Novel medical approaches to vision restoration have been reconceptualized to expand treatment options available for patients suffering from degenerative eye diseases, which include, but are not limited to, age-related macular degeneration (AMD), retinitis pigmentosa, corneal blindness, glaucoma, and trauma-induced cortical blindness.
With advancements in biomedical engineering, researchers and physicians can now offer their patients various vision-restoring treatment options to alleviate the debilitating effects of eye diseases that were once considered permanent.
Here, we will discuss new approaches to restoring vision, as well as the advantages and disadvantages of each treatment.
The global impact of vision loss on public health
The World Health Organization (WHO) classifies vision loss according to near or distance vision impairment, which is then subclassified according to severity level based on visual acuity.
The WHO reports that approximately 2.2 billion people suffer from near or distance vision loss globally, with about half of these cases classified as preventable.1
When further expanding this data to analyze those more likely to suffer from visual impairments throughout their lifetime, the prevalence of vision loss in low to middle-income regions is four times higher than in high-income regions. Additionally, patients’ age and population growth have been found to be the leading risk factors that can increase the prevalence of vision loss.1
The prevalence of vision loss in the United States
The Centers for Disease Control and Prevention (CDC) has listed five criteria to determine whether vision loss is a current public health problem.
The five criteria outlined by the CDC include the following questions:
- Does vision loss affect a lot of people?
- Does vision loss contribute to a significant burden in terms of morbidity, quality of life, and cost?
- Has vision loss recently increased, and will it increase in the future?
- Is vision loss perceived as a threat by the public?
- Is it feasible to act on vision loss at a community or public health level?2
Based on the aforementioned criteria, the CDC found significant data supporting that vision loss is a public health problem. Specifically, the CDC found that approximately 3.4 million people over 40 are blind or visually impaired, with an estimated 80 million Americans diagnosed with potentially blinding eye diseases.2
Furthermore, the CDC concluded that with the rising population growth rates amongst older individuals, the number of elderly patients experiencing vision loss will continue to accelerate.2
Biomedical approaches to vision restoration
The growing rates of vision loss have motivated researchers and physicians to utilize novel biomedical approaches and treatments to restore patients’ vision. Vision restoration allows healthcare providers to offer patients a series of noninvasive to minimally invasive treatment options that can either partially or fully restore their vision.
Throughout the 20th century, ophthalmologists employed cutting-edge surgical techniques with the hopes of altering refractive capacity. This employment has paved the way for advancements in modern therapies used today.
The evolution of vision restoration techniques
As ophthalmologic research and innovation evolve, new surgical techniques and devices are created with the goal of maximizing and restoring patients’ vision.
- 1939: Dr. Tsutomu Sato performed the world’s first radial keratotomy to reduce corneal curvature and improve nearsightedness.
- 1972: Dr. Svyatoslac Fyodorov expanded the work of Dr. Sato and perfected the radical keratotomy method to optimize myopic surgical treatments.
- 1981: Dr. John Taboada and his colleagues first experimented with the excimer laser for corneal surface treatments.
- 1985: Dr. Theo Seiler and Dr. Gregor Wollensak performed the first excimer photorefractive keratectomy (PRK) laser correction to treat myopia, hyperopia, and astigmatism.
- 1989: Dr. Lucio Buratto performed the first laser assisted in-situ keratomileusis (LASIK) Excimer laser vision correction.3
- 2010: The US Federal Drug Administration (FDA) approved the femtosecond laser-assisted cataract surgery, which allowed corneal incisions for capsulotomy, astigmatism correction, lens softening or fragmentation, and multifocal lens implantation.
- This method expanded on the 1967 work of Dr. Charles Kelman, who introduced phacoemulsification, which allowed for safe cataract removals.4
Novel approaches to vision restoration
The following section outlines the advantages and disadvantages of novel approaches currently being utilized and explored for restoring vision.
