Clinical Applications of Cell Encapsulation Technology

  • Edorta Santos-Vizcaino
  • Gorka Orive
  • Jose Luis Pedraz
  • Rosa Maria HernandezEmail author
Part of the Methods in Molecular Biology book series (MIMB, volume 2100)


Cell encapsulation comprises immunoisolation three-dimensional systems for housing therapeutic cells that secrete bioactive compounds de novo and in a sustained manner. This allows transplantation of multiple allo- or xenogeneic cells without the aid of immunosuppressant drugs. Recent advances in the field have provided improvements to these cell-based drug delivery systems, which have gained the attention of the scientific community and inspired many biotechnological companies to develop their own product candidates. From micro- to macroencapsulation devices, this chapter describes some of the most important approaches that are being currently tested in late-stage clinical trials and are likely to reach the market as future game changers. Most studies involve the treatment of diabetes, eye disorders, and diseases of the central nervous system. However, many other pathologies are also amenable to benefit from this technology. Latest advances to overcome major pending challenges related to biosafety and efficacy are also discussed.

Key words

Cell encapsulation Clinical trials Cell therapy Drug delivery Immunoisolation devices 


  1. 1.
    Spector M (2018) Biomedical materials to meet the challenges of the aging epidemic. Biomed Mater 13:030201PubMedCrossRefGoogle Scholar
  2. 2.
    Annabi N, Tamayol A, Uquillas JA, Akbari M, Bertassoni LE, Cha C, Camci-Unal G, Dokmeci MR, Peppas NA, Khademhosseini A (2014) 25th anniversary article: rational design and applications of hydrogels in regenerative medicine. Adv Mater 26:85–124PubMedCrossRefGoogle Scholar
  3. 3.
    de Vos P, Lazarjani HA, Poncelet D, Faas MM (2014) Polymers in cell encapsulation from an enveloped cell perspective. Adv Drug Deliv Rev 67:15–34PubMedCrossRefGoogle Scholar
  4. 4.
    Santos E, Orive G, Calvo A, Catena R, Fernández-Robredo P, Layana AG, Hernández RM, Pedraz JL (2012) Optimization of 100 μm alginate-poly-l-lysine-alginate capsules for intravitreous administration. J Control Release 158:443–450PubMedCrossRefGoogle Scholar
  5. 5.
    Veiseh O, Doloff JC, Ma M, Vegas AJ, Tam HH, Bader AR, Li J, Langan E, Wyckoff J, Loo WS, Jhunjhunwala S, Chiu A, Siebert S, Tang K, Hollister-Lock J, Aresta-Dasilva S, Bochenek M, Mendoza-Elias J, Wang Y, Qi M, Lavin DM, Chen M, Dholakia N, Thakrar R, Lacik I, Weir GC, Oberholzer J, Greiner DL, Langer R, Anderson DG (2015) Size- and shape-dependent foreign body immune response to materials implanted in rodents and non-human primates. Nat Mater 14:643–651PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Eyjolfsdottir H, Eriksdotter M, Linderoth B, Lind G, Juliusson B, Kusk P, Almkvist O, Andreasen N, Blennow K, Ferreira D, Westman E, Nennesmo I, Karami A, Darreh-Shori T, Kadir A, Nordberg A, Sundström E, Wahlund LO, Wall A, Wiberg M, Winblad B, Seiger Å, Wahlberg L, Almqvist P (2016) Targeted delivery of nerve growth factor to the cholinergic basal forebrain of Alzheimer’s disease patients: application of a second-generation encapsulated cell biodelivery device. Alzheimers Res Ther 8:30PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Lathuiliere A, Laversenne V, Astolfo A, Kopetzki E, Jacobsen H, Stampanoni M, Bohrmann B, Schneider BL, Aebischer P (2016) A subcutaneous cellular implant for passive immunization against amyloid-beta reduces brain amyloid and tau pathologies. Brain 139:1587–1604PubMedCrossRefGoogle Scholar
  8. 8.
    Neufeld T, Ludwig B, Barkai U, Weir GC, Colton CK, Evron Y, Balyura M, Yavriyants K, Zimermann B, Azarov D, Maimon S, Shabtay N, Rozenshtein T, Lorber D, Steffen A, Willenz U, Bloch K, Vardi P, Taube R, de Vos P, Lewis EC, Bornstein SR, Rotem A (2013) The efficacy of an immunoisolating membrane system for islet xenotransplantation in minipigs. PLoS One 8:e70150PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Ludwig B, Rotem A, Schmid J, Weir GC, Colton CK, Brendel MD, Neufeld T, Block NL, Yavriyants K, Steffen A, Ludwig S, Chavakis T, Reichel A, Azarov D, Zimermann B, Maimon S, Balyura M, Rozenshtein T, Shabtay N, Vardi P, Bloch K, de Vos P, Schally AV, Bornstein SR, Barkai U (2012) Improvement of islet function in a bioartificial pancreas by enhanced oxygen supply and growth hormone releasing hormone agonist. Proc Natl Acad Sci U S A 109:5022–5027PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Agulnick AD, Ambruzs DM, Moorman MA, Bhoumik A, Cesario RM, Payne JK, Kelly JR, Haakmeester C, Srijemac R, Wilson AZ, Kerr J, Frazier MA, Kroon EJ, D’Amour KA (2015) Insulin-producing endocrine cells differentiated in vitro from human embryonic stem cells function in macroencapsulation devices in vivo. Stem Cells Transl Med 4:1214–1222PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Kumagai-Braesch M, Jacobson S, Mori H, Jia X, Takahashi T, Wernerson A, Flodstrom-Tullberg M, Tibell A (2013) The TheraCyte device protects against islet allograft rejection in immunized hosts. Cell Transplant 22:1137–1146PubMedCrossRefGoogle Scholar
  12. 12.
