How are we improving the delivery to back of the eye? Advances and challenges of novel therapeutic approaches

References

• Kim YC, Chiang B, Wu X, et al. Ocular delivery of macromolecules. J Control Release. 2014 Sep;28(190):172–181.
   Web of Science ®Google Scholar
• Gower NJ, Barry RJ, Edmunds MR, et al. Drug discovery in ophthalmology: past success, present challenges, and future opportunities. BMC Ophthalmol. 2016;16:11.
   PubMed Web of Science ®Google Scholar
• Villegas VM, Aranguren LA, Kovach JL, et al. Current advances in the treatment of neovascular age-related macular degeneration. Expert Opin Drug Deliv. 2016 Aug;2:1–10.
   Web of Science ®Google Scholar
• Kompella UB, Amrite AC, Pacha Ravi R, et al. Nanomedicines for back of the eye drug delivery, gene delivery, and imaging. Prog Retin Eye Res. 2013 Sep;36:172–198.
   PubMed Web of Science ®Google Scholar
• Kaur IP, Kakkar S. Nanotherapy for posterior eye diseases. J Control Release. 2014 Nov;10(193):100–112.
   Web of Science ®Google Scholar
• Eljarrat-Binstock E, Pe’er J, Domb AJ. New techniques for drug delivery to the posterior eye segment. Pharm Res. 2010 Apr;27(4):530–543.
   PubMed Web of Science ®Google Scholar
• Gaudana R, Ananthula HK, Parenky A, et al. Ocular drug delivery. AAPS J. 2010 Sep;12(3):348–360.
   PubMed Web of Science ®Google Scholar
• Barar J, Aghanejad A, Fathi M, et al. Advanced drug delivery and targeting technologies for the ocular diseases. Bioimpacts. 2016;6(1):49–67.
   PubMed Web of Science ®Google Scholar
• Boddu SH, Gupta H, Patel S. Drug delivery to the back of the eye following topical administration: an update on research and patenting activity. Recent Pat Drug Deliv Formul. 2014 Apr;8(1):27–36.
   PubMedGoogle Scholar
• Peptu CA, Popa M, Savin C, et al. Modern drug delivery systems for targeting the posterior segment of the eye. Curr Pharm Des. 2015;21(42):6055–6069.
   PubMed Web of Science ®Google Scholar
• Patel A, Cholkar K, Agrahari V, et al. Ocular drug delivery systems: an overview. World J Pharmacol. 2013;2(2):47–64.
   PubMedGoogle Scholar
• Mandal A, Agrahari V, Khurana V, et al. Transporter effects on cell permeability in drug delivery. Expert Opin Drug Deliv. 2016 Aug;5:1–17.
   Web of Science ®Google Scholar
• Rowe-Rendleman CL, Durazo SA, Kompella UB, et al. Drug and gene delivery to the back of the eye: from bench to bedside. Invest Ophthalmol Vis Sci. 2014 Apr;55(4):2714–2730.
   PubMed Web of Science ®Google Scholar
• Agrahari V, Agrahari V, Hung WT, et al. Composite nanoformulation therapeutics for long-term ocular delivery of macromolecules. Mol Pharm. 2016 Sep;13(9):2912–2922.
   PubMed Web of Science ®Google Scholar
• Falavarjani KG, Nguyen QD. Adverse events and complications associated with intravitreal injection of anti-VEGF agents: a review of literature. Eye (Lond). 2013 Jul;27(7):787–794.
   PubMed Web of Science ®Google Scholar
• Moore DJ, Clover GM. The effect of age on the macromolecular permeability of human Bruch’s membrane. Invest Ophthalmol Vis Sci. 2001 Nov;42(12):2970–2975.
   PubMed Web of Science ®Google Scholar
• Rai Udo J, Young SA, Thrimawithana TR, et al. The suprachoroidal pathway: a new drug delivery route to the back of the eye. Drug Discov Today. 2015 Apr;20(4):491–495.
