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

Expert Opinion on Drug Delivery

Volumn 14, Issue 10, 2017, Pages 1145-1162

  Agrahari, Vibhuti ^a   Agrahari, Vivek ^a   Mandal, Abhirup ^a   Pal, Dhananjay ^a   Mitra, Ashim K ^a  

^a UNIVERSITY OF MISSOURI KANSAS CITY   (United States)

Author keywords

age related macular degeneration; drug delivery; encapsulated cell technology; nanocarriers; nanotechnology; Ocular barriers; posterior eye diseases; stem cell transplantation; stimuli responsive

Indexed keywords

DENDRIMER; DRUG; LIPOSOME; NANOCOMPOSITE; NANOCRYSTAL; VASCULOTROPIN ANTIBODY;

AGE RELATED MACULAR DEGENERATION; BLOOD EYE BARRIER; CELL ENCAPSULATION; CELL TRANSPLANTATION; DRUG ADMINISTRATION ROUTE; DRUG DELIVERY SYSTEM; HEAT SENSITIVITY; HUMAN; HYDROGEL; IMPLANT; LIGHT; MICELLE; MICROELECTROMECHANICAL SYSTEM; NANOTECHNOLOGY; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); POSTERIOR EYE SEGMENT; RETINA CELL; REVIEW; EYE DISEASE;

CELL TRANSPLANTATION; DRUG DELIVERY SYSTEMS; EYE DISEASES; HUMANS; NANOTECHNOLOGY; POSTERIOR EYE SEGMENT;

EID: 85029157852     PISSN: 17425247     EISSN: 17447593     Source Type: Journal    
DOI: 10.1080/17425247.2017.1272569     Document Type: Review

References (128)

