups. RESULTS: Epithelium-off CXL caused a median actin cytoskeleton loss with a demarcation at 274 µm in rabbits and 173 µm in horses. In non-CXL-treated controls, we observed a median actin cytoskeleton loss with a demarcation at 134 µm in rabbits and 149 µm in horses. No effect was detected in the epithelium-on procedure. CONCLUSIONS: CXL penetration depth, as determined by a novel ex vivo fluorescent assay, shows clear differences between species. A distinct effect was observed following epithelium-off CXL treatment in the anterior stroma of rabbits, but no different effect was observed in horses in comparison with nontreated controls. Different protocols need to be established to effectively treat equine patients with infectious corneal disease.

Long-Term Results from an Epiretinal Prosthesis to Restore Sight to the Blind.

PURPOSE: Retinitis pigmentosa (RP) is a group of inherited retinal degenerations leading to blindness due to photoreceptor loss. Retinitis pigmentosa is a rare disease, affecting only approximately 100 000 people in the United States. There is no cure and no approved medical therapy to slow or reverse RP. The purpose of this clinical trial was to evaluate the safety, reliability, and benefit of the Argus II Retinal Prosthesis System (Second Sight Medical Products, Inc, Sylmar, CA) in restoring some visual function to subjects completely blind from RP. We report clinical trial results at 1 and 3 years after implantation. DESIGN: The study is a multicenter, single-arm, prospective clinical trial. PARTICIPANTS: There were 30 subjects in 10 centers in the United States and Europe. Subjects served as their own controls, that is, implanted eye versus fellow eye, and system on versus system off (native residual vision). METHODS: The Argus II System was implanted on and in a single eye (typically the worse-seeing eye) of blind subjects. Subjects wore glasses mounted with a small camera and a video processor that converted images into stimulation patterns sent to the electrode array on the retina. MAIN OUTCOME MEASURES: The primary outcome measures were safety (the number, seriousness, and relatedness of adverse events) and visual function, as measured by 3 computer-based, objective tests. RESULTS: A total of 29 of 30 subjects had functioning Argus II Systems implants 3 years after implantation. Eleven subjects experienced a total of 23 serious device- or surgery-related adverse events. All were treated with standard ophthalmic care. As a group, subjects performed significantly better with the system on than off on all visual function tests and functional vision assessments. CONCLUSIONS: The 3-year results of the Argus II trial support the long-term safety profile and benefit of the Argus II System for patients blind from RP. Earlier results from this trial were used to gain approval of the Argus II by the Food and Drug Administration and a CE mark in Europe. The Argus II System is the first and only retinal implant to have both approvals.

Matched comparison study of total and partial epithelium removal in corneal cross-linking.

PURPOSE: To compare the 1-year results of total versus partial epithelium removal in corneal cross-linking in the treatment of progressive keratoconus. METHODS: This retrospective study compared the results of total (the total group) versus partial (the partial group) approaches of epithelium removal in corneal cross-linking. Eighty eyes of 65 patients (40 eyes in each group) were enrolled. The mean age of the participants was 25.48 ± 4.80 years and 62.5% were male. One-year changes in vision parameters, refraction, and Pentacam (Oculus Optikgeräte GmbH, Wetzlar, Germany) indices were compared between the two groups using repeated measures analysis of variance. RESULTS: One year after corneal cross-linking, uncorrected distance visual acuity in the total and partial group improved by 0.13 ± 0.42 and 0.12 ± 0.36 logMAR (P = .447), respectively, and corrected distance visual acuity improved by 0.00 ± 0.19 and 0.13 ± 0.20 logMAR (P = .001), respectively. Spherical equivalent decreased by 0.44 ± 1.25 diopters (D) in the total group and 0.56 ± 1.47 D in the partial group (P = .710). The decrease in maximum keratometry was 0.39 ± 0.93 and 0.01 ± 0.95 D in the total and partial group, respectively (P = .037), and the decrease in mean keratometry was 0.42 ± 0.93 and 0.00 ± 0.65 D (P = .015), respectively. Central corneal thickness decreased by 18.39 ± 20.66 µm in the total group and 0.11 ± 13.29 µm in the partial group (P < .001). CONCLUSIONS: One year after corneal cross-linking, both approaches showed similar results in terms of uncorrected distance visual acuity. With the partial approach, there was slightly better corrected distance visual acuity improvement and central corneal thickness maintenance, but slightly better corneal flattening was achieved with the total removal. Long-term studies are needed to compare these two approaches in terms of stability of results and stopping the progression of keratoconus.

Failure analysis of adhesive restorations with SEM and OCT: from marginal gaps to restoration loss.

OBJECTIVE: The objective of this study was to analyse the failure mode of adhesive interfaces by comparing OCT and scanning electron microscope (SEM) analysis of class V restoration margins located on enamel and dentin. MATERIALS AND METHODS: Three groups were tested that differed in the application of a 3-step etch-and-rinse adhesive system (OptiBond FL) prior to cavity filling with restorative composite resin (Clearfil AP-X). After tooth restoration and polishing, the samples were loaded in a fatigue machine, and adhesive interfaces were evaluated with OCT and SEM. RESULTS: Important and complementary information could be obtained with OCT analysis in respect to how marginal defects can propagate inside the cavity, compromising the restoration's long-term performance. A self-etching effect was observed with OptiBond FL due to the presence of an acidic primer (GPDM) within its composition. Our results could show that areas of bonding and gaps coexisted within the same restoration. CONCLUSIONS: When marginal imperfections, or non-continuous margins, were detected by SEM, also imperfections beneath the surface could be observed at the tooth-restoration interface with OCT. Restoration loss occurred above the borderline of 50% of marginal gaps on enamel and dentin. CLINICAL RELEVANCE: Marginal discrepancies of adhesive restorations can propagate inside the cavity and lead to restoration loss.

Treatment of bullous keratopathy with corneal collagen cross-linking in two dogs.

OBJECTIVE: Corneal collagen cross-linking with riboflavin and UV-A (CXL) decreases corneal oedema and increases visual acuity in human patients with bullous keratopathy. Presumed mechanisms are an increase in collagen packing density and a reduction in stromal swelling pressure. We present two cases in which CXL was used to treat bullous keratopathy in dogs. PROCEDURES: Four eyes of two dogs with painful bullous keratopathy-induced corneal erosions that were resistant to prior therapy were treated with CXL. Both corneas of the second patient were dehydrated to ± 400 µm corneal thickness using topical 70% glycerol solution immediately prior to CXL. Follow-up included slit-lamp examination, fluorescein staining and photographic documentation in both cases and high-resolution ultrasound examination in the second patient. RESULTS: All four eyes were comfortable and fluorescein negative at 1-week post-CXL and remained so for the rest of the follow-up period (17.5 months for case 1 and 6 months for case 2). The owner of the first patient reported a less oedematous cornea and improvement in vision that lasted for 6 months. Despite a reported lack of improvement in vision in the second patient, corneal thickness initially decreased, but was back at baseline thickness at the 4-month recheck. CONCLUSIONS: Similar to humans, CXL might become a useful treatment option for bullous keratopathy-induced therapy-resistant corneal erosions in dogs. Patient comfort was greatly improved, but corneal thickness decrease was not as long-lasting as reported for humans. The presently used protocols might need modification to fit the dog cornea.