Fabiano Cade

In vivo performance of a drug-eluting contact lens to treat glaucoma for a month

For nearly half a century, contact lenses have been proposed as a means of ocular drug delivery, but achieving controlled drug release has been a significant challenge. We have developed a drug-eluting contact lens designed for prolonged delivery of latanoprost for the treatment of glaucoma, the leading cause of irreversible blindness worldwide. Latanoprost-eluting contact lenses were created by encapsulating latanoprost-poly(lactic-co-glycolic acid) films in methafilcon by ultraviolet light polymerization. In vitro and in vivo studies showed an early burst of drug release followed by sustained release for one month. Contact lenses containing thicker drug-polymer films demonstrated released a greater amount of drug after the initial burst. In vivo, single contact lenses were able to achieve, for at least one month, latanoprost concentrations in the aqueous humor that were comparable to those achieved with topical latanoprost solution, the current first-line treatment for glaucoma. The lenses appeared safe in cell culture and animal studies. This contact lens design can potentially be used as a treatment for glaucoma and as a platform for other ocular drug delivery applications.

Intraocular Pressure Measurement by Radio Wave Telemetry

PURPOSE To determine the biocompatibility of a new wireless intraocular pressure (IOP) transducer (WIT) in rabbit eyes and to correlate its measurements with other pressure-measuring devices. METHODS The WIT is a ring-shaped intraocular device that allows wireless IOP measurements through radiofrequency. It was implanted into six eyes of New Zealand White rabbits after extracapsular lens extraction. A sham rabbit eye with no transducer implanted was used as a control. The animals were observed and examined by microscopy at various intervals up to 25 months after surgery. IOP was measured at various intervals by pneumotonometry, tonometry, WIT, and manometry. The data from the various devices were compared and analyzed for reproducibility. Two eyes were enucleated at 5.5 and 20 months after implantation and analyzed by histology. RESULTS The WIT appears to be well tolerated in the rabbit eye, with no evidence of significant inflammation or scar formation by microscopic in vivo examination. Histology did not reveal intraocular inflammation or membrane formation. Repeated IOP measurements with pneumotonometry, tonometry, and the WIT resulted in SDs of 2.70 mm Hg, 3.35 mm Hg, and 0.81 mm Hg, respectively. The concordance between the WIT and direct manometry measurements was high. A downward drift in IOP measured by the WIT was noted in three rabbits, necessitating recalibration. CONCLUSIONS The WIT is well tolerated by the rabbit eye. Its measurements are reproducible and in close concordance with manometry. A downward IOP drift warrants further investigation.

Glaucoma in eyes with severe chemical burn, before and after keratoprosthesis.

Purpose: The purpose of this study was to evaluate the incidence of glaucoma in eyes with severe chemical burn, before and after keratoprosthesis. Methods: A retrospective chart review of 28 eyes of 23 patients with severe ocular chemical burns who had undergone Boston Keratoprosthesis (BKPro) surgery at the Massachusetts Eye and Ear Infirmary, between 1990 and 2010. The incidence and severity of the outcome of glaucoma, preoperatively and postoperatively, were reviewed. Related issues, such as type of chemical burn; visual acuity (VA); device retention rate; number and nature of previous, concomitant, and subsequent procedures; and incidence of other postoperative complications, were reviewed for a median follow-up time of 57 months. Results: The number of eyes with a preoperative history or signs of glaucoma was 21, 9 of which had glaucoma progression after BKPro implantation. In addition, 2 more eyes developed glaucoma postoperatively. Preoperative vision was counting fingers or worse in all eyes. Best-corrected postoperative VA ranged from no light perception to 20/20. Seventeen eyes (61%) achieved 20/60 or better VA at some point during their follow-up, but only 9 (32%) maintained 20/60 at the last follow-up. Of the 28 eyes, 6 had the BKPro replaced once and 1 had it replaced twice. Superimposed, 8 of the most severely burned patients developed retinal detachment postoperatively. Conclusions: Glaucoma is very common in eyes with severe chemical burns. A keratoprosthesis can rehabilitate vision, but postoperative glaucoma can be difficult to manage.

