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Abstract

Retinal hypoxia stands as a pivotal yet often underappreciated factor in the etiology and progression of many retinal disorders such as glaucoma, hypertensive retinopathy, diabetic retinopathy, retinal vein occlusions, and retinal artery occlusions. Current treatment methodologies fail to directly address the underlying pathophysiology of hypoxia and aim to improve ischemia through alternative methods. In this review, we discuss the critical role of retinal hypoxia in the pathogenesis of various retinal diseases and highlight the need for innovative therapeutic strategies that address the root cause of these conditions. As our understanding of retinal hypoxia continues to evolve, the emergence of new technologies holds the promise of more effective treatments, offering hope to patients at risk of vision loss.

Plain language summary

A review of old and new therapeutic strategies for addressing oxygen deprivation in retinal diseases

This paper talks about how lack of oxygen in the retina can cause different eye diseases like glaucoma, diabetic retinopathy, and retinal artery occlusions. It explains how our current treatments don’t directly fix this lack of oxygen, but rather try to help in other ways. The paper also discusses the science behind why these diseases happen and what happens in the eye when there’s not enough oxygen. Ultimately, we finish our discussion with an overview of novel technology that are currently being used in other fields and could be applied in these eye disorders.

Keywords

hypoxia oxygen nanodelivery oxygen therapy retina retinal hypoxia

Introduction

Sight is one of the key senses that humans use to assess their surroundings, and the retina is one of the most metabolically active organs in the human body.^1–4 The metabolism of the retina is finely controlled to allow for enough vascular supply to power the neural transmission of light. These factors work closely together, where damage to the vasculature affects the light-transmitting cells. Hypoxia leads to the loss of the retinal ganglion cells (RGCs) via either apoptosis or necrosis, preventing the transmission of light to the visual cortex.³

Retinal hypoxia encompasses a rather broad family of conditions.^3,5,6 The common mechanism of these disorders provides a promising target for effective therapeutics. In this review, we discuss the common pathophysiology shared by this family of hypoxic retinal disorders and current therapeutic innovations that primarily address oxygen deficiency to improve treatment outcomes.

Pathophysiology of retinal hypoxia

Anatomically, the retina is supplied by branches of the ophthalmic artery, which comes from the internal carotid artery. The central retinal artery and short posterior ciliary arteries perfuse the inner retina.⁷ The retina is supplied by two vascular systems: the choriocapillaris and the central retinal artery. The choriocapillaris supplies the layers of the outer retina, including the retinal pigment epithelium and photoreceptors, which are oxygenated by the choriocapillaris through diffusion. The central retinal artery supplies oxygen to the inner retina, the retina ganglion cells, and the retinal nerve fiber layers.^7–9 Retinal oxygenation is regulated by circulation of the vascular inner and avascular outer layers. However, the control of oxygen in the retinal arteries and the choroid differs.¹⁰ The retinal arteries are controlled through vasogenic factors released from the endothelium based on intraocular pressure and the metabolic needs of the retina, while choroid perfusion is controlled neurally through sympathetic activation and metabolic factors. The central retinal artery is not as affected by sympathetic innervation.^8,11,12

Retinal pericytes are one key regulator of vascular flow in both the choroid and retina, acting as protective factors against retinal hypoxia. Pericytes sit around the retinal vessels and regulate neurovascular coupling and blood flow within the choroid and the retina through intra-pericyte tunneling nanotubes.^13–15 The nanotubes are gap junctions that can carry organelles like the mitochondria and support Ca²⁺ release for nerve function. Pericytes express several genes (FOXP1, Ang2, and VEGFR2) that support retinal vessels in times of stress and injury and cover almost 85% of the retinal microvasculature.¹³ Even more so, pericytes are essential in the postnatal period to help develop the blood-retinal barrier. Loss of pericytes leads to the breakdown of this barrier, leading to the infiltration of immune cells and the formation of microhemorrhages.¹⁶ Blood-retinal barrier breakdown has been implicated in glaucoma due to damage caused by high pressure and also in diabetic retinopathy due to high-glucose-related reactive oxygen species.^13,15,16

The retina maintains its energy requirements through aerobic respiration and β-oxidation.¹⁷ However, under metabolic stress and hypoxia, the retina relies more heavily on alternate metabolic pathways such as the pentose phosphate pathway and anaerobic metabolism.⁵ Interestingly, hypoxia was also found to lead to an increase in β-oxidation, indicating that this pathway is utilized in both normal and pathological conditions.^5,17 The changes in metabolic pathways can help the cell survive hypoxia.

The primary driver of hypoxia-induced changes in the retina is the activation of hypoxia-inducible factor 1-α (HIF-1α), leading to downstream activation of vascular endothelial growth factor (VEGF) and nitric oxide synthase (NOS), as shown in Figure 1.^3,18–20 Additional methods of vascular regulation in the retina are through a local renin-angiotensin system, endothelin-1, and adenosine.^21–23 Pericytes also play an additional role here, as VEGF not only increases pericyte proliferation but also increases angiogenesis.¹⁸ The top seven genes that HIF-1α activates promote the conversion of metabolic processes from oxidative phosphorylation to glycolysis are essential to helping the cell survive hypoxia.^6,24 Of note, with each retinal hypoxia pathology, the system is affected slightly differently. Overproduction of both VEGF and NOS is associated with vasodilation and permeability of retinal vessels, allowing for infiltration of immune cells for the removal of lost tissue.¹⁹ The resulting breakdown of the blood-retinal barrier allows for the pathological accumulation of fluid in extracellular and intracellular spaces, leading to vasogenic or cytotoxic edema, respectively.²⁵ Additionally, this increased vascular permeability is associated with endothelial dysfunction, microaneurysm and leukocyte vascular plugs that can further damage the tissue, especially in diabetic retinopathy.²⁶

Figure 1.

The pathophysiology of retinal hypoxia on retinal ganglion cells.^3,20

In addition to vascular effects of hypoxia on the retina, the RGC also reacts to hypoxia based on NOS and VEGF. There are many causes of RGC death, including excessive release of glutamate and excitatory neurotoxicity. One theory that has been debated so far is the concept of excitatory neurotoxicity. NOS itself produces nitric oxide, which induces vasodilation to encourage better oxygenation in the face of hypoxia.^19,26,27 The increase in glutamate damages the neuron by affecting ion concentration, which disrupts electric and immune homeostasis in the RGCs. Excessive glutamate leads to activation of ionotropic glutamate receptors that cause an increased release of calcium within the cells. The high levels of calcium lead to metabolic failure due to inappropriate activation of enzymes that can affect membrane potential and can prevent signal transmission that may lead to vision loss.^3,28 Lastly, the over-release of glutamate also leads to increased production of tumor necrosis factor-α and interleukin 1β, further exacerbating cell damage.²⁹

For each of the pathologies discussed below, RGC death pathophysiology will differ. The excitotoxicity theory is just one of the many theories involved in understanding RGC death, and is often related to retinal artery occlusions (RAOs).³ For instance, this same theory of excitotoxicity was shown to be ineffective in glaucoma with the memantine trials, showing that a treatment used to prevent excitatory neurotoxicity, worked well in the mouse model but did not delay glaucoma disease progression in humans.³⁰ Other theories for the cause of RGC loss in glaucoma include other theories also include mitochondrial impairment, endoplasmic reticulum stress, axon transport failure, inflammation, and oxidative stress.^20,31 In diabetic retinopathy, there is evidence that cellular damage occurs before the onset of vascular damage due to glutamate excitotoxicity, axon transport failure, and loss of insulin sensitivity.^32–34 The various causes of RGC cell death often interact, leading to complex pathologies where the interplay between different mechanisms might impact treatment outcomes.

