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Retinopathy of prematurity (ROP) is a vasoproliferative retinal disorder. Although its clinical presentation, classification, and treatment has been known in detail for several years, ROP remains as one of the leading causes of treatable childhood blindness worldwide, mainly in middle-income countries. Understanding ROPs epidemiology, pathophysiology, and risk factors enables better timely screening, monitoring, and treatment. ROP is a complex disease, which needs a multidisciplinary team to ensure appropriate care and management.

Clinical investigation of gene- and stem cell-based therapies has greatly expanded in recent years with treatment aimed at a diverse array of inherited retinal disorders (IRDs) (Garafalo et al. Prog Retin Eye Res, 2019:100827; Takahashi et al. Ophthalmic Genet, 2018;39:560–568) and non-hereditary retinal degenerations. Access to the subretinal and/or suprachoroidal space (SCS) is of particular interest for targeted delivery of retinal genetic or cellular therapeutics. Surgical approaches for suprachoroidal and suprachoroidal-to-subretinal gene and cell therapy delivery continue to be refined as new treatment modalities are developed. The safety, efficacy and durability of emerging therapies will also need to be validated in the context of their delivery method. This chapter will explore the potential advantages of therapeutic delivery via the SCS and compare with other approaches. More research is warranted to improve technique-related safety, ease of use, and reproducibility of the current methodologies.

Nerve growth factor (NGF) plays a crucial role in retinal disorders, as suggested by in vitro/in vivo models. The major effect embraces the neuroprotective activity on retinal ganglion cells (RGCs) undergoing degeneration, as observed in experimental diabetic retinopathy, age-related and diabetic macular degeneration, and some vitreoretinal diseases. Focused experiments suggested that locally applied NGF (intravitreal delivery) not only allowed the counteraction of RGC degeneration but also provided data for a whole retina restoration. The currently available retinal microsurgery allows the collection of human aqueous and more interesting vitreous (vitreal reflux) humors. The recent biomolecular analysis highlights the possibility to identify disease-associated biomarkers and allow the monitoring of retinal impairments with sustain to the retinal imaging. Coupled to other soluble mediators, NGF has been quantified in aqueous (slightly expressed) from diabetic retinopathy-suffering patients (cataract surgery) and vitreal reflux (significantly impaired) of diabetic macular degeneration-suffering patients (intravitreal surgery). Although the reasons of these NGF impairments are not fully comprehended, some retinal cells (glial cells, bipolar neurons, and RGCs) have been recognized partially responsible for these local changes.Taken together, the recent progress in the ocular microsurgeries might be associated with sampling of small amount of ocular humors, allowing the collection of biochemical information about diseased retina and the monitoring of treatment. The chance to detect NGF and likewise other neuroprotective or pro-/anti-inflammatory factors in these fluids would open to the possibility to identify biomarkers of early diagnosis or monitoring of retinal disease evolution/therapy (precision medicine).

One of the most common degenerative retinal disorders is “pathologic myopia that is defined by an axial length of more than 26.5 mm (high myopia) in the presence of posterior staphyloma.

Retinal disorders are progressive in nature and remain passive for years together without causing any visual indication of disorder even to the subject themselves. Hence automated and intelligent methods of analysis of retinal scanned images are quite necessary to improve accuracy and detection time to aid in early detection and consequent treatment. This paper presents the findings of a vast literature survey done with respect to automated detection techniques by analyzing their underlying principles and obtained performance results. The entire survey has been done based on two main evaluation metrics namely detection accuracy and time of convergence. This is based on the underlying principle that migration from manual and conventional methods to automated systems is to improve the accuracy by overcoming the errors incurred in manual detection methods and at the same time to reduce the painstakingly long time required in the manual method of observation and detection. This paper proposes a computation complexity reduction mechanism in dehazing by utilizing the convolution properties of deep belief neural networks to train the data sets in the least possible time with improved image quality.

The vitreous is the transparent gel in the posterior segment. Vitreous degeneration can be associated with common ophthalmic symptoms and pathologies. The retina is derived from the optic vesicle, with the outer wall becoming the retinal pigment epithelium, and an inner wall that becomes the neural retina. The retina lines the inside of the eye, that convert light focused onto it into neural signals, and send these signals on to the brain for visual recognition. This chapter aims to discuss the presentation and management of some commonly seen pathologies of the vitreous and surgical management of retinal disorders.

