Protection of Islets of Langerhans From Interleukin-1 Toxicity by Artificial Membranes

Zekorn, T; Siebers, U; Bretzel, Reinhard G.; Renardy, M.; Planck, H.; Zschocke, P.; Federlin, K.

doi:10.1097/00007890-199009000-00007

Cited by 29 publications

(7 citation statements)

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“…To understand the mechanisms by which the membrane protects the islets in vivo, we evaluated the effect of cytokines on encapsulated islets. A previous study showed that islets are protected against IL-1␤ in vitro (26), whereas other reports suggested that cytokines could cross the membrane and affect the function of the encapsulated islets (15,27). Our results confirm that cytokines can cross the membrane and damage the islet cells contained inside the capsules.…”

Section: Tablesupporting

confidence: 84%

Complete Protection of Islets Against Allorejection and Autoimmunity by a Simple Barium-Alginate Membrane

Duvivier‐Kali

Omer²,

Parent³

et al. 2001

Diabetes

264

199

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We describe a new technique for microencapsulation with high-mannuronic acid (high-M) alginate crosslinked with BaCl 2 without a traditional permselective component, which allows the production of biocompatible capsules that allow prolonged survival of syngeneic and allogeneic transplanted islets in diabetic BALB/c and NOD mice for >350 days. The normalization of the glycemia in the transplanted mice was associated with normal glucose profiles in response to intravenous glucose tolerance tests. After explantation of the capsules, all mice became hyperglycemic, demonstrating the efficacy of the encapsulated islets. The retrieved capsules were free of cellular overgrowth and islets responded to glucose stimulation with a 5-to 10-fold increase of insulin secretion. Transfer of splenocytes isolated from transplanted NOD mice to NOD/SCID mice adoptively transferred diabetes, indicating that NOD recipients maintained islet-specific autoimmunity. In conclusion, we have developed a simple technique for microencapsulation that prolongs islet survival without immunosuppression, providing complete protection against allorejection and the recurrence of autoimmune diabetes. Diabetes 50: 1698 -1705, 2001 I slet transplantation represents an important alternative for the treatment of type 1 diabetes but still requires immunosuppressive agents with their serious side effects (1). One approach to avoid such treatment is to protect islets from the host's immune system with a semipermeable, biocompatible membrane (2,3). Transplantation of islets contained in alginate-poly-L-lysine (PLL) capsules was first described by Lim and Sun (4). Numerous studies have shown successful reversal of diabetes by transplantation of islets enclosed in alginate-PLL capsules in streptozotocin-induced animals (5-9). However, limited success has been reported in spontaneously diabetic NOD mice, a model of autoimmune diabetes (10 -13). Various factors have been implicated in the failure of encapsulated islets. A cellular reaction surrounding the capsules has often been observed, which could lead to depletion of oxygen and nutrients (14) or production of toxic cytokines (15). This accumulation of cells could be due to an immune response to the contained islets or to bioincompatibility of the capsular materials (16,17). Failure might also be attributed to problems with ␤-cell viability in the capsules (18).Protection of porcine islets remains a goal of encapsulation, but xenografts might be more difficult to protect than allografts, as suggested by studies performed with permeable polymer membranes (19,20). This concept is important because of the improved prospects for obtaining an abundant supply of human ␤-cells from precursor cells (21,22). The goal of this study was to determine whether stable biocompatible alginate microcapsules without a permselective component, such as PLL or polyethylene-glycol, would be able to protect mouse islets against allorejection and autoimmunity. RESEARCH DESIGN AND METHODSIslet isolation. Islets were isolated from ma...