    Olabisi RM (2015) Cell microencapsulation with synthetic polymers. J Biomed Mater Res A 103:846–859PubMedCrossRefGoogle Scholar
  13. 13.
    Uludag H, De Vos P, Tresco PA (2000) Technology of mammalian cell encapsulation. Adv Drug Deliv Rev 42:29–64PubMedCrossRefGoogle Scholar
  14. 14.
    Fjord-Larsen L, Kusk P, Torp M, Sørensen JCH, Ettrup K, Bjarkam CR, Tornøe J, Juliusson B, Wahlberg LU (2012) Encapsulated cell biodelivery of transposon-mediated high-dose NGF to the Göttingen mini pig basal forebrain. Open Tissue Eng Regen Med J 5:35–42CrossRefGoogle Scholar
  15. 15.
    Cornolti R, Figliuzzi M, Remuzzi A (2009) Effect of micro- and macroencapsulation on oxygen consumption by pancreatic islets. Cell Transplant 18:195–201PubMedCrossRefGoogle Scholar
  16. 16.
    del Burgo LS, Ciriza J, Espona-Noguera A, Illa X, Cabruja E, Orive G, Hernández RM, Villa R, Pedraz JL, Alvarez M (2018) 3D printed porous polyamide macrocapsule combined with alginate microcapsules for safer cell-based therapies. Sci Rep 8:8512CrossRefGoogle Scholar
  17. 17.
    Paredes Juárez GA, Spasojevic M, Faas MM, de Vos P (2014) Immunological and technical considerations in application of alginate-based microencapsulation systems. Front Bioeng Biotechnol 2:26PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Krishnamurthy N, Gimi B (2011) Encapsulated cell grafts to treat cellular deficiencies and dysfunction. Crit Rev Biomed Eng 39(6):473–491PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Nafea EH, Marson A, Poole-Warren LA, Martens PJ (2011) Immunoisolating semi-permeable membranes for cell encapsulation: focus on hydrogels. J Control Release 154:110–122PubMedCrossRefGoogle Scholar
  20. 20.
    Vaithilingam V, Tuch BE (2011) Islet transplantation and encapsulation: an update on recent developments. Rev Diabet Stud 8:51–67PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    An D, Chiu A, Flanders JA, Song W, Shou D, Lu YC, Grunnet LG, Winkel L, Ingvorsen C, Christophersen NS, Fels JJ, Sand FW, Ji Y, Qi L, Pardo Y, Luo D, Silberstein M, Fan J, Ma M (2018) Designing a retrievable and scalable cell encapsulation device for potential treatment of type 1 diabetes. Proc Natl Acad Sci U S A 115:E263–E272PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Song S, Roy S (2016) Progress and challenges in macroencapsulation approaches for type 1 diabetes (T1D) treatment: cells, biomaterials, and devices. Biotechnol Bioeng 113:1381–1402PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Farina M, Alexander JF, Thekkedath U, Ferrari M, Grattoni A (2019) Cell encapsulation: overcoming barriers in cell transplantation in diabetes and beyond. Adv Drug Deliv Rev 139:92–115PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Dimitrioglou N, Kanelli M, Papageorgiou E, Karatzas T, Hatziavramidis D (2019) Paving the way for successful islet encapsulation. Drug Discov Today 24(3):737–748. Scholar
  25. 25.
    Orive G, Emerich D, Khademhosseini A, Matsumoto S, Hernández R, Pedraz J, Desai T, Calafiore R, de Vos P (2018) Engineering a clinically translatable bioartificial pancreas to treat type I diabetes. Trends Biotechnol 36:445–456PubMedCrossRefGoogle Scholar
  26. 26.
    Soon-Shiong P, Heintz RE, Merideth N, Yao QX, Yao Z, Zheng T, Murphy M, Moloney MK, Schmehl M, Harris M, Mendez R, Mendez R, Sandford PA (1994) Insulin independence in a type 1 diabetic patient after encapsulated islet transplantation. Lancet 343:950–951PubMedCrossRefGoogle Scholar
  27. 27.
    Elliott RB, Escobar L, Tan PLJ, Muzina M, Zwain S, Buchanan C (2007) Live encapsulated porcine islets from a type 1 diabetic patient 9.5 yr after xenotransplantation. Xenotransplantation 14:157–161PubMedCrossRefGoogle Scholar
  28. 28.
