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Biosynthetic corneas

Advances in tissue engineering are reducing obstacles to the manufacturing of cornea replacements

Roibeard O’hEineachain

Posted: Thursday, February 1, 2018

Fagerholm P, Lagali NS, Ong JA, Merrett K, Jackson WB, Polarek JW, Suuronen EJ, Liu Y, Brunette I, Griffith M. Stable corneal regeneration four years after implantation of a cell-free recombinant human collagen scaffold. Biomaterials. 2014 Mar;35(8):2420-7.

Several teams around the world are bringing biosynthetic corneas closer to a clinically useful stage of development, offering genuine hope in the battle against global corneal blindness, said Isabelle Brunette MD, FRCSC, at the XXXV Congress of the ESCRS in Lisbon, Portugal.

“There is a huge need for alternatives to native tissue for corneal replacement. Corneal blindness is the third most common cause of blindness worldwide, affecting 28 million individuals either unilaterally or bilaterally. But there is only one cornea available for every 70 patients that need one,” said Dr Brunette, Maisonneuve-Rosemont Hospital, Québec, Canada.

Four categories of tissue-engineered corneas are currently under investigation. These are: Acellular inert materials impermeable to cells, such as the PMMA optical stem of a KPro for instance; biomaterials enhanced with cells at time of production; stromal substitutes entirely engineered from cells; and acellular biomaterials that act as a scaffold to be repopulated by host corneal cells.

BIOMATERIALS
The current best example of this type of biosynthetic cornea is probably that of the University of Granada, Spain. Their cornea consists of a fibrin and agarose scaffold containing human corneal fibroblasts and is covered with an epithelial layer. Nanostructuration ensures adequate stiffness and resistance. The researchers have recently reported their research protocol for a randomised, controlled, open-label study comparing these new implants with human amniotic membranes for ALK in patients with severe trophic corneal ulcers refractory to conventional treatment.

A LIVING GRAFT
The basic principle behind stromal substitutes entirely engineered from cells, is that corneal cells in culture maintain their ability to secrete and deposit extracellular matrix in vitro, allowing for the production of thick sheets of cellularised stroma, where the interaction between the cells and their environment is preserved, Dr Brunette explained.

She added that she and her collaborators from the LOEX in Québec, Canada, have demonstrated the biocompatibility and functionality of stromal lamellar grafts entirely tissue-engineered from corneal stromal cells and transplanted in vivo in the cornea of a large animal model. Four months after transplantation, these stromal grafts were highly transparent, with no signs of rejection.

In addition, all corneal layers were re-innervated and had the multi-layered lamellar structure typical of native stroma. The normal stromal components were also present. This keratocytes-generated stroma, however, remains too soft for full thickness stromal replacement.

ACELLULAR BIOMATERIALS
The category furthest advanced towards clinical use is represented by biomaterials that are acellular at the time of implantation and promote repopulation by the host’s cells and nerves once transplanted in the living cornea. A stromal substitute of this type developed by May Griffith PhD and her associates at the University of Ottawa, Canada, has shown promising short- and long-term results in a small series of patients.

The 10 patients who received the implants in a phase I clinical trial conducted by Per Fagerholm MD in Sweden showed a mean gain of best corrected vision of more than five lines, without any sign of rejection at four years’ follow-up.

Furthermore, confocal microscopy showed that the implants were repopulated by host stromal cells and nerves. Patients with these biosynthetic corneas recovered sensitivity faster than those who underwent penetrating keratoplasty. However, the implants being too soft to be sutured, overlying sutures were necessary, which delayed epithelial healing and contributed to astigmatism.

Since then, Dr Griffith and her associates have developed a second recombinant human collagen reinforced with MPC, a synthetic phospholipid with anti-inflammatory properties. In the three patients who received the implants for chronic corneal ulcers, chemical burns or graft failure, the biosynthetic grafts relieved pain and discomfort and improved visual acuity from 6/600 to light perception before surgery to 6/38 to 6/200 after surgery.

Dr Brunette noted that several groups in the world, including her own, have also conducted research on the viability of a tissue engineered corneal endothelium. Advantages over standard DMEK would include the ability to use one donor cornea for multiple patients and a better control of tissue quality. This technology would also allow to generate endothelium from autologous cells, thus eliminating the risk for immune rejection.

Isabelle Brunette: i.brunett@videotron.ca


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