What Is Subretinal Fibrosis? Causes and Treatments

Subretinal fibrosis is a buildup of scar tissue beneath the retina that permanently disrupts the light-sensing cells responsible for central vision. It develops most often as a late consequence of the “wet” form of age-related macular degeneration, where abnormal blood vessels invade the space under the retina and trigger a wound-healing response that, once established, current therapies cannot reverse. The scarring is especially destructive because it sits directly beneath the macula, the small region you rely on for reading, recognizing faces, and seeing fine detail. Understanding how this scar tissue forms, what drives it, and where treatment research stands is useful for anyone navigating a diagnosis or caring for someone who is.

Where the Scar Tissue Sits and Why It Matters

Your retina is a thin sheet of nerve tissue lining the back of the eye. Directly behind the retina sits a single layer of support cells called the retinal pigment epithelium (RPE), which nourishes photoreceptors and clears away their metabolic waste. In subretinal fibrosis, scar tissue accumulates in the narrow space between the photoreceptors and the RPE, or between the RPE and the blood-vessel layer (choroid) beneath it. This scar contains large amounts of structural proteins like collagen, fibronectin, and laminin, along with immune cells and cells that have transformed into scar-producing myofibroblasts.¹ The resulting fibrous sheet physically separates photoreceptors from their blood supply and support cells, starving them and eventually killing them. Because the damage targets the macula, even a small patch of fibrosis can cause a dense blind spot in the center of your visual field while peripheral vision stays intact.

The Link to Wet Age-Related Macular Degeneration

The overwhelming majority of subretinal fibrosis cases arise from neovascular (wet) AMD. In this disease, abnormal new blood vessels grow from the choroid into or beneath the retina, a process called macular neovascularization. These vessels are fragile and leaky: they hemorrhage, ooze fluid, and deposit proteins where they do not belong. The body treats this invasion much like a wound, sending immune cells and triggering repair pathways. Over time, the “repair” overshoots and deposits dense scar tissue. Subretinal fibrosis is widely described as the end-stage outcome of neovascular AMD, the point at which vision loss becomes irreversible.²

Wet AMD is not the only trigger. Myopic choroidal neovascularization, a condition where abnormal vessels develop in highly nearsighted eyes, can also lead to subretinal fibrosis. In a study tracking eyes with myopic choroidal neovascularization treated with anti-VEGF injections, roughly a third developed subretinal fibrosis within a year. Those eyes had more frequent progression of tissue thinning, less recovery of photoreceptor structure, and worse visual results.³ Other causes of choroidal neovascularization, including ocular histoplasmosis and inflammatory eye conditions, can produce subretinal fibrosis by the same general mechanism: leaky abnormal vessels provoke a wound-healing cascade that ends in scarring.

How the Scar Forms at a Cellular Level

The central event in subretinal fibrosis is something called epithelial-mesenchymal transition, or EMT. In plain terms, the normally stationary RPE cells that sit beneath your retina undergo a personality change: they stop behaving like support cells, shed their usual markers, and start acting like scar-producing cells (myofibroblasts). Once transformed, they churn out collagen and other structural proteins, building the fibrous sheet that destroys vision.⁴ Extensive research supports EMT of RPE cells as a critical driver of the scarring, though the full chain of molecular triggers is still not completely mapped out.⁵

Multiple signaling pathways push RPE cells toward that transformation. One of the best-studied is TGF-β (transforming growth factor beta), a molecular signal that plays a starring role in scarring throughout the body, not just in the eye. When TGF-β levels rise in the subretinal space, it activates downstream pathways that tell RPE cells to ramp up collagen production and adopt a myofibroblast identity. Connective tissue growth factor (CTGF) sits further down the cascade, amplifying the fibrotic signal. Research in mouse models has shown that both TGF-β and Wnt signaling pathways are significantly ramped up in retinas prone to subretinal fibrosis.⁶

The immune system adds fuel. The complement system, a branch of innate immunity that normally helps clear debris and fight infection, becomes overactive in AMD. Complement activation products like C5a can directly push RPE cells toward EMT through receptor-mediated signaling. This means the immune inflammation and the scarring process are not separate problems but are intertwined: inflammation feeds fibrosis, and fibrosis sustains inflammation.⁷

The Anti-VEGF Paradox

If you or someone you know has wet AMD, the standard treatment is regular eye injections of anti-VEGF drugs like ranibizumab, aflibercept, or bevacizumab. These medications block vascular endothelial growth factor, the signal that drives abnormal blood vessel growth, and they have been transformative for preserving vision. But here is the uncomfortable reality: anti-VEGF therapy does not prevent subretinal fibrosis. Scar tissue can develop or progress in treated eyes even when there is no major bleeding under the retina.⁸

This happens because anti-VEGF drugs address the vascular component of AMD, the leaky new blood vessels, but they do not shut down the fibrotic cascades already in motion. The wound-healing machinery involving TGF-β, CTGF, complement activation, and EMT keeps running even after the vessels are quieted. Some researchers have raised the question of whether repeated anti-VEGF treatment might even alter the wound-healing environment in ways that favor fibrosis over angiogenesis, though this remains debated. What is clear is that a substantial proportion of patients who receive consistent anti-VEGF therapy over years eventually develop some degree of subretinal fibrosis. This gap between controlling vessel growth and preventing scarring is one of the biggest unmet needs in retinal medicine.

