A boussinesq model of natural convection in the human eye and the formation of Krukenberg's spindle

The cornea of the human eye is cooled by the surrounding air and by evaporation of the tear film. The temperature difference between the cornea and the iris (at core body temperature) causes circulation of the aqueous humor in the anterior chamber of the eye. Others have suggested that the circulation pattern governs the shape of the Krukenberg spindle, a distinctive vertical band of pigment on the posterior cornea surface in some pathologies. We modeled aqueous humor flow the human eye, treating the humor as a Boussinesq fluid and setting the corneal temperature based on infrared surface temperature measurements. The model predicts convection currents in the anterior chamber with velocities comparable to those resulting from forced flow through the gap between the iris and lens. When paths of pigment particles are calculated based on the predicted flow field, the particles circulate throughout the anterior chamber but tend to be near the vertical centerline of the eye for a greatest period of time. Further, the particles are usually in close proximity to the cornea only when they are near the vertical centerline. We conclude that the convective flow pattern of aqueous humor is consistent with a vertical pigment spindle. © 2002 Biomedical Engineering Society. PAC2002: 4266Ew, 8710+e, 8719Pp     

Aqueous humor dynamics and the iris

Solutes concentration in the aqueous humor of the eye is highest near the ciliary processes in the posterior chamber (p.c.) and lowest near the trabecular meshwork in the anterior chamber (a.c.). The high osmotic gradient across the semipermeable iris causes it to easily move forward at this location and occasionally occlude the iridocorneal angle. Vector analysis of the forces generated by miosis helps explain on osmotic grounds why it reduces the intraocular pressure, while at the same time the analysis elucidates the reason for the higher frequency of angle closure glaucoma when the anterior chamber is shallow.     

基于双光子共聚焦成像的急性高眼压大鼠小梁网孔隙率变化研究

目的获取不同眼压下小梁网组织深层结构信息,为小梁网房水外排通道生理功能的探索奠定组织形态学基础。方法将4只SD大鼠分成A、B两组每组2只,处死后于左眼球分别加压40mm Hg(A组)、加压60 mm Hg(B组),维持24 h。右眼均为未加压对照组,利用双光子共聚焦成像系统采集每只眼球的小梁网组织形态图:从眼底剖开眼球后照射前房角小梁网处,每2μm采集图像,直至图像模糊停止。结果未加压的对照组眼球小梁网处胶原纤维排列较为规则,孔隙明显,小梁网与周围组织界限分明。加压40 mm Hg的A组眼球小梁网胶原纤维出现了部分塌缩,小梁网与周围组织出现融合,偶尔可见一些孔隙,胶原纤维排列呈无序状态。加压60 mm Hg的B组眼球小梁网胶原纤维断裂较明显,临管区被挤压到完全塌陷,与周围组织已无法分辨。A、B两组动物的小梁网均表现出骨架断裂,组织变薄,逐渐与周围组织融为一体,以及出现远端的巩膜静脉塌缩的现象。与A组眼球相比,B组眼球的葡萄膜小梁网孔隙率略有增加。结论急性眼内压升高可能引发房水外排通道结构异常,主要表现为前房角小梁网组织压缩、巩膜静脉塌陷。这一解剖结构异常造成房水排出困难,从而又加剧了眼内压的升高。     

Rho GTPase/Rho Kinase Inhibition as a Novel Target for the Treatment of Glaucoma

Rho kinase (ROCK1 and ROCK2) is a serine/threonine kinase that serves as an important downstream effector of Rho GTPase, and plays a critical role in regulating the contractile tone of smooth muscle tissues in a calcium-independent manner. Several lines of experimental evidence indicate that modulating ROCK activity within the aqueous humor outflow pathway using selective inhibitors could achieve very significant benefits for the treatment of increased intraocular pressure in patients with glaucoma. The rationale for such an approach stems from experimental data suggesting that both ROCK and Rho GTPase inhibitors can increase aqueous humor drainage through the trabecular meshwork, leading to a decrease in intraocular pressure. In addition to their ocular hypotensive properties, inhibitors of both ROCK and Rho GTPase have been shown to enhance ocular blood flow, retinal ganglion cell survival and axon regeneration. These properties of the ROCK and Rho GTPase inhibitors indicate that targeting the Rho GTPase/ROCK pathway with selective inhibitors represents a novel therapeutic approach aimed at lowering increased intraocular pressure in glaucoma patients.     

