Abstract:
:Recent phase 1 trials of embryonic stem cell and induced pluripotent stem cell (iPSCs) derived RPE transplants for the treatment of macular degeneration have demonstrated the relative safety of this process. However, there is concern over clumping, thickening, folding, and wrinkling of the transplanted RPE. To deliver a flat RPE monolayer, current phase 1 trials are testing synthetic substrates for RPE transplantation. These substrates, however, cause localized inflammation and fibrosis in animal models due to long degradation times. Here we describe the use of thin fibrin hydrogels as a support material for the transplantation of RPE. Fibrin was formed into a mechanically rigid support that allow for easy manipulation with standard surgical instruments. Using fibrinolytic enzymes, fibrin hydrogels were degraded on the scale of hours. The rate of degradation could be controlled by varying the fibrinolytic enzyme concentration used. RPE cells degraded fibrin spontaneously. To preserve the fibrin support during differentiation of iPSCs to RPE, media was supplemented with the protease inhibitor aprotinin. iPSC-RPE on fibrin gels remained viable, generated monolayers with characteristic cobblestone appearance and dark pigmentation, and expressed mRNA and protein markers characteristic of RPE in the eye. Following differentiation of the cells, addition of fibrinolytic enzymes fully and rapidly degraded the fibrin support leaving behind an intact, viable iPSC-RPE monolayer. In conclusion, human fibrin hydrogels provide a xeno-free support on which iPSCs can be differentiated to RPE cells for transplant which can be rapidly degraded under controlled conditions using fibrinolytic enzymes without adverse effects to the cells. STATEMENT OF SIGNIFICANCE:Stem cell-derived retinal pigment epithelial (RPE) cell transplantation is currently in phase 1 clinical trials for macular degeneration (MD). A major obstacle in these studies is delivering the RPE as a living, flat sheets without leaving behind foreign materials in the retina. Here we investigate the suitability of using hydrogels made from human blood-derived proteins for RPE transplant. Our data shows that these fibrin hydrogels are rigid enough for use in surgery, support growth of stem cell-derived RPE, and are easily degraded within hours without damage to the RPE sheet. These fibrin hydrogels offer a promising solution to transplant RPE for patients with MD.
journal_name
Acta Biomaterjournal_title
Acta biomaterialiaauthors
Gandhi JK,Manzar Z,Bachman LA,Andrews-Pfannkoch C,Knudsen T,Hill M,Schmidt H,Iezzi R,Pulido JS,Marmorstein ADdoi
10.1016/j.actbio.2017.11.058subject
Has Abstractpub_date
2018-02-01 00:00:00pages
134-146eissn
1742-7061issn
1878-7568pii
S1742-7061(17)30755-9journal_volume
67pub_type
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journal_title:Acta biomaterialia
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pub_type: 杂志文章
doi:10.1016/j.actbio.2012.01.003
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pub_type: 杂志文章,评审
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pub_type: 杂志文章
doi:10.1016/j.actbio.2020.11.050
更新日期:2021-02-01 00:00:00
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pub_type: 杂志文章
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更新日期:2020-09-01 00:00:00
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pub_type: 杂志文章
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更新日期:2019-10-01 00:00:00
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pub_type: 杂志文章
doi:10.1016/j.actbio.2009.07.003
更新日期:2010-02-01 00:00:00
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journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2015.10.044
更新日期:2016-01-01 00:00:00
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doi:10.1016/j.actbio.2009.06.022
更新日期:2010-02-01 00:00:00
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更新日期:2019-09-01 00:00:00
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doi:10.1016/j.actbio.2009.12.050
更新日期:2010-07-01 00:00:00
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更新日期:2020-09-15 00:00:00
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journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2015.07.037
更新日期:2015-10-01 00:00:00
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pub_type: 杂志文章
doi:10.1016/j.actbio.2021.01.044
更新日期:2021-01-30 00:00:00
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journal_title:Acta biomaterialia
pub_type: 杂志文章
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更新日期:2016-07-01 00:00:00
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journal_title:Acta biomaterialia
pub_type: 杂志文章
doi:10.1016/j.actbio.2008.08.001
更新日期:2009-01-01 00:00:00
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pub_type: 杂志文章
doi:10.1016/j.actbio.2011.01.034
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