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Cited by 200Pancreatic function and diabetesTissue Engineering and Regenerative MedicineHydrogels: synthesis, properties, applications

Designing a retrievable and scalable cell encapsulation device for potential treatment of type 1 diabetes

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An, Duo, Chiu, Alan, Flanders, James A., Song, Wei, Shou, Dahua, Lu, Yen-Chun, Grunnet, Lars G., Winkel, Louise +11 more·2018·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1708806115PMC PMC5777032
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Abstract

Significance: Cell encapsulation holds great potential as a better treatment for type 1 diabetes. An encapsulation system that is scalable to a clinically relevant capacity and can be retrieved or replaced whenever needed is highly desirable for clinical applications. Here we report a cell encapsulation device that is readily scalable and conveniently retrievable through a minimally invasive laparoscopic procedure. We demonstrated its mechanical robustness and facile mass transfer as well as its durable function in diabetic mice. We further showed, as a proof of concept, its scalability and retrievability in dogs. We believe this encapsulation device may contribute to a cellular therapy for type 1 diabetes and potentially other endocrine disorders and hormone-deficient diseases.

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  1. [2]Nathan DM, et al. Diabetes Control and Complications Trial Research Group The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329:977–986. doi: 10.1056/NEJM199309303291401. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  2. [3]Shapiro AMJ, et al. International trial of the Edmonton protocol for islet transplantation. N Engl J Med. 2006;355:1318–1330. doi: 10.1056/NEJMoa061267. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  3. [4]Weir GC, Bonner-Weir S. Scientific and political impediments to successful islet transplantation. Diabetes. 1997;46:1247–1256. doi: 10.2337/diab.46.8.1247. [DOI] [PubMed] [Google Scholar] · DOI
  4. [6]Orive G, et al. Cell encapsulation: Promise and progress. Nat Med. 2003;9:104–107. doi: 10.1038/nm0103-104. [DOI] [PubMed] [Google Scholar] · DOI
  5. [8]Scharp DW, Marchetti P. Encapsulated islets for diabetes therapy: History, current progress, and critical issues requiring solution. Adv Drug Deliv Rev. 2014;67-68:35–73. doi: 10.1016/j.addr.2013.07.018. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  6. [9]Calafiore R, Basta G. Clinical application of microencapsulated islets: Actual prospectives on progress and challenges. Adv Drug Deliv Rev. 2014;67–68:84–92. doi: 10.1016/j.addr.2013.09.020. [DOI] [PubMed] [Google Scholar] · DOI
  7. [10]Vaithilingam V, Tuch BE. Islet transplantation and encapsulation: An update on recent developments. Rev Diabet Stud. 2011;8:51–67. doi: 10.1900/RDS.2011.8.51. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  8. [12]Orive G, et al. Cell encapsulation: Technical and clinical advances. Trends Pharmacol Sci. 2015;36:537–546. doi: 10.1016/j.tips.2015.05.003. [DOI] [PubMed] [Google Scholar] · DOI
  9. [13]Ledford H. Stem-cell success poses immunity challenge for diabetes. Nature. 2014;514:281. doi: 10.1038/514281a. [DOI] [PubMed] [Google Scholar] · DOI
  10. [14]Colton CK. Oxygen supply to encapsulated therapeutic cells. Adv Drug Deliv Rev. 2014;67–68:93–110. doi: 10.1016/j.addr.2014.02.007. [DOI] [PubMed] [Google Scholar] · DOI
  11. [15]Papas KK, Avgoustiniatos ES, Suszynski TM. Effect of oxygen supply on the size of implantable islet-containing encapsulation devices. Panminerva Med. 2016;58:72–77. [PubMed] [Google Scholar]
  12. [16]Papas KK, et al. Macroencapsulated human islet viability is drastically reduced in vivo as the number of islets per device is increased. Transplantation. 2013;96:S71. [Google Scholar]
