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Biologic or biomechanical therapy capable of replacing the β cell mass has the potential to positively impact the health and well being of millions of people with insulindependent diabetes. Research in this area stands at a pivotal moment at which a number of viable strategies exist or are under development. Broad application depends on achieving both technical and financial feasibility. The ultimate goal of a "true cure," in which diabetic individuals achieve euglycemia with a single procedure associated with minimal risk, without long-termtoxic drugs, and unfettered by external devices and/or frequent monitoring, appears to still be some years away. However, dramatic progress has been achieved toward themore proximate objectives of improved glycemic control and elimination of hypoglycemia and long-term vascular complications. Long-term whole organ pancreas and isolated islet results have improved significantly over the last decade,with the latter now approaching the success of the former in insulin independence rates at the 5-year mark. It seems likely that allogeneic pancreas and islet transplantation will remain a treatment of choice for the foreseeable future in kidney recipients already obligated to lifelong immunosuppression until a more complete and permanent restoration of euglycemia is available. Nascent tolerance promoting protocols could aid in improving the risk-to-benefit balance for both islets and whole organ pancreas. With the present supply of transplantable pancreases used optimally, nomore than 13% of the annual incident cases of T1D can be cured. In practical terms though, today, fewer than 5% of the annual incident cases are transplanted. The reality of the limited supply of deceased donor organs ultimately constrains the impact of islet and pancreas transplantation and compels researchers to press forward to develop broader strategies such as the AP, xenogeneic islets, and stem cell-derived β cells for which the supply will be limitless; in these areas, recent progress has been most impressive. The AP continues to be refined withmore sophisticated delivery algorithms, improved sensors and exploration of mobile device control. For xenogeneic islets, dramatic progress is evident in the long-term survival of porcine islets in primates using genetically modified donors and/or improved biologic immunosuppressants. Microencapsulation and macroencapsulation devices that exclude direct immunity by physical means may further aid in fostering xenogeneic islet graft survival but will likely find their primary place in the containment and protection of early versions of stem cell-derived allogeneic β cells. Deriving functional β cells from stem cells has experienced the most celebrated recent advances. Improved differentiation protocols that permit large scale/ unlimited production of IPCs are nowavailable, and although "normal" β-cell function has not yet been achieved, the ever quickening pace of progress suggests they are not far off. Importantly, this therapeutic modality will ultimately need to confront the likely requirement for a containment device and the need to be retransplanted periodically. These blemishes notwithstanding, the tremendous perceived potential of the approach for clinical application is evident in the huge venture capital investment that was rapidly garnered after the report of the most recent advance in embryonic stem cell differentiation into proper β cells. Consistent with the informal survey we conducted, iPS-derived β cells, which currently suffer from regulatory hurdles and the lack of a viable business model, and the seemingly more remote regeneration of native β cells,may offer the ultimate chance for a personalized true cure of insulin-dependent diabetes by avoidance of barrier devices and toxic immunosuppressive drugs. The research agenda we have detailed is designed to facilitate full exploration of the potential of each proposed β-cell replacement solution so the optimal therapy is advanced as quickly as possible. Success in this endeavor will require broad and deep financial support from philanthropic (JDRF, Diabetes Research and Wellness Foundation, ADA, and so on) and public funding agencies worldwide; the investment needed is large but the potential reward will be profound. It is imperative that high impact, scientifically sound approaches are not overwhelmed by industry, private, or venture capital-supported priorities just because they hold a more lucrative near-term business model; scientific merit should dictate the course. The adherence of the historical funding agencies to traditional peer-reviewed methodology will be the incubator of novel approaches. This is a rapidly evolving landscape, and new data and novel ideas may radically divert the path forward. However, the diverse recent progress is tangible and undeniable, and the next decade is bound to witness a fascinating unfolding of competing solutions to cure insulin-dependent diabetes. Our assessment of the data presented creates the opportunity for IPITA/TTS to endorse the following broad agenda for specific support by the peer-reviewed agencies.

Item does not contain fulltext Radiotracer imaging is characterised by high in vivo sensitivity, with a detection limit in the lower picomolar range. Therefore, radiotracers represent a valuable tool for imaging pancreatic beta cells. High demands are made of radiotracers for in vivo imaging of beta cells. Beta cells represent only a small fraction of the volume of the pancreas (usually 1-3%) and are scattered in the tiny islets of Langerhans throughout the organ. In order to be able to measure a beta cell-specific signal, one has to rely on highly specific tracer molecules because current in vivo imaging technologies do not allow the resolution of single islets in humans non-invasively. Currently, a considerable amount of preclinical data are available for several radiotracers and three are under clinical evaluation. We summarise the current status of the evaluation of these tracer molecules and put forward recommendations for their further evaluation.

Beta cell replacement has the potential to restore euglycemia in patients with insulin dependent diabetes. While great progress has been made in establishing allogeneic islet transplantation from deceased donors as the standard of care for those with the most labile diabetes, it is also clear that the deceased donor organ supply cannot possibly treat all those who could benefit from restoration of a normal beta cell mass, especially if immunosuppression were not required. Against this background, the International Pancreas and Islet Transplant Association (IPITA) in collaboration with the Harvard Stem Cell Institute (HSCI), the Juvenile Diabetes Research Foundation (JDRF), and the Helmsley Foundation held a 2-day Key Opinion Leaders Meeting in Boston in 2016 to bring together experts in generating and transplanting beta cells derived from stem cells. The following summary highlights current technology, recent significant breakthroughs, unmet needs and roadblocks to stem-cell-derived beta cell therapies, with the aim of spurring future preclinical collaborative investigations and progress toward the clinical application of stem cell-derived beta cells.

