Biomaterial enhancement of stem cell transplant efficacy for macular degeneration No effective therapies yet exist for advanced macular degeneration. Restoring vision in severe cases requires replacing both retinal pigmented epithelium (RPE) and photoreceptors because photoreceptors require functional RPE to survive. However, no approach to replace both cell types has yet been introduced. Further, previous attempts to replace photoreceptors have met limited success in rodent models, likely because of low survival rates and restricted distribution of transplanted cells. This project integrates solutions to both of these challenges: we propose to transplant human embryonic stem (ES) cell-derived primitive retinal stem cells (hpRSCs), a cell population that is more pluripotent than cell types previously transplanted to restore vision. We have shown that hpRSCs yield both RPE and photoreceptors in vitro and in vivo;replacing both cell types in vivo would yield longer-lasting visual improvements, as transplant-derived RPE would support transplant-derived photoreceptors. In order to develop a maximally effective therapy, we will deliver hpRSCs in an injectable hydrogel whose biochemistry and mechanics closely match those of the ocular extracellular matrix, which has recently been shown to uniformly distribute transplanted cells across the retina. This project stands to position ES cell-derived RPCs for translation into the clinic. The key to this advance is the collaboration between the PIs, bringing together a leader in macular degeneration models and the differentiation of stem cells into retinal neurons (Zhang) with a biomaterials research group (Almutairi). The Zhang group's expertise will ensure that this project advances development of HAMC for ocular transplantation significantly: previous work has not employed relevant animal models, so the impact of the material on transplanted cells'differentiation and functional recovery has not yet been assessed. Further, it has relied on cells that are easiest to derive, whereas this project will employ ES cell-derived RPCs, which are the only clinically viable option. By completion of this project, we expect to: 1. Assess the effect of HAMC delivery on survival and distribution of subretinally injected retinal stem cells 2. Define the effect of HAMC on the ability of retinal stem cells to differentiate into RPE and photoreceptors in vitro and in vivo 3. Identify the delivery method that maximizes visual improvement ensuing from subretinal injection of retinal stem cells in Royal College of Surgeons (RCS) rats

Public Health Relevance

Transplantation of stem cell-derived retinal cells holds great promise for the treatment of advanced macular degeneration;replacing photoreceptors would recover patients'vision. However, current approaches have only shown limited success because most transplanted cells die or remain in a small area of the retina. To overcome these limitations, we will develop a method of transplantation involving delivery in biopolymer hydrogels.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
Project #
Application #
Study Section
Program Officer
Shen, Grace L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Diego
Schools of Pharmacy
La Jolla
United States
Zip Code
Stubelius, Alexandra; Sheng, Wangzhong; Lee, Sangeun et al. (2018) Disease-Triggered Drug Release Effectively Prevents Acute Inflammatory Flare-Ups, Achieving Reduced Dosing. Small 14:e1800703
Sheng, Wangzhong; He, Sha; Seare, William J et al. (2017) Review of the progress toward achieving heat confinement-the holy grail of photothermal therapy. J Biomed Opt 22:80901
He, Sha; Johnson, Noah J J; Nguyen Huu, Viet Anh et al. (2017) Simultaneous Enhancement of Photoluminescence, MRI Relaxivity, and CT Contrast by Tuning the Interfacial Layer of Lanthanide Heteroepitaxial Nanoparticles. Nano Lett 17:4873-4880
Suarez, Sophia L; Muñoz, Adam; Mitchell, Aaron et al. (2016) Degradable acetalated dextran microparticles for tunable release of an engineered hepatocyte growth factor fragment. ACS Biomater Sci Eng 2:197-204
Wang, Wenqiu; Gawlik, Katarzyna; Lopez, Joe et al. (2016) Genetic and environmental factors strongly influence risk, severity and progression of age-related macular degeneration. Signal Transduct Target Ther 1:16016
Zhang, Zhen-Ning; Freitas, Beatriz C; Qian, Hao et al. (2016) Layered hydrogels accelerate iPSC-derived neuronal maturation and reveal migration defects caused by MeCP2 dysfunction. Proc Natl Acad Sci U S A 113:3185-90
Johnson, Noah J J; He, Sha; Nguyen Huu, Viet Anh et al. (2016) Compact Micellization: A Strategy for Ultrahigh T1 Magnetic Resonance Contrast with Gadolinium-Based Nanocrystals. ACS Nano 10:8299-307
Carling, Carl-Johan; Olejniczak, Jason; Foucault-Collet, Alexandra et al. (2016) Efficient Red Light Photo-Uncaging of Active Molecules in Water Upon Assembly into Nanoparticles. Chem Sci 7:2392-2398
El Halawany, Ahmed; He, Sha; Hodaei, Hossein et al. (2016) Enhanced UV upconversion emission using plasmonic nanocavities. Opt Express 24:13999-4009
Chan, Minnie; Lux, Jacques; Nishimura, Tomoki et al. (2015) Long-Lasting and Efficient Tumor Imaging Using a High Relaxivity Polysaccharide Nanogel Magnetic Resonance Imaging Contrast Agent. Biomacromolecules 16:2964-71

Showing the most recent 10 out of 14 publications