Yuichiro Ogura

Poly(vinyl alcohol) hydrogels as soft contact lens material

A new type of soft contact lens was developed from the poly(vinyl alcohol) (PVA) hydrogel prepared by a low temperature crystallization technique using a water-dimethyl sulfoxide mixed solvent. The PVA contact lens materials had a water content of 78% and a tensile strength of 50 kg/cm2, five times as strong as that of commercial poly(2-hydroxyethyl methacrylate) soft contact lens. The amount of proteins adsorbed to the PVA soft hydrogel material was half to one thirtieth of that of conventional soft contact lenses. Histological and scanning electron microscopic observation of rabbit eyes which had worn the PVA soft contact lens for 12 weeks showed no difference in corneal epithelium and cell arrangement in the corneal epithelium from the non-wearing eyes.

Biodegradable scleral plugs for vitreoretinal drug delivery

Intraocular controlled drug release is one way to facilitate drug efficacy and decrease side effects that occur with systemic administration. Vitreoretinal drug delivery with the biodegradable scleral plug has been investigated. The scleral plug, which is made of biodegradable polymers and drugs, can be implanted at the pars plana using a simple procedure, and it gradually releases effective doses of drugs with polymer biodegradation for several months. The release profiles of the drugs were dependent on the kind of polymers used, their molecular weights, and the amount of drug in the plug. The plugs are effective for treating vitreoretinal diseases such as proliferative vitreoretinopathy. The implantation site was replaced with connective tissue. Electroretinography and histologic studies revealed little retinal toxicity. This implantable scleral plug was supposed to be advantageous for diseases such as cytomegalovirus retinitis that respond to repeated intravitreal injections and for vitreoretinal disorders that require vitrectomy.

Pathogenetic Potential of Leukocytes in Diabetic Retinopathy

Recently, increasing interest has been directed toward the role of leukocytes in microvascular disorders including diabetic retinopathy because of their large cell volume, high cytoplasmic rigidity, natural tendency to stick to the vascular endothelium, and capacity to generate toxic superoxide radicals and proteolytic enzymes. Leukocytes in diabetes are reported to be less deformable and more activated, and may be involved in capillary non-perfusion, endothelial cell damage, and vascular leakage in the retinal microcirculation. In fact, histological studies show many capillary occlusions by leukocytes and capillary dropout or degeneration associated with leukocytes in the diabetic retina. Serial acridine orange leukocyte fluorography and fluorescein angiography studies also identify trapped leukocytes directly associated with areas of downstream non-perfusion in the diabetic retinal microcirculation. More recent studies suggest that adhesion molecules may mediate retinal leukocyte stasis (leukostasis) in diabetes and a reduction in the leukostasis by anti-adhesion antibodies can suppress retinal vascular leakage. In addition, some agents inhibiting leukostasis are reported to improve retinal abnormalities induced by diabetes. Thus, leukostasis in the retinal microcirculation can be a new promising target in the treatment of diabetic retinopathy.

Retinal Nerve Fiber Layer Defect as an Early Manifestation of Diabetic Retinopathy

PURPOSEnAn incidence of and risk factors for retinal nerve fiber layer defect were investigated in patients with type II diabetes mellitus and compared with that of age-matched control subjects.nnnMETHODSnThe authors photographed the retinal nerve fiber layer of the right eye in each of 137 patients with diabetes and 144 healthy control subjects. The level of diabetic retinopathy ranged from levels 1 (no microaneurysm) to 4 (eyes with localized intra-retinal microvascular abnormalities or venous beading). Risk factors for the nerve fiber layer defect analyzed were age of patients, visual acuity, axial length, optic disc size, glycosylated hemoglobin, systolic blood pressure, and level of diabetic retinopathy.nnnRESULTSnDefects of the retinal nerve fiber layer were found in 6/30 (20%) eyes with level 1 retinopathy, 8/14 (57%) eyes with level 2 retinopathy, 24/47 (51%) eyes with level 3 retinopathy, and 36/46 (78%) eyes with level 4 retinopathy. These defect incidences were significantly higher than that of the control group, which had 5/144 (3.5%) defects (P < or = 0.001). Risk factors for this nerve defect were level of diabetic retinopathy (P = 0.002), high systolic blood pressure (P = 0.0232), and patients age (P = 0.0478). Not correlated with the incidence of the retinal nerve fiber layer defect were visual acuity, disc size, axial length, and glycosylated hemoglobin level at the time of examination.nnnCONCLUSIONnThese findings suggest that the retinal nerve fiber layer defect is common in patients with early diabetic retinopathy. Risk factors for this defect were higher level of diabetic retinopathy, systemic hypertension, and advanced age.