Implantable devices for vision restoration
Intracortical visual prosthesis (ICVP)
Patients suffering from complete blindness have historically resorted to alternative rehabilitation training to enhance their quality of life and to perform activities of daily living (ADLs). Although these alternative rehabilitation methods have been proven successful, as they have taught patients strategies to complete ADLs with senses other than vision, new research has paved the way for a Phase I clinical trial involving an intracortical visual prosthesis (ICVP) for people with blindness.5
Clinical research in intracortical visual prostheses
A team of researchers at the Illinois Institute of Technology partnered with neurosurgeons at Rush University Medical Center to develop an implantable ICVP designed to bypass the retina and optic nerve and directly provide electrical stimulation to the visual cortex of the brain. This artificial visual system was proposed for patients who lost their vision as an adult but had normal to near-normal vision in their first ten years of life.6
In early 2022, researchers and neurosurgeons were able to successfully implant a wireless device composed of 25 stimulators and a total of 400 electrodes within the visual cortex of a blind individual.7 Following the procedure, this patient and all future participants in the Phase I trial are given 1 month to recover, and their assessment takes place over the course of 1 to 3 years.
The Chicago Lighthouse is a social service organization responsible for providing participants with follow-up assessments, which occur 2 to 3 times in the first year for approximately 6 hours per visit. Return visits occur every few months until the end of the 3 years.6
The goal of these follow-up assessments is to monitor the vision-restoring capacity of patients who were previously blind and to measure the magnitude of electrical stimulation provided to the visual cortex via the wireless device.
Advantages of intracortical visual prosthesis:
- The ICVP Phase I clinical trial offers people who are completely blind the opportunity to regain some visual capacity, even if it is in the form of light perception.
- ICVP allows for electrical stimulation of the visual cortex in patients with extensive damage to the retina and the optic nerve, bypassing the necessary visual pathway to activate the visual processing centers of the brain.
- The clinical trial utilizes biocompatible electrodes that offer excellent spatial resolution, temporal resolution, and cell specificity.
- ICVP allows for the targeting of localized brain regions for efficient surgical implantation.8
Disadvantages of intracortical visual prosthesis:
- ICVP has limited penetration to deeper layers of the visual cortex, which limits access to certain vision regions.
- ICVP electrodes can lead to phototoxicity and tissue damage of the visual cortex, preventing future treatment.
- The procedure can lead to an immediate or delayed immune response, offering some risk of neurological inflammation and toxicity in the near future.8
Implantable miniature telescope (IMT) for wet and dry AMD
Age-related macular degeneration is a progressive eye disease that comes in two forms: dry or wet. Dry AMD is characterized as a retinal pigment epithelium (RPE) dysfunction leading to photoreceptor loss and retinal atrophy.
Conversely, wet age-related macular degeneration is characterized as the neovascularization of blood vessels between the RPE and Bruch’s membrane. The formation of abnormal blood vessels leads to the leakage of blood and fluid, which accumulates beneath the macula and results in its damage.
Dry AMD accounts for approximately 85 to 90% of AMD cases, while wet AMD accounts for approximately 10 to 15%. Together, both forms result in the progressive loss of central vision, which leads to blindness.9 Patients who suffer from AMD tend to be older. In addition to AMD, this subgroup of patients may also have coexisting ocular diseases, such as cataract formation.
Clinical research in implantable miniature telescopes
The implantable miniature telescope (IMT) is an FDA-approved implantable device that has been recently developed to treat patients with late-stage AMD and to perform cataract removals. Specifically, after its implantation, the IMT is utilized to magnify images within a patient’s central vision.
Candidates for the IMT are those with bilateral, end-stage AMD who have also successfully gained a five-letter improvement on a visual acuity chart using a trial external telescope. Patients are not candidates to receive the IMT if they have active wet AMD or had prior cataract surgery.
The surgical procedure for the IMT begins with routine steps for cataract removal. Ophthalmologists begin by removing the clouded lens of the eye. Normally during cataract surgery, a plastic intraocular lens (IOL) would be implanted in place of the clouded natural lens; however, instead of using an artificial IOL, surgeons will implant the IMT.
