A porcine islet-encapsulation device that enables long-term discordant xenotransplantation in immunocompetent diabetic mice

Ajima, Kumiko; Tsuda, Naoto; Takaki, Tadashi; Furusako, Shoji; Matsumoto, Shigeki; Shinohara, Koya; Yamashita, Yzumi; Amano, Sayaka; Oyama, Chinatsu; Shimoda, Masayuki

doi:10.1016/j.crmeth.2022.100370

Cited by 10 publications

(8 citation statements)

References 86 publications

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“…Further work is needed to develop the optimal supportive matrix that can advantage the device characteristics, that is, gels that are injectable and retrievable via a needle. It has also been reported that during the isolation of porcine islets, the cleavage process results in islets of heterogeneous sizes and morphology making porcine islets particularly fragile compared to human islets ( 82 ). Convection-based devices may introduce different challenges for preparing the graft than conventional diffusion-based macrodevices.…”

Section: Discussionmentioning

confidence: 99%

A bioengineered artificial interstitium supports long-term islet xenograft survival in nonhuman primates without immunosuppression

Oppler,

Hocum Stone,

Leishman

et al. 2024

Sci. Adv.

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Cell-based therapies hold promise for many chronic conditions; however, the continued need for immunosuppression along with challenges in replacing cells to improve durability or retrieving cells for safety are major obstacles. We subcutaneously implanted a device engineered to exploit the innate transcapillary hydrostatic and colloid osmotic pressure generating ultrafiltrate to mimic interstitium. Long-term stable accumulation of ultrafiltrate was achieved in both rodents and nonhuman primates (NHPs) that was chemically similar to serum and achieved capillary blood oxygen concentration. The majority of adult pig islet grafts transplanted in non-immunosuppressed NHPs resulted in xenograft survival >100 days. Stable cytokine levels, normal neutrophil to lymphocyte ratio, and a lack of immune cell infiltration demonstrated successful immunoprotection and averted typical systemic changes related to xenograft transplant, especially inflammation. This approach eliminates the need for immunosuppression and permits percutaneous access for loading, reloading, biopsy, and recovery to de-risk the use of “unlimited” xenogeneic cell sources to realize widespread clinical translation of cell-based therapies.

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Section: Discussionmentioning

confidence: 99%

A bioengineered artificial interstitium supports long-term islet xenograft survival in nonhuman primates without immunosuppression

Oppler,

Hocum Stone,

Leishman

et al. 2024

Sci. Adv.

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“…In one study, neonatal porcine islets were encapsulated in a stable and permeable alginate gel and enclosed in a biocompatible, immunoprotective membrane, and transplanted in the abdominal cavities of immunocompetent diabetic mice. Islet xenograft survival, rapid lowering of blood glucose and long-term glycemic control for >200 days was achieved without any immunosuppressants ( 50 ). Furthermore, the devices were shown to retain their integrity after they were retrieved and re-transplanted in new immunocompetent diabetic mice.…”

Section: Human Allogeneic Primary Islet Transplantation and Its Assoc...mentioning

confidence: 99%

“…Micro-capsules have an optimal surface-to-volume ratio compared to macro-capsules that require vascularization and sufficient oxygenation to improve islet survival and function. Biomaterials used for microencapsulation are often made of natural polymers such as alginate ( 55 ), agarose ( 68 ), chitosan ( 52 ) but also synthetic polymers such as polyethylene glycol (PEG) that form a hydrogel ( 50 , 54 , 56 , 69 ) ( Table 1 ). Microencapsulation encompasses a semi-permeable membrane that has demonstrated some success in providing immune protection and mechanical stability in mice ( 50 , 52 ), NHP ( 55 ) models and human studies ( 51 , 53 ).…”

Section: Innovations In Bio-engineering and Cell-based Approaches For...mentioning

confidence: 99%

“…Biomaterials used for microencapsulation are often made of natural polymers such as alginate ( 55 ), agarose ( 68 ), chitosan ( 52 ) but also synthetic polymers such as polyethylene glycol (PEG) that form a hydrogel ( 50 , 54 , 56 , 69 ) ( Table 1 ). Microencapsulation encompasses a semi-permeable membrane that has demonstrated some success in providing immune protection and mechanical stability in mice ( 50 , 52 ), NHP ( 55 ) models and human studies ( 51 , 53 ). However, microencapsulation requires more complex and individualized fabrication processes ( 70 ), as opposed to macroencapsulation devices that may be easier to manufacture, are more easily retrievable after implantation, and are more favourable for commercialization.…”

Section: Innovations In Bio-engineering and Cell-based Approaches For...mentioning

confidence: 99%

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Innovations in bio-engineering and cell-based approaches to address immunological challenges in islet transplantation

Ho,

Teo,

2024

Front. Immunol.