Overall, vision loss is mediated by a breakdown of the fine balance between retinal vasculature and the metabolic needs of the retinal neural cells, which are key for vision transmission. While the retina does have mechanisms to protect cells from hypoxia, patients with retinal hypoxia will inevitably begin to lose their vision due to irreversible retinal cell damage. In the next part of this review, we discuss various hypoxic pathologies including glaucoma, diabetic retinopathy, hypertensive retinopathy, and RAOs as well as their current treatment methodologies used to address the underlying pathologies.

Glaucoma and retinal hypoxia

Glaucoma, the leading cause of irreversible blindness worldwide, encompasses a family of neurodegenerative diseases, all of which feature a clinically characteristic optic neuropathy.^35,36 While the specific pathogenesis of glaucoma remains poorly understood, the primary cause of vision loss is associated with elevated intraocular pressure. The high pressure leads to damage to the optic nerve and eventual loss of RGCs.³⁷ The primary treatments for glaucoma, accordingly, aim at reducing intraocular pressure.

The two prevailing theories for glaucoma include the “mechanical” and the “vascular” theories.^38,39 The vascular hypothesis of glaucoma proposes that RGC axons that cross the optic nerve head undergo oxygen and nutrient insufficiency because of compromised blood flow due to elevated intraocular pressure. The unmyelinated axons of the optic nerve head are thought to be highly vulnerable to the decreased oxygen/nutrient supply, due to extremely high energy requirements served by a high local density of mitochondria.^40,41 The mechanical theory proposes that the elevated intraocular pressure causes compression of the nerve bundles, preventing transmission of visual signals through the optic nerve.⁴² Over the past few years, there has been increasing support for the vascular hypothesis over the mechanical hypothesis due to the presence of oxidative markers associated with hypoxia in the retina, aqueous humor, and blood serum.^43–45

While glaucoma is normally considered a pressure-related pathology, another form of glaucoma is normal tension glaucoma (NTG). It is associated with multifactorial optic neuropathy characterized by gradual RGC death and vision loss, even though the intraocular pressure remains within normal limits. In this case, problems in ocular blood flow occur due to vasospasm, small vessel disease, or autoregulation dysfunction. NTG is known to be associated with systemic disorders including Alzheimer’s, migraine, and hypotension that are associated with dysautoregulation, which might lead to NTG.⁴⁶ In migraine and hypotension, random transient vasospasm leads to dysregulation of blood flow in the eye, leading to microinfarction of the optic nerve.^47–50 Alzheimer’s also has a similar pathophysiology, where vascular dysregulation from amyloid deposits changes blood flow.^51,52 These changes in blood flow lead to endothelial dysfunction and activation of the HIF-1α pathway.

The current treatments for all forms of glaucoma include medications that reduce pressure within the eye to promote improved blood flow. The first line agents are β-blockers and prostaglandin analogs, which help reduce intraocular pressure by decreasing the formation of aqueous humor or by increasing the uveoscleral outflow.^53–55 Other medications include carbonic anhydrase inhibitors and α-adrenergic agonists that also similarly treat intraocular pressure by modulating the amount of aqueous humor in the eye.⁵⁶

In addition to these standard treatments, a limited body of research has suggested that hyperbaric oxygen therapy (HBOT) may improve outcomes in glaucoma through two distinct mechanisms. First, HBOT has been shown to reduce intraocular pressure in animal models and healthy test subjects.⁵⁷ As such, it has been suggested that this reduction in intraocular pressure may improve glaucoma progression.^58–60 Second, HBOT may also improve glaucoma directly through improved retinal oxygenation, in line with the role of RGC oxygen deprivation in the vascular hypothesis of glaucoma. HBOT is known to induce hyperoxygenation of the retina, despite vasoconstriction induced by the high arterial PO₂.^60–64 Correspondingly, limited clinical studies have shown reduced visual field loss in glaucoma patients, even without meaningful changes in intraocular pressure.^65–67 Considering these results, therapies targeting improved retinal oxygenation to reduce intraocular pressure and/or improve tissue oxygen delivery for the treatment of glaucoma warrant further investigation.

RAOs and hypoxia

RAO is a sudden blockage of the central retinal artery or one of its branches leading to sudden, painless monocular vision loss, similar to that of a stroke.^68,69 There are three different types of RAOs: central retinal artery occlusion (CRAO), branch retinal artery occlusion (BRAO), and transient monocular vision loss.^70–72 CRAO is a condition in which the central retinal artery becomes blocked such that an individual with CRAO will experience painless monocular vision loss in the affected eye.^70,73 BRAO is a similar condition where a branch of the central retinal artery is affected, typically leading to less severe symptoms as compared to CRAO.^73,74

RAOs have a similar pathophysiology of a stroke through thrombosis or emboli. Embolic RAOs are more common and these emboli can travel from the carotid artery or heart.^69,70,72 Other causes of RAOs include intravascular events, increased orbital pressure, and intraocular pressure.⁷⁵ The mechanism of action is associated with glutamate excitotoxicity and excess calcium released due to cell necrosis.³ Permanent damage to the retina occurs within 2 h of ischemia.⁷⁶ Acutely, CRAO and BRAO are signified by a pale retina and the classic macular “cherry red spot” observed on visualization and imaging of the fundus, indicating an ischemic retina.⁷⁷ Chronically, signs of an RAO include a pale optic disk, thinning of the retina tissue, attenuated vessels, retinal pigment epithelial mottling, and severely decreased vision.⁷⁸

There is currently no standard treatment for RAOs. Some small studies have explored treatment options such as thrombolytics or other conservative management options, including those that increase the blood oxygen content or reduce intraocular pressure to improve perfusion as well as anti-inflammatory agents.^79,80 Thrombolytics, either intravenous or intra-arterial, have shown the most promise for RAO treatment thus far, but are only effective within a small window of 4.5 h since symptom onset.^69,80 Additionally, intra-arterial thrombolysis is associated with a high rate of stroke.⁸⁰ However, for some patients, RAOs can resolve spontaneously within the first 7 days of symptoms onset resulting in spontaneous reperfusion, but the result is ischemic retinal death. Additionally, the average time to presentation for RAOs tends to be over 24 h, making most patients ineligible for therapy.^81–83 All other therapeutic options have also shown limited efficacy.

Alternative options are more conservative to help the clot dislodge on its own. Oxygen-enhancing treatments such as vasodilators and HBOT increase the amount of oxygen getting to the retina. Sublingual isosorbide dinitrate with ocular massage, inhaled carbogen, and pentoxifylline have been studied as vasodilators with pentoxifylline showing the most promise.^79,84–89 Pentoxyphyline showed an almost 5× increase in systolic and diastolic blood flow when compared to a placebo.⁸⁷ All other treatments showed only a modest, non-statistically significant improvement in oxygenation.

The other oxygen-enhancing therapy that has been investigated is the use of HBOT to increase the partial pressure of oxygen in arterial blood.⁷⁹ With normal physiology, only 50% of oxygen is delivered to the retina, but up to 97% of oxygen can be delivered to the retina in an HBOT.⁸⁰ In line with this theoretical benefit, there is a growing body of research showing benefits in retinal occlusion outcomes with HBOT therapy. A variety of small clinical trials, case reports, and case series have shown benefits, primarily in visual acuity outcomes, with HBOT therapy.^90–106 Additionally, a meta-analysis of seven randomized controlled trials using HBOT as a part of combined or standalone therapy in RAO found that treatment with HBOT leads to improved visual outcomes.¹⁰⁶ Although a promising treatment, the overall studies conducted with HBOT in RAO tend to be small, and deployment of HBOT is difficult, leading to limited utilization of HBOT in retinal oxygen therapy.^60,107–109 Despite these limitations, HBOT is a recommended therapeutic option in patients refractory to traditional treatments or ineligible for revascularization or anterior chamber paracentesis.

