The development of fluid transport systems was a key event in the evolution of animals and plants. While within vertebrates branched geometries predominate, the choriocapillaris, which is the microvascular bed that is responsible for the maintenance of the outer retina, has evolved a planar topology. Here we examine the flow and mass transfer properties associated with this unusual geometry. We show that as a result of the form of the choriocapillaris, the blood flow is decomposed into a tessellation of functional vascular segments of various shapes delineated by separation surfaces across which there is no flow, and in the vicinity of which the transport of passive substances is diffusion-limited. The shape of each functional segment is determined by the distribution of arterioles and venules and their respective relative flow rates. We also show that, remarkably, the mass exchange with the outer retina is a function of the shape of each functional segment. In addition to introducing a novel framework in which the structure and function of the metabolite delivery system to the outer retina may be investigated in health and disease, the present work provides a general characterisation of the flow and transfers in multipole Hele-Shaw configurations.

Genome-wide association studies have identified the chromosome 10q26 (Chr10) locus, which contains the age-related maculopathy susceptibility 2 (ARMS2) and high temperature requirement A serine peptidase 1 (HTRA1) genes, as the strongest genetic risk factor for age-related macular degeneration (AMD) [L.G. Fritsche et al., Annu. Rev. Genomics Hum. Genet. 15, 151–171, (2014)]. To date, it has been difficult to assign causality to any specific single nucleotide polymorphism (SNP), haplotype, or gene within this region because of high linkage disequilibrium among the disease-associated variants [J. Jakobsdottir et al. Am. J. Hum. Genet. 77, 389–407 (2005); A. Rivera et al. Hum. Mol. Genet. 14, 3227–3236 (2005)]. Here, we show that HTRA1 messenger RNA (mRNA) is reduced in retinal pigment epithelium (RPE) but not in neural retina or choroid tissues derived from human donors with homozygous risk at the 10q26 locus. This tissue-specific decrease is mediated by the presence of a noncoding, cis-regulatory element overlapping the ARMS2 intron, which contains a potential Lhx2 transcription factor binding site that is disrupted by risk variant rs36212733. HtrA1 protein increases with age in the RPE–Bruch’s membrane (BM) interface in Chr10 nonrisk donors but fails to increase in donors with homozygous risk at the 10q26 locus. We propose that HtrA1, an extracellular chaperone and serine protease, functions to maintain the optimal integrity of the RPE–BM interface during the aging process and that reduced expression of HTRA1 mRNA and protein in Chr10 risk donors impairs this protective function, leading to increased risk of AMD pathogenesis. HtrA1 augmentation, not inhibition, in high-risk patients should be considered as a potential therapy for AMD.

The choriocapillaris is a capillary bed located in a thin layer adjacent to the outer retina and is part of the oxygen delivery system to the photoreceptors of the eye. The blood flow is approximately planar and is serviced by microvessels, which join the choriocapillaris through inlets perpendicular to its plane. Capillaries are densely organised and separated by avascular septal posts, which direct the blood flow. The capillary bed is composed of a juxtaposition of tessellating vascular units called lobules, which are filled and drained independently from each other. A theoretical analysis of the blood flow in an idealised model of a lobule of the choriocapillaris is developed and studied. Lobules are modelled as tessellating polygonal prisms, where the upper and lower surfaces correspond to planar parallel membranes. The septae are modelled as cylinders randomly distributed between the two membranes. Feeding arterioles and draining venules are modelled as inlets and outlets connecting at the lower surface of the prism perpendicularly to the plane of the lobule. An inlet is placed inside the lobule, while an outlet is placed at each of the vertices. The polygonal prism can be formally subdivided into a set of triangular prisms with one inlet and two outlets, each of them located at one of the vertices. The triangular prisms are taken to be isosceles, and are therefore characterised by a vertex angle ω at the inlet and a span L. The flow is viscously dominated, and is investigated in the lubrication limit, in which the characteristic thickness of the prism is much smaller than the diameter of the cylinders. As a result of the geometry, a stagnation point is located midway between the outlets. A separation streamline joins the inlet and the stagnation point. The pressure drop p and the average fluid particle residence time T are analysed as a function of the angle at the inlet ω and the septae volume fraction Φ. When no cylinders are present (Φ = 0), an analytical expression for the pressure field is calculated by conformal mapping. Close to the triangle walls, the flow is quasi-parallel and characterised by a shorter fluid particle residence time. In the vicinity of the stagnation point, the velocity decreases and the residence time diverges logarithmically with the distance to the stagnation streamline. The minimum in pressure drop corresponds to a maximum in residence time, and is obtained for ω = π/2. Asymptotic expressions for the pressure drop and average residence time are formulated in both the limits ω 1 and π − ω 1. The impact of Φ on the flow is characterised by solving the equations for the flow numerically and using the Darwin drift framework. We show that the pressure drop is approximately proportional to 1 + 2Φ for relatively small Φ, and that T is proportional to 1 − Φ regardless of the void fraction or shape of the septae. In the case Φ = 0, the average † Email address for correspondence: moussa.zouache.10@ucl.ac.uk 38 M. A. Zouache, I. Eames and P. J. Luthert residence time equals the volume of ...