There are currently two models of the IMT: one has a 2.2x magnification setting with a larger available visual field for patients (approximately 24 degrees). The second model has a 2.7x magnification with a smaller, more limited visual field (approximately 20 degrees). Based on the patient’s specific needs, providers determine which IMT model is most appropriate.
Clinical trials for the IMT have shown an average improvement of 3.6 lines on a visual acuity chart, which represents either a 20/160 to 20/80 visual acuity improvement or a 20/200 to 20/100 increase. As a result, the IMT offers patients the opportunity for central vision restoration to combat degenerative eye diseases that lead to central vision loss.10
Advantages of IMT for vision restoration:
- Approximately 75% of patients who receive the IMT have at least a two-line or more improvement in their visual acuity on an eye chart exam. Additionally, approximately 60% of patients who receive the IMT have at least a three-line or more improvement, and approximately 40% of patients have at least a four-line or more improvement.
- Approximately 52% of patients reported an overall increase in the quality of their life after receiving the IMT.
- IMT implantation does not alter normal eye movements, as the IMT is placed inside the eye where the natural lens would normally be. This implantation method allows vision to remain strong with normal eye movements rather than requiring head turning to track objects in a patient’s visual field.11
Disadvantages of IMT for vision restoration:
- The IMT is a pea-sized device utilized in place of an IOL during cataract removal. The size of the IMT is slightly larger than an artificial IOL, requiring a larger incision and increased surgical complications.
- Due to the loss of corneal epithelial cells during IMT implantation, approximately 12% of patients can develop corneal edema during a 5-year recovery window, which may require a corneal transplant in the future.
- Approximately 11% of patients report a loss of vision over a 5-year post-surgery window, and approximately 27% report a loss over an 8-year window.
- IMTs can cause a decrease in depth perception, resulting in an uncomfortable transition period for patients to adapt to their new visual standard.11
Stem cell therapies for vision restoration
Corneal stem cell therapy
The cornea is composed of epithelial cells that contribute to its natural protective properties as the outer layer of the eye. Additionally, the cornea is surrounded by a structure called the limbus, which houses corneal stem cells and allows the cornea to have a regenerative capacity. During stem cell differentiation, immature stem cells produced in the limbus will migrate to the outer corneal surface and mature into epithelial cells.
Through this process, the cornea can naturally replace cells when they are either destroyed or undergo programmed cell death. However, if the areas of the cornea that produce stem cells are damaged due to trauma, infection, or degenerative eye disease, the regenerative nature of corneal epithelial cells will be lost.12
Clinical research in corneal stem cell therapy
Dr. Ula Jurkanas of Massachusetts’s Eye and Ear investigated 13 participants who had undergone extensive damage to the stem cell-producing areas of their corneas. In her work, she detailed how even if patients undergo a corneal transplant without stem cells being actively available, that transplant will ultimately deteriorate from the lack of peripheral stem cell support to the centrally placed transplanted tissue.
To combat this issue, Dr. Jurkanas collected healthy donor corneal stem cells and partnered with Dr. Jerome Ritz at the Dana-Farber Cancer Institute of Boston. Dr. Ritz cultured the sample of human corneal stem cells and significantly expanded the quantity for clinical utilization. Together, Dr. Jurkanas and Dr. Ritz treated patients via the placement of cultured stem cells to the damaged portions of patients’ corneas and ultimately restored a degree of visual acuity for their clinical trial participants.12
The work of Dr. Jurkanas and Dr. Ritz expanded the possibilities of stem cell research for restoring vision, which is evident in the research conducted by Dr. Kohji Nishida of Osaka University in Japan. Dr. Nishida harvested pluripotent stem cells from donors and grew corneal stem cells from scratch.