Quantitative Analysis of Lens Changes After Vitrectomy by Fluorophotometry

We measured the amount of autofluorescence in the lens to evaluate quantitatively lens changes after vitrectomy. Thirteen phakic patients, ranging in age from 12 to 75 years, were studied after unilateral vitrectomy, with a follow-up period of more than two years (range, 26 to 55 months). Autofluorescence in the lens was measured at the center along the ocular axis by fluorophotometry. Lens autofluorescence in the eyes that underwent vitrectomy was significantly higher than in the contralateral eyes that were not operated on (P = .0003). The increase of autofluorescence was correlated significantly with the age at time of vitrectomy (P = .0008). There was no correlation between the increase in autofluorescence and the length of postoperative follow-up or the use of air during vitrectomy. Based on these results, we believe that oxidation of lens proteins intraoperatively may be one of the causes of development of nuclear cataract after vitrectomy.

Controlled intraocular delivery of ganciclovir with use of biodegradable scleral implant in rabbits

Abstract We evaluated biodegradable scleral implants as a controlled intraocular delivery system of ganciclovir (GCV) for the treatment of cytomegalovirus retinitis in rabbits. The scleral implants (weight, 8.5 mg; length, 5 mm) were made of poly( dl -lactide) (PLA) or poly( dl -lactide-co-glycolide) (PLGA) and contained various amounts of GCV. The in vitro release studies demonstrated a triphasic release pattern. The 10% GCV-loaded scleral implant made from PLA with a molecular weight of 130 000 released GCV for 6 months. The in vivo release and biodegradation were studied using the 25% GCV-loaded implant made from PLGA( 75 25 ) with a molecular weight of 121 000 in pigmented rabbits. The GCV concentration in the range of ED 90 for human CMV was maintained in the vitreous for over 3 months and in the retina/choroid for over 5 months. The GCV concentration was greater in the retina/choroid than in the vitreous throughout the study. The scleral implants showed two phases of biodegradation: lagtime and erosion. In the erosion phase, the weight of PLGA dropped remarkably. All the scleral implants were separated into two pieces at the site of scleral penetration and displaced into the vitreous 10 weeks after implantation. The fragments disappeared from the vitreous and the subconjunctival space 5 months after implantation. Our findings suggest that the biodegradable scleral implant may be a promising device for the intraocular drug delivery of GCV.

New surgical approach for removing massive foveal hard exudates in diabetic macular edema

OBJECTIVEnTo examine the efficacy of surgical removal of foveal hard exudates in diabetic macular edema and to determine the expression of vascular endothelial growth factor (VEGF) in the excised specimens.nnnDESIGNnCohort study.nnnPARTICIPANTSnSeven eyes of six patients with massive subfoveal hard exudate due to diabetic macular edema were examined. The average age of the patient was 56 years (range, 46-60 years).nnnINTERVENTIONnPars plana vitrectomy for removal of massive foveal exudates was performed.nnnMAIN OUTCOME MEASURESnPreoperative and postoperative visual acuity and complications were recorded; immunohistochemical staining for VEGF and other cell markers for macrophage and pigment epithelial cells in excised specimens was performed.nnnRESULTSnPostoperative best-corrected visual acuity improved by two or more lines of Snellen equivalent in five eyes (71%) (P = 0.0061). VEGF, identified by anticytokeratin and CD68 antibodies, was expressed in pigment epithelial cells and macrophages invading the hard exudates.nnnCONCLUSIONnSurgical removal of foveal hard exudates might be effective in low-vision patients with diabetic maculopathy. VEGF might play a role in the formation and persistence of foveal hard exudates in diabetic macular edema.

Quantitative analysis of diabetic macular edema after scatter laser photocoagulation with the scanning retinal thickness analyzer.

PURPOSEnTo define the effect of scatter laser photocoagulation on foveal retinal thickness.nnnMETHODSnA commercial scanning retinal thickness analyzer was used to measure retinal thickness. The foveal retinal thickness was measured at the central area of the fundus (0.4 x 0.4 mm). The method was applied to 20 consecutive patients (mean age, 52.4 +/-16.9 years) with diabetic retinopathy. Measurements were performed before and 6 weeks after scatter photocoagulation. Patients were examined by fluorescein angiography and slit-lamp biomicroscopy to detect macular edema.nnnRESULTSnMean foveal thickness before scatter photocoagulation was 187+/-45 microm, increasing to 221+/-46 microm after the treatment (P = 0.0001). The foveal thickness increased in 12 eyes (60%). Laser treatment increased macular permeability in two eyes (10%). Biomicroscopic examination revealed central macular thickening in one eye (5%). Visual acuity was reduced in four eyes (20%).nnnCONCLUSIONSnOur results suggest that subclinical macular edema occurs after scatter laser photocoagulation. The retinal thickness analyzer is a sensitive tool for early detection of macular edema after laser treatment, because increases in retinal thickness as small as 34 microm cannot be assessed by slit-lamp biomicroscopy.