Patient-derived human-induced pluripotent stem cells (iPSCs) have been critical in advancing our understanding of the underlying mechanisms of numerous retinal disorders. Many of these retinal disorders have no effective treatment and result in severe visual impairment and even blindness. Among the retinal degenerative diseases modeled by iPSCs are age-related macular degeneration (AMD), glaucoma, Leber congenital amaurosis (LCA), retinitis pigmentosa (RP), and autosomal dominant retinitis pigmentosa (adRP). In addition to studying retinal disease ontogenesis and pathology, hiPSCs have clinical and pharmacological applications, such as developing drug screening and gene therapy approaches and new cell-based clinical treatments. Recent studies have primarily focused on three retinal cell fates – retinal pigmented epithelium cells (RPE), retinal ganglion cells (RGCs), and photoreceptor cells – and have demonstrated that hiPSCs have great potential for increasing our knowledge of and developing treatments for retinal degenerative disorders.

Inherited retinal dystrophies (IRDs) are a broad group of neurodegenerative disorders associated with reduced or deteriorating visual system. In the retina, cells are under constant oxidative stress, leading to elevated reactive oxygen species (ROS) generation that induces mitochondrial dysfunction and alteration of the mitochondrial network. This mitochondrial dysfunction combined with mutations in mitochondrial DNA and nuclear genes makes photoreceptors and retinal ganglion cells more susceptible to cell death. In this minireview, we focus on mitochondrial dynamics and their contribution to neuronal degeneration underlying IRDs, with particular attention to Leber hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (DOA), and propose targeting cell resilience and mitochondrial dynamics modulators as potential therapeutic approaches for retinal disorders.

The ability to noninvasively monitor retinal abnormalities using imaging and cognitive and electrophysiological assessment has made it possible to carefully characterize genetic influences on retinal health. Because genetic retinal traits in animal species are not commonly detrimental to survival beyond birth, it is possible to document the natural history of retinal disease. Human quality of life is greatly impacted by retinal disease, and blindness carries a significant financial burden to society. Because of these compelling reasons, there is an ongoing medical need to study the effect of genetic mutations on retinal health and to develop therapies to address them. Transgenic animal models have aided in these missions, but there are opportunities for novel gene discovery and a development of greater understanding of retinal physiology using animal models that develop naturally occurring heritable retinal disorders. In this chapter, the advantages and disadvantages of transgenic and spontaneous vertebrate animal models of human inherited retinal disease are debated, in particular those of carnivore species, and the potential resource of spontaneous heritable retinal disorders in inbred nondomestic carnivore species is discussed.

Optical Coherence Tomography (OCT) is one of the most vital tools for diagnosing and tracking progress of medication of various retinal disorders. Many methods have been proposed to aid with the analysis of retinal images due to the intricacy of retinal structures, the tediousness of manual segmentation and variation from different specialists. However image artifacts, in addition to inhomogeneity in pathological structures, remain a challenge, with negative influence on the performance of segmentation algorithms. In this paper we present an automatic retinal layer segmentation method, which comprises of fuzzy histogram hyperbolization and graph cut methods. We impose hard constraints to limit search region to sequentially segment 8 boundaries and 7 layers of the retina on 150 OCT B-Sans images, 50 each from the temporal, nasal and center of foveal regions. Our method shows positive results, with additional tolerance and adaptability to contour variance and pathological inconsistence of the retinal structures in all regions.

The retina is an essential part of the human eye. It is a very small part at the subsequent pole of the human eye, and it is composed of a tissue cell that can detect the presence of light. The tissue is sensitive enough to detect the amount of light present, its intensity, and a range of different wavelengths as well. These tissues generate nerve signals, and those signals are passed to the brain via the optic nerve. If the retina malfunctions, then different retinal disorders can occur such as diabetic retinopathy, glaucoma, and pathologic myopia. These can be considered the major causes of total loss of vision throughout the world.

Retinitis pigmentosa (RP) encompasses a heterogeneous group of inherited retinal disorders characterized by progressive photoreceptor and/or retinal pigment epithelial (RPE) degenerations with a prevalence approximately 1 in 4000 in the general population. Over 70 causative genes have been defined in RP families, and a number of animal models have been identified so far. However there have been no widely recognized treatments able to recover or reverse the degenerating retina, to prevent the disease deterioration, ultimately to restore the remaining vision. Therapeutics advancements have been achieved including gene therapy, pharmacotherapy, cell replacement, neurotrophic factors, and retinal prosthesis. In this review, we focus on the pharmaceutical drugs for RP with emphases on the context of drug discovery, development, and clinical translation.