The two most common genetic contributors to age-related macular degeneration (AMD), a leading cause of irreversible vision loss worldwide, are variants associated with CFH-CFHR5 on chromosome 1 (Chr1) and ARMS2/HTRA1 on chromosome 10 (Chr10). We sought to determine if risk and protective variants associated with these two loci drive differences in macular retinal thickness prior and subsequent to the onset of clinically observable signs of AMD. We considered 299 individuals (547 eyes) homozygous for risk variants or haplotypes on Chr1 or Chr10 exclusively (Chr1-risk and Chr10-risk, respectively) or homozygous for a neutral haplotype (Chr1-neu), for the protective I62 tagged haplotype (Chr1-prot-I62) or for the protection conferring CFHR1/3 deletion haplotype (Chr1-prot-del) on Chr1 without any risk alleles on Chr10. Among eyes with no clinically observable signs of AMD, the deletion of CFHR1/3, which is strongly protective against this disease, is associated with significantly thicker retinas in the perifovea. When controlling for age, Chr10-risk eyes with early or intermediate AMD have thinner retinas as compared to eyes from the Chr1-risk group with similar disease severity. Our analysis indicates that this difference likely results from distinct biological and disease initiation and progression events associated with Chr1- and Chr10-directed AMD.

Background Single-variant associations with age-related macular degeneration (AMD), one of the most prevalent causes of irreversible vision loss worldwide, have been studied extensively. However, because of a lack of refinement of these associations, there remains considerable ambiguity regarding what constitutes genetic risk and/or protection for this disease, and how genetic combinations affect this risk. In this study, we consider the two most common and strongly AMD-associated loci, the CFH-CFHR5 region on chromosome 1q32 (Chr1 locus) and ARMS2/HTRA1 gene on chromosome 10q26  (Chr10 locus). Results By refining associations within the CFH-CFHR5 locus, we show that all genetic protection against the development of AMD in this region is described by the combination of the amino acid-altering variant CFH I62V (rs800292) and genetic deletion of CFHR3/1. Haplotypes based on CFH I62V, a CFHR3/1 deletion tagging SNP and the risk variant CFH Y402H are associated with either risk, protection or neutrality for AMD and capture more than 99% of control- and case-associated chromosomes. We find that genetic combinations of CFH-CFHR5 haplotypes (diplotypes) strongly influence AMD susceptibility and that individuals with risk/protective diplotypes are substantially protected against the development of disease. Finally, we demonstrate that AMD risk in the ARMS2/HTRA1 locus is also mitigated by combinations of CFH-CFHR5 haplotypes, with Chr10 risk variants essentially neutralized by protective CFH-CFHR5 haplotypes. Conclusions Our study highlights the importance of considering protective CFH-CFHR5 haplotypes when assessing genetic susceptibility for AMD. It establishes a framework that describes the full spectrum of AMD susceptibility using an optimal set of single-nucleotide polymorphisms with known functional consequences. It also indicates that protective or preventive complement-directed therapies targeting AMD driven by CFH-CFHR5 risk haplotypes may also be effective when AMD is driven by ARMS2/HTRA1 risk variants.

Aging is associated with a broad range of visual impairments that can have dramatic consequences on the quality of life of those impacted. These changes are driven by a complex series of alterations affecting interactions between multiple cellular and extracellular elements. The resilience of many of these interactions may be key to minimal loss of visual function in aging; yet many of them remain poorly understood. In this review, we focus on the relation between retinal neurons and their respective mass transport systems. These metabolite delivery systems include the retinal vasculature, which lies within the inner portion of the retina, and the choroidal vasculature located externally to the retinal tissue. A framework for investigation is proposed and applied to identify the structures and processes determining retinal mass transport at the cellular and tissue levels. Spatial variability in the structure of the retina and changes observed in aging are then harnessed to explore the relation between variations in neuron populations and those seen among retinal metabolite delivery systems. Existing data demonstrate that the relation between inner retinal neurons and their mass transport systems is different in nature from that observed between the outer retina and choroid. The most prominent structural changes observed across the eye and in aging are seen in Bruch’s membrane, which forms a selective barrier to mass transfers at the interface between the choroidal vasculature and the outer retina.

