Tsutomu Yasukawa

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.

Long-term sustained release of ganciclovir from biodegradable scleral implant for the treatment of cytomegalovirus retinitis

The previous scleral implant composed of poly(D, L-lactide-co-glycolide) with ganciclovir (GCV) had some disadvantages such as the second burst in the late phase of release. In this study, the GCV release rate from scleral implants was modified by blending poly(D,L-lactide) (PLA) of two different molecular weights. The scleral implants were prepared by blending PLA-70000 (molecular weight: 70000) and PLA-5000 (molecular weight: 5000) or PLA-130000 (molecular weight: 130000) and PLA-5000 at weight ratios of 100/0, 95/5, 90/10, 80/20, and 0/100. In vitro release tests were performed in 0.1 M phosphate-buffered solution (pH 7.4) at 37 degrees C. An increase in the blended amount of PLA-5000 clearly accelerated the GCV release and the onset of the second burst in the late phase of release tended to delay. The two implants both prepared at a blend ratio of 80/20 successfully prevented the second burst and the GCV release profiles followed the pseudozero-order kinetics after the initial burst as resulting from a diffusional mechanism following Higuchis equation. Duration of the sustained GCV release could be controlled by changing the blending ratio of high and low molecular weight PLA. The 25% GCV-loaded scleral implants composed of PLA-70000 and PLA-5000 with a blending ratio of 80/20 were implanted in pigmented rabbit eyes. The GCV concentrations in the vitreous after implantation of PLA-70000/PLA-5000 scleral implant with a blending ratio of 80/20 were maintained in the range of effective level for 6 months without a significant burst. Our results suggest that the blended implants are promising for the intraocular controlled drug delivery over a period of several months to one year to treat cytomegalovirus retinitis.

Biodegradable scleral implant for intravitreal controlled release of ganciclovir

Abstract · Background: The aims of this study were to develop biodegradable scleral implants that could overcome previously reported disadvantages such as an adverse burst in the late phase of release and to investigate the release profile of modified scleral implants in vitro and in vivo. · Methods:The modified scleral implants (weight 8.5 mg, length 5 mm) were made of mixtures of poly(dl-lactide) (PLA) with different molecular weights and contained 25 weight % of ganciclovir (GCV). The release of GCV was evaluated in vitro by spectrophotometry. Intravitreal GCV concentrations in vivo were measured by high- performance liquid chromatography following plug implantation in pigmented rabbits. The biocompatibility of the device was determined by indirect ophthalmoscopy and light microscopy. · Results:The in vitro release studies showed stable, long-term sustained and slow release. The in vivo release studies showed that the implants had long-term release in the diffusional phase of the triphasic release pattern and only a minor adverse burst of GCV in the late phase. No significant retinal toxicity was observed by histologic examination.  · Conclusion: Our findings showed that this newly modified scleral implant may provide suitable intravitreal drug delivery for treatment of cytomegalovirus retinitis.

Active drug targeting with immunoconjugates to choroidal neovascularization

Purpose. Active drug targeting with monoclonal antibody to neovascular vessels may be a potential treatment for choroidal neovascularization (CNV) in age-related macular degeneration (AMD). Endoglin (CD105) is a proliferating endothelial cell marker with excellent potential for targeting. The goals of this study were to investigate the expression of CD105 in CNV membranes surgically excised from patients with AMD and CNV lesions induced by intense laser photocoagulation in a cynomolgus monkey and to evaluate the in vitro effect of immunoconjugates on endothelial cells. Methods. CNV membranes were surgically excised from 10 patients with AMD. Experimental CNV was induced by intense laser photocoagulation in a cynomolgus monkey. Immunolocalization of CD105 on frozen sections of CNV lesions was studied by immunohistochemical evaluation. Anti-von Willebrands factor antibody was used as an endothelial cell marker. The cytotoxic effect of immunoconjugates of anti-CD105 monoclonal antibody and dextran binding mitomycin C on human umbilical vein endothelial cells (HUVECs) was evaluated in vitro. Results. Endothelial cells demonstrated strong immunoreactivity of CD105 in all surgically excised CNV membranes. In the monkey eye, CD105-positive cells were detected only in CNV lesions but not in normal chorioretinal tissues. Immunoconjugates with anti-CD105 monoclonal antibody showed a specific inhibitory effect on proliferating HU-VECs. Conclusions. These results suggest that anti-CD105 monoclonal antibody-mediated drug targeting has a potential to treat CNV in AMD.

