Encapsulation of pancreatic islets for transplantation in diabetes: the untouchable islets

doi:10.1016/S1471-4914(02)02381-X

Trends in Molecular Medicine

Volume 8, Issue 8, 1 August 2002, Pages 363-366

https://doi.org/10.1016/S1471-4914(02)02381-X Get rights and content

Abstract

The aim of encapsulation of pancreatic islets is to transplant in the absence of immunosuppression. It is based on the principle that transplanted tissue is protected from the host immune system by an artificial membrane. Encapsulation allows for application of insulin-secreting cells of animal or other surrogate sources, to overcome human islet shortage. The advantages and pitfalls of the approaches developed so far are discussed and compared, together with some recent progress, in view of applicability in clinical islet transplantation.

Section snippets

Immunoisolation approaches

Immunoisolating devices can be categorized into three types: intravascular macrocapsules, which are connected as a shunt to the systemic circulation; extravascular macrocapsules, which are transplanted subcutaneously or intraperitoneally; and extravascular microcapsules containing individual islets, which are mostly transplanted in the peritoneal cavity (Fig. 1, Table 1).

The intravascular devices provide the advantage that the encapsulated islets are in close contact with the blood stream,

Novel insight in factors determining the success of encapsulated islet grafts

Microencapsulated islets have shown some success in a clinical trial [9] and in preclinical studies in large mammals 10., 11.. These studies show survival of microencapsulated islet grafts in vivo for periods varying between one and 12 months. Although this illustrates the clinical applicability of microencapsulated islets, it also demonstrates a common and pertinent problem, as graft survival was always temporary and never permanent. A major cause for this limited survival is the host reaction

Concluding remarks

In the past decade, it has become increasingly clear that problems associated with immunoisolation of pancreatic islets can be overcome by a step-wise approach of the questions involved. Now that immunoisolation has become a reproducible procedure in small mammals, it is mandatory to scale-up the procedure and to address potential obstacles for clinical application. This includes human biocompatibility testing and adjustments of the system to the human diabetic immune system. However, recent

Acknowledgements

A.F. Hamel is greatly acknowledged for preparing the illustrations. B.J. de Haan, L. Marselli and R. Lupi are acknowledged for their support in the experiments described.

