Subretinal Delivery of Ultrathin Rigid-Elastic Cell Carriers Using a Metallic Shooter Instrument and Biodegradable Hydrogel Encapsulation

Age related macular degeneration (AMD), retinitis pigmentosa, and other RPE related diseases are the most common causes for irreversible loss of vision in adults in industrially developed countries. RPE transplantation appears to be a promising therapy, as it may replace dysfunctional RPE, restore its function, and thereby vision.Here we describe a method for transplanting a cultured RPE monolayer on a scaffold into the subretinal space (SRS) of rabbits. After vitrectomy xenotransplants were delivered into the SRS using a custom made shooter consisting of a 20-gauge metallic nozzle with a polytetrafluoroethylene (PTFE) coated plunger. The current technique evolved in over 150 rabbit surgeries over 6 years. Post-operative follow-up can be obtained using non-invasive and repetitive in vivo imaging such as spectral domain optical coherence tomography (SD-OCT) followed by perfusion-fixed histology.The method has well-defined steps for easy learning and high success rate. Rabbits are considered a large eye animal model useful in preclinical studies for clinical translation. In this context rabbits are a cost-efficient and perhaps convenient alternative to other large eye animal models.

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“…The rabbits underwent postoperative in vivo follow up using SD-OCT and histologic processing as described by Stanzel et al 27 ( Figure 2). Fig.…”

Section: Representative Resultsmentioning

confidence: 99%

A Step by Step Protocol for Subretinal Surgery in Rabbits

Al-Nawaiseh

Thieltges

Liu

et al. 2016

JoVE

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“…Both approaches have undergone preclinical animal studies and are being investigated in human clinical trials. 19,71,86,87 Demonstrating efficacious delivery and functional recovery in an animal model are essential prerequisites before proceeding to clinical trials. Researchers have demonstrated the feasibility of transplanting hESC-derived RPE on Parylene-C into the subretinal space of the Royal College of Surgeons (RCS) rat, an important animal model of blindness.…”

Section: Delivery Methods For Cell Suspensions Versus Adherent Cells mentioning

confidence: 99%

“…87 However, to avoid batch-to-batch variation of naturally derived products such as gelatin, synthetic platform devices are preferred over organic substrates for clinical procedures. Additional tools must be designed when transplanting therapeutic cells on a substrate into larger mammals.…”

Section: Delivery Methods For Cell Suspensions Versus Adherent Cells mentioning

confidence: 99%

Pluripotent Stem Cell-Based Therapies in Combination with Substrate for the Treatment of Age-Related Macular Degeneration

Pennington

Clegg

2016

Journal of Ocular Pharmacology and Therapeutics

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Age-related macular degeneration (AMD) is the leading cause of blindness in the western world, which severely decreases the quality of life in the patients and places an economic burden on their families and society. The disease is caused by the dysfunction of a specialized cell layer in the back of the eye called the retinal pigmented epithelium (RPE). Pluripotent stem cells can provide an unlimited source of RPE, and laboratories around the world are investigating their potential as therapies for AMD. To ensure the precise delivery of functional RPE to the diseased site, some groups are developing a therapy composed of mature RPE monolayers on a supportive scaffold for transplantation as an alternative to injecting a single-cell suspension. This review summarizes methods of generating RPE from pluripotent stem cells, compares biodegradable and biostable materials as scaffolds, and describes the specific combination of human embryonic stem cell-derived RPE on Parylene-C membranes, which is scheduled to begin clinical trials in the United Sates in 2016. Stem cellderived RPE monolayers on scaffolds hold great promise for the treatment of AMD and other retinal diseases.

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“…The investigators performed pars plana vitrectomy and induced a subretinal bleb with a 41-gauge needle, and utilised a novel infusion cannula with two side ports, to reduce the stream of fluid over the subretinal bleb, thereby avoiding collapse of the bleb or uncontrolled tearing of the retinotomy. 78 Despite elegant demonstration of delivery into the appropriate anatomical space, implantation of polyester implants without RPE cells resulted in development of a multilayered fibrocellular scar tissue, and almost complete atrophy of photoreceptors overlying the implant, with evidence of intraretinal cyst formation on OCT scanning. This may have occurred because of the mechanical separation of photoreceptors from the RPE by the implant.…”

Section: Delivery Of a Patch Graftmentioning

confidence: 99%

“…Similar atrophic changes have been observed after subretinal implantation of artificial retina chips and it was hypothesised that a more permeable carrier may result in a better preserved outer retinal architecture. 78 Implantation into rabbit eyes of the polyester carrier with RPE derived from human embryonic stem cells resulted in 95% survival at four weeks. 79 Prevention and control of PVR PVR is an inflammatory and fibrotic process that occurs in patients with retinal holes or tears.…”

Section: Delivery Of a Patch Graftmentioning

confidence: 99%

Retinal pigment epithelium transplantation: concepts, challenges, and future prospects

Alexander

Thomson

Luff

et al. 2015

Eye

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The retinal pigment epithelium (RPE) is a single layer of cells that supports the light-sensitive photoreceptor cells that are essential for retinal function. Age-related macular degeneration (AMD) is a leading cause of visual impairment, and the primary pathogenic mechanism is thought to arise in the RPE layer. RPE cell structure and function are well understood, the cells are readily sustainable in laboratory culture and, unlike other cell types within the retina, RPE cells do not require synaptic connections to perform their role. These factors, together with the relative ease of outer retinal imaging, make RPE cells an attractive target for cell transplantation compared with other cell types in the retina or central nervous system. Seminal experiments in rats with an inherited RPE dystrophy have demonstrated that RPE transplantation can prevent photoreceptor loss and maintain visual function. This review provides an update on the progress made so far on RPE transplantation in human eyes, outlines potential sources of donor cells, and describes the technical and surgical challenges faced by the transplanting surgeon. Recent advances in the understanding of pluripotent stem cells, combined with novel surgical instrumentation, hold considerable promise, and support the concept of RPE transplantation as a regenerative strategy in AMD.

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Subretinal Delivery of Ultrathin Rigid-Elastic Cell Carriers Using a Metallic Shooter Instrument and Biodegradable Hydrogel Encapsulation

Abstract: A novel shooter instrument design allows for safe and atraumatic transvitreal delivery of hydrogel-encapsulated, ultrathin, rigid-elastic carriers into the subretinal space. The procedure may be used in the future to deliver cultured RPE.

Cited by 70 publications

References 39 publications

A Step by Step Protocol for Subretinal Surgery in Rabbits

A Step by Step Protocol for Subretinal Surgery in Rabbits

Pluripotent Stem Cell-Based Therapies in Combination with Substrate for the Treatment of Age-Related Macular Degeneration

Retinal pigment epithelium transplantation: concepts, challenges, and future prospects

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