Drug delivery to the eye still is a challenge due to its intricate anatomical structure. Posterior segment delivery is much more challenging due to the acellular nature of the vitreous humor and the longer diffusion distance to the retina. Iontophoresis is a noninvasive technique that facilitates the movement of charged drug molecules into tissues by an electric field. Using iontophoresis, it is possible to achieve therapeutic concentrations faster by modulating the intensity and duration of the applied current. Transscleral iontophoretic delivery is gaining pace and is considered as an alternative for a safe and more effective treatment to retinal disorders. This chapter intends to highlight various aspects of iontophoresis, with a special emphasis on transscleral delivery of drugs and drug-loaded nanocarrier systems for treating disorders in the back of the eye. Finally, a section on toxic effects of iontophoresis to various ocular tissues is included.

The formation of solid tissues is not a simple aggregation of individual cells but rather an ordered assembly of cells connected by junctions. These junctions provide a diffusion barrier as well as mechanical support and a conduit for signalling changes in the environment to the cells. Cell junctions are functionally categorized as occluding (e.g. tight junctions, TJs), anchoring (e.g. adherens junctions, AJs) and communicating junctions (e.g. gap junctions). Each type of the cell junction is formed by protein complexes with extracellular domains and/or intracellular domains, which bind partners that provide scaffolding and signalling components. Cell junctions are ubiquitously expressed in multiple tissues and organs, including the retina. In the retina, their biological impact is not limited to regulating tissue growth and development. Disruption of the complexes mediates both congenital and postnatal pathogenesis. In this review, we will focus on cell junctions, specifically AJs and TJs in the external limiting membrane, in order to articulate their influence on pathophysiology of the retina.

Age-related macular degeneration (AMD), diabetic retinopathy (DR), myopic choroidal neovascularization (mCNV) and retinal vein occlusion (RVO) taken together are leading cause of blindness worldwide. Neovascularization in these retinal disorders is induced largely by vascular endothelial growth factor A (VEGF-A) and progresses rapidly to blindness if left untreated. VEGF-A, with a central role in both normal and pathologic vascular growth within the eye, binds to VEGF-A receptors (e.g., Flt-1) on the vascular endothelium and promotes angiogenesis in response to hypoxia and other stimuli. The current standard of care in managing AMD, DR, mCNV and RVO is VEGF antibodies administered through intravitreal route to block VEGF activity, which underlies the CNV. Although this therapy improves visual acuity in a substantial proportion of patients, significant number of patients experience persistent CNV leakage, fibrotic scarring and/or geographic atrophy. Most patients do not achieve substantial visual improvement and a third of treated eyes progress to legal blindness. Thus, a novel therapeutic strategy, which improves outcomes while providing inhibition of angiogenesis with acceptable safety profile, is an urgent and unmet medical need. In this review, we discuss the role of VEGF and VEGF receptors in angiogenesis and the current and potential future angiogenesis based therapies for AMD, DR, mCNV and RVO.

Cell therapies are currently in clinical development for the treatment of a number of retinal disorders. Such therapies must be delivered to the subretinal space, which has traditionally been accomplished through conventional pars plana vitrectomy with the creation of a retinotomy and subsequent transfer of cells. Delivering cells in this fashion is thought to incur a risk of retinal detachment and the development of proliferative vitreoretinopathy. Indeed, preclinical studies of palucorcel (human umbilical tissue derived cells developed by Janssen Research & Development for the treatment of geographic atrophy secondary to age related macular degeneration) delivered using this tranvitreal approach suggested that the presence of these cells in the vitreous had the potential to stimulate ERM formation and retinal detachments due to PVR. Accordingly, Janssen began to explore alternative routes to the subretinal space. After considering a number of potential techniques, they developed a novel approach using the suprachoroidal space as a conduit to the posterior pole. This approach involves the creation of a sclerotomy, introduction of a specialized cannula into the suprachoroidal space, advancement of the cannula under direct visualization to the desired delivery site, advancement of an internal needle through the choroid into the subretinal space, and delivery of cells. The system has completed small-scale preclinical validation studies and is now being tested in conjunction with clinical trials of palucorcel for the treatment of geographic atrophy secondary to ARMD. There is optimism surrounding these trials as well as the device’s specific design to access the subretinal space.

During development, blood vessel networks adapt to gradual changes in the oxygen required by surrounding tissue, shear stress, and mechanical stretch. The possible adaptations include remodeling the vessel network and thickening the walls of blood vessels. However, the treatment of several vascular diseases including cerebral arteriovenous malformations, arteriosclerosis, aneurysms, and vascular retinal disorders, may lead to abrupt changes that could produce hemorrhage or other problems. Modeling the hemodynamic behavior of a blood vessel network may help assess or even diminish the risks associated with each treatment. In this work, we briefly describe the radiological studies available to study the anatomy and hemodynamics of a patient. We then describe the segmentation, smoothing, healing, skeletonyzation, and meshing processes that are needed to obtain an initial model for the numerical simulations. Additionally, we state some important concepts about blood rheology and blood vessel elasticity. Further, we include a system of equations to describe the interaction between flowing blood and the elastic blood vessels.

