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Fibrin hydrogels as a xenofree and rapidly degradable support for transplantation of retinal pigment epithelium monolayers.
Acta Biomater. 2018 02; 67:134-146.AB

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.

Authors+Show Affiliations

Department of Ophthalmology, Mayo Clinic, Rochester, MN, United States.Department of Ophthalmology, Mayo Clinic, Rochester, MN, United States.Department of Ophthalmology, Mayo Clinic, Rochester, MN, United States.Department of Ophthalmology, Mayo Clinic, Rochester, MN, United States.Department of Ophthalmology, Mayo Clinic, Rochester, MN, United States.Department of Ophthalmology, Mayo Clinic, Rochester, MN, United States.Department of Ophthalmology, Mayo Clinic, Rochester, MN, United States.Department of Ophthalmology, Mayo Clinic, Rochester, MN, United States.Department of Ophthalmology, Mayo Clinic, Rochester, MN, United States.Department of Ophthalmology, Mayo Clinic, Rochester, MN, United States. Electronic address: marmorstein.alan@mayo.edu.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29233750

Citation

Gandhi, Jarel K., et al. "Fibrin Hydrogels as a Xenofree and Rapidly Degradable Support for Transplantation of Retinal Pigment Epithelium Monolayers." Acta Biomaterialia, vol. 67, 2018, pp. 134-146.
Gandhi JK, Manzar Z, Bachman LA, et al. Fibrin hydrogels as a xenofree and rapidly degradable support for transplantation of retinal pigment epithelium monolayers. Acta Biomater. 2018;67:134-146.
Gandhi, J. K., Manzar, Z., Bachman, L. A., Andrews-Pfannkoch, C., Knudsen, T., Hill, M., Schmidt, H., Iezzi, R., Pulido, J. S., & Marmorstein, A. D. (2018). Fibrin hydrogels as a xenofree and rapidly degradable support for transplantation of retinal pigment epithelium monolayers. Acta Biomaterialia, 67, 134-146. https://doi.org/10.1016/j.actbio.2017.11.058
Gandhi JK, et al. Fibrin Hydrogels as a Xenofree and Rapidly Degradable Support for Transplantation of Retinal Pigment Epithelium Monolayers. Acta Biomater. 2018;67:134-146. PubMed PMID: 29233750.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Fibrin hydrogels as a xenofree and rapidly degradable support for transplantation of retinal pigment epithelium monolayers. AU - Gandhi,Jarel K, AU - Manzar,Zahid, AU - Bachman,Lori A, AU - Andrews-Pfannkoch,Cynthia, AU - Knudsen,Travis, AU - Hill,Matthew, AU - Schmidt,Hannah, AU - Iezzi,Raymond, AU - Pulido,Jose S, AU - Marmorstein,Alan D, Y1 - 2017/12/09/ PY - 2017/09/13/received PY - 2017/11/15/revised PY - 2017/11/30/accepted PY - 2017/12/14/pubmed PY - 2018/8/21/medline PY - 2017/12/14/entrez KW - Fibrin KW - Hydrogel degradation KW - Retinal pigment epithelium KW - Tissue engineering SP - 134 EP - 146 JF - Acta biomaterialia JO - Acta Biomater VL - 67 N2 - : 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. SN - 1878-7568 UR - https://www.unboundmedicine.com/medline/citation/29233750/Fibrin_hydrogels_as_a_xenofree_and_rapidly_degradable_support_for_transplantation_of_retinal_pigment_epithelium_monolayers_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1742-7061(17)30755-9 DB - PRIME DP - Unbound Medicine ER -