   PubMed Web of Science ®Google Scholar
• Tetz M, Rizzo S, Augustin AJ. Safety of submacular suprachoroidal drug administration via a microcatheter: retrospective analysis of European treatment results. Ophthalmologica. 2012;227(4):183–189.
   PubMed Web of Science ®Google Scholar
• Kang-Mieler JJ, Osswald CR, Mieler WF. Advances in ocular drug delivery: emphasis on the posterior segment. Expert Opin Drug Deliv. 2014 Oct;11(10):1647–1660.
   PubMed Web of Science ®Google Scholar
• Delplace V, Payne S, Shoichet M. Delivery strategies for treatment of age-related ocular diseases: from a biological understanding to biomaterial solutions. J Control Release. 2015 Dec;10(219):652–668.
   Web of Science ®Google Scholar
• Wong WL, Su X, Li X, et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob Health. 2014 Feb;2(2):e106–16.
   PubMed Web of Science ®Google Scholar
• Jager RD, Mieler WF, Miller JW. Age-related macular degeneration. N Engl J Med. 2008 Jun 12;358(24):2606–2617.
   PubMed Web of Science ®Google Scholar
• Das A, McGuire PG, Rangasamy S. Diabetic macular edema: pathophysiology and novel therapeutic targets. Ophthalmology 2015;122:1375–1394.
   Google Scholar
• Agarwal A, Rhoades WR, Hanout M, et al. Management of neovascular age-related macular degeneration: current state-of-the-art care for optimizing visual outcomes and therapies in development. Clin Ophthalmol. 2015;9:1001–1015.
   PubMed Web of Science ®Google Scholar
• Nazari H, Zhang L, Zhu D, et al. Stem cell based therapies for age-related macular degeneration: the promises and the challenges. Prog Retin Eye Res. 2015 Sep;48:1–39.
   PubMed Web of Science ®Google Scholar
• Ambati J, Atkinson JP, Gelfand BD. Immunology of age-related macular degeneration. Nat Rev Immunol. 2013 Jun;13(6):438–451.
   PubMed Web of Science ®Google Scholar
• Shaw PX, Stiles T, Douglas C, et al. Oxidative stress, innate immunity, and age-related macular degeneration. AIMS Mol Sci. 2016;3(2):196–221.
   PubMed Web of Science ®Google Scholar
• Smith AG, Kaiser PK. Emerging treatments for wet age-related macular degeneration. Expert Opin Emerg Drugs. 2014 Mar;19(1):157–164.
   PubMed Web of Science ®Google Scholar
• Ozkiris A. Anti-VEGF agents for age-related macular degeneration. Expert Opin Ther Pat. 2010 Jan;20(1):103–118.
   PubMed Web of Science ®Google Scholar
• Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol. 2001 Oct;119(10):1417–1436.
   PubMed Web of Science ®Google Scholar
• Rishi E, Rishi P, Sharma V, et al. Long-term outcomes of combination photodynamic therapy with ranibizumab or bevacizumab for treatment of wet age-related macular degeneration. Oman J Ophthalmol. 2016 May-Aug;9(2):87–92.
   PubMedGoogle Scholar
• Yang S, Zhao J, Sun X. Resistance to anti-VEGF therapy in neovascular age-related macular degeneration: a comprehensive review. Drug Des Devel Ther. 2016;10:1857–1867.
   PubMed Web of Science ®Google Scholar
• Eandi CM, Alovisi C, De Sanctis U, et al. Treatment for neovascular age related macular degeneration: the state of the art. Eur J Pharmacol. 2016 Sep;787:78–83.
   Google Scholar
• Zhou B, Wang B. Pegaptanib for the treatment of age-related macular degeneration. Exp Eye Res. 2006 Sep;83(3):615–619.
   PubMed Web of Science ®Google Scholar
• Lu X, Sun X. Profile of conbercept in the treatment of neovascular age-related macular degeneration. Drug Des Devel Ther. 2015;9:2311–2320.