Radiation therapy for ocular choroidal neovascularization (Phase I/II study): Preliminary report

PURPOSE/OBJECTIVEnChoroidal neovascularization (CNV) is a major cause of severe loss of visual acuity in some ocular diseases such as age-related macular degeneration (ARMD) and angioid streaks. Laser photocoagulation has been used to treat patients with subfoveal neovascular lesions with well-demarcated boundaries. However, the treatment method is usually associated with a large decrease in visual acuity. Therefore, indications for this treatment are very limited. Recently, some investigators reported the effect of low dose irradiation on the subretinal neovascular membranes in CNV. We conducted a Phase I/II study to determine the toxicity and efficacy of external photon beam radiotherapy in patients with CNV.nnnMETHODS AND MATERIALSnBetween April, 1994 and July, 1995, 36 patients with choroidal neovascularization (34 with ARMD and 2 with angioid streaks) were treated with radiation therapy. Treatment planning was performed using a CT simulator that enables real-time treatment planning from multiple CT slices. The clinical target volume that included the macula and optic disc received a dose of 10 Gy/5 fractions/1 week (first 18 eyes) or 20 Gy/10 fractions/2 weeks (last 18 eyes). All eyes were irradiated with a single lateral 6 MV photon beam, angled 10 degrees posteriorly to exclude the ipsilateral lens and the contralateral eye from the radiation field. The ipsilateral lens was irradiated with less than 10% of the total reference dose. The field size averaged 3.0 x 2.5 cm. Records of the 17 eyes with CNV referred to our hospital in 1993, which satisfied the eligibility criteria for this study, were retrospectively analyzed for comparison.nnnRESULTSnThere was no significant acute morbidity. All patients were followed regularly by both ophthalmologists and radiation oncologists. Cataract formation after 1 year of the treatment was observed in one patient who had received a dose of 20 Gy. One patient who had received 20 Gy complained of transient dry-eye sensation 2 months after treatment, but this had disappeared spontaneously by the fourth month. The subjective symptoms, visual acuity, and size of the neovascular membrane were evaluated at 6 and 12 months after treatment in each patient. In the group of patients irradiated with 10 Gy and with 20 Gy, respectively, subjective symptoms improved in five and seven eyes, did not change in seven and four eyes, and deteriorated in six and six eyes at 12 months. Although visual acuity was significantly decreased in the control group, the patients in both irradiated groups did not show such a decrease in visual acuity. The size of the neovascular membrane in the control group progressed significantly. However, the patients in the 20 Gy group showed significant regression of the membrane, although those in the 10 Gy group showed no significant change in size.nnnCONCLUSIONnThis Phase I/II study including a dose escalation study showed that radiation therapy seems to be useful for CNV. The dose of 20 Gy in 10 fractions was more useful in treating neovascular membranes than the dose of 10 Gy in five fractions. These results have encouraged us to start a multicenter randomized prospective study of the treatment of CNV with radiation therapy.

Tacrolimus (FK506) Attenuates Leukocyte Accumulation After Transient Retinal Ischemia

BACKGROUND AND PURPOSEnTacrolimus, an immunosuppressant agent, has been shown to reduce tissue injury and leukocyte accumulation after transient ischemia. This study was designed to evaluate quantitatively the inhibitory effects of tacrolimus on leukocyte rolling and on subsequent leukocyte accumulation in vivo after transient retinal ischemia and the protective effects of tacrolimus on ischemia-induced neural damage.nnnMETHODSnRetinal ischemia was induced for 60 minutes in anesthetized pigmented rats by temporary ligation of the optic sheath. Tacrolimus was administered at 10 minutes after ischemic induction. At 4, 12, 24, and 48 hours after reperfusion, leukocyte behavior in the retinal microcirculation was evaluated in vivo with acridine orange digital fluorography. After 7 days of reperfusion, ischemia-induced retinal damage was evaluated histologically.nnnRESULTSnTreatment with tacrolimus suppressed leukocyte rolling; the maximum number of rolling leukocytes was reduced by 60.1% at 12 hours after reperfusion (P<0.05). In tacrolimus-treated rats, the velocity of rolling leukocytes was significantly faster than in vehicle-treated rats (P<0.01). The subsequent leukocyte accumulation was reduced by 61.6% at 24 hours after reperfusion (P<0.01). Histological examination demonstrated the protective effect of tacrolimus on ischemia-induced retinal damage, which was more substantial in the inner retina (P<0.01).nnnCONCLUSIONSnThe present study demonstrated the inhibitory effect of tacrolimus on leukocyte rolling and on subsequent leukocyte accumulation and the therapeutic potency to neural injury after transient retinal ischemia.