Advances in islet encapsulation technologies

A Correction to this article was published on 28 April 2017

This article has been updated

Key Points

  • The autoimmune response in type 1 diabetes combined with the response to allogeneic cell transplantation remains a formidable barrier to transplant success that currently requires the use of powerful immunosuppressive drugs.

  • Encapsulation strategies have the potential to ameliorate these responses to promote survival post-transplantation, with modifications to the biomaterial chemistry, the incorporation of biologics or cell co-transplantation being used to avoid lifelong immunosuppression.

  • Allogeneic islets are the current standard for clinical use; however, the supply of these islets is insufficient to meet the need for patients. Alternative sources such as human embryonic stem cell-derived β-cells and porcine islets have the potential to satisfy demand, although efficacy, safety and regulatory issues remain to be addressed.

  • Vascularization of the transplant site is being developed to enhance islet function post-transplantation by providing the nutrients necessary for survival, while also allowing the sensing of glucose and the distribution of insulin. Oxygen is frequently the limiting factor and oxygen delivery systems are also being developed to complement the vascularization process.

  • A small number of islet encapsulation systems have been applied clinically, all of which have demonstrated good safety profiles, although it is too early to evaluate functional outcomes.

Abstract

Type 1 diabetes is an autoimmune disorder in which the immune system attacks and destroys insulin-producing islet cells of the pancreas. Although islet transplantation has proved to be successful for some patients with type 1 diabetes, its widespread use is limited by islet donor shortage and the requirement for lifelong immunosuppression. An encapsulation strategy that can prevent the rejection of xenogeneic islets or of stem cell-derived allogeneic islets can potentially eliminate both of these barriers. Although encapsulation technology has met several challenges, the convergence of expertise in materials, nanotechnology, stem cell biology and immunology is allowing us to get closer to the goal of encapsulated islet cell therapy for humans.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Islet and β-cell transplantation systems.

Change history

  • 28 March 2017

    In this article, the University of Edmonton was referred to instead of the University of Alberta and the article cited as reference 10 was incorrect. These errors have been corrected in the online version.

References

  1. 1

    Centers for Disease Control and Prevention. Diabetes report card 2014. CDC http://www.cdc.gov/diabetes/pdfs/library/diabetesreportcard2014.pdf (2015).

  2. 2

    National Center for Chronic Disease Prevention and Health Promotion. National diabetes statistics report, 2014: estimates of diabetes and its burden in the United States. CDC http://www.cdc.gov/diabetes/pubs/statsreport14/national-diabetes-report-web.pdf (2014).

  3. 3

    Ryan, E. A. et al. Five-year follow-up after clinical islet transplantation. Diabetes 54, 2060–2069 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. 4

    Barton, F. B. et al. Improvement in outcomes of clinical islet transplantation: 1999–2010. Diabetes Care 35, 1436–1445 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. 5

    Shapiro, A. M. et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N. Engl. J. Med. 343, 230–238 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 6

    Shapiro, A. M. et al. International trial of the Edmonton protocol for islet transplantation. N. Engl. J. Med. 355, 1318–1330 (2006).

    CAS  Article  Google Scholar 

  7. 7

    Hering, B. J. et al. Phase 3 trial of transplantation of human islets in type 1 diabetes complicated by severe hypoglycemia. Diabetes Care 39, 1230–1240 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8

    Stanekzai, J., Isenovic, E. R. & Mousa, S. A. Treatment options for diabetes: potential role of stem cells. Diabetes Res. Clin. Pract. 98, 361–368 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. 9

    Hentze, H. et al. Teratoma formation by human embryonic stem cells: evaluation of essential parameters for future safety studies. Stem Cell Res. 2, 198–210 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  10. 10

    Kieffer, T.J. Closing in on mass production of mature human beta cells. Cell Stem Cell. 18, 699–702 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. 11

    de Vos, P., Spasojevic, M. & Faas, M. M. Treatment of diabetes with encapsulated islets. Adv. Exp. Med. Biol. 670, 38–53 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12

    Vaithilingam, V. & Tuch, B. E. Islet transplantation and encapsulation: an update on recent developments. Rev. Diabet. Stud. 8, 51–67 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  13. 13

    Soon-Shiong, P. et al. Insulin independence in a type 1 diabetic patient after encapsulated islet transplantation. Lancet 343, 950–951 (1994).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14

    Scharp, D. W. & Marchetti, P. Encapsulated islets for diabetes therapy: history, current progress, and critical issues requiring solution. Adv. Drug Deliv. Rev. 67–68, 35–73 (2014).

  15. 15

    Desai, T. A., West, T., Cohen, M., Boiarski, T. & Rampersaud, A. Nanoporous microsystems for islet cell replacement. Adv. Drug Deliv. Rev. 56, 1661–1673 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16

    Omer, A. et al. Exercise induces hypoglycemia in rats with islet transplantation. Diabetes 53, 360–365 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. 17

    Trivedi, N. et al. Islets in alginate macrobeads reverse diabetes despite minimal acute insulin secretory responses. Transplantation 71, 203–211 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18

    Nyitray, C. E. et al. Polycaprolactone thin-film micro- and nanoporous cell-encapsulation devices. ACS Nano 9, 5675–5682 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 19

    Bisceglie, V. V. Uber die antineoplastiche Immunitat. E. Krebsforch 40, 141–158 (in German) (1933).

