Long-Term Safety of Transplanting Human Bone Marrow Stromal Cells into the Extravascular Spaces of the Choroid of Rabbits.

Incurable neuroretinal degeneration diseases cause severe vision loss and blindness in millions of patients worldwide. In previous studies, we demonstrated that transplanting human bone marrow stromal cells (hBMSCs) in the extravascular spaces of the choroid (EVSC) of the Royal College of Surgeon rats ameliorated retinal degeneration for up to 5 months. Assessing the safety of hBMSC treatment and graft survival in a large animal is a crucial step before initiating clinical trials. Here, we transplanted hBMSCs into the EVSC compartment of New Zealand White rabbits. No immunosuppressants were used. Transplanted cells were spread across the EVSC covering over 80 percent of the subretinal surface. No cells were detected in the sclera. Cells were retained in the EVSC compartment 10 weeks following transplantation. Spectral domain optical coherence tomography (SD-OCT) and histopathology analysis demonstrated no choroidal hemorrhages, retinal detachment, inflammation, or any untoward pathological reactions in any of transplanted eyes or in the control noninjected contralateral eyes. No reduction in retinal function was recorded by electroretinogram up to 10 weeks following transplantation. This study demonstrates the feasibility and safety of transplanting hBMSCs in the EVSC compartment in a large eye model of rabbits.

A minimally invasive adjustable-depth blunt injector for delivery of pharmaceuticals into the posterior pole.

PURPOSE: To investigate the feasibility and safety of a novel minimally invasive adjustable-depth blunt injector for pharmaceuticals delivery into the posterior segment. METHODS: Indocyanine green (ICG), sodium fluorescein and iron oxide nanoparticles (IONPs) were injected using the new injector into the extravascular spaces of the choroid (EVSC) compartment of rabbits and cadaver pig eyes. Spectral domain optical coherence tomography (SD-OCT), fundus imaging and histology analysis were performed for assessment of injection safety and efficacy. RESULTS: Indocyanine green, fluorescein and IONPs were detected across the EVSC in rabbit eyes, covering over 80 per cent of the posterior eye surface. Injected IONPs were retained in the EVSC for at least 2 weeks following injection. No retinal detachment, choroidal haemorrhage or inflammation was detected in any of the injected eyes. In cadaver pig eyes, ICG was detected across the EVSC. CONCLUSIONS: This novel minimally invasive delivery system may be used to safely deliver large volumes of pharmaceuticals into a new treatment reservoir compartment - the EVSC which can serve as a depot, in close proximity to the retina, covering most of the surface of the back of the eye without insertion of surgical instruments under the central retina. This system is predicted to enhance the therapeutic effect of treatments for posterior eye disorders.

[A novel system for minimally invasive transplantation of bone marrow derived stem cells as a thin layer in the subretina and extravascular spaces of the choroid--for treatment of retinal degeneration].

BACKGROUND: Incurable retinal degenerations affect millions worldwide. Stem cell transplantation rescued visual functions in animal models of retinal degeneration. In those studies, cells were transplanted in subretinal "blebs". A limited number of cells could be injected and photoreceptor rescue was restricted to areas in proximity to the injection sites. PURPOSE: To develop a minimally-invasive surgical system for stem cell transplantation in the subretina and extravascular spaces of the choroid. METHODS: A novel syringe with flexible needle and adjustable pin was developed. Human bone marrow mesenchymal stem cells [hBM-MSCs) were transplanted in the eyes of RCS rats and NZW rabbits through a longitudinal triangular scleral incision. No immunosuppressants were used. Retinal function was determined by electroretinogram analysis and retinal structure was determined by histological analysis and optical coherence tomography (OCT). RESULTS: Transplanted cells were identified as a thin layer across the subretina and extravascular spaces of the choroid. In RCS rats, cell transplantation delayed photoreceptor degeneration across the entire retina and significantly enhanced retinal functions. No changes in retinal functions were recorded in rabbits following transplantation. No retinal detachment or choroidal hemorrhages were observed. CONCLUSIONS: The novel syringe facilitates cell transplantation across the subretina and extravascular spaces of the choroid using a minimally-invasive procedure. Human BM-MSC transplantation using this system ameliorates retinal degeneration in the animal model. DISCUSSION: This new transplantation system may increase the therapeutic effect of other cell-based therapies and therapeutic agents. This study is expected to lead directly to phase I clinical trials for autologous hBM-MSCs transplantation in patients with retinal degeneration.