Numerical Solution of Ocular Fluid Dynamics in a Rabbit Eye: Parametric Effects

Numerical calculations of the aqueous humor dynamics in the anterior chamber of a rabbit's eye are presented to delineate the basic flow mechanisms. The calculations are based on a geometrical model of the eye, which represents the Trabecular meshwork (TM) as a multilayered porous zone of specified pore sizes and void fraction. The outer surface of the cornea is assumed to be at a fixed temperature (corresponding to the ambient temperature), while the iris surface is assumed to be at the core body temperature. Results are obtained for both the horizontal upward-facing orientation of the eye, and the vertical orientation of the eye. Parameters varied include: the temperature difference between the iris and the cornea to underscore the important role of buoyancy in driving the aqueous humor flow; and, the pupil size reflecting different levels of ambient light. Buoyancy is observed to be the dominant driving mechanism for the convective motion in both orientations of the eye. Variations in the pupil size appear to have little influence on the IOP or flow distribution in view of the dominant role of buoyancy in controlling the flow motion. The study provides distributions of the shear stress and flow patterns and delineates the important role of the eye-orientation on these results.     

Numerical Simulations of Ethacrynic Acid Transport from Precorneal Region to Trabecular Meshwork

Topical application of drugs for treatment of intraocular diseases is often limited by inadequate transport and induced toxicity in corneal tissues. To improve the drug delivery, a mathematical model was developed to numerically simulate the transport process of ethacrynic acid (ECA), a potential drug for glaucoma treatment, in the anterior segment of a typical human eye. The model considered diffusion of ECA in all tissues and the aqueous humor (AH) as well as convection of ECA in the AH. The simulation results showed that ECA concentration in the eye depended on the rate of AH production, the half-life of ECA in the precorneal tear film, and the transport parameters in the model. In addition, the main pathway for ECA clearance from the eye was the trabecular meshwork (TM) and the rate of clearance was approximately proportional to the AH production rate. The model predicted that the most effective approach to improving topical drug delivery was to prolong its half-life in the precorneal tear film. These simulation results and model prediction, which could be verified experimentally, might be useful for improving delivery of ECA and other therapeutic agents to the TM as well as other tissues in the anterior segment of the eye.     

Effects of copper depletion andd-penicillamine treatment on the ocular inflammatory response

Rabbits placed on a copper (Cu)-deficient diet for four weeks had lower plasma Cu concentration, ferroxidase activity, and antioxidant activity than rabbits fed an identical Cu-adequate basel diet. Inflamed aqueous humor from rabbits on the Cu deficient diet also had less Cu, ferroxidase and antioxidant activity than inflamed aqueous humor from control rabbits. These differences mirrored antioxidant activity than inflamed aqueous humor from control rabbits. These differences mirrored changes in plasma levels. Furthermore, there was an increase in cellular infiltration into the aqueous humor of Cu-deficient rabbits. It is hypothesized that in Cu-deficient rabbits there is an increase in free radical production and formation of chemotactic substances in the eye due to the decreased aqueous humor concentration of the endogenous antioxidant, ceruloplasmin. It is therefore likely that ceruloplasmin plays a protective role in the intraocular inflammatory response.     

3D simulation of the aqueous flow in the human eye

Glaucoma results in an increase in the resistance of the aqueous humor outflow, which in turn leads to an increase of the intraocular pressure (IOP). Several treatments are proposed to reduce and stabilize the IOP that include medications, filtering surgery and glaucoma drainage devices (GDD). So far computational fluid dynamics (CFD) modeling of the eye drainage system has not yet been well studied. Therefore our goal was to provide a 3D CFD model of the eye based on the anatomy of a real human eye. Such a tool would serve for future evaluation of new glaucoma surgical techniques involving, for example, GDD. The model was based on stacks of microphotographs from human eye slides from which digital processing of the images of the eye structure and 3D reconstruction of the model were performed. Simulations of the distribution of pressure and flow velocity in the model of a healthy eye gave results comparable to physiology references. Mimicking glaucoma conditions led to an increase of the IOP from normal range, which went down to lower values after a filtering procedure. Further refinements in the boundary conditions for the filtering procedure shall improve the accuracy of this innovative tool for modeling glaucoma surgery.     