    Calafiore R, Basta G, Luca G, Lemmi A, Montanucci MP, Calabrese G, Racanicchi L, Mancuso F, Brunetti P (2006) Microencapsulated pancreatic islet allografts into nonimmunosuppressed patients with type 1 diabetes: first two cases. Diabetes Care 29:137–138PubMedCrossRefGoogle Scholar
  29. 29.
    Basta G, Montanucci P, Luca G, Boselli C, Noya G, Barbaro B, Qi M, Kinzer KP, Oberholzer J, Calafiore R (2011) Long-term metabolic and immunological follow-up of nonimmunosuppressed patients with type 1 diabetes treated with microencapsulated islet allografts: four cases. Diabetes Care 34:2406–2409PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Tuch BE, Keogh GW, Williams LJ, Wu W, Foster JL, Vaithilingam V, Philips R (2009) Safety and viability of microencapsulated human islets transplanted into diabetic humans. Diabetes Care 32:1887–1889PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Living Cell Technologies (LCT). December 2019
  32. 32.
    Diatranz Otsuka Ltd (DOL). December 2019
  33. 33.
    Hillberg AL, Kathirgamanathan K, Lam JB, Law LY, Garkavenko O, Elliott RB (2013) Improving alginate-poly-L-ornithine-alginate capsule biocompatibility through genipin crosslinking. J Biomed Mater Res B Appl Biomater 101(2):258–268. Scholar
  34. 34.
    Open-label investigation of the safety and effectiveness of DIABECELL® in patients with Type I diabetes mellitus. December 2019
  35. 35.
    Open-label investigation of the safety and effectiveness of DIABECELL® in patients with type 1 diabetes mellitus. December 2019
  36. 36.
    Open-label Investigation of the safety and effectiveness of DIABECELL® in patients with type 1 diabetes mellitus. December 2019
  37. 37.
    Matsumoto S, Abalovich A, Wechsler C, Wynyard S, Elliott RB (2016) Clinical benefit of islet xenotransplantation for the treatment of type 1 diabetes. EBioMedicine 12:255–262PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Morozov VA, Wynyard S, Matsumoto S, Abalovich A, Denner J, Elliott R (2017) No PERV transmission during a clinical trial of pig islet cell transplantation. Virus Res 227:34–40PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Sernova Corp. December 2019
  40. 40.
    Pepper AR, Pawlick R, Gala-Lopez B, MacGillivary A, Mazzuca DM, White DJ, Toleikis PM, Shapiro AM (2015) Diabetes is reversed in a murine model by marginal mass syngeneic islet transplantation using a subcutaneous cell pouch device. Transplantation 99:2294–2300PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Pepper AR, Pawlick R, Bruni A, Wink J, Rafiei Y, O’Gorman D, Yan-Do R, Gala-Lopez B, Kin T, MacDonald PE (2017) Transplantation of human pancreatic endoderm cells reverses diabetes post transplantation in a prevascularized subcutaneous site. Stem Cell Reports 8:1689–1700PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    A Phase I/II study of the safety and efficacy of Sernova’s Cell Pouch™ for therapeutic islet transplantation. December 2019
  43. 43.
    A safety, tolerability and efficacy study of Sernova’s Cell Pouch™ for clinical islet transplantation. December 2019
  44. 44.
    ViaCyte, Inc. December 2019
  45. 45.
    D’Amour KA, Agulnick AD, Eliazer S, Kelly OG, Kroon E, Baetge EE (2005) Efficient differentiation of human embryonic stem cells to definitive endoderm. Nat Biotechnol 23:1534PubMedCrossRefGoogle Scholar
  46. 46.
    D’Amour KA, Bang AG, Eliazer S, Kelly OG, Agulnick AD, Smart NG, Moorman MA, Kroon E, Carpenter MK, Baetge EE (2006) Production of pancreatic hormone–expressing endocrine cells from human embryonic stem cells. Nat Biotechnol 24:1392PubMedCrossRefGoogle Scholar
  47. 47.
    Kelly OG, Chan MY, Martinson LA, Kadoya K, Ostertag TM, Ross KG, Richardson M, Carpenter MK, D’Amour KA, Kroon E (2011) Cell-surface markers for the isolation of pancreatic cell types derived from human embryonic stem cells. Nat Biotechnol 29:750PubMedCrossRefGoogle Scholar
  48. 48.
    Schulz TC, Young HY, Agulnick AD, Babin MJ, Baetge EE, Bang AG, Bhoumik A, Cepa I, Cesario RM, Haakmeester C (2012) A scalable system for production of functional pancreatic progenitors from human embryonic stem cells. PLoS One 7:e37004PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Kroon E, Martinson LA, Kadoya K, Bang AG, Kelly OG, Eliazer S, Young H, Richardson M, Smart NG, Cunningham J (2008) Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. Nat Biotechnol 26:443PubMedCrossRefGoogle Scholar
  50. 50.