    Article  Google Scholar 

  20. 20

    Algire, G. H. & Legallais, F. Y. Recent developments in the transparent-chamber technique as adapted to the mouse. J. Natl Cancer Inst. 10, 225–253 (1949).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Algire, G. H., Weaver, J. M. & Prehn, R. T. Growth of cells in vivo in diffusion chambers. I. Survival of homografts in immunized mice. J. Natl Cancer Inst. 15, 493–507 (1954).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Prehn, R. T., Weaver, J. M. & Algire, G. H. The diffusion-chamber technique applied to a study of the nature of homograft resistance. J. Natl Cancer Inst. 15, 509–517 (1954).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Weaver, J. M., Algire, G. H. & Prehn, R. T. The growth of cells in vivo in diffusion chambers. II. The role of cells in the destruction of homografts in mice. J. Natl Cancer Inst. 15, 1737–1767 (1955).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Chang, T. M. Semipermeable microcapsules. Science 146, 524–525 (1964).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25

    Lim, F. & Sun, A. M. Microencapsulated islets as bioartificial endocrine pancreas. Science 210, 908–910 (1980).

    CAS  Article  Google Scholar 

  26. 26

    O'Shea, G. M., Goosen, M. F. & Sun, A. M. Prolonged survival of transplanted islets of Langerhans encapsulated in a biocompatible membrane. Biochim. Biophys. Acta 804, 133–136 (1984).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27

    Klock, G. et al. Production of purified alginates suitable for use in immunoisolated transplantation. Appl. Microbiol. Biotechnol. 40, 638–643 (1994).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28

    Otterlei, M. et al. Induction of cytokine production from human monocytes stimulated with alginate. J. Immunother. 10, 286–291 (1991).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29

    Sawhney, A. S., Pathak, C. P. & Hubbell, J. A. Interfacial photopolymerization of poly(ethylene glycol)-based hydrogels upon alginate-poly(l-lysine) microcapsules for enhanced biocompatibility. Biomaterials 14, 1008–1016 (1993).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30

    Sefton, M. V. & Stevenson, W. T. K. Microencapsulation of live animal cells using polyacrylates. Adv. Polym. Sci. 107, 143–197 (1993).

    CAS  Article  Google Scholar 

  31. 31

    Wang, T. et al. An encapsulation system for the immunoisolation of pancreatic islets. Nat. Biotechnol. 15, 358–362 (1997). Examines the composition of microcapsules with regards to suitability for cell encapsulation.

    CAS  Article  Google Scholar 

  32. 32

    Souza, Y. E. et al. Islet transplantation in rodents. Do encapsulated islets really work? Arq. Gastroenterol. 48, 146–152 (2011).

    Article  Google Scholar 

  33. 33

    Duvivier-Kali, V. F., Omer, A., Lopez-Avalos, M. D., O'Neil, J. J. & Weir, G. C. Survival of microencapsulated adult pig islets in mice in spite of an antibody response. Am. J. Transplant. 4, 1991–2000 (2004).

    CAS  Article  Google Scholar 

  34. 34

    Duvivier-Kali, V. F., Omer, A., Parent, R. J., O'Neil, J. J. & Weir, G. C. Complete protection of islets against allorejection and autoimmunity by a simple barium-alginate membrane. Diabetes 50, 1698–1705 (2001). Early demonstration of immunoprotective effects of the microencapsulation approach.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. 35

    Gates, R. J., Hunt, M. I., Smith, R. & Lazarus, N. R. Return to normal of blood-glucose, plasma-insulin, and weight gain in New Zealand obese mice after implantation of islets of Langerhans. Lancet 2, 567–570 (1972).

    CAS  Article  Google Scholar 

  36. 36

    Strautz, R. L. Studies of hereditary-obese mice (obob) after implantation of pancreatic islets in Millipore filter capsules. Diabetologia 6, 306–312 (1970).

    CAS  Article  Google Scholar 

  37. 37

    Brauker, J., Martinson, L. A., Young, S. K. & Johnson, R. C. Local inflammatory response around diffusion chambers containing xenografts. Nonspecific destruction of tissues and decreased local vascularization. Transplantation 61, 1671–1677 (1996).

    CAS  Article  Google Scholar 

  38. 38

    Brauker, J. H. et al. Neovascularization of synthetic membranes directed by membrane microarchitecture. J. Biomed. Mater. Res. 29, 1517–1524 (1995).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. 39

    Suzuki, K. et al. Function and survival of macroencapsulated syngeneic islets transplanted into streptozocin-diabetic mice. Transplantation 66, 21–28 (1998).

    CAS  Article  Google Scholar 

  40. 40

    Soon-Shiong, P. et al. Long-term reversal of diabetes by the injection of immunoprotected islets. Proc. Natl Acad. Sci. USA 90, 5843–5847 (1993).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. 41

    Dufrane, D., Goebbels, R. M., Saliez, A., Guiot, Y. & Gianello, P. Six-month survival of microencapsulated pig islets and alginate biocompatibility in primates: proof of concept. Transplantation 81, 1345–1353 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  42. 42

    Elliott, R. B. et al. Intraperitoneal alginate-encapsulated neonatal porcine islets in a placebo-controlled study with 16 diabetic cynomolgus primates. Transplant. Proc. 37, 3505–3508 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. 43

    Storrs, R., Dorian, R., King, S. R., Lakey, J. & Rilo, H. Preclinical development of the Islet Sheet. Ann. NY Acad. Sci. 944, 252–266 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. 44

    Robertson, R. P. Islet transplantation as a treatment for diabetes — a work in progress. N. Engl. J. Med. 350, 694–705 (2004).