Diabetic retinopathy and hypoxia

Diabetic retinopathy is a leading cause of reduced visual acuity and blindness in patients with type 1 and type 2 diabetes mellitus. Diabetic retinopathy has a global prevalence of 22.27% in those with diabetes.¹¹⁰ Diabetic retinopathy remains one of the leading causes of vision loss overall and is expected to have increasing prevalence over the next few decades.¹¹⁰ The pathophysiology of diabetic retinopathy is complex and is thought to involve a combination of oxidative stress, inflammation, neovascularization, neurodegeneration, and neurovascular unit dysfunction.¹¹¹

Hypoxia and retinal oxygen deprivation play a critical positive feedback role in microvascular dysfunction and neovascularization. Hypoxia plays a role in initiating microvascular damage, and, as the disease progresses, worsening hypoxia contributes to microaneurysm formation, capillary necrosis, and neovascularization. More specifically, early endothelial cell death leads to increased capillary permeability, loss of vascular perfusion, and microaneurysm formation. This vaso-degeneration eventually leads to areas of retinal hypoperfusion and hypoxia, increasing the production of VEGF and neovascularization.^111,112 Neovascularization is a key component of proliferative diabetic retinopathy, while microaneurysm formation and increased vascular permeability are key components of diabetic macular edema.¹¹¹ As such, hypoxia contributes significantly to these two sight-threatening endpoints of diabetic retinopathy.¹¹²

Currently, anti-VEGF is the leading treatment used to prevent neovascularization and stabilize disease. Emerging research demonstrates improvement of retinal perfusion following treatment with anti-VEGF. In particular, improvements in perfusion have been noted on ultrawide-field fluorescein angiography and a slowing of the progression of non-perfusion has been documented in patients undergoing anti-VEGF treatment.^113,114 More recent treatments have included antibodies that target VEGF-A and Angpt-2 for longer-term neovascularization prevention.¹¹⁵ Treatment with panretinal laser photocoagulation (PRP) is also common in the management of diabetic retinopathy. This older treatment modality is thought to increase choroidal oxygenation and decrease metabolic oxygen load by destroying outer regions of the retina, thereby relieving hypoxia in regions spared by PRP.¹¹⁶ However, the scarring caused by PRP causes reduction of visual field in treated patients.

Given the critical nature of tissue hypoxia in both the early and late stages of diabetic retinopathy, HBOT is a promising therapeutic approach. Specifically, HBOT leads to hyperoxygenation of the retina resulting in reduced production of VEGF, helping prevent neovascularization and macular edema.^61–63,117 Importantly, hyperoxygenated choroidal vasculature appears to provide excess oxygen to the retina despite vasoconstriction induced by the high arterial PO₂.^62,63,96,114 Furthermore, elevated VEGF levels are found in types of both proliferative and nonproliferative diabetic retinopathy, lending HBOT as a potential treatment for both disease states.^96,117

In line with this theoretical benefit, a small set of studies have shown that HBOT therapy can lead to improved features of diabetic retinopathy in humans, including clinical trials and a case report showing improved visual acuity as well as a prospective cohort study showing stabilization/regression of diabetic retinopathy lesions.^60,118–122 Additional research has been done in diabetic rat models, showing reduced vascular permeability and improved retinal response to light.^123–125 Ultimately, this research shows that improving retinal oxygenation is a promising therapeutic target for the treatment of diabetic retinopathy.

Current use of oxygen therapy and new technology applications

Currently, HBOT is the primary method of oxygen delivery for the treatment of ocular disorders, including RAO, diabetic retinopathy, and glaucoma. While HBOT has been shown to improve visual acuity and other metrics associated with disease progression, HBOT is an expensive and often inaccessible form of treatment. Additionally, HBOT is associated with a variety of ocular and systemic side effects. In particular, hyperoxic myopia is a common side effect of HBOT leading to progressive visual change over the course of treatment but is typically reversible.^{61,62,126–133} HBOT is also associated with permanent cataract formation with visual loss, although these changes occur gradually and typically become severe only during longitudinal treatment regiments of greater than 150 sessions, a longer treatment course than required for most conditions.^133,134 In premature infants, HBOT can result in retinopathy of prematurity.^135–138 Systemically, the most common side effect of HBOT is middle ear barotrauma, which is typically mild but can in rare cases result in conductive or sensorineural hearing loss as well as vertigo.¹³⁵ Other common side effects include temporary sinus and dental pain from mild barotrauma that resolves with the cessation of treatment.¹³⁶ Less frequently, HBOT can lead to severe pulmonary barotrauma and central nervous system oxygen toxicity, with rare reported cases of pneumothorax and seizures.¹³⁶

Overall, the development of novel, targeted oxygen delivery methodologies for ocular disorders may help eliminate the systemic side effects associated with HBOT and improve access to treatment. Hyperoxic myopia likely occurs due to oxidative changes in the crystalline lens of the eye, leading to a corresponding change in the refractive index of the lens.^128,139 Correspondingly, there is some evidence that suggests that increasing systemic oxygenation while reducing the partial pressure of oxygen in contact with the external eye, such as through an oronasal mask, helps prevent the occurrence of and improves recovery from hyperoxic myopia.^140,141 Cataract formation in HBOT therapy is also thought to occur due to oxidative stress on the crystalline lens.^134,135,142 However, there is no similar data directly demonstrating reduced cataract risk with reduced delivery of oxygen partial pressure to the eye surface. As such, therapies that improve oxygenation of the eye vasculature without increasing oxygen delivered to the external eye surface, may be less likely to induce hyperoxic myopia, but may carry similar risk of cataract formation with extensive use.

Other novel, targeted oxygen delivery modalities for the treatment of retinal disease have been proposed in the literature. One study aimed to develop an oxygen delivery system that consists of stable, nontoxic oxygen nanobubbles (ONBs) encapsulated in medical-grade water. The ONBs were characterized to be stable in storage, non-cytotoxic in vitro, have good oxygen retention, and successfully release oxygen to mitigate ischemic conditions in the retina.¹⁴³ Specifically, the CRAO model of ischemia/perfusion showed that ONBs were able to mitigate oxygen deprivation and thus preserve anatomical and functional outcomes in rat eyes.^144–146 While HBOT does increase oxygen delivery to the retina, it only lasts while the patient is in the HBOT chamber.^61,62 ONBs allow the opportunity to titrate the delivery of oxygen directly into the vitreous cavity and retina lasts at least 12 h and allows for continuous oxygenation.¹⁴⁴

Additionally, other methods of oxygen delivery originally designed to treat other pathologies may apply to retinal hypoxia.¹⁴⁷ In recent years, there have been several studies showing the efficacy of oxygen nanodelivery for a variety of treatments, as seen in Table 1.¹⁴⁸ Oxygen nanodelivery methods can be subdivided into three major categories: Hypoxia-relieving, oxygen-carrying, and oxygen-producing nanomaterials.^149,150 Hypoxia-relieving nanomaterials are those that directly address hypoxia by improving blood flow or targeting HIF-1α directly. Of the options for oxygen nanodelivery, nanoparticles represent a more conservative approach, much like the current method for treating retinal hypoxia.^149,151 This could be a promising approach for treatment of long-term retinal hypoxia associated with changes in vasculature and local structures. Oxygen-carrying and oxygen-producing nanomaterials directly deliver oxygen to the tissue. Oxygen-carrying nanoparticles use perfluorocarbons, hemoglobin, or other oxygen-binding materials to release oxygen in tissues. Some challenges with oxygen-carrying nanoparticles include stability of the particle, poor circulation time, and premature release of oxygen.^152–154 Oxygen-producing nanomaterials use catalase that converts locally produced peroxide (H₂O₂) into oxygen, allowing delivery of oxygen to ischemic tissues only.^150,155,156 There is already a diverse body of research into oxygen-producing nanoparticles that could allow for improved retinal oxygenation and decreased retinal loss in both chronic and acute retinal hypoxia.