Drug targeting to choroidal neovascularization

Subfoveal choroidal neovascularization (CNV) causes significant visual loss, especially in patients with age-related macular degeneration (AMD). Several pharmaceutical treatments that use anti-angiogenic agents have been tried to inhibit the activity of CNV experimentally and clinically. In general, however, systemically administered drugs may reach not only targeted tissues but also other tissues, resulting in unwanted side effects. Also, to maintain therapeutic levels of the drugs in targeted tissues, frequent administration for an extended period of time is required. To solve these problems, drug delivery systems targeted to the CNV are being developed. Anatomic characteristics of CNV tissues resemble those of tumor vasculature, exhibiting enhanced permeability and retention effect. Drug targeting to CNV may be feasible in the same manner as it is to tumors. In this review, we describe two approaches of drug targeting to CNV: passive targeting and active targeting.

Traumatic cataract with a ruptured posterior capsule from a nonpenetrating ocular injury

Abstract An 11‐year‐old boy had posterior lens capsule rupture resulting from a nonpenetrating (blunt trauma) injury to the eye. A rapidly developing cataract required pars plana lensectomy. This report suggests that posterior capsule rupture may occur secondary to blunt trauma and progressive cataract formation after posterior capsule rupture may require surgery soon after the injury.

Comparison of ciliary sulcus fixation techniques for posterior chamber intraocular lenses

Objective: To anatomically and histologically evaluate suturing techniques for sulcus fixation of posterior chamber intraocular lenses. Setting: Kitano Hospital, Osaka, Japan. Methods: The reproducibility of three suturing techniques (perpendicular to the eye wall; parallel to the iris; midway between perpendicular to the eye wall and parallel to the iris) were evaluated in a postmortem eye. Histologic sections of another eye and ultrasound biomicroscopy (UBM) images of 21 normal eyes were evaluated to determine the safety zone for the needle to avoid damaging adjacent structures. Results: The ciliary sulcus was completely penetrated in the three techniques in 100, 40, and 70% of cases, respectively. The histologic sections and the UBM images showed that when sutures were placed perpendicular to the eye wall, there was the possibility of postoperative angle closure and suturing parallel to the iris might damage adjacent structures because of a narrow safety zone. Conclusions: The needle should penetrate obliquely, as in the technique in which the suturing is midway between perpendicular to the eye wall and parallel to the iris. This technique provides better reproducibility and causes less damage to adjacent tissue.

Cataract surgery in a patient with severe chronic iritis and corneal endothelial damage

Abstract We report a patient with broad anterior synechias and corneal endothelial damage. The patient had chronic iritis and cataracts secondary to the chronic iritis in both eyes. Because the right eye had broad anterior synechias and severe corneal endothelial damage, extracapsuiar cataract extraction and intraocular lens implantation were performed through the basal iris. Good postoperative visual acuity was obtained. The cornea showed little trauma from the surgery and remained clear 36 months postoperatively.

Experimental proliferative vitreoretinopathy in rabbits by delivery of bioactive proteins with gelatin microspheres

Graphical abstract Figure. No caption available. &NA; Proliferative vitreoretinopathy (PVR) is a challenging pathological condition, often causing failure of retinal detachment surgery. The purpose of this study was to evaluate the feasibility of a delivery system of bioactive proteins using anionic and cationic gelatin microspheres and to establish a new PVR model in rabbits by intraocular sustained delivery of basic fibroblast growth factor (bFGF) and interferon‐beta (IFN&bgr;). Anionic and cationic gelatin microspheres were prepared and immersed in bFGF and IFN&bgr; solution, respectively, to yield a polyion complex between gelatin matrix and a bioactive protein. The bFGF‐impregnated microspheres were injected into the subretinal space in rabbit eyes. At week 2, the IFN&bgr;‐impregnated microspheres also were injected into the same space. Control eyes received gelatin microspheres without bFGF or IFNß, or both. The eyes then were observed for 8 weeks by ophthalmoscopy, fundus photography, and fluorescein angiography. The eyes also were evaluated histologically. In the group with both bFGF and IFN&bgr;, the number of eyes with more severe PVR increased over time. Histologic examination showed retinal folds. In contrast, no proliferative changes were seen in any control groups. Subretinal implantation of bFGF and IFN&bgr;‐impregnated gelatin microspheres induced reproducible PVR in rabbit eyes. This study guaranteed delivery of bioactive proteins with gelatin microspheres.