    CAS  Article  Google Scholar 

  45. 45

    Najjar, M. et al. Fibrin gels engineered with pro-angiogenic growth factors promote engraftment of pancreatic islets in extrahepatic sites in mice. Biotechnol. Bioeng. 112, 1916–1926 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. 46

    Pepper, A. R. et al. Diabetes is reversed in a murine model by marginal mass syngeneic islet transplantation using a subcutaneous cell pouch device. Transplantation 99, 2294–2300 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. 47

    Sernova Corp. Sernova's Cell Pouch System. Sernova http://www.sernova.com/technology (accessed 1 Nov 2016).

  48. 48

    Gu, Y. et al. Development of a new method to induce angiogenesis at subcutaneous site of streptozotocin-induced diabetic rats for islet transplantation. Cell Transplant. 10, 453–457 (2001).

    CAS  Article  Google Scholar 

  49. 49

    Wang, R. N. & Rosenberg, L. Maintenance of beta-cell function and survival following islet isolation requires re-establishment of the islet–matrix relationship. J. Endocrinol. 163, 181–190 (1999). Shows the importance of the microenvironment in islet function.

    CAS  Article  Google Scholar 

  50. 50

    Hauge-Evans, A. C., Squires, P. E., Persaud, S. J. & Jones, P. M. Pancreatic beta-cell-to-beta-cell interactions are required for integrated responses to nutrient stimuli: enhanced Ca2+ and insulin secretory responses of MIN6 pseudoislets. Diabetes 48, 1402–1408 (1999).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  51. 51

    Chowdhury, A., Dyachok, O., Tengholm, A., Sandler, S. & Bergsten, P. Functional differences between aggregated and dispersed insulin-producing cells. Diabetologia 56, 1557–1568 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. 52

    Nyitray, C. E., Chavez, M. G. & Desai, T. A. Compliant 3D microenvironment improves β-cell cluster insulin expression through mechanosensing and β-catenin signaling. Tissue Eng. Part A 20, 1888–1895 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. 53

    Dusseault, J. et al. Evaluation of alginate purification methods: effect on polyphenol, endotoxin, and protein contamination. J. Biomed. Mater. Res. A 76, 243–251 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Peterson, K. P., Peterson, C. M. & Pope, E. J. Silica sol-gel encapsulation of pancreatic islets. Proc. Soc. Exp. Biol. Med. 218, 365–369 (1998).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  55. 55

    Vegas, A. J. et al. Combinatorial hydrogel library enables identification of materials that mitigate the foreign body response in primates. Nat. Biotechnol. 34, 345–352 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  56. 56

    Vegas, A. J. et al. Long term glycemic control using polymer-encapsulated human stem cell-derived β cells in immune-competent mice. Nat. Med. 22, 306–311 (2016). Demonstration of long-term glycaemic control using a microencapsulation strategy in an immune-competent animal model.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  57. 57

    Pedraza, E., Coronel, M. M., Fraker, C. A., Ricordi, C. & Stabler, C. L. Preventing hypoxia-induced cell death in beta cells and islets via hydrolytically activated, oxygen-generating biomaterials. Proc. Natl Acad. Sci. USA 109, 4245–4250 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  58. 58

    Rokstad, A. M. et al. Alginate microbeads are complement compatible, in contrast to polycation containing microcapsules, as revealed in a human whole blood model. Acta Biomater. 7, 2566–2578 (2011).

    CAS  Article  Google Scholar 

  59. 59

    Mendelsohn, A. & Desai, T. Inorganic nanoporous membranes for immunoisolated cell-based drug delivery. Adv. Exp. Med. Biol. 670, 104–125 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. 60

    Allen, J. et al. Tunable microfibers suppress fibrotic encapsulation via inhibition of TGFβ signaling. Tissue Eng. Part A 22, 142–150 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  61. 61

    Mitsuo, M. et al. Efficacy of mesh reinforced polyvinylalcohol tube as a novel device for bioartificial pancreas: a functional study of rat islets in vivo. Transplant. Proc. 24, 2939–2940 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62

    Tomei, A. A. et al. Device design and materials optimization of conformal coating for islets of Langerhans. Proc. Natl Acad. Sci. USA 111, 10514–10519 (2014).

    CAS  Article  Google Scholar 

  63. 63

    Colton, C. K. Oxygen supply to encapsulated therapeutic cells. Adv. Drug Deliv. Rev. 67–68, 93–110 (2014). Comprehensive review of the oxygen requirements of encapsulation devices.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  64. 64

    Alberts, B. et al. Molecular Biology of the Cell (Garland Publishing, 1994).

    Google Scholar 

  65. 65

    Branden, C. & Tooze, J. Introduction to Protein Structure (Garland Publishing, 1991).

    Google Scholar 

  66. 66

    La Flamme, K. E., LaTempa, T. J., Grimes, C. A. & Desai, T. A. The effects of cell density and device arrangement on the behavior of macroencapsulated beta-cells. Cell Transplant. 16, 765–774 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  67. 67

    Sabek, O. M. et al. Characterization of a nanogland for the autotransplantation of human pancreatic islets. Lab. Chip 13, 3675–3688 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  68. 68

    Cantley, J., Grey, S. T., Maxwell, P. H. & Withers, D. J. The hypoxia response pathway and β-cell function. Diabetes Obes. Metab. 12 (Suppl. 2), 159–167 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  69. 69

    Ballian, N. & Brunicardi, F. C. Islet vasculature as a regulator of endocrine pancreas function. World J. Surg. 31, 705–714 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  70. 70

    Dionne, K. E., Colton, C. K. & Yarmush, M. L. Effect of hypoxia on insulin secretion by isolated rat and canine islets of Langerhans. Diabetes 42, 12–21 (1993).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  71. 71

    Sato, Y. et al. Cellular hypoxia of pancreatic β-cells due to high levels of oxygen consumption for insulin secretion in vitro. J. Biol. Chem. 286, 12524–12532 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  72. 72

    Dulong, J. L. & Legallais, C. A theoretical study of oxygen transfer including cell necrosis for the design of a bioartificial pancreas. Biotechnol. Bioeng. 96, 990–998 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  73. 73

    Papas, K. K., Avgoustiniatos, E. S. & Suszynski, T. M. Effect of oxygen supply on the size of implantable islet-containing encapsulation devices. Panminerva Med. 58, 72–77 (2016).