There is considerable interest in using macroencapsulation devices as a delivery strategy for transplanting insulin-producing cells. This review aims to summarize recent advances, to highlight remaining challenges, and to provide recommendations for the field. A variety of new device designs have been reported to improve biocompatibility and to provide protection for islet/beta cells from immune destruction while allowing continuous secretion of insulin. Some of these new approaches are in clinical trials, but more research is needed to determine how sufficient beta-cell mass can be transplanted in a clinically applicable device size, and that insulin is secreted with kinetics that will safely provide adequate controls of glucose levels. Macroencapsulation is a potential solution to transplant beta cells without immunosuppression in diabetes patients, but new strategies must be developed to show that this approach is feasible.

The International Pancreas and Islet Transplant Association (IPITA), in conjunction with the Transplantation Society (TTS), convened a workshop to consider the future of pancreas and islet transplantation in the context of potential competing technologies that are under development, including the artificial pancreas, transplantation tolerance, xenotransplantation, encapsulation, stem cell derived beta cells, beta cell proliferation, and endogenous regeneration. Separate workgroups for each topic and then the collective group reviewed the state of the art, hurdles to application, and proposed research agenda for each therapy that would allow widespread application. Herein we present the executive summary of this workshop that focuses on obstacles to application and the research agenda to overcome them; the full length article with detailed background for each topic is published as an online supplement to Transplantation.

To the Editor: Single-centre or collaborative efforts have been made to provide human pancreatic islets for use in basic science research. These include the Integrated Islet Distribution Program in the USA [1], the Human Islet Distribution Program for Basic Research at the University of Alberta in Canada [2] and the Oxford Islet Transplant Program in the UK. The European Consortium for Islet Transplantation (ECIT) set up the human islet distribution programme for basic research (http://ecit.dri-sanraffaele.org/en/activeprogram/index.html) in 2006 to distribute high-quality human islets to the European diabetes research community. The programme currently involves the San Raffaele Scientific Institute (Milan, Italy), the Hopitaux Universitaires de Geneve, (Geneve, Switzerland), Uppsala University Hospital (Uppsala, Sweden) and the Centre Hospitalier Regional Universitaire de Lille (France). The programme is coordinated by the San Raffaele Diabetes Research Institute and receives financial support from the JDRF. A web-based platform was developed in 2009 to coordinate and track programme activity (http://ecit.dri-sanraffaele.org/en/register/ index.html). Islet isolation and shipment were performed according to centre protocols. Here we report on programme activity over the past 5 years (from 1 November 2009 to 31 October 2014). One-hundred and twenty research groups have completed the online registration process. Of these, 66 users havemade at least one application to receive islets. A total of 93 applications were submitted from 13 countries: Switzerland (n=26), Sweden (n=13), Israel (n=13), Germany (n=12), France (n=9), Italy (n=7), Spain (n=4), Denmark (n=3), UK (n=2) and one each from Austria, Norway, Ireland and Finland. The total number of islets requested was 106.187 million (Fig. 1a). An ideal islet purity of ≥70% was requested in 97% of the applications. In terms of applications from individual research groups, the median number of requested islets was 20×10 (IQR 12.5×10) in 20 (IQR 37.5) shipments. Over the years the requests for human pancreatic islets from the programme for use in basic science research have increased substantially, with the number of islets requested reaching 31.042 million in 2014. The designated use of the islets in basic science, as stated on the request form to the ECIT centres, are shown in Fig. 1c, categorised into different areas of research. Over the first 5 years of the programme, a total of 31.643 million human islets have been distributed throughout 1,130 shipments (Fig 1a,b). The production and delivery of islets by the ECIT centres have been stable over the years. However, because of the burgeoning demand for islets and the lack of funding to cover additional islet isolation procedures, the R. Nano :R. Melzi :A. Mercalli : L. Piemonti (*) Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy e-mail: piemonti.lorenzo@hsr.it

Diabetes, a large and growing worldwide health concern, affects the functional mass of the pancreatic beta cell, which in turn affects the glucose regulation of the body. Successful transplantation of cadaveric islets and pancreata for patients with uncontrolled type 1 diabetes has provided proof-of-concept for the development of commercial cell therapy approaches to treat diabetes. Three broad issues must be addressed before surrogate insulin-producing cells can become a reality: the development of a surrogate beta-cell source, immunoprotection, and translation. Cell therapy for diabetes is a real possibility, but many questions remain; through the collaborative efforts of multiple stakeholders this may become a reality.

Liver sinusoidal endothelial cells (SECs) are generally refractory to extended in vitro culture. In an attempt to recreate some features of the complex set of cues arising from the liver parenchyma, we cocultured adult rat liver SECs, identified by the expression of the marker SE-1, with primary adult rat hepatocytes in a 3D culture system that provides controlled microscale perfusion through the tissue mass. The culture was established in a medium containing serum and VEGF, and these factors were then removed to assess whether cells with the SE-1 phenotype could be supported by the local microenvironment in vitro. Rats expressing enhanced green fluorescent protein (EGFP) in all liver cells were used for isolation of the SE-1-positive cells added to cocultures. By the 13th day of culture, EGFP-expressing cells had largely disappeared from 2D control cultures but exhibited moderate proliferation in 3D perfused cultures. SE-1-positive cells were present in 3D cocultures after 13 days, and these cultures also contained Kupffer cells, stellate cells, and CD31-expressing endothelial cells. Global transcriptional profiling did not reveal profound changes between 2D and 3D cultures in expression of most canonical angiogenic factors but suggested changes in several pathways related to endothelial cell function.