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Enhancing longevity of immunoisolated pancreatic islet grafts by modifying both the intracapsular and extracapsular environment
2023, Acta Biomaterialia
Type 1 diabetes mellitus (T1DM) is a chronic metabolic disease characterized by autoimmune destruction of pancreatic β cells. Transplantation of immunoisolated pancreatic islets might treat T1DM in the absence of chronic immunosuppression. Important advances have been made in the past decade as capsules can be produced that provoke minimal to no foreign body response after implantation. However, graft survival is still limited as islet dysfunction may occur due to chronic damage to islets during islet isolation, immune responses induced by inflammatory cells, and nutritional issues for encapsulated cells. This review summarizes the current challenges for promoting longevity of grafts. Possible strategies for improving islet graft longevity are also discussed, including supplementation of the intracapsular milieu with essential survival factors, promotion of vascularization and oxygenation near capsules, modulation of biomaterials, and co-transplantation of accessory cells. Current insight is that both the intracapsular as well as the extracapsular properties should be improved to achieve long-term survival of islet-tissue. Some of these approaches reproducibly induce normoglycemia for more than a year in rodents. Further development of the technology requires collective research efforts in material science, immunology, and endocrinology.
Islet immunoisolation allows for transplantation of insulin producing cells in absence of immunosuppression and might facilitate the use of xenogeneic cell sources or grafting of cells obtained from replenishable cell sources. However, a major challenge to date is to create a microenvironment that supports long-term graft survival. This review provides a comprehensive overview of the currently identified factors that have been demonstrated to be involved in either stimulating or reducing islet graft survival in immunoisolating devices and discussed current strategies to enhance the longevity of encapsulated islet grafts as treatment for type 1 diabetes. Although significant challenges remain, interdisciplinary collaboration across fields may overcome obstacles and facilitate the translation of encapsulated cell therapy from the laboratory to clinical application.
Inclusion of extracellular matrix molecules and necrostatin-1 in the intracapsular environment of alginate-based microcapsules synergistically protects pancreatic β cells against cytokine-induced inflammatory stress
2022, Acta Biomaterialia
Immunoisolation of pancreatic islets in alginate-based microcapsules is a promising approach for grafting of islets in absence of immunosuppression. However, loss and damage to the extracellular matrix (ECM) during islet isolation enhance susceptibility of islets for inflammatory stress. In this study, a combined strategy was applied to reduce this stress by incorporating ECM components (collagen type IV/RGD) and necroptosis inhibitor, necrostatin-1 (Nec-1) in alginate-based microcapsules in vitro. To demonstrate efficacy, viability and function of MIN6 β-cells and human islets in capsules with collagen type IV/RGD and/or Nec-1 was investigated in presence and absence of IL-1β, IFN-γ and TNF-α. The combination of collagen type IV/RGD and Nec-1 had higher protective effects than the molecules alone. Presence of collagen type IV/RGD and Nec-1 in the intracapsular environment reduced cytokine-induced overproduction of free radical species and unfavorable shifts in mitochondrial dynamics. In addition, the ECM components collagen type IV/RGD prevented a cytokine induced suppression of the FAK/Akt pathway. Our data indicate that the inclusion of collagen type IV/RGD and Nec-1 in the intracapsular environment prevents islet-cell loss when exposed to inflammatory stress, which might contribute to higher survival of β-cells in the immediate period after transplantation. This approach of inclusion of stress reducing agents in the intracapsular environment of immunoisolating devices may be an effective way to enhance the longevity of encapsulated islet grafts.
Islet-cells in immunoisolated alginate-based microcapsules are very susceptible to inflammatory stress which impacts long-term survival of islet grafts. Here we show that incorporation of ECM components (collagen type IV/RGD) and necrostatin-1 (Nec-1) in the intracapsular environment of alginate-based capsules attenuates this susceptibility and promotes islet-cell survival. This effect induced by collagen type IV/RGD and Nec-1 was probably due to lowering free radical production, preventing mitochondrial dysfunction and by maintaining ECM/integrin/FAK/Akt signaling and Nec-1/RIP1/RIP3 signaling. Our study provides an effective strategy to extend longevity of islet grafts which might be of great potential for future clinical application of immunoisolated cells.
Bioartificial pancreas: Challenges and progress
2020, Principles of Tissue Engineering
The principle of the bioartificial pancreas is based on immunoisolation of insulin-producing cells in immunoprotective but semipermeable capsules that protect cells from the host immune system. Three concepts are currently being developed into clinically applicable devices: intravascular macrocapsules, extravascular macrocapsules, and microcapsules. These approaches are critically reviewed in the view of future clinical application. Much progress has been made in the development of suitable biomaterials for this field of application. Emerging developments are the application of antibiofouling polymers as well as application of polymer brushes and immunomodulatory biomaterials that elicit minimal or no tissue responses. Challenges that remain are finding means to support the longevity of tissues in the capsules. Conceivable approaches to support this are inclusion of cell-death inhibitors as well as extracellular matrix molecules. A replenishable cell source is needed to start efficacy studies in humans.
