Abstract
Retina, being a visceral layer of eye, has attracted the attention of researchers all over the world. Due to its complex cellular architecture and coordination, in vitro replication of retinal functions has been a daunting task. Ex-vivo/in vivo animal retinal models are limited by their ethical concerns, cost, reproducibility, and prolonged experimental duration. Over the years, microfluidic perfusion devices have captured significant interest as in vitro models for investigating cellular functions, in a controlled system. Mimicking of retinal architecture and cellular functions via in vitro retina-on-chip (RoC) model has opened newer avenues for understanding retinal-complexity, retinal diseases, and also for high-throughput evaluation of retinal drugs. Development of retinal organoids within RoCs has thus offered potential of reducing the burden on animal investigations, while enabling numerous experimental runs within a relatively short period of time. This chapter emphasizes on the technological advancements in the area of RoC, the fabrication methods employed in device construction, and its application to mimic in vivo retinal milieu for pre-clinical research.
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References
Cora V, Haderspeck J, Antkowiak L, Mattheus U, Neckel PH, Mack AF, Bolz S, Ueffing M, Pashkovskaia N, Achberger K, Liebau S (2019) A cleared view on retinal organoids. Cells 8(5):391. https://doi.org/10.3390/cells8050391
Eiraku M, Takata N, Ishibashi H, Kawada M, Sakakura E, Okuda S, Sekiguchi K, Adachi T, Sasai Y (2011) Self-organizing optic-cup morphogenesis in three-dimensional culture. Nature 472(7341):51–56. https://doi.org/10.1038/nature09941
Zhong X, Gutierrez C, Xue T, Hampton C, Vergara MN, Cao L-H, Peters A, Park TS, Zambidis ET, Meyer JS et al (2014) Generation of three-dimensional retinal tissue with functional photoreceptors from human iPSCs. Nat Commun 5:4047. [CrossRef]-retina
Shafaie S, Hutter V, Cook MT, Brown MB, Chau DYS (2016) In vitro cell models for ophthalmic drug development applications. Biores Open Access 5(1):94–108. https://doi.org/10.1089/biores.2016.0008. Published online 2016 Apr 1
Ubels JL, Clousing DP (2005) In vitro alternatives to the use of animals in ocular toxicology testing. Ocul Surf 3(3):126–142. https://doi.org/10.1016/s1542-0124(12)70195-7
Toropainen E (2007) Corneal Epithelial Cell Culture Model for Pharmaceutical Studies. University of Kuopio distributor: Kuopio University Library
Nakano T, Ando S, Takata N, Kawada M, Muguruma K, Sekiguchi K, et al (2012) Self-formation of optic cups and storable stratified neural retina from human ESCs. Cell Stem Cell [Internet]. [cited 2021 Aug 31];10(6):771–85. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1934590912002421
Soo JY, Jansen J, Masereeuw R, Little MH (2018) Advances in predictive in vitro models of drug-induced nephrotoxicity. Nat Rev Nephrol 14(6):378–393. https://doi.org/10.1038/s41581-018-0003-9. PMID: 29626199; PMCID: PMC6013592
Achberger K, Haderspeck JC, Kleger A, Liebau S (2019) Stem cell-based retina models. Adv Drug Deliv Rev 140:33–50
Wikswo JP (2014) The relevance and potential roles of microphysiological systems in biology and medicine. Exp Biol Med 239(9):1061–1072
Peiffer RL Jr, Pohm-Thorsen L, Corcoran K (1994) Models in ophthalmology and vision research. In: The biology of the laboratory rabbit, pp 409–433. https://doi.org/10.1016/B978-0-12-469235-0.50025-7. Epub 2013 Oct 21
Volland S, Esteve-Rudd J, Hoo J, Yee C, Williams DS (2015) A comparison of some organizational characteristics of the mouse central retina and the human macula. PLoS One 10(4):e0125631. https://doi.org/10.1371/journal.pone.0125631
Zhang B, Korolj A, Lai BF, Radisic M (2018) Advances in organ-on-a-chip engineering. Nat Rev Mater 3(8):257–278
Puleo CM, Ambrose WM, Takezawa T, Elisseeff J, Wang TH (2009) Integration and application of vitrified collagen in multilayered microfluidic devices for corneal microtissue culture. Lab Chip 9(22):3221–3227