How Doctors Detect and Monitor Fibrosis

Subretinal fibrosis is diagnosed primarily through retinal imaging, not a blood test or biopsy. Optical coherence tomography (OCT), which creates cross-sectional images of the retina using light waves, is the workhorse. On OCT scans, fibrosis appears as a dense band of hyperreflective material beneath the retina, often thicker and more uniform than the fluid or hemorrhage seen in active wet AMD. The thickness of this material has been found to independently influence visual acuity: thicker deposits correlate with worse vision.⁹

A newer variation, OCT angiography, can map blood flow within and around the scar. Subretinal fibrosis typically shows limited blood flow, confined to residual large-caliber vessels and their branches, rather than the active branching network seen in an untreated neovascular membrane.¹⁰ This distinction helps clinicians tell fibrosis apart from active disease, which matters for treatment decisions: anti-VEGF injections help active leakage but do little for established scar. Fundus photography, which captures a wide-angle image of the back of the eye, can also reveal fibrosis as a pale, well-defined area in the macula, though OCT provides much more detail about its depth and structure.

Experimental Anti-Fibrotic Therapies

Because no approved drug directly targets subretinal fibrosis today, research is focused on intercepting the molecular pathways described above. The approaches cluster around a few strategies.

Blocking TGF-β Signaling

Since TGF-β is a master driver of fibrosis, neutralizing it is a logical target. In a mouse model, an antibody that blocks TGF-β reduced subretinal fibrosis area by about 65% compared to untreated controls.¹¹ The challenge is that TGF-β does many other jobs in the body, including regulating immune responses and maintaining tissue integrity, so broadly blocking it risks serious side effects. Researchers are looking for ways to inhibit TGF-β locally in the eye or to target only the specific downstream steps (like Smad2/3 signaling) that lead to fibrosis without disrupting everything else TGF-β does.

Targeting CTGF

Connective tissue growth factor sits at a bottleneck in the fibrotic cascade, amplifying the final steps of scar formation across multiple inflammatory and angiogenic pathways. A study using intravitreal injections of an antibody that neutralizes CTGF showed significant reduction in scar area associated with choroidal neovascular membranes compared to both untreated and placebo controls.¹² Because CTGF sits downstream of multiple fibrosis triggers, blocking it could potentially catch scarring regardless of which upstream signal started the process. This is still preclinical work, though.

Repurposing Existing Drugs

Fenofibrate, a medication already approved for lowering cholesterol and triglycerides, has shown anti-fibrotic effects in the retina. In a mouse model with a genetic predisposition to subretinal fibrosis, fenofibrate suppressed both TGF-β-Smad2/3 signaling and Wnt signaling, and it reduced levels of CTGF in the retina.⁶ Drug repurposing is attractive because safety profiles are already established, potentially shortening the path to clinical use. Whether fenofibrate’s anti-fibrotic effect in mice translates to meaningful benefit in human eyes remains to be demonstrated in clinical trials.

Gene Therapy and MicroRNA Approaches

Some of the most forward-looking research targets the fibrotic process at the genetic level. MicroRNAs are small molecules that can dial down the activity of specific genes. One line of research has found that boosting a particular microRNA, miR-24, can suppress EMT in multiple cell types by dampening TGF-β/SMAD3 and related pathways, cutting off fibrosis at its root.¹³ Another strategy uses a virus-based delivery system (rAAV) to carry multiple microRNAs targeting a signaling pathway called MAPK into the eye. In a mouse model, this approach reduced both new blood vessel leakage and EMT, and the combination of multiple microRNAs outperformed single-target approaches.¹⁴ These are early-stage studies in animals, but they represent a fundamentally different approach: rather than injecting a drug every few weeks, a one-time gene therapy could potentially provide lasting protection against fibrosis.

Natural compounds are also being explored. Luteolin, a flavonoid found in many fruits and vegetables, reduced subretinal fibrosis and EMT in a laser-induced mouse model by suppressing Smad2/3 and YAP signaling. Whether plant-derived compounds like this can reach therapeutic concentrations in the human eye remains an open question, but they expand the list of molecular targets under investigation.

