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Bioprinted 3D outer retina barrier uncovers RPE-dependent choroidal phenotype in advanced macular degeneration


Age-related macular degeneration (AMD), a leading cause of blindness, initiates in the outer-blood-retina-barrier (oBRB) formed by the retinal pigment epithelium (RPE), Bruch’s membrane, and choriocapillaris. The mechanisms of AMD initiation and progression remain poorly understood owing to the lack of physiologically relevant human oBRB models. To this end, we engineered a native-like three-dimensional (3D) oBRB tissue (3D-oBRB) by bioprinting endothelial cells, pericytes, and fibroblasts on the basal side of a biodegradable scaffold and establishing an RPE monolayer on top. In this 3D-oBRB model, a fully-polarized RPE monolayer provides barrier resistance, induces choriocapillaris fenestration, and supports the formation of Bruch’s-membrane-like structure by inducing changes in gene expression in cells of the choroid. Complement activation in the 3D-oBRB triggers dry AMD phenotypes (including subRPE lipid-rich deposits called drusen and choriocapillaris degeneration), and HIF-α stabilization or STAT3 overactivation induce choriocapillaris neovascularization and type-I wet AMD phenotype. The 3D-oBRB provides a physiologically relevant model to studying RPE–choriocapillaris interactions under healthy and diseased conditions.

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Fig. 1: Design of 3D-oBRB.
Fig. 2: Engineering of 3D-oBRB.
Fig. 3: Capillary maturation in 3D-oBRB.
Fig. 4: RPE maturity in 3D-oBRB.
Fig. 5: RPE-dependent choroid degeneration in dry and wet AMD models of 3D-oBRB.
Fig. 6: Bevacizumab treatment suppresses wet AMD in 3D-oBRB.

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Data availability

The scRNA-seq data generated in this study have been deposited in the Gene Expression Omnibus database under accession code GSE214928. These RNA-seq data are openly available without any restriction. All the processed data are available within the article. All the raw data generated in this study are provided in Source Data files. Source data for Fig. 6 are available in a figshare repository at Source data are provided with this paper.

Code availability

Angiogenesis quantification was performed on MATLAB version 2019b (Mathworks). The custom MATLAB code is available in Supplementary Information.


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The authors thank R. Fariss, NEI Biological Imaging Core, M. Abu from NEI histology core for processing the samples for TEM and taking images, D. McGaughey OGVFB, NEI for advice on scRNA-seq data analysis. This work was supported by funds from the NEI Intramural Research Program to K.B., NCATS intramural funds to M.J.S., M.F., and I.S., NHLBI intramural funds to M.B., Department of Defense grant (grant number 11831456) to M.J.S. and K.B., and Cures Acceleration Network program to M.J.S. and M.F.

Author information

Authors and Affiliations



Conceptualization: K.B., M.J.S, and M.F.; methodology: K.B., R.Q., E.N, M.J.S, T.V., I.S., and M.F.; Investigation: R.Q., E.N, M.J.S, C.H., R.S., T.S.P., C.K., C.T., C.W., A.S., R.D., D.B., P.D., K.D., S.M., G. C., M.B., A.M., and F.B.; analysis: Y.-C.C., K.B., R.Q., E.N, and M.J.S.; project administration: R.Q., E.N, and M.J.S; writing, review, and editing: K.B., E.N, M.J.S, and M.F; funding acquisition: K.B. M.F., M.B., I.S., and M.J.S.; resources: K.B. and M.F.; supervision: K.B. and M.F.

Corresponding author

Correspondence to Kapil Bharti.

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Competing interests

The authors have an approved patent on this technology in Australia (#AU2017359330B2) and a pending patent in the US (#US20190290803A1).

Peer review

Peer review information

Nature Methods thanks Reinhold Medina, Botond Roska, Ruchira Singh for their contribution to the peer review of this work. Primary Handling Editor: Madhura Mukhopadhyay, in collaboration with the Nature Methods team.

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Extended data

Extended Data Fig. 1 Pericytes colocalize to capillaries.

a-c, Pericytes immunostained with NG2 (a, green), α-SMA (b, green), and PDGFR-β (c, green) and ECs immunostained with CD31 (magenta). (n = 3), scale bars, 30 μm.