Chen LJ, Ito S, Kai H, Nagamine K, Nagai N, Nishizawa M, Abe T, Kaji H (2017) Microfluidic co-cultures of retinal pigment epithelial cells and vascular endothelial cells to investigate choroidal angiogenesis. Sci Rep 7(1):1–9
Mishra S, Thakur A, Redenti S, Vazquez M (2015) A model microfluidics-based system for the human and mouse retina. Biomed Microdevices 17(6):107
Mathur A, Loskill P, Shao K, Huebsch N, Hong S, Marcus SG, Marks N, Mandegar M, Conklin BR, Lee LP, Healy KE (2015) Human iPSC-based cardiac microphysiological system for drug screening applications. Sci Rep 5(1):1–7
Huh D, Matthews BD, Mammoto A, Montoya-Zavala M, Hsin HY, Ingber DE (2010) Reconstituting organ-level lung functions on a chip. Science 328:1662–1668
Wilmer MJ, Ng CP, Lanz HL, Vulto P, Suter-Dick L, Masereeuw R (2016) Kidney-on-a-chip technology for drug-induced nephrotoxicity screening. Trends Biotechnol 34(2):156–170
Nakao Y, Kimura H, Sakai Y, Fujii T (2011) Bile canaliculi formation by aligning rat primary hepatocytes in a microfluidic device. Biomicrofluidics 5(2):022212
Clevers H (2016) Modeling development and disease with organoids. Cell 165(7):1586–1597. https://doi.org/10.1016/j.cell.2016.05.082
Clevers HC (2019) Organoids: avatars for personalized medicine. Keio J Med 68(4):95. https://doi.org/10.2302/kjm.68-006-ABST
De Crignis E, Hossain T, Romal S, Carofiglio F, Moulos P, Khalid MM et al (2021) Application of human liver organoids as a patient-derived primary model for HBV infection and related hepatocellular carcinoma. eLife [Internet] 10:e60747. [cited 2021 Aug 30]
Willoughby CE, Ponzin D, Ferrari S, Lobo A, Landau K, Omidi Y (2010) Anatomy and physiology of the human eye: effects of mucopolysaccharidoses disease on structure and function - a review: Anatomy and physiology of the eye. Clin Exp Ophthalmol 38:2–11
Gill JS, Georgiou M, Kalitzeos A, Moore AT, Michaelides M (2019) Progressive cone and cone-rod dystrophies: clinical features, molecular genetics and prospects for therapy. Br J Ophthalmol 103(5):711–720
Kalargyrou AA, Pearson RA (2020) Photoreceptor transplantation: re-evaluating the mechanisms that underlie rescue. In: Fritzsch B (ed) The senses: a comprehensive reference, 2nd edn. Elsevier, Oxford, pp 614–629. [Internet] [cited 2021 Oct 4]
Susan De Remer. Layers of the Retina. Discovery Eye Foundation [Internet]. [cited 2021 Oct 5]. Available from: https://discoveryeye.org/layers-of-the-retina
Ajioka I, Martins RAP, Bayazitov IT, Donovan S, Johnson DA, Frase S et al (2007) Differentiated horizontal interneurons clonally expand to form metastatic retinoblastoma in mice. Cell 131:378–390. https://doi.org/10.1016/j.cell.2007.09.036
Ueno S, Nishiguchi KM, Tanioka H, Enomoto A, Yamanouchi T, Kondo M et al (2013) Degeneration of retinal ON bipolar cells induced by serum including autoantibody against TRPM1 in mouse model of paraneoplastic retinopathy. PLoS One 8(11):e81507
Nagashima K, Kikuchi F, Suzuki Y, Abe T (1981) Retinal amacrine cell involvement in Tay-Sachs disease. Acta Neuropathol 53(4):333–336
External limiting membrane - Membranum limitans externum [Internet]. IMAIOS. Available from: https://www.imaios.com/en/e-Anatomy/Anatomical-Parts/External-limiting-membrane
Macular Hole | National Eye Institute [Internet]. [cited 2021 Oct 18]. Available from: https://www.nei.nih.gov/learn-about-eye-health/eye-conditions-and-diseases/macular-hole
Retinal Tears - Patients - The American Society of Retina Specialists [Internet]. [cited 2021 Oct 5]. Available from: https://www.asrs.org/patients/retinal-diseases/26/retinal-tears
Retinal detachment - Diagnosis and treatment - Mayo Clinic [Internet]. [cited 2021 Oct 18]. Available from: https://www.mayoclinic.org/diseases-conditions/retinal-detachment/diagnosis-treatment/drc-20351348
Blair K, Czyz CN (2021) Retinal Detachment [Internet]. StatPearls [Internet]. StatPearls Publishing. [cited 2021 Oct 4]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK551502/
Vujosevic S, Midena E (2013) Retinal layers changes in human preclinical and early clinical diabetic retinopathy support early retinal neuronal and Müller cells alterations. J Diabet Res 2013:e905058
