The Corneal Comeback

Amid a global donor shortage, the pioneering CALEC therapy is transforming corneal regeneration, offering new hope for sight restoration

A tiny biopsy, a big breakthrough. From lab-grown limbal cells to xeno-free grafts with staying power, CALEC is turning heads—and healing eyes—in the race to restore sight after limbal stem cell loss. Here’s why the future of corneal regeneration might just be cultivated.

In the vast and varied garden of ophthalmology, some tissues bounce back like weeds, while others—once injured—wither away. Limbal stem cells fall into the former category…until they don’t. These tiny powerhouses, tucked into the outer edge of the cornea, usually excel at regenerating the eye’s surface. But when they’re lost to trauma burns or disease, the result—limbal stem cell deficiency (LSCD)—can leave the cornea vulnerable and vision in jeopardy.

Now, a pioneering therapy called CALEC (cultivated autologous limbal epithelial cells) transplantation is offering a glimmer of hope for patients once left with few options.

Inside the cornea’s regeneration station

To understand why CALEC is such a breakthrough, it helps to zoom in on the cornea’s finely tuned ecosystem. “The wonderful thing about the cornea is that it has this regenerative ability to keep creating the epithelium,” said Prof. Dr. Sorcha Ni Dhubhghaill, head of ophthalmology at University Hospital Brussels. “The epithelium is a bit like the skin that protects the front of the eye. And every time you blink, you lose a few of those cells.”

Enter limbal stem cells, the behind-the-scenes workers responsible for maintaining renewal. Nestled in the limbus, these cells steadily pump out fresh corneal epithelial cells to maintain the eye’s clarity and protection. “We can only reproduce these layers if we’ve got a cell population that keeps growing,” said Prof. Ni Dhubhghaill. “That’s what we call a stem cell population.”

But these aren’t just any stem cells. Corneal epithelial cells are highly specialized: they must be transparent and protective. “They’re hard to make,” she added. “They need to stay transparent, and they need to protect all the underlying structures.”

The fallout can be dramatic if that stem cell source is damaged. “When you don’t have these cells, you end up with an exposed corneal stroma,” Prof. Ni Dhubhghaill explained. “And the corneal stroma is like an Irishman. It’s wonderfully specialized, but it can’t look after itself. It needs the epithelium to protect it so it can do the structural work.”

From there, two things typically happen, and neither is ideal. First, the eye might try to self-repair by growing conjunctival tissue over the cornea. “But the conjunctiva is not transparent,” she noted. “It will eventually grow blood vessels, and it will have a vascularized appearance, so while it’s protective, it obliterates the functional ability of the cornea.”

The second, more alarming outcome? A total loss of protection that can lead to corneal perforation and, ultimately, loss of the eye.

The evolution of limbal stem cell therapies

The journey to treat LSCD has come a long way, from high-stakes risks to high-tech solutions. Back in the day, treatment meant removing a hefty chunk of limbal tissue from a patient’s good eye and transplanting it to the damaged one. It worked, but at a potentially steep cost.

“The problem here is, what if you risk the good eye?” asked Prof. Ni Dhubhghaill. “That’s not acceptable to a patient who’s already gone through literal trauma. It is very hard to justify risking a good eye in order to help the bad eye.”

A major leap forward happened about 15 years ago when a team in Italy, led by Prof. Graziella Pellegrini, flipped the script. Instead of harvesting large amounts of tissue, they took a small biopsy and used cell culture to multiply the limbal stem cells in the lab.

“Rather than run the risk with a very small transplant, they expanded them in culture, grew them in a large number, put them on fibrin layers, and they used co-culture with 3T3 mouse feeder cells to really boost that population of stem cells,” explained Prof. Ni Dhubhghaill. This led to the development of Holoclar (Holostem Advanced Therapies; Modena, Italy), one of the first therapies of its kind to be approved by the European Medical Association (EMA).

Holoclar was a big win, but not a perfect one. “You still need one good eye,” she explained. “So, in terms of restoring patients from total blindness, it didn’t really do that. But it did improve their worst eye.” Plus, the process was complex and costly, making it a tough sell for many healthcare systems.

