Subretinal Therapy: Technological Solutions to Surgical and Immunological Challenges

Abstract

Recent advances in ocular gene and cellular therapy rely on precisely controlled subretinal delivery. Due to its inherent limitations, manual delivery can lead to iatrogenic damage to the retina, the retinal pigment epithelium, favor reflux into the vitreous cavity. In addition, it suffers from lack of standardization, variability in delivery and the need to maintain proficiency. With or without surgical damage, an eye challenged with an exogenous viral vector or transplanted cells will illicit an immune response. Understanding how such a response manifests itself and to what extent immune privilege protects the eye from a reaction can help in anticipating short- and long-term consequences. Avoidance of spillover from areas of immune privilege to areas which either lack or have less protection should be part of any mitigation strategy. In that regard, robotic technology can provide reproducible, standardized delivery which is not dependent on speed of injection. The advantages of microprecision medical robotic technology for precise targeted deliveries are discussed.

Keywords: cell therapy; gene therapy; immune response; ocular robotics; retina; subretinal delivery.

Figure 1

Surgical approaches for subretinal delivery. Intravitreal injection (A), subretinal injection (B), and suprachoroidal injection through a microneedle (C). Intravitreal injection fills the vitreous body and exposes all intraocular surfaces in contact with the vitreous to the vectors or cells. Subretinal injection, delivers the therapeutic suspension immediately under the sensory retina, into the subretinal space, a virtual space between the photoreceptors and the retinal pigment epithelium (RPE). Suprachoroidal injection by a microneedle, delivers the therapeutic suspension into to the suprachoroidal space, a virtual space between choroid and sclera.

Figure 2

Transvitreal subretinal injection without pars plana vitrectomy. Intraoperative OCT picture showing absence of reflux after the subretinal injection in a non-vitrectomized living porcine eye. Intact vitreous may act as a plug and prevent reflux into the vitreous body, as we have observed in these subretinal injections experiments carried out in live pigs.

Figure 3

Difference in Precision and Accuracy in a schematic on the right and a dynamic task on the left. Picture and schematic representations of experiments using a laser vibrometer and video recording to assess the ability of a surgeon to superimpose or maintain the blue line with the tip of an instrument (A) held in hand. Precision refers to the degree of reproducibility of the motion, while accuracy refers to the contiguousness achieved in reference to an intended target.

Figure 4

Telemanipulated robotic surgical system. The Preceyes surgical system (Preceyes bv, Eindhoven, The Netherlands) allows the surgeon to control a robotic instrument manipulator (A) located on the side of the headrest via a motion controller (B) held in one hand of the surgeon, while endoillumination is provided by a light pipe (C) held in the other hand. A particular advantage is the non-obstructive design of the robot, allowing for hybrid manual/robotic surgery and natural integration with the regular work flow of ophthalmic surgery sessions.

Figure 5

Comparison of static stability between manual (A) and robotic assisted (B) simulated subretinal injections. The red and green lines correspond, respectively, to the beginning and the end of the fluid injection. The ability to hold the instrument steadily at the point of insertion during this maneuver was measured to deviate around 40–266 μm, depending on the individual surgeon, when surgeries were performed manually as compared to a deviation of 1–2 μm with robotic assistance. Note that spikes in the robotic assisted procedure measurement were due to artifacts.

Figure 6

Reflux and bleb formation as seen by intraoperative OCT in an ex-vivo porcine model using a solution containing a contrast agent. Intraoperative OCT pictures of subretinal injection using an assistive robotic system (B) reduces the incidence of reflux from 100 to 20% and increases the rate of successful bleb formation from 40 to 100% in this porcine eye model, as compared to manual subretinal injection (A).