Alginate encapsulation as long-term immune protection of allogeneic pancreatic islet cells transplanted into the omental bursa of macaques

The transplantation of pancreatic islet cells could restore glycaemic control in patients with type 1 diabetes. Microspheres for islet encapsulation have enabled long-term glycaemic control in rodent models of diabetes; however, humans transplanted with equivalent microsphere formulations have exper...

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Published inNature biomedical engineering Vol. 2; no. 11; pp. 810 - 821
Main Authors Bochenek, Matthew A., Veiseh, Omid, Vegas, Arturo J., McGarrigle, James J., Qi, Meirigeng, Marchese, Enza, Omami, Mustafa, Doloff, Joshua C., Mendoza-Elias, Joshua, Nourmohammadzadeh, Mohammad, Khan, Arshad, Yeh, Chun-Chieh, Xing, Yuan, Isa, Douglas, Ghani, Sofia, Li, Jie, Landry, Casey, Bader, Andrew R., Olejnik, Karsten, Chen, Michael, Hollister-Lock, Jennifer, Wang, Yong, Greiner, Dale L., Weir, Gordon C., Strand, Berit Løkensgard, Rokstad, Anne Mari A., Lacik, Igor, Langer, Robert, Anderson, Daniel G., Oberholzer, Jose
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group UK 01.11.2018
Nature Publishing Group
Subjects
13/1
13/107
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13/51
13/62
14/34
14/63
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692/308/2778
692/308/575
692/699/2743/137/1418
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Alginates
Alginic acid
Animal models
Biomedical and Life Sciences
Biomedical Engineering/Biotechnology
Biomedicine
Clinical trials
Diabetes
Diabetes mellitus (insulin dependent)
Encapsulation
Fibrosis
Immunomodulation
Immunosuppression
Implantation
Insulin
Islet cells
Microspheres
Pancreas transplantation
Pancreatic islet transplantation
Peritoneum
Sedimentation
Transplantation
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Summary:The transplantation of pancreatic islet cells could restore glycaemic control in patients with type 1 diabetes. Microspheres for islet encapsulation have enabled long-term glycaemic control in rodent models of diabetes; however, humans transplanted with equivalent microsphere formulations have experienced only transient islet graft function owing to a vigorous foreign-body response (FBR), to pericapsular fibrotic overgrowth (PFO) and, in upright bipedal species, to the sedimentation of the microspheres within the peritoneal cavity. Here, we report the results of the testing in non-human primate (NHP) models of seven alginate formulations that were efficacious in rodents, including three that led to transient islet graft function in clinical trials. All formulations elicited significant FBR and PFO 1 month post implantation; however, three chemically modified, immune-modulating alginate formulations elicited a reduced FBR. In conjunction with a minimally invasive transplantation technique into the bursa omentalis of NHPs, the most promising chemically modified alginate derivative (Z1-Y15) protected viable and glucose-responsive allogeneic islets for 4 months without the need for immunosuppression. Chemically modified alginate formulations may enable the long-term transplantation of islets for the correction of insulin deficiency. Transplantation of pancreatic islet cells encapsulated in alginate microspheres into the omental bursa of the peritoneal cavity of NHPs significantly reduces FBRs and extends the longevity of the cells.
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Present address: Sigilon Therapeutics, Inc., 161 First St., Cambridge, MA 02142, USA and Department of Bioengineering, Rice University, Houston, TX 77005, USA
Present address: Department of Chemical and Biomolecular Engineering, North Carolina State University, 911 Partners Way, Raleigh, NC 27606, USA
Present address: Department of Surgery and Biomedical Engineering, University of Virginia, PO Box 800709, Charlottesville, VA 22908, USA
Additional Information
Correspondence should be addressed to Dr. Jose Oberholzer and any material requests should be addressed to Dr. Dan Anderson.
Present address: Chemistry Department, Boston University, 590 Commonwealth Ave., Boston, MA 02215, USA
Author Contributions
M.A.B., O.V., A.J.V., J.J.M., D.G.A., and J.O. designed experiments, analyzed data and wrote the manuscript. M.A.B., O.V., A.J.V., J.J.M., M.Q., E.M., M.O., J.C.D., J.E.M., M.N., A.K., C.C.Y., D.I., S.G., J.L., C.L., A.R.B., K.O., M.C., Y.W., and J.O. performed experiments. J.H.L., D.L.G., G.C.W., B.L.S., A.A.R., I.L., and R.L. provided conceptual advice and technical support. R.L., D.G.A., and J.O. supervised the study. All of the authors discussed the results and assisted in the preparation of the manuscript.
ISSN:2157-846X
2157-846X
DOI:10.1038/s41551-018-0275-1