    Rezania A, Bruin JE, Arora P, Rubin A, Batushansky I, Asadi A, O’dwyer S, Quiskamp N, Mojibian M, Albrecht T (2014) Reversal of diabetes with insulin-producing cells derived in vitro from human pluripotent stem cells. Nat Biotechnol 32:1121PubMedCrossRefGoogle Scholar
  51. 51.
    van der Torren, Cornelis R, Zaldumbide A, Duinkerken G, Brand-Schaaf SH, Peakman M, Stangé G, Martinson L, Kroon E, Brandon EP, Pipeleers D (2017) Immunogenicity of human embryonic stem cell-derived beta cells. Diabetologia 60:126–133PubMedCrossRefGoogle Scholar
  52. 52.
    A Safety, Tolerability, and efficacy study of VC-01™ combination product in subjects with Type I diabetes mellitus. December 2019
  53. 53.
    Semma Therapeutics. December 2019
  54. 54.
    Millman JR, Xie C, Van Dervort A, Gürtler M, Pagliuca FW, Melton DA (2016) Generation of stem cell-derived β-cells from patients with type 1 diabetes. Nat Commun 7:11463PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Veres A, Faust AL, Bushnell HL, Engquist EN, Kenty JH, Harb G, Poh Y, Sintov E, Gürtler M, Pagliuca FW (2019) Charting cellular identity during human in vitro β-cell differentiation. Nature 569:368PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Ludwig B, Ludwig S, Steffen A, Knauf Y, Zimerman B, Heinke S, Lehmann S, Schubert U, Schmid J, Bleyer M, Schonmann U, Colton CK, Bonifacio E, Solimena M, Reichel A, Schally AV, Rotem A, Barkai U, Grinberg-Rashi H, Kaup FJ, Avni Y, Jones P, Bornstein SR (2017) Favorable outcome of experimental islet xenotransplantation without immunosuppression in a nonhuman primate model of diabetes. Proc Natl Acad Sci U S A 114:11745–11750PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Ludwig B, Reichel A, Steffen A, Zimerman B, Schally AV, Block NL, Colton CK, Ludwig S, Kersting S, Bonifacio E, Solimena M, Gendler Z, Rotem A, Barkai U, Bornstein SR (2013) Transplantation of human islets without immunosuppression. Proc Natl Acad Sci U S A 110:19054–19058PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Carlsson P, Espes D, Sedigh A, Rotem A, Zimerman B, Grinberg H, Goldman T, Barkai U, Avni Y, Westermark GT (2018) Transplantation of macroencapsulated human islets within the bioartificial pancreas βAir to patients with type 1 diabetes mellitus. Am J Transplant 18:1735–1744PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Beta-O2 Technologies Ltd. December 2019
  60. 60.
    Sneddon JB, Tang Q, Stock P, Bluestone JA, Roy S, Desai T, Hebrok M (2018) Stem cell therapies for treating diabetes: progress and remaining challenges. Cell Stem Cell 22:810–823PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Orive G, Santos-Vizcaino E, Pedraz JL, Hernandez RM, Ramirez JEV, Dolatshahi-Pirouz A, Khademhosseini A, Peppas NA, Emerich DF (2019) 3D cell-laden polymers to release bioactive products in the eye. Prog Retin Eye Res 68:67–82PubMedCrossRefGoogle Scholar
  62. 62.
    Neurotech Pharmaceuticals, Inc. December 2019
  63. 63.
    Tao W, Wen R, Goddard MB, Sherman SD, O’Rourke PJ, Stabila PF, Bell WJ, Dean BJ, Kauper KA, Budz VA (2002) Encapsulated cell-based delivery of CNTF reduces photoreceptor degeneration in animal models of retinitis pigmentosa. Invest Ophthalmol Vis Sci 43:3292–3298PubMedGoogle Scholar
  64. 64.
    Ciliary Neurotrophic Factor (CNTF) Safety trial in patients with macular telangiectasia (Mactel). December 2019
  65. 65.
    Chew EY, Clemons TE, Peto T, Sallo FB, Ingerman A, Tao W, Singerman L, Schwartz SD, Peachey NS, Bird AC (2015) Ciliary neurotrophic factor for macular telangiectasia type 2: results from a Phase 1 safety trial. Am J Ophthalmol 159:659–666.e1PubMedCrossRefGoogle Scholar
  66. 66.
    Clemons TE, Chew EY, Peto T, Sallo FB, Leung I (2016) Ciliary neurotrophic factor for macular telangiectasia type 2: 48 month results from the Phase 1 safety trial. In: Investigative ophthalmology and visual science conference: 2016 annual meeting of the Association for Research in Vision and Ophthalmology, ARVO 2016 United States, vol 57, p 2038Google Scholar
  67. 67.
    A Phase 2 multicenter randomized clinical trial of CNTF for MacTel. December 2019
  68. 68.
    Chew EY, Clemons TE, Jaffe GJ, Johnson CA, Farsiu S, Lad EM, Guymer R, Rosenfeld P, Hubschman J, Constable I, Wiley H, Singerman LJ, Gillies M, Comer G, Blodi B, Eliott D, Yan J, Bird A, Friedlander M (2019) Effect of ciliary neurotrophic factor on retinal neurodegeneration in patients with macular telangiectasia type 2: a randomized clinical trial. Ophthalmology 126:540–549PubMedCrossRefGoogle Scholar
  69. 69.
    A study to determine the safety and efficacy of Renexus® in macular telangiectasia Type 2. December 2019
  70. 70.