    PubMed  PubMed Central  Google Scholar 

  74. 74

    Suszynski, T. M., Avgoustiniatos, E. S. & Papas, K. K. Intraportal islet oxygenation. J. Diabetes Sci. Technol. 8, 575–580 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  75. 75

    Pileggi, A. et al. Reversal of diabetes by pancreatic islet transplantation into a subcutaneous, neovascularized device. Transplantation 81, 1318–1324 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  76. 76

    Pepper, A. R. et al. A prevascularized subcutaneous device-less site for islet and cellular transplantation. Nat. Biotechnol. 33, 518–523 (2015). Demonstration of prevascularization of encapsulation devices as a strategy to promote cell survival.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  77. 77

    Veriter, S. et al. Improvement of subcutaneous bioartificial pancreas vascularization and function by coencapsulation of pig islets and mesenchymal stem cells in primates. Cell Transplant. 23, 1349–1364 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  78. 78

    Zisch, A. H. et al. Cell-demanded release of VEGF from synthetic, biointeractive cell ingrowth matrices for vascularized tissue growth. FASEB J. 17, 2260–2262 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  79. 79

    Ehrbar, M. et al. Cell-demanded liberation of VEGF121 from fibrin implants induces local and controlled blood vessel growth. Circ. Res. 94, 1124–1132 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  80. 80

    Harrison, B. S., Eberli, D., Lee, S. J., Atala, A. & Yoo, J. J. Oxygen producing biomaterials for tissue regeneration. Biomaterials 28, 4628–4634 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  81. 81

    Oh, S. H., Ward, C. L., Atala, A., Yoo, J. J. & Harrison, B. S. Oxygen generating scaffolds for enhancing engineered tissue survival. Biomaterials 30, 757–762 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  82. 82

    Bloch, K. et al. Photosynthetic oxygen generator for bioartificial pancreas. Tissue Eng. 12, 337–344 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  83. 83

    Ludwig, B. et al. Transplantation of human islets without immunosuppression. Proc. Natl Acad. Sci. USA 110, 19054–19058 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  84. 84

    Wu, C. L., Lin, L. Y., Yang, J. S., Chan, M. C. & Hsueh, C. M. Attenuation of lipopolysaccharide-induced acute lung injury by treatment with IL-10. Respirology 14, 511–521 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  85. 85

    Trivedi, N., Steil, G. M., Colton, C. K., Bonner-Weir, S. & Weir, G. C. Improved vascularization of planar membrane diffusion devices following continuous infusion of vascular endothelial growth factor. Cell Transplant. 9, 115–124 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  86. 86

    Phelps, E. A., Templeman, K. L., Thule, P. M. & Garcia, A. J. Engineered VEGF-releasing PEG-MAL hydrogel for pancreatic islet vascularization. Drug Deliv. Transl Res. 5, 125–136 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  87. 87

    Krieger, J. R. et al. Spatially localized recruitment of anti-inflammatory monocytes by SDF-1α-releasing hydrogels enhances microvascular network remodeling. Biomaterials 77, 280–290 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. 88

    Kwee, B. J. & Mooney, D. J. Manipulating the intersection of angiogenesis and inflammation. Ann. Biomed. Eng. 43, 628–640 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  89. 89

    Chong, A. S. & Alegre, M. L. The impact of infection and tissue damage in solid-organ transplantation. Nat. Rev. Immunol. 12, 459–471 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  90. 90

    Falschlehner, C., Schaefer, U. & Walczak, H. Following TRAIL's path in the immune system. Immunology 127, 145–154 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  91. 91

    Pearl-Yafe, M. et al. The dual role of Fas-ligand as an injury effector and defense strategy in diabetes and islet transplantation. Bioessays 28, 211–222 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  92. 92

    Miller, S. D., Turley, D. M. & Podojil, J. R. Antigen-specific tolerance strategies for the prevention and treatment of autoimmune disease. Nat. Rev. Immunol. 7, 665–677 (2007).

    CAS  Article  Google Scholar 

  93. 93

    Lau, H. T., Yu, M., Fontana, A. & Stoeckert, C. J. Jr. Prevention of islet allograft rejection with engineered myoblasts expressing FasL in mice. Science 273, 109–112 (1996).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  94. 94

    Yolcu, E. S. et al. Pancreatic islets engineered with SA-FasL protein establish robust localized tolerance by inducing regulatory T cells in mice. J. Immunol. 187, 5901–5909 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  95. 95

    Su, J. et al. Anti-inflammatory peptide-functionalized hydrogels for insulin-secreting cell encapsulation. Biomaterials 31, 308–314 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  96. 96

    Elias, D. et al. Vaccination against autoimmune mouse diabetes with a T-cell epitope of the human 65-kDa heat shock protein. Proc. Natl Acad. Sci. USA 88, 3088–3091 (1991).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  97. 97