Biocompatibility and biofilm inhibition of N,N-hexyl,methyl-polyethylenimine bonded to Boston Keratoprosthesis materials

The biocompatibility and antibacterial properties of N,N-hexyl,methyl-polyethylenimine (HMPEI) covalently attached to the Boston Keratoprosthesis (B-KPro) materials was evaluated. By means of confocal and electron microscopies, we observed that HMPEI-derivatized materials exert an inhibitory effect on biofilm formation by Staphylococcus aureus clinical isolates, as compared to the parent poly(methyl methacrylate) (PMMA) and titanium. There was no additional corneal epithelial cell cytotoxicity of HMPEI-coated PMMA compared to that of control PMMA in tissue cultures in vitro. Likewise, no toxicity or adverse reactivity was detected with HMPEI-derivatized PMMA or titanium compared to those of the control materials after intrastromal or anterior chamber implantation in rabbits in vivo.

Alkali burn to the eye: protection using TNF-α inhibition.

Purpose: The aim of this study was to evaluate early retinal damage after induction of ocular surface alkali burns and the protective effects of tumor necrosis factor alpha (TNF-&agr;) blockade. Methods: Alkali injury was induced in mouse corneas by using 1 N NaOH. Retinal damage was assessed using a terminal deoxynucleotidyl transferase 2′-deoxyuridine 5-triphosphate nick end labeling (TUNEL) assay, 15 minutes to 14 days postburn. Immune cell infiltration was assessed by CD45 immunolocalization. Retinal cytokines were quantified using the enzyme-linked immunosorbent assay for interleukin (IL)1&bgr;, IL2, IL6, TNF-&agr;, CCL5, and macrophage inflammatory protein-1&agr;. Protection against retinal damage was attempted with a single dose of either anti–TNF-&agr; antibody (infliximab, 6.25 mg/kg) or control immunoglobulin G (IgG), administered intraperitoneally 15 minutes after the burn was inflicted. Corneal injury was evaluated by using TUNEL and CD45 immunolocalization and by quantifying corneal neovascularization. Results: There was significant damage to the retina within 24 hours of the corneal burn being inflicted. TUNEL+ labeling was present in 80% of the retinal ganglion cells, including a few CD45+ cells. There was a 10-fold increase in the retinal inflammatory cytokines in the study groups compared with that in controls. A single intraperitoneal dose of anti–TNF-&agr; antibody, administered 15 minutes after the burn, markedly reduced retinal TUNEL+, CD45+ labeling, and inflammatory cytokine expression, compared with that in the controls. Additionally, TNF-&agr; blockade caused a marked reduction in corneal neovascularization, and in cornea TUNEL and CD45 labeling, 5 days after the burn. Conclusions: This study shows that alkali corneal burns can induce significant retinal damage within 24 hours. A single dose of anti–TNF-&agr; antibody, administered 15 minutes after inflicting the burn, provides significant retinal and corneal protection. This could lead to the discovery of novel therapies for patients with alkali injuries.

Chemical burns to the eye: paradigm shifts in treatment.