Table 1.

Summary of various oxygen nanodelivery methods and their applications.

Author (year)	Nanoparticle formulation	Application	Method
Zhuang et al. (2018)¹⁵²	Hybrid natural-synthetic polymer-based nanoemulsion	Hemorrhagic shock	Oxygen carrier
Khan et al. (2019)¹⁵⁵	Ultrasound activated doxorubicin conjugated lipid-based nanobubbles	Improve chemotherapy penetration into hypoxic solid tumors	Oxygen producer
Kim et al. (2021)¹⁵³	Pegylated lipid nanoparticles	Treatment of molar incisor hypomineralization to improve dentin and enamel production	Oxygen carrier
Han et al. (2022)¹⁵⁶	Maillard reaction-based catalase and dextran sulfate-based oxygen delivery	Pancreatic cancer	Oxygen producer
Kim et al. (2023)¹⁵⁴	Oxygen-carrying hemoglobin-based gel that produces reactive oxygen species with infrared laser	Solid tumor therapy	Oxygen carrier
Guan et al. (2022)¹⁵⁷	Polymer-based nanoparticles functionalized with catalase for oxygen delivery	Acute myocardial infarction	Oxygen producer
Li et al. (2016)¹⁵¹	Gold-nanoparticle and recombinant endostatin	Stabilize tumor vasculature	Hypoxia-reliever

The repression of HIF-1α genes has been heavily studied in the context of cancer.¹⁵⁸ While the hypoxia response through HIF-1α activation in the retina is adaptive and not a process that needs to be halted, downstream suppression of HIF could be an effective target for retinal hypoxia for future treatments.^111,159 In Table 2, different uses of nanodelivery methods for HIF-1α targeting are reviewed. Many of the innovations discussed below-utilized nanoparticles that are selectively absorbed and activated in hypoxic tissues or contain a HIF-1α neutralizing element. Some of these nanoparticles are formulated to release in hypoxic areas with variable cargo, while others had HIF-1α neutralizing cargo.¹⁶⁰ A similar application of HIF-1α neutralization could be applied to downstream targets in the retina.

Table 2.

Summary of various HIF-1α targeted nanodelivery methods and their applications.

Author (year)	Nanoparticle formulation	Application	Method
Imai et al. (2015)¹⁶¹	Hemagglutinating virus of Japan-liposome method	Oral squamous cell carcinoma	HIF-1α inhibiting oligodeoxynucleotides
Thambi et al. (2014)¹⁶²	Hypoxia-responsive nanoparticles → self-assembly nanoparticles with hydrophobically modified 2-nitroimidazole derivative conjugated to the backbone of the carboxymethyl dextran	Squamous carcinoma (immortalized cell line testing only)	Doxorubicin
Poon et al. (2011)¹⁶³	Multilayer polyelectrolyte assemblies (pH-sensitive outer sheath layer)	HeLa, MDA-MB-435, KB, and A549 cells	Targets cancer cells during hypoxia
Liu et al. (2012)¹⁶⁴	Micellar nanoparticles	Prostate cancer	siRNA against HIF-1α
Thomas et al. (2020)¹⁶⁵	Antibiotic encapsulated syndecan-1 actively targeted nanoparticle	Pancreatic cancer	Echinomycin
Li et al. (2019)¹⁶⁶	Mesoporous silica nanoparticle with thermally sensitive nucleus targeting agent and anti-CD133 surface modification	Cancer stem cells	Chemotherapy loaded
Zhao et al. (2015)¹⁶⁷	Lipid-polymer hybrid nanoparticle	Pancreatic cancer	Gemcitabine and HIF-1α
Yang et al. (2016)¹⁶⁸	Silver nanoparticles	Immortalized cancer cell line	Silver in nanoparticle is used as treatment

HIF-1α, hypoxia-inducible factor 1-α.

Conclusion

It is evident that hypoxia plays a critical role in the pathophysiology of many retinal diseases. As the retina poorly adapts to hypoxic environments, there is a need to develop better technologies for combating hypoxia. There are a limited number of retinal disease treatments that directly address hypoxia. HBOT is the most commonly used oxygen treatment for these disorders, but cost and accessibility prevent widespread use. While there is a large body of current research on oxygen nanodelivery in other areas of medicine, few have applied such treatment options to treat retinal hypoxia. Technologies for targeted delivery could be the wave of the future in ultimately saving someone’s vision. While this review is limited given the primary focus on oxygen therapy in ophthalmology, future work could focus on a co-delivery system with a drug and assessment of clinical efficacy, cost, accessibility, and adaptation of these treatments among diverse patient populations.

Footnotes

Acknowledgements

None.

Declarations

ORCID iDs

Bhargavee Gnanasambandam

Justin Huynh

References

Anderson

Jr Saltzman

HA.

Retinal oxygen utilization measured by hyperbaric blackout. Arch Ophthalmol 1964; 72: 792–795.

Ames

III . Energy requirements of CNS cells as related to their function and to their vulnerability to ischemia: a commentary based on studies on retina. Can J Physiol Pharmacol 1992; 70: S158–S164.

Kaur

Foulds

Ling

E-A.

Hypoxia-ischemia and retinal ganglion cell damage. Clin Ophthalmol 2008; 2: 879–889.

Sickel

Electrical and metabolic manifestations of receptor and higher-order neuron activity in vertebrate retina. Adv Exp Med Biol 1972; 24: 101–118.

Fortmann

Grant

MB.

Molecular mechanisms of retinal ischemia. Curr Opin Physiol 2019; 7: 41–48.

Scott

Fruttiger

Oxygen-induced retinopathy: a model for vascular pathology in the retina. Eye 2010; 24: 416–421.

Kiel

. Anatomy. In: The ocular circulation. Morgan & Claypool Life Sciences, https://www.ncbi.nlm.nih.gov/books/NBK53329/ (2010, accessed 24 September 2023).

Lejoyeux

Benillouche

Ong

, et al. Choriocapillaris: fundamentals and advancements. Prog Retin Eye Res 2022; 87: 100997.

Luo

Uehara

Zhang

, et al. Photoreceptor avascular privilege is shielded by soluble VEGF receptor-1. eLife 2013; 2: e00324.

10.

Wangsa-Wirawan

Linsenmeier

RA.

Retinal oxygen: fundamental and clinical aspects. Arch Ophthalmol 2003; 121: 547–557.

11.

Reiner

Fitzgerald

MEC

Del Mar

, et al. Neural control of choroidal blood flow. Prog Retin Eye Res 2018; 64: 96–130.

12.

Harris

Ciulla

Chung

, et al. Regulation of retinal and optic nerve blood flow. Arch Ophthalmol 1998; 116: 1491–1495.

13.

Santos

GSP

Prazeres

PHDM

Mintz

, et al. Role of pericytes in the retina. Eye 2018; 32: 483–486.

14.

Alarcon-Martinez

Villafranca-Baughman

Quintero

, et al. Interpericyte tunnelling nanotubes regulate neurovascular coupling. Nature 2020; 585: 91–95.

15.

