Design and development of a novel artificial Bruch's membrane for ocular-based therapies

Abstract

Age-related macular degeneration is a complex disorder causing irreversible loss of central vision in nearly 50 million individuals globally. The underlying pathology of this degenerative disorder is poorly understood, but impairment of the retinal pigment epithelium (RPE) layer and its supportive structure, the Bruch’s membrane (BrM), are considered to be of critical importance to disease onset and progression.

Although the less common form of this disease (neovascular or wet AMD) can be managed in most patients, the prevalent geographic or dry form of AMD has no treatment. Consequently, several therapeutic strategies are being persued to develop a long-lasting and effective treatment. Replacement of the damaged RPE and BrM offers the simplest form of therapy that has the potential to bring about the most rapid patient benefits. Studies along these lines have sought to directly inject RPE cell suspensions into rodent disease models. However, this has resulted in reflux of cells from the site of injection or misformed grafts.

Such issues may be circumvented by creating a biocompatible prosthetic BrM, onto which a monolayer of RPE cells can be grown, and then transplanted sub-retinally. Hence, methyl methacrylate and poly(ethylene glycol) methacrylate, two compounds approved for safe clinical applications, were previously used in our laboratory to create an artificial electrospun BrM scaffold.

In this project, the biophysical properties of this first generation BrM scaffold have been refined, such that its thickness, tensile strength, diffusional characteristics and surface properties were more akin to native BrM. Its suitability has been tested by culturing primary mouse RPE cells for long periods. These findings indicated that RPE grown on this novel synthetic BrM scaffold formed stable monolayers and expressed cell-specific markers, adopting structural as well as functional specialisations observed in the native RPE.

A further modification to this scaffold using anthracene resulted in a BrM mimic that had an improved biophysical characteristic, with initial subretinal transplantation experiments carried out by clinical colleagues indicating that this artificial scaffold can potentially act as a promising BrM replacement for AMD patients, as well as those suffering from rare conditions such as retinitis pigmentosa.

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Identifiers

ORCID for Andrew Lotery: orcid.org/0000-0001-5541-4305

ORCID for Angela Cree: orcid.org/0000-0002-1987-8900

ORCID for Martin Grossel: orcid.org/0000-0001-7469-6854

ORCID for J. Arjuna Ratnayaka: orcid.org/0000-0002-1027-6938

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