New approaches for keratoconus

Bioengineered stromal lenticules are showing promise in the treatment of keratoconus and hyperopia

Roibeard O’hEineachain

Posted: Thursday, April 1, 2021

Neil Lagali PhD

Intrastromal implantation of bioengineered lenticules can be effective in the treatment of keratoconus and hyperopia suggest preliminary results from recent clinical trials.
“New laboratory-made bioengineered stroma could theoretically provide unlimited tissue for refractive and therapeutic purposes,” Neil Lagali PhD and Professor, Department of Biomedical and Clinical Sciences, Linkoping University, Sweden, told the 38th Congress of the ESCRS.
Bioengineered stromal tissues could in the future provide a means for mass-producing made-to-order stromal lenticules that are customised in thickness and shape for use in refractive, tectonic and keratoconus treatments. Unlike lenticules made from donor tissue, their supply is not limited by the availability of donor corneas from eye banks and tissue preservation is very simple. Moreover, the implants are non-allogeneic, reducing the chance of rejection. Bioengineered stromal tissue may also provide additional functions that human tissue cannot.
Prof Lagali noted that in a meta-analysis of studies of patients undergoing deep anterior lamellar keratoplasty (DALK) procedures for keratoconus, the rejection rate for the stromal transplants was 3-to-24%. However, not enough intrastromal lenticule implantations have been performed to date to determine the technique’s rejection rate. In addition, keratoplasty using allogeneic tissue involves the use of immunosuppressant agents, which carry their own risks of IOP increase, cataract and corneal thinning.
Research into decellularised human corneal stromal has shown promising results. In the first human study, Jorge Alió and his associates implanted decellularised corneal lenticules obtained from eye bank corneas in five advanced keratoconus patients. They decellularised the tissue with 0.1% sodium dodecylsulfate (SDS) and deoxyribonuclease (DNase). The 120µm thick stromal implants maintained their stability within the cornea without complications for at least 12 months (Alió del Barrio IL. et al., Am J Ophthalmol.2018;186:47-58), Prof Lagali said.
“But decellularisation still requires a source of human donor cornea tissue,” he pointed out.
Prof Lagali noted that as an alternative to human corneal tissue, he along with his collaborator Assoc Prof Mehrdad Rafat, Linköping University and their associates have been developing collagen-based bioengineered tissues for intrastromal implantation. They start with the base chemical building block of medical-grade porcine collagen. They then take this material and synthetically cross-link it in the laboratory and make it transparent, mechanically strong and customisable in size, thickness and swelling.
Prof Lagali and his associates have also developed a procedure for implanting the bioengineered lenticules. They call the procedure FLISK, an acronym for femtosecond laser-enabled intrastromal keratoplasty. It involves using the laser to create a pocket for implantation of a lenticule or replacing diseased or scarred corneal stromal tissue, which can first be removed using the laser, prior to insertion of a stromal replacement.
Positive results of intrastromal implantation of the bioengineered tissue, first in a rabbit model and then in a pig model, have led to the first clinical trial with the material. The ongoing prospective study involves a series of advanced keratoconus patients who underwent implantation of Link Cor® (LinkoCare Life Sciences AB, Sweden) a stromal substitute with thickness ranging from 200-440µm, personalised to the patient’s requirements. Preliminary results of the trial have been very promising.
He noted that in patients with 12-months’ follow-up, corneas have remained stable, with increased thickness, significant flattening and regularity compared to preoperative values. In addition, the patients are now contact lens tolerant and their best-corrected visual acuity has improved significantly. Furthermore, the increased corneal thickness now makes them suitable candidates for refractive surgery. There were no cases of scarring or rejection.
Clinical trials have also begun with the use of the bioengineered stroma tissue in the form of a specially designed lenticule for the treatment of presbyopia, called CorVision® MicroLens (LinkoCare Life Sciences AB, Sweden). As with the FLISK procedure for keratoconus, the lenticule is implanted into femtosecond laser-created pocket in the central stroma.
Early findings from a phase I trial with the implant procedure, conducted by Pavel Stodulka MD and his associates in the Czech Republic, show that at three months’ follow-up all of the first 10 patients to undergo the treatment achieved an uncorrected near visual acuity (UCNVA) of Jaeger 1 (0.0 logMAR), compared to a mean preoperative UCNVA of 0.64 logMAR.
Bioengineered implants may also have a future role in delivering drugs to the eye. Implants loaded with active substances during fabrication can then release the drug in a slow controlled manner, prolonging its physiological effects. In an in vitro experiment, a bioengineered stromal lenticule loaded with recombinant nerve growth factor released the drug first in an initial burst lasting about 10 days, followed by a linear release curve, so that by two months 25% of the agent had been released (Xeroudaki et al., Sci Rep. 2020;10:16936). That means the implants would release nerve growth factor for over half a year, he said.
“There will continue to be growth in the use of human donor lenticules for additive keratoplasty, but with widespread use we may see an increase in cases of stromal rejection. Decellularisation of lenticules is one promising way of overcoming this. However, use of the thicker donor lenticules required when treating keratoconus is limited by what the eye bank can provide. Bioengineered stroma, in contrast, could in principle provide an unlimited supply of non-allogeneic stromal tissue without any need for donor corneas, or any need for decellularisation,” Prof Lagali concluded.