Growth in endothelial keratoplasty (EK) procedure volume, according to the latest Eye Banking Statistical Report, and an inadequate supply of donor corneas outside the United States are powerful motivations for innovation. 
 
In this article, I discuss four emerging technologies for the treatment of corneal endothelial disease: (1) femtosecond lasers, (2) biomaterials engineering, (3) biosynthetic engineering, and (4) corneal endothelial cell therapy.
 
1. Femtosecond Lasers
The use of femtosecond lasers in corneal tissue preparation and for EK are well established. A recent retrospective analysis confirmed that risk of graft rejection and re-bubbling are significantly reduced in F-DMEK.1 These innovations continue, with vendors adding features, such as roll-on/roll-off mobility (the most recent), to facilitate surgical technique and/or improve the patient experience. 
 
Eye banks have also become increasingly sophisticated at providing pre-cut tissue or tissue layers for corneal procedures. 
 
2. Biomaterials Engineering
Also referred to as “bio-printing,” this technology uses porcine collagen, recombinant human collagen, or combinations of biomaterials and biosynthetics (example: collagen + chemical crosslinking) to fabricate corneal tissue in varying thicknesses for EK procedures.

Biosynthetic corneas made of synthetically cross-linked human collagen and porcine collagen have been out licensed for additional clinical and commercial development.

Other manufacturers are exploring the use of a proprietary bio-printing platform to fabricate a cellular matrix of human corneal tissue, growth factors, and cross-link materials. This technology is in the pre-clinical phase.

Bio-engineering approaches are characteristic of cells/tissue with inherent immune privilege, nutritional capabilities, biologic function, and a finite supply of source biomaterials with limited lifecycles. 

Eye banks have also become increasingly sophisticated at providing pre-cut tissue or tissue layers for corneal procedures. 

3. Biosynthetic  Engineering
This includes a biocompatible/biodegradable polyester, polycaprolactane (PCL) as a potential source material for corneal tissue engineering. One innovator is developing a flexible acrylic polymer used to produce artificial corneal tissue of varying thicknesses for Descemet Stripping Endothelial Keratoplasty/ Descemet's membrane endothelial keratoplasty procedures. Another innovator is culturing corneal endothelial cells seeded onto a biocompatible hydrogel.2
 
Synthetic materials are regulated as medical devices, with typically rapid regulatory timelines. Synthetic production does not rely on human corneal tissue (or other biomaterials). This technology is in its early stages, so further studies are needed to assess the long-term in vivo compatibility of these non-biological materials.

4. Cell Therapy
Cells used in cell therapies may be derived from: human embryonic stem cells (hESCs), induced pluripotent stem cells (iPSCs), human umbilical tissue-derived cells (hUTCs), or fully differentiated human cells from various organs, connective tissues, etc.  

Stem cells have the capacity to differentiate into specialized cell types, which can then be applied to cell regeneration, addressing a variety of therapeutic categories. Regulating stem cell differentiation and “turning off” cell reproduction poses potential safety risks.Fully differentiated cells possess all the essential biologic functions inherent to their specific cell types.  

Cell therapy may offer a potentially favorable and scalable option. Cells from one donor can be expanded ex-vivo to treat many recipients. Human corneal endothelial cells (HCECs) do not reproduce in vivo: a person is born with a finite number of HCECs, which over time will degrade or deteriorate due to age, disease, or surgical trauma.

Professor Shigeru Kinoshita at Kyoto Prefecture University of Medicine (KPUM) developed a combination cell therapy (fully differentiated HCECs and rho kinase inhibitor) and conducted a first-in-human trial of 11 subjects suffering from bullous keratopathy in 2018,3 with a follow-up publication of five-year outcomes in 2021.4

Kinoshita/KPUM have out-licensed this intellectual property for additional clinical and commercial development targeting corneal endothelial dystrophies with additional ex-U.S. studies performed in 2020 to 2022. In total, over 130 subjects with corneal endothelial disease have now been treated with this cell therapy. The company that in-licensed Kinoshita’s invention received regulatory approval in Japan, and will launch a clinical trial in the United States in 2023.

Another cell therapy involves the in vitro proliferation of differentiated HCECs with biocompatible magnetic nanoparticles. A Phase 1 study is currently under way to treat corneal edema secondary to corneal endothelial dysfunction in eyes that qualify for surgery involving full-thickness corneal transplantation or EK.5 Safety data from 9 subjects treated in this study was presented at the 2022 ARVO meeting.6

Stem cells have the capacity to differentiate into specialized cell types, which can then be applied to cell regeneration, addressing a variety of therapeutic categories.

Other innovators are using iPSCs to produce HCECs. Last year, an exploratory clinical study was initiated at Keio University in Japan, to examine the safety and efficacy of iPS cell-derived corneal endothelial cell substitutes for bullous keratopathy in 3 subjects. As of this publication date, no data are yet available.

Numerous research projects (and recent publications) are under way at Singapore Eye Research Institute, including corneal endothelial cell therapy, corneal gene therapy, and corneal stromal cell therapy.

In addition to addressing the chronic worldwide shortage of donor corneas, these cell therapy procedures may prove to be less invasive and more tolerable than endothelial keratoplasty – due to lower risk of rejection than EK or penetrating keratoplasty - which in turn could mean less onerous recovery for patients.

Keeping Tabs
It’s an exciting time for innovations in EK, and a space for us all to follow with interest. CP

References:

1. Sorkin N, Gouvea L, Din N, et al. Five-Year Safety and Efficacy of Femtosecond Laser-Assisted Descemet Membrane Endothelial Keratoplasty. Cornea. 2023 Feb 1;42(2):145-149. 
 
2. Wang TJ, Wang IJ, Hu FR, Young TH. Applications of Biomaterials in Corneal Endothelial Tissue Engineering. Cornea. 2016:35 Suppl 1:S25-S30.
 
3. Kinoshita S, Koizumi N, Ueno M, et al. Injection of Cultured Cells with a ROCK Inhibitor for Bullous Keratopathy. N Engl J Med. 2018:15;378(11):995-1003.
 
4. Kohsaka N, Imai K, Ueno M, et al. Five-Year Follow-up of First 11 Patients Undergoing Injection of Cultured Corneal Endothelial Cells for Corneal Endothelial Failure. Ophthalmology. 2021:128(4):504-514.

5. U.S. National Library of Medicine. Clinicaltrials.gov. Study of Safety and Tolerability of EO2002 in the Treatment of Corneal Edema.  https://classic.clinicaltrials.gov/ct2/show/NCT04894110?recrs=ab&cond=Corneal+Edema&cntry=US&draw=2. Accessed August 16, 2023.

6. Kunzevitzky N, Fleming C, Thoele JK, Goldberg R, Goldberg JL. Phase 1 Multicenter Study of Magnetic Cell Therapy for Corneal Edema Invest. Ophthalmol. & Vis. Sci.  ARVO Annual Meeting Abstract. June 2022.

Dr. Farid is director of the cornea, cataract, and refractive surgery and vice chair of ophthalmic faculty at the Gavin Herbert Eye Institute at the University of California Irvine. She is a member of the Aurion Biotech medical advisory board and a consultant for CorneaGen.