Alarcon-Martinez

Shiga

Villafranca-Baughman

, et al. Pericyte dysfunction and loss of interpericyte tunneling nanotubes promote neurovascular deficits in glaucoma. Proc Natl Acad Sci U S A 2022; 119: e2110329119.

16.

Ferland-McCollough

Slater

Richard

, et al. Pericytes, an overlooked player in vascular pathobiology. Pharmacol Ther 2017; 171: 30–42.

17.

Joyal

J-S

Sun

Gantner

, et al. Retinal lipid and glucose metabolism dictates angiogenesis through the lipid sensor Ffar1. Nat Med 2016; 22: 439–445.

18.

Iyer

Kotch

Agani

, et al. Cellular and developmental control of O₂ homeostasis by hypoxia-inducible factor 1α. Genes Dev 1998; 12: 149–162.

19.

Kaur

Sivakumar

Foulds

WS.

Early response of neurons and glial cells to hypoxia in the retina. Invest Ophthalmol Vis Sci 2006; 47: 1126–1141.

20.

Vernazza

Oddone

Tirendi

, et al. Risk factors for retinal ganglion cell distress in glaucoma and neuroprotective potential intervention. Int J Mol Sci 2021; 22: 7994.

21.

Phipps

Dixon

Jobling

, et al. The renin-angiotensin system and the retinal neurovascular unit: a role in vascular regulation and disease. Exp Eye Res 2019; 187: 107753.

22.

Luo

Shen

Jiang

, et al. Ocular blood flow autoregulation mechanisms and methods. J Ophthalmol 2015; 2015: 864871.

23.

Yamagishi

Yonekura

Yamamoto

, et al. Vascular endothelial growth factor acts as a pericyte mitogen under hypoxic conditions. Lab Invest 1999; 79: 501–509.

24.

Country

MW.

Retinal metabolism: a comparative look at energetics in the retina. Brain Res 2017; 1672: 50–57.

25.

Marmor

MF.

Mechanisms of fluid accumulation in retinal edema. Doc Ophthalmol 1999; 97: 239–249.

26.

Mrugacz

Bryl

Zorena

Retinal vascular endothelial cell dysfunction and neuroretinal degeneration in diabetic patients. Journal of Clinical Medicine 2021; 10: 458.

27.

S-Y

ACY

. Hypoxia-induced oxidative stress in ischemic retinopathy. Oxid Med Cell Longev 2012; 2012: 426769.

28.

Adachi

Kashii

Masai

, et al. Mechanism of the pathogenesis of glutamate neurotoxicity in retinal ischemia. Graefes Arch Clin Exp Ophthalmol 1998; 236: 766–774.

29.

Boccuni

Fairless

Retinal glutamate neurotransmission: from physiology to pathophysiological mechanisms of retinal ganglion cell degeneration. Life (Basel) 2022; 12: 638.

30.

Al-Kharashi

AS.

Role of oxidative stress, inflammation, hypoxia and angiogenesis in the development of diabetic retinopathy. Saudi J Ophthalmol 2018; 32: 318–323.

31.

Weinreb

Liebmann

Cioffi

, et al. Oral memantine for the treatment of glaucoma: design and results of 2 randomized, placebo-controlled, phase 3 studies. Ophthalmology 2018; 125: 1874–1885.

32.

Nickells

RW.

The cell and molecular biology of glaucoma: mechanisms of retinal ganglion cell death. Invest Ophthalmol Vis Sci 2012; 53: 2476–2481.

33.

Potilinski

Lorenc

Perisset

, et al. Mechanisms behind retinal ganglion cell loss in diabetes and therapeutic approach. Int J Mol Sci 2020; 21: 2351.

34.

Bikbova

Oshitari

Baba

, et al. Neurotrophic factors for retinal ganglion cell neuropathy – with a special reference to diabetic neuropathy in the retina. Curr Diabetes Rev 2014; 10: 166–176.

35.

Zhang

Inoue

Dong

, et al. Alterations in retrograde axonal transport in optic nerve of type I and type II diabetic rats. Kobe J Med Sci 1998; 44: 205–215.

36.

McMonnies

Reactive oxygen species, oxidative stress, glaucoma and hyperbaric oxygen therapy. J Optom 2018; 11: 3–9.

37.

Allison

Patel

Alabi

. Epidemiology of glaucoma: the past, present, and predictions for the future. Cureus; 12: e11686.

38.

Weinreb

Leung

CKS

Crowston

, et al. Primary open-angle glaucoma. Nat Rev Dis Primers 2016; 2: 16067.

39.

Morgan

D-Y.

Mechanism theories of glaucoma. In: Sun

Dai

(eds) Medical treatment of glaucoma. Singapore: Springer, 2019, pp.33–66.

40.

Faiq

Sofi

RA.

A glimpse into the mysteries of glaucoma: from theories to clinics. Oman J Ophthalmol 2019; 12: 1–3.

41.

Flammer

Mozaffarieh

Autoregulation, a balancing act between supply and demand. Can J Ophthalmol 2008; 43: 317–321.

42.

Galassi

Giambene

Varriale

Systemic vascular dysregulation and retrobulbar hemodynamics in normal-tension glaucoma. Invest Ophthalmol Vis Sci 2011; 52: 4467.

43.

Yamamoto

Kitazawa

Vascular pathogenesis of normal-tension glaucoma: a possible pathogenetic factor, other than intraocular pressure, of glaucomatous optic neuropathy. Prog Retin Eye Res 1998; 17: 127–143.

44.

Benoist d’Azy

Pereira

Chiambaretta

, et al. Oxidative and anti-oxidative stress markers in chronic glaucoma: a systematic review and meta-analysis. PLoS One 2016; 11: e0166915.

45.

Farkas

Chowers

Hackam

, et al. Increased expression of iron-regulating genes in monkey and human glaucoma. Invest Ophthalmol Vis Sci 2004; 45: 1410–1417.

46.

Chidlow

Wood

JPM

Casson

RJ.

Investigations into hypoxia and oxidative stress at the optic nerve head in a rat model of glaucoma. Front Neurosci 2017; 11: 478.

47.

Fan

Wang

Tang

, et al. Ocular blood flow and normal tension glaucoma. Biomed Res Int 2015; 2015: 308505.

48.

Charlson

de Moraes

Link

, et al. Nocturnal systemic hypotension increases the risk of glaucoma progression. Ophthalmology 2014; 121: 2004–2012.

49.

Broadway

Drance

SM.

Glaucoma and vasospasm. Br J Ophthalmol 1998; 82: 862–870.

50.

Drance

Anderson

Schulzer

, et al. Risk factors for progression of visual field abnormalities in normal-tension glaucoma. Am J Ophthalmol 2001; 131: 699–708.

51.

Orgül

Kaiser

Flammer

, et al. Systemic blood pressure and capillary blood-cell velocity in glaucoma patients: a preliminary study. Eur J Ophthalmol 1995; 5: 88–91.

52.

Tian

, et al. Integrated paper-based microfluidic devices for point-of-care testing. Analytical Methods 2018; 10: 3567–3581.

53.

Sugiyama

Utsunomiya

Ota

, et al. Comparative study of cerebral blood flow in patients with normal-tension glaucoma and control subjects. Am J Ophthalmol 2006; 141: 394–396.

54.

Hedman

Alm

A pooled-data analysis of three randomized, double-masked, six-month clinical studies comparing the intraocular pressure reducing effect of latanoprost and timolol. Eur J Ophthalmol 2000; 10: 95–104.

55.

Lee

Higginbotham

EJ.

Glaucoma and its treatment: a review. Am J Health Syst Pharm 2005; 62: 691–699.

56.

Bettin

Di Matteo

Glaucoma: present challenges and future trends. Ophthalmic Res 2013; 50: 197–208.