Diagnosis and treatment - Mayo Clinic [Internet]. [cited 2021 Oct 18]. Available from: https://www.mayoclinic.org/diseases-conditions/diabetic-retinopathy/diagnosis-treatment/drc-20371617?p=1
Macular Hole: Symptoms, Treatments [Internet]. Cleveland Clinic. [cited 2021 Oct 4]. Available from: https://my.clevelandclinic.org/health/diseases/14208-macular-hole
Achberger K, Probst C, Haderspeck J, Bolz S, Rogal J, Chuchuy J et al (2019) Human Retina-on-a-Chip: merging organoid and organ-on-a-chip technology to generate complex multi-layer tissue models in a human retina-on-a-chip platform. elife 8:e46188
Fligor CM, Langer KB, Sridhar A, Ren Y, Shields PK, Edler MC et al (2018) Three-dimensional retinal organoids facilitate the investigation of retinal ganglion cell development, organization and neurite outgrowth from human pluripotent stem cells. Sci Rep 8(1):14520
Koens R, Tabata Y, Serrano JC, Aratake S, Yoshino D, Kamm RD et al (2020) Microfluidic platform for three-dimensional cell culture under spatiotemporal heterogeneity of oxygen tension. APL Bioeng 4(1):016106
Dodson KH, Echevarria FD, Li D, Sap**ton RM, Edd JF (2015) Retina-on-a-chip: a microfluidic platform for point access signaling studies. Biomed Microdevices 17(6):114
Retina-on-a-chip provides powerful tool for studying eye disease - Science Daily [Internet]. [cited 2021 Oct 5]. Available from: https://www.sciencedaily.com/releases/2019/08/190827095104.htm
Chung M, Lee S, Lee BJ, Son K, Jeon NL, Kim JH (2018) Wet-AMD on a chip: modeling outer blood-retinal barrier in vitro. Adv Healthc Mater 7(2):1700028
Peter Loskill Lab | Retina on Chip [Internet]. [cited 2021 Oct 5]. Available from: http://loskill-lab.com/retinachip.html
Pattanayak P, Singh SK, Gulati M, Vishwas S, Kapoor B, Chellappan DK et al (2021) Microfluidic chips: recent advances, critical strategies in design, applications and future perspectives. Microfluid Nanofluid 25(12):99
Su P-J, Liu Z, Zhang K, Han X, Saito Y, **a X et al (2015) Retinal synaptic regeneration via microfluidic guiding channels. Sci Rep 5(1):13591
Chen L-J, Ito S, Kai H, Nagamine K, Nagai N, Nishizawa M et al (2017) Microfluidic co-cultures of retinal pigment epithelial cells and vascular endothelial cells to investigate choroidal angiogenesis. Sci Rep 7(1):3538
Arık YB, Buijsman W, Loessberg-Zahl J, Cuartas-Vélez C, Veenstra C, Logtenberg S et al (2021) Microfluidic organ-on-a-chip model of the outer blood–retinal barrier with clinically relevant read-outs for tissue permeability and vascular structure. Lab Chip 21(2):272–283
Chung BG, Choo J (2010) Microfluidic gradient platforms for controlling cellular behavior. Electrophoresis 31(18):3014–3027
Fiorini GS, Chiu DT (2005) Disposable microfluidic devices: fabrication, function, and application. BioTechniques 38(3):429–446
Yeste J, GarcÃa-RamÃrez M, Illa X, Guimerà A, Hernández C, Simó R et al (2017) A compartmentalized microfluidic chip with crisscross microgrooves and electrophysiological electrodes for modeling the blood–retinal barrier. Lab Chip 18(1):95–105
Soft lithography for micro- and nanoscale patterning | Nature Protocols [Internet]. [cited 2021 Oct 28]. Available from:https://www.nature.com/articles/nprot.2009.234?WT.feed_name=subjects_soft-lithography
Prabhakar P, Sen RK, Dwivedi N, Khan R, Solanki PR, Srivastava AK et al (2021) 3D-printed microfluidics and potential biomedical applications. Front Nanotechnol 3:6
Agarwal S, Wendorff JH, Greiner A (2008) Use of electrospinning technique for biomedical applications. Polymer 49(26):5603–5621
Xue Y, Seiler MJ, Tang WC, Wang JY, Delgado J, McLelland BT et al (2021) Retinal organoids on-a-chip: a micro-millifluidic bioreactor for long-term organoid maintenance. Lab Chip 21(17):3361–3377
Chuchuy J, Rogal J, Ngo T, Stadelmann K, Antkowiak L, Achberger K et al (2021) Integration of electrospun membranes into low-absorption thermoplastic organ-on-chip. ACS Biomater Sci Eng 7(7):3006–3017
Moraes C, Mehta G, Lesher-Perez SC, Takayama S (2012) Organs-on-a-Chip: a focus on compartmentalized microdevices. Ann Biomed Eng 40:1211–1227
Van der Meer AD, Van den Berg A (2012) Organs-on-chips: breaking the in vitro impasse. Integr Biol (Camb) 4:461–576. https://doi.org/10.1039/c2ib00176d
