Long-term Efficacy and Biocompatibility of Encapsulated Islet Transplantation With Chitosan-Coated Alginate Capsules in Mice and Canine Models of Diabetes

Yang, Hae Kyung; Ham, Dong-Sik; Park, Heon‐Seok; Rhee, Marie; You, Young Hye; Kim, Min Jung; Shin, Ju‐Young; Kim, Onyou; Khang, Gilson; Hong, Tae Ho; Kim, Jiwon; Lee, Seung‐Hwan; Cho, Jae‐Hyoung; Yoon, Kun‐Ho

doi:10.1097/tp.0000000000000927

Cited by 48 publications

(36 citation statements)

References 39 publications

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“…First, fibrosis forms around the capsule after transplantation, which not only blocks the movement of oxygen and nutrients but also triggers a foreign body reaction (De Groot, Schuurs, & van Schilfgaarde, ; Fritschy et al, ). To minimize the fibrotic reaction around alginate capsules, our group used chitosan for the second layer coating on the alginate microcapsules and demonstrated a remarkable decrease in fibrotic reactions (Yang et al, ). Second, hypoxia develops because there is no blood vessel formation in the early stage of transplantation, and oxygen supply to the transplanted encapsulated islets in the peritoneal cavity of the recipient is supplied only by diffusion (Krishnan & Ko, ).…”

Section: Introductionmentioning

confidence: 99%

Improvement of islet function and survival by integration of perfluorodecalin into microcapsules in vivo and in vitro

Lee

Park

Yang

et al. 2018

J Tissue Eng Regen Med

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Hypoxic injury of islets is a major obstacle for encapsulated islet transplantation into the peritoneal cavity. To improve oxygen delivery to encapsulated islets, we integrated 20% of the oxygen carrier material, perfluorodecalin (PFD), in alginate capsules mixed with islets (PFD-alginate). Integration of PFD clearly improved islet viability and decreased reactive oxygen species production compared to islets encapsulated with alginate only (alginate) and naked islets exposed to hypoxia in vitro. In PFD-alginate capsules, HIF-1α expression was minimal, and insulin expression was well maintained. Furthermore, the best islet function represented by glucose-stimulated insulin secretion was observed for the PFD-alginate capsules in hypoxic condition. For the in vivo study, the same number of naked islets and encapsulated islets (alginate and PFD-alginate) was transplanted into streptozotocin-induced diabetic mice. Nonfasting blood glucose levels and the area under the curve for glucose based on intraperitoneal glucose tolerance tests in the PFD-alginate group were lower than in the alginate group. The harvested islets stained positive for insulin in all groups, but the ratio of dead cell area was 4 times higher in the alginate group than in the PFD-alginate group. In conclusion, integration of PFD in alginate microcapsules improved islet function and survival by minimizing the hypoxic damage of islets after intraperitoneal transplantation.

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Section: Introductionmentioning

confidence: 99%

Improvement of islet function and survival by integration of perfluorodecalin into microcapsules in vivo and in vitro

Lee

Park

Yang

et al. 2018

J Tissue Eng Regen Med

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“…Another recent study has shown that coating alginate microcapsules with chitosan significantly improved its biocompatibility by reducing PFO. In this study, the authors showed that chitosan-coated alginate microcapsules significantly reduced PFO and normalized blood glucose levels for up to 1 year both in a canine allotransplantation and rodent xenotransplantation model [125]. However, despite all the surface-modification strategies to reduce PFO and improve graft survival in small animal models, as outlined above, none of them have been successful in large animals, thereby undermining the clinical significance of the above approaches.…”

Section: Modification Of Alginate Microcapsulesmentioning

confidence: 84%

Encapsulated Islet Transplantation: Where Do We Stand?

2017

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Transplantation of pancreatic islets encapsulated within immuno-protective microcapsules is a strategy that has the potential to overcome graft rejection without the need for toxic immunosuppressive medication. However, despite promising preclinical studies, clinical trials using encapsulated islets have lacked long-term efficacy, and although generally considered clinically safe, have not been encouraging overall. One of the major factors limiting the long-term function of encapsulated islets is the host's immunological reaction to the transplanted graft which is often manifested as pericapsular fibrotic overgrowth (PFO). PFO forms a barrier on the capsule surface that prevents the ingress of oxygen and nutrients leading to islet cell starvation, hypoxia and death. The mechanism of PFO formation is still not elucidated fully and studies using a pig model have tried to understand the host immune response to empty alginate microcapsules. In this review, the varied strategies to overcome or reduce PFO are discussed, including alginate purification, altering microcapsule geometry, modifying alginate chemical composition, co-encapsulation with immunomodulatory cells, administration of pharmacological agents, and alternative transplantation sites. Nanoencapsulation technologies, such as conformal and layer-by-layer coating technologies, as well as nanofiber, thin-film nanoporous devices, and silicone based NanoGland devices are also addressed. Finally, this review outlines recent progress in imaging technologies to track encapsulated cells, as well as promising perspectives concerning the production of insulin-producing cells from stem cells for encapsulation.

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“…Tuch et al [20] reported thick fibrous tissue around intraperitoneally transplanted micro-encapsulated human islets 16 months after transplantation [20]. On the other hand, Yang et al [46] reported that chitosan-coating improved the biocompatibility of alginateencapsulated islets, enabling long-term function of intraperitoneally transplanted microencapsulated allogeneic islets [46]. Since EVOH has excellent biocompatibility, our EVOH bag causes minimal foreign body reactions and EVOH-enveloped macro-encapsulated islets are expected to exert their function for a long period of time.…”

Section: Discussionmentioning

confidence: 99%

Our Steps toward Subcutaneous Transplantation of Macro-Encapsulated Islets

et al. 2019

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Background: Diabetes mellitus (DM) can be cured or greatly ameliorated by adequate insulin secretion from a relatively small volume of insulin-producing cells. Cell encapsulation enables allo-and even xeno-geneic cell therapy without immunosuppression. However, recent clinical trials show that micro-encapsulated islets are not fully retrievable after transplantation. By contrast, macro-encapsulated islets can be retrieved when necessary. As to the transplantation site, subcutaneous tissue can be promising, if new strategy can overcome the hypoxic status due to hypovascularity. In this review article, we summarized the development of macro-encapsulated islets and approaches toward subcutaneous transplantation in our laboratory over more than two decades. Our results repeatedly show that islets and encapsulated islets can be transplanted in various sites including subcutaneous tissue after pretreatment of neovascular induction. As to macro-encapsulation devices, our laboratory firstly developed mesh-reinforced poly

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Long-term Efficacy and Biocompatibility of Encapsulated Islet Transplantation With Chitosan-Coated Alginate Capsules in Mice and Canine Models of Diabetes

Cited by 48 publications

References 39 publications

Improvement of islet function and survival by integration of perfluorodecalin into microcapsules in vivo and in vitro

Improvement of islet function and survival by integration of perfluorodecalin into microcapsules in vivo and in vitro

Encapsulated Islet Transplantation: Where Do We Stand?

Our Steps toward Subcutaneous Transplantation of Macro-Encapsulated Islets

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