57.

Schmidl

Schmetterer

Garhöfer

, et al. Pharmacotherapy of glaucoma. J Ocul Pharmacol Ther 2015; 31: 63–77.

58.

Van de Veire

Germonpre

Renier

, et al. Influences of atmospheric pressure and temperature on intraocular pressure. Invest Ophthalmol Vis Sci 2008; 49: 5392–5396.

59.

Gallin-Cohen

Podos

Yablonski

ME.

Oxygen lowers intraocular pressure. Invest Ophthalmol Vis Sci 1980; 19: 43–48.

60.

Ersanli

Akin

Yildiz

, et al. The effect of hyperbaric oxygen on intraocular pressure. Undersea Hyperb Med 2006; 33: 1–4.

61.

Lin

Chen

Wald

, et al. Hyperbaric oxygen therapy in ophthalmic practice: an expert opinion. Expert Rev Ophthalmol 2020; 15: 119–126.

62.

Butler

Hagan

Murphy-Lavoie

Hyperbaric oxygen therapy and the eye. Undersea Hyperb Med 2008; 35: 333–387.

63.

Frayser

Saltzman

Anderson

, et al. The effect of hyperbaric oxygenation on retinal circulation. Arch Ophthalmol 1967; 77: 265–269.

64.

James

PB.

Hyperbaric oxygen and retinal vascular changes. Med J Aust 1985; 142: 163–164.

65.

Jampol

LM.

Oxygen therapy and intraocular oxygenation. Trans Am Ophthalmol Soc 1987; 85: 407–437.

66.

Oguz

Sobaci

The use of hyperbaric oxygen therapy in ophthalmology. Surv Ophthalmol 2008; 53: 112–120.

67.

Bojić

Kovacević

Andrić

, et al. Hyperbaric oxygen dose of choice in the treatment of glaucoma. Arh Hig Rada Toksikol 1993; 44: 239–247.

68.

Bojić

Raĉiĉ

Goŝović

, et al. The effect of hyperbaric oxygen breathing on the visual field in glaucoma. Acta Ophthalmol 1993; 71: 315–319.

69.

Smith

Benson

Tennant

, et al. Central retinal artery occlusion: a retrospective study of disease presentation, treatment, and outcomes. Can J Ophthalmol 2023; 58: 318–323.

70.

Hayreh

Podhajsky

Zimmerman

MB.

Branch retinal artery occlusion: natural history of visual outcome. Ophthalmology 2009; 116: 1188–1194.e1–4.

71.

Farris

Waymack

. Central retinal artery occlusion. In: StatPearls. Treasure Island (FL): StatPearls Publishing, http://www.ncbi.nlm.nih.gov/books/NBK470354/ (2023, accessed 10 May 2023).

72.

Hoyer

Kahlert

Güney

, et al. Central retinal artery occlusion as a neuro-ophthalmological emergency: the need to raise public awareness. Eur J Neurol 2021; 28: 2111–2114.

73.

Ørskov

Vorum

Larsen

, et al. Clinical risk factors for retinal artery occlusions: a nationwide case–control study. Int Ophthalmol 2022; 42: 2483–2491.

74.

Schorr

Rossi

Stein

, et al. Characteristics and outcomes of retinal artery occlusion. Stroke 2020; 51: 800–807.

75.

Terao

Fujino

Ahmed

Risk factors and treatment strategy for retinal vascular occlusive diseases. J Clin Med 2022; 11: 6340.

76.

Lee

Kim

Jung

, et al. Iatrogenic ophthalmic artery occlusion and retinal artery occlusion. Prog Retin Eye Res 2020; 78: 100848.

77.

Hayreh

Weingeist

TA.

Experimental occlusion of the central artery of the retina. IV: retinal tolerance time to acute ischaemia. Br J Ophthalmol 1980; 64: 818–825.

78.

Tripathy

Patel

BC.

Cherry red spot. In: StatPearls. Treasure Island (FL): StatPearls Publishing, http://www.ncbi.nlm.nih.gov/books/NBK539841/ (2023, accessed 18 August 2023).

79.

Ahn

Woo

Park

, et al. Retinal and choroidal changes and visual outcome in central retinal artery occlusion: an optical coherence tomography study. Am J Ophthalmol 2015; 159: 667–676.e1.

80.

Cugati

Varma

Chen

, et al. Treatment options for central retinal artery occlusion. Curr Treat Options Neurol 2013; 15: 63–77.

81.

Mac Grory

Schrag

Biousse

, et al. Management of central retinal artery occlusion: a scientific statement from the American Heart Association. Stroke 2021; 52: e282–e294.

82.

Rudkin

Lee

Chen

CS.

Central retinal artery occlusion: timing and mode of presentation. Eur J Neurol 2009; 16: 674–677.

83.

Shah

Gilbert

Melles

, et al. Central retinal artery occlusion: time to presentation and diagnosis. Ophthalmol Retina 2023; 7: 527–531.

84.

Feltgen

Neubauer

Jurklies

, et al. Multicenter study of the European Assessment Group for Lysis in the Eye (EAGLE) for the treatment of central retinal artery occlusion: design issues and implications. EAGLE Study report no. 1 : EAGLE Study report no. 1. Graefes Arch Clin Exp Ophthalmol 2006; 244: 950–956.

85.

Rumelt

Dorenboim

Rehany

Aggressive systematic treatment for central retinal artery occlusion. Am J Ophthalmol 1999; 128: 733–738.

86.

Arend

Harris

Martin

, et al. Retinal blood velocities during carbogen breathing using scanning laser ophthalmoscopy. Acta Ophthalmol (Copenh) 1994; 72: 332–336.

87.

Atebara

Brown

Cater

Efficacy of anterior chamber paracentesis and carbogen in treating acute nonarteritic central retinal artery occlusion. Ophthalmology 1995; 102: 2029–2034; discussion 2034-2035.

88.

Incandela

Cesarone

Belcaro

, et al. Treatment of vascular retinal disease with pentoxifylline: a controlled, randomized trial. Angiology 2002; 53(Suppl 1): S31–S34.

89.

Fraser

Adams

Interventions for acute non-arteritic central retinal artery occlusion. Cochrane Database Syst Rev 2009; 2009: CD001989.

90.

Masters

Westgard

Hendriksen

, et al. Case series of hyperbaric oxygen therapy for central retinal artery occlusion. Retin Cases Brief Rep 2021; 15: 783–788.

91.

Bagli

Çevik

MT.

Effect of hyperbaric oxygen treatment in central retinal artery occlusion. Undersea Hyperb Med 2018; 45: 421–425.

92.

Lopes

Basto

Henriques

, et al. Hyperbaric oxygen therapy in retinal arterial occlusion: epidemiology, clinical approach, and visual outcomes. Case Rep Ophthalmol Med 2019; 2019: 9765938.

93.

Weymouth

Pedersen

Central retinal artery occlusion associated with carotid artery occlusion. Clin Pract Cases Emerg Med 2019; 3: 233–236.

94.

Johnson

Cooper

JS.

Retinal artery and vein occlusions successfully treated with hyperbaric oxygen. Clin Pract Cases Emerg Med 2019; 3: 338–340.

95.

Yilmaz

Durukan

AH.

Disorganization of the retinal inner layers as a prognostic factor in eyes with central retinal artery occlusion. Int J Ophthalmol 2019; 12: 990–995.

96.

Kim

Cha

Lee

, et al. Successful treatment of central retinal artery occlusion using hyperbaric oxygen therapy. Clin Exp Emerg Med 2018; 5: 278–281.

97.

