Curr Diab Rep (2011) 11:434–444 inability to achieve full remission of hyperglycemia in diabetic dogs transplanted with auto-, allo-, or xenogeneic- encapsulated islets. The later studies did not use immuno- suppression but the authors speculated that the decrease in transplanted islet-to-surface ratio and fibrotic overgrowth affected the efficiency of these grafts [90]. Whether immunosuppression is required to prolong microencapsulated islets is debated. In an ideal situation, encapsulated allogeneic or xenogenic islets would have long-term survival with minimal immune response and no requirement for immunosuppression. However, the micro- capsule fabrication and composition have fallen short of this expectation [93]. Recent reports are now attempting to combine microcapsule optimization with immunosuppres- sion to determine whether graft function can be extended. For example, Safley et al. [94, 95] observed that inhibition of T-cell costimulatory molecules CD28/B7 by CTLA-Ig in NOD mice transplanted with microencapsulated porcine islets extended graft function compared with no treatment. Similar results were also seen elsewhere [96]. Safley et al. [94, 95] showed that empty microcapsules did not elicit an immune response and it was the presence of the xenogenic islets that attracted large numbers of leukocytes to the transplantation site. Others showed that the composition of the microcapsules also affects the biocompatibility of the microcapsule [93]. In this report, cyclosporin A treatment of rats transplanted with low or high guluronic acid alginate bovine-encapsulated islets increased the longevity of the graft by at least twofold. Cyclosporin A decreased the amount of fibrotic overgrowth on the low guluronic alginate, with similar results in empty microcapsules [93]. Much of the experimental work with alginate microcapsules has used nonstandardized and varying alginate composi- tions with varying results [10]. Clinical application, conversely, requires clinical-grade alginate and rigorous evaluation of the product [97]. Conclusions Pancreatic islet transplantation has come a long way in almost 40 years, but is still generally considered an experimental procedure. Advances in the fields of material science, nanotechnology, immunology, and islet transplan- tation have been able to shed some light on how we might be able to improve long-term survival and function of pancreatic islet transplants. What’s next? We think it would be beneficial to use the knowledge of β-cell interactions within its native environment and recreate this islet niche as best as possible in a carrier or capsule (Fig. 1). We envision creating a “microenvironment” for human islets that would include not only the islets, but accessory cells, proteins, and possibly local immunosuppression housed within a bio- 441 compatible material. The material would support islets for the time required for the body to recreate a supportive microenvironment around the transplantation site and eventually be degraded so that a suitable islet micro-organ would remain. These activities provide the alternative for human islets and must be complemented by efforts in encapsulation so that other sources of β cells (e.g., xenogeneic islets and stem cell–derived β cells) can also find their way to clinical therapy. Acknowledgments This work was supported by the DFG-Center for Regenerative Therapies Dresden, Cluster of Excellence (FZT 111) and the Federal Ministry of Education and Research, Germany (01GN0945). D. J. 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