    A study to determine the safety and efficacy of Renexus® in macular telangiectasia Type 2. December 2019
  71. 71.
    Shpak AA, Guekht AB, Druzhkova TA, Kozlova KI, Gulyaeva NV (2017) Ciliary neurotrophic factor in patients with primary open-angle glaucoma and age-related cataract. Mol Vis 23:799–809PubMedPubMedCentralGoogle Scholar
  72. 72.
    NT-501 CNTF implant for glaucoma: safety, neuroprotection and neuroenhancement. December 2019
  73. 73.
    Study of NT-501 encapsulated cell therapy for glaucoma neuroprotection and vision restoration. December 2019
  74. 74.
    Zhang K, Hopkins JJ, Heier JS, Birch DG, Halperin LS, Albini TA, Brown DM, Jaffe GJ, Tao W, Williams GA (2011) Ciliary neurotrophic factor delivered by encapsulated cell intraocular implants for treatment of geographic atrophy in age-related macular degeneration. Proc Natl Acad Sci U S A 108:6241–6245PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Birch DG, Weleber RG, Duncan JL, Jaffe GJ, Tao W, Ciliary Neurotrophic Factor Retinitis Pigmentosa Study Groups (2013) Randomized trial of ciliary neurotrophic factor delivered by encapsulated cell intraocular implants for retinitis pigmentosa. Am J Ophthalmol 156:283–292.e1PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Talcott KE, Ratnam K, Sundquist SM, Lucero AS, Lujan BJ, Tao W, Porco TC, Roorda A, Duncan JL (2011) Longitudinal study of cone photoreceptors during retinal degeneration and in response to ciliary neurotrophic factor treatment. Invest Ophthalmol Vis Sci 52:2219–2226PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Kauper K, McGovern C, Sherman S, Heatherton P, Rapoza R, Stabila P, Dean B, Lee A, Borges S, Bouchard B (2012) Two-year intraocular delivery of ciliary neurotrophic factor by encapsulated cell technology implants in patients with chronic retinal degenerative diseases. Invest Ophthalmol Vis Sci 53:7484–7491PubMedCrossRefGoogle Scholar
  78. 78.
    Luo XM, Lin H, Wang W, Geaney MS, Law L, Wynyard S, Shaikh SB, Waldvogel H, Faull RL, Elliott RB, Skinner SJ, Lee JE, Tan PL (2013) Recovery of neurological functions in non-human primate model of Parkinson’s disease by transplantation of encapsulated neonatal porcine choroid plexus cells. J Parkinsons Dis 3:275–291PubMedCrossRefPubMedCentralGoogle Scholar
  79. 79.
    Wise AK, Fallon JB, Neil AJ, Pettingill LN, Geaney MS, Skinner SJ, Shepherd RK (2011) Combining cell-based therapies and neural prostheses to promote neural survival. Neurotherapeutics 8:774–787PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Skinner SJ, Geaney MS, Lin H, Muzina M, Anal AK, Elliott RB, Tan PL (2009) Encapsulated living choroid plexus cells: potential long-term treatments for central nervous system disease and trauma. J Neural Eng 6:065001. Epub 2009 Oct 23CrossRefPubMedGoogle Scholar
  81. 81.
    Huang S, Wang J, He X, Li Z, Pu J, Shi W (2014) Secretion of BDNF and GDNF from free and encapsulated choroid plexus epithelial cells. Neurosci Lett 566:42–45PubMedCrossRefGoogle Scholar
  82. 82.
    Lindvall O, Wahlberg LU (2008) Encapsulated cell biodelivery of GDNF: a novel clinical strategy for neuroprotection and neuroregeneration in Parkinson’s disease? Exp Neurol 209:82–88PubMedCrossRefGoogle Scholar
  83. 83.
    Snow B, Taylor K, Stoessl J, Bok A, Simpson M, McAuley D, Macdonald L, Durbin K, Lee J, Lin H (2015) Safety and clinical effects of NTCELL®[Immunoprotected (alginate-encapsulated) porcine choroid plexus cells for xenotransplantation] in patients with Parkinson’s disease (PD): 26 weeks follow-up. Mov Disord 30Google Scholar
  84. 84.
    Open-label investigation of the safety and clinical effects of NTCELL® in patients with Parkinson’s disease. December 2019
  85. 85.
    Investigation of the safety and efficacy of NTCELL® [Immunoprotected (alginate-encapsulated) porcine choroid plexus cells for xenotransplantation] in patients with Parkinson’s disease. December 2019
  86. 86.
    Snow B, Mulroy E, Bok A, Simpson M, Smith A, Taylor K, Lockhart M, Lam BJ, Frampton C, Schweder P (2019) A Phase IIb, randomised, double-blind, placebo-controlled, dose-ranging investigation of the safety and efficacy of NTCELL®[Immunoprotected (alginate-encapsulated) porcine choroid plexus cells for xenotransplantation] in patients with Parkinson’s disease. Parkinsonism Relat Disord 61:88–93PubMedCrossRefGoogle Scholar
  87. 87.