Butler

Hagan

Van Hoesen

, et al. Management of central retinal artery occlusion following successful hyperbaric oxygen therapy: case report. Undersea Hyperb Med 2018; 45: 101–107.

98.

Elder

Rawstron

Davis

Hyperbaric oxygen in the treatment of acute retinal artery occlusion. Diving Hyperb Med 2017; 47: 233–238.

99.

Soares

Gomes

Mendonça

, et al. The efficacy of hyperbaric oxygen therapy in the treatment of central retinal artery occlusion. BMJ Case Rep 2017; 2017: bcr2017220113.

100.

Altintas

AGK

. Efficacy of early hyperbaric oxygen therapy in central retinal artery occlusion. Int J Clin Exp Ophthalmol 2017; 1: 023–028.

101.

Rozenberg

Hadad

Peled

, et al. Hyperbaric oxygen treatment for non-arteritic central retinal artery occlusion retrospective comparative analysis from two tertiary medical centres. Eye (Lond) 2022; 36: 1261–1265.

102.

Beiran

Goldenberg

Adir

, et al. Early hyperbaric oxygen therapy for retinal artery occlusion. Eur J Ophthalmol 2001; 11: 345–350.

103.

Menzel-Severing

Siekmann

Weinberger

, et al. Early hyperbaric oxygen treatment for nonarteritic central retinal artery obstruction. Am J Ophthalmol 2012; 153: 454-459.e2.

104.

Hadanny

Maliar

Fishlev

, et al. Reversibility of retinal ischemia due to central retinal artery occlusion by hyperbaric oxygen. Clin Ophthalmol 2016; 11: 115–125.

105.

Yip

SCL

CKL

. Hyperbaric oxygen therapy for central retinal artery occlusion: experience in Hong Kong. Hong Kong J Ophthalmol 24, https://www.hkjo.hk/index.php/hkjo/article/view/281 (2020, accessed 27 December 2023).

106.

Beiran

Reissman

Scharf

, et al. Hyperbaric oxygenation combined with nifedipine treatment for recent-onset retinal artery occlusion. Eur J Ophthalmol 1993; 3: 89–94.

107.

Chen

, et al. Oxygen therapy in patients with retinal artery occlusion: a meta-analysis. PLoS One 2018; 13: e0202154.

108.

Celebi

ARC

. Hyperbaric oxygen therapy for central retinal artery occlusion: patient selection and perspectives. Clin Ophthalmol 2021; 15: 3443–3457.

109.

Youn

Lavin

Patrylo

, et al. Current treatment of central retinal artery occlusion: a national survey. J Neurol 2018; 265: 330–335.

110.

Teo

Tham

Y-C

, et al. Global prevalence of diabetic retinopathy and projection of burden through 2045: systematic review and meta-analysis. Ophthalmology 2021; 128: 1580–1591.

111.

Shinojima

Lee

Tsubota

, et al. Retinal diseases regulated by hypoxia – basic and clinical perspectives: a comprehensive review. J Clin Med 2021; 10: 5496.

112.

Wei

Sun

Fan

, et al. The pathophysiological mechanisms underlying diabetic retinopathy. Front Cell Dev Biol 2022; 10: 963615.

113.

Lechner

O’Leary

Stitt

AW.

The pathology associated with diabetic retinopathy. Vision Res 2017; 139: 7–14.

114.

Nanji

Sarohia

Xie

, et al. Anti-vascular endothelial growth factor therapy and retinal non-perfusion in diabetic retinopathy: a meta-analysis of randomised trials. Acta Ophthalmol 2024; 102: e31–e41.

115.

Levin

Rusu

Orlin

, et al. Retinal reperfusion in diabetic retinopathy following treatment with anti-VEGF intravitreal injections. Clin Ophthalmol 2017; 11: 193–200.

116.

Tremolada

Del Turco

Lattanzio

, et al. The role of angiogenesis in the development of proliferative diabetic retinopathy: impact of intravitreal anti-VEGF treatment. Exp Diabetes Res 2012; 2012: e728325.

117.

Yamada

Hackett

, et al. Hyperoxia causes decreased expression of vascular endothelial growth factor and endothelial cell apoptosis in adult retina. J Cell Physiol 1999; 179: 149–156.

118.

Ishida

Usui

Yamashiro

, et al. VEGF164 is proinflammatory in the diabetic retina. Invest Ophthalmol Vis Sci 2003; 44: 2155–2162.

119.

Ogura

Kiryu

Takahashi

, et al. [Visual improvement in diabetic macular edema by hyperbaric oxygen treatment]. Nippon Ganka Gakkai Zasshi 1988; 92: 1456–1460.

120.

Averous

Erginay

Timsit

, et al. Resolution of diabetic macular oedema following high altitude exercise. Acta Ophthalmol Scand 2006; 84: 830–831.

121.

Krott

Heller

Aisenbrey

, et al. Adjunctive hyperbaric oxygenation in macular edema of vascular origin. Undersea Hyperb Med 2000; 27: 195–204.

122.

Maalej

Khallouli

Choura

, et al. The effects of hyperbaric oxygen therapy on diabetic retinopathy: a preliminary study. J Fr Ophtalmol 2020; 43: 133–138.

123.

Madsen

Skov

Hansen

, et al. Hyperbaric oxygen treatment for diabetic retinopathy and neuropathy in a streptozotocin induced diabetic rat model. J Biomed Sci Eng 2021; 14: 391–401.

124.

Chen

The effects of hyperbaric oxygen therapy on diabetic retinopathy. Invest Ophthalmol Vis Sci 2003; 44: 4017.

125.

Chang

Y-H

Chen

P-L

Tai

M-C

, et al. Hyperbaric oxygen therapy ameliorates the blood–retinal barrier breakdown in diabetic retinopathy. Clin Exp Ophthalmol 2006; 34: 584–589.

126.

Lyne

AJ.

Ocular effects of hyperbaric oxygen. Trans Ophthalmol Soc U K (1962) 1978; 98: 66–68.

127.

Evanger

Vaagbø

Haugen

Short-term effects on ocular variables immediately after hyperbaric oxygen exposures. Undersea Hyperb Med 2018; 45: 395–402.

128.

Johnson

Bryson

Clark

, et al. Hyperbaric oxygen therapy induces a lenticular myopic shift even with shorter treatment protocol: a preliminary report. In: Weisse

Hockwin

Green

, et al. (eds) Ocular toxicology. Boston, MA: Springer US, pp. 235–240.

129.

Fledelius

Jansen

Thorn

Refractive change during hyperbaric oxygen therapy. A clinical trial including ultrasound oculometry. Acta Ophthalmol Scand 2002; 80: 188–190.

130.

Evanger

Vaagbø

Thorsen

, et al. Posterior segment changes of the eye during hyperbaric oxygen therapy. Undersea Hyperb Med 2014; 41: 589–96.

131.

Anderson

Farmer

JC.

Hyperoxic myopia. Trans Am Ophthalmol Soc 1978; 76: 116–124.

132.

Churchill

Deru

Wilson

, et al. Rates of visual acuity change in patients receiving hyperbaric oxygen in monoplace and multiplace chambers. Undersea Hyperb Med 2016; 43: 217–223.

133.

Tibbles

Edelsberg

JS.

Hyperbaric-oxygen therapy. N Engl J Med 1996; 334: 1642–1648.

134.

Palmquist

Philipson

Barr

PO.

Nuclear cataract and myopia during hyperbaric oxygen therapy. Br J Ophthalmol 1984; 68: 113–117.

135.

Riedl

Škiljić

Arnell

, et al. Myopic shift and lens turbidity following hyperbaric oxygen therapy – a prospective, longitudinal, observational cohort study. Acta Ophthalmol 2019; 97: 596–602.

136.