Simulation of aqueous humor hydrodynamics in human eye heat transfer

The need to develop accurate representation of the human eye for the purpose of physiological studies is important to ensure that the predicted results are reliable. The presence of natural circulation of aqueous humor (AH) is evident from clinical, experimental and simulated observations. Most of the thermal models of the human eye that are found in the literature, however, had assumed a stagnant AH inside the anterior chamber. In this paper, a two-dimensional model of the human eye is developed where the circulation of AH inside the anterior chamber is included. The effects of the AH flow on the temperature distribution inside the eye are investigated. The natural circulation of AH is found to increase the temperature and distorts the temperature profile in the cornea and anterior chamber. Further investigations, where an artificial heat source is introduced inside the human eye suggest that AH flow plays a role in the heat transfer at the anterior region of the eye although this has yet to be quantified experimentally.     

The course of carrageenin-induced iridocyclitis in rabbits

On the basis of biochemical indices in the aqueous humor of the eye strictly related to intensity of inflammation, and morphologic observations with the slit-lamp microscope, dynamics of experimental carrageenin-induced inflammation of the anterior chamber of the eye was studied. Carrageenin-induced inflammation was characterized by intensity of changes in the aqueous humor within a few hours after infection of the inflammatory factor. Peak intensity of the disease process was observed six hours after administration of the inflammatory factor. Protein levels, seromucoid, sialic acid and proteolytic activity in the aqueous humor were correlated with intensity of clinical symptoms observed with the slit lamp. Carrageenin-induced inflammation of the anterior chamber of the eye is an entirely local reaction since the blood serum showed no significant abnormalities of the parameters that were studied. This model, based on biochemical and biomicroscopic studies, may prove useful in the studies of the dynamics of inflammation of the anterior chamber of the eye and for evaluation of anti-inflammatory drugs used in ophthalmology.     

Effects of aqueous humor hydrodynamics on human eye heat transfer under external heat sources

The majority of the eye models developed in the late 90s and early 00s considers only heat conduction inside the eye. This assumption is not entirely correct, since the anterior and posterior chambers are filled aqueous humor (AH) that is constantly in motion due to thermally-induced buoyancy. In this paper, a three-dimensional model of the human eye is developed to investigate the effects AH hydrodynamics have on the human eye temperature under exposure to external heat sources. If the effects of AH flow are negligible, then future models can be developed without taking them into account, thus simplifying the modeling process. Two types of external thermal loads are considered; volumetric and surface irradiation. Results showed that heat convection due to AH flow contributes to nearly 95% of the total heat flow inside the anterior chamber. Moreover, the circulation inside the anterior chamber can cause an upward shift of the location of hotspot. This can have significant consequences to our understanding of heat-induced cataractogenesis.     

Short note: Aqueous humour water clusters: the importance of the physical properties of the aqueous humour in primary open angle glaucoma

The size, form and charge of the stabilized water clusters present in the aqueous humour of the mammalian eye influence the facility for aqueous flow through the pupillary ball valve and through the trabecular meshwork. The properties of the clusters can be influenced in many different ways, all of which can influence the anterior and posterior chamber intraocular pressures as well as the uveoscleral outflow.     

Studies on the induction of anterior chamber-associated immune deviation (ACAID). III. Induction of ACAID depends upon intraocular transforming growth factor-beta.

