Abstract
Transplantation of stem cell-derived retinal pigment epithelium (RPE) cells is a promising potential therapy for currently incurable retinal degenerative diseases like advanced dry age-related macular degeneration. In this study, we designed a set of clinically applicable devices for subretinal implantation of RPE grafts, towards the overarching goal of establishing enabling technologies for cell-based therapeutic approaches to regenerate RPE cells. This RPE transplant kit includes a custom-designed trephine for the production of RPE transplants, a carrier for storage and transportation, and a surgical device for subretinal delivery of RPE transplants. Cell viability assay confirmed biocompatibility of the transplant carrier and high preservation of RPE transplants upon storage and transportation. The transplant surgical device combines foldable technology that minimizes incision size, controlled delivery speed, no fluid reflux, curved translucent tip, usability of loading and in vivo reloading, and ergonomic handle. Furthermore, the complementary design of the transplant carrier and the delivery device resulted in proper grasping, loading, and orientation of the RPE transplants into the delivery device. Proof-of-concept transplantation studies in a porcine model demonstrated no damage or structural change in RPE transplants during surgical manipulation and subretinal deployment. Post-operative assessment confirmed that RPE transplants were delivered precisely, with no damage to the host retina or choroid, and no significant structural change to the RPE transplants. Our novel surgical kit provides a comprehensive set of tools encompassing RPE graft manufacturing to surgical implantation rendering key enabling technologies for pre-clinical and clinical phases of stem cell-derived RPE regenerative therapies.
Highlights
Retinal pigment epithelium (RPE) plays an important role in supporting normal photoreceptor function (Strauss, 2005)
We previously demonstrated that human-induced pluripotent stem cells can form three-dimensional retinal organoids containing neural retina and retinal pigment epithelium (RPE) cells in vitro (Zhong et al, 2014; FloresBellver et al, 2021)
To generate human-induced pluripotent stem cells (hiPSC)-derived RPE monolayers to use as substrate for our RPE transplants, we harvested the RPE spheroids from retinal organoids (Figure 1A), and cultured the dissociated RPE cells on 10 μm thick transparent polyester membranes
Summary
Retinal pigment epithelium (RPE) plays an important role in supporting normal photoreceptor function (Strauss, 2005). Clinical trials involving transplantation of embryonic stem cell-derived RPE in patients with AMD showed promising safety and efficacy outcomes (Da Cruz et al, 2018; Kashani et al, 2018; Mehat et al, 2018). The above-mentioned clinical trials have used two different cell delivery modalities: an RPE cell suspension or RPE monolayers. Fernandes et al developed a tissue injector with a lumen and jaws; the jaws allow grasping and loading the RPE graft into the lumen of the injector and minimizes trauma to the graft and host tissue (Fernandes et al, 2017). An optimal subretinal delivery device would minimize incision size within the retina and sclera, provide atraumatic delivery of the RPE graft to the subretinal space, and allow adequate manipulation and visualization of the transplant during delivery. There is no optimal device that has combined all of these features
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