    Zanin-Zhorov, A. et al. Heat shock protein 60 enhances CD4+ CD25+ regulatory T cell function via innate TLR2 signaling. J. Clin. Invest. 116, 2022–2032 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  98. 98

    Takasaki, W., Kajino, Y., Kajino, K., Murali, R. & Greene, M. I. Structure-based design and characterization of exocyclic peptidomimetics that inhibit TNF α binding to its receptor. Nat. Biotechnol. 15, 1266–1270 (1997).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  99. 99

    Dumont, C. M., Park, J. & Shea, L. D. Controlled release strategies for modulating immune responses to promote tissue regeneration. J. Control. Release 219, 155–166 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  100. 100

    Cuff, C. A., Martiney, J. A., Berman, J. W. & Brosnan, C. F. Differential effects of transforming growth factor-β1 on interleukin-1-induced cellular inflammation and vascular permeability in the rabbit retina. J. Neuroimmunol. 70, 21–28 (1996).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  101. 101

    Martinez, F. O., Sica, A., Mantovani, A. & Locati, M. Macrophage activation and polarization. Front. Biosci. 13, 453–461 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  102. 102

    Tuch, B. E. et al. Safety and viability of microencapsulated human islets transplanted into diabetic humans. Diabetes Care 32, 1887–1889 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  103. 103

    Karin, N. The multiple faces of CXCL12 (SDF-1α) in the regulation of immunity during health and disease. J. Leukoc. Biol. 88, 463–473 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  104. 104

    Sanchez-Martin, L. et al. The chemokine CXCL12 regulates monocyte-macrophage differentiation and RUNX3 expression. Blood 117, 88–97 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  105. 105

    Chen, G. et al. Intragraft CD11b+IDO+ cells mediate cardiac allograft tolerance by ECDI-fixed donor splenocyte infusions. Am. J. Transplant. 12, 2920–2929 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  106. 106

    Bonnamain, V. et al. Expression of heme oxygenase-1 in neural stem/progenitor cells as a potential mechanism to evade host immune response. Stem Cells 30, 2342–2353 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  107. 107

    Nazmi, A., Mohamed Arif, I., Dutta, K., Kundu, K. & Basu, A. Neural stem/progenitor cells induce conversion of encephalitogenic T cells into CD4+-CD25+-FOXP3+ regulatory T cells. Viral Immunol. 27, 48–59 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  108. 108

    Wang, L. et al. Neural stem/progenitor cells modulate immune responses by suppressing T lymphocytes with nitric oxide and prostaglandin E2. Exp. Neurol. 216, 177–183 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  109. 109

    Chen, T. et al. Alginate encapsulant incorporating CXCL12 supports long-term allo- and xenoislet transplantation without systemic immune suppression. Am. J. Transplant. 15, 618–627 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  110. 110

    Montane, J. et al. CCL22 prevents rejection of mouse islet allografts and induces donor-specific tolerance. Cell Transplant. 24, 2143–2154 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  111. 111

    Liu, J. M. et al. Transforming growth factor-beta 1 delivery from microporous scaffolds decreases inflammation post-implant and enhances function of transplanted islets. Biomaterials 80, 11–19 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. 112

    Madden, L. R. et al. Proangiogenic scaffolds as functional templates for cardiac tissue engineering. Proc. Natl Acad. Sci. USA 107, 15211–15216 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  113. 113

    Yan, Z., Zhuansun, Y., Chen, R., Li, J. & Ran, P. Immunomodulation of mesenchymal stromal cells on regulatory T cells and its possible mechanism. Exp. Cell Res. 324, 65–74 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  114. 114

    Lee, S. et al. Analysis on migration and activation of live macrophages on transparent flat and nanostructured titanium. Acta Biomater. 7, 2337–2344 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  115. 115

    Cao, H., McHugh, K., Chew, S. Y. & Anderson, J. M. The topographical effect of electrospun nanofibrous scaffolds on the in vivo and in vitro foreign body reaction. J. Biomed. Mater. Res. A 93, 1151–1159 (2010).

    PubMed  PubMed Central  Google Scholar 

  116. 116

    Saino, E. et al. Effect of electrospun fiber diameter and alignment on macrophage activation and secretion of proinflammatory cytokines and chemokines. Biomacromolecules 12, 1900–1911 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  117. 117

    Veiseh, O. et al. Size- and shape-dependent foreign body immune response to materials implanted in rodents and non-human primates. Nat. Mater. 14, 643–651 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  118. 118

    Barbeau, D. J. et al. Early growth response-2 signaling mediates immunomodulatory effects of human multipotential stromal cells. Stem Cells Dev. 23, 155–166 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  119. 119

    English, K. Mechanisms of mesenchymal stromal cell immunomodulation. Immunol. Cell Biol. 91, 19–26 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  120. 120

    Luz-Crawford, P. et al. Mesenchymal stem cells generate a CD4+CD25+Foxp3+ regulatory T cell population during the differentiation process of Th1 and Th17 cells. Stem Cell Res. Ther. 4, 65 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  121. 121

    Obermajer, N. et al. Conversion of Th17 into IL-17Aneg regulatory T cells: a novel mechanism in prolonged allograft survival promoted by mesenchymal stem cell-supported minimized immunosuppressive therapy. J. Immunol. 193, 4988–4999 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  122. 122

    Ezquer, F. et al. The antidiabetic effect of mesenchymal stem cells is unrelated to their transdifferentiation potential but to their capability to restore Th1/Th2 balance and to modify the pancreatic microenvironment. Stem Cells 30, 1664–1674 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  123. 123

    Uccelli, A., Moretta, L. & Pistoia, V. Mesenchymal stem cells in health and disease. Nat. Rev. Immunol. 8, 726–736 (2008).