   PubMed Web of Science ®Google Scholar
• Holz FG, Dugel PU, Weissgerber G, et al. Single-chain antibody fragment vegf inhibitor rth258 for neovascular age-related macular degeneration: a randomized controlled study. Ophthalmology. 2016 May;123(5):1080–1089.
   PubMed Web of Science ®Google Scholar
• Souied EH, Devin F, Mauget-Faysse M, et al. Treatment of exudative age-related macular degeneration with a designed ankyrin repeat protein that binds vascular endothelial growth factor: a phase I/II study. Am J Ophthalmol. 2014 Oct;158(4):724–32e2.
   PubMed Web of Science ®Google Scholar
• Amadio M, Govoni S, Pascale A. Targeting VEGF in eye neovascularization: what’s new?: A comprehensive review on current therapies and oligonucleotide-based interventions under development. Pharmacol Res. 2016 Jan;103:253–269.
   PubMed Web of Science ®Google Scholar
• Pozarowska D, Pozarowski P. The era of anti-vascular endothelial growth factor (VEGF) drugs in ophthalmology, VEGF and anti-VEGF therapy. Cent Eur J Immunol. 2016;41(3):311–316.
   PubMed Web of Science ®Google Scholar
• Mitra AK, Agrahari V, Mandal A, et al. Novel delivery approaches for cancer therapeutics. J Control Release. 2015 Dec;10(219):248–268.
   Web of Science ®Google Scholar
• Meng J, Agrahari V, Youm I. Advances in targeted drug delivery approaches for the central nervous system tumors: the inspiration of nanobiotechnology. J Neuroimmune Pharmacol. 2016 Jul 23.
   PubMed Web of Science ®Google Scholar
• Takashima Y, Tsuchiya T, Igarashi Y, et al. [Non-invasive ophthalmic liposomes for nucleic acid delivery to posterior segment of eye]. Yakugaku Zasshi. 2012;132(12):1365–1370.
   PubMed Web of Science ®Google Scholar
• Davis BM, Normando EM, Guo L, et al. Topical delivery of Avastin to the posterior segment of the eye in vivo using annexin A5-associated liposomes. Small. 2014 Apr 24;10(8):1575–1584.
   PubMed Web of Science ®Google Scholar
• Abrishami M, Zarei-Ghanavati S, Soroush D, et al. Preparation characterization, and in vivo evaluation of nanoliposomes-encapsulated bevacizumab (avastin) for intravitreal administration. Retina. 2009 May;29(5):699–703.
   PubMed Web of Science ®Google Scholar
• Elsaid N, Jackson TL, Elsaid Z, et al. PLGA microparticles entrapping chitosan-based nanoparticles for the ocular delivery of ranibizumab. Mol Pharm. 2016 Sep 6;13(9):2923–2940.
   PubMed Web of Science ®Google Scholar
• Huu VA, Luo J, Zhu J, et al. Light-responsive nanoparticle depot to control release of a small molecule angiogenesis inhibitor in the posterior segment of the eye. J Control Release. 2015 Feb;28(200):71–77.
   Web of Science ®Google Scholar
• Hirani A, Grover A, Lee YW, et al. Triamcinolone acetonide nanoparticles incorporated in thermoreversible gels for age-related macular degeneration. Pharm Dev Technol. 2016;21(1):61–67.
   PubMed Web of Science ®Google Scholar
• Varshochian R, Riazi-Esfahani M, Jeddi-Tehrani M, et al. Albuminated PLGA nanoparticles containing bevacizumab intended for ocular neovascularization treatment. J Biomed Mater Res A. 2015 Oct;103(10):3148–3156.
   PubMed Web of Science ®Google Scholar
• Huang D, Wang L, Dong Y, et al. A novel technology using transscleral ultrasound to deliver protein loaded nanoparticles. Eur J Pharm Biopharm. 2014 Sep;88(1):104–115.
   PubMed Web of Science ®Google Scholar
• Ying L, Tahara K, Takeuchi H. Drug delivery to the ocular posterior segment using lipid emulsion via eye drop administration: effect of emulsion formulations and surface modification. Int J Pharm. 2013 Sep 10;453(2):329–335.
