Noninvasive assessment of retinal vascular oxygen content among normal and diabetic human subjects: a study using hyperspectral computed tomographic imaging spectroscopy.

PURPOSE: This pilot study was aimed to demonstrate the clinical feasibility of using hyperspectral computed tomographic spectroscopy to measure blood oxygen content in human retinal vessels. METHODS: All procedures were performed under a University of Southern California Institutional Review Board-approved protocol and after obtaining informed consent. Fifty-seven subjects with and without diabetic retinopathy were dilated for standard fundus photography. Fundus photographs and retinal vascular oxygen measurements (oximetry) were made using a custom-made hyperspectral computed tomographic imaging spectrometer coupled to a standard fundus camera. Oximetry measurements were made along arteries (Aox) and veins (Vox) within vessel segments that were 1 to 2 disk diameters from the optic disk. RESULTS: For all control subjects (n = 45), mean Aox and Vox were 93 ± 7% and 65 ± 5% (P = 0.001), respectively. For all diabetic subjects (n = 12), mean Aox and Vox were 90 ± 7% and 68 ± 5% (P = 0.001), respectively. In subjects with proliferative diabetic retinopathy, Aox was significantly lower, and Vox was significantly higher than other groups (85 ± 4% and 71 ± 4%, respectively; P = 0.04, analysis of variance). There was a highly significant difference in the arteriovenous difference between subjects with proliferative diabetic retinopathy and those in the control group (14 vs. 26%, P = 0.003). CONCLUSION: Hyperspectral computed tomographic spectroscopy is a clinically feasible method for measurement and analysis of vascular oxygen content in retinal health and disease. This study uses the techniques relevant to oximetry; however, the breadth of spectral data available through this method may be applicable to study other anatomical and functional features of the retina in health and disease.

Effect of multiple injections of small divided doses vs single injection of intravitreal bevacizumab on retinal neovascular model in rabbits.

BACKGROUND: To compare effects of multiple injections of small divided doses of intravitreal bevacizumab vs a single injection using a retinal neovascular model in rabbits. METHODS: We assigned 12 pigmented rabbits to four groups of three each. All groups received an intravitreal injection of vascular endothelial growth factor (VEGF, 10 microg) on the first day. Group A received an intravitreal loading dose of bevacizumab (0.5 mg) on day 3, followed by five smaller injections (0.15 mg), one every third day. Those in groups B and C received a single intravitreal injection of bevacizumab (1.25 mg) on day 3, followed by five injections of sham, one every third day in group C. Group D received only intravitreal VEGF. Follow-up examinations were performed for 26 days. RESULTS: In groups A and B, vascular changes associated with VEGF injection decreased substantially in the first 3 days, and continued to show gradual regression during each follow-up interval. No statistically significant differences were found between the changes of mean retinal thicknesses in groups A and B in both areas. In group C, the extra sham injections did not lead to any further vascular changes. The mean retinal thickness in groups B and C did not have a statistically significant difference during the follow-up period. In group D, vascular changes resolved more gradually than in other groups. The difference in retinal thickness between group D and the other groups was statistically significant on day 6 in both groups (medullary and inferior part; p = 0.0003) and in medullary wing on day 12 (p = 0.03). CONCLUSIONS: Frequent smaller doses of bevacizumab can control VEGF-induced vascular changes as well as the currently utilized model of single large monthly injections. Dividing of currently used single injection (1.25 mg) of bevacizumab to multiple small doses can control VEGF-induced vascular changes as effectively as one large injection.

A passive MEMS drug delivery pump for treatment of ocular diseases.

An implantable manually-actuated drug delivery device, consisting of a refillable drug reservoir, flexible cannula, check valve, and suture tabs, was investigated as a new approach for delivering pharmaceuticals to treat chronic ocular diseases. Devices are fabricated by molding and bonding three structured layers of polydimethylsiloxane. A 30 gauge non-coring needle was used to refill the reservoir; this size maximized the number of repeated refills while minimizing damage to the reservoir. The check valve cracking pressure was 76 +/- 8.5 mmHg (mean +/- SE, n = 4); the valve sustained > 2000 mmHg of reverse pressure without leakage. Constant delivery at 1.57 +/- 0.2 microL/sec and 0.61 +/- 0.2 microL/sec (mean +/- SE, n = 4) under 500 mmHg and 250 mmHg of applied pressure, respectively, was obtained in benchtop experiments. The valve closing time constant was 10.2 s for 500 mmHg and 14.2 s for 250 mmHg. Assembled devices were successfully demonstrated in benchtop, ex vivo, and in vivo experiments.

A refillable microfabricated drug delivery device for treatment of ocular diseases.

An implantable manually-actuated microfabricated drug delivery device was demonstrated as a new approach for delivering therapeutic compounds to ocular tissue in acute in vitro, ex vivo, and in vivo studies.

Seronegative granulomatous polyangiitis with central retinal artery occlusion as the initial manifestation.

