Artificial cornea for patients at high risk for rejection of donor tissue

Vision is the most important sense for the perception of our environment. We perceive up to 80% of our impressions from our surrounding through our eyes and loss of this sense adversely affects a person’s quality of life. The human eye that is protected by eyelids has a complex structure and anatomy and damage to any part of it can impair vision. One example is loss of corneal transparency leading to corneal blindness. Treatment to reverse the process of blindness requires transplantation of cornea. Globally, it is estimated that 23 million individuals, from whom over 90% live in low to middle-income countries are affected by corneal blindness [1]. The availability of cornea from donors for patient grafting vastly outstrips the demand (there is currently about one donation for every 70 demands) [1, 2]. Also, a 49% risk of rejection of the transplanted cornea exists for the patient with inflammation and severe eye pathologies like burned cornea which is a common hazard at certain workplaces. While prevention through safety factors is essential, to help the large population of people who are already suffering from corneal blindness a means of producing artificial corneas is needed.

To address this need, Dr. May Griffith has spent two decades researching for the development of biomaterial-enabled regeneration of cornea as an alternative to cornea donation and her research activity has significantly advanced had this area of medicine. Dr. Griffith received her PhD in 1990 from the department of anatomy at the University of Toronto. She had previously held affiliation with the faculty of vision at the University of Ottawa and Linköping University in Sweden before recently joining the University of Montreal as a professor in the department of ophthalmology. In 2018, Dr. Griffith and the group of her collaborators affiliated with different research institutes across the world published the results of their pre-clinical study on the transplantation of a new artificial cornea in patients with a high risk of rejection. They reported the results of a year of follow-up on a pig model, and two years of post-operation follow-up of seven patients who received the new artificial cornea. All the patients selected for their research were blind due to HSV infection, burn of the cornea or scarred cornea. Also, all patients except one had discomfort or pain in their eyes. In the last follow-up on the condition of the patients, while none of the patients were suffering anymore from the pains, three of them regained their vision.

I had the chance to interview Dr. Griffith in early March. This interview was conducted in the laboratory of Dr. Griffith in Maisonneuve-Rosemont hospital located in the north of Montreal. There, she leads a group of researchers and graduate students in developing artificial organs for implantation inside the body. We talked about the result of her recent publication, its background, and the challenges encountered while conducting this research. In her paper, preclinical results of grafting an artificial cornea fabricated by comprising human collagen of type III (RHCIII) incorporated with the chemical compound of 2-methacryloyloxyethyl phosphorylcholine (MPC) as a structural element within the implant is reported. Previous research from Dr. Griffith and her team had proven the effectiveness of RHCIII implants for corneal blind patients with low risk of rejection. That result was proved with a pre-clinical study with four years of follow-up of the conditions on the patients.

One of the topics that I was curious about was the process of proposing RHCIII-MPC as a solution for the development of an artificial cornea as a solution for the patients with high risk of rejection. The answer to my question was interesting and the research needed to yield the answer took more than a decade. In fact, this project started in 2003 and many stages were completed before reaching preclinical study. Stages that are typical steps in the development of synthesis organs for grafting in the body. The initial stage was a series of in vitro experiments to investigate the biocompatibility of different candidate materials for living cells. At this step, different materials were tested to examine their biocompatibility with cultured cells in the laboratory. As Dr. Griffith said, the majority of the projects of the graduate students who work under her supervision are conducted in this stage. The outcome of this stage is narrowing down the number of choices of materials to fewer options for in vivo experiment. In the next stage, the biocompatibility of the materials is investigated by subcutaneous implanting under the skin of the mouse animal model. From this stage, the best materials will be selected to be tested on the rabbit model in the form of a grafted artificial cornea. The artificial cornea can be fabricated with 3D printing technology and transplanted to the animal by surgery. The goal of the research at this level is finding the best material as an artificial alternative of the natural cornea that mimics the function of this organ. For testing RHCIII-MPC implant on the rabbit animal model, they prepared animal models by inducing alkali-burns on their cornea and implanting the artificial cornea on the animal by surgery. Then, they compared RHCIII-MPC implants with RHCIII which was previously tested in human. It was found that the RHCIII-MPC is a better solution as it prohibits corneal vascularization which is a measure for predicting the success of cornea implantation. Dr. Griffith and her group published this result in the Journal of Investigative Ophthalmology & Visual Science in 2011.

The next stage is testing the new artificial cornea on swine animal models as it is the closest model to human. At this level, performing the experiments has to be done by third-party institutions which significantly increases the cost of the experiments. The cost of the test on each animal model for this experiment was about $300k. So, it requires proper planning of the experiment with a comprehensive body of the evidence supporting the importance of the experiment. The experiment on testing the RHCIII-MPC cornea on the pig animal model was part of the results reported in the topic paper of this interview. Results from implanting the cornea in pigs after 12 months of post-treatment follow-ups had been promising so the experiment proceeded to the pre-clinical phase. Results of the pre-clinical test, as stated earlier, were successful for helping corneal impairment patients, especially patients considered to have a high chance of rejection of the donated cornea. These results are valuable for receiving certificates from regulatory organizations like FDA or Canada Health for use in human as a clinical treatment. Figure 1 illustrates the developmental steps in this project.

However, it was mentioned in the paper that one of the patients was excluded from the study after the first month due to the growth of fungi around the cornea. This pathology was concluded not to be related to the grafting of the cornea, and the patient underwent a different treatment. I was curious about his situation. Did the patient continue his life with the grafted cornea or was it removed, what was their condition after being excluded from the study? I asked Dr. Griffith who explained that because the experiment was a preclinical test, a second therapy, which is in common clinical use, was used to address the complications and in this case, the patient received a new cornea from a donor.

I wanted to know if the published results have reached the endpoint for this research. Some years ago, six corneal blind patients at high risk of rejection, received a novel type of artificial cornea improved their condition, either major improvement by regaining their vision or minor by treating the pains they patient have had due to being exposed to light or tearing. So, is that it? Problem solved? But Dr. Griffith said that this project is continuing and the report on a four-year follow-up of the patients will be published in the future. As a result, an effective substitute for the corneal donation with the potential of mass-production is introduced through this project. Considering the high demand and limited availability, it is a big medical advancement.

In 2016, Dr. Griffith joined the University of Montreal where she is continuing researching the development of new biomaterial-enabled artificial organs. During the last year, she also was working on establishing her new laboratory in the Maisonneuve-Rosemont Hospital. The new laboratory is now ready, and Dr. Griffith and her team are preparing to move in their new laboratory. I believe that big news of the development of new artificial organs will come out from the activities of her research team.

Figure 1 – Steps of developing the synthesis material. (A) shows the stages of the progress of the project of developing the synthesis cornea and sample pictures of implantation to a rabbit, and pig animal model and the pre-clinical study. (B) is a schematic of the narrowing the number of candidate material in the course of the progress of a research project for developing biomaterial-enabled synthesis organs.

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References:

  1. Gain, Philippe, et al. “Global survey of corneal transplantation and eye banking.” JAMA ophthalmology 134.2 (2016): 167-173.
  2. Oliva, Matthew S., Tim Schottman, and Manoj Gulati. “Turning the tide of corneal blindness.” Indian journal of ophthalmology60.5 (2012): 423.

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