A hydrogel-based stem cell delivery system to treat retinal degenerative diseases.

Regenerative strategies for retinal degenerative diseases are limited by poor cellular survival, distribution and integration after transplantation to the sub-retinal space. To overcome this limitations a stem cell delivery system was developed, taking advantage of the minimally-invasive, injectable and biodegradable properties of a blend of hyaluronan and methylcellulose (HAMC). The physical and biological properties of this unique HAMC formulation were studied. HAMC supported retinal stem-progenitor cell (RSPC) survival and proliferation in vitro. The blend was a viscous solution, exhibiting properties ideal for delivery to the sub-retinal space. In vivo transplantation studies in mice were carried out to investigate both the biodegradability of HAMC in the sub-retinal space over 7 days and the potential of HAMC as a cell delivery vehicle. RSPCs delivered in HAMC were more evenly distributed in the sub-retinal space than those delivered in traditional saline solutions, suggesting that HAMC is a promising vehicle for cellular delivery to the degenerating retina overcoming previously reported barriers to tissue integration in the retina such as cellular aggregation and non-contiguous distribution.

[1]  Gerald Liew,et al.  Ranibizumab for neovascular age-related macular degeneration. , 2007, The New England journal of medicine.

[2]  G. Rubin,et al.  Long‐term visual and microperimetry outcomes following autologous retinal pigment epithelium choroid graft for neovascular age‐related macular degeneration , 2008, Clinical & experimental ophthalmology.

[3]  B. Klein,et al.  Overview of epidemiologic studies of diabetic retinopathy. , 2007, Ophthalmic epidemiology.

[4]  L. Ambrosio,et al.  In Vitro and in vivo Behaviour of Biodegradable and Injectable PLA/PGA Copolymers Related to Different Matrices , 2007, The International journal of artificial organs.

[5]  Robert Langer,et al.  A microfabricated scaffold for retinal progenitor cell grafting. , 2008, Biomaterials.

[6]  E. Balazs Medical Applications of Hyaluronan and its Derivatives , 1991 .

[7]  R. Hogg,et al.  Visual function and dysfunction in early and late age-related maculopathy , 2006, Progress in Retinal and Eye Research.

[8]  G. Walters,et al.  New paradigms in the treatment of wet AMD: the impact of anti-VEGF therapy , 2009, Eye.

[9]  S. R. Kaufman Developments in age-related macular degeneration: Diagnosis and treatment. , 2009, Geriatrics.

[10]  I. Ahmad,et al.  Stem Cell Therapy for Retinal Degeneration: Retinal Neurons from Heterologous Sources , 2005, Seminars in ophthalmology.

[11]  H. Kaplan,et al.  Stem cells as tools in regenerative therapy for retinal degeneration. , 2009, Archives of ophthalmology.

[12]  Chi-Chao Chan,et al.  Molecular pathology of age-related macular degeneration , 2009, Progress in Retinal and Eye Research.

[13]  G. Wnek,et al.  The use of progenitor cell/biodegradable MMP2-PLGA polymer constructs to enhance cellular integration and retinal repopulation. , 2010, Biomaterials.

[14]  I. Kirov,et al.  Multipotent retinal progenitors express developmental markers, differentiate into retinal neurons, and preserve light-mediated behavior. , 2004, Investigative ophthalmology & visual science.

[15]  N. Congdon,et al.  Important causes of visual impairment in the world today. , 2003, JAMA.

[16]  D. Chen,et al.  Robust neural integration from retinal transplants in mice deficient in GFAP and vimentin , 2003, Nature Neuroscience.

[17]  D. van der Kooy,et al.  Retinal stem cells in the adult mammalian eye. , 2000, Science.

[18]  Charles H Tator,et al.  Fast-gelling injectable blend of hyaluronan and methylcellulose for intrathecal, localized delivery to the injured spinal cord. , 2006, Biomaterials.

[19]  Charles Tator,et al.  Intrathecal drug delivery strategy is safe and efficacious for localized delivery to the spinal cord. , 2007, Progress in brain research.

[20]  J. Leroux,et al.  Novel injectable neutral solutions of chitosan form biodegradable gels in situ. , 2000, Biomaterials.

[21]  D. Zack,et al.  Characteristics of progenitor cells derived from adult ciliary body in mouse, rat, and human eyes. , 2007, Investigative ophthalmology & visual science.