Pluripotent stem cells are self-renewing cells that can differentiate into any of the three primary groups of cells in the human body. Dr. Nishida opted to utilize pluripotent stem cells as his starting point since they are easier to grow in volume and do not require the initial utilization of healthy donors to culture stem cells.
As a result, Dr. Nishida was able to successfully transplant stem cell sheaths for four participants in his clinical trial after growing corneal epithelial cells from pluripotent stem cells.12
Advantages of corneal stem cell therapy for vision restoration:
- Corneal stem cells do not form tumors and have the capability to form patient-specific cells via cell culture and implantation.
- Corneal stem cells from adult donors lack the capacity for cancerous potential.
Disadvantages of corneal stem cell therapy for vision restoration:
- Adult donors for corneal epithelial cells have limited potency and self-renewal potential due to their donor dependence.
- Corneal stem cell culturing from adult donors is time-consuming and expensive.
Retinal stem cell therapy
As previously discussed, macular degeneration is a degenerative eye disease that leads to macula damage and the dysfunction of retinal epithelial cells. The leading cause of blindness in patients over 60 is macular degeneration.12
With similar principles seen in corneal stem cell therapy, researchers are also investigating retinal stem cell therapy. The retina is an embryonic derivative of the diencephalon of the forebrain, which ultimately develops into the neural retina and retinal pigment epithelium during embryogenesis. The neural retina comprises seven retinal cell types, which develop in a specific order from multipotent progenitor cells.
The order of the seven retinal cell types:
- Retinal ganglion cells
- Cones
- Horizontal cells
- Amacrine cells
- Bipolar neurons
- Rods
- Müller glia (MG) cells.
Clinical research in retinal stem cell therapy
Researchers have particularly focused on MG cells when studying retinal stem cell therapy. MG cells have proved to be a vital component of the mature retina, as they are responsible for retinal homeostasis and maintaining the inner blood-retinal barrier. Moreover, MG cells harbor stem cell characteristics, indicating regenerative capacity.
MG cells located in the retina periphery have been shown to display more stem cell features than centrally located MG cells. With the discovery of this potential seen in MG cells, researchers can now investigate their use with stem cell therapy.13
Slembrouck-Berc et al. investigated the regenerative potential of MG cells, as they have been found to display traditional stem cell properties in many species, particularly in fish. Specifically, their analysis determined that when standing alone, MG cells from mammals studied in vivo fail to grow into retinal neurons. However, when MG cells are reprogrammed into induced pluripotent stem cells (iPSCs), the MG-derived iPSCs can then differentiate into retinal tissue.
This investigation established a specific maturation process required to reprogram the MG cells into iPSCs, which allows for the regenerative capacity of retinal tissue that can be later implanted in patients.
As a result, the researchers established a platform to investigate further the clinical use of MG cells and their role in retinal stem cell therapy. Their goal was to offer patients stem cell implants that have regenerative capacities.14
Advantages of retinal stem cell therapy for vision restoration:
- iPSCs have the ability to generate autologous, patient-specific cells capable of forming a variety of retinal cells for treatment.
- iPSCs have an unlimited capacity for self-renewal and have a low risk of rejection due to the autologous nature of cells.
- iPSCs have no associated ethical concerns, as they are lab-produced cells.15
Disadvantages of retinal stem cell therapy for vision restoration:
- iPSCs can form tumors if they are not properly differentiated under controlled experimental conditions.
- iPSCs are dependent on specific maturation processes to either activate or suppress specific genetic sequences.15
3D bioprinting of biosynthetic eye tissue for vision restoration
The outer blood-retina barrier in the posterior eye consists of the retinal pigment epithelium, choriocapillaris, and Bruch’s membrane. Bruch’s membrane is responsible for the exchange of nutrients and waste removal between the choriocapillaris and RPE.