   PubMed Web of Science ®Google Scholar
• Zhang L, Si T, Fischer AJ, et al. Coaxial electrospray of ranibizumab-loaded microparticles for sustained release of anti-VEGF therapies. Plos One. 2015;10(8):e0135608.
   PubMed Web of Science ®Google Scholar
• Yandrapu SK, Upadhyay AK, Petrash JM, et al. Nanoparticles in porous microparticles prepared by supercritical infusion and pressure quench technology for sustained delivery of bevacizumab. Mol Pharm. 2013 Dec 2;10(12):4676–4686.
   PubMed Web of Science ®Google Scholar
• Ye Z, Ji YL, Ma X, et al. Pharmacokinetics and distributions of bevacizumab by intravitreal injection of bevacizumab-PLGA microspheres in rabbits. Int J Ophthalmol. 2015;8(4):653–658.
   PubMed Web of Science ®Google Scholar
• Osswald CR, Kang-Mieler JJ. Controlled and extended release of a model protein from a microsphere-hydrogel drug delivery system. Ann Biomed Eng. 2015 Nov;43(11):2609–2617.
   PubMed Web of Science ®Google Scholar
• Patel S, Garapati C, Chowdhury P, et al. Development and evaluation of dexamethasone nanomicelles with potential for treating posterior uveitis after topical application. J Ocul Pharmacol Ther. 2015 May;31(4):215–227.
   PubMed Web of Science ®Google Scholar
• Ma F, Nan K, Lee S, et al. Micelle formulation of hexadecyloxypropyl-cidofovir (HDP-CDV) as an intravitreal long-lasting delivery system. Eur J Pharm Biopharm. 2015;89:271–279.
   PubMed Web of Science ®Google Scholar
• Yavuz B, Pehlivan SB, Vural I, et al. In vitro/in vivo evaluation of dexamethasone–PAMAM dendrimer complexes for retinal drug delivery. J Pharm Sci. 2015 Nov;104(11):3814–3823.
   PubMed Web of Science ®Google Scholar
• Wu X, Yu G, Luo C, et al. Synthesis and evaluation of a nanoglobular dendrimer 5-aminosalicylic acid conjugate with a hydrolyzable schiff base spacer for treating retinal degeneration. ACS Nano. 2014 Jan 28;8(1):153–161.
   PubMed Web of Science ®Google Scholar
• Coursey TG, Henriksson JT, Marcano DC, et al. Dexamethasone nanowafer as an effective therapy for dry eye disease. J Control Release. 2015 Sep;10(213):168–174.
   Web of Science ®Google Scholar
• Yuan X, Marcano DC, Shin CS, et al. Ocular drug delivery nanowafer with enhanced therapeutic efficacy. ACS Nano. 2015 Feb 24;9(2):1749–1758.
   PubMed Web of Science ®Google Scholar
• Tuomela A, Liu P, Puranen J, et al. Brinzolamide nanocrystal formulations for ophthalmic delivery: reduction of elevated intraocular pressure in vivo. Int J Pharm. 2014 Jun 5;467(1–2):34–41.
   PubMed Web of Science ®Google Scholar
• Gupta S, Samanta MK, Raichur AM. Dual-drug delivery system based on in situ gel-forming nanosuspension of forskolin to enhance antiglaucoma efficacy. AAPS Pharmscitech. 2010 Mar;11(1):322–335.
   PubMed Web of Science ®Google Scholar
• Xu X, Weng Y, Xu L, et al. Sustained release of Avastin(R) from polysaccharides cross-linked hydrogels for ocular drug delivery. Int J Biol Macromol. 2013 Sep;60:272–276.
   PubMed Web of Science ®Google Scholar
• Tyagi P, Barros M, Stansbury JW, et al. Light-activated, in situ forming gel for sustained suprachoroidal delivery of bevacizumab. Mol Pharm. 2013 Aug 5;10(8):2858–2867.