    Wahlberg LU, Lind G, Almqvist PM, Kusk P, Tornøe J, Juliusson B, Söderman M, Selldén E, Seiger Å, Eriksdotter-Jönhagen M, Linderoth B (2012) Targeted delivery of nerve growth factor via encapsulated cell biodelivery in Alzheimer disease: a technology platform for restorative neurosurgery. J Neurosurg 117:340–347PubMedCrossRefGoogle Scholar
  88. 88.
    Eriksdotter-Jonhagen M, Linderoth B, Lind G, Aladellie L, Almkvist O, Andreasen N, Blennow K, Bogdanovic N, Jelic V, Kadir A, Nordberg A, Sundstrom E, Wahlund LO, Wall A, Wiberg M, Winblad B, Seiger A, Almqvist P, Wahlberg L (2012) Encapsulated cell biodelivery of nerve growth factor to the basal forebrain in patients with Alzheimer’s disease. Dement Geriatr Cogn Disord 33:18–28PubMedCrossRefGoogle Scholar
  89. 89.
    Fjord-Larsen L, Kusk P, Emerich DF, Thanos C, Torp M, Bintz B, Tornoe J, Johnsen AH, Wahlberg LU (2012) Increased encapsulated cell biodelivery of nerve growth factor in the brain by transposon-mediated gene transfer. Gene Ther 19:1010–1017PubMedCrossRefGoogle Scholar
  90. 90.
    Bloch J, Bachoud-Levi AC, Deglon N, Lefaucheur JP, Winkel L, Palfi S, Nguyen JP, Bourdet C, Gaura V, Remy P, Brugieres P, Boisse MF, Baudic S, Cesaro P, Hantraye P, Aebischer P, Peschanski M (2004) 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 15:968–975PubMedCrossRefGoogle Scholar
  91. 91.
    Lohr M, Hoffmeyer A, Kroger J, Freund M, Hain J, Holle A, Karle P, Knofel WT, Liebe S, Muller P, Nizze H, Renner M, Saller RM, Wagner T, Hauenstein K, Gunzburg WH, Salmons B (2001) Microencapsulated cell-mediated treatment of inoperable pancreatic carcinoma. Lancet 357:1591–1592PubMedCrossRefGoogle Scholar
  92. 92.
    Salmons B, Lohr M, Gunzburg WH (2003) Treatment of inoperable pancreatic carcinoma using a cell-based local chemotherapy: results of a Phase I/II clinical trial. J Gastroenterol 38(Suppl 15):78–84PubMedGoogle Scholar
  93. 93.
    Austrianova Biotechnology GmbH. December 2019
  94. 94.
    PharmaCyte Biotech. December 2019
  95. 95.
    Heile A, Brinker T (2011) Clinical translation of stem cell therapy in traumatic brain injury: the potential of encapsulated mesenchymal cell biodelivery of glucagon-like peptide-1. Dialogues Clin Neurosci 13:279–286PubMedPubMedCentralGoogle Scholar
  96. 96.
    Aebischer P, Schluep M, Deglon N, Joseph JM, Hirt L, Heyd B, Goddard M, Hammang JP, Zurn AD, Kato AC, Regli F, Baetge EE (1996) Intrathecal delivery of CNTF using encapsulated genetically modified xenogeneic cells in amyotrophic lateral sclerosis patients. Nat Med 2:696–699PubMedCrossRefGoogle Scholar
  97. 97.
    Hasse C, Klöck G, Schlosser A, Zimmermann U, Rothmund M (1997) Parathyroid allotransplantation without immunosuppression. Lancet 350:1296–1297PubMedCrossRefGoogle Scholar
  98. 98.
    Strain AJ, Neuberger JM (2002) A bioartificial liver—state of the art. Science 295:1005–1009PubMedCrossRefGoogle Scholar
  99. 99.
    Lee S, Lee J, Lee D, Park H, Kim Y, Park MN, Noh J, Jung JG, Lee JE, Yang MS (2018) Phase 1/2a trial of a bioartificial liver support system (LifeLiver) for acute liver failure patients. Transplantation 102:S123CrossRefGoogle Scholar
  100. 100.
    Orive G, Santos E, Pedraz JL, Hernández RM (2014) Application of cell encapsulation for controlled delivery of biological therapeutics. Adv Drug Deliv Rev 67:3–14PubMedCrossRefPubMedCentralGoogle Scholar
  101. 101.
    Hashemi M, Kalalinia F (2015) Application of encapsulation technology in stem cell therapy. Life Sci 143:139–146PubMedCrossRefPubMedCentralGoogle Scholar
  102. 102.
    Zhao S, Zhang L, Han J, Chu J, Wang H, Chen X, Wang Y, Tun N, Lu L, Bai X (2016) Conformal nanoencapsulation of allogeneic T cells mitigates graft-versus-host disease and retains graft-versus-leukemia activity. ACS Nano 10:6189–6200PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Mao AS, Ozkale B, Shah NJ, Vining KH, Descombes T, Zhang L, Tringides CM, Wong SW, Shin JW, Scadden DT, Weitz DA, Mooney DJ (2019) Programmable microencapsulation for enhanced mesenchymal stem cell persistence and immunomodulation. Proc Natl Acad Sci U S A 116:15392–15397PubMedCrossRefPubMedCentralGoogle Scholar
  104. 104.
