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Scientists have carried out a pilot study using corneal implants derived from collagen found in pig skin that restored the vision of 20 people with corneal disease. This study shows promise for the treatment of corneal blindness using bioengineered implants as an alternative to donated human corneas, which are in short supply.
The results are published in the journal Nature Biotechnology.
The World Health Organization states that blindness due to problems with the cornea – the transparent, dome-shaped outer layer of the eye, formed mostly from collagen – is the fourth most common cause of blindness globally. Approximately 12.7 million people worldwide are affected by corneal blindness. In these cases, infection, inflammation and scarring can damage the cornea, affecting its transparency and ability to refract light and consequently affecting vision.
Corneal transplants, also known as keratoplasty, taken from human donors remain the best option for the complete curative treatment of corneal blindness. Keratoconus – a disease where the cornea thins and bulges outwards – is the leading indication for corneal transplants. However, due to a shortage of suitable donor corneas, and the highest burden of corneal blindness occurring in low- to middle-income countries with poor transplant infrastructure, just 1 in 70 people in need of a corneal transplant will actually receive one.
To address the lack of suitable corneas available for transplant, research in this field has concentrated on bioengineering tissue suitable for corneal transplantation. In the current study, the researchers created cell-free corneal tissue by engineering collagen extracted from pig skin collected as a by-product of the food industry. This material was found to successfully restore vision in a trial of human patients with keratoconus, addressing the increasing demand for corneal transplants and the lack of donated human corneas for transplant.
The researchers engineered their corneal implant, dubbed the bioengineered porcine construct, double crosslinked (BPCDX), using purified, medical-grade type I collagen extracted from pig skin. The BPCDX was able to mimic the properties of the cornea including the ability to transmit light. Containing no cells or viable biological material, it is classified as a class III medical device.
Prof. Neil Lagali, professor in experimental ophthalmology at Linköping University and senior author of the study, spoke to Technology Networks to explain further how the implant is produced, “Briefly, the purified collagen is rehydrated and crosslinked with a non-toxic chemical crosslinker that is water soluble and washes out of the implant. Its only effect is to bind together the collagen fibers to make the implant stronger. Then, in a second step, the implant – to which a small amount of riboflavin (vitamin B2) was added – is exposed to UVA light which photochemically binds the collagen fibers further, to result in a very robust implant which is a hydrogel containing almost 90% water.”
Lagali and colleagues then demonstrated how biocompatible the implants would be – i.e., how they would behave after implantation and whether they could be toxic or harmful – once transplanted into the human eye. Seeding the implants in vitro with human corneal epithelial cells, the researchers demonstrated that the epithelial cells grew and remained of normal appearance after 16 days of co-culture.
Importantly, the BPCDX implants were then certified by independent labs that they met sterility safety levels and underwent various biocompatibility tests to assure that they were non-toxic, non-irritating, non-sensitizing and generally well-tolerated. Additionally, shelf-life stability tests showed that BPCDX devices had a minimum shelf-life of two years, much longer than human donor tissue which can only be held in storage for one to two weeks.
Once the BPCDX implants had been shown to be bio-compatible, researchers next evaluated the performance of the implant as a keratoconus treatment in a pig model of the disease. Five Göttingen minipigs underwent surgery to remove a 250 µm thick, 7 mm diameter region of the cornea to mimic the thinning observed in keratoconus, before receiving identically sized BPCDX inserts. Six months after surgery, the corneas of all five pigs remained transparent and there was no significant degradation or change in thickness.
After a successful trial in pigs, the researchers progressed to evaluating the corneal implants in human keratoconus patients. Using laser-assisted surgery, BPCDX implants were added to the native corneal tissue of 20 keratoconus patients in Iran and India, places where corneal blindness is common and there is a shortage of donated corneas. Vision in all trial participants had improved to an equivalent degree as would be achieved with transplants of human donor tissue, and of the 14 patients that were classified as legally blind prior to surgery, none were blind in the operated eye at the end of their follow-up period. In fact, three trial participants in India who were blind prior to the trial attained perfect 20/20 vision.
Speaking to Technology Networks, Lagali summarized some of the key implications of these findings: “Because keratoconus is a leading indication for corneal transplantation in many regions of the world including Europe, Australia and Asian countries, we believe the BPCDX could significantly reduce the demand for donor corneal tissue in the future. But more importantly, we believe it could reach people who have poor access to eye care, as the BPCDX can be shipped literally anywhere and stored in a refrigerator prior to use. This opens up the procedure to many centers and rural areas that do not have eye banks.”
Elaborating on the next steps required to confirm the efficacy of the BPCDX implants, Lagali said, “We need to conduct randomized clinical trials with a larger number of patients, so we are working on getting funding for that. Once we can demonstrate this is effective in a randomized trial, then we will apply for authorization to market this as a product, in order to make it available to large populations, in particular in low- and middle-income countries.”
Prof. Neil Lagali was speaking to Sarah Whelan, Science Writer for Technology Networks.
Reference: Rafat M, Jabbarvand M, Sharma N, et al. Bioengineered corneal tissue for minimally invasive vision restoration in advanced keratoconus in two clinical cohorts. Nat Biotechnol. 2022:1-12. doi: 10.1038/s41587-022-01408-w