[22]  J. Motsch,et al.  Eye surgery in the elderly. , 2003, Best practice & research. Clinical anaesthesiology.

[23]  T. Ciulla,et al.  Current and future pharmacological intervention for diabetic retinopathy , 2005, Expert opinion on emerging drugs.

[24]  R. Sidman,et al.  Spare the rod and spoil the eye , 2005, British Journal of Ophthalmology.

[25]  Kelly Shintani,et al.  Review and update: current treatment trends for patients with retinitis pigmentosa. , 2009, Optometry.

[26]  A. Adamis,et al.  Ocular neovascularization: an epidemiologic review. , 1998, Survey of ophthalmology.

[27]  T. Desai,et al.  Survival, migration and differentiation of retinal progenitor cells transplanted on micro-machined poly(methyl methacrylate) scaffolds to the subretinal space. , 2007, Lab on a chip.

[28]  J. Sugarman Human stem cell ethics: beyond the embryo. , 2008, Cell stem cell.

[29]  T. Desai,et al.  Retinal tissue engineering using mouse retinal progenitor cells and a novel biodegradable, thin-film poly(e-caprolactone) nanowire scaffold , 2008, Journal of ocular biology, diseases, and informatics.

[30]  T. Zahir,et al.  Biodegradable Polymer Composite Grafts Promote the Survival and Differentiation of Retinal Progenitor Cells , 2005, Stem cells.

[31]  Hideki Mori,et al.  Observational examination of aggregation and migration during early phase of neurosphere culture of mouse neural stem cells. , 2007, Journal of bioscience and bioengineering.

[32]  D. Schwartz,et al.  Human vitreous hyaluronidase: isolation and characterization. , 1996, Current eye research.

[33]  P. Gouras,et al.  Long-Term Outcome of RPE Allografts in Non-Immunosuppressed Patients with AMD , 1999, European journal of ophthalmology.

[34]  R. Mcinnes,et al.  Loss of retinal progenitor cells leads to an increase in the retinal stem cell population in vivo , 2006, The European journal of neuroscience.

[35]  William L. Neeley,et al.  Engineering retinal progenitor cell and scrollable poly(glycerol-sebacate) composites for expansion and subretinal transplantation. , 2009, Biomaterials.

[36]  Joel Rosenblatt,et al.  Collagen gel systems for sustained delivery and tissue engineering. , 2003, Advanced drug delivery reviews.

[37]  Charles Tator,et al.  A new paradigm for local and sustained release of therapeutic molecules to the injured spinal cord for neuroprotection and tissue repair. , 2009, Tissue engineering. Part A.

[38]  M. Tammi,et al.  Hyaluronan in the interphotoreceptor matrix of the eye: species differences in content, distribution, ligand binding and degradation. , 1998, Experimental eye research.

[39]  D. van der Kooy,et al.  Facile isolation and the characterization of human retinal stem cells. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[40]  H. Klassen,et al.  Stem cells and retinal repair , 2004, Progress in Retinal and Eye Research.

[41]  E. Berson,et al.  Neural retinal cell transplantation: ideal versus reality. , 1999, Ophthalmology.

[42]  J. Hollyfield Hyaluronan and the functional organization of the interphotoreceptor matrix. , 1999, Investigative ophthalmology & visual science.

[43]  S. Hayasaka,et al.  Lysosomal hyaluronidase in the subretinal fluid of patients with rhegmatogenous retinal detachments. , 1982, American journal of ophthalmology.

[44]  E. Lavik,et al.  Fabrication of degradable polymer scaffolds to direct the integration and differentiation of retinal progenitors. , 2005, Biomaterials.

[45]  G. Prestwich,et al.  Hyaluronate derivatives in drug delivery. , 1998, Critical reviews in therapeutic drug carrier systems.

[46]  P. Algvere Human fetal RPE transplants in age related macular degeneration (ARMD) , 1996 .

[47]  F. Chen,et al.  RPE transplantation and its role in retinal disease , 2007, Progress in Retinal and Eye Research.

[48]  Steven Nusinowitz,et al.  Mouse models of age-related macular degeneration. , 2006, Experimental eye research.

[49]  M. Shoichet,et al.  An injectable drug delivery platform for sustained combination therapy. , 2009, Journal of controlled release : official journal of the Controlled Release Society.