    Catena R, Santos E, Orive G, Hernández RM, Pedraz JL, Calvo A (2010) Improvement of the monitoring and biosafety of encapsulated cells using the SFGNESTGL triple reporter system. J Control Release 146:93–98PubMedCrossRefPubMedCentralGoogle Scholar
  105. 105.
    Goren A, Dahan N, Goren E, Baruch L, Machluf M (2010) Encapsulated human mesenchymal stem cells: a unique hypoimmunogenic platform for long-term cellular therapy. FASEB J 24:22–31PubMedCrossRefPubMedCentralGoogle Scholar
  106. 106.
    Olabisi RM, Lazard ZW, Franco CL, Hall MA, Kwon SK, Sevick-Muraca EM, Hipp JA, Davis AR, Olmsted-Davis EA, West JL (2010) Hydrogel microsphere encapsulation of a cell-based gene therapy system increases cell survival of injected cells, transgene expression, and bone volume in a model of heterotopic ossification. Tissue Eng Part A 16:3727–3736PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Santos-Vizcaino E, Haley H, Gonzalez-Pujana A, Orive G, Hernandez RM, Luker GD, Pedraz JL (2019) Monitoring implantable immunoisolation devices with intrinsic fluorescence of genipin. J Biophotonics 12:e201800170PubMedCrossRefPubMedCentralGoogle Scholar
  108. 108.
    Huebsch N, Arany PR, Mao AS, Shvartsman D, Ali OA, Bencherif SA, Rivera-Feliciano J, Mooney DJ (2010) Harnessing traction-mediated manipulation of the cell/matrix interface to control stem-cell fate. Nat Mater 9:518–526PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Trappmann B, Gautrot JE, Connelly JT, Strange DGT, Li Y, Oyen ML, Cohen Stuart MA, Boehm H, Li B, Vogel V, Spatz JP, Watt FM, Huck WTS (2012) Extracellular-matrix tethering regulates stem-cell fate. Nat Mater 11:642–649PubMedCrossRefPubMedCentralGoogle Scholar
  110. 110.
    Chaudhuri O, Gu L, Klumpers D, Darnell M, Bencherif SA, Weaver JC, Huebsch N, Lee HP, Lippens E, Duda GN, Mooney DJ (2016) Hydrogels with tunable stress relaxation regulate stem cell fate and activity. Nat Mater 15:326–334PubMedCrossRefGoogle Scholar
  111. 111.
    Wilson JL, Najia MA, Saeed R, McDevitt TC (2014) Alginate encapsulation parameters influence the differentiation of microencapsulated embryonic stem cell aggregates. Biotechnol Bioeng 111:618–631PubMedCrossRefPubMedCentralGoogle Scholar
  112. 112.
    Chan E, Lim T, Voo W, Pogaku R, Tey BT, Zhang Z (2011) Effect of formulation of alginate beads on their mechanical behavior and stiffness. Particuology 9:228–234CrossRefGoogle Scholar
  113. 113.
    Gonzalez-Pujana A, Rementeria A, Blanco FJ, Igartua M, Pedraz JL, Santos-Vizcaino E, Hernandez RM (2017) The role of osmolarity adjusting agents in the regulation of encapsulated cell behavior to provide a safer and more predictable delivery of therapeutics. Drug Deliv 24:1654–1666PubMedCrossRefPubMedCentralGoogle Scholar
  114. 114.
    Lv H, Li L, Sun M, Zhang Y, Chen L, Rong Y, Li Y (2015) Mechanism of regulation of stem cell differentiation by matrix stiffness. Stem Cell Res Ther 6:103PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Walters NJ, Gentleman E (2015) Evolving insights in cell–matrix interactions: elucidating how non-soluble properties of the extracellular niche direct stem cell fate. Acta Biomater 11:3–16PubMedCrossRefGoogle Scholar
  116. 116.
    Cipitria A, Salmeron-Sanchez M (2017) Mechanotransduction and growth factor signalling to engineer cellular microenvironments. Adv Healthc Mater 6(15). Scholar
  117. 117.
    Gonzalez-Pujana A, Santos-Vizcaino E, García-Hernando M, Hernaez-Estrada B, de Pancorbo MM, Benito-Lopez F, Igartua M, Basabe-Desmonts L, Hernandez RM (2019) Extracellular matrix protein microarray-based biosensor with single cell resolution: integrin profiling and characterization of cell-biomaterial interactions. Sensors Actuators B Chem 299:126954CrossRefGoogle Scholar
  118. 118.
    King SR, Dorian R, Storrs RW (2001) Requirements for encapsulation technology and the challenges for transplantation of islets of Langerhans. Graft 4:491CrossRefGoogle Scholar
  119. 119.
    Barkai U, Rotem A, de Vos P (2016) Survival of encapsulated islets: more than a membrane story. World J Transplant 6:69–90PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Ortner V, Kaspar C, Halter C, Töllner L, Mykhaylyk O, Walzer J, Günzburg WH, Dangerfield JA, Hohenadl C, Czerny T (2012) Magnetic field-controlled gene expression in encapsulated cells. J Control Release 158:424–432PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Santos E, Larzabal L, Calvo A, Orive G, Pedraz JL, Hernandez RM (2013) Inactivation of encapsulated cells and their therapeutic effects by means of TGL triple-fusion reporter/biosafety gene. Biomaterials 34(4):1442–1451. Scholar
  122. 122.