PURPOSE: To report a case of central retinal artery occlusion in a patient with autopsy-verified granulomatous polyangiitis (GP) with negative cytoplasmic antineutrophil cytoplasmic antibody. METHODS: Case report. RESULTS: A 61-year-old Hispanic man with history of tuberculosis was admitted to the hospital with worsening dyspnea. Two weeks later, he experienced sudden vision loss due to central retinal artery occlusion in his right eye. A CT of the lung revealed multiple opacities. He developed renal failure during his hospital stay. A serum cytoplasmic antineutrophil cytoplasmic antibody test was negative. Pulmonary biopsy disclosed chronic inflammation with no evidence of granuloma formation or vasculitis. He died of acute respiratory distress due to bilateral deep vein thrombosis of his lower extremities. Autopsy revealed GP. CONCLUSION: Granulomatous polyangiitis is a multisystem vasculitic disorder. Central retinal artery occlusion as the presenting manifestation of GP is very uncommon. This report demonstrates the difficulty of diagnosing GP, particularly when initial diagnostic assays (including both serology and biopsy) were negative for GP.

Acute variations in retinal vascular oxygen content in a rabbit model of retinal venous occlusion.

PURPOSE: To study the variation in intravascular oxygen saturation (oximetry) during an acute retinal vein occlusion (RVO) using hyperspectral computed tomographic spectroscopy based oximetry measurements. METHODS: Thirty rabbits were dilated and anesthetized for experiments. Baseline oximetry measurements were made using a custom-made hyperspectral computed tomographic imaging spectrometer coupled to a fundus camera. RVO were induced using argon green laser following an intravenous injection of Rose Bengal. RVO induction was confirmed by fluorescein angiography. Retinal oximetry measurements were repeated in arterial and venous branches one hour after RVO induction and up to 4 weeks afterwards. Comparison of retinal oximetry before and after vein occlusion was made using the Student T-test. RESULTS: One hour after RVO induction, we observed statistically significant reductions in the intravascular oxygen saturation in temporal retinal arteries (85.1 ± 6.1% vs. 80.6 ± 6.6%; p<0.0001) and veins (71.4 ± 5.5% vs. 64.0 ± 4.7%; p<0.0001). This decrease was reversible in animals that spontaneously recannulated the vein occlusion. There were no statistically significant differences in oxygen saturation in the nasal control arteries and veins before and after temporal vein RVO induction. CONCLUSIONS: We demonstrate, for the first time, acute changes in the intravascular oxygen content of retinal vessels 1 hour after RVO. These changes are reversible upon spontaneous recannulation of retinal vessels. This study demonstrates that hyperspectral computer tomographic spectroscopy based oximetry can detect physiological variations in intravascular retinal oxygen saturation. The study also provides the first qualitative and quantitative evidence of the variation in retinal vascular oxygen content directly attributable to an acute retinal vein occlusion.

Mini drug pump for ophthalmic use.

PURPOSE: To evaluate the feasibility of developing a novel mini drug pump for ophthalmic use. METHODS: Using principles of microelectromechanical systems engineering, a mini drug pump was fabricated. The pumping mechanism is based on electrolysis and the pump includes a drug refill port as well as a check valve to control drug delivery. Drug pumps were tested first on the bench-top and then after implantation in rabbits. For the latter, we implanted 4 elliptical (9.9 x 7.7 x 1.8 mm) non-electrically active pumps into 4 rabbits. The procedure is similar to implantation of a glaucoma aqueous drainage device. To determine the ability to refill and also the patency of the cannula, at intervals of 4-6 weeks after implantation, we accessed the drug reservoir with a transconjunctival needle and delivered approximately as low as 1 microL of trypan blue solution (0.06%) into the anterior chamber. Animals were followed by slit lamp examination, photography, and fluorescein angiography. RESULTS: Bench-top testing showed 2.0 microL/min delivery when using 0.4 mW of power for electrolysis. One-way valves showed reliable opening pressures of 470 mmHg. All implanted devices refilled at 4-6 weeks intervals for 4-6 months. No infection was seen. No devices extruded. No filtering bleb formed over the implant. CONCLUSIONS: A prototype ocular mini drug pump was built, implanted, and refilled. Such a platform needs more testing to determine the long term biocompatibility of an electrically-controlled implanted pump. Testing with various pharmacological agents is needed to determine its ultimate potential for ophthalmic use.

Mini drug pump for ophthalmic use.

PURPOSE: To evaluate the feasibility of developing a novel mini drug pump for ophthalmic use. METHODS: Using principles of microelectromechanical systems engineering, a mini drug pump was fabricated. The pumping mechanism is based on electrolysis, and the pump includes a drug refill port as well as a check valve to control drug delivery. Drug pumps were tested first on the benchtop and then after implantation in rabbits. For the latter, we implanted 4 elliptical (9.9 x 7.7 x 1.8 mm) non-electrically active pumps into 4 rabbits. The procedure is similar to implantation of a glaucoma seton. To determine the ability to refill and also the patency of the cannula, at intervals of 4 to 6 weeks after implantation, we accessed the drug reservoir with a transconjunctival needle and delivered approximately as low as 1 microL of trypan blue solution (0.06%) into the anterior chamber. Animals were followed up by slit-lamp examination, photography, and fluorescein angiography. RESULTS: Benchtop testing showed 2.0 microL/min delivery when using 0.4 mW of power for electrolysis. One-way valves showed reliable opening pressures of 470 mm Hg. All implanted devices refilled at 4- to 6-week intervals for 4 to 6 months. No infection was seen. No devices extruded. No filtering bleb formed over the implant. CONCLUSIONS: A prototype ocular mini drug pump was built, implanted, and refilled. Such a platform needs more testing to determine the long-term biocompatibility of an electrically controlled implanted pump. Testing with various pharmacologic agents is needed to determine its ultimate potential for ophthalmic use.