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Section: Tablesupporting

confidence: 84%

Complete Protection of Islets Against Allorejection and Autoimmunity by a Simple Barium-Alginate Membrane

Duvivier‐Kali

Omer²,

Parent³

et al. 2001

Diabetes

264

199

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“…Alginate‐poly‐ L ‐Lysine capsules have been synthesized with a MWCO between 14,500 and 44,000 g/mol, as determined by measuring the diffusion of linear dextran molecules and model proteins 21. Other natural and synthetic polymer membrane studies have targeted a MWCO of 50,000 g/mol 22–27…”

Section: Discussionmentioning

confidence: 99%

Effects of PEG hydrogel crosslinking density on protein diffusion and encapsulated islet survival and function

Weber

Lopez

Anseth

2008

J Biomedical Materials Res

265

255

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The rational design of immunoprotective hydrogel barriers for transplanting insulin-producing cells requires an understanding of protein diffusion within the hydrogel network and how alterations to the network structure affect protein diffusion. Hydrogels of varying crosslinking density were formed via the chain polymerization of dimethacrylated PEG macromers of varying molecular weight, and the diffusion of six model proteins with molecular weights ranging from 5,700 to 67,000 g/mol was observed in these hydrogel networks. Protein release profiles were used to estimate diffusion coefficients for each protein/gel system that exhibited Fickian diffusion. Diffusion coefficients were on the order of 10−6 to 10−7 cm2/s, such that protein diffusion time scales (td = L2/D) from 0.5 mm thick gels vary from 5 minutes to 24 hours. Adult murine islets were encapsulated in PEG hydrogels of varying crosslinking density, and islet survival and insulin release was maintained after two weeks of culture in each gel condition. While the total insulin released during a one hour glucose stimulation period was the same from islets in each sample, increasing hydrogel crosslinking density contributed to delays in insulin release from hydrogel samples within the one hour stimulation period.

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“…The advantage of preventing the penetration of cytokines (MW 15,000 to 35,000 Da) is not clear since most published successfully encapsulated islet transplantations have been done using microcapsules with a MW cut-off of >50,000 Da (when this parameter is mentioned). [35][36][37] On the other hand, what is the minimal MW cut-off that will allow adequate islet nutrition and function? There are even fewer data that address this question.…”

Section: Discussionmentioning

confidence: 99%

Studies on small (<350 ?m) alginate-poly-L-lysine microcapsules. V. Determination of carbohydrate and protein permeation through microcapsules by reverse-size exclusion chromatography

Robitaille

Leblond

Bourgeois

et al. 2000

J. Biomed. Mater. Res.

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Membrane molecular weight (MW) cut-off is a critical factor for immunoprotection of transplanted microencapsulated cells as well as for graft survival. Our goal was to study dextran and protein permeation through small (<350 microm in diameter) alginate-poly-L-lysine microcapsules made with an electrostatic system. Microcapsules were packed into a column, and gel-sieving chromatography was performed with proteins and dextrans of known MW. The objectives of this study were (1) to validate this approach for the assessment of the MW cut-off of <350 microm-in-diameter microcapsules and (2) to evaluate the effect on MW cut-off of changes in experimental conditions. Elution profiles of proteins suggest that the MW cut-off of our small microcapsules lies between 14,500 and 44,000 Da whereas dextrans > or =19,000 Da were excluded. The increase in poly-L-lysine (PLL) concentration from 0.02 to 0.08% reduced the MW cut-off. Increasing the PLL MW from 11.6 to 69.6 kDa induced no change in the MW cut-off. The results also show that the method can be used to discriminate between adsorption and absorption and that insulin diffuses freely across the microcapsule membrane. This method will be useful in establishing the ideal MW cut-off, in optimizing microcapsule characteristics, and in performing routine quality controls.

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Protection of Islets of Langerhans From Interleukin-1 Toxicity by Artificial Membranes

Cited by 29 publications

References 0 publications

Complete Protection of Islets Against Allorejection and Autoimmunity by a Simple Barium-Alginate Membrane

Complete Protection of Islets Against Allorejection and Autoimmunity by a Simple Barium-Alginate Membrane

Effects of PEG hydrogel crosslinking density on protein diffusion and encapsulated islet survival and function

Studies on small (<350 ?m) alginate-poly-L-lysine microcapsules. V. Determination of carbohydrate and protein permeation through microcapsules by reverse-size exclusion chromatography

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