Made of collagen protein from pig's skin, the implant resembles the human cornea and is more than a pipe dream for an estimated number of 12.7 million people around the world who are blind due to their diseased corneas. The implant is a promising alternative to the transplantation of donated human corneas, which are scarce in under-developed and developing countries, where the need for them is greatest.

Neil Lagali, professor at the Department of Biomedical and Clinical Sciences at LiU, and Mehrdad Rafat, adjunct associate professor (senior lecturer) at LiU’s Department of Biomedical Engineering and founder and CEO of the company LinkoCare Life Sciences AB, which manufactures the bioengineered corneas used in the study, told IE that their marvelous finding was the result of some 20-plus years of work.

"It has been the longtime goal of many researchers to try solving the problem of shortage in supply of donor corneas for transplantation. And so, we were very interested in addressing it using innovative materials and technologies," says Lagali.

Adding to it, Rafat says that several research groups have been working on what would be expensive technologies to solve the problem. "But, when Neil and I decided to focus on this project, we took the factor of affordability into account, as we wanted to commercialize the technology and create an impact in people's lives," says Rafat.

A 'drive-through' eye surgery

Currently, the only way to regain vision from a diseased cornea is to receive a transplanted one from a human donor. Sadly, the statistics paint a poor picture - only one in 70 patients receive a cornea transplant. What's worse is that most who require cornea transplants live in low and middle-income countries with limited access to treatments.

The researchers developed a new, minimally invasive method to treat the disease keratoconus, in which the cornea becomes very thin and bulges outward, leading to blindness. "Though there are many different causes and diseases of the cornea that can lead to visual impairment and blindness, We focused on keratoconus, which is one of the big diseases that cause loss of vision," says Lagali.

There are methods to treat keratoconus if detected early. A keratoconus patient's cornea at an advanced stage would be surgically removed and replaced by a donated cornea, an invasive surgery performed at larger university hospitals.

"In many countries, there are large populations affected by this disease. But it isn't detected early and it progresses over time, leading to visual impairment and blindness. At this stage, only a transplant can help. But there's a severe shortage of donor tissue," says Lagali.

Other researchers have been making advances with artificial cornea. But, Rafat states that when a possibility for repairing body tissues and organs arises, it's better to repair than to replace the damaged organ completely. And that is one of the approaches the researchers have taken.

"Instead of removing their corneas, we left them intact: We created a pocket and added a bioengineered corneal tissue. There are many benefits to this technology, from the engineering and clinical perspective. Firstly, it helps patients to recover faster: They require less medication post-surgery. The surgery in itself is less invasive and barely complicated, and the healing process is accelerated. I like to call it 'drive-through' eye surgery because it takes only 15 minutes to perform the entire surgery as opposed to corneal transplantation, which may take half a day, and requires continuous follow-up," explains Rafat, who was behind the design and development of the implants.

Affordable, compatible, uncomplicated

To create an alternative to the human cornea, the researchers sought collagen molecules derived from pig skin that was purified and produced under stringent conditions for human use.

"Affordability was a primary factor. Some researchers use recombinant collagens, which isn't affordable for a lot of people. Several scientists, researchers, and regulatory authorities did oppose our research, but now we've proved that it is safe. Pigs are similar to humans in many aspects and are a good model for preclinical testing," says Rafat.

The risk of zoonotic diseases would have been a concern. But, "we don't use the animal tissue directly. We only use the collagen, which is derived from animal tissue. All the other biological components are removed from this collagen," stresses Rafat.

Lagali interjects: "One of the reasons we chose the material was because the normal human cornea in itself is made of collagen. Also, pig collagen is already being used in cosmetic surgery. So it's not entirely new to the medical field."

To construct the implant, the researchers stabilized the loose collagen molecules, forming a robust and transparent material that can stand handling and implantation in the eye.

According to Rafat, two other factors considered while choosing the material were safety and naturalism. "To implant something in the human eye, or any body part for that matter, you need to ensure that the material is biocompatible. We followed a bottom-up approach where we started with simple materials and then kept enhancing the mechanical properties whilst uncompromising biocompatibility and light transmissibility," he explains.

The researchers also didn't have to fret about the compatibility of the corneal material, as it was an in-built property, independent of the patient. "The material doesn't contain any cells or biological components that would stimulate or trigger the immune system. We didn't even have one case of rejection - whereas, with human donor cornea, there's always a risk," says Rafat.

Mission success: 20/20 Vision

Surgeons in Iran and India have used the surgical method and implants. Both the countries have many people who have corneal blindness and low vision - and there's a significant lack of donated corneas and treatment options. The clinical cohort comprised 20 people who were either blind or on the verge of losing sight due to advanced keratoconus.

As Rafat aforementioned, the operations were free from complications. The tissue healed fast, and an eight-week treatment with immunosuppressive eye drops sufficed to prevent implant rejection. The patients were followed for two years, and zero complications were noted during that time.

The researchers mentioned that the final results were indeed astonishing. "What surprised us the most was how well the implants worked in restoring the vision. We thought that more work was needed on optimization - the thickness, shape, all of it can be changed and adjusted. But without any of it, we got very good visual results as good as, or even better than a normal corneal transplant. Three patients from India who had been blind [14 of the 20 patients were blind] before the study ended up with 20/20 vision so that was a great surprise," says Lagali.

The rest of the patients ended up with an excellent vision. "The most important thing is that all of them crossed the threshold - from low vision or blindness to good vision. In terms of making a difference in their daily activities, it's a big change and makes a huge difference," he says.

Rafat adds that patients who had zero tolerance to contact lenses before the surgery become tolerant. "So, in combination with our implants, these patients can also use contact lenses to improve their vision."

Another significant element that comes into play is the shelf-life of the bioengineered corneas. While donated corneas must be used within two weeks, these bioengineered ones can be stored for up to two years before use. Also, there is no wastage in case of a failed operation, as there are no donated tissues involved.

One of the aspects that the researchers were adamant about was scalability. "From the beginning, we decided to make the manufacturing processes scalable by introducing automation as well as avoiding additional materials that can complicate the process. We have modular cooling rooms, that can easily be extended and expanded. At the same time, we are incorporating 3D bioprinting into our technology," says Rafat.

A reality in three to five years

The researchers intend to test the implant in a larger population. "We've 20 patients now, but we would like to have larger and randomized clinical trials, which is necessary to show the effectiveness and low-risk factor of the implant. Once we acquire funding, we can get approvals to market this as a product. Also, in the future, our goal is to customize these implants for every group of patients to improve their vision to a greater result. This is required as each patient is unique with different stages of keratoconus corneas," says Lagali.

Rafat adds: "At the same time, we're working on the regulatory aspects of the technology to ensure that we meet the ISO standards and prepare the implant for mass production."

How soon will the implants be accessible?

"I would say maybe three to five years. Maybe Mehrdad is more optimistic," says Lagali.

"It depends," says Rafat. "The main barrier right now is getting through regulatory requirements and receive market approval. We know that our bioengineered corneas are safe and effective, and that they work. We've plenty of evidence but we have to pass through these hurdles. That may delay access to this technology for everyone. But yes, I'm optimistic - I would say three years. We also have similar collagen products which will be available within one or two years."

The groundbreaking technology is compelling: the bioengineered implant is made of natural tissues, the surgery is non-complicated and safe, it has so-far restored vision in 20 people affected by low vision/blindness, and the recovery period is extremely short. But, most of all, it could act as a real savior in those lesser-developed countries where keratoconus is a growing problem. "And so, this really is our main target. Our technology and method for implantation are designed to reach such people who wouldn't normally have access to the medical care needed," adds Lagali.