  13. [17]Smink AM, Faas MM, de Vos P. Toward engineering a novel transplantation site for human pancreatic islets. Diabetes. 2013;62:1357–1364. doi: 10.2337/db12-1553. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  14. [18]Jacobs-Tulleneers-Thevissen D, et al. Beta Cell Therapy Consortium EU-FP7 Sustained function of alginate-encapsulated human islet cell implants in the peritoneal cavity of mice leading to a pilot study in a type 1 diabetic patient. Diabetologia. 2013;56:1605–1614. doi: 10.1007/s00125-013-2906-0. [DOI] [PubMed] [Google Scholar] · DOI
  15. [19]Wang T, et al. An encapsulation system for the immunoisolation of pancreatic islets. Nat Biotechnol. 1997;15:358–362. doi: 10.1038/nbt0497-358. [DOI] [PubMed] [Google Scholar] · DOI
  16. [20]Cui H, et al. Long-term metabolic control of autoimmune diabetes in spontaneously diabetic nonobese diabetic mice by nonvascularized microencapsulated adult porcine islets. Transplantation. 2009;88:160–169. doi: 10.1097/TP.0b013e3181abbfc1. [DOI] [PubMed] [Google Scholar] · DOI
  17. [21]Soon-Shiong P, et al. Long-term reversal of diabetes by the injection of immunoprotected islets. Proc Natl Acad Sci USA. 1993;90:5843–5847. doi: 10.1073/pnas.90.12.5843. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  18. [22]Wang T, et al. Successful allotransplantation of encapsulated islets in pancreatectomized canines for diabetic management without the use of immunosuppression. Transplantation. 2008;85:331–337. doi: 10.1097/TP.0b013e3181629c25. [DOI] [PubMed] [Google Scholar] · DOI
  19. [23]Elliott RB, et al. Intraperitoneal alginate-encapsulated neonatal porcine islets in a placebo-controlled study with 16 diabetic cynomolgus primates. Transplant Proc. 2005;37:3505–3508. doi: 10.1016/j.transproceed.2005.09.038. [DOI] [PubMed] [Google Scholar] · DOI
  20. [24]Sun Y, Ma X, Zhou D, Vacek I, Sun AM. Normalization of diabetes in spontaneously diabetic cynomologus monkeys by xenografts of microencapsulated porcine islets without immunosuppression. J Clin Invest. 1996;98:1417–1422. doi: 10.1172/JCI118929. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  21. [25]de Vos P. Cell encapsulation: Ready for the next step. Adv Drug Deliv Rev. 2014;67–68:1–2. [Google Scholar]
  22. [26]Elliott RB, et al. Live encapsulated porcine islets from a type 1 diabetic patient 9.5 yr after xenotransplantation. Xenotransplantation. 2007;14:157–161. doi: 10.1111/j.1399-3089.2007.00384.x. [DOI] [PubMed] [Google Scholar] · DOI
  23. [27]Omer A, et al. Survival and maturation of microencapsulated porcine neonatal pancreatic cell clusters transplanted into immunocompetent diabetic mice. Diabetes. 2003;52:69–75. doi: 10.2337/diabetes.52.1.69. [DOI] [PubMed] [Google Scholar] · DOI
  24. [28]Orive G, Emerich D, De Vos P. Encapsulate this: The do’s and don’ts. Nat Med. 2014;20:233. doi: 10.1038/nm.3486. [DOI] [PubMed] [Google Scholar] · DOI
  25. [31]Vegas AJ, et al. Long-term glycemic control using polymer-encapsulated human stem cell-derived beta cells in immune-competent mice. Nat Med. 2016;22:306–311. doi: 10.1038/nm.4030. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  26. [32]Tuch BE, et al. Safety and viability of microencapsulated human islets transplanted into diabetic humans. Diabetes Care. 2009;32:1887–1889. doi: 10.2337/dc09-0744. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  27. [33]Pepper AR, et al. A prevascularized subcutaneous device-less site for islet and cellular transplantation. Nat Biotechnol. 2015;33:518–523. doi: 10.1038/nbt.3211. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  28. [34]Matsumoto S, Tomiya M, Sawamoto O. Current status and future of clinical islet xenotransplantation. J Diabetes. 2016;8:483–493. doi: 10.1111/1753-0407.12395. [DOI] [PubMed] [Google Scholar] · DOI