A new chapter for LSCD

Now comes CALEC, the next-gen solution developed by Massachusetts Eye and Ear (USA). Like earlier therapies, CALEC uses a small biopsy from a healthy eye, but with critical upgrades to how the cells are cultivated and transplanted.

One of the standout features? It’s xeno-free. “That means the elimination of all potential animal products,” explained Prof. Ni Dhubhghaill. “Ten years ago, I used to think, I’m not as worried about animal products as I am worried about human products,’ because, at that time, we weren’t really thinking so much about the transition of diseases from animal to human.”

“We think about that a lot now because of what happened with COVID and how we know that it can jump from species,” she added. “So going xeno-free, I think, is a huge advantage of the approach from the [CALEC] group.”

CALEC also swaps out fibrin for amniotic membrane as the cell growth layer—a change that seems to be paying off. “Amniotic membrane is known to be a very beneficial wound healing addition,” Prof. Ni Dhubhghaill noted. “And what we are seeing from their published results is even better outcomes than what we had seen before. They’re getting quite high rates of success.”

The CALEC procedure

The CALEC procedure is a carefully choreographed bit of modern medicine. Here’s how it works, according to a detailed write-up in Nature Communications:

It all starts with a tiny limbal biopsy—just one clock hour’s worth—taken from the patient’s healthy eye using only topical anesthesia. This sliver of tissue is then whisked away in an animal-free solution to the lab, where the real magic begins.¹

In the lab, a two-step manufacturing process takes over. Stage 1 involves growing the limbal cells in plastic until they reach confluency. In Stage 2, the cells are transferred to a de-epithelialized amniotic membrane, where they continue to expand until they’re ready to go.¹

Throughout the entire process, these cells are subjected to a rigorous lineup of quality checks, including cell count, viability, phenotype, proliferation and sterility. And just in case, the team makes two CALEC constructs from every biopsy: one for transplant and one for backup.¹

Once the construct is ready, the patient heads into surgery. First, the surgeon removes the fibrovascular pannus from the damaged eye. Then the CALEC graft—carefully trimmed to 17 mm—is sutured to the limbus using fine 10-0 nylon stitches. A bandage contact lens is placed over the eye, and the patient starts a course of preservative-free antibiotics, steroids and serum tears to support healing.¹

What the trial revealed

The Phase I/II clinical trial of CALEC, conducted at Massachusetts Eye and Ear, delivered some eye-catching results. Between 2016 and 2021, 15 participants with unilateral LSCD were enrolled, and 14 of them received CALEC grafts.¹

The main focus was on feasibility and safety, and the big question was: could a tiny biopsy reliably yield a viable graft? The answer was a resounding yes. Ninety-three percent (14 out of 15) of biopsies passed quality control and were deemed transplant ready.¹

As for safety, the news was equally reassuring. Only one major complication occurred in a recipient’s eye: a bacterial infection eight months post-op, linked to long-term contact lens wear, not the CALEC itself. No serious issues arose in any of the donor or recipient eyes.¹

On the efficacy front, results were encouraging. By the three-month mark, half of the participants had already achieved “complete success”—defined as a major improvement in the corneal surface. That figure rose to 79% at 12 months and held steady at 77% by 18 months. When including cases of “partial success” (reduced vascularization or symptom relief), overall success rates hit 86%, 93% and 92% at 3, 12 and 18 months, respectively.¹

As Prof. Ni Dhubhghaill put it, “This is very encouraging because these are some of the most notoriously difficult patients to treat. So any subsequent improvement on the previous knowledge is always welcome, and it is very encouraging that there is further evolution in the field.”

CALEC caveats

That said, even promising treatments come with their share of hurdles. One big unknown is durability. “The big question for us and for everybody in the field is how long will it last?” Prof. Ni Dhubhghaill noted. The 18-month results are hopeful, but longer-term data will be key in determining how well these grafts hold up over time.

Then there’s the issue of the stem cell niche. In a healthy eye, limbal stem cells live in a protected three-dimensional structure, like VIPs in a private suite. But the CALEC graft sits exposed on the cornea, which means these stem cells may take more wear and tear than nature intended, raising concerns about their long-term survival.

CALEC also isn’t a one-size-fits-all solution. It’s currently limited to patients with one healthy eye to donate tissue, ruling it out for those with bilateral LSCD. Plus, the manufacturing process is no walk in the park. It requires specialized labs and skilled personnel, which may limit widespread accessibility.