1. Kim YC, Chiang B, Wu X, et al. Ocular delivery of macromolecules. J Control Release. 2014 Sep;28(190):172–181.
2. Gower NJ, Barry RJ, Edmunds MR, et al. Drug discovery in ophthalmology:past success, present challenges, and future opportunities. BMC Ophthalmol. 2016;16:11.
3. 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.
4. 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.• Key applications of nanotechnology are discussed in this review. Additionally, nanofabricated delivery systems including implants, films, microparticles, and nanoparticles are described.
5. Kaur IP, Kakkar S., Nanotherapy for posterior eye diseases. J Control Release. 2014 Nov;10(193):100–112.• This review discusses various pathways available for effective delivery to and clearance from the posterior eye. Promise held by nanocarrier systems for effective delivery and selective targeting is also discussed.
6. 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.
7. Gaudana R, Ananthula HK, Parenky A, et al. Ocular drug delivery. AAPS J. 2010 Sep;12(3):348–360.
8. Barar J, Aghanejad A, Fathi M, et al. Advanced drug delivery and targeting technologies for the ocular diseases. Bioimpacts. 2016;6(1):49–67.• In the current study, recent advancements on ocular targeted therapies are reviewed and discussed.
9. 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.
10. 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.
11. Patel A, Cholkar K, Agrahari V, et al. Ocular drug delivery systems:an overview. World J Pharmacol. 2013;2(2):47–64.•• This review summarizes the existing conventional formulations for ocular delivery and their advancements followed by current nanotechnology based formulation developments.
12. 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.
13. 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.
14. 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.• Discusses about the development of composite nanoformulations and their application in long-term delivery of macromolecule drugs.
15. 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.
16. 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.
17. 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.
18. 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.
19. 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.• This review summarizes currently available and recent developments for ocular drug delivery to both the anterior and posterior segments. Modes of delivery, including topical, systemic, transscleral/periocular and intravitreal, are discussed with their corresponding examples including the advantages and disadvantages are highlighted.
20. 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.•• This review provides a summary and discussion of the most recent strategies employed for the delivery of both drugs and cells to treat a variety of age-related eye diseases. The current challenges and limitations to ocular delivery and how the use of innovative materials can overcome these issues and ultimately provide treatment for age-related degeneration and regeneration of lost tissues are emphasized.
21. 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.
22. Jager RD, Mieler WF, Miller JW. Age-related macular degeneration. N Engl J Med. 2008 Jun 12;358(24):2606–2617.
23. Das A, McGuire PG, Rangasamy S. Diabetic macular edema:pathophysiology and novel therapeutic targets. Ophthalmology 2015;122:1375–1394.
24. 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.
25. 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.•• This review outlines the current knowledge surrounding the application of hESC-RPE and iPSC-RPE in AMD. Several strategies to improve the stem cell-based treatments for AMD are discussed.
26. Ambati J, Atkinson JP, Gelfand BD. Immunology of age-related macular degeneration. Nat Rev Immunol. 2013 Jun;13(6):438–451.
27. 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.
28. Smith AG, Kaiser PK. Emerging treatments for wet age-related macular degeneration. Expert Opin Emerg Drugs. 2014 Mar;19(1):157–164.
29. Ozkiris A. Anti-VEGF agents for age-related macular degeneration. Expert Opin Ther Pat. 2010 Jan;20(1):103–118.
30. 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.
31. 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.
32. 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.
33. 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.• This review provides an overview of available data form clinical trials supporting the use of anti-VEGF molecules for the treatment of AMD.
34. Zhou B, Wang B. Pegaptanib for the treatment of age-related macular degeneration. Exp Eye Res. 2006 Sep;83(3):615–619.
35. Lu X, Sun X. Profile of conbercept in the treatment of neovascular age-related macular degeneration. Drug Des Devel Ther. 2015;9:2311–2320.
36. 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.
37. 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.
38. 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.
39. 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.
40. Mitra AK, Agrahari V, Mandal A, et al. Novel delivery approaches for cancer therapeutics. J Control Release. 2015 Dec;10(219):248–268.
41. 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.
42. 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.
43. 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.
44. 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.
45. 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.
46. 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.• A novel nanoparticle depot platform for on-demand drug delivery using a far ultraviolet (UV) light-degradable polymer, which allows noninvasively triggered drug release using brief, low-power light exposure, is developed.
47. 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.
48. 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.
49. 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.
50. 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.
51. 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.
52. 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.
53. 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.
54. 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.
55. 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.
56. 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.
57. 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.
58. 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.
59. 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.
60. 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.
61. 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.
62. 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.
63. 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.
64. 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.
65. 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.
66. 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.
67. 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.
68. 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.
69. Agrahari V, Agrahari V, Mitra AK. Nanocarrier fabrication and macromolecule drug delivery:challenges and opportunities. Ther Deliv. 2016;7(4):257–278.• In this excellent review, the advantages and limitations of several routes of administration, novel delivery systems and, fabrication approaches to make nanoformulations in different shapes and sizes are summarized.
70. Bochot A, Fattal E. Liposomes for intravitreal drug delivery:a state of the art. J Control Release. 2012 Jul 20;161(2):628–634.
71. Akbarzadeh A, Rezaei-Sadabady R, Davaran S, et al. Liposome:classification, preparation, and applications. Nanoscale Res Lett. 2013;8(1):102.
72. 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.
73. 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.
74. 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.
75. 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.
76. Sharma OP, Patel V, Mehta T. Nanocrystal for ocular drug delivery:hope or hype. Drug Deliv Transl Res. 2016 Aug;6(4):399–413.
77. 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.• In this review, an overview of the developments in hydrogel research from simple networks to smart materials is discussed.
78. 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.•• This article provides an overview of diseases of the posterior segment of the eye describes currently available implants to treat such conditions and discusses advantages and disadvantages of various implant locations. Finally, stimuli-responsive drug delivery technologies that have been investigated for, or have the potential to be applied to, drug delivery to the back of the eye are discussed.
79. 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.
80. 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.
81. 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.
82. 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.
83. Wang J, Jiang A, Joshi M, et al. Drug delivery implants in the treatment of vitreous inflammation. Mediators Inflamm. 2013;2013:780634.
84. 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.
85. 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.
86. 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.
87. 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.
88. 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.
89. 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.
90. 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.
91. 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.
92. 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.
93. 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.
94. Christie JG, Kompella UB. Ophthalmic light sensitive nanocarrier systems. Drug Discov Today. 2008 Feb;13(3–4):124–134.
95. 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.• This article reviews the types of thermoresponsive polymers. Promising biomedical applications are described for injectable formulations, which include solubilization of small hydrophobic drugs and delivery of labile biopharmaceutics, cell encapsulation, and tissue regeneration. Furthermore, combinations of thermoresponsive hydrogels and various NCs as promising systems for sustained drug delivery are discussed through selected examples.
96. 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.• The present review summarizes the latest developments in in situ gel technology, with regard to ophthalmic drug delivery.
97. 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.
98. 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.
99. 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.• An update on recent advances in transscleral and transcorneal ultrasound-mediated drug delivery is provided.
100. 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.
101. 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.
102. 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.
103. 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.
104. Jarrett SG, Boulton ME. Consequences of oxidative stress in age-related macular degeneration. Mol Aspects Med. 2012 Aug;33(4):399–417.
105. 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.
106. Mead B, Berry M, Logan A, et al. Stem cell treatment of degenerative eye disease. Stem Cell Res. 2015 May;14(3):243–257.
107. 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.•• Different cell sources and their properties are discussed. A new source of human RPE and the protocol for RPE differentiation of retinal stem cells derived from adult ciliary bodies of post-mortem donors is explained.
108. 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.
109. 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.• A thorough explanation of RPE-derived mechanisms in AMD pathology is provided.
110. De Jong PT. Age-related macular degeneration. N Engl J Med. 2006 Oct 5; 355(14):1474–1485.•• In this excellent review, the clinical features of AMD, physiology of the aging macula and to mechanisms implicated in the cause is discussed.
111. 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.•• This paper provides a concise overview of the stem cell sources most commonly used, weighing their therapeutic potential on the basis of their technical strengths/limitations, their ethical implications, and the extent of the progress achieved to date.
112. Klassen H. Stem cells in clinical trials for treatment of retinal degeneration. Expert Opin Biol Ther. 2016;16(1):7–14.
113. Zarbin M. Cell-based therapy for degenerative retinal disease. Trends Mol Med. 2016 Feb;22(2):115–134.• This review discusses about characteristics of stem cell therapy in the eye and the challenges to clinical implementation that are being confronted today.
114. 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.
115. 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.
116. 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.
117. Kundu J, Michaelson A, Baranov P, et al. Approaches to cell delivery:substrates and scaffolds for cell therapy. Dev Ophthalmol. 2014;53:143–154.
118. 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.
119. 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.
120. 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.
121. 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.
122. 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.
123. 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.
124. Tao W. Application of encapsulated cell technology for retinal degenerative diseases. Expert Opin Biol Ther. 2006 Jul;6(7):717–726.
125. 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.
126. 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.
127. 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.
128. 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.