Synthetic poly(ethylene glycol)-based microfluidic islet encapsulation reduces graft volume for delivery to highly vascularized and retrievable transplant site
2019, American Journal of Transplantation
Transplant of hydrogel-encapsulated allogeneic islets has been explored to reduce or eliminate the need for chronic systemic immunosuppression by creating a physical barrier that prevents direct antigen presentation. Although successful in rodents, translation of alginate microencapsulation to large animals and humans has been hindered by large capsule sizes (≥500 μm diameter) that result in suboptimal nutrient diffusion in the intraperitoneal space. We developed a microfluidic encapsulation system that generates synthetic poly(ethylene glycol)-based microgels with smaller diameters (310 ± 14 μm) that improve encapsulated islet insulin responsiveness over alginate capsules and allow transplant within vascularized tissue spaces, thereby reducing islet mass requirements and graft volumes. By delivering poly(ethylene glycol)-encapsulated islets to an isolated, retrievable, and highly vascularized site via a vasculogenic delivery vehicle, we demonstrate that a single pancreatic donor syngeneic islet mass exhibits improved long-term function over conventional alginate capsules and close integration with transplant site vasculature. In vivo tracking of bioluminescent allogeneic encapsulated islets in an autoimmune type 1 diabetes murine model showed enhanced cell survival over unencapsulated islets in the absence of chronic systemic immunosuppression. This method demonstrates a translatable alternative to intraperitoneal encapsulated islet transplant.
Type 1 Diabetes Mellitus reversal via implantation of magnetically purified microencapsulated pseudoislets
2019, International Journal of Pharmaceutics
Microencapsulation of pancreatic islets for the treatment of Type I Diabetes Mellitus (T1DM) generates a high quantity of empty microcapsules, resulting in high therapeutic graft volumes that can enhance the host’s immune response. We report a 3D printed microfluidic magnetic sorting device for microcapsules purification with the objective to reduce the number of empty microcapsules prior transplantation. In this study, INS1E pseudoislets were microencapsulated within alginate (A) and alginate-poly-L-lysine-alginate (APA) microcapsules and purified through the microfluidic device. APA microcapsules demonstrated higher mechanical integrity and stability than A microcapsules, showing better pseudoislets viability and biological function. Importantly, we obtained a reduction of the graft volume of 77.5% for A microcapsules and 78.6% for APA microcapsules. After subcutaneous implantation of induced diabetic Wistar rats with magnetically purified APA microencapsulated pseudoislets, blood glucose levels were restored into normoglycemia (<200 mg/dL) for almost 17 weeks. In conclusion, our described microfluidic magnetic sorting device represents a great alternative approach for the graft volume reduction of microencapsulated pseudoislets and its application in T1DM disease.
Bioengineering, biomaterials, and β-cell replacement therapy
2019, Transplantation, Bioengineering, and Regeneration of the Endocrine Pancreas: Volume 2
The field of biomaterials, regenerative medicine, and bioengineering has in the last decade connected with islet transplantation research. This chapter describes some of the more recent advances and gives some typical examples of biomaterials and fabrication techniques used for the creation of a β-cell replacement device with some emphasis on 3D printing. After this chapter the reader should have a general understanding of biomaterials and some of the bioengineering strategies used to create a tailor-made implant for extrahepatic islet or β-cell transplantation.

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Trends in Molecular Medicine

Research updateEncapsulation of pancreatic islets for transplantation in diabetes: the untouchable islets

Abstract

Section snippets

Immunoisolation approaches

Novel insight in factors determining the success of encapsulated islet grafts

Concluding remarks

Acknowledgements

Lancet

Cell Transplant.

Transplant. Proc.

Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen

N. Engl. J. Med.

Biocompatibility Issues

Considerations for successful transplantation of encapsulated pancreatic islets

Diabetologia

Maintenance of normoglycemia in diabetic mice by subcutaneous xenografts of encapsulated islets

Science

Glucose control and long-term survival in biobreeding/Worcester rats after intraperitoneal implantation of hydrophilic macrobeads containing porcine islets without immunosuppression

Transplantation

Protection of encapsulated human islets implanted without immunosuppression in patients with type I or type II diabetes and in nondiabetic control subjects

Diabetes

Insulin secretion by rat islet isografts of a defined endocrine volume after transplantation to three different sites

Diabetologia

Research update
Encapsulation of pancreatic islets for transplantation in diabetes: the untouchable islets