   PubMed Web of Science ®Google Scholar
• Rauck BM, Friberg TR, Medina Mendez CA, et al. Biocompatible reverse thermal gel sustains the release of intravitreal bevacizumab in vivo. Invest Ophthalmol Vis Sci. 2014 Jan;55(1):469–476.
   PubMed Web of Science ®Google Scholar
• Wang CH, Hwang YS, Chiang PR, et al. Extended release of bevacizumab by thermosensitive biodegradable and biocompatible hydrogel. Biomacromolecules. 2012 Jan 9;13(1):40–48.
   PubMed Web of Science ®Google Scholar
• Xie B, Jin L, Luo Z, et al. An injectable thermosensitive polymeric hydrogel for sustained release of Avastin(R) to treat posterior segment disease. Int J Pharm. 2015 Jul 25;490(1–2):375–383.
   PubMed Web of Science ®Google Scholar
• Patel SP, Vaishya R, Patel A, et al. Optimization of novel pentablock copolymer based composite formulation for sustained delivery of peptide/protein in the treatment of ocular diseases. J Microencapsul. 2016;33(2):103–113.
   PubMed Web of Science ®Google Scholar
• Agrahari V, Agrahari V, Mitra AK. Nanocarrier fabrication and macromolecule drug delivery: challenges and opportunities. Ther Deliv. 2016;7(4):257–278.
   PubMed Web of Science ®Google Scholar
• Bochot A, Fattal E. Liposomes for intravitreal drug delivery: a state of the art. J Control Release. 2012 Jul 20;161(2):628–634.
   PubMed Web of Science ®Google Scholar
• Akbarzadeh A, Rezaei-Sadabady R, Davaran S, et al. Liposome: classification, preparation, and applications. Nanoscale Res Lett. 2013;8(1):102.
   PubMed Web of Science ®Google Scholar
• Herrero-Vanrell R, Bravo-Osuna I, Andres-Guerrero V, et al. The potential of using biodegradable microspheres in retinal diseases and other intraocular pathologies. Prog Retin Eye Res. 2014 Sep;42:27–43.
   PubMed Web of Science ®Google Scholar
• Vaishya RD, Khurana V, Patel S, et al. Controlled ocular drug delivery with nanomicelles. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2014 Sep-Oct;6(5):422–437.
   PubMed Web of Science ®Google Scholar
• Cholkar K, Patel A, Vadlapudi AD, et al. Novel nanomicellar formulation approaches for anterior and posterior segment ocular drug delivery. Recent Pat Nanomed. 2012;2(2):82–95.
   PubMedGoogle Scholar
• Rodriguez Villanueva J, Navarro MG, Rodriguez Villanueva L. Dendrimers as a promising tool in ocular therapeutics: latest advances and perspectives. Int J Pharm. 2016 Sep 10;511(1):359–366.
   PubMed Web of Science ®Google Scholar
• Sharma OP, Patel V, Mehta T. Nanocrystal for ocular drug delivery: hope or hype. Drug Deliv Transl Res. 2016 Aug;6(4):399–413.
   PubMed Web of Science ®Google Scholar
• Buwalda SJ, Boere KW, Dijkstra PJ, et al. Hydrogels in a historical perspective: from simple networks to smart materials. J Control Release. 2014 Sep;28(190):254–273.
   Web of Science ®Google Scholar
• Yasin MN, Svirskis D, Seyfoddin A, et al. Implants for drug delivery to the posterior segment of the eye: a focus on stimuli-responsive and tunable release systems. J Control Release. 2014 Dec;28(196):208–221.
   Web of Science ®Google Scholar
• Lee SS, Hughes P, Ross AD, et al. Biodegradable implants for sustained drug release in the eye. Pharm Res. 2010 Oct;27(10):2043–2053.
   PubMed Web of Science ®Google Scholar
• Bourges JL, Bloquel C, Thomas A, et al. Intraocular implants for extended drug delivery: therapeutic applications. Adv Drug Deliv Rev. 2006 Nov 15;58(11):1182–1202.