  29. [35]Lindvall O, Wahlberg LU. Encapsulated cell biodelivery of GDNF: A novel clinical strategy for neuroprotection and neuroregeneration in Parkinson’s disease? Exp Neurol. 2008;209:82–88. doi: 10.1016/j.expneurol.2007.08.019. [DOI] [PubMed] [Google Scholar] · DOI
  30. [36]Zheng Y, et al. Directional water collection on wetted spider silk. Nature. 2010;463:640–643. doi: 10.1038/nature08729. [DOI] [PubMed] [Google Scholar] · DOI
  31. [37]Srinivasarao M, Collings D, Philips A, Patel S. Three-dimensionally ordered array of air bubbles in a polymer film. Science. 2001;292:79–83. doi: 10.1126/science.1057887. [DOI] [PubMed] [Google Scholar] · DOI
  32. [38]Bognitzki M, et al. Nanostructured fibers via electrospinning. Adv Mater. 2001;13:70–72. [Google Scholar]
  33. [39]Quéré D, di Meglio JM, Brochard-Wyart F. Spreading of liquids on highly curved surfaces. Science. 1990;249:1256–1260. doi: 10.1126/science.249.4974.1256. [DOI] [PubMed] [Google Scholar] · DOI
  34. [40]Duprat C, Protière S, Beebe AY, Stone HA. Wetting of flexible fibre arrays. Nature. 2012;482:510–513. doi: 10.1038/nature10779. [DOI] [PubMed] [Google Scholar] · DOI
  35. [41]Akbari M, et al. Composite living fibers for creating tissue constructs using textile techniques. Adv Funct Mater. 2014;24:4060–4067. doi: 10.1002/adfm.201303655. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  36. [42]Krishnan R, Alexander M, Robles L, Foster CE, 3rd, Lakey JR. Islet and stem cell encapsulation for clinical transplantation. Rev Diabet Stud. 2014;11:84–101. doi: 10.1900/RDS.2014.11.84. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  37. [43]Bray N. Biomaterials: Modified alginates provide a long-term disguise against the foreign body response. Nat Rev Drug Discov. 2016;15:158. doi: 10.1038/nrd.2016.41. [DOI] [PubMed] [Google Scholar] · DOI
  38. [44]Gurruchaga H, et al. Advances in cell encapsulation technology and its application in drug delivery. Expert Opin Drug Deliv. 2015;12:1251–1267. doi: 10.1517/17425247.2015.1001362. [DOI] [PubMed] [Google Scholar] · DOI
  39. [45]De Vos P, Wolters GHJ, Fritschy WM, Van Schilfgaarde R. Obstacles in the application of microencapsulation in islet transplantation. Int J Artif Organs. 1993;16:205–212. [PubMed] [Google Scholar]
  40. [46]Ricordi C, et al. Islet isolation assessment in man and large animals. Acta Diabetol Lat. 1990;27:185–195. doi: 10.1007/BF02581331. [DOI] [PubMed] [Google Scholar] · DOI
  41. [47]Bruin JE, et al. Treating diet-induced diabetes and obesity with human embryonic stem cell-derived pancreatic progenitor cells and antidiabetic drugs. Stem Cell Reports. 2015;4:605–620. doi: 10.1016/j.stemcr.2015.02.011. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  42. [48]Gaber AO, et al. Human islet graft function in NOD-SCID mice predicts clinical response in islet transplant recipients. Transplant Proc. 2004;36:1108–1110. doi: 10.1016/j.transproceed.2004.04.055. [DOI] [PubMed] [Google Scholar] · DOI
  43. [49]Stokes RA, et al. Transplantation sites for human and murine islets. Diabetologia. 2017;60:1961–1971. doi: 10.1007/s00125-017-4362-8. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  44. [50]Robertson RP, Lanz KJ, Sutherland DER, Kendall DM. Prevention of diabetes for up to 13 years by autoislet transplantation after pancreatectomy for chronic pancreatitis. Diabetes. 2001;50:47–50. doi: 10.2337/diabetes.50.1.47. [DOI] [PubMed] [Google Scholar] · DOI
  45. [52]Millman JR, et al. Generation of stem cell-derived β-cells from patients with type 1 diabetes. Nat Commun. 2016;7:11463. doi: 10.1038/ncomms11463. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  46. [53]Anonymous First stem cell-derived islets in humans. Nat Biotechnol. 2014;32:959. [Google Scholar]