The pattern dystrophies form a clinically and genetically heterogeneous group of retinal phenotypes including adult-onset foveomacular vitelliform dystrophy (AFVD), butterfly-shaped pigment dystrophy (BPD), reticular dystrophy of the retinal pigment epithelium, pseudo-Stargardt pattern dystrophy (multifocal pattern dystrophy simulating Stargardt disease/fundus flavimaculatus), and fundus pulverulentus. The pattern dystrophies constitute a group of retinal disorders characterized by a variety of deposits of yellow, orange, or gray pigment, predominantly in the macular area. The age at onset in pattern dystrophies is highly variable, but patients tend to remain asymptomatic until the 5th decade or may even remain asymptomatic throughout life. The course of pattern dystrophies is often benign, although severe vision loss occurs in up to 50 % of the affected individuals after the age of 70, as a result of chorioretinal atrophy and/or the development of choroidal neovascularization.

The clinical presentation and the genetic background of hereditary retinal disorders are heterogeneous (at present the pathogenic roles of more than 100 genes are known). Below we discuss the diseases in an order based on the anatomical localization of the pathology (the primarily affected retinal layers), without being exhaustive.

The developmental macular disorders form part of a heterogeneous group of retinal disorders that are an important cause of visual impairment in children. The macular abnormality is present from birth and is usually nonprogressive, but rarely, visual loss may occur as a result of choroidal neovascularisation. Although there have been considerable advances made in recent years in our understanding of the clinical phenotypes, natural history and molecular genetics of these developmental disorders, many of the causative genes have yet to be identified. It is anticipated that new genetic technologies, such as next-generation sequencing, will soon lead to discovery of such genes; this new information will result in improved understanding of the biology of macular development and will be the first step in developing new therapies.

Congenital stationary night blindness (CNSB) is a clinically and genetic diverse group of nonprogressive retinal disorders that is characterized by stable poor vision in low light (night blindness). CNSB can be classified either functionally by electrophysiology or fundus phenotypes. ERG can distinguish a “complete” form or CNSB type 1 with absent rod function, from an “incomplete” form or CNSB type 2 with reduced rod and cone function. Phenotypically, CNSB can have a normal appearing fundus or an abnormal fundus (includes Oguchi’s disease and fundus albipunctatus).

A number of retinal degenerative diseases may be amenable to treatment with continuous intraocular delivery of therapeutic agents that cannot be delivered effectively to the retina via systemic or topical administration. Among these disorders are lysosomal storage diseases resulting from deficiencies in soluble lysosomal enzymes. Most cells, including those of the retina, are able to take up these enzymes and incorporate them in active form into their lysosomes. In theory, therefore, continuous intraocular administration of a normal form of a soluble lysosomal enzyme should be able to cure the molecular defect in the retinas of subjects lacking this enzyme. Experiments were conducted to determine whether genetically modified bone marrow-derived stem cells implanted into the vitreous could be used as -vehicles for continuous delivery of such enzymes to the retina. Bone marrow-derived mesenchymal stem cells (MSCs) from normal mice were implanted into the vitreous of mice undergoing retinal degeneration as a result of a mutation in the PPT1 gene. The implanted cells appeared to survive indefinitely in the vitreous without proliferating or invading the retina. This indicates that intravitreal implantation of MSCs is likely a safe means of long-term delivery of proteins synthesized by the implanted cells. Experiments have been initiated to test the efficacy of using genetically modified autologous MSCs to inhibit retinal degeneration in a canine model of neuronal ceroid lipofuscinosis.

Inherited retinal dystrophies (IRDs) are an extremely heterogeneous group of genetic diseases for which currently no effective treatment strategies exist. Over the last decade, significant progress has been made utilizing gene augmentation therapy for a few genetic subtypes of IRD, although several technical challenges so far prevent a broad clinical application of this approach for other forms of IRD. Many of the mutations leading to these retinal diseases affect pre-mRNA splicing of the mutated genes . Antisense oligonucleotide (AON)-mediated splice modulation appears to be a powerful approach to correct the consequences of such mutations at the pre-mRNA level , as demonstrated by promising results in clinical trials for several inherited disorders like Duchenne muscular dystrophy, hypercholesterolemia and various types of cancer. In this mini-review, we summarize ongoing pre-clinical research on AON-based therapy for a few genetic subtypes of IRD , speculate on other potential therapeutic targets, and discuss the opportunities and challenges that lie ahead to translate splice modulation therapy for retinal disorders to the clinic.