   PubMed Web of Science ®Google Scholar
• Thrimawithana TR, Young S, Bunt CR, et al. Drug delivery to the posterior segment of the eye. Drug Discov Today. 2011 Mar;16(5–6):270–277.
   PubMed Web of Science ®Google Scholar
• Haghjou N, Soheilian M, Abdekhodaie MJ. Sustained release intraocular drug delivery devices for treatment of uveitis. J Ophthalmic Vis Res. 2011 Oct;6(4):317–329.
   PubMedGoogle Scholar
• Wang J, Jiang A, Joshi M, et al. Drug delivery implants in the treatment of vitreous inflammation. Mediators Inflamm. 2013;2013:780634.
   PubMed Web of Science ®Google Scholar
• Bansal P, Garg S, Sharma Y, et al. Posterior segment drug delivery devices: current and novel therapies in development. J Ocul Pharmacol Ther. 2016 Apr;32(3):135–144.
   PubMed Web of Science ®Google Scholar
• Meng E, Hoang T. MEMS-enabled implantable drug infusion pumps for laboratory animal research, preclinical, and clinical applications. Adv Drug Deliv Rev. 2012 Nov;64(14):1628–1638.
   PubMed Web of Science ®Google Scholar
• Lo R, Li PY, Saati S, et al. A passive MEMS drug delivery pump for treatment of ocular diseases. Biomed Microdevices. 2009 Oct;11(5):959–970.
   PubMed Web of Science ®Google Scholar
• Thakur Singh RR, Tekko I, McAvoy K, et al. Minimally invasive microneedles for ocular drug delivery. Expert Opin Drug Deliv. 2016 Aug;25:1–13.
   Web of Science ®Google Scholar
• Park SH, Lee KJ, Lee J, et al. Microneedle-based minimally-invasive measurement of puncture resistance and fracture toughness of sclera. Acta Biomater. 2016;44:286–294.
   PubMed Web of Science ®Google Scholar
• Mahlumba P, Choonara YE, Kumar P, et al. Stimuli-responsive polymeric systems for controlled protein and peptide delivery: future implications for ocular delivery. Molecules. 2016 Jul;21(8):1002–1022.
   Google Scholar
• Agrahari V, Zhang C, Zhang T, et al. Hyaluronidase-sensitive nanoparticle templates for triggered release of HIV/AIDS microbicide in vitro. AAPS J. 2014 Mar;16(2):181–193.
   PubMed Web of Science ®Google Scholar
• Porta IBM, Eckstein C, Xifre-Perez E, et al. Sustained, controlled and stimuli-responsive drug release systems based on nanoporous anodic alumina with layer-by-layer polyelectrolyte. Nanoscale Res Lett. 2016 Dec;11(1):372.
   PubMed Web of Science ®Google Scholar
• Zhang T, Zhang C, Agrahari V, et al. Spray drying tenofovir loaded mucoadhesive and pH-sensitive microspheres intended for HIV prevention. Antiviral Res. 2013 Mar;97(3):334–346.
   PubMed Web of Science ®Google Scholar
• Agrahari V, Meng J, Ezoulin MJ, et al. Stimuli-sensitive thiolated hyaluronic acid based nanofibers: synthesis, preclinical safety and in vitro anti-HIV activity. Nanomedicine (Lond). 2016 Nov;11(22):2935–2958.
   PubMed Web of Science ®Google Scholar
• Christie JG, Kompella UB. Ophthalmic light sensitive nanocarrier systems. Drug Discov Today. 2008 Feb;13(3–4):124–134.
   PubMed Web of Science ®Google Scholar
• Matanovic MR, Kristl J, Grabnar PA. Thermoresponsive polymers: insights into decisive hydrogel characteristics, mechanisms of gelation, and promising biomedical applications. Int J Pharm. 2014 Sep 10; 472(1–2):262–275.
   PubMed Web of Science ®Google Scholar
• Agrawal AK, Das M, Jain S. In situ gel systems as ‘smart’ carriers for sustained ocular drug delivery. Expert Opin Drug Deliv. 2012 Apr;9(4):383–402.