In AMD, lipoprotein deposits called “drusen” develop on the outer portion of Bruch’s membrane, therefore inhibiting its function. As a result, photoreceptors in the back of the eye become oxygen and nutrient deficient, which results in cell damage and death, and ultimately causes blindness.16
Clinical research in 3D bioprinting of biosynthetic eye tissue
To better understand the formation of drusen deposits and their involvement in AMD, researchers investigated the use of patient stem cells and 3D bioprinting. Dr. Kapil Bharti of the National Eye Institute (NEI) investigated 3D bioprinting, beginning with three immature stem cell derivatives: pericytes, endothelial cells, and fibroblasts. After collecting these stem cell derivatives, Dr. Bharti and his team combined the three cell populations into a hydrogel formula that was printed onto a biodegradable scaffold, which allowed the cells to grow in a specific formation.
During this investigation, researchers allowed approximately 7 days for the three cell types to grow in size and quantity. On Day 9 of the experiment, RPE cells were placed on the opposite side of the biodegradable scaffold and then given approximately 42 days to mature fully. The purpose of placing these stem cell derivatives on each side of the biodegradable scaffold was to mimic the distinct layering of the outer blood-retina barrier and form a model identical to its structure.
After an identical model of the outer blood-retina barrier is formed, researchers can investigate its properties and therapeutic conditions, which can be studied in the future to prevent the progression of AMD and other degenerative retinal diseases.16
Using 3D bioprinting allows for the fabrication and growth of human cell tissue in a laboratory setting. With the initial donation and expansion of stem cell populations in vitro, researchers can formulate a hydrogel and augment specific growth patterns to develop a representative human tissue model.
The impact of 3D bioprinting on ocular treatments
Additionally, 3D bioprinting has also shown clinical applications when studying corneal blindness. Specifically, the cornea of the eye is the outermost eye tissue that protects the eye from the outside environment and allows light to focus on the retina.
The cornea is a vulnerable eye tissue, and injury to it can lead to corneal blindness, which affects approximately 12 million people worldwide. Currently, corneal transplants are an option for patients suffering from corneal blindness; however, corneal transplants require a one-to-one donor-to-recipient transplant, which limits the number of procedures completed each year. 3D bioprinting expands the number of corneas that can be transplanted each year because it allows for developing a biosynthetic alternative to donor tissue.
Similarly to 3D printing of retinal eye tissue, 3D bioprinting for the cornea begins with collecting human stem cells and growing them on a scaffold. During this process, stem cells can be directly manipulated to build a structure that has the same size, shape, and function of natural corneal tissue.
Thus, 3D bioprinting expands the number of available samples that can be used for corneal transplants each year and can provide potentially vision-saving treatment to more patients in the future.17
Advantages of 3D bioprinting for vision restoration:
- Establishes relevant retinal tissue models that can be utilized to expand our knowledge of the poorly understood mechanisms related to AMD.
- Establishes a precise system to quantify stem cell structures related to the cornea and retina.
- Allows researchers to experiment with therapeutic conditions that can slow the progression of degenerative eye diseases.
- Provides 3D-engineered eye tissue with the same dimensions and functionality as natural eye structures.16
- Offers an increase in bioengineered corneas that can be utilized as an alternative to the one-to-one donor-to-recipient corneal transplant.17
Disadvantages of 3D bioprinting for vision restoration:
- 3D bioprinting is a very time-consuming and expensive process for establishing a highly specific eye model representative of human eye tissue.16
- The process of formulating a hydrogel with the correct mixed ratio of stem cell components can lead to faulty eye models.
- After the utilization of biosynthetic corneal tissue for transplant, there are concerns of fibrosis and scarring, which might require patients to receive a future corneal transplant.17
Optogenetic therapy for vision restoration
Retinitis pigmentosa is a progressive retinal disease caused by 71 known genetic mutations and leads to the rapid degeneration of retinal photoreceptors. Symptoms begin with a loss of peripheral vision due to the initial damage to peripheral photoreceptors, and over time, patients also lose their central vision as central photoreceptors begin to deteriorate later in the course of the disease.