Extended Data Fig. 2 ECs, pericytes, and fibroblast are essential for formation of dense and stable capillary-bed.

a, b, EC only bioink; c, d, EC + pericyte bioink; e, f, EC + fibroblasts bioink; g, h, EC + pericyte + fibroblasts bioink 7 days (a, c, e, g) and 10 days (b, d, f, h) after bioprinting. Tissues fixed at analyzed for GFP expression (green) (n = 4). Scale bars, 500 μm.

Extended Data Fig. 3 Time course of fenestration marker expression in 3D-oBRB.

a-d, 3D vascular growth within tissues fixed at week 1 (a), week 2 (b), week 3 (c), and week 4 (d). Tissues were immunostained with FELS (green) and CD31 (magenta). Scale bars, 50 μm. n = 3.

Extended Data Fig. 4 ECM protein expressions in 3D-oBRB.

a-f, 3D reconstructed images of tissues immunostained for CD31 (magenta, a-f), nuclei (blue, a-f), LAMININ (LMN, green a, b), ELASTIN (ELN, green, c, d), COLLAGEN IV (COL IV, green, e, f), viewed at the subRPE level (a, c, e) and choriocapillaris level (b, d, f). N = 3. g, cross section of 3D-oBRB immunostained for Bruch’s membrane proteins LAMININ (yellow) and COLLAGEN IV (COL IV, magenta). Nuclei stained with DAPI (cyan). N = 3. Scale bar, 10μm.

Extended Data Fig. 5 Time course study of dry AMD phenotype induction in 3D-oBRB.

a-l, Nile red (yellow), anti-CD31 (magenta), and Hoechst (nucleus, blue) stained en face images of RPE (a-f), RPE-proximal choriocapillaris (g-l), and RPE-distal choriocapillaris (m-r) from 3D-oBRB treated with complement incompetent human serum (CI-HS, a, c, e, g, i, k, m, o, q) complement competent human serum (CC-HS, b, d, f, h, j, l, n, p, r) for 2, 4, and 7 days. Scale bars, 60 μm (a-l), 300 μm (m-r) n = 3. s-x, Nile red (yellow), anti-CD31 (magenta), and Hoechst (nucleus, blue) stained lateral view 3D rendered images of 3D-oBRB, treated with CI-HS (s, u, w) or CC-HS (t, v, x).

Extended Data Fig. 6 ML228 treatment on 2D-iRPE and 3D-oBRB.

a-f, RPE monoculture at 48 hr (a,d), 96 hr (b,e), and 2 weeks (c,f) from the beginning of ML228 (2 µM; 96 hr) treatment, immunostained with HIF-1α (magenta), ZO-1 (green), and Hoeschst (blue). DMSO uused to dissolve ML228 was used as the vehicle. Scale bars, 30 µm. (n = 3) g, TER measurement of 2D-iRPE without or with ML228 treatment (n = 3). Data are presented as mean values +/− SEM. Two-way ANOVA, Tukey’s multiple comparisons test were used for statistical analysis. h, ZO-1 staining based morphometry analysis of individual cell area in vehicle and ML228-treated samples was performed, (n = 1644, number of cells). Data are presented as mean values with standard deviation. ANOVA and Tukey’s multiple comparisons test were used for statistical analysis.

Source data

Extended Data Fig. 7 Activation of HIF-1α in RPE induces type-I CNV-like phenotype in 3D-oBRB.

a-h, immunostaining of tissues with anti-CD31 (magenta), anti-HIF-1α (yellow) antibodies, and staining for F-ACTIN (cyan), and nuclei (blue). Tissues were treated with either vehicle (DMSO, a,e), or ML228 (2 μM) on apical side of RPE only (b,f), or basal side of choroid only (c,g), or both sides (d,h). Red arrowheads indicate type-I CNV-like phenotype, white arrowheads indicate examples of HIF-1α translocation to the nuclei. (n = 3), scale bars, 50 μm. i, TER measurements normalized to ctrl. (n = 6). Data are presented as mean values +/− SEM. ANOVA and Tukey’s multiple comparisons test. j, k, pseudo 3D-projected side views of 3D-oBRB immunostained with anti-CD31 (magenta), anti-COL IV (yellow), anti-LAMININ (cyan) antibodies, and nuclei (blue). Tissues were treated with either vehicle (DMSO, j), or ML228 (2 μM) on apical side of RPE only (k). Arrowheads indicate type-I CNV-like phenotype in ML228-treated (k) tissues with choriocapillaris (CC) penetrating through the Bruch’s membrane (BM). (n = 3), scale bars, 10 μm.