  47. [54]Calafiore R. Alginate microcapsules for pancreatic islet cell graft immunoprotection: Struggle and progress towards the final cure for type 1 diabetes mellitus. Expert Opin Biol Ther. 2003;3:201–205. doi: 10.1517/14712598.3.2.201. [DOI] [PubMed] [Google Scholar] · DOI
  48. [55]Hentze H, et al. Teratoma formation by human embryonic stem cells: Evaluation of essential parameters for future safety studies. Stem Cell Res (Amst) 2009;2:198–210. doi: 10.1016/j.scr.2009.02.002. [DOI] [PubMed] [Google Scholar] · DOI
  49. [56]Onoe H, et al. Metre-long cell-laden microfibres exhibit tissue morphologies and functions. Nat Mater. 2013;12:584–590. doi: 10.1038/nmat3606. [DOI] [PubMed] [Google Scholar] · DOI
  50. [57]Raof NA, Padgen MR, Gracias AR, Bergkvist M, Xie Y. One-dimensional self-assembly of mouse embryonic stem cells using an array of hydrogel microstrands. Biomaterials. 2011;32:4498–4505. doi: 10.1016/j.biomaterials.2011.03.011. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  51. [58]Lee KH, Shin SJ, Park Y, Lee SH. Synthesis of cell-laden alginate hollow fibers using microfluidic chips and microvascularized tissue-engineering applications. Small. 2009;5:1264–1268. doi: 10.1002/smll.200801667. [DOI] [PubMed] [Google Scholar] · DOI
  52. [59]Zhang S, et al. Creating polymer hydrogel microfibres with internal alignment via electrical and mechanical stretching. Biomaterials. 2014;35:3243–3251. doi: 10.1016/j.biomaterials.2013.12.081. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  53. [60]Yu Y, et al. Flexible fabrication of biomimetic bamboo-like hybrid microfibers. Adv Mater. 2014;26:2494–2499. doi: 10.1002/adma.201304974. [DOI] [PubMed] [Google Scholar] · DOI
  54. [61]An D, et al. Developing robust, hydrogel-based, nanofiber-enabled encapsulation devices (NEEDs) for cell therapies. Biomaterials. 2015;37:40–48. doi: 10.1016/j.biomaterials.2014.10.032. [DOI] [PubMed] [Google Scholar] · DOI
  55. [62]Lacy PE, Kostianovsky M. Method for the isolation of intact islets of Langerhans from the rat pancreas. Diabetes. 1967;16:35–39. doi: 10.2337/diab.16.1.35. [DOI] [PubMed] [Google Scholar] · DOI

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Authors
An, D., Chiu, A., Flanders, J. A., Song, W., Shou, D., Lu, Y.-C., Grunnet, L. G., Winkel, L., Ingvorsen, C., Christophersen, N. S., Fels, J. J., Sand, F. W., Ji, Y., Qi, L., Pardo, Y., Luo, D., Silberstein, M., Fan, J., & Ma, M.
Affiliations
  • Cornell University (US)
  • Novo Nordisk (Denmark) (DK)
  • University of Michigan (US)
  • Chinese Academy of Sciences (CN)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2017-12-26
Volume
115
Issue
2
Pages
E263-E272
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.1708806115
PMC
PMC5777032
OpenAlex
W2776885898
Cited by
200
References
0
Citations by year
2026: 10 · 2025: 10 · 2024: 26 · 2023: 32 · 2022: 22 · 2021: 31 · 2020: 25 · 2019: 32 · 2018: 12
FWCI
19.34
Type
journal article
Language
en
Open access
Licence
www.pnas.org/site/aboutpnas/licenses.xhtml (vor, 182 d)
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institute of Diabetes and Digestive and Kidney Diseases (P30DK020572)
Topics
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Hydrogels: synthesis, properties, applications
Keywords
type 1 diabetes, islet transplantation, alginate hydrogel, in situ crosslinking, immunoprotection, retrievability, scalability, human islets, rat islets, cell therapy, C57BL/6 mice, SCID/beige mice
MeSH terms
Alginates, Animals, Diabetes Mellitus, Experimental, Dimethylformamide, Dogs, Hexuronic Acids, Humans, Islets of Langerhans, Islets of Langerhans Transplantation, Mice, SCID, Polymethyl Methacrylate, Hydrogels, Glucuronic Acid, Mice, Rats, Cell- and Tissue-Based Therapy

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