Abstract
The severe worldwide shortage of donor organs, and severe pathologies placing patients at high risk for rejecting conventional cornea transplantation, have left many corneal blind patients untreated. Following successful pre-clinical evaluation in mini-pigs, we tested a biomaterials-enabled pro-regeneration strategy to restore corneal integrity in an open-label observational study of six patients. Cell-free corneal implants comprising recombinant human collagen and phosphorylcholine were grafted by anterior lamellar keratoplasty into corneas of unilaterally blind patients diagnosed at high-risk for rejecting donor allografts. They were followed-up for a mean of 24 months. Patients with acute disease (ulceration) were relieved of pain and discomfort within 1–2 weeks post-operation. Patients with scarred or ulcerated corneas from severe infection showed better vision improvement, followed by corneas with burns. Corneas with immune or degenerative conditions transplanted for symptom relief only showed no vision improvement overall. However, grafting promoted nerve regeneration as observed by improved touch sensitivity to near normal levels in all patients tested, even for those with little/no sensitivity before treatment. Overall, three out of six patients showed significant vision improvement. Others were sufficiently stabilized to allow follow-on surgery to restore vision. Grafting outcomes in mini-pig corneas were superior to those in human subjects, emphasizing that animal models are only predictive for patients with non-severely pathological corneas; however, for establishing parameters such as stable corneal tissue and nerve regeneration, our pig model is satisfactory. While further testing is merited, we have nevertheless shown that cell-free implants are potentially safe, efficacious options for treating high-risk patients.
Highlights
In tissue engineering and regenerative medicine, exciting new biomaterials and technologies such as 3D printing have produced very promising results in animal models, showing regeneration in a range of organs.[1]
The human cornea is a relatively simple tissue comprising three main layers, an outer multilayered epithelium, a middle stroma consisting of a largely collagenous extracellular matrix and cells arranged in layers, and an inner single-layered endothelium
recombinant human collagen type III (RHCIII)-methacryloyloxyethyl phosphorylcholine (MPC) implants have been evaluated in a range of animal models including mice,[28] rabbits[18] and mini-pigs.[20]
Summary
In tissue engineering and regenerative medicine, exciting new biomaterials and technologies such as 3D printing have produced very promising results in animal models, showing regeneration in a range of organs.[1]. The human cornea is a relatively simple tissue comprising three main layers, an outer multilayered epithelium, a middle stroma consisting of a largely collagenous extracellular matrix and cells arranged in layers, and an inner single-layered endothelium. It is highly innervated but avascular, and is optically transparent to allow entry of light into the eye for vision. Given the magnitude of the problem with an estimated 1.52 million new cases of corneal blindness per year,[6] cost-effective, cell-free biomaterials implants that promote endogenous regeneration while minimizing the regulatory and scientific challenges of specialized cleanrooms[14] and immune rejection, are attractive clinical options. Comprising carbodiimide-crosslinked recombinant human collagen type III (RHCIII) stimulated stable regeneration in conventional cornea grafted patients.[15,16] for use in high-risk
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