Every ophthalmologist knows that prompt irrigation is critical after a chemical injury of the eye. This should be continued on the way to the emergency room where standard procedure requires topical anesthetics, cleaning the fornices of any particulate material, and copious irrigation with fluid until litmus tests of the tear film approach neutrality. The value of standard intravenous solutions as ocular irrigants is now being called into question. In most countries, physiological saline is the standard used in industries, laboratories, and hospital emergency rooms. Countering this approach, Paterson et al have shown that physiological saline lavage of an alkali-injured rabbit eye results in only a negligible decrease of aqueous pH. Only paracentesis and reformation of the anterior chamber with phosphate buffer rapidly lowered the pH to physiological levels. Perhaps surprisingly, lavage with tap water is more effective than saline. More importantly, however, Reim et al have demonstrated, again in rabbits, that a borate buffer (Cederroth Eye Wash; Cederroth AB, Upplands Väsby, Sweden) is far more effective in reducing aqueous pH after alkali injury. Alternatively, an amphoteric class of substances (Diphoterine or Previn solutions; Prevor, Cologne, Germany) can be effective. These irrigating solutions are now in place at many workplaces and in hospitals, particularly in Europe. The rest of the world, including the United States, should follow. For acid injuries, which are less penetrating, the composition of the solution is far less critical. After lavage of the eye, what should come next? The use of topical steroids is somewhat controversial. No comprehensive human studies are available for guidance. Topical steroids might be used in milder injuries, along with prophylactic antibiotics and a bandage contact lens for a brief period. If topical steroids are given in a severe injury, then the use must be limited to a week or 2, and then rapidly tapered to avoid stromal ulceration and perforation. These latter events are the result of unbridled inflammation and ineffective corneal stromal repair. There is now substantial experimental and human data indicating that concomitant use of topical ascorbate 10% and topical citrate 10% reduces the risk of ulceration by enhancing fibroblastic repair of collagen and glycosaminoglycans and inhibiting the invasion and degranulation of neutrophils in the cornea, respectively. Collagenase inhibitors (tetracyclines, acetylcysteine, and so on) might diminish ulceration. Surgical placement of an amniotic membrane overlay, to protect naked stroma, can suppress the inflammatory process. Despite the fact that no medication is known to successfully clear the cornea after a severe chemical injury, limitation of the inflammation has a salutary effect on subsequent attempts at rehabilitation. What then constitutes the most significant threat to eventual visual outcome? The answer is glaucoma! High-pressure intraocular spikes can occur immediately after an alkali injury and can persist indefinitely. They are often missed when attention is directed at the cornea. Applanation tonometry is often imprecise or unreadable on an injured cornea, and any other device might be deemed undesirable for fear of damage to any existing or regenerating epithelium. Intraocular pressure measurement by digital palpation of the eye is crude but can be helpful. Paracentesis during the initial phases shortly after the injury, repeated if necessary, could relieve pressure over the short term by the exit of necrotic tissue and protein clogging the trabecular meshwork. The secondary glaucoma resulting from chemical insult is less responsive to traditional glaucoma medications, which must be used.

Reliable intraocular pressure measurement using automated radio-wave telemetry.

Purpose To present an autonomous intraocular pressure (IOP) measurement technique using a wireless implantable transducer (WIT) and a motion sensor. Methods The WIT optical aid was implanted within the ciliary sulcus of a normotensive rabbit eye after extracapsular clear lens extraction. An autonomous wireless data system (AWDS) comprising of a WIT and an external antenna aided by a motion sensor provided continuous IOP readings. The sensitivity of the technique was determined by the ability to detect IOP changes resulting from the administration of latanoprost 0.005% or dorzolamide 2%, while the reliability was determined by the agreement between baseline and vehicle (saline) IOP. Results On average, 12 diurnal and 205 nocturnal IOP measurements were performed with latanoprost, and 26 diurnal and 205 nocturnal measurements with dorzolamide. No difference was found between mean baseline IOP (13.08±2.2 mmHg) and mean vehicle IOP (13.27±2.1 mmHg) (P=0.45), suggesting good measurement reliability. Both antiglaucoma medications caused significant IOP reduction compared to baseline; latanoprost reduced mean IOP by 10% (1.3±3.54 mmHg; P<0.001), and dorzolamide by 5% (0.62±2.22 mmHg; P<0.001). Use of latanoprost resulted in an overall twofold higher IOP reduction compared to dorzolamide (P<0.001). Repeatability was ±1.8 mmHg, assessed by the variability of consecutive IOP measurements performed in a short period of time (≤1 minute), during which the IOP is not expected to change. Conclusion IOP measurements in conscious rabbits obtained without the need for human interactions using the AWDS are feasible and provide reproducible results.

Analysis of four aberrometers for evaluating lower and higher order aberrations.