Surgical Options and Their Limits

For eyes where fibrosis has already destroyed central vision, some surgeons have attempted to physically remove the scar. Techniques developed as early as the late 1980s used vitreous surgery to peel subretinal scars or extract hemorrhage from beneath the macula. In small case series, visual acuity improved in most treated patients, though the surgery carried real risks, including retinal detachment associated with the incisions needed to access the scar.¹⁵

Longer-term follow-up of surgical scar removal has been sobering. In one study that tracked outcomes over two years, eight of ten patients initially gained one to two lines of visual acuity after surgery, and one patient temporarily reached 20/60 vision. But the procedure invariably left behind defects in the RPE layer and underlying blood vessel tissue, and the two-year recurrence rate for neovascularization was 40%. The recurring membranes were often atypical, more fibrous and less vascular than the originals.¹⁶ These results help explain why submacular surgery never became standard of care for AMD fibrosis. Removing the scar removes the support layer the retina needs, and the wound-healing response that caused the original scar often produces a new one.

A more ambitious surgical concept is RPE transplantation: after removing the scar, surgeons implant a patch of healthy RPE cells to replace the damaged layer. Early experiments with both autologous grafts (using the patient’s own peripheral RPE tissue) and donor tissue showed proof of concept. One patient with an autologous graft improved from counting fingers to 20/400 vision over 14 months and was fixating over the transplanted cells. A donor graft in a second patient, however, became encapsulated in a membrane without improving vision.¹⁷ Modern versions of this approach use stem cell-derived RPE sheets rather than donor tissue, which may improve consistency and availability.

Stem Cell-Derived RPE and the Fibrosis Problem

Stem cell therapy for AMD has attracted enormous attention. The idea is elegant: grow fresh RPE cells in the lab from stem cells, then transplant them beneath the retina to replace the cells lost to disease. Several clinical trials have demonstrated that these transplanted cells can form a monolayer, express the right markers, carry out normal phagocytic function, and preserve vision in the short term. But fibrosis haunts these efforts too. In longer-term follow-up, transplant survival has been limited. In one set of experiments, RPE monolayer characteristics were maintained early on, but at eleven months survival was observed in only half the eyes. The lost grafts were associated with peri-membrane fibrosis, immune activation through macrophages, and EMT of the transplanted cells themselves, the same transformation that causes the original disease.¹⁸

This is a humbling finding. Even when you replace the damaged cells with fresh ones, the hostile subretinal environment, still rich in inflammatory signals and fibrotic triggers, can transform the new cells the same way it transformed the originals. Solving this means either pre-treating the subretinal space to calm the inflammatory and fibrotic milieu before transplantation, or engineering the replacement cells to resist EMT. Some labs are exploring both strategies simultaneously, combining anti-fibrotic agents with stem cell grafts. The success of cell replacement therapy may ultimately hinge on cracking the fibrosis problem first.

Machine Learning and the Search for New Targets

One of the obstacles in developing anti-fibrotic treatments is that researchers still do not have a complete picture of which genes matter most in driving scar severity. Hundreds of genes are differentially expressed in fibrotic lesions compared to healthy tissue, and traditional approaches to sorting through them are slow. Recent work has applied machine learning frameworks to predict which genes are most strongly correlated with lesion severity in mouse models of AMD, then cross-referenced those predictions with known druggable targets.¹⁹ The hope is that computational approaches can narrow the search space, flagging a handful of high-value targets from the hundreds of candidates so that experimental work can focus where it is most likely to pay off. This is upstream of therapy, a tool for accelerating drug discovery rather than a treatment itself, but it reflects how urgently the field is trying to find traction against a condition that has resisted treatment so far.

Living with Subretinal Fibrosis

For people already living with central vision loss from subretinal fibrosis, low-vision rehabilitation is the most practical resource available right now. This includes magnifying devices, large-print and audio alternatives for reading, specialized lighting, and training in using peripheral vision more effectively. Occupational therapists who specialize in low vision can help with everyday tasks like cooking, managing medications, and navigating public spaces. Many people with macular scarring retain good peripheral vision and can remain independent with the right support.

If you are receiving anti-VEGF injections for wet AMD and wondering about fibrosis risk, continuing treatment remains important. Anti-VEGF therapy does not prevent scarring, but it controls the vessel leakage and bleeding that feed the fibrotic process. Stopping treatment tends to accelerate both neovascularization and fibrosis. Regular OCT monitoring allows your retina specialist to track whether fibrosis is developing and to adjust expectations accordingly. There is no current evidence that any dietary supplement, over-the-counter product, or alternative therapy prevents or reverses subretinal fibrosis. The research pipeline is genuinely active, but the honest timeline for clinically available anti-fibrotic therapies is measured in years, not months.