Cited by 973D Printing in Biomedical ResearchPancreatic function and diabetesTissue Engineering and Regenerative Medicine

Organoid microphysiological system preserves pancreatic islet function within 3D matrix

Open access
Patel, S. N., Ishahak, M., Chaimov, D., Velraj, A., LaShoto, D., Hagan, D. W., Buchwald, P., Phelps, E. A. +2 more·2021·Science Advances

Abstract

A customized microphysiological system supports the perifusion and in situ multiparametric assessment of 3D islet organoids.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1126/sciadv.aba5515

Cites

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Relying on active fluid flow rather than passive diffusion for nutrient transport can greatly enhance the viability and performance of islets within a macroencapsulation device.

    “this study highlights that relying on active fluid flow rather than passive diffusion for nutrient transport can greatly enhance the viability and performance of islets within a macroencapsulation device.”

    From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [95]

    The Results sections on rodent islet viability and human islet culture report better viability and preserved insulin responses with continuous flow than with static culture. The Discussion says improved nutrient delivery is a likely explanation, but notes that flow may have other effects. The experiments used an in vitro microphysiological chip with alginate-embedded islets, not a macroencapsulation device, so that device-specific extension is not established. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

No citation lists for this paper

No citation lists for this paper yet — checked again daily.

References 69 · Cited by 97

Research works printed but not linked: 65

  1. [2]S. Breslin, L. O’Driscoll, Three-dimensional cell culture: The missing link in drug discovery. Drug Discov. Today 18, 240– 249 (2013). 23073387
  2. [4]N. J. Hart, A. C. Powers, Use of human islets to understand islet biology and diabetes: Progress, challenges and suggestions. Diabetologia 62, 212– 222 (2019). 30547228 PMC6325002
  3. [5]C. Ricordi, J. S. Goldstein, A. N. Balamurugan, G. L. Szot, T. Kin, C. Liu, C. W. Czarniecki, B. Barbaro, N. D. Bridges, J. Cano, W. R. Clarke, T. L. Eggerman, L. G. Hunsicker, D. B. Kaufman, A. Khan, D.-E. Lafontant, E. Linetsky, X. Luo, J. F. Markmann, A. Naji, O. Korsgren, J. Oberholzer, N. A. Turgeon, D. Brandhorst, X. Chen, A. S. Friberg, J. Lei, L.-J. Wang, J. J. Wilhelm, J. Willits, X. Zhang, B. J. Hering, A. M. Posselt, P. G. Stock, A. M. J. Shapiro, X. Chen, National Institutes of Health-sponsored clinical islet transplantation consortium phase 3 trial: Manufacture of a complex cellular product at eight processing facilities. Diabetes 65, 3418– 3428 (2016). 27465220 PMC5079635
  4. [6]K. K. Papas, H. De Leon, T. M. Suszynski, R. C. Johnson, Oxygenation strategies for encapsulated islet and beta cell transplants. Adv. Drug Deliv. Rev. 139, 139– 156 (2019). 31077781
  5. [7]L. Rosenberg, R. Wang, S. Paraskevas, D. Maysinger, Structural and functional changes resulting from islet isolation lead to islet cell death. Surgery 126, 393– 398 (1999). 10455912
  6. [8]D. W. Scharp, P. Marchetti, Encapsulated islets for diabetes therapy: History, current progress, and critical issues requiring solution. Adv. Drug Deliv. Rev. 67-68, 35– 73 (2014). 23916992
  7. [9]K. Y. Lee, D. J. Mooney, Alginate: Properties and biomedical applications. Prog. Polym. Sci. 37, 106– 126 (2012). 22125349 PMC3223967
  8. [10]J. W. Haycock, in 3D Cell Culture (Springer, 2011), pp. 1–15.
  9. [11]S. N. Bhatia, D. E. Ingber, Microfluidic organs-on-chips. Nat. Biotechnol. 32, 760– 772 (2014). 25093883
  10. [12]S. K. Sia, G. M. Whitesides, Microfluidic devices fabricated in poly(dimethylsiloxane) for biological studies. Electrophoresis 24, 3563– 3576 (2003). 14613181
  11. [13]D. Hoelzle, M. Lake, C. Narciso, K. Cowdrick, T. Storey, S. Zhang, J. Zartman, Microfluidic device design, fabrication, and testing protocols. Protoc. Exch. 10.1038/protex.2015.069, (2015). · DOI
  12. [14]G. Lenguito, D. Chaimov, J. R. Weitz, R. Rodriguez-Diaz, S. A. K. Rawal, A. Tamayo-Garcia, A. Caicedo, C. L. Stabler, P. Buchwald, A. Agarwal, Resealable, optically accessible, PDMS-free fluidic platform for ex vivo interrogation of pancreatic islets. Lab Chip 17, 772– 781 (2017). 28157238 PMC5330806
  13. [15]P. Buchwald, A local glucose-and oxygen concentration-based insulin secretion model for pancreatic islets. Theor. Biol. Med. Model. 8, 20 (2011). 21693022 PMC3138450
  14. [16]C. Ricordi, D. W. R. Gray, B. J. Hering, D. B. Kaufman, G. L. Warnock, N. M. Kneteman, S. P. Lake, N. J. M. London, C. Socci, R. Alejandro, Y. Zeng, D. W. Scharp, G. Viviani, L. Falqui, A. Tzakis, R. G. Bretzel, K. Federlin, G. Pozza, R. F. L. James, R. V. Rajotte, V. Di Carlo, P. J. Morris, D. E. R. Sutherland, T. E. Starzl, D. H. Mintz, P. E. Lacy, Islet isolation assessment in man and large animals. Acta Diabetol. Lat. 27, 185– 195 (1990). 2075782
  15. [17]M. M. Coronel, R. Geusz, C. L. Stabler, Mitigating hypoxic stress on pancreatic islets via in situ oxygen generating biomaterial. Biomaterials 129, 139– 151 (2017). 28342320 PMC5497707
  16. [18]P.-O. Carlsson, P. Liss, A. Andersson, L. Jansson, Measurements of oxygen tension in native and transplanted rat pancreatic islets. Diabetes 47, 1027– 1032 (1998). 9648824
  17. [19]R. Olsson, P.-O. Carlsson, A low-oxygenated subpopulation of pancreatic islets constitutes a functional reserve of endocrine cells. Diabetes 60, 2068– 2075 (2011). 21788581 PMC3142080
  18. [20]E. S. Avgoustiniatos, “Oxygen diffusion limitations in pancreatic islet culture and immunoisolation,” thesis, Massachusetts Institute of Technology, Cambridge, MA (2002).
  19. [21]K. E. Dionne, C. K. Colton, M. L. Lyarmush, Effect of hypoxia on insulin secretion by isolated rat and canine islets of Langerhans. Diabetes 42, 12– 21 (1993). 8420809
  20. [22]P. Rorsman, L. Eliasson, E. Renström, J. Gromada, S. Barg, S. Göpel, The cell physiology of biphasic insulin secretion. Physiology 15, 72– 77 (2000). 11390882
  21. [23]A. F. Adewola, D. Lee, T. Harvat, J. Mohammed, D. T. Eddington, J. Oberholzer, Y. Wang, Microfluidic perifusion and imaging device for multi-parametric islet function assessment. Biomed. Microdevices 12, 409– 417 (2010). 20300858
  22. [24]O. Cabrera, M. C. Jacques-Silva, D. M. Berman, A. Fachado, F. Echeverri, R. Poo, A. Khan, N. S. Kenyon, C. Ricordi, P.-O. Berggren, A. Caicedo, Automated, high-throughput assays for evaluation of human pancreatic islet function. Cell Transplant. 16, 1039– 1048 (2008). 18351020 PMC3529176
  23. [25]K. Maedler, J. Oberholzer, P. Bucher, G. A. Spinas, M. Y. Donath, Monounsaturated fatty acids prevent the deleterious effects of palmitate and high glucose on human pancreatic β-cell turnover and function. Diabetes 52, 726– 733 (2003). 12606514
  24. [27]R. P. Robertson, J. Harmon, P. O. T. Tran, V. Poitout, β-Cell glucose toxicity, lipotoxicity, and chronic oxidative stress in type 2 diabetes. Diabetes 53, S119– S124 (2004). 14749276
  25. [28]T.-W. Chen, T. J. Wardill, Y. Sun, S. R. Pulver, S. L. Renninger, A. Baohan, E. R. Schreiter, R. A. Kerr, M. B. Orger, V. Jayaraman, L. L. Looger, K. Svoboda, D. S. Kim, Ultrasensitive fluorescent proteins for imaging neuronal activity. Nature 499, 295– 300 (2013). 23868258 PMC3777791
  26. [29]B. J. van Meer, H. de Vries, K. S. A. Firth, J. van Weerd, L. G. J. Tertoolen, H. B. J. Karperien, P. Jonkheijm, C. Denning, A. P. IJzerman, C. L. Mummery, Small molecule absorption by PDMS in the context of drug response bioassays. Biochem. Biophys. Res. Commun. 482, 323– 328 (2017). 27856254 PMC5240851
  27. [30]M. Adiraj Iyer, D. T. Eddington, Storing and releasing rhodamine as a model hydrophobic compound in polydimethylsiloxane microfluidic devices. Lab Chip 19, 574– 579 (2019). 30681692
  28. [31]A. L. Glieberman, B. D. Pope, J. F. Zimmerman, Q. Liu, J. P. Ferrier Jr., J. H. R. Kenty, A. M. Schrell, N. Mukhitov, K. L. Shores, A. B. Tepole, D. A. Melton, M. G. Roper, K. K. Parker, Synchronized stimulation and continuous insulin sensing in a microfluidic human Islet on a Chip designed for scalable manufacturing. Lab Chip 19, 2993– 3010 (2019). 31464325 PMC6814249
  29. [32]E. Berthier, E. W. K. Young, D. Beebe, Engineers are from PDMS-land, biologists are from polystyrenia. Lab Chip 12, 1224– 1237 (2012). 22318426
  30. [33]K. Ren, W. Dai, J. Zhou, J. Su, H. Wu, Whole-Teflon microfluidic chips. Proc. Natl. Acad. Sci. U.S.A. 108, 8162– 8166 (2011). 21536918 PMC3100936
  31. [34]I. R. Sweet, D. L. Cook, R. W. Wiseman, C. J. Greenbaum, Å. Lernmark, S. Matsumoto, J. C. Teague, K. A. Krohn, Dynamic perifusion to maintain and assess isolated pancreatic islets. Diabetes Technol. Ther. 4, 67– 76 (2002). 12017423
  32. [35]P. Buchwald, A. Tamayo-Garcia, V. Manzoli, A. A. Tomei, C. L. Stabler, Glucose-stimulated insulin release: Parallel perifusion studies of free and hydrogel encapsulated human pancreatic islets. Biotechnol. Bioeng. 115, 232– 245 (2018). 28865118 PMC5699962
  33. [36]P. Buchwald, FEM-based oxygen consumption and cell viability models for avascular pancreatic islets. Theor. Biol. Med. Model. 6, 5 (2009). 19371422 PMC2678100
  34. [37]P. Buchwald, X. Wang, A. Khan, A. Bernal, C. Fraker, L. Inverardi, C. Ricordi, Quantitative assessment of islet cell products: Estimating the accuracy of the existing protocol and accounting for islet size distribution. Cell Transplant. 18, 1223– 1235 (2009). 19818209
  35. [38]R. R. MacGregor, S. J. Williams, P. Y. Tong, K. Kover, W. V. Moore, L. Stehno-Bittel, Small rat islets are superior to large islets in in vitro function and in transplantation outcomes. Am. J. Physiol. Endocrinol. Metab. 290, E771– E779 (2006). 16303846
  36. [39]A. P. Gilmore, Anoikis. Cell Death Differ. 12, 1473– 1477 (2005). 16247493
  37. [40]J. Grossmann, Molecular mechanisms of “detachment-induced apoptosis—Anoikis”. Apoptosis 7, 247– 260 (2002). 11997669
  38. [41]S. M. Frisch, H. Francis, Disruption of epithelial cell-matrix interactions induces apoptosis. J. Cell Biol. 124, 619– 626 (1994). 8106557 PMC2119917
  39. [42]J. C. Stendahl, D. B. Kaufman, S. I. Stupp, Extracellular matrix in pancreatic islets: Relevance to scaffold design and transplantation. Cell Transplant. 18, 1– 12 (2009). 19476204 PMC2724969
  40. [43]K. Jiang, D. Chaimov, S. N. Patel, J.-P. Liang, S. C. Wiggins, M. M. Samojlik, A. Rubiano, C. S. Simmons, C. L. Stabler, 3-D physiomimetic extracellular matrix hydrogels provide a supportive microenvironment for rodent and human islet culture. Biomaterials 198, 37– 48 (2019). 30224090 PMC6397100
  41. [44]L. A. Llacua, B. J. de Haan, P. de Vos, Laminin and collagen IV inclusion in immunoisolating microcapsules reduces cytokine-mediated cell death in human pancreatic islets. J. Tissue Eng. Regen. Med. 12, 460– 467 (2018). 28508555
  42. [45]K. A. Homan, N. Gupta, K. T. Kroll, D. B. Kolesky, M. Skylar-Scott, T. Miyoshi, D. Mau, M. T. Valerius, T. Ferrante, J. V. Bonventre, J. A. Lewis, R. Morizane, Flow-enhanced vascularization and maturation of kidney organoids in vitro. Nat. Methods 16, 255– 262 (2019). 30742039 PMC6488032
  43. [46]Y. Jun, J. Lee, S. Choi, J. H. Yang, M. Sander, S. Chung, S.-H. Lee, In vivo–mimicking microfluidic perfusion culture of pancreatic islet spheroids. Sci. Adv. 5, eaax4520 (2019). 31807701 PMC6881167
  44. [47]J. D. Rivas-Carrillo, A. Soto-Gutierrez, N. Navarro-Alvarez, H. Noguchi, T. Okitsu, Y. Chen, T. Yuasa, K. Tanaka, M. Narushima, A. Miki, H. Misawa, Y. Tabata, H.-S. Jun, S. Matsumoto, I. J. Fox, N. Tanaka, N. Kobayashi, Cell-permeable pentapeptide V5 inhibits apoptosis and enhances insulin secretion, allowing experimental single-donor islet transplantation in mice. Diabetes 56, 1259– 1267 (2007). 17287463
  45. [48]O. Alcazar, P. Buchwald, Concentration-dependency and time profile of insulin secretion: Dynamic perifusion studies with human and murine islets. Front. Endocrinol. 10, 680 (2019). PMC6783504 31632354
  46. [49]J. S. Mohammed, Y. Wang, T. A. Harvat, J. Oberholzer, D. T. Eddington, Microfluidic device for multimodal characterization of pancreatic islets. Lab Chip 9, 97– 106 (2009). 19209341 PMC3759253
  47. [50]M. Skelin Klemen, J. Dolenšek, M. Slak Rupnik, A. Stožer, The triggering pathway to insulin secretion: Functional similarities and differences between the human and the mouse β cells and their translational relevance. Islets 9, 109– 139 (2017). 28662366 PMC5710702
  48. [51]J. Pi, Q. Zhang, J. Fu, C. G. Woods, Y. Hou, B. E. Corkey, S. Collins, M. E. Andersen, ROS signaling, oxidative stress and Nrf2 in pancreatic beta-cell function. Toxicol. Appl. Pharmacol. 244, 77– 83 (2010). 19501608 PMC2837798
  49. [52]Y.-J. Chen, T. Yamazoe, K. F. Leavens, F. L. Cardenas-Diaz, A. Georgescu, D. Huh, P. Gadue, B. Z. Stanger, iPreP is a three-dimensional nanofibrillar cellulose hydrogel platform for long-term ex vivo preservation of human islets. JCI Insight 4, e124644 (2019). PMC6948755 31672937
  50. [53]S. Cechin, S. Álvarez-Cubela, J. A. Giraldo, R. D. Molano, S. Villate, C. Ricordi, A. Pileggi, L. Inverardi, C. A. Fraker, J. Domínguez-Bendala, Influence of in vitro and in vivo oxygen modulation on β cell differentiation from human embryonic stem cells. Stem Cells Transl. Med. 3, 277– 289 (2014). 24375542 PMC3952934
  51. [54]C. A. Fraker, S. Álvarez, P. Papadopoulos, J. Giraldo, W. Gu, C. Ricordi, L. Inverardi, J. Domínguez-Bendala, Enhanced oxygenation promotes β-cell differentiation in vitro. Stem Cells 25, 3155– 3164 (2007). 17761759
  52. [55]M. M. F. Qadir, S. Álvarez-Cubela, J. Weitz, J. K. Panzer, D. Klein, Y. Moreno-Hernández, S. Cechin, A. Tamayo, J. Almaça, H. Hiller, M. Beery, I. Kusmartseva, M. Atkinson, S. Speier, C. Ricordi, A. Pugliese, A. Caicedo, C. A. Fraker, R. L. Pastori, J. Domínguez-Bendala, Long-term culture of human pancreatic slices as a model to study real-time islet regeneration. Nat. Commun. 11, 3265 (2020). 32601271 PMC7324563
  53. [56]C. Gravena, P. C. Mathias, S. J. H. Ashcroft, Acute effects of fatty acids on insulin secretion from rat and human islets of Langerhans. J. Endocrinol. 173, 73– 80 (2002). 11927386
  54. [57]C. S. Olofsson, S. Collins, M. Bengtsson, L. Eliasson, A. Salehi, K. Shimomura, A. Tarasov, C. Holm, F. Ashcroft, P. Rorsman, Long-term exposure to glucose and lipids inhibits glucose-induced insulin secretion downstream of granule fusion with plasma membrane. Diabetes 56, 1888– 1897 (2007). 17456851
  55. [58]I. T. Kuok, A. M. Rountree, S.-R. Jung, I. R. Sweet, Palmitate is not an effective fuel for pancreatic islets and amplifies insulin secretion independent of calcium release from endoplasmic reticulum. Islets 11, 51– 64 (2019). 31084524 PMC6548485
  56. [59]S. Xu, S. M. Nam, J.-H. Kim, R. Das, S.-K. Choi, T. T. Nguyen, X. Quan, S. J. Choi, C. H. Chung, E. Y. Lee, I.-K. Lee, A. Wiederkehr, C. B. Wollheim, S.-K. Cha, K.-S. Park, Palmitate induces ER calcium depletion and apoptosis in mouse podocytes subsequent to mitochondrial oxidative stress. Cell Death Dis. 6, e1976 (2015). 26583319 PMC4670935
  57. [60]M. Nemecz, A. Constantin, M. Dumitrescu, N. Alexandru, A. Filippi, G. Tanko, A. Georgescu, The distinct effects of palmitic and oleic acid on pancreatic beta cell function: The elucidation of associated mechanisms and effector molecules. Front. Pharmacol. 9, 1554 (2019). 30719005 PMC6348268
  58. [61]C. Warnotte, P. Gilon, M. Nenquin, J.-C. Henquin, Mechanisms of the stimulation of insulin release by saturated fatty acids: A study of palmitate effects in mouse β-cells. Diabetes 43, 703– 711 (1994). 8168648
  59. [62]M. Garcia-Contreras, A. Tamayo-Garcia, K. L. Pappan, G. A. Michelotti, C. L. Stabler, C. Ricordi, P. Buchwald, Metabolomics study of the effects of inflammation, hypoxia, and high glucose on isolated human pancreatic islets. J. Proteome Res. 16, 2294– 2306 (2017). 28452488 PMC5557342
  60. [63]E. A. Phelps, C. Cianciaruso, I. P. Michael, M. Pasquier, J. Kanaani, R. Nano, V. Lavallard, N. Billestrup, J. A. Hubbell, S. Baekkeskov, Aberrant accumulation of the diabetes autoantigen GAD65 in Golgi membranes in conditions of ER stress and autoimmunity. Diabetes 65, 2686– 2699 (2016). 27284108 PMC5001175
  61. [64]H. L. Lanz, A. Saleh, B. Kramer, J. Cairns, C. P. Ng, J. Yu, S. J. Trietsch, T. Hankemeier, J. Joore, P. Vulto, R. Weinshilboum, L. Wang, Therapy response testing of breast cancer in a 3D high-throughput perfused microfluidic platform. BMC Cancer 17, 709 (2017). 29096610 PMC5668957
  62. [65]E. L. Moreno, S. Hachi, K. Hemmer, S. J. Trietsch, A. S. Baumuratov, T. Hankemeier, P. Vulto, J. C. Schwamborn, R. M. T. Fleming, Differentiation of neuroepithelial stem cells into functional dopaminergic neurons in 3D microfluidic cell culture. Lab Chip 15, 2419– 2428 (2015). 25902196
  63. [66]M. Jang, P. Neuzil, T. Volk, A. Manz, A. Kleber, On-chip three-dimensional cell culture in phaseguides improves hepatocyte functions in vitro. Biomicrofluidics 9, 034113 (2015). 26180570 PMC4482807
  64. [68]R. Bottino, L. A. Fernandez, C. Ricordi, R. Lehmann, M. F. Tsan, R. Oliver, L. Inverardi, Transplantation of allogeneic islets of Langerhans in the rat liver: Effects of macrophage depletion on graft survival and microenvironment activation. Diabetes 47, 316– 323 (1998). 9519734
  65. [69]A. Pisania, G. C. Weir, J. J. O’Neil, A. Omer, V. Tchipashvili, J. Lei, C. K. Colton, S. Bonner-Weir, Quantitative analysis of cell composition and purity of human pancreatic islet preparations. Lab. Invest. 90, 1661– 1675 (2010). 20697378 PMC2966538

Authors
Patel, S. N., Ishahak, M., Chaimov, D., Velraj, A., LaShoto, D., Hagan, D. W., Buchwald, P., Phelps, E. A., Agarwal, A., & Stabler, C. L.
Affiliations
  • University of Florida (US)
  • University of Miami (US)
  • University of Florida Health (US)
Corresponding author
  • Patel, S. N.
  • Ishahak, M.
  • Agarwal, A.
  • Stabler, C. L.
Venue
Science Advances
Published
2021-02-12
Volume
7
Issue
7
ISSN
2375-2548 (ISSN-L)
OpenAlex
W3128226077
Cited by
97
References
69
Citations by year
2026: 7 · 2025: 22 · 2024: 14 · 2023: 27 · 2022: 21 · 2021: 6
FWCI
5.17
Type
journal article
Language
en
Open access
Locations
  • Science Advances (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (UC4 DK104208, UG3 DK122638)
  • Human Islet Research Network (F31DK118860)
  • Integrated Islet Distribution Program (IIDP) at City of Hope (2UC4DK098085)
  • Human Islet Cell Processing Facility at the Diabetes Research Institute
Topics
  • Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
Keywords
pancreatic islets, organoids, microphysiological systems, dynamic culture, hypoxia, insulin secretion, organoid viability, computational modeling, high-content imaging

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review