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Human allogeneic pancreatic islet transplantation is a life-changing treatment for patients with severe Type 1 Diabetes (T1D) who suffer from hypoglycemia unawareness and high risk of severe hypoglycemia. However, intensive immunosuppression is required to prevent immune rejection of the graft, that may in turn lead to undesirable side effects such as toxicity to the islet cells, kidney toxicity, occurrence of opportunistic infections, and malignancies. The shortage of cadaveric human islet donors further limits islet transplantation as a treatment option for widespread adoption. Alternatively, porcine islets have been considered as another source of insulin-secreting cells for transplantation in T1D patients, though xeno-transplants raise concerns over the risk of endogenous retrovirus transmission and immunological incompatibility. As a result, technological advancements have been made to protect transplanted islets from immune rejection and inflammation, ideally in the absence of chronic immunosuppression, to improve the outcomes and accessibility of allogeneic islet cell replacement therapies. These include the use of microencapsulation or macroencapsulation devices designed to provide an immunoprotective environment using a cell-impermeable layer, preventing immune cell attack of the transplanted cells. Other up and coming advancements are based on the use of stem cells as the starting source material for generating islet cells ‘on-demand’. These starting stem cell sources include human induced pluripotent stem cells (hiPSCs) that have been genetically engineered to avoid the host immune response, curated HLA-selected donor hiPSCs that can be matched with recipients within a given population, and multipotent stem cells with natural immune privilege properties. These strategies are developed to provide an immune-evasive cell resource for allogeneic cell therapy. This review will summarize the immunological challenges facing islet transplantation and highlight recent bio-engineering and cell-based approaches aimed at avoiding immune rejection, to improve the accessibility of islet cell therapy and enhance treatment outcomes. Better understanding of the different approaches and their limitations can guide future research endeavors towards developing more comprehensive and targeted strategies for creating a more tolerogenic microenvironment, and improve the effectiveness and sustainability of islet transplantation to benefit more patients.

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“…However, the subcutaneous site is poorly vascularized, and it must be modified before transplantation in order to support islet grafts [ 4 ]. Various subcutaneous approaches have been developed for delivering grafts, including the use of devices [ 5 , 6 ], biomaterials [ 7 , 8 ], endothelial cells [ 9 ], and fibroblasts [ 10 ]. Although all these approaches have improved islet engraftment to some degree, a large number of islets are still necessary to achieve normoglycemia.…”

Section: Introductionmentioning

confidence: 99%

A Gelatin Hydrogel Nonwoven Fabric Enhances Subcutaneous Islet Engraftment in Rats

Saito,

Inagaki,

Nakamura

et al. 2023

Cells

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Although subcutaneous islet transplantation has many advantages, the subcutaneous space is poor in vessels and transplant efficiency is still low in animal models, except in mice. Subcutaneous islet transplantation using a two-step approach has been proposed, in which a favorable cavity is first prepared using various materials, followed by islet transplantation into the preformed cavity. We previously reported the efficacy of pretreatment using gelatin hydrogel nonwoven fabric (GHNF), and the length of the pretreatment period influenced the results in a mouse model. We investigated whether the preimplantation of GHNF could improve the subcutaneous islet transplantation outcomes in a rat model. GHNF sheets sandwiching a silicone spacer (GHNF group) and silicone spacers without GHNF sheets (control group) were implanted into the subcutaneous space of recipients three weeks before islet transplantation, and diabetes was induced seven days before islet transplantation. Syngeneic islets were transplanted into the space where the silicone spacer was removed. Blood glucose levels, glucose tolerance, immunohistochemistry, and neovascularization were evaluated. The GHNF group showed significantly better blood glucose changes than the control group (p < 0.01). The cure rate was significantly higher in the GHNF group (p < 0.05). The number of vWF-positive vessels was significantly higher in the GHNF group (p < 0.01), and lectin angiography showed the same tendency (p < 0.05). The expression of laminin and collagen III around the transplanted islets was also higher in the GHNF group (p < 0.01). GHNF pretreatment was effective in a rat model, and the main mechanisms might be neovascularization and compensation of the extracellular matrices.

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A porcine islet-encapsulation device that enables long-term discordant xenotransplantation in immunocompetent diabetic mice

Cited by 10 publications

References 86 publications

A bioengineered artificial interstitium supports long-term islet xenograft survival in nonhuman primates without immunosuppression

A bioengineered artificial interstitium supports long-term islet xenograft survival in nonhuman primates without immunosuppression

Innovations in bio-engineering and cell-based approaches to address immunological challenges in islet transplantation

A Gelatin Hydrogel Nonwoven Fabric Enhances Subcutaneous Islet Engraftment in Rats

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