   PubMed Web of Science ®Google Scholar
• Chen X, Li X, Zhou Y, et al. Chitosan-based thermosensitive hydrogel as a promising ocular drug delivery system: preparation, characterization, and in vivo evaluation. J Biomater Appl. 2012 Nov;27(4):391–402.
   PubMed Web of Science ®Google Scholar
• Yin H, Gong C, Shi S, et al. Toxicity evaluation of biodegradable and thermosensitive PEG-PCL-PEG hydrogel as a potential in situ sustained ophthalmic drug delivery system. J Biomed Mater Res B Appl Biomater. 2010 Jan;92(1):129–137.
   PubMed Web of Science ®Google Scholar
• Lafond M, Aptel F, Mestas JL, et al. Ultrasound-mediated ocular delivery of therapeutic agents: a review. Expert Opin Drug Deliv. 2016 Jun;27:1–12.
   Web of Science ®Google Scholar
• Nabili M, Shenoy A, Chawla S, et al. Ultrasound-enhanced ocular delivery of dexamethasone sodium phosphate: an in vivo study. J Ther Ultrasound. 2014;2:6.
   PubMedGoogle Scholar
• Svirskis D, Travas-Sejdic J, Rodgers A, et al. Electrochemically controlled drug delivery based on intrinsically conducting polymers. J Control Release. 2010 Aug 17;146(1):6–15.
   PubMed Web of Science ®Google Scholar
• Ramtin A, Seyfoddin A, Coutinho FP, et al. Cytotoxicity considerations and electrically tunable release of dexamethasone from polypyrrole for the treatment of back-of-the-eye conditions. Drug Deliv Transl Res. 2016 Dec;6(6):793–799.
   PubMed Web of Science ®Google Scholar
• Lo R, Li PY, Saati S, et al. A refillable microfabricated drug delivery device for treatment of ocular diseases. Lab Chip. 2008 Jul;8(7):1027–1030.
   PubMed Web of Science ®Google Scholar
• Jarrett SG, Boulton ME. Consequences of oxidative stress in age-related macular degeneration. Mol Aspects Med. 2012 Aug;33(4):399–417.
   PubMed Web of Science ®Google Scholar
• Xu Q, He C, Xiao C, et al. Reactive oxygen species (ROS) responsive polymers for biomedical applications. Macromol Biosci. 2016 May;16(5):635–646.
   PubMed Web of Science ®Google Scholar
• Mead B, Berry M, Logan A, et al. Stem cell treatment of degenerative eye disease. Stem Cell Res. 2015 May;14(3):243–257.
   PubMed Web of Science ®Google Scholar
• Bertolotti E, Neri A, Camparini M, et al. Stem cells as source for retinal pigment epithelium transplantation. Prog Retin Eye Res. 2014 Sep;42:130–144.
   PubMed Web of Science ®Google Scholar
• Heller JP, Martin KR. Enhancing RPE cell-based therapy outcomes for AMD: the role of bruch’s membrane. Transl Vis Sci Technol. 2014 Jun;3(3):11.
   PubMedGoogle Scholar
• Kinnunen K, Petrovski G, Moe MC, et al. Molecular mechanisms of retinal pigment epithelium damage and development of age-related macular degeneration. Acta Ophthalmol. 2012 Jun;90(4):299–309.
   PubMed Web of Science ®Google Scholar
• De Jong PT. Age-related macular degeneration. N Engl J Med. 2006 Oct 5; 355(14):1474–1485.
   PubMed Web of Science ®Google Scholar
• Canto-Soler V, Flores-Bellver M, Vergara MN. Stem cell sources and their potential for the treatment of retinal degenerations. Invest Ophthalmol Vis Sci. 2016 Apr 1; 57(5):ORSFd1–9.
   PubMed Web of Science ®Google Scholar
• Klassen H. Stem cells in clinical trials for treatment of retinal degeneration. Expert Opin Biol Ther. 2016;16(1):7–14.