Huh D, Hamilton GA, Ingber DE (2011) From 3D cell culture to organs-on-chips. Trends Cell Biol 21:745–754. https://doi.org/10.1016/j.tcb.2011.09.005
Polini A, Prodanov L, Bhise NS, Manoharan V, Dokmeci MR, Khademhosseini A (2014) Organs-on-a-chip: a new tool for drug discovery. Expert Opin Drug Discov 9:335–352. https://doi.org/10.1517/17460441.2014.886562
Singh RK, Nasonkin IO (2020) Limitations and promise of retinal tissue from human pluripotent stem cells for develo** therapies of blindness. Front Cell Neurosci 14:179
Capowski EE, Samimi K, Mayerl SJ, Phillips MJ, Pinilla I, Howden SE, Saha J, Jansen AD, Edwards KL, Jager LD et al (2019) Reproducibility and staging of 3D human retinal organoids across multiple pluripotent stem cell lines. Development 146:dev171686
Zhang Z, Xu Z, Yuan F, ** K, **ang M (2021) Retinal organoid technology: where are we now? Int J Mol Sci 22:10244. https://doi.org/10.3390/ijms221910244
Kim L, Toh YC, Voldman J, Yu H (2007) A practical guide to microfluidic perfusion culture of adherent mammalian cells. Lab Chip 7(6):681–694
Wright CB, Becker SM, Low LA, Tagle DA, Paul A (2020) Sieving. improved ocular tissue models and eye-on-a-chip technologies will facilitate ophthalmic drug development. J Ocul Pharmacol Ther 36(1):25–29
Wang Z, He X, Qiao H, Chen P (2019) Global trends of organoid and organ-on-a-chip in the past decade: a bibliometric & comparative study. Tissue Eng. https://doi.org/10.1089/ten.TEA.2019.0251
Cai S, He L, Zheng F, Kong F, Dao M, Karniadakis GE, Suresh S (2021) Artificial intelligence velocimetry and microaneurysm-on-a-chip for three-dimensional analysis of blood flow in physiology and disease. Proc Natl Acad Sci U S A 118(13):e2100697118. https://doi.org/10.1073/pnas.2100697118
Hailstone M, Waithe D, Samuels TJ, Yang L, Costello I, Arava Y, Robertson E, Parton RM, Davis I (2020) CytoCensus, map** cell identity and division in tissues and organs using machine learning. elife 9:e51085
Mazerik JN, Becker S, Sieving PA (2018) 3-D retina organoids: building platforms for therapies of the future. Cell Med 10:1–6
Wright CB, Becker SM, Low LA, Tagle DA, Sieving PA (2020) Improved ocular tissue models and eye-on-a-chip technologies will facilitate ophthalmic drug development. J Ocul Pharmacol Ther 36(1):25–29. https://doi.org/10.1089/jop.2018.0139
Flaxman SR, Bourne RRA, Resnikoff S, Ackland P, Braithwaite T, Cicinelli MV, Das A, Jonas JB, Keeffe J, Kempen JH, Leasher J, Limburg H, Naidoo K, Pesudovs K, Silvester A, Stevens GA, Tahhan N, Wong TY, Taylor HR (2017) Global causes of blindness and distance vision impairment 1990-2020: a systematic review and meta-analysis. Lancet Glob Health 5(12):e1221–e1234
Wong CH, Siah KW, Lo AW (2019) Estimation of clinical trial success rates and related parameters. Biostatistics 20(2):273–286
Aasen DM, Vergara MN (2020) New drug discovery paradigms for retinal diseases: a focus on retinal organoids. J Ocul Pharmacol Ther 36(1):18–24. https://doi.org/10.1089/jop.2018.0140
Gordois A, Cutler H, Pezzullo L et al (2012) An estimation of the worldwide economic and health burden of visual impairment. Glob Public Health 7(5):465–481. https://doi.org/10.1080/17441692.2011.634815
Bleijs M, van de Wetering M, Clevers H, Drost J (2019) Xenograft and organoid model systems in cancer research. EMBO J 38(15):e101654. https://doi.org/10.15252/embj.2019101654
Achberger K, Cipriano M, Düchs M, Schön C, Michelfelder S, Stierstorfer B, Lamla T, Kauschke SG, Chuchuy J, Roosz J, Mesch L, Cora V, Pars S, Pashkovskaia N, Corti S, Kleger A, Kreuz S, Maier U, Liebau S, Loskill P (2021) Human stem cell-based retina-on-chip as new translational model for validation of AAV retinal gene therapy vectors. Stem Cell Rep. https://doi.org/10.1101/2021.03.02.433550
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Upadhyay, U., Kumaran, A., Yadav, S., Majumder, A., Dandekar, P. (2022). Microfluidic Retina-on-Chip. In: Mohanan, P.V. (eds) Microfluidics and Multi Organs on Chip . Springer, Singapore. https://doi.org/10.1007/978-981-19-1379-2_17
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