We study the flow and transport of heat or mass, modelled as passive scalars, within a basic geometrical unit of a three-dimensional multipolar flow – a triangular prism – characterised by a side length $L$, a normalised thickness $0.01\leqslant \unicode[STIX]{x1D700}\leqslant 0.1$ and an apex angle $0<\unicode[STIX]{x1D6FC}<\unicode[STIX]{x03C0}$, and connected to inlet and outlet pipes of equal normalised radius $0.01\leqslant \unicode[STIX]{x1D6FF}\leqslant 0.1$ perpendicularly to the plane of the flow. The flow and scalar fields are investigated over the range $0.1\leqslant Re_{p}\leqslant 10$ and $0.1\leqslant Pe_{p}\leqslant 1000$, where $Re_{p}$ and $Pe_{p}$ are respectively the Reynolds and Péclet numbers imposed at the inlet pipe when either a Dirichlet ($\text{D}$) or a Neumann ($\text{N}$) scalar boundary condition is imposed at the wall unattached to the inlets and outlets. A scalar no-flux boundary condition is imposed at all the other walls. An axisymmetric model is applied to understand the flow and scalar transport in the inlet and outlet regions, which consist of a turning region close to the pipe centreline and a channel region away from it. A separate two-dimensional model is then developed for the channel region by solving the integral form of the momentum and scalar advection–diffusion equations. Analytical relations between geometrical, flow and scalar transport parameters based on similarity and integral methods are generated and agree closely with numerical solutions. Finally, three-dimensional numerical calculations are undertaken to test the validity of the axisymmetric and depth-averaged analyses. Dominant flow and scalar transport features vary dramatically across the flow domain. In the turning region, the flow is a largely irrotational straining flow when $\unicode[STIX]{x1D700}\geqslant \unicode[STIX]{x1D6FF}$ and a dominantly viscous straining flow when $\unicode[STIX]{x1D700}\ll \unicode[STIX]{x1D6FF}$. The thickness of the scalar boundary layer scales to the local Péclet number to the power $1/3$. The diffusive flux $j_{d}$ and the scalar $C_{s}$ at the wall where ($\text{D}$) or ($\text{N}$) is imposed, respectively, are constant. In the channel region, the flow is parabolic and dominated by a source flow near the inlet and an irrotational straining flow away from it. When $(\text{D})$ is imposed the scalar decreases exponentially with distance from the inlet and the normalised scalar transfer coefficient converges to $\unicode[STIX]{x1D6EC}_{\infty }=2.5694$. When $(\text{N})$ is imposed, $C_{s}$ varies proportionally to surface area. Transport in the straining region downstream of the inlet is diffusion-limited, and $j_{d}$ and $C_{s}$ are functions of the geometrical parameters $L$, $\unicode[STIX]{x1D700}$, $\unicode[STIX]{x1D6FC}$ and $\unicode[STIX]{x1D6FF}$. In addition to describing the fundamental properties of the flow and passive transport in multipolar configurations, the present work demonstrates how geometrical and flow parameters should be set to control transfers in the different regions of the flow domain.

The purpose of this study was to characterize foveal pit morphology in an African (Ghanaian) population, to compare it to that of a Caucasian group and to determine if it varied with age in the two populations. Methods: The depth, diameter, slope, and volume of the foveal pit were interpolated from optical coherence tomography volume scans recorded in 84 Ghanaian and 37 Caucasian individuals. Their association with age, sex, and ethnicity was investigated using multilevel regression models. Results: The foveal pit differed significantly in width, slope, and volume between Ghanaian men and women (P < 0.001), but only in width and volume between Caucasian men and women (P < 0.01). In Ghanaians, age was associated with a narrowing of the foveal depression and a reduction of its volume. Overall, these changes were more pronounced in women as compared to men and were largely absent from the Caucasian group. When controlled for age, the foveal pit of Ghanaians was significantly wider and larger in volume as compared to the Caucasian group (P < 0.001). Conclusions: The morphology of the foveal pit differs between African and Caucasian individuals. These anatomic differences should be considered when examining differences in prevalence and clinical features of vitreoretinal disorders involving the fovea between the two populations. Translational Relevance: Differences in retinal anatomy may partly explain variations in the prevalence and clinical features of retinal diseases between Africans and Caucasians. Such differences should be adequately considered in diagnoses and monitoring of ocular diseases in patients with African ancestry.