Purpose To compare the measurements of lower and higher order aberrations (HOA) of 4 commonly used aberrometers. Setting Massachusetts Eye & Ear Infirmary, Boston, USA. Design Prospective, cross-sectional study, in a controlled, single-blinded fashion. Methods Multiple readings were obtained in 42 eyes of 21 healthy volunteers, at a single visit, with each of the following aberrometers: Alcon LADARWave®, Visx WaveScan®, B & L Zywave®, and Wavelight Allegro Analyzer®. Results were compared and analyzed in regards to the lower and HOA, to the different wavefront sensing devices and software, Tscherning and Hartmann–Shack and between the Fourier and Zernike algorithms. Statistical analysis included Bland-Altman plots, Intraclass Correlation Coefficient (ICC), multiple comparison tests with Analysis of Variance and Kruskal-Wallis. Significant level was set to p<0.05 and alpha level correction was adjusted under the Bonferroni criteria. Results Most measurements of all 4 aberrometers were comparable. However, statistically significant differences were found between the aberrometers in total HOA (tHOA), spherical aberration (SA), horizontal coma and astigmatism (2,2). LADARwave and Wavescan showed significant differences in tHOA (P<0.001, ICC = 0.549, LoA = 0.19±0.5) and in SA (P<0.001, ICC = 0.733, LoA = 0.16±0.37). Wavescan showed a significant difference compared to Zywave (p<0.001, ICC = 0.920, LoA = 0.09±0.13) in SA. Comparisons between Allegro Analyzer and Zywave demonstrated significant differences in both Horizontal Coma (3,1) (p<0.001, ICC = −0.207, LoA = −0.15±0.48) and Astigmatism (2,2) (P = 0.003, ICC = −0.965, LoA = 0.2±2.5). Allegro Analyzer also differed from Wavescan in Horizontal Coma (3,1) (P<0.001, ICC = 0.725, LoA = −0.07±0.25). Conclusions Although some measurements were comparable predominately in the lower order aberrations, significant differences were found in the tHOA, SA, horizontal coma and astigmatism. Our analysis suggests that sensor design contributes to agreement in lower order aberrations, and Fourier and Zernike expansion might disagree in higher order aberrations. Therefore, comparison between aberrometers was generally possible with some exceptions in higher order measurements.

Keratoprosthesis in the fight against corneal blindness in developing countries

hy should we attempt to develop keratoprostheses (KPros) for corneal blindness when standardcorneal transplantation is so well established and relatively safe? It is true that penetrating kera-toplasty, or variations thereof such as endothelial keratoplasty or deep anterior lamellar keratoplasty,are often effective measures in the surgical management of corneal opacification from various causes.However, there are at least two reasons why we need a viable alternative beyond such standard measures.One is due to widespread shortage of donor material and health resources in general, and the other - moreimportant - is the failure rate of keratoplasty in severe cases. Thus we need a back up procedure that can succeedwhen keratoplasty has failed - and particularly so in the Developing World with its high incidence of cornealdisease.According to recent studies, the World Health Organization (WHO) estimates that the global number ofpeople who are considered blind is 39 million

Chemical burns of the eye: The role of retinal injury and new therapeutic possibilities

Purpose: To propose a new treatment paradigm for chemical burns to the eye - in the acute and chronic phases. Methods: Recent laboratory and clinical data on the biology and treatment of chemical burns are analyzed. Results: Corneal blindness from chemical burns can now be successfully treated with a keratoprosthesis, on immediate and intermediate bases. Long term outcomes, however, are hampered by early retinal damage causing glaucoma. New data suggest that rapid diffusion of inflammatory cytokines posteriorly (TNF-&agr;, etc) can severely damage the ganglion cells. Prompt anti-TNF-&agr; treatment is markedly neuroprotective. Long term profound reduction of the intraocular pressure is also vital. Conclusion: A new regimen, in addition to standard treatment, for severe chemical burns is proposed. This involves tumor necrosis factor alpha (TNF-&agr;) inhibition promptly after the accident (primarily for retinal neuroprotection), prophylactic maximal lowering of the intraocular pressure (starting immediately), and keratoprosthesis implantation in a later quiet state.