    CAS  Article  Google Scholar 

  124. 124

    Ding, Y. et al. Mesenchymal stem cells prevent the rejection of fully allogenic islet grafts by the immunosuppressive activity of matrix metalloproteinase-2 and -9. Diabetes 58, 1797–1806 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  125. 125

    Kerby, A., Jones, E. S., Jones, P. M. & King, A. J. Co-transplantation of islets with mesenchymal stem cells in microcapsules demonstrates graft outcome can be improved in an isolated-graft model of islet transplantation in mice. Cytotherapy 15, 192–200 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  126. 126

    Graham, J. G. et al. PLG scaffold delivered antigen-specific regulatory T cells induce systemic tolerance in autoimmune diabetes. Tissue Eng. Part A 19, 1465–1475 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  127. 127

    Marek, N. et al. Coating human pancreatic islets with CD4+CD25highCD127 regulatory T cells as a novel approach for the local immunoprotection. Ann. Surg. 254, 512–518 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  128. 128

    Caridade, M., Graca, L. & Ribeiro, R. M. Mechanisms underlying CD4+ Treg immune regulation in the adult: from experiments to models. Front. Immunol. 4, 378 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. 129

    Luo, X., Miller, S. D. & Shea, L. D. Immune tolerance for autoimmune disease and cell transplantation. Annu. Rev. Biomed. Eng. 18, 181–205 (2016). Discussion of current immune-tolerance strategies for cell therapies.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  130. 130

    Tang, Q. & Lee, K. Regulatory T-cell therapy for transplantation: how many cells do we need? Curr. Opin. Organ Transplant. 17, 349–354 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  131. 131

    Safinia, N., Scotta, C., Vaikunthanathan, T., Lechler, R. I. & Lombardi, G. Regulatory T cells: serious contenders in the promise for immunological tolerance in transplantation. Front. Immunol. 6, 438 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. 132

    Bluestone, J. A. et al. Type 1 diabetes immunotherapy using polyclonal regulatory T cells. Sci. Transl Med. 7, 315ra189 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. 133

    Putnam, A. L. et al. Clinical grade manufacturing of human alloantigen-reactive regulatory T cells for use in transplantation. Am. J. Transplant. 13, 3010–3020 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  134. 134

    Veerapathran, A., Pidala, J., Beato, F., Yu, X. Z. & Anasetti, C. Ex vivo expansion of human Tregs specific for alloantigens presented directly or indirectly. Blood 118, 5671–5680 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  135. 135

    Nagaraju, S. et al. Islet xenotransplantation from genetically engineered pigs. Curr. Opin. Organ Transplant. 18, 695–702 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  136. 136

    Hering, B. J. et al. Prolonged diabetes reversal after intraportal xenotransplantation of wild-type porcine islets in immunosuppressed nonhuman primates. Nat. Med. 12, 301–303 (2006). Demonstration of successful encapsulation of xenogeneic islets in a large animal model.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  137. 137

    Cardona, K. et al. Long-term survival of neonatal porcine islets in nonhuman primates by targeting costimulation pathways. Nat. Med. 12, 304–306 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  138. 138

    Shin, J. S. et al. Long-term control of diabetes in immunosuppressed nonhuman primates (NHP) by the transplantation of adult porcine islets. Am. J. Transplant. 15, 2837–2850 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  139. 139

    van der Windt, D. J. et al. Long-term controlled normoglycemia in diabetic non-human primates after transplantation with hCD46 transgenic porcine islets. Am. J. Transplant. 9, 2716–2726 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  140. 140

    Thompson, P. et al. Islet xenotransplantation using gal-deficient neonatal donors improves engraftment and function. Am. J. Transplant. 11, 2593–2602 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  141. 141

    Thompson, P. et al. Alternative immunomodulatory strategies for xenotransplantation: CD40/154 pathway-sparing regimens promote xenograft survival. Am. J. Transplant. 12, 1765–1775 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  142. 142

    Thompson, P. et al. CD40-specific costimulation blockade enhances neonatal porcine islet survival in nonhuman primates. Am. J. Transplant. 11, 947–957 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  143. 143

    Bottino, R. et al. Pig-to-monkey islet xenotransplantation using multi-transgenic pigs. Am. J. Transplant. 14, 2275–2287 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  144. 144

    Hawthorne, W. J. et al. Control of IBMIR in neonatal porcine islet xenotransplantation in baboons. Am. J. Transplant. 14, 1300–1309 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  145. 145

    Lowe, M. et al. A novel monoclonal antibody to CD40 prolongs islet allograft survival. Am. J. Transplant. 12, 2079–2087 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  146. 146

    Gibly, R. F. et al. Advancing islet transplantation: from engraftment to the immune response. Diabetologia 54, 2494–2505 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  147. 147

    Dufrane, D., Goebbels, R. M. & Gianello, P. Alginate macroencapsulation of pig islets allows correction of streptozotocin-induced diabetes in primates up to 6 months without immunosuppression. Transplantation 90, 1054–1062 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  148. 148

    Hecht, G. et al. Embryonic pig pancreatic tissue for the treatment of diabetes in a nonhuman primate model. Proc. Natl Acad. Sci. USA 106, 8659–8664 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  149. 149

    Hering, B. J. & Walawalkar, N. Pig-to-nonhuman primate islet xenotransplantation. Transpl. Immunol. 21, 81–86 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  150. 150

    Cui, H. et al. Long-term metabolic control of autoimmune diabetes in spontaneously diabetic nonobese diabetic mice by nonvascularized microencapsulated adult porcine islets. Transplantation 88, 160–169 (2009).