Source data

Extended Data Fig. 8 STAT3 overexpression in the RPE induces type-I CNV-like phenotype in 3D-oBRB.

a-l, en face views (a-h), and pseudo 3D-projected side views (i, j) of 3D-oBRB immunostained at week 6 with anti-CD31(magenta), anti-STAT3 (yellow) antibodies, and stained for nuclei (blue), containing wildtype iRPE (a-d, i), STAT3 overexpressing iRPE (e-h, j). BM – Bruch’s membrane, CC – choriocapillaris. N = 3. Scale bars, 50 μm (a-c, e-g), 10 μm (i, j). k, TER measurements normalized to control from 2D-iRPE monoculture. (N = 8). Data are presented as mean values +/− SEM. Unpaired t-test was used for statistical analysis.

Source data

Extended Data Fig. 9 Bevacizumab suppresses type-I CNV-like phenotype in 3D-oBRB.

a-c, Images of deep choroidal regions of (a) vehicle, (b) ML228, (c) ML228 + Bevacizumab treated 3D-oBRB, immunostained for CD31 (red) and stained for Hoechst (blue). Scale bars, 350 μm. (n = 4). d-h, en face views (d-g), and pseudo 3D-projected side views (h) of STAT3 overexpressing 3D-oBRB treated with Bevacizumab immunostained at week 6 with anti-CD31(magenta), anti-STAT3 (yellow) antibodies, and stained for nuclei (blue). BM – Bruch’s membrane, CC – choriocapillaris. N = 3. Scale bars, 50 μm (d-g), 10 μm (h). i, TER measurements normalized to control of STAT3 overexpressing 3D-oBRB and STAT3 overexpressing 3D-oBRB treated with Bevacizumab. (n = 4), Data are presented as mean values + /- SEM. One-way ANOVA and Tukey’s multiple comparisons test were used for statistical analysis.

Source data

Supplementary information

Supplementary information

Supplementary Tables 1–4, Supplementary Figs 1–21, legends for Supplementary Videos 1–7, Angiogenesis quantification MATLAB code, and Supplementary Protocol.

Reporting Summary

Supplementary Video 1

Bioprinting of vascularized tissue with GFP-positive ECs and VEGF-dependent angiogenesis from day 4 to day 6.

Supplementary Video 2

Pericytes and EC tubes in the context of 3D vascularized tissue at day 7.

Supplementary Video 3

3D-oBRB tissue model.

Supplementary Video 4

ELASTIN and LAMININ formation in 3D-oBRB tissue model (z-stack).

Supplementary Video 5

ELASTIN and LAMININ formation in 3D-oBRB tissue model.

Supplementary Video 6

Complement induced dry AMD model.

Supplementary Video/ Movie 7

HIF-1α induced CNV in 3D-oBRB with anti-VEGF (Bevacizumab) treatment.

Supplementary Data 1

Statistical source data for Supplementary Fig. 4.

Supplementary Data 2

Unprocessed gels or blots, unprocessed figure for Supplementary Fig. 21.

Source data

Source Data Fig. 1

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Source Data Fig. 5

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Source Data Fig. 6

Statistical source data and source data (Fig. is on Figshare (

Source Data Extended Data Fig 6

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Source Data Extended Data Fig 7

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Source Data Extended Data Fig 8

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Source Data Extended Data Fig 9

Statistical source data.

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Song, M.J., Quinn, R., Nguyen, E. et al. Bioprinted 3D outer retina barrier uncovers RPE-dependent choroidal phenotype in advanced macular degeneration. Nat Methods 20, 149–161 (2023).

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