Heyboer

Sharma

Santiago

, et al. Hyperbaric oxygen therapy: side effects defined and quantified. Adv Wound Care 2017; 6: 210–224.

137.

Ashton

Ward

Serpell

Role of oxygen in the genesis of retrolental fibroplasia; a preliminary report. Br J Ophthalmol 1953; 37: 513–520.

138.

Teoh

Boo

Ong

, et al. Duration of oxygen therapy and exchange transfusion as risk factors associated with retinopathy of prematurity in very low birthweight infants. Eye (Lond) 1995; 9(Pt 6): 733–737.

139.

Evanger

Pierscionek

Vaagbø

, et al. Myopic shift during hyperbaric oxygenation attributed to lens index changes. Optom Vis Sci 2015; 92: 1076.

140.

Evanger

Haugen

Irgens

, et al. Ocular refractive changes in patients receiving hyperbaric oxygen administered by oronasal mask or hood. Acta Ophthalmol Scand 2004; 82: 449–453.

141.

Bennett

Hui

See

, et al. The myopic shift associated with hyperbaric oxygen administration is reduced when using a mask delivery system compared to a hood – a randomised controlled trial. Diving Hyperb Med 2019; 49: 245–252.

142.

Gesell

Trott

De novo cataract development following a standard course of hyperbaric oxygen therapy. Undersea Hyperb Med 2007; 34: 389–392.

143.

Messerschmidt

Ren

Tsipursky

, et al. Characterization of oxygen nanobubbles and in vitro evaluation of retinal cells in hypoxia. Transl Vis Sci Technol 2023; 12: 16.

144.

Tsipursky

Messerschmidt

Ren

, et al. Injectable oxygen carriers for the treatment of retinal ischemia. Invest Ophthalmol Vis Sci 2023; 64: 2616.

145.

Ren

Messerschmidt

Tsipursky

, et al. Oxygen nanobubbles-embedded hydrogel as wound dressing to accelerate healing. ACS Appl Nano Mater 2023; 6: 13116–13126.

146.

Fayyaz

Jabeen

Tsipursky

, et al. Dextran-based oxygen nanobubbles for treating inner retinal hypoxia. ACS Appl Nano Mater 2021; 4: 6583–6593.

147.

Bhandari

Cui

Elzey

, et al. Oxygen nanobubbles revert hypoxia by methylation programming. Sci Rep 2017; 7: 9268.

148.

Chen

, et al. Oxygen-generating hybrid polymeric nanoparticles with encapsulated doxorubicin and chlorin e6 for trimodal imaging-guided combined chemo-photodynamic therapy. Theranostics 2018; 8: 1558–1574.

149.

Zhang

Tang

Fang

, et al. Nanotechnological strategies to increase the oxygen content of the tumor. Front Pharmacol 14, https://www.frontiersin.org/articles/10.3389/fphar.2023.1140362 (2023, accessed 27 December 2023).

150.

Afshari

Akhavan

Hamblin

, et al. Review of oxygenation with nanobubbles: possible treatment for hypoxic COVID-19 patients. ACS Appl Nano Mater 2021; 4: 11386–11412.

151.

Zhao

, et al. Gold nanoparticle–mediated targeted delivery of recombinant human endostatin normalizes tumour vasculature and improves cancer therapy. Sci Rep 2016; 6: 30619.

152.

Zhuang

Ying

Spiekermann

, et al. Biomimetic nanoemulsions for oxygen delivery in vivo. Adv Mater 2018; 30: 1804693.

153.

Kim

E-J

Lee

J-E

Yoon

, et al. Hypoxia-responsive oxygen nanobubbles for tissues-targeted delivery in developing tooth germs. Front Cell Dev Biol 9, https://www.frontiersin.org/articles/10.3389/fcell.2021.626224 (2021, accessed 28 September 2023).

154.

Kim

Yoon

Kim

, et al. Upconverting nanoparticle-containing erythrocyte-sized hemoglobin microgels that generate heat, oxygen and reactive oxygen species for suppressing hypoxic tumors. Bioact Mater 2023; 22: 112–126.

155.

Khan

Hwang

Lee

, et al. Anti-tumor drug-loaded oxygen nanobubbles for the degradation of HIF-1α and the upregulation of reactive oxygen species in tumor cells. Cancers 2019; 11: 1464.

156.

Han

Jeong

Irudayaraj

Nanocatalase-based oxygen-generating nanocarriers for active oxygen delivery to relieve hypoxia in pancreatic cancer. ACS Appl Nano Mater 2022; 5: 17248–17257.

157.

Guan

Niu

Wen

, et al. Rescuing cardiac cells and improving cardiac function by targeted delivery of oxygen-releasing nanoparticles after or even before acute myocardial infarction. ACS Nano 2022; 16: 19551–19566.

158.

Talekar

Tran

T-H

Amiji

Translational nano-medicines: targeted therapeutic delivery for cancer and inflammatory diseases. AAPS J 2015; 17: 813–827.

159.

Sharma

Sinha

Shrivastava

Therapeutic targeting hypoxia-inducible factor (HIF-1) in cancer: cutting gordian knot of cancer cell metabolism. Front Genet 2022; 13: 849040.

160.

Sun

Zhou

Yang

, et al. Modulating hypoxia inducible factor-1 by nanomaterials for effective cancer therapy. WIREs Nanomed Nanobiotechnol 2022; 14: e1766.

161.

Imai

Ishibashi

Nariai

, et al. Transfection of hypoxia-inducible factor-1 decoy oligodeoxynucleotides suppresses expression of vascular endothelial growth factor in oral squamous cell carcinoma cells. J Oral Pathol Med 2012; 41: 675–681.

162.

Thambi

Deepagan

Yoon

, et al. Hypoxia-responsive polymeric nanoparticles for tumor-targeted drug delivery. Biomaterials 2014; 35: 1735–1743.

163.

Poon

Chang

Zhao

, et al. Layer-by-layer nanoparticles with a pH-sheddable layer for in vivo targeting of tumor hypoxia. ACS Nano 2011; 5: 4284–4292.

164.

Liu

X-Q

Xiong

M-H

Shu

X-T

, et al. Therapeutic delivery of siRNA silencing HIF-1 alpha with micellar nanoparticles inhibits hypoxic tumor growth. Mol Pharm 2012; 9: 2863–2874.

165.

Thomas

Samykutty

Gomez-Gutierrez

, et al. Actively targeted nanodelivery of echinomycin induces autophagy-mediated death in chemoresistant pancreatic cancer in vivo. Cancers 2020; 12: 2279.

166.

Yan

Suo

, et al. Nucleus-targeted nano delivery system eradicates cancer stem cells by combined thermotherapy and hypoxia-activated chemotherapy. Biomaterials 2019; 200: 1–14.

167.

Zhao

, et al. Co-delivery of HIF1α siRNA and gemcitabine via biocompatible lipid-polymer hybrid nanoparticles for effective treatment of pancreatic cancer. Biomaterials 2015; 46: 13–25.

168.

Yang

Yao

Cao

, et al. Silver nanoparticles inhibit the function of hypoxia-inducible factor-1 and target genes: insight into the cytotoxicity and antiangiogenesis. Int J Nanomedicine 2016; 11: 6679–6692.

Addressing retinal hypoxia: pathophysiology,therapeutic innovations,and future prospects

Abstract

Plain language summary

Keywords

Introduction

Pathophysiology of retinal hypoxia

Glaucoma and retinal hypoxia

RAOs and hypoxia

Diabetic retinopathy and hypoxia

Current use of oxygen therapy and new technology applications

Conclusion

Footnotes

Acknowledgements

Declarations

ORCID iDs

References