    Article  Google Scholar 

  151. 151

    Cowan, P. J., Ayares, D., Wolf, E. & Cooper, D. K. First update of the International Xenotransplantation Association consensus statement on conditions for undertaking clinical trials of porcine islet products in type 1 diabetes — chapter 2b: genetically modified source pigs. Xenotransplantation 23, 32–37 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  152. 152

    Cooper, D. K., Ekser, B., Ramsoondar, J., Phelps, C. & Ayares, D. The role of genetically engineered pigs in xenotransplantation research. J. Pathol. 238, 288–299 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  153. 153

    Ellis, C., Lyon, J. G. & Korbutt, G. S. Optimization and scale-up isolation and culture of neonatal porcine islets: potential for clinical application. Cell Transplant. 25, 539–547 (2015). Discusses the current issues associated with the use of porcine islets in cell-based therapy.

    Article  Google Scholar 

  154. 154

    Pagliuca, F. W. et al. Generation of functional human pancreatic β cells in vitro. Cell 159, 428–439 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  155. 155

    Russ, H. A. et al. Controlled induction of human pancreatic progenitors produces functional beta-like cells in vitro. EMBO J. 34, 1759–1772 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  156. 156

    Rezania, A. et al. Reversal of diabetes with insulin-producing cells derived in vitro from human pluripotent stem cells. Nat. Biotechnol. 32, 1121–1133 (2014).

    CAS  Article  Google Scholar 

  157. 157

    Rezania, A. et al. Maturation of human embryonic stem cell-derived pancreatic progenitors into functional islets capable of treating pre-existing diabetes in mice. Diabetes 61, 2016–2029 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  158. 158

    D'Amour, K. A. et al. Efficient differentiation of human embryonic stem cells to definitive endoderm. Nat. Biotechnol. 23, 1534–1541 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  159. 159

    D'Amour, K. A. et al. Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells. Nat. Biotechnol. 24, 1392–1401 (2006). Development of stem cell-derived endocrine cells for hormone production.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  160. 160

    Kroon, E. et al. Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. Nat. Biotechnol. 26, 443–452 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  161. 161

    Bruin, J. E. et al. Maturation and function of human embryonic stem cell-derived pancreatic progenitors in macroencapsulation devices following transplant into mice. Diabetologia 56, 1987–1998 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  162. 162

    Kirk, K., Hao, E., Lahmy, R. & Itkin-Ansari, P. Human embryonic stem cell derived islet progenitors mature inside an encapsulation device without evidence of increased biomass or cell escape. Stem Cell Res. 12, 807–814 (2014).

    CAS  Article  Google Scholar 

  163. 163

    Motte, E. et al. Composition and function of macroencapsulated human embryonic stem cell-derived implants: comparison with clinical human islet cell grafts. Am. J. Physiol. Endocrinol. Metab. 307, E838–E846 (2014).

    CAS  Article  Google Scholar 

  164. 164

    Rezania, A. et al. Enrichment of human embryonic stem cell-derived NKX6.1-expressing pancreatic progenitor cells accelerates the maturation of insulin-secreting cells in vivo. Stem Cells 31, 2432–2442 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  165. 165

    Ariyachet, C. et al. Reprogrammed stomach tissue as a renewable source of functional β cells for blood glucose regulation. Cell Stem Cell 18, 410–421 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  166. 166

    Weizman, A., Michael, I., Wiesel-Motiuk, N., Rezania, A. & Levenberg, S. The effect of endothelial cells on hESC-derived pancreatic progenitors in a 3D environment. Biomater. Sci. 2, 1706–1714 (2014).

    CAS  Article  Google Scholar 

  167. 167

    Basta, G. et al. Long-term metabolic and immunological follow-up of nonimmunosuppressed patients with type 1 diabetes treated with microencapsulated islet allografts: four cases. Diabetes Care 34, 2406–2409 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  168. 168

    Calafiore, R. et al. Microencapsulated pancreatic islet allografts into nonimmunosuppressed patients with type 1 diabetes: first two cases. Diabetes Care 29, 137–138 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  169. 169

    Calafiore, R. et al. Standard technical procedures for microencapsulation of human islets for graft into nonimmunosuppressed patients with type 1 diabetes mellitus. Transplant. Proc. 38, 1156–1157 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  170. 170

    Barkai, U. et al. Enhanced oxygen supply improves islet viability in a new bioartificial pancreas. Cell Transplant. 22, 1463–1476 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  171. 171

    Neufeld, T. et al. The efficacy of an immunoisolating membrane system for islet xenotransplantation in minipigs. PLoS ONE 8, e70150 (2013). Development of macroencapsulation device for xenotransplantation.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  172. 172

    Thomlinson, R. H. & Gray, L. H. The histological structure of some human lung cancers and the possible implications for radiotherapy. Br. J. Cancer 9, 539–549 (1955).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  173. 173

    Sorenby, A. K. et al. Macroencapsulation protects against sensitization after allogeneic islet transplantation in rats. Transplantation 82, 393–397 (2006).

    Article  CAS  Google Scholar 

  174. 174

    Sorenby, A. K. et al. Preimplantation of an immunoprotective device can lower the curative dose of islets to that of free islet transplantation: studies in a rodent model. Transplantation 86, 364–366 (2008).

