Corneal transplants make up the bulk of human tissue transplants today, but the increasing demand for donor tissue and risks of suboptimal outcomes, immune rejection and graft failure have spurred researchers to investigate other options—namely, stromal stem cell therapy.

A recent paper summarizes the available preclinical and clinical evidence on this treatment option and reports that a few types of cellular therapy show promise for stromal regeneration and corneal thickness enhancement. Preclinical studies:

• Collagen-based scaffolds. Decellularized corneal stroma is the most promising current approach. Multiple sections can be obtained from a single donor cornea, including xenogenic donors such as pigs. These decellularized sections have been recellularized with adipose-derived human adult stem cells in animal studies. In both preclinical and clinical studies, transplanted cells survived and differentiated into corneal keratocytes and integrated completely with the implant to mimic natural corneal strength and transparency with no rejection episodes. However, the researchers noted this approach is limited by the need for donor tissue. Synthetic scaffolds, however, don’t require human donor tissue, but laboratory production costs are high, and they fall short of mimicking the transparency and strength of human corneas.
• Stem cell therapy without scaffolds. This model aims to generate new extracellular corneal matrices within the corneal stroma without a scaffold. Different approaches include direct intrastromal transplantation and implantation at the ocular surface, intravenous or anterior chamber. Differentiation was successful with autologous, adipose-derived human adult stem cells in keratoconus. Clinical and preclinical evidence has shown that direct intrastromal implantation of mesenchymal stem cells within the cornea results in production of the extracellular corneal matrix but not in quantities sufficient to restore corneal thickness in advanced keratoconus.
• Mesenchymal stem cell exosomes. These secrete paracrine factors like VEGF that promote cell migration and keratocyte survival. Studies hypothesize that direct treatment with these exosome growth factors can provide the benefits of cellular therapy without the cellular component itself. One study found that exosomes in culture media had immunosuppressive properties that significantly reduced stromal scarring in vivo. The authors noted that “the use of mesenchymal stem cell exosomes (without their cellular component) could overcome some of the limitations and risks associated with the direct delivery of stem cells to humans in vivo if exosomes could be applied topically.”

Clinical studies:

• Femto-assisted refractive stromal lenticule addition. The popularity of SMILE procedures has resulted in more widely available corneal donor tissue. One approach involves femto-assisted, small incision, sutureless, intrastromal lamellar keratoplasty as an alternative to corneal transplantation. The stromal lenticule addition in this procedure resulted in improved visual acuity, a thicker lenticule and a reduction of 7.00D in the max keratometry reading, one study reported. “This procedure increases corneal thickness, providing additional strength to the weakened cornea and anterior corneal flattening when using a negative meniscus-shaped lenticule,” the authors said. It’s also been shown to induce corneal reinnervation.
• Stromal stem cell therapy for advanced keratoconus. In one study, autologous, adipose-derived human adult stem cells were implanted in patients with advanced keratoconus. Tissue was obtained with liposuction and cultured. Each affected eye received an injection of the cultured cells in a buffered solution in the stromal pocket. During the three-year follow-up period, no haze or infection was observed, and patients recovered full transparency within the first day post-op. All cases continued to improve, with increased cell density over 12 months and statistically significant increases in the anterior, mid and posterior surfaces of decellularized and recellularized laminas in the anterior and posterior host stroma.

The researchers concluded that implantation of autologous, adipose-derived human adult stem cells, decellularized human corneal stroma and allogenic SMILE lenticule corneal inlays may be effective therapies for keratoconus. Corneal stromal regeneration and corneal thickness enhancement are the strongest options for corneal stroma therapy, they noted.