Cost is another consideration. While CALEC may be more affordable than Holoclar, it’s still a complex process. As Prof. Ni Dhubhghaill pointed out, the treatment must ultimately prove to be cost-effective to remain viable in the long run.

And let’s not forget the clock. Once the final CALEC product is ready, there’s a 24-hour window to get it surgically implanted. That tight turnaround can pose logistical challenges, especially in places where coordination between the lab and operating room isn’t exactly seamless.

A peek into the future

With the Phase I/II trial of CALEC showing such encouraging results, the road ahead is looking wide open for researchers. A number of exciting possibilities are already on the table.

One of the biggest next steps is exploring allogeneic approaches, using donor cells instead of the patient’s own. This could be a game changer for people with bilateral LSCD. As Dr. Jerome Ritz, executive director of the Connell-O’Reilly Cell Manipulation Core Facility (CMCF), put it in a news release, “Our future hope is to set up an allogeneic manufacturing process starting with limbal stem cells from a normal cadaveric donor eye.” If successful, this approach could dramatically expand CALEC’s reach. ²

Another focus is extending the shelf life of CALEC grafts. Right now, the grafts must be transplanted within 24 hours of manufacture, which is not exactly ideal for shipping or scheduling. Developing preservation methods to keep these cells viable for longer would give surgeons more flexibility and patients more access.

Then there’s the need for larger, randomized trials. While the early data are promising, studies involving more patients across multiple centers will help fine-tune outcomes and uncover what factors predict success (or signal trouble).

READ MORE: Cash, Corneas and Controversy

Implications for clinical practice

Though CALEC isn’t quite ready for prime time, it’s already casting a long shadow of promise across the corneal surgery landscape.

For patients with unilateral LSCD who haven’t responded to traditional treatments, CALEC offers something that’s been in short supply: genuine hope. With its high success rates and stellar safety profile in clinical trials, CALEC could soon become a powerful new tool in the corneal surgeon’s kit.

But it’s not just about patching things up. By restoring a healthy ocular surface, CALEC may make previously ineligible patients viable candidates for corneal transplantation—essentially giving them a second shot at sight. That’s no small feat for a condition as stubborn as LSCD.

Perhaps most significantly, CALEC signals a major shift in how we treat severe corneal damage. Instead of simply managing symptoms, we’re stepping into the realm of true regenerative therapy, where the goal isn’t just comfort, but actual healing.

Cultivating a clear future

Think of CALEC as the ophthalmologist’s version of propagating a plant from a cutting. By taking just a sliver of limbal stem cells from a healthy eye and coaxing it to grow into transplantable tissue, the procedure is essentially gardening at the cellular level—and early results show it works beautifully.

Sure, there are still weeds to pull. Long-term durability remains an open question, the manufacturing process is complex, and it currently can’t help patients with bilateral LSCD. But even with those caveats, the success of CALEC marks a leap forward in the field of corneal regenerative medicine.

As Prof. Ni Dhubhghaill put it, “I think the approach and the success rates are very, very encouraging.” And she’s not alone. As research continues and larger trials unfold, CALEC may evolve from a cutting-edge experiment to mainstream solution. In the ever-growing garden of ophthalmologic innovation, CALEC is a bold new bloom—one that just might bear life-changing fruit.

Editor’s Note: This content is intended exclusively for healthcare professionals. It is not intended for the general public. Products or therapies discussed may not be registered or approved in all jurisdictions, including Singapore. A version of this article was first published in CAKE Issue 26.

References

Jurkunas UV, Kaufman AR, Yin J, et al. Cultivated autologous limbal epithelial cell (CALEC) transplantation for limbal stem cell deficiency: A Phase I/II clinical trial of the first xenobiotic-free, serum-free, antibiotic-free manufacturing protocol developed in the US. Nat Commun. 2025;16:1607.
Novel Stem Cell Therapy Repairs Irreversible Corneal Damage in Clinical Trial. Mass General Brigham. March 4, 2025. Available at: https://www.massgeneralbrigham.org/en/about/newsroom/press-releases/calec-stem-cell-therapy-clinical-trial-repairs-corneal-damage. Accessed on June 6, 2025.