   PubMed Web of Science ®Google Scholar
• Zarbin M. Cell-based therapy for degenerative retinal disease. Trends Mol Med. 2016 Feb;22(2):115–134.
   PubMed Web of Science ®Google Scholar
• Li Y, Tsai YT, Hsu CW, et al. Long-term safety and efficacy of human-induced pluripotent stem cell (iPS) grafts in a preclinical model of retinitis pigmentosa. Mol Med. 2012;18:1312–1319.
   PubMed Web of Science ®Google Scholar
• Hu Q, Friedrich AM, Johnson LV, et al. Memory in induced pluripotent stem cells: reprogrammed human retinal-pigmented epithelial cells show tendency for spontaneous redifferentiation. Stem Cells. 2010 Nov;28(11):1981–1991.
   PubMed Web of Science ®Google Scholar
• Carr AJ, Smart MJ, Ramsden CM, et al. Development of human embryonic stem cell therapies for age-related macular degeneration. Trends Neurosci. 2013 Jul;36(7):385–395.
   PubMed Web of Science ®Google Scholar
• Kundu J, Michaelson A, Baranov P, et al. Approaches to cell delivery: substrates and scaffolds for cell therapy. Dev Ophthalmol. 2014;53:143–154.
   PubMedGoogle Scholar
• Gullapalli VK, Sugino IK, VanPatten Y, et al. Impaired RPE survival on aged submacular human Bruch’s membrane. Exp Eye Res. 2005 Feb;80(2):235–248.
   PubMed Web of Science ®Google Scholar
• Sun K, Cai H, Tezel TH, et al. Bruch’s membrane aging decreases phagocytosis of outer segments by retinal pigment epithelium. Mol Vis. 2007;13:2310–2319.
   PubMed Web of Science ®Google Scholar
• Xiang P, Wu KC, Zhu Y, et al. A novel Bruch’s membrane-mimetic electrospun substrate scaffold for human retinal pigment epithelium cells. Biomaterials. 2014 Dec;35(37):9777–9788.
   PubMed Web of Science ®Google Scholar
• Shadforth AM, George KA, Kwan AS, et al. The cultivation of human retinal pigment epithelial cells on Bombyx mori silk fibroin. Biomaterials. 2012 Jun;33(16):4110–4117.
   PubMed Web of Science ®Google Scholar
• Treharne AJ, Thomson HA, Grossel MC, et al. Developing methacrylate-based copolymers as an artificial Bruch’s membrane substitute. J Biomed Mater Res A. 2012 Sep;100(9):2358–2364.
   PubMed Web of Science ®Google Scholar
• Emerich DF, Orive G, Thanos C, et al. Encapsulated cell therapy for neurodegenerative diseases: from promise to product. Adv Drug Deliv Rev. 2014 Apr;67-68:131–141.
   PubMed Web of Science ®Google Scholar
• Tao W. Application of encapsulated cell technology for retinal degenerative diseases. Expert Opin Biol Ther. 2006 Jul;6(7):717–726.
   PubMedGoogle Scholar
• Gooch N, Burr RM, Holt DJ, et al. Design and in vitro biocompatibility of a novel ocular drug delivery device. J Funct Biomater. 2013;4(1):14–26.
   PubMedGoogle Scholar
• Sadiq MA, Hanout M, Sarwar S, et al. Platelet-derived growth factor inhibitors: a potential therapeutic approach for ocular neovascularization. Dev Ophthalmol. 2016;55:310–316.
   PubMedGoogle Scholar
• Jaffe GJ, Eliott D, Wells JA, et al. 1 Study of intravitreous e10030 in combination with ranibizumab in neovascular age-related macular degeneration. Ophthalmology. 2016 Jan;123(1):78–85.
   PubMed Web of Science ®Google Scholar
• Santos E, Pedraz JL, Hernandez RM, et al. Therapeutic cell encapsulation: ten steps towards clinical translation. J Control Release. 2013 Aug 28;170(1):1–14.
   PubMed Web of Science ®Google Scholar