    Article  Google Scholar 

  175. 175

    Kumagai-Braesch, M. et al. The TheraCyte device protects against islet allograft rejection in immunized hosts. Cell Transplant. 22, 1137–1146 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  176. 176

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/results/NCT02239354 (2015).

  177. 177

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01652911 (2016).

  178. 178

    Berman, D. M. et al. Bioengineering the endocrine pancreas: intraomental islet transplantation within a biologic resorbable scaffold. Diabetes 65, 1350–1361 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  179. 179

    Willems, C. & Vankelecom, H. Pituitary cell differentiation from stem cells and other cells: toward restorative therapy for hypopituitarism? Regen. Med. 9, 513–534 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  180. 180

    Shea, L. D., Woodruff, T. K. & Shikanov, A. Bioengineering the ovarian follicle microenvironment. Annu. Rev. Biomed. Eng. 16, 29–52 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  181. 181

    Bao, Q. et al. Aging and age-related diseases — from endocrine therapy to target therapy. Mol. Cell. Endocrinol. 394, 115–118 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  182. 182

    Stover, N. P. & Watts, R. L. Spheramine for treatment of Parkinson's disease. Neurotherapeutics 5, 252–259 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  183. 183

    Bloch, J. et al. Neuroprotective gene therapy for Huntington's disease, using polymer-encapsulated cells engineered to secrete human ciliary neurotrophic factor: results of a phase I study. Hum. Gene Ther. 15, 968–975 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  184. 184

    Yu, J. et al. The use of human mesenchymal stem cells encapsulated in RGD modified alginate microspheres in the repair of myocardial infarction in the rat. Biomaterials 31, 7012–7020 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  185. 185

    Zhang, H., Zhu, S. J., Wang, W., Wei, Y. J. & Hu, S. S. Transplantation of microencapsulated genetically modified xenogeneic cells augments angiogenesis and improves heart function. Gene Ther. 15, 40–48 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  186. 186

    Goren, A., Dahan, N., Goren, E., Baruch, L. & Machluf, M. Encapsulated human mesenchymal stem cells: a unique hypoimmunogenic platform for long-term cellular therapy. FASEB J. 24, 22–31 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. 187

    Dubrot, J. et al. Delivery of immunostimulatory monoclonal antibodies by encapsulated hybridoma cells. Cancer Immunol. Immunother. 59, 1621–1631 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  188. 188

    Mellor, A. L. & Munn, D. H. Creating immune privilege: active local suppression that benefits friends, but protects foes. Nat. Rev. Immunol. 8, 74–80 (2008). Reviews strategies for local immune modulation.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  189. 189

    Glotz, D. & Tambur, A. Stratifying patients based on epitope mismatching: ready for primetime? Am. J. Transplant. 15, 2021–2022 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  190. 190

    Spierings, E. Minor histocompatibility antigens: past, present, and future. Tissue Antigens 84, 374–360 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. 191

    Yuan, R. et al. Erythropoietin: a potent inducer of peripheral immuno/inflammatory modulation in autoimmune EAE. PLoS ONE 3, e1924 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. 192

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01652911 (2016).

  193. 193

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01739829 (2014).

  194. 194

    US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT00790257 (2016).

  195. 195

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01379729 (2013).

  196. 196

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02239354 (2015).

  197. 197

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02064309 (2016).

  198. 198

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02213003 (2016).

Download references

Acknowledgements

Financial support for this work was provided by R01EB009910 (L.D.S.) and JDRF (T.D. and L.D.S.).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Tejal Desai.

Ethics declarations

Competing interests

L.D.S. has financial interests in Cour Pharmaceuticals Development Co. T.D. is a scientific founder of Encellin Inc., a cell therapy device company. The University of California, San Francisco (UCSF) has filed a provisional patent application on a macroencapsulation technology for cell-based therapy.

PowerPoint slides

Glossary

Type 1 diabetes

(T1D). A chronic condition of aberrant glucose homeostasis that is characterized by a severe deficiency of insulin secretion resulting from atrophy of the islets of Langerhans.

β-Cells

Insulin-secreting cells of the islets of Langerhans.

Hyperglycaemia

Elevated blood glucose above normal levels.

Hypoglycaemia

Suppressed blood glucose below normal levels.

Immunosuppression

Suppression (such as, by drugs or disease) of the immune response.

Xenogeneic

Derived from, originating in or being a member of another species.

Encapsulation

To surround, encase or protect in or as if in a capsule.

Normoglycaemia

The presence of a normal concentration of glucose in the blood.

Vascularization

The formation of blood vessels.

Syngeneic

Involving, derived from, or being genetically identical or similar individuals of the same species, especially with respect to antigenic interaction.

Allogeneic

Involving, derived from or being individuals of the same species that are sufficiently genetically dissimilar to interact antigenically.

Fibrosis

A condition marked by an increase in interstitial fibrous or scar tissue.

Immunogenicity

The ability of a particular substance to provoke an immune response in the body of a human or an animal.

Hypoxia

A deficiency of oxygen reaching the tissues of the body.

Self-tolerance

The failure to mount an immune response to a person's own proteins and other antigens.

Cytokines

Members of a class of immunoregulatory proteins (interleukin or interferon) that are secreted by cells especially of the immune system.

Regulatory T cells

(Treg cells). A subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens and prevent autoimmune disease.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Desai, T., Shea, L. Advances in islet encapsulation technologies. Nat Rev Drug Discov 16, 338–350 (2017). https://doi.org/10.1038/nrd.2016.232

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing