Micro-fabricated scaffolds lead to efficient remission of diabetes in mice

Mijke Buitinga, Frank Assen, Maaike Hanegraaf, Paul Wieringa, Janneke Hilderink, Lorenzo Moroni, Roman Truckenmüller, Clemens van Blitterswijk, Gert-Willem Römer, Francoise Carlotti, Eelco de Koning, Marcel Karperien, Aart van Apeldoorn

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Abstract

Despite the clinical success of intrahepatic islet transplantation in treating type 1 diabetes, factors specific to this transplantation site hinder long-term insulin independence. The adoption of alternative, extravascular sites likely improve islet survival and function, but few locations are able to sufficiently confine islets in order to facilitate engraftment. This work describes a porous microwell scaffold with a well-defined pore size and spacing designed to guarantee islet retention at an extrahepatic transplantation site and facilitate islet revascularization. Three techniques to introduce pores were characterized: particulate leaching; solvent casting on pillared wafers; and laser drilling. Our criteria of a maximum pore diameter of 40 μm were best achieved via laser drilling. Transplantation studies in the epididymal fat of diabetic mice elucidated the potential of this porous scaffold platform to restore blood glucose levels and facilitate islet engraftment. Six out of eight mice reverted to stable normoglycemia with a mean time to remission of 6.2 ± 3.2 days, which was comparable to that of the gold standard of renal subcapsular islet grafts. In contrast, when islets were transplanted in the epididymal fat pad without a microwell scaffold, only two out of seven mice reverted to stable normoglycemia. Detailed histological evaluation four weeks after transplantation found a comparable vascular density in scaffold-seeded islets, renal subcapsular islets and native pancreatic islets. However, the vascularization pattern in scaffold-seeded islets was more inhomogeneous compared to native pancreatic islets with a higher vascular density in the outer shell of the islets compared to the inner core. We also observed a corresponding decrease in the beta-cell density in the islet core. Despite this, our data indicated that islets transplanted in the microwell scaffold platform were able to maintain a viable beta-cell population and restore glycemic control. Furthermore, we demonstrated that the microwell scaffold platform facilitated detailed analysis at a subcellular level to correlate design parameters with functional physiological observations.
Original languageEnglish
Pages (from-to)10-22
JournalBiomaterials
Volume135
DOIs
Publication statusPublished - Aug 2017

Fingerprint

Medical problems
Scaffolds
Transplantation
Islets of Langerhans
Blood Vessels
Lasers
Kidney
Islets of Langerhans Transplantation
Oils and fats
Type 1 Diabetes Mellitus
Drilling
Blood Glucose
Adipose Tissue
Fats
Cell Count
Insulin
Transplants
Grafts
Leaching
Pore size

Keywords

  • METIS-321973
  • IR-104296

Cite this

Buitinga, M., Assen, F., Hanegraaf, M., Wieringa, P., Hilderink, J., Moroni, L., ... van Apeldoorn, A. (2017). Micro-fabricated scaffolds lead to efficient remission of diabetes in mice. Biomaterials, 135, 10-22. https://doi.org/10.1016/j.biomaterials.2017.03.031
Buitinga, Mijke ; Assen, Frank ; Hanegraaf, Maaike ; Wieringa, Paul ; Hilderink, Janneke ; Moroni, Lorenzo ; Truckenmüller, Roman ; van Blitterswijk, Clemens ; Römer, Gert-Willem ; Carlotti, Francoise ; de Koning, Eelco ; Karperien, Marcel ; van Apeldoorn, Aart. / Micro-fabricated scaffolds lead to efficient remission of diabetes in mice. In: Biomaterials. 2017 ; Vol. 135. pp. 10-22.
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Buitinga, M, Assen, F, Hanegraaf, M, Wieringa, P, Hilderink, J, Moroni, L, Truckenmüller, R, van Blitterswijk, C, Römer, G-W, Carlotti, F, de Koning, E, Karperien, M & van Apeldoorn, A 2017, 'Micro-fabricated scaffolds lead to efficient remission of diabetes in mice' Biomaterials, vol. 135, pp. 10-22. https://doi.org/10.1016/j.biomaterials.2017.03.031

Micro-fabricated scaffolds lead to efficient remission of diabetes in mice. / Buitinga, Mijke; Assen, Frank; Hanegraaf, Maaike; Wieringa, Paul; Hilderink, Janneke; Moroni, Lorenzo; Truckenmüller, Roman; van Blitterswijk, Clemens; Römer, Gert-Willem; Carlotti, Francoise; de Koning, Eelco; Karperien, Marcel; van Apeldoorn, Aart.

In: Biomaterials, Vol. 135, 08.2017, p. 10-22.

Research output: Contribution to journalArticleAcademicpeer-review

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T1 - Micro-fabricated scaffolds lead to efficient remission of diabetes in mice

AU - Buitinga, Mijke

AU - Assen, Frank

AU - Hanegraaf, Maaike

AU - Wieringa, Paul

AU - Hilderink, Janneke

AU - Moroni, Lorenzo

AU - Truckenmüller, Roman

AU - van Blitterswijk, Clemens

AU - Römer, Gert-Willem

AU - Carlotti, Francoise

AU - de Koning, Eelco

AU - Karperien, Marcel

AU - van Apeldoorn, Aart

N1 - Online first

PY - 2017/8

Y1 - 2017/8

N2 - Despite the clinical success of intrahepatic islet transplantation in treating type 1 diabetes, factors specific to this transplantation site hinder long-term insulin independence. The adoption of alternative, extravascular sites likely improve islet survival and function, but few locations are able to sufficiently confine islets in order to facilitate engraftment. This work describes a porous microwell scaffold with a well-defined pore size and spacing designed to guarantee islet retention at an extrahepatic transplantation site and facilitate islet revascularization. Three techniques to introduce pores were characterized: particulate leaching; solvent casting on pillared wafers; and laser drilling. Our criteria of a maximum pore diameter of 40 μm were best achieved via laser drilling. Transplantation studies in the epididymal fat of diabetic mice elucidated the potential of this porous scaffold platform to restore blood glucose levels and facilitate islet engraftment. Six out of eight mice reverted to stable normoglycemia with a mean time to remission of 6.2 ± 3.2 days, which was comparable to that of the gold standard of renal subcapsular islet grafts. In contrast, when islets were transplanted in the epididymal fat pad without a microwell scaffold, only two out of seven mice reverted to stable normoglycemia. Detailed histological evaluation four weeks after transplantation found a comparable vascular density in scaffold-seeded islets, renal subcapsular islets and native pancreatic islets. However, the vascularization pattern in scaffold-seeded islets was more inhomogeneous compared to native pancreatic islets with a higher vascular density in the outer shell of the islets compared to the inner core. We also observed a corresponding decrease in the beta-cell density in the islet core. Despite this, our data indicated that islets transplanted in the microwell scaffold platform were able to maintain a viable beta-cell population and restore glycemic control. Furthermore, we demonstrated that the microwell scaffold platform facilitated detailed analysis at a subcellular level to correlate design parameters with functional physiological observations.

AB - Despite the clinical success of intrahepatic islet transplantation in treating type 1 diabetes, factors specific to this transplantation site hinder long-term insulin independence. The adoption of alternative, extravascular sites likely improve islet survival and function, but few locations are able to sufficiently confine islets in order to facilitate engraftment. This work describes a porous microwell scaffold with a well-defined pore size and spacing designed to guarantee islet retention at an extrahepatic transplantation site and facilitate islet revascularization. Three techniques to introduce pores were characterized: particulate leaching; solvent casting on pillared wafers; and laser drilling. Our criteria of a maximum pore diameter of 40 μm were best achieved via laser drilling. Transplantation studies in the epididymal fat of diabetic mice elucidated the potential of this porous scaffold platform to restore blood glucose levels and facilitate islet engraftment. Six out of eight mice reverted to stable normoglycemia with a mean time to remission of 6.2 ± 3.2 days, which was comparable to that of the gold standard of renal subcapsular islet grafts. In contrast, when islets were transplanted in the epididymal fat pad without a microwell scaffold, only two out of seven mice reverted to stable normoglycemia. Detailed histological evaluation four weeks after transplantation found a comparable vascular density in scaffold-seeded islets, renal subcapsular islets and native pancreatic islets. However, the vascularization pattern in scaffold-seeded islets was more inhomogeneous compared to native pancreatic islets with a higher vascular density in the outer shell of the islets compared to the inner core. We also observed a corresponding decrease in the beta-cell density in the islet core. Despite this, our data indicated that islets transplanted in the microwell scaffold platform were able to maintain a viable beta-cell population and restore glycemic control. Furthermore, we demonstrated that the microwell scaffold platform facilitated detailed analysis at a subcellular level to correlate design parameters with functional physiological observations.

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Buitinga M, Assen F, Hanegraaf M, Wieringa P, Hilderink J, Moroni L et al. Micro-fabricated scaffolds lead to efficient remission of diabetes in mice. Biomaterials. 2017 Aug;135:10-22. https://doi.org/10.1016/j.biomaterials.2017.03.031