Retinitis pigmentosa affects more than 2 million individuals worldwide, and there are no known cures. Late-stage retinitis pigmentosa leads to peripheral and central vision loss, resulting in complete blindness.18
Optogenetic vision therapy is a gene-independent, vision-restoring approach researchers are currently studying to combat the late-stage effects of retinitis pigmentosa and other degenerative retinal diseases. Optogenetic vision therapy can target four retinal cell types: cones, bipolar cells, amacrine cells, and retinal ganglion cells. Recent data supports that optogenetic therapy is most effective when specifically targeting retinal ganglion cells.
Clinical research in 3D bioprinting of biosynthetic eye tissue
The main function of photoreceptors is to capture light and transmit an electrical signal throughout retinal cells, the optic nerve, and the visual cortex of the brain for processing. However, photoreceptors are lost in patients suffering from retinitis pigmentosa, and light cannot be captured initially. The underlying mechanisms of optogenetic therapy are to specifically target the retinal cells that are unable to receive electrical stimulation from photoreceptors.
Research has shown that although photoreceptors may be lost, retinal cells remain alive and are functional. This pivotal finding led to developing the PIONEER Phase 1/2a clinical trial that utilizes optogenetic therapy to restore patients’ vision.19 The PIONEER Phase 1/2a study involves a step-based approach to bypass photoreceptors and directly stimulate light-sensitive retinal ganglion cells. Specifically, participants receive an intravitreal injection containing an adeno-associated viral vector with the light-sensing protein ChrimsonR.
After the intraocular injection, retinal ganglion cells become transfected with ChrimsonR, leading to ChrimsonR expression. As a result, researchers can now target the modified retinal ganglion cells with photostimulation using photostimulating goggles to excite the ChrimsonR proteins on the newly photosensitive retinal ganglion cells. This process allows light to be captured by retinal ganglion cells and lets it bypass the damaged photoreceptors that were lost due to degenerative retinal disease.
Optogenetic therapy is in early clinical trials; however, recent data on dose-escalation of intraocular injections containing ChrimsonR are safe in patients. These initial findings support the future use of optogenetic therapy and its potential for combating eye diseases caused by the loss of retinal photoreceptors.19
Advantages of optogenetic therapy for vision restoration:
- Optogenetic photostimulation allows for better localization and conductance over the dendritic tree, which can be quantitatively evaluated based on the dose-escalation of intraocular injections.
- Photostimulation via photostimulating goggles allows for a highly reproducible and stable stimulation of retinal ganglion cells. This reproducible electrical activity minimizes variation across testing trials, increasing experimental validity.
- Photostimulation allows for a moderately controlled wavelength to excite the photosensitive ChrimsonR proteins of the retinal ganglion cells.20
Disadvantages of optogenetic therapy for vision restoration:
- Data has shown an approximate 100Hz variation in wavelength doses administered by photostimulating goggles. This finding can lead to variable degrees of the excitation of retinal ganglion cells compared to previous treatment trials.
- Optogenetic therapy is an early-phase clinical trial, and data is limited to a small cohort of patients with diseases such as retinitis pigmentosa.
- Intraocular injections require dose-escalation, showing that each injection that contains ChrimsonR has a potentially short time span of clinical use and that no established dose has been marked as optimal.20
Conclusion
Clinical research has exponentially evolved over the last 50 years as scientists and physicians continue to develop novel approaches to restoring patients’ vision. Furthermore, as the field of biomedical engineering expands and data computing capabilities grow, researchers can now expedite their analyses and provide real-time clinical results.
Advanced eye diseases were once considered permanent diagnoses that left patients seeking alternative treatment options to assist them in completing their activities of daily living. However, with novel approaches that target implantable visual devices, stem cell therapy, 3D bioprinting, optogenetic therapy, and many more, physicians can introduce the next chapter of vision-restoring capabilities to their patients.
As a result, the future appears bright for novel vision-restoring approaches, and eyecare providers can continue to monitor the progress of these studies as new data emerges.