Delayed hypersensitivity (DH), the prototypical form of cell-mediated immune responsiveness, is mediated with the participation of considerable nonspecific inflammation which necessarily disrupts the anatomic integrity of involved and adjacent tissues. Damage of this type is of minor consequence to many visceral and cutaneous organs, but is of devastating consequence for organs such as the eye and the brain. At least in the case of the eye, the organ is remarkably adept at regulating the immune system's ability to respond to intraocular antigens by selectively down-regulating both the induction and expression of delayed hypersensitivity while leaving other effector modalities intact. This ability of the eye to selectivity down-regulate systemic DH responses to intracamerally inoculated antigens is known as anterior chamber-associated immune deviation (ACAID) and is mediated in part by antigen-specific regulatory T cells. Recent work suggests that macrophages (M phi) that reside in the iris and ciliary body can migrate out of an antigen-bearing eye and activate regulatory T cells within the spleen. In an effort to understand the mechanism by which intraocular M phi interact with antigen in the anterior chamber of the eye (AC) and subsequently induce splenic regulatory cells in ACAID, we have investigated what role, if any, the AC microenvironment itself plays in ACAID induction. The results reveal that CD45- parenchymal iris/ciliary cells secrete a soluble factor(s) locally and into the aqueous humor which endows resident, mature M phi with ACAID-inducing capabilities. Mice receiving infusions of these altered, antigen-pulsed M phi are incapable of mounting a significant DH response following immunization with antigen in adjuvant. Importantly, the ACAID-inducing effect is achieved when conventional, extraocular M phi are exposed in vitro to a soluble factor present in aqueous humor or culture SN from iris and ciliary body cells. Further investigations into the identity of this factor reveal it to be transforming growth factor-beta (TGF-beta). The role of TGF-beta in the generation of ACAID, as well as the implications of these findings to an understanding of immunologic privilege in general, are discussed.     

Non-secretion of mutant proteins of the glaucoma gene myocilin in cultured trabecular meshwork cells and in aqueous humor

Until recently, very little was known about the molecular mechanisms responsible for the development of glaucoma, a leading cause of blindness worldwide. Mutations in the glaucoma gene myocilin (MYOC, GLC1A) are associated with elevated intraocular pressure and the development of autosomal dominant juvenile glaucoma and a subset of adult-onset glaucoma. MYOC is expressed in the trabecular meshwork (TM), a tissue responsible for drainage of aqueous humor from the eye, and the tissue involved in elevated intraocular pressure associated with glaucoma. To better understand the role of MYOC in glaucoma pathogenesis, we examined the expression of normal and mutant myocilin in cultured ocular (TM) and non-ocular cells as well as in the aqueous humor of patients with and without MYOC glaucoma. Normal myocilin was secreted from cultured cells, but very little to no myocilin was secreted from cells expressing five different mutant forms of MYOC. In addition, no mutant myocilin was detected in the aqueous humor of patients harboring a nonsense MYOC mutation (Q368X). Co-transfection of cultured cells with normal and mutant myocilin led to suppression of normal myocilin secretion. These studies suggest that MYOC glaucoma is due either to insufficient levels of secreted myocilin or to compromised TM cell function caused by congestion of the TM secretory pathway.     

Ascorbate in aqueous humor protects against myeloperoxidase-induced oxidation.

Chemotactic factors can cause polymorphonuclear leukocytes to release the contents of azurophilic granules, including the enzymes beta-glucuronidase and myeloperoxidase. In the presence of aqueous humor from the anterior chamber of the rabbit eye, the supernatant from stimulated leukocytes contains beta-glucuronidase, but myeloperoxidase is not detectable. Studies with aqueous humor and partially purified human myeloperoxidase suggest that this phenomenon is not due to a failure of enzyme release. The factor responsible for the inability to detect MPO in the assay system is heat-labile, dialyzable, and reversed by ascorbate oxidase. Comparable assay inhibition is produced by ascorbic acid at a concentration present in either human or rabbit aqueous humor. The ability of aqueous humor to protect against myeloperoxidase-induced oxidation may contribute to several diverse phenomena, including the susceptibility of the eye to Candida infection and a prolonged half-life for several inflammatory mediators in the anterior chamber.     