    Deglon N, Heyd B, Tan SA, Joseph JM, Zurn AD, Aebischer P (1996) Central nervous system delivery of recombinant ciliary neurotrophic factor by polymer encapsulated differentiated C2C12 myoblasts. Hum Gene Ther 7:2135–2146PubMedCrossRefGoogle Scholar
  123. 123.
    Calafiore R, Basta G (2014) Clinical application of microencapsulated islets: actual prospectives on progress and challenges. Adv Drug Deliv Rev 67–68:84–92PubMedCrossRefGoogle Scholar
  124. 124.
    Kim AR, Hwang JH, Kim HM, Kim HN, Song JE, Yang YI, Yoon KH, Lee D, Khang G (2013) Reduction of inflammatory reaction in the use of purified alginate microcapsules. J Biomater Sci Polym Ed 24:1084–1098PubMedCrossRefGoogle Scholar
  125. 125.
    Basta G, Calafiore R (2011) Immunoisolation of pancreatic islet grafts with no recipient’s immunosuppression: actual and future perspectives. Curr Diab Rep 11:384PubMedCrossRefGoogle Scholar
  126. 126.
    Lee KY, Mooney DJ (2012) Alginate: properties and biomedical applications. Prog Polym Sci 37:106–126PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Ørning P, Hoem KS, Coron AE, Skjåk-Bræk G, Mollnes TE, Brekke O, Espevik T, Rokstad AM (2016) Alginate microsphere compositions dictate different mechanisms of complement activation with consequences for cytokine release and leukocyte activation. J Control Release 229:58–69PubMedCrossRefGoogle Scholar
  128. 128.
    Rokstad AM, Brekke O, Steinkjer B, Ryan L, Kolláriková G, Strand BL, Skjåk-Bræk G, Lacík I, Espevik T, Mollnes TE (2011) Alginate microbeads are complement compatible, in contrast to polycation containing microcapsules, as revealed in a human whole blood model. Acta Biomater 7:2566–2578PubMedCrossRefGoogle Scholar
  129. 129.
    Gravastrand C, Hamad S, Fure H, Steinkjer B, Ryan L, Oberholzer J, Lambris JD, Lacík I, Mollnes TE, Espevik T (2017) Alginate microbeads are coagulation compatible, while alginate microcapsules activate coagulation secondary to complement or directly through FXII. Acta Biomater 58:158–167. Scholar
  130. 130.
    Sigilon Therapeutics. December 2019
  131. 131.
    Vegas AJ, Veiseh O, Gurtler M, Millman JR, Pagliuca FW, Bader AR, Doloff JC, Li J, Chen M, Olejnik K, Tam HH, Jhunjhunwala S, Langan E, Aresta-Dasilva S, Gandham S, McGarrigle JJ, Bochenek MA, Hollister-Lock J, Oberholzer J, Greiner DL, Weir GC, Melton DA, Langer R, Anderson DG (2016) Long-term glycemic control using polymer-encapsulated human stem cell-derived beta cells in immune-competent mice. Nat Med 22:306–311PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Vegas AJ, Veiseh O, Doloff JC, Ma M, Tam HH, Bratlie K, Li J, Bader AR, Langan E, Olejnik K (2016) Combinatorial hydrogel library enables identification of materials that mitigate the foreign body response in primates. Nat Biotechnol 34:345–352PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Bochenek MA, Veiseh O, Vegas AJ, McGarrigle JJ, Qi M, Marchese E, Omami M, Doloff JC, Mendoza-Elias J, Nourmohammadzadeh M (2018) Alginate encapsulation as long-term immune protection of allogeneic pancreatic islet cells transplanted into the omental bursa of macaques. Nat Biomed Eng 2:810PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Liu Q, Chiu A, Wang L, An D, Zhong M, Smink AM, de Haan BJ, de Vos P, Keane K, Vegge A (2019) Zwitterionically modified alginates mitigate cellular overgrowth for cell encapsulation. Nat Commun 10:1–14CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2020

Authors and Affiliations

  • Edorta Santos-Vizcaino
    • 1
    • 2
  • Gorka Orive
    • 1
    • 2
    • 3
    • 4
  • Jose Luis Pedraz
    • 1
    • 2
  • Rosa Maria Hernandez
    • 1
    • 2
    Email author
  1. 1.NanoBioCel Group, Laboratory of Pharmaceutics, School of PharmacyUniversity of the Basque Country (UPV/EHU)Vitoria-GasteizSpain
  2. 2.Biomedical Research Networking Centre in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN)Vitoria-GasteizSpain
  3. 3.University Institute for Regenerative Medicine and Oral Implantology—UIRMI (UPV/EHU-Fundación Eduardo Anitua)VitoriaSpain
  4. 4.BTI Biotechnology InstituteVitoriaSpain

Personalised recommendations