Subretinal delivery and anchorage via angiogenesis of a polyester cell carrier for retinal pigment epithelial transplantation

• Applicants: Dr. Kirsten Borchers; Dr. Boris Stanzel
• Subject Area: Ophthalmology ; Biomaterials
• Term: from 2014 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 250537947

The retinal pigment epithelium (RPE) is essential for retinal homeostasis. Its dysfunction significantly contributes to the pathophysiology of age-related macular degeneration (AMD), a leading cause of blindness. AMD patients have no curative treatment option to date. If an in vitro cultured RPE transplant can be stably anchored under the retina and its metabolism ensured, then this may be a potentially curative treatment option for AMD.Currently autologous RPE/choroid patch grafts are being performed in select patients, but suffer from high complication rates. Clinical trials with suspensions of stem cell derived RPE cells in AMD patients are underway. However, RPE suspensions may fail to survive or function on aged submacular Bruchs membrane. RPE grafts on cell carriers were proposed to significantly improve long-term function and surgical manipulation. Previous work revolved around how to bring cells grown in the laboratory under the retina. To date, long-term considerations for carrier-graft bio-integration have remained unaddressed.This project proposal aims to develop foil-supported cultured RPE grafts. We propose a novel, 2nd generation approach, whereby the carrier is bio-functionalized to ensure anchorage and metabolism following implantation through therapeutic angiogenesis. To achieve this, the bottom surface will be equipped with a coating containing a growth factor reservoir and cell attachment peptides, in order to investigate the induction of vessel outgrowth from the underlying choriocapillaris in synergy with intrinsic stimuli. Migration of choroidal endothelial cells, adhesion to the transplants functionalized lower surface and maturing into capillaries will be triggered by growth factor elution and intrinsic stimuli from the transplanted RPE. To enable transport of signaling molecules, nutrients and oxygen over the foil, it must exhibit adequate porosity. To protect the graft during the surgical procedure it will be temporarily encapsulated into a thermosensitive biodegradable hydrogel based on gelatin. To stabilize the subretinal space during implantation hyaluronic acid will be evaluated as an injectable hydrogel based on its shear thinning properties.For the development of a multi-functional encapsulated implant along with its evaluation for therapeutic efficacy the University of Bonn and the Fraunhofer Institute for Interfacial Engineering and Biotechnology IGB, Stuttgart, plan a collaborative project. Dr. Stanzel (Bonn) will contribute with his expertise in human RPE culture and animal surgery. Dr. Borchers (Stuttgart) scientific experience encompasses development of biomaterials, surface coatings for endothelial cell attachment, encapsulation of growth factors and chemical modification of biologic origin hydrogels.Should above preclinical testing prove successful, then this concept may become applied in clinical trials in patients with AMD, with the prospect of avoiding preventable age-related blindness.

• DFG Programme: Research Grants