Diffusion of fosfomycin into the human and rabbit eye (aqueous humor and vitreous body)

The intraocular distribution of fosfomycin was studied in 32 patients undergoing cataract surgery and in 8 rabbits after experimental infection of one eye by Staphylococcus aureus. Concentrations found 1 to 6 hours after termination of a 4 g fosfomycin infusion ranged from 14 to 18.8 mg/l in the aqueous humor and 8 to 12.5 mg/l in the vitreous body. These levels are higher than the MICs for 80 to 90% of the bacteria responsible for endophthalmitis. In each rabbit, the fosfomycin concentration in the infected eye as compared to the healthy eye was increased 2.5 to 5--fold for the aqueous humor and 4.9 to 19.2--fold for the vitreous body. Fosfomycin, in association with a third generation cephalosporin (ceftriaxone) or one of the new quinolones (pefloxacin) can be recommended for the prevention or early treatment of endophthalmitis.     

Chemotactic activity in aqueous humor from patients with anterior uveitis

Anterior uveitis, inflammation of the iris or ciliary body of the eye, may be associated with a variety of systemic diseases. Although a leukocytic infiltrate is characteristic of anterior uveitis, few studies have sought to detect factors in aqueous humor that could attract neutrophils or monocytes into the anterior chamber. Using modified Boyden chambers, we found that a 5% concentration of aqueous humor from patients with anterior uveal inflammation induced monocyte movement comparable to optimal or near-optimal concentrations of C (complement)5a or platelet-derived growth factor. Aqueous humor from patients with anterior uveitis induced significantly more monocyte migration than did aqueous humor from two sets of controls (either patients undergoing cataract extraction or patients with posterior uveitis). "Checkerboard" or gradient analysis indicated that a majority of inflammatory disease samples induced monocyte chemotaxis (directed migration) while the control aqueous humor consistently induced chemokinesis (stimulated random migration) (P less than 0.02). Despite their ability to induce monocyte migration, samples tended to induce minimal neutrophil migration with the exception of aqueous humor that was obtained from one patient with acute anterior disease. This sample induced marked chemokinesis. Identification of chemotactic activity may clarify the pathogenesis of uveitis and the characterization of leukocyte migration factors in aqueous humor may help define subsets of anterior uveal inflammation.     

一氧化氮在人工晶体植入术后眼内炎症反应中的作用

目的:探讨一氧化氮(NO)在人工晶体植入术后眼内炎症反应中的作用。方法:将新西兰白兔随机分成3组:(1)对照组;(2)L-精氨酸(L-Arg)组;(3)N-硝基-L-精氨酸(L-NNA)组。各组动物均施行晶体囊外摘除术(ECCE)+人工晶体囊袋内植入术(IOL),并于术后0、1、3、7、14、30 d观察术后眼内炎症反应,包括检查角膜水肿和前房渗出、房水细胞计数和分类;同时测定房水NO₂^-/NO₃^-含量。结果:L-Arg组前房渗出、房水细胞总数和NO₂^-/NO₃^-含量均高于对照组;而L-NNA组前房渗出、房水细胞总数和房水NO₂^-/NO₃^-含量均低于对照组。结论:NO在人体晶体植入术后眼内炎症反应中起一定的作用;使用NOS抑制剂可减少NO产生,降低术后眼内炎症反应。     

兔眼房水引流至不同部位的降眼压效果

目的 观察并比较3种途径（引流至角膜缘、赤道部及眼后节）植入医用硅胶管降眼压的效果。方法 选择健康新西兰白兔45只,单眼植入医用硅胶管将房水引流。根据植入途径分为角膜缘组、赤道部组和眼后节组,每组15只。结果 对各实验组术前、术后眼压值进行统计对比,术后4周内眼后节组降眼压幅度最大（26.6%）,赤道部组次之（16.2%）,角膜缘组最小（1.2%）;术后1、2和4周,赤道部组、角膜缘组、眼后节组的术前、术后眼压值比较差异均有统计学意义（P<0.01）;术后4周,眼后节组眼压下降幅度最大,且各组间眼压值差异均有统计学意义（P<0.01）。结论 将房水引流至眼后节时眼压下降幅度大,可为临床手术提供参考。     

The relationship between cytokine level and nitric oxide content in aqueous humor after intraocular lens implantation

The relationship between